TW202336035A - Methods and compositions to treat autoimmune diseases and cancer - Google Patents

Abstract

Provided are molecular constructs that target tumor necrosis factor receptor 1 (TNFR1) and/or tumor necrosis factor receptor 2 (TNFR2). The constructs are for treating diseases, disorders, and conditions in which these receptors and/or TNF are involved in the etiology or in which their inhibition or activation thereof can ameliorate the disease, disorder, and condition or a symptom thereof. Among the constructs provided herein, are TNFR1 antagonist constructs that are engineered to inhibit TNFR1 function, and to eliminate any TNFR1 agonist activity. The constructs provided herein include agonists and antagonists of TNFR1 and TNFR2. TNFR1 antagonist constructs are engineered to inhibit TNFR1 function, and in some embodiments, are engineered to avoid agonist activity. Included also are agonists and antagonists of TNFR2. Agonists of TNFR2 increase regulatory T-cell function to control acute or chronic inflammation. Antagonists of TNFR2 decrease regulatory T-cell function thus increasing immunity, and are for treating cancer and certain immunodeficiency diseases. Methods of treatment of the various diseases in which TNF and its receptors play a role also are provided. Also provided are growth factor ligand trap constructs.

Description

Methods and compositions for treating autoimmune diseases and cancer

This application relates to nucleic acid constructs and encoded products for use as anti-TNF therapies. The diseases to be treated are diseases in which TNF receptors and/or TNF or TNF/TNF receptor pathways are involved or play a role in their etiology. Incorporation by reference of electronically provided sequence listing

An electronic version of the sequence listing is attached, the contents of which are incorporated by reference in their entirety. The electronic file was created on February 16, 2022, has a size of 2 million bytes, and is titled 5301SEQTW1.txt.

Anti-TNF therapy/TNF blocker (a biological disease-modifying antirheumatic drug; DMARD) is typically prescribed after known DMARD failure. These therapies include monoclonal antibodies (mAbs), such as the chimeric mAb infliximab ( ^Remicade® ); containing murine variable regions and human IgG1 constant regions, and the fully human mAb (IgG1) adalimumab (adalimumab, e.g. sold under the trademark ^Humira® ) and golimumab ( ^Simponi® antibody); PEGylated humanized Fab' fragments of mAbs targeting TNF, certolizumab pegol , ^Cimzia® antibody); and TNFR2 fusion proteins, such as the TNFR2-Fc fusion protein etanercept (sold under the trademark ^Enbrel® ), which contains an extracellular binding site for human TNFR2 fused to the Fc of human IgG1 receptor area. The drugs sold under the trademarks ^Remsima® and ^Inflectra® are biosimilars of infliximab, approved in the European Union for the treatment of various autoimmune and chronic inflammatory diseases and conditions. These TNF-chelating TNF inhibitors are used to treat a variety of diseases and conditions, including, for example, RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis (JIA), and/or inflammatory bowel disease ( IBD; such as Crohn's disease and ulcerative colitis).

However, such therapies are associated with serious side effects, including, for example, an increased risk of sepsis and serious infections such as listeriosis, reactivation of tuberculosis, reactivation of hepatitis B/C, reactivation of herpes zoster, and Reactivation of invasive fungal and other opportunistic infections, including Mycobacterium tuberculosis ( M. tuberculosis ) infection. These therapies have been shown to induce macrophage apoptosis in rheumatoid synovium. Infliximab is associated with increased apoptosis of inflammatory cell infiltrates in the intestine of patients with Crohn's disease. Other antirheumatic drugs, such as methotrexate and glucocorticoids, can also induce immune cell apoptosis (see, eg, Vigna-Pérez et al. (2005) Clin. Exp. Immunol. 141(2):372-380). These therapeutic agents may also cause progression of severe congestive heart failure, drug-induced lupus and demyelinating central nervous system (CNS) disease, as well as lymphoma and non-melanoma skin cancer (see, e.g., Benjamin et al. Disease Modifying Anti- Rheumatic Drugs (DMARDs) [Updated February 27, 2020]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2020. Available from: (ncbi.nlm.nih.gov/ books/NBK507863/). Other adverse side effects include liver damage, demyelinating diseases/CNS disorders, lupus, psoriasis, sarcoidosis and increased susceptibility to other autoimmune diseases, and cancer, including lymphoma and solid malignancies (See, e.g., Dong et al. (2016) Proc. Natl. Acad. Sci. USA 113(43):12304-12309; Zalevsky et al. (2007) J. Immunol. 179:1872-1883; Zoran et al. (2019) Sci . Rep. 9:17231). Therefore, the use of these therapeutics, particularly in chronic diseases/conditions that require long-term administration, such as arthritis and inflammatory bowel disease (IBD), is limited. Use of Anti-TNF Approximately 30% of RA patients do not respond to therapy, or the benefit from treatment is not sustained (see, e.g., McCann et al. (2014) Arthritis & Rheumatology 66(10):2728-2738). Also in non-RA patients receiving anti-TNF therapeutics Anergy can occur. Depending on the anti-TNF agent, 13-33% of treated patients do not respond to treatment, and up to 46% of treated patients cease responding, leading to discontinuation or dose increase (see, e.g., Richter et al. 2019) MABS 11(4):653-665). Therefore, therapies with improved therapeutic efficacy and safety are needed.

Molecular constructs targeting tumor necrosis factor receptor 1 (TNFR1) and/or tumor necrosis factor receptor 2 (TNFR2) and nucleic acids encoding them are provided. The constructs are useful in the treatment of diseases, disorders and conditions in which such receptors and/or TNF are involved in the cause or in which inhibition or activation of such receptors and/or TNF ameliorates the disease, disorder and/or condition or symptoms thereof. Constructs provided herein include agonists and antagonists of TNFR1 and TNFR2. TNFR1 antagonist constructs are engineered to inhibit TNFR1 function and avoid TNFR1 agonist activity. Also included are agonists and antagonists of TNFR2. Agonists of TNFR2 increase regulatory T cell function to control acute or chronic inflammation. Antagonists of TNFR2 reduce regulatory T cell function, thereby improving immunity, and are used to treat cancer and certain immunodeficiency diseases.

Cells have two TNF receptors: TNFR1 and TNFR2. These pathways balance each other in normal physiology. TNF/TNFR1 drives inflammation, while TNF/TNFR2 is anti-inflammatory. TNFR2 is generally activated later than TNFR1 and therefore does not immediately contribute to useful TNF-induced inflammation, but is activated later to inhibit overactivation of inflammatory pathways. Simultaneously inhibiting both pathways eliminates the inflammatory inhibitory effect of TNFR2. Existing TNF blockers limit their efficacy because the anti-inflammatory Treg-generating factor (TNFR2) is reduced/eliminated.

In addition to other properties that differ from previous therapeutic agents targeting TNF/TNFR, the constructs provided herein inhibit TNFR1 signaling or activity without compromising the ability of the treated individual to fight opportunistic infections. Among the constructs provided herein is a modified single-chain antibody that specifically targets and inhibits TNFR1 but does not antagonize TNFR2, thereby preventing transient activation of TNFR1 via receptor clustering. The constructs provided herein silence the TNF inflammatory pathway mediated by TNFR1, but preserve and in some embodiments enhance the healing pathway of TNFR2. These constructs can be administered to treat indications for which TNF blockers have failed. Among the constructs provided herein are constructs that specifically inhibit tumor necrosis factor receptor type 1; such constructs are provided for the treatment of diseases, disorders and conditions in which TNF or its receptors play a role in the cause or symptoms Methods and uses.

Existing anti-TNF drugs block excessive inflammation that occurs in autoimmune diseases including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, axial spondyloarthritis, ankylosing spondylitis, and psoriatic arthritis , psoriasis, Crohn's disease, pediatric Crohn's disease and ulcerative colitis. The constructs herein can be used to treat the same disease but avoid harmful or undesirable side effects. The constructs provided herein are more effective than previous therapeutics at inhibiting inflammatory cytokines in vivo, such as the TNFR2-Fc fusion protein etanercept (sold under the trademark ^Enbrel® ), while retaining regulatory T cell function. Such constructs may include activity modulators or property modulators to increase serum half-life and have demonstrated activity in blocking TNFR1 signaling, such as in a TNF assay comparing activity to adalimumab and/or etanercept. middle.

As established in mouse models, these constructs preserve macrophage function better than adalimumab, indicating that they do not cause opportunistic infections; they are also substantially more effective than adalimumab or etanercept. Treg function is better preserved and is also therapeutically effective in treating diseases, disorders and conditions such as rheumatoid arthritis. In some specific examples, Kd ≤ 1 nM, and t1 _/2 in vivo is about 10-12 days. The constructs may be administered by any route appropriate for the specific indication. Routes include, but are not limited to, subcutaneous, intravenous, intratumoral, intrahepatic, local, transmucosal, intradermal, and any other suitable route.

The constructs provided in this article are as follows. The construct provided is a tumor necrosis factor receptor 1 (TNFR1) antagonist construct of formula 1: (TNFR1 inhibitor) _n - linker _p - (activity modulator) _q , where: each of n and q is an integer, and is each independently 1, 2 or 3; p is 0, 1, 2 or 3; TNFR1 inhibitor is a molecule that binds to TNFR1 to inhibit (antagonize) the activity of TNFR1; activity modulator is and does not have activity Compared with the construct of the modulator, the part that modulates or changes the activity or pharmacological properties of the construct; and the linker increases the flexibility of the construct, and/or alleviates or reduces the steric effect of the construct or its interaction with the receptor. interaction, and/or increase the solubility of the construct in aqueous media. The linker may contain a plurality of component linkers, including chemical linkers, polypeptide linkers, and combinations thereof. Constructs can be linked via chemical and/or physical bonds. The construct can be a fusion protein.

TNFR1 inhibitors may comprise domain antibodies (dAbs) or single chain antibodies. Constructs include constructs in which the TNFR1 inhibitor is a domain antibody (dAb) and the activity modulator is not an unmodified single Fc region or human serum albumin antibody. For example, the activity modulator (or property modulator) is a modified Fc region or is human serum albumin. In the construct, the TNFR1 inhibitor can be an inhibitor that inhibits TNFR1 signaling, and/or an activity modulator that increases the serum half-life of the construct. For example, constructs include Fc in which the activity modulator is albumin or modified to have reduced or no ADCC (antibody-dependent cytotoxicity) activity and/or to have reduced or no CDC (complement-dependent cytotoxicity) activity. 's structure. TNFR1 inhibitors can be inhibitors that inhibit the activity of TNFR1 but do not antagonize the activity of tumor necrosis factor receptor 2 (TNFR2). TNFR1 inhibitors can be inhibitors that inhibit TNFR1 signaling.

Multispecific constructs are also provided. For example, multispecific constructs are provided that include a TNFRl inhibitor and a Treg expander, wherein the bispecific construct interacts with two different target receptors or antigens or epitopes on the receptors. Among the multispecific constructs are constructs with bispecificity for TNFR1 and Treg expanders. The Treg expander can be a TNFR2 agonist.

The construct may include linkers to provide flexibility, increase solubility and/or alleviate and/or reduce steric hindrance and/or Van der Waals interactions. The constructs optionally, but typically, contain activity modulators to alter or modulate the activity or properties of the construct. Provide a construct having the formula 2: (TNFR1 inhibitor) _n ― (activity modulator) _r1 ― (linker (L)) _p ― (activity modulator) _r2 ― (TNFR2 agonist) _q , or (TNFR1 inhibitor agent) _n ―(activity modulator) _r1 ―(linker (L)) _p ―(activity modulator) _r2 ―(Treg amplifying agent) _q , where: n= 1, 2 or 3, p= 1, 2 or 3, q = 0, 1 or 2, and each of r1 and r2 is independently 0, 1 or 2; and as long as the construct interacts with TNFR1 and TNFR2 to antagonize TNFR1 and agonize TNFR2, or has Treg amplifier activity, the components can be arranged in the specified order or any other order. For example, constructs in which a TNFR1 inhibitor moiety inhibits the binding of TNFα to TNFR1 and/or inhibits signaling are included in any construct provided herein.

Constructs of formula 3a or 3b are also provided: (TNFR2 agonist or Treg amplifier) _n ― linker _p ― (activity modulator) _q , Formula 3a, or (activity modulator) _q ― linker _p ― ( TNFR2 agonist or Treg expander) _n , Formula 3b, where: each of n and q is an integer, and each is independently 1, 2 or 3; p is 0, 1, 2 or 3; activity Modulators are moieties that alter the pharmacological properties or activity of the construct; TNFR2 agonists interact with TNFR2 to produce TNFR2 activity; Treg expanders include TNFR2 agonists and are molecules that cause an increase in Treg cells; and linkers Increase flexibility and/or alleviate or reduce the steric hindrance effect of the construct or its interaction with the receptor; and/or change the solubility of the construct. In some embodiments, the activity modulator is an Fc region or a modified Fc region or a short FcRnBP; and the linker includes a hinge region, or is a linker including G and S residues. An example of a linker is one that increases the serum half-life of the construct. For example, the linker can have the sequence shown in any of SEQ ID NOs: 812-834, or be a PEG portion linker. In some embodiments, the construct includes an activity modulator, which is a modified Fc region or a peptide that increases the serum half-life of the construct. The Fc region can be an Fc dimer; the Fc region can be modified to have reduced ADCC and/or CDC activity, such as an Fc modified to have reduced or no ADCC activity.

In the constructs provided herein, the TNFR1 inhibitor is any one as defined in the sequence listing, listed below, or known in the art; the Treg amplifier is any one known in the art. , is a TNFR2 agonist or is any Treg amplifying agent shown in the sequence listing or known in the technical field; the linker is any of the sequence listing or listed below or known in the technical field; and activity Modulators are any of the constructs shown in the sequence listing, known in the art, and/or shown below.

Constructs provided are TNFR1 antagonist constructs that include a TNFR1 inhibitor that specifically targets and inhibits TNFR1 but does not antagonize a single chain antibody or antigen-binding portion of TNFR2, thereby preventing TNFR1 from passing through the receptor. Gather and activate instantly. In such constructs comprising an antibody or antigen-binding portion thereof, the antibody or antigen-binding fragment thereof may contain modifications that improve the pharmacological properties and/or structure of the construct.

In any construct provided herein, the construct includes a component that enhances TNFR2 signaling to thereby increase regulatory T cell (Treg) expression, thereby providing TNFR1 antagonism and simultaneously (or substantially simultaneously) increasing Treg expression. Performance. In the constructs provided herein, the TNFR1 inhibitor can be a single chain antibody that inhibits TNFR1 by inhibiting TNFR1 signaling, such as wherein the antibody portion or antigen-binding portion of the construct inhibits the binding of TNFα to TNFR1. Among the constructs are TNFR1 inhibitors, which are constructs that do not inhibit the binding of TNFα to TNFR1, but do inhibit the antibody or antigen-binding portion of TNFR1 signaling. The property or activity that can be adjusted/modified can be serum half-life.

Constructs may include Fc modified to eliminate ADCC and/or CDC activity. The construct may comprise an Fc dimer, such that one Fc monomer contains a hole and the other a knob, to form a heterodimer. For example, according to the EU numbering, the pestle mutant line is selected from S354C, T366Y, T366W and T394W; and according to the EU numbering, the mortar mutation line is selected from the group consisting of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V, whereby the Fc monomer Form heterodimers. In some embodiments where the construct includes an Fc, the Fc is from trastuzumab. The construct can be dimerized by fusion of the N-terminus to the C-terminus of trastuzumab.

In some embodiments where the construct includes a linker, the linker is or includes a hinge region from the Fc region. For example, where the hinge region is from trastuzumab and it is linked to the Fc region. Constructs include constructs comprising a linker attached to an anti-TNFR1 antagonist antibody or antigen-binding portion thereof. The linker can be linked to the anti-TNFRl antagonist antibody, or antigen-binding portion thereof, and to the Fc region directly or via the hinge region. The Fc region or modified Fc region includes, for example, the amino acid sequence shown in any one of SEQ ID NOs: 10, 12, 14, 16, 27, 30, 1469 and 1470.

Constructs that bind to nascent Fc receptors (FcRn) are also provided. For example, a TNFR1 construct is provided that includes a short FcRn-binding peptide (FcRnBP), wherein the short FcRn-binding peptide (FcRnBP) provides interaction of the construct with FcRn and contains 6-25 or 10-20 amino acid residues. base. For example, FcRnBP contains 12-20 residues or 15 residues or 16 residues. An example of this is a TNFR1 antagonist construct in which the FcRn binding peptide (FcRnBP) comprises or consists of any of the peptides of SEQ ID NOs: 48-51. Constructs include TNFR1 constructs containing Fc heterodimers, where one Fc monomer contains an ethyl and the other contains a pestle, and the resulting Fc dimer is a heterodimer.

The construct provided is a TNFR1 antagonist construct, which includes: a TNFR1 inhibitor; an Fc dimer; and a Treg expander, wherein: the Fc dimer contains two complementary Fc monomers; the TNFR1 inhibitor is linked to a Fc monomer, and the Treg amplifying agent is linked to another Fc monomer. In such constructs, the Treg expander can be a TNFR2 agonist. It may further comprise a second Treg amplifying agent linked to the same Fc monomer as the TNFRl inhibitor, wherein the first and second Treg amplifying agents are the same or different. The second Treg expander can be a TNFR2 agonist. In some embodiments, the Treg expanding agents are the same. A TNFR1 inhibitor can be an inhibitor that inhibits or blocks TNFR1 signaling. In some embodiments, a TNFR1 inhibitor binds to TNFR1 and blocks or inhibits TNFα binding and TNFR1 signaling. In some embodiments, a TNFR1 inhibitor binds to TNFR1, does not interfere with TNFα binding, and blocks or inhibits TNFR1 signaling. In some embodiments of these constructs, the Treg expander is a TNFR2 agonist. A TNFR2 agonist can be an agonist that stimulates or induces TNFR2 signaling. Examples of Treg amplifying agents are TNFR2 agonists, which are scFv, VHH single domain antibodies or Fab of TNFR2 agonist monoclonal antibodies. In such constructs, the Treg amplifying agent can be a TNFR2 agonist, which is a small molecule or a nucleic acid aptamer or a peptide aptamer.

Any of these constructs that are or are also TNFR2 agonists are also provided. The TNFR2 agonist is a construct of formula 3a or 3b, wherein: formula 3a is (Treg amplifier) _n - linker _p - (activity modulator) _q , and formula 3b is (activity modulator) _q - linker _p ―(Treg amplifying agent) _n . In this equation, each of n and q is an integer and is each independently 1, 2, or 3; p is 0, 1, 2, or 3; the active modulator is a construct with no active modulator present The part that modulates or changes the activity or pharmacological properties of the construct compared with the construct; and the linker increases the flexibility of the construct, and/or alleviates or reduces the steric hindrance effect of the construct or its interaction with the receptor, and/or increase the solubility of the construct in aqueous media. In any of these constructs, the Treg expander in the construct is a TNFR2 agonist. For example, TNFR2 agonists stimulate or induce TNFR2 signaling. In other examples, the Treg amplifying agent is a TNFR2 agonist, which is a scFv, VHH single domain antibody, or Fab of a TNFR2 agonist monoclonal antibody. The Treg amplifying agent can be a TNFR2 agonist, which is a small molecule or nucleic acid or peptide aptamer. In constructs containing all or a portion of trastuzumab, such as the Fc portion and/or the Fc and hinge region, or modified forms thereof, the construct can be obtained by fusion to the N-terminus of the C-terminus of trastuzumab. And dimerization.

Provided constructs comprise a TNFRl inhibitor moiety linked to one or more Treg expanders via a central PEG linker, or comprise at least two identical or different TNFRl inhibitors, or comprise two identical or different Treg expanders. Additive. Constructs that include a PEG moiety, such as a central PEG linker, may include branched PEG moieties linked to a TNFRl inhibitor and one or more Treg expanders. An example is a construct having a structure selected from Formulas 4A to 4D: Formula 4A: ,or n is 1 to 5; R ¹ is H or CH ₃ or CH ₂ CH ₃ or other C1-C5 alkyl It is a TNFR1 inhibitor (TNFR1 antagonist); It is a Treg amplifying agent; or formula 4B: For TNFR1 inhibitors (TNFR1 antagonists) is a Treg amplifying agent; n is 1 to 5; or formula 4C: is a TNFR1 inhibitor (TNFR1 antagonist), or a Treg expander; and n is 1 to 5; or Formula 4D: or , each of which are the same or different and are each independently selected from TNFR1 inhibitors (TNFR1 antagonists) and TNFR2 agonists; the activity modulator is optional and can be linked to any suitable locus in the molecule; and n is 1 to 5.

In TNFR1 antagonist constructs and other constructs provided herein, the Treg expander can be a TNFR2 agonist. Such constructs may include an activity modulator, such as where the activity modulator is an Fc region, or an Fc region that includes a hinge region or other linker; and the Fc region or Fc region with a hinge region is modified to reduce or eliminate ADCC and/or Fc for CDC activity. Examples are constructs in which the Fc or modified Fc is an IgG Fc or is an IgG1 or IgG4 Fc, and/or is a construct that binds to a nascent Fc receptor (FcRn). An example of such a construct is a construct wherein: the construct includes a short FcRn-binding peptide (FcRnBP), wherein the short FcRn-binding peptide (FcRnBP) provides interaction of the construct with FcRn, and contains 6-25, such as 10 - 20 amino acid residues; or wherein the FcRnBP contains 12-20 residues or 15 residues or 16 residues, such as wherein the FcRn-binding peptide (FcRnBP) contains or consists of any of SEQ ID NOs: 48-51 Peptide composition.

Also provided are TNFR1 antagonist constructs of any formula described above and in this application, which include: a) a TNFR1 inhibitor moiety that is TNFR1 selective; b) optionally one or more linkers; and c ) An optional half-life extension part, wherein the antagonist construct includes at least one of b) and c). In such constructs, TNFR1-selective antagonists selectively bind and inhibit TNFR1 signaling, but not TNFR2 signaling. As described above for the construct, the TNFRl inhibitor, linker and other components may be as described above. These include TNFR1 inhibitors that are selective antagonists, constructs that include antigen-binding fragments that selectively bind to and inhibit TNFR1 signaling but not TNFR2 signaling. For example, an antigen-binding fragment that selectively binds to and inhibits TNFR1 signaling but not TNFR2 signaling may comprise a domain antibody (dAb), scFv, or Fab fragment. In any of the constructs described herein, the TNFR1 inhibitor comprises an antigen-binding fragment of a human anti-TNFR1 antagonist monoclonal antibody. For example, the human anti-TNFR1 antagonist monoclonal antibody is H398 comprising SEQ ID NO: 678, or ATROSAB, or an antigen-binding portion thereof, or has at least 95% sequence identity with SEQ ID NO: 31 or 32 or 673 or 678 The specific sequence, or the antigen-binding portion thereof that binds to TNFR1. Examples of TNFR1 inhibitors are inhibitors that comprise domain antibodies (dAbs) and the antigen-binding portion thereof, or comprise or are at least 95% identical to the amino acid sequence shown in any one of SEQ ID NOs: 52-672. A sequence identical to a sequence retaining TNFR1 inhibitor activity; and/or a retained TNFR1 inhibitor comprising or having at least 90% or 95% sequence identity with the scFv shown in any of SEQ ID NOs: 673-678 Variants of these polypeptides that are active; and/or contain a Fab set forth in any of SEQ ID NOs: 679-682 or retain TNFR1 inhibitory or binding activity having at least 90% or 95% sequence identity thereto and/or a nanobody comprising a sequence shown in SEQ ID NO: 683 or 684 or a sequence that retains TNFR1 inhibitor or binding activity with at least 90% or 95% sequence identity thereto. Among the TNFR1 inhibitors are, for example, inhibitors that include dominant negative tumor necrosis factor (DN-TNF) or TNF muteins, such as DN-TNF or TNF muteins, which are soluble TNF molecules that contain one or more DNFR1 Selectively inhibits amino acid substitutions selected from: V1M, L29S, L29G, L29Y, R31C, R31E, R31N, R32Y, R32W, C69V, A84S, V85T, S86T, Y87H, Q88N, T89Q, I97T, C101A, A145R, E146R, L29S/R32W, L29S/S86T, R32W/ S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T, I97T/A145R, V1M/R31C/C69V/Y87H/C101A/A145R and A84S/V85T/S86T/Y87H/Q88N/ T89Q, Reference is made to the sequence of soluble TNF shown in SEQ ID NO: 2. For example, a TNFR1 inhibitor is a TNF mutein that includes the residue sequence shown in any one of SEQ ID NOs: 701-703, or is identical to that set forth in any one of SEQ ID NOs: 701-703. The residue sequences shown, or fragments thereof, have at least or at least about 90% or 95% sequence identity and retain TNFR1 inhibitory activity.

Any of the foregoing constructs provided herein may include a linker, wherein the linker comprises all or a portion of the hinge sequence of trastuzumab, SCDKTH corresponding to residues 222-227 of SEQ ID NO: 26 or up to and including or having the sequence The entire sequence of the hinge region of trastuzumab, EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26), or at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues thereof, Or residues ESKYGPPCPPCP from residues 212-223 of SEQ ID NO: 29, or a sequence having at least 98% or 99% sequence identity thereto as a linker. For example, the construct may comprise a linker, wherein the linker comprises the sequence SCDKTH corresponding to residues 222-227 of SEQ ID NO: 26. The construct may comprise a linker that contains glycine and serine (GS) residues instead of or in addition to another of the linkers, ie, a GS linker. Exemplary GS linkers for any construct provided herein include selected from (GlySer) _n , where n=1-10; ( _GlySer2 ); ( _Gly4Ser ) _n , where n=1-10; ( _Gly3Ser ) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSSGS connector. Also included are linkers that include a GS linker and all or part of the hinge sequence of trastuzumab corresponding to residues EPKSCDKTHTCPPCP (residues 219-233 of SEQ ID NO: 26). For example, the linker may include a GS linker. and contains only or contains the sequence SCDKTH from the hinge sequence corresponding to residues 217-222 of SEQ ID NO: 31. Such linkers include, for example, linkers comprising the GS linker and all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29.

The constructs herein may contain active modulators. Activity modulators include any activity modulators described herein, including those described above and below and other activity modulators known to those of ordinary skill in the art; activity modulators alter the activity of the construct or characteristic. The activity modulator may be one that is a half-life extending moiety, which is an IgG Fc, a polyethylene glycol (PEG) molecule, or human serum albumin (HSA). Examples of IgG Fc are IgGl or IgG4 Fc. The IgG1 Fc can be the Fc of trastuzumab shown in SEQ ID NO: 27 or an amino acid sequence with at least 95% sequence identity thereto; the IgG4 Fc can be the Fc of trastuzumab shown in SEQ ID NO: 30 The Fc of the monoclonal antibody or its amino acid sequence with at least 95% sequence identity. For example, the IgG1 Fc is the Fc of human IgG1 set forth in SEQ ID NO: 10, and the IgG4 Fc is the Fc of human IgG4 set forth in SEQ ID NO: 16.

Constructs described herein include constructs that are or contain inhibitors of TNFR1. These include constructs in which TNFR1 inhibitors are monovalent. These may include linkers, such as where the linker comprises (Gly ₄ Ser) ₃ , and/or a linker comprising (Gly ₄ Ser) ₃ and SCDKTH (residues 217-222 of SEQ ID NO: 31); and/or Or a linker comprising (Gly ₄ Ser) ₃ and a hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26; and/or a linker comprising (Gly ₄ Ser) ₃ and corresponding to SEQ ID NO: 26 NO: Linker of the hinge sequence of nivolumab at residues 212-223 of NO: 29. Examples of constructs provided herein that inhibit TNFR1 are constructs that include the sequence of residues set forth in any of SEQ ID NOs: 704-764, or that inhibit TNFR1 and have the same sequence as in SEQ ID NOs: 704-764 A construct in which the residue sequences shown in any one have at least, or at least about 95%, sequence identity.

Provided herein are TNFR1 antagonist constructs. These include TNFR1 constructs comprising a short FcRn-binding peptide (FcRnBP); and the short FcRn-binding peptide (FcRnBP) provides for interaction of the construct with FcRn and contains 6-25, such as 10-20, amino acid residues. Constructs, such as FcRnBP containing 12-20 residues or 15 residues or 16 residues, such as FcRn-binding peptide (FcRnBP) containing any of the peptides of SEQ ID NO: 48-51 or having at least about 95 % sequence identity peptide, or FcRn binding peptide (FcRnBP) construct consisting of any of the peptides of SEQ ID NO: 48-51.

Other exemplary TNFR1 inhibitory constructs provided herein include constructs comprising: a) a domain antibody that inhibits TNFR1; b) a linker that increases flexibility, reduces steric hindrance, or increases solubility; and c) a half-life extending moiety. Included are such constructs in which the half-life extending moiety is not human serum albumin antibody or unmodified Fc. Such constructs include constructs that are TNFRl antagonists comprising: a) a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or any of SEQ ID NOs: 673-678 The scFv, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or the TNF mutant protein of any one of SEQ ID NO: 685-703; b) GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= and _c ) half _{- life} The extended part, which is IgG Fc. In these constructs or any construct provided herein that includes one or more of these components, the GS linker can be (GGGGS) ₃ ; and the IgG Fc can be the Fc of trastuzumab or Na Fc of Vulumab.

Other constructs provided herein as TNFRl antagonist constructs include constructs comprising: a) a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or SEQ ID NOs: 673-678 The scFv of any one, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of any one of SEQ ID NO: 683 or 684, or any one of SEQ ID NO: 685-703 TNF mutein; b) a linker selected from all or a portion of the hinge sequence of trastuzumab and all or a portion of the hinge sequence of nivolumab; and c) a half-life extending portion, which is an IgG Fc. In such constructs, the linker may comprise all or part of the hinge sequence of trastuzumab, where the IgG Fc is the Fc of trastuzumab. In other embodiments, the linker may comprise all or part of the hinge sequence of nivolumab, wherein the IgG Fc is the Fc of nivolumab.

Any construct provided herein as a TNFR1 antagonist construct is provided, comprising: a) a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or any of SEQ ID NOs: 673-678 A scFv of one, or a Fab of any one of SEQ ID NO: 679-682, or a Nanobody of SEQ ID NO: 683 or 684, or a TNF mutation of any one of SEQ ID NO: 685-703 Protein; b) The first linker, which is a GS linker, is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; ; and GSSSGS; c) a second linker selected from all or a portion of the hinge sequence of trastuzumab and all or a portion of the hinge sequence of nivolumab; and d) a half-life extending portion, which is an IgG Fc .

In some embodiments, such constructs may contain a first linker that is a GS linker (GGGGS) ₃ ; and a second linker comprising the sequence SCDKTH (residues 217-222 of SEQ ID NO: 31); and IgG Fc is the Fc of trastuzumab. In other specific examples, the first linker is a GS linker (GGGGS) ₃ ; the second linker includes all or part of the hinge sequence of nivolumab; and the IgG Fc is the Fc of nivolumab.

Provided are constructs that are TNFR1 agonists, comprising: a) a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or a scFv of any of SEQ ID NOs: 673-678, Or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or the TNF mutant protein of any one of SEQ ID NO: 685-703; b) GS A linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5 ; (SerGly ₄ ) _n , where n = 1-5; (GlySerSerGly) _n , where n = 1-5; GSGGSSGG; GSSSSGSGSGSSG; GSSSGGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and c) half-life extension portion, It is a PEG molecule. The GS linker can be any one described herein or known to one of ordinary skill in the art, such as (GGGGS) ₃ . The PEG molecule may be a PEG molecule having a molecular weight of at least 25 kDa, typically at least 30 kDa or greater, such as at least 40 kDa or 50 kDa, or 60 kDa, or 80 kDa or greater.

Provided constructs are TNFR1 agonist constructs comprising: a) a domain antibody (dAb) of any of SEQ ID NO: 52-672, or any of SEQ ID NO: 673-678 The scFv, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or the TNF mutant protein of any one of SEQ ID NO: 685-703; b) GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= and _c ) half _{- life} Extension, which is human serum albumin. An example of a linker is any linker described herein, such as where the GS linker is (GGGGS) ₃ .

The primary amino acid sequence of any construct provided herein (the constructs described above and below) can be optimized or modified to eliminate immunogenic sequences or immunogenic epitopes. For example, in a construct containing an IgG Fc, the IgG Fc can be modified to include one or more of the following modifications: a) modifications that introduce knobs-into-holes; b) increase or enhance nascent Fc Modification of receptor (FcRn) recycling; and c) modification of reducing or eliminating immune effector function. In such constructs and in any construct containing an IgG Fc, the hammer mutations may be selected from the group consisting of S354C, T366Y, T366W, and T394W according to EU numbering; and the hammer mutations may be selected from the group consisting of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V. Such TNFR1 antagonist constructs may be constructs with modifications that increase or enhance FcRn recycling selected from one or more of the following: T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E according to EU numbering , T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M252Y/S254T/T256E, H433K/ N434F/Y436H, N434F/Y436H, T250Q /M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E294del/T307P/N434Y and T256N/A378V/S383N/N434Y. TNFR1 antagonist constructs can be modified to reduce or eliminate immune effector functions, such as immune effector functions selected from the group consisting of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated cytotoxicity. One or more of induced phagocytosis (ADCP). For example, in these TNFR1 antagonist constructs, modifications that reduce or eliminate immune effector functions are selected from one or more of the following: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A.

A TNFRl antagonist or multispecific construct may comprise a central PEG linker moiety; and the construct may comprise a modified Fc region, such as those described above, wherein the Fc region is a modified IgG Fc and the modified IgG Fc comprises One or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to EU numbering, the pestle mutant line is selected from S354C, T366Y, T366W and T394W; and According to EU numbering, the acetabulum mutant lines were selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance one or more immune effector functions, wherein: The immune effector function is selected from one or more of CDC, ADCC and ADCP; and Modifications that increase or enhance immune effector functions are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan introduced at residue N297; afucosylated glycan introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/ E333S; K326M/E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S3 24T; S267E/H268F/S324T; G236A/ I332E/S267E/H268F/S324T; E345R; and E345R/E430G/S440Y.

In some embodiments of any construct that includes an Fc region, the construct can include an IgG1 Fc that includes one or more modifications to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb. For example, according to EU numbering, the modification that increases binding to FcγRIIb is selected from one or more of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K.

Constructs that are Treg expander constructs are also provided. Included in such constructs are constructs comprising: a) Treg amplifiers; b) linkers, wherein the linkers increase the flexibility of the construct, and/or mitigate or reduce the steric hindrance effect of the construct or its Interaction with the receptor, and/or increasing the solubility of the construct in aqueous media; and c) activity modulator, wherein the activity modulator is one that modulates or changes the construct compared to the construct in the absence of the activity modulator. Active or pharmacological properties. The Treg expander can be a TNFR2 agonist. These constructs may further comprise a TNFRl inhibitor. In some specific examples, the TNFR2 agonist is a TNFR2 selective agonist.

Provided are constructs described herein that are TNFR2 agonist constructs, comprising: a) a TNFR2 agonist; b) a linker, wherein the linker increases the flexibility of the construct, and/or moderates or reduces the construct steric hindrance effect or its interaction with the receptor, and/or increase the solubility of the construct in the aqueous medium; and c) activity modulator, wherein the activity modulator is compared with the construct without the activity modulator, A portion that modulates or alters the activity or pharmacological properties of a construct. In TNFR2 agonist constructs, the TNFR2 agonist can be a TNFR2 selective agonist. The construct may contain an activity modulator, such as an activity modulator as a half-life extending moiety. The construct may be a TNFR2 agonist construct that selectively activates or antagonizes TNFR2 without activating or antagonizing TNFR1. Included are TNFR2 agonist constructs wherein the TNFR2 agonist binds to one or more epitopes within TNFR2. These include human TNFR2. Such epitopes include, for example, epitopes selected from one or more of the epitopes comprising or consisting of the amino acid sequences shown in SEQ ID NOs: 839-865, 1202 and 1204.

TNFR2 agonist constructs are provided, wherein the TNFR2 agonist comprises an antigen-binding fragment of an agonist human anti-TNFR2 antibody or a humanized anti-TNFR2 antibody, or an antigen-binding portion thereof, or a single chain form thereof. An example of such an antibody is an agonist anti-TNFR2 antibody selected from MR2-1 (also designated ab8161; US Patent No. 9,821,010) or MAB2261 (US Patent No. 9,821,010). The TNFR2 agonist can be an antigen-binding fragment selected from dAb, scFv or Fab fragments. In some specific examples, the TNFR2 agonist is a TNFR2 selective agonist. Selective agonists may include the TNFR2 agonist TNF mutein. Exemplary TNFR2-selective agonist muteins include, but are not limited to, soluble TNF variants comprising one or more TNFR2-selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D ,A145H/E146S/S147D,A145H/ S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A14 5D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S and combinations of any of the foregoing, refer to SEQ ID NO: 2. For example, a TNFR2 agonist is a TNF mutein comprising the mutation D143N/A145R.

In TNFR2 agonist constructs, linkers include any linker described herein or known to one of ordinary skill in the art for use as a linker. Exemplary linkers comprise all or a portion of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26, or the navoid sequence corresponding to residues 212-223 of SEQ ID NO: 29. All or part of the hinge sequence of the monoclonal antibody, or a sequence with at least 95% sequence identity thereto. Other exemplary linkers comprise or consist of the sequence SCDKTH corresponding to residues 217-222 of SEQ ID NO: 31. The linker may be a glycine-serine (GS) linker such as, but not limited to, selected from (GlySer) _n , where n= 1-10; ( _GlySer2 ); ( _Gly4Ser ) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG ; GGSSGGSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and the GS linker of GSSSGS. The linker may comprise a combination of linkers, such as a GS linker and all or part of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26, or a GS linker and a linker corresponding to SEQ ID NO: 26 The sequence SCDKTH of residues 217-222 of ID NO: 31, or the GS linker and the linker corresponding to all or part of the hinge sequence of nivolumab of residues 212-223 of SEQ ID NO: 29.

All constructs provided herein may include active modulators that alter or modulate the properties or activity of the construct. For example, half-life extending moieties are activity or property modulators. Examples of such are IgG Fc, polyethylene glycol (PEG) molecules, and human serum albumin (HSA), or parts or derivatives of variants thereof, as discussed above and below. For example, in some, the IgG Fc is an IgG1 or IgG4 Fc. An example of an IgG1 Fc is the Fc of trastuzumab shown in SEQ ID NO: 27; and an example of an IgG4 Fc is the Fc of nivolumab shown in SEQ ID NO: 30; a human version, wherein the IgG1 Fc is the Fc of human IgG1 shown in SEQ ID NO: 10, and the IgG4 Fc is the Fc of human IgG4 shown in SEQ ID NO: 16.

In some embodiments of TNFR2 agonist constructs, the TNFR2 agonist is monovalent; in other embodiments, it is multivalent, such as divalent or trivalent. TNFR2 constructs may contain linkers as described herein. For example, the linker may comprise Gly-Ser, such as (Gly ₄ Ser) ₃ or (Gly ₄ Ser) ₃ and SCDKTH (residues 217-222 of SEQ ID NO: 31), or (Gly ₄ Ser) ₃ and The hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26, or (Gly ₄ Ser) ₃ and the sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29 The hinge sequence, or a variant of any of the foregoing with at least 95% sequence identity thereto. Such constructs may also include activity modulators, such as those as half-life extending moieties, such as PEG or HSA as described above. The size of the PEG moiety is at least 20 kDa, typically at least 30 kDa or greater, as described above and below.

Also provided are TNFR2 agonist constructs comprising: a) a TNFR2 agonist that binds to one or more epitopes within human TNFR2 selected from the group consisting of SEQ ID NOs: 839-865, 1202 And the epitope shown in 1204; b) GS linker, which is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; ; GGSSGGSSGGGSSGGSSG; and GSSSGS; and c) an activity modulator that is a half-life extending moiety, the half-life extending moiety being IgG Fc.

As described above, in illustrative embodiments, the GS linker can be (GGGGS) ₃ ; and the IgG Fc is the Fc of trastuzumab or the Fc of nivolumab.

Other TNFR2 agonist constructs include: a) TNFR2 agonist, which binds to one or more epitopes in human TNFR2, and these epitopes are selected from the epitopes shown in SEQ ID NO: 839-865, 1202 and 1204; b) a linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab; and c) Activity modulator, which is a half-life extending moiety, the half-life extending moiety is IgG Fc. Examples of linkers and activity modulators are the hinge sequence of trastuzumab; and the IgG Fc is the Fc of trastuzumab, or all or part of the hinge sequence of nivolumab; and the IgG Fc is nivolumab Resist Fc.

In other specific examples, a TNFR2 construct includes: a) a TNFR2 agonist that binds to one or more epitopes within human TNFR2 selected from the group consisting of SEQ ID NOs: 839-865, 1202, and The epitope shown in 1204; b) the first linker, which is a GS linker, selected from (GlySer) _n , where n=1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n = 1-10; (Gly ₃ Ser) _n , where n = 1-5; (SerGly ₄ ) _n , where n = 1-5; (GlySerSerGly) _n , where n = 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; c) a second linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab; and d) activity Modulator, which is a half-life extending moiety, and the half-life extending moiety is IgG Fc. An example of such a construct is that the first GS linker is (GGGGS) ₃ and the second linker contains the sequence SCDKTH (residues 217-222 of SEQ ID NO: 31); and the IgG Fc is the Fc of trastuzumab 's structure. In other specific examples, the first linker is (GGGGS) ₃ and the second linker includes all or part of the hinge sequence of nivolumab; and the IgG Fc is the Fc of nivolumab.

In some specific examples, the construct is a TNFR2 agonist construct comprising: a) a TNFR2 agonist comprising an antigen-binding fragment of an agonist human anti-TNFR2 antibody selected from MR2-1 or MAB2261; b) A linker comprising: i) a GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser ) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSSGS; and/or ii) all or part of the hinge sequence of trastuzumab or all or part of the hinge sequence of nivolumab; and c) activity modulator, which is selected from IgG1 or IgG4 Fc, PEG molecules and the half-life extending portion of human serum albumin (HSA), wherein: IgG1 Fc is the Fc of human IgG1 shown in SEQ ID NO: 10, or is the Fc of trastuzumab shown in SEQ ID NO: 27 ; and the PEG molecule has a molecular weight of at least or at least about 30 kDa.

In some specific examples, the construct is a TNFR2 agonist construct comprising: a) a TNFR2-selective TNF mutein, which is a soluble TNF variant comprising one or more TNFR2-selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88 N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146 D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D14 3V/A145S, refer to SEQ ID NO: 2 ; b) linker, which includes: i) GS linker, which is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; ( Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GGSSGGSSGGGSSGGSSG; and GSSSGS; and/or ii) all or part of the hinge sequence of trastuzumab or all or part of the hinge sequence of nivolumab; and c) an activity modulator, which is selected from IgG1 or IgG4 Fc , PEG molecules and the half-life extending portion of human serum albumin (HSA), wherein: IgG1 Fc is the Fc of human IgG1 shown in SEQ ID NO: 10, or is trastuzumab shown in SEQ ID NO: 27 The Fc of the antibody; and the PEG molecule has a molecular weight of at least or at least about 30 kDa.

In some specific examples, the construct is a TNFR2 agonist construct comprising: a) a TNFR2 TNF mutein comprising mutation D143N/A145R; b) a (GGGGS) ₃ linker; and c) an activity modulator that is The half-life extending part is the Fc of trastuzumab or the Fc of nivolumab.

In some specific examples, the construct is a TNFR2 agonist construct comprising a) a TNFR2-selective TNF mutein comprising mutation D143N/A145R; b) a (GGGGS) ₃ linker and comprising the sequence SCDKTH (SEQ ID NO: 31 residues 217-222) of the second linker; and c) an activity modulator, which is a half-life extending portion, and the half-life extending portion is the Fc of trastuzumab.

In some specific examples, the construct is a TNFR2 agonist construct comprising: a) a TNFR2-selective TNF mutein comprising mutation D143N/A145R; b) a (GGGGS) ₃ linker and a hinge comprising nivolumab a second linker of all or part of the sequence; and c) an activity modulator that is a half-life extending portion, the half-life extending portion being the Fc of nivolumab.

In some specific examples, the construct is a TNFR2 agonist construct comprising: a) TNFR2-selective TNF mutant protein containing mutation D143N/A145R; b) a linker comprising all or part of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26; and c) The half-life extending part, which is the Fc of trastuzumab.

In some specific examples, the construct is a TNFR2 agonist construct comprising: a) TNFR2-selective TNF mutant protein containing mutation D143N/A145R; b) a linker comprising all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29; and c) Activity modulator, which is a half-life extending portion, and the half-life extending portion is the Fc of nivolumab.

TNFR1 antagonist constructs, TNFR2 agonist constructs, and both are provided, in which the IgG Fc is a monomer or dimer. Constructs provided herein may contain dAb (or Vhh). Constructs may comprise Vhh single or double strands containing dAbs. These constructs may contain HSA linked to the dAb either directly or via a linker. HSA and dAb can be linked in any order, such as the C-terminus of the dAb being linked to the N-terminus of HSA directly or via a linker such as any of the linkers described above. Examples of such structures include: a) linked via a linker to residues 20-732 of HSA as shown in SEQ ID NO: 1475, i.e. dAb Dom1h-131-206 of SEQ ID NO: 59, or to the construct of SEQ ID NO: 1475 or A construct having at least 95%, 96%, 97%, 98%, 99% sequence identity to residues 20-732 of SEQ ID NO: 1475 and having TNFR1 antagonist activity; or b) The dAb shown in any one of SEQ ID NO: 53-83 and 503-671 and its variants having at least 95%, 96%, 97%, 98%, 99% sequence identity thereto, by The construct has TNFR1 antagonist activity; or c) a dAb having the sequence shown in any of SEQ ID NOs: 57-59 and variants thereof having at least 95% sequence identity thereto, whereby the construct has TNFR1 antagonist activity; or d) The dAb designated as DOM1h-131-206 of SEQ ID NO: 59 and its variants having at least 95%, 96%, 97%, 98%, 99% sequence identity thereto and having TNFR1 antagonist activity; or e) A combination of any of a)-d); or f) The humanized sequence of any of a)-f) or a sufficient portion of the construct in which it is administered to a human being is humanized, a sufficient portion of which, when administered to a human, is sufficient to eliminate or reduce the resistance to the construct any immune response in the body.

A construct provided herein that is a TNFR1 construct may further comprise a TNFR2 agonist, or the construct may be a TNFR2 agonist construct. In constructs comprising a TNFR2 agonist, the TNFR2 agonist can be modified to eliminate an amino acid sequence or epitope that is immunogenic in the individual to be treated, such as for administration to a human individual. In a construct containing a TNFR2 agonist, it can be a TNFR2 selective agonist. These constructs may include modified IgG Fc. For example, an IgG Fc may contain one or more of the following modifications: a) Modification by introducing pestle and mortar; b) Modifications that increase or enhance recycling of nascent Fc receptors (FcRn); and c) Modifications that reduce or eliminate immune effector functions selected from complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis ( ADCP) one or more. Examples of such modifications are: a) The modification introduced into the pestle and mortar is selected from: One or more mutations selected from S354C, T366Y, T366W and T394W according to the EU number; and According to EU numbering, one or more mutations are selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V, whereby Fc forms a dimer; b) According to the EU number, the modification that increases or enhances FcRn recycling is selected from T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W , N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/ N434S, V259I/V308F, V259I/V308F /M428L, one or more of E294del/T307P/N434Y and T256N/A378V/S383N/N434Y; and c) The modification that reduces or eliminates the immune effector function is selected from one or more of the following: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A.

Constructs provided herein include TNFR2 agonist constructs containing modified IgG Fc, wherein the IgG Fc includes one or more of the following modifications: a) One or more modifications introducing a pestle and mortar, wherein: According to EU numbering, the pestle mutant line is selected from S354C, T366Y, T366W and T394W; and According to EU numbering, the acetabulum mutant lines were selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector function is selected from one or more of CDC, ADCC and ADCP; and Modifications that increase or enhance immune effector functions are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan is introduced at residue N297; afucosylated glycan is introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y.

Constructs provided herein that are TNFR2 agonist constructs may comprise a modified IgG1 Fc, such as wherein the Fc is modified to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb, which may include increasing binding to FcγRIIb Grooming. Examples of such modifications are modifications selected from one or more of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K, according to EU numbering.

Constructs provided are or comprise TNFR2 agonist constructs that selectively activate or agonize TNFR2 without activating or antagonizing TNFR1. Such constructs include constructs comprising: a) a TNFR2 agonist; b) one or more linkers; and c) an activity modulator that is a half-life extending moiety, wherein: a TNFR2 agonist construct is a construct comprising A fusion protein of a single-chain TNFR2-selective TNF mutein trimer and a multimerization domain, and contains the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut -L1-TNFmut-L2-TNFmut-L3-MD (Formula III); MD is the multimerization domain and each is the same or different; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 can be the same or different Different connectors. The TNF mutein may comprise one or more TNFR2-selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N , D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146 D/S147D, A145N/E146D/S147D , A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E146T/S147D A145R/S147T, E146D/S147D, D143V /F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2, such as TNFR2 selective mutation D143N/A145R. In these constructs, the multimerization domain may be selected from the group consisting of EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO: 811), and the trimerization domain of chicken tenascin C (TNC) (SEQ ID NO: 804 (residues 110-139 of SEQ ID NO: 805) or the trimerization domain of human TNC (residues 110-139 of SEQ ID NO: 806, SEQ ID NO: 807), or have at least 95% or 96% similarity therewith. , 97%, 98%, 99% sequence identity and its variants. For example, the multimerization domain is IgG1 Fc or IgG4 Fc, and IgG1 Fc or IgG4 Fc is also a half-life extending moiety. These constructs contain linkers, including any linkers described herein and any linkers known to those of ordinary skill in the art. Exemplary of such constructs are the L1, L2 and/or L3 linkers independently selected from (GGGGS) _n , where n = 1-5, and all or part of the stem region of TNF (SEQ ID NO: 812) or in combination therewith Constructs of variants thereof having at least 95%, 96%, 97%, 98%, 99% sequence identity. These constructs include constructs in which the linker between the TNFR2 agonist and the half-life extending moiety is selected from (GlySer) _n , where n=1-10; ( _GlySer2 ); ( _Gly4Ser ) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSSGSGSGSSG; GSSSGSGSGSSGG; GGSSGG; GGSSGGSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and the GS linker of GSSSGS; or a linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab; or its combination. The half-life extending moiety may be selected from: IgG1 Fc, which is the Fc of human IgG1 shown in SEQ ID NO: 10 or the Fc of trastuzumab shown in SEQ ID NO: 27; IgG4 Fc, which is SEQ ID The Fc of human IgG4 as set forth in NO: 16 or the Fc of nivolumab as set forth in SEQ ID NO: 30; a PEG molecule of at least or at least about 30 kDa in size; human serum albumin (HSA), and thereto Variants having a polypeptide portion with at least 95%, 96%, 97%, 98%, 99% sequence identity.

Provided constructs are or include TNFR2 agonist constructs. Such constructs include constructs containing the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula III), where : a) MD is the multimerization domain; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 are the same or different linkers, where: i) MD is selected from EHD2 (SEQ ID NO: 808) , MHD2 (SEQ ID NO: 811), the trimerization domain of chicken tenascin C (TNC) (residues 110-139 of SEQ ID NO: 804; SEQ ID NO: 805) or the trimerization domain of human TNC ( Residues 110-139 of SEQ ID NO: 806, SEQ ID NO: 807); ii) L1, L2 and L3 are each (GGGGS) _n , where n = 1-5, or the stem region of TNF (SEQ ID NO: 812), or a mixture thereof; and iii) a TNF mutein comprising the TNFR2 selective mutation D143N/A145R; b) a half-life extending portion selected from: IgG1 Fc, which is shown in SEQ ID NO: 10 The Fc of human IgG1 or the Fc of trastuzumab shown in SEQ ID NO: 27; The Fc of IgG4, which is the Fc of human IgG4 shown in SEQ ID NO: 16 or shown in SEQ ID NO: 30 the Fc of nivolumab; a PEG molecule of at least or at least about 30 kDa in size; and human serum albumin (HSA); and c) a linker between a TNFR2 selective agonist and a half-life extending moiety, wherein the The linker includes: GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where _{or connect _} The child is selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab; or a combination thereof.

Constructs include TNFR2 agonist constructs comprising the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula III ), where MD is the multimerization domain; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 are the same or different linkers, and wherein: i) MD is selected from IgG1 Fc or IgG4 Fc; ii ) L2 and L3 in Formula II, and L1 and L2 in Formula III are each independently (GGGGS) _n , where n = 1-5, or all or part of the stem region of TNF (SEQ ID NO: 812), or a combination thereof; iii) Each of L1 in Formula II and L3 in Formula III is independently selected from: a GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ) ;(Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGG; GGSSGGSSGGGSSGGSSG; and GSSSGS; or a linker selected from all or part of the hinge sequence of trastuzumab and all of the hinge sequence of nivolumab or a part thereof; or a combination thereof; and iv) the TNF mutein comprises the TNFR2 selective mutation D143N/A145R. In these constructs, the MD can be selected from: IgG1 Fc, which is the Fc of human IgG1 set forth in SEQ ID NO: 10 or the Fc of trastuzumab set forth in SEQ ID NO: 27; or IgG4 Fc, which is the Fc of human IgG4 shown in SEQ ID NO: 16 or the Fc of nivolumab shown in SEQ ID NO: 30; or a combination thereof or at least 95%, 96%, 97%, Variants with 98% or 99% sequence identity.

An exemplary construct is one that includes an IgG1 Fc where the MD is trastuzumab and the linker between the MD and the adjacent TNF mutein is trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26 All or part of the hinge sequence, or a construct in which the MD is the IgG1 Fc of trastuzumab and the linker between the MD and the adjacent TNF mutein includes the sequence SCDKTH (residues 217-222 of SEQ ID NO: 31) . An exemplary construct is a construct comprising an IgG1 Fc where the MD is trastuzumab, wherein the linker between the MD and the adjacent TNF mutein includes (Gly ₄ Ser) ₃ and the residue corresponding to SEQ ID NO: 26 The hinge sequence of trastuzumab based on base 219-233. In some specific examples, the MD is the IgG1 Fc of trastuzumab, and the linker between the MD and the adjacent TNF mutein includes (Gly ₄ Ser) ₃ and SCDKTH (residues 222-31 of SEQ ID NO: 31 227), wherein MD is the IgG4 Fc of nivolumab, and the linker between the MD and the adjacent TNF mutein includes the hinge of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29 All or part of the sequence, or those in which the MD is the IgG4 Fc of nivolumab and the linker between the MD and the adjacent TNF mutein includes (Gly ₄ Ser) ₃ and the residue corresponding to SEQ ID NO: 29 All or part of the hinge sequence of nivolumab based on 212-223.

Constructs herein, including agonist constructs, may be modified to eliminate immunogenic sequences, such as sequences that are immunogenic in humans. Provided herein are TNFR2 agonist constructs wherein the TNFR2 agonist is modified to eliminate an immunogenic sequence or epitope that is immunogenic in an individual, such as a human individual.

In constructs provided herein that are TNFR2 agonist constructs and include modified IgG Fc, the IgG Fc may include one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that reduce or eliminate immune effector functions, wherein: The immune effector function is selected from one or more of CDC, ADCC and ADCP; and Modifications that reduce or eliminate immune effector functions are selected from one or more of the following: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A.

Any of the foregoing constructs are provided, which are TNFR2 agonist constructs comprising a modified IgG Fc, wherein the IgG Fc comprises one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector function is selected from one or more of CDC, ADCC and ADCP; and Modifications that increase or enhance immune effector functions are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan introduced at residue N297; afucosylated glycan introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y.

Any of the aforementioned TNFR2 agonist constructs are provided, comprising an IgG1 Fc modified to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb. Examples of this are modifications that increase binding to FcγRIIb and are selected from one or more of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K according to EU numbering. construct.

Constructs provided herein can be multispecific in that they interact with two or more targets. An example of such a multispecific construct is a multispecific TNFR1 inhibitor/TNFR2 agonist construct and has either of the following formulas: (TNFR1 inhibitor) _n - linker (L) _p - (TNFR2 antagonist agent) _q (Formula I), or (TNFR1 inhibitor) _n ― linker (L) _p ― (TNFR2 antagonist) _q , or (TNFR1 inhibitor) _n ― (TNFR2 antagonist) _q ― linker (L) _p , or (TNFR2 antagonist) _q - (TNFR1 inhibitor) _n - linker (L) _p , or any of the above, which includes an activity modulator selected as needed, where: n= 1 or 2, p = 1, 2 or 3, and q = 1 or 2; a TNFR1 inhibitor interacts with TNFR1 to inhibit its activity; an activity modulator is one that modulates or changes the activity of the construct compared to a construct in the absence of the activity modulator or pharmacological properties; and linkers, such as increasing the solubility of the construct, or increasing flexibility, or changing the steric hindrance effect of the construct. Such constructs include multispecific TNFR1 inhibitor/TNFR2 agonist constructs, wherein: the TNFR1 inhibitor selectively inhibits or antagonizes TNFR1 signaling but not TNFR2 signaling; and the TNFR1 inhibitor does not interfere with TNFR2 signaling. Activating or stimulating effects; TNFR2 agonists selectively activate or agonize TNFR2 signaling without activating or stimulating TNFR1 signaling; and TNFR2 agonists do not interfere with the inhibitory or antagonizing effects of TNFR1. Examples of such constructs are constructs with the following a)-c): a) The TNFR1 inhibitor is selected from: i) The antigen-binding fragment of a human anti-TNFR1 antagonist monoclonal antibody selected from H398 or ATROSAB or having A polypeptide with a sequence of at least 95% sequence identity; or ii) a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or a scFv of any of SEQ ID NOs: 673-678, or Fab of any one of SEQ ID NO: 679-682, or Nanobody of SEQ ID NO: 683 or 684, or TNF mutant protein of any one of SEQ ID NO: 701-703, or with the aforementioned polypeptide Any of the polypeptides having a sequence of at least 95% sequence identity and being a TNFR1 inhibitor; or iii) a dominant negative tumor necrosis factor (DN-TNF) or a TNF mutant protein containing a soluble TNF molecule, which has a or multiple amino acid substitutions that confer selective inhibition of TNFR1 and are selected from the following: V1M, L29S, L29G, L29Y, R31C, R31E, R31N, R32Y, R32W, C69V, A84S, V85T, S86T, Y87H, Q88N , T89Q, I97T, C101A, A145R, E146R, L29S/R32W, L29S/S86T, R32W/S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T, I97T/A145R, V 1M/R31C /C69V/Y87H/C101A/A145R and A84S/V85T/S86T/Y87H/Q88N/T89Q, refer to the sequence of soluble TNF shown in SEQ ID NO: 2; b) The linker is selected from: i) GS linker, It is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSGSGSGSSGSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and/or ii) corresponding to SEQ ID NO : All or part of the hinge sequence of trastuzumab at residues 219-233 of SEQ ID NO: 26, or all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29; and iii) IgG1 or IgG4 Fc, wherein: IgG1 Fc is selected from the IgG1 Fc of human IgG1 shown in SEQ ID NO: 10, or the IgG1 Fc of trastuzumab shown in SEQ ID NO: 27; IgG4 Fc Is selected from the IgG4 Fc of human IgG4 shown in SEQ ID NO: 16, or the IgG4 Fc of nivolumab shown in SEQ ID NO: 30; and if necessary, the Fc includes one or more inlet adapters and/ or modifications that increase or enhance nascent Fc receptor (FcRn) recycling and/or reduce or eliminate immune effector functions; and c) TNFR2 agonists are selected from: i) one or more epitopes within human TNFR2 Binding antigen-binding fragments selected from the epitopes shown in SEQ ID NOs: 839-865, 1202 and 1204; or ii) agonist human anti-TNFR2 selected from MR2-1 or MAB2261 An antigen-binding fragment of an antibody; or iii) a TNFR2-selective TNF mutein, which is a soluble TNF variant comprising one or more TNFR2-selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I /E146G/S147D、A145H/E146S/ S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E14 6G/S147D, A145D/S147D, A145K/ E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2; or iv) a single gene containing mutation D143N/A145R chain TNFR2-selective TNF mutein trimers, wherein the TNF mutein is linked by (GGGGS) _n , where n = 1-5, or all or part of the stem region of TNF (SEQ ID NO: 812); or v) TNFR2 selection A sexual agonist comprising the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula III); wherein MD is Multimerization domain; TNFmut is a TNFR2-selective TNF mutant protein; and L1, L2 and L3 are the same or different linkers, and wherein: MD system is selected from EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO : 811), the trimerization domain of chicken tenascin C (TNC) (residues 110-139 of SEQ ID NO: 804; SEQ ID NO: 805) or the trimerization domain of human TNC (residues 110-139 of SEQ ID NO: 806) Residues 110-139, SEQ ID NO: 807); L1, L2 and L3 are each (GGGGS) _n , where n = 1-5, or all or part of the stem region of TNF (SEQ ID NO: 812), or A mixture thereof; and a TNF mutein comprising the TNFR2 selective mutation D143N/A145R.

Other such constructs include multispecific TNFR1 antagonist/TNFR2 agonist constructs, wherein: a) the TNFR1 inhibitor comprises a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or SEQ ID The scFv of any one of NO: 673-678, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or SEQ ID NO: 701-703 Any one of the TNF mutant proteins, or a sequence with at least or at least about 95% sequence identity; b) the linker includes (GGGGS) ₃ , including residues 222-227 of the sequence SCDKTH (SEQ ID NO: 26 ) and the Fc of trastuzumab; and c) a TNFR2 agonist comprising a TNFR2-selective TNF mutein, which is a soluble TNF variant comprising one or more TNFR2-selective mutations selected from the following: K65W , D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T 89S/A145S/E146A/S147D, Q88N /A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S1 47D, A145T/E146D/S147D, A145D /E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A1 45S, refer to SEQ ID NO: 2.

Other such multispecific constructs are those in which: a) the TNFR1 inhibitor comprises a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or SEQ ID NOs: 673-678 The scFv of any one, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of any one of SEQ ID NO: 683 or 684, or any one of SEQ ID NO: 701-703 TNF mutant protein, or a sequence with at least or at least about 95% sequence identity thereto; b) the linker includes (GGGGS) ₃ , all or part of the hinge sequence of nivolumab and the Fc of nivolumab; and c ) TNFR2 agonists comprise TNFR2-selective TNF muteins, which are soluble TNF variants containing one or more TNFR2-selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R , A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S14 7D, A145H/E146S/S147D, A145H /S147D、L29V/A145D/E146D/S147D、A145N/E146D/S147D、A145T/E146S/S147D、A145Q/E146D/S147D、A145T/E146D/S147D、A145D/E146G/S147D、A1 45D/S147D, A145K/E146D/S147T , A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2.

Other such multispecific constructs are those in which: a) the TNFR1 inhibitor comprises a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or SEQ ID NOs: 673-678 The scFv of any one, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of any one of SEQ ID NO: 683 or 684, or any one of SEQ ID NO: 701-703 TNF mutant protein, or a sequence having at least or at least about 95% sequence identity thereto; b) the linker includes (GGGGS) ₃ and the Fc of trastuzumab; and c) the TNFR2 agonist includes a TNFR2-selective TNF mutation A protein that is a soluble TNF variant comprising one or more TNFR2 selective mutations selected from the group consisting of: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D ,L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A1 45R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2.

Other such multispecific constructs are those in which: a) the TNFR1 inhibitor comprises a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or SEQ ID NOs: 673-678 The scFv of any one, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of any one of SEQ ID NO: 683 or 684, or any one of SEQ ID NO: 701-703 TNF mutein, or a sequence having at least or at least about 95% sequence identity thereto; b) the linker comprises (GGGGS) ₃ and the Fc of nivolumab; and c) the TNFR2 agonist comprises a TNFR2-selective TNF mutein , which is a soluble TNF variant comprising one or more TNFR2 selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H , E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29 V/A145D/E146D/S147D, A145N /E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E 146T/S147D, A145R/S147T, E146D /S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, and any combination of the aforementioned mutations, refer to SEQ ID NO: 2.

Such multispecific constructs may include a modified Fc, wherein the IgG Fc includes one or more of the following modifications: a) Modification by introducing pestle and mortar; b) Modifications that increase or enhance recycling of nascent Fc receptors (FcRn); and c) Modifications that reduce or eliminate immune effector functions. An example of an Fc containing pestle and mortar modifications is: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V.

Other examples are multispecific constructs comprising an Fc, such as wherein the Fc contains a modification that increases or enhances FcRn recycling, which is selected from one or more of the following: T250Q, T250R, M252F, M252W, according to EU numbering M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M2 52Y/S254T/T256E, H433K/N434F/ Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E294del/T307P/N434Y and T256N/A378V/S383N/N4 34Y. Fc may include modifications to immune effector functions selected from complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP). one or more. Fc may include modifications to reduce or eliminate the immune effector functions of IgG1 and/or IgG4: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 G237A, E318A, D265A, E233P, N297A, N297Q, N297D, N297G, N297G/D265A, A330L, D270A, P329A, P331A, K322A, V264A and F241A; and/or Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A.

The IgG Fc may contain one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector function is selected from one or more of CDC, ADCC and ADCP; and Modifications that increase or enhance immune effector functions are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan is introduced at residue N297; afucosylated glycan is introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y.

Other such multispecific constructs are constructs comprising an IgG1 Fc modified to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb. Examples of this are modifications that increase binding to FcγRIIb and are selected from one or more of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K according to EU numbering. construct.

Also provided are constructs that are multispecific TNFRl antagonist/TNFR2 agonist, the TNFRl antagonist being monovalent; and the TNFR2 agonist being monovalent. Also provided are multispecific constructs that are multispecific TNFR1 antagonist/TNFR2 agonist constructs, wherein the TNFR1 antagonist is monovalent; and the TNFR2 agonist is bivalent.

In some specific examples, the multispecific construct is a multispecific TNFR1 antagonist/TNFR2 agonist construct, wherein: a) the TNFR1 antagonist is selected from: i) a human anti-TNFR1 antagonist selected from H398 or ATROSAB An antigen-binding fragment of a monoclonal antibody; or ii) a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or a scFv of any one of SEQ ID NO: 673-678, or SEQ ID NO : The Fab of any one of 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or the TNF mutant protein of any one of SEQ ID NO: 701-703, or has at least or at least approximately A sequence with 95% sequence identity; or iii) a dominant negative tumor necrosis factor (DN-TNF) or a TNF mutein containing a soluble TNF molecule with one or more of the following that confer selective inhibition of TNFR1 and is selected from the following Amino acid substitution: V1M, L29S, L29G, L29Y, R31C, R31E, R31N, R32Y, R32W, C69V, A84S, V85T, S86T, Y87H, Q88N, T89Q, I97T, C101A, A145R, E146R, L29S/R32W, L29S/S86T, R32W/S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T, I97T/A145R, V1M/R31C/C69V/Y87H/C101A/A145R and A84S/V85T/ S86T/ Y87H/Q88N/T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2; b) the linker is a branched PEG molecule with a size of at least or at least about 30 kDa; and c) the TNFR2 agonist is selected from : i) An antigen-binding fragment that binds to one or more epitopes in human TNFR2, which epitopes are selected from the epitopes shown in SEQ ID NO: 839-865, 1202 and 1204; or ii ) an antigen-binding fragment of a agonist human anti-TNFR2 antibody selected from MR2-1 or MAB2261; or iii) a TNFR2-selective TNF mutein, which is a soluble TNF comprising one or more TNFR2-selective mutations selected from Variants: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T , Q88N/T89S/A145S/E146A /S147D、Q88N/A145I/E146G/S147D、A145H/E146S/S147D、A145H/S147D、L29V/A145D/E146D/S147D、A145N/E146D/S147D、A145T/E146S/S147D、A14 5Q/E146D/S147D, A145T/E146D /S147D、A145D/E146G/S147D、A145D/S147D、A145K/E146D/S147T、A145R/E146T/S147D、A145R/S147T、E146D/S147D、D143V/F144L/A145S、S95C/G1 48C and D143V/A145S, refer to SEQ ID _OR NO: 812) is connected in whole or in part; or v) a TNFR2 selective agonist comprising the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut-L1-TNFmut- L2-TNFmut-L3-MD (Formula III); where MD is the multimerization domain; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 are the same or different linkers, and where: MD is selected From the trimerization domain of EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO: 811), chicken tenascin C (TNC) (residues 110-139 of SEQ ID NO: 804; SEQ ID NO: 805) or the trimerization domain of human TNC (residues 110-139 of SEQ ID NO: 806, SEQ ID NO: 807); L1, L2 and L3 are each (GGGGS) _n , where n = 1-5, or of TNF All or a portion of the stem region (SEQ ID NO: 812), or a mixture thereof; and the TNF mutein comprises the TNFR2 selective mutation D143N/A145R.

Multispecific constructs are also provided in which each of the TNFR1 antagonist and TNFR2 agonist is monovalent. Constructs are also provided in which the TNFR1 antagonist is monovalent and the TNFR2 agonist is bivalent.

The constructs provided herein can be used in the treatment and use to treat a variety of diseases, disorders and conditions. The multispecific constructs provided are multispecific TNFR1 antagonists/TNFR2 agonists for the treatment of, or in the etiology of, chronic inflammatory, autoimmune, neurodegenerative, demyelinating or respiratory diseases or conditions. A disease, condition or disorder characterized by excessive expression of TNF or dysregulation of TNFR1 signaling. Multispecific TNFR1 antagonist/TNFR2 agonist constructs are provided for the treatment of chronic inflammatory, autoimmune, neurodegenerative, demyelinating or respiratory diseases or conditions, or in which overexpression of TNF or TNFR1 is the cause. Use in diseases, conditions or disorders characterized by dysregulation of signaling.

Compositions comprising any of the constructs provided herein in a pharmaceutically acceptable carrier or vehicle are also provided. Such compositions may be used in or in methods of treating diseases, disorders and conditions, such as, but not limited to, treating chronic inflammatory, autoimmune, neurodegenerative, demyelinating or respiratory diseases or A disorder, or a disease, condition or disorder characterized in its etiology by overexpression of TNF or dysregulation of TNFRl signaling. Examples of chronic inflammatory, autoimmune, neurodegenerative, demyelinating or respiratory diseases or disorders, or diseases, conditions or disorders are those characterized in their etiology by excessive expression of TNF or dysregulated TNFR1 signaling. or illness. These include diseases, disorders and conditions selected from: rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), spondyloarthritis, ankylosing spondylitis, KRAS Rohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), uveitis, fibrotic diseases, endometriosis, lupus, multiple sclerosis (MS), congestive heart failure, cardiovascular Disease, myocardial infarction (MI), atherosclerosis, metabolic disease, interleukin release syndrome, septic shock, sepsis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), SARS-CoV-2, Influenza, acute and chronic neurodegenerative diseases, demyelinating diseases and disorders, stroke, Alzheimer's disease, Parkinson's disease, Behçet's disease, Dupuytren's disease , Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), pancreatitis, type I diabetes, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, graft rejection, graft-versus-host disease (GvHD) , pulmonary inflammation, pulmonary diseases and conditions, asthma, cystic fibrosis, idiopathic pulmonary fibrosis, acute fulminant viral or bacterial infection, pneumonia, genetic diseases with TNF/TNFR1 as the causative pathological mediator, Periodic fever syndrome or cancer. In particular, constructs provided herein, such as, but not limited to, TNFR1 antagonist constructs, can be used in uses, methods of treatment, and compositions for treating rheumatoid arthritis.

Also provided herein are constructs that are TNFR2 antagonist constructs, comprising a TNFR2 antagonist and optionally a linker and optionally an activity modulator. Such a construct has, for example, the formula 5: (TNFR2 antagonist) _n ― linker _p ― (activity modulator) _q , or linker _p ― (activity modulator) _q ― (TNFR2 antagonist) _n , where: n and Each of q is an integer and is independently 1, 2 or 3; p is 0, 1, 2 or 3; a TNFR2 antagonist interacts with TNFR2 to inhibit (antagonize) TNFR2 activity, thereby inhibiting Treg A molecule that proliferates and/or induces its death, and can also inhibit the proliferation and induce the death of tumor cells expressing TNFR2; an activity modulator is a molecule that modulates or changes the activity of the construct compared with a construct without an active modulator or Part of the pharmacological properties; and the linker increases the flexibility of the construct, and/or alleviates or reduces the steric effect of the construct or its interaction with the receptor, and/or increases the solubility of the construct in aqueous media .

In these constructs, the activity modulator and the linker are each defined and described above and below for the construct. It can be used in treatment methods and uses, and in pharmaceutical compositions.

TNFR2 antagonists can be used in various diseases, disorders and conditions, such as reducing and/or inhibiting the proliferation of myeloid-derived suppressor cells (MDSCs); and/or inducing MDSCs by binding to TNFR2 expressed on the surface of MDSCs present in the tumor microenvironment Apoptosis in cells; and/or inducing the expansion of effector T cells, including cytotoxic CD8 ⁺ T cells, by inhibiting Treg expansion and activity. TNFR2 antagonists in the construct include antibodies, antigen-binding fragments thereof, or single-chain antibodies that contain, for example, one or more of the residues KCRPG (corresponding to residues 142-146 of SEQ ID NO: 4) in human TNFR2 an epitope, or a larger epitope containing residues 130-149, 137-144 or 142-149, or at least 5 consecutive or discontinuous residues within such epitopes, and does not bind to Binds to the epitope of residue KCSPG (corresponding to residues 56-60 of SEQ ID NO: 4); or binds to the TNFR2 epitope PECLSCGS (corresponding to residues 91-98 of SEQ ID NO: 4), RICTCRPG (corresponding to at residues 116-123 of SEQ ID NO: 4), CAPLRKCR (corresponding to residues 137-144 of SEQ ID NO: 4), LRKCRPGFGVA (corresponding to residues 140-150 of SEQ ID NO: 4), and/or VVCKPCAPGTFSN (corresponding to residues 159-171 of SEQ ID NO: 4), and/or contains at least 5 consecutive or Epitope binding of discontinuous residues. For example, an antibody, fragment thereof, or single-chain form thereof binds to an epitope containing one or more residues of the KCRPG sequence (SEQ ID NO: 840) with greater affinity than the same antibody or antigen-binding fragment containing human TNFR2 The affinity of the peptide with the KCSPG sequence (SEQ ID NO: 839) is at least 10 times greater. In some specific examples of TNFR2 antagonist constructs, the TNFR2 antagonist is an antibody or a fragment or single chain form of an antibody selected from: TNFRAB1 (for the sequences of the heavy chain and light chain of TNFRAB1, respectively, see SEQ ID NO: 1212 and 1213), TNFRAB2 and TNFR2A3 (for a description of these antibodies, see, for example, U.S. Patent Publication No. 2019/0144556); containing TNFRAB1 (QRVDGYSSYWYFDV; corresponding to residues 99-112 of SEQ ID NO: 1212), TNFRAB2 (ARDDGSYSPFDYWG; SEQ ID NO: 1217) or TNFR2A3 (ARDDGSYSPFDYFG; SEQ ID NO: 1223) CDR-H3 sequence or antibodies and antibody fragments and single-chain forms with a CDR-H3 sequence that has at least about 85% sequence identity with it. For example, TNFRAB1 specifically binds to residues 130-149 of KCRPG containing TNFR2 residues with a 40-fold higher affinity than residues 48-67 of KCSPG containing TNFR2 residues. In some embodiments, a TNFR2 antagonist binds to one or more epitopes in TNFR2 selected from: The epitope containing residues 137-144 (CAPLRKCR; SEQ ID NO: 851) includes the position of human TNFR2 Antigens containing one or more residues in 80-86 (DSTYTQL; SEQ ID NO: 1247), 91-98 (PECLSCGS; SEQ ID NO: 1248) and/or 116-123 (RICTCRPG; SEQ ID NO: 1249) The epitope; and the epitope targeted by TNFR2A3, which is selected from the group consisting of residues 140-150 of human TNFR2 (LRKCRPGFGVA; SEQ ID NO: 1463) and contains the first epitope of the KCRPG motif, and/or contains human The second epitope of residues 159-171 of TNFR2 (VVCKPCAPGTFSN; SEQ ID NO: 1464).

In some specific examples, the TNFR2 antagonist in the construct is an antibody, a fragment thereof, or a single chain form thereof, which contains a CDR having the sequence set forth in any one of SEQ ID NOs: 1214, 1215, and 1231-1233 -H1 amino acid, CDR-H2 sequence shown in any one of SEQ ID NO: 1216, 1224 and 1230, CDR shown in any one of SEQ ID NO: 1217, 1223 and 1225-1229 - the H3 sequence, and/or the CDR-H3 of TNFRAB1 corresponding to residues 99-112 of SEQ ID NO: 1212; the CDR-L1 sequence shown in any of SEQ ID NO: 1218 and 1234-1236, and/or the CDR-L1 sequence of TNFRAB1 corresponding to residues 24-33 of SEQ ID NO: 1213; the CDR-L2 sequence shown in any of SEQ ID NO: 1219, 1220, 1237 and 1238, or The CDR-L2 sequence of TNFRAB1 corresponding to residues 49-55 of SEQ ID NO: 1213; and/or the CDR-L3 sequence shown in any of SEQ ID NO: 1221, 1222 and 1241-1244, or One or more of the CDR-L3 sequences of TNFRAB1 corresponding to residues 88-96 of SEQ ID NO: 1213; and/or the CDR-H1 of the common sequence of the human antibody heavy chain variable domain of SEQ ID NO: 1245 and the CDR-H2 sequence is replaced with the corresponding CDR sequence of a phenotypically neutral TNFR2-specific antibody, and/or the CDR-L1, CDR-L2 and CDR-L3 of the human antibody light chain variable domain sequence of SEQ ID NO: 1246 The sequence is replaced with the corresponding CDR sequence of a phenotypically neutral TNFR2-specific antibody to generate a humanized antagonist TNFR2 antibody. For example, a construct includes a TNFR2 antagonist that specifically binds to an epitope within TNFR2 set forth in any of SEQ ID NOs: 1247-1464. In some specific examples, the TNFR2 antagonist specifically binds to an epitope selected from: (a) Human TNFR2 contains one or more epitopes corresponding to one or more of the KCRPG residues 142-146 of SEQ ID NO: 4, or contains residues 130-149, 137-144 or larger epitopes 142-149, or at least 5 contiguous or discontinuous residues within such epitopes, and are not identical to KCSPG containing residues 56-60 corresponding to residues 56-60 of SEQ ID NO: 4 Epitope binding; and/or (b) One or more TNFR2 epitopes, which comprise the following amino acid sequences: PECLSCGS corresponding to residues 91-98 of SEQ ID NO: 4, and/or RICTCRPG corresponding to residues 116-123 of SEQ ID NO: 4, and/or CAPLRKCR, corresponding to residues 137-144 of SEQ ID NO: 4), and/or LRKCRPGFGVA, corresponding to residues 140-150 of SEQ ID NO: 4), and/or VVCKPCAPGTFSN (corresponding to residues 140-150 of SEQ ID NO: 4) residues 159-171), and/or An epitope containing at least 5 consecutive or discontinuous residues within residues 75-128, 86-103, 111-128 or 150-190 of SEQ ID NO: 4.

In some specific examples, a TNFR2 antagonist construct includes a TNFR2 antagonist, which is a small molecule. For example, TNFR2 antagonists are thalidomide or analogs thereof, such as lenalidomide and pomalidomide.

In some embodiments, a TNFR2 antagonist construct includes a TNFR2 antagonist that reduces FoxP3 expression and inhibits the suppressive activity of Tregs. Examples of such antagonists are histone deacetylase inhibitors that reduce FoxP3 expression and inhibit the suppressive activity of Tregs. Examples of such inhibitors are panobinostat or cyclophosphamide or triptolide.

TNFR2 constructs are useful in methods and uses for treating infectious diseases and treating cancers expressing TNFR2. Examples of such cancers are cancers selected from: T-cell lymphomas such as Hodgkin's lymphoma and cutaneous non-Hodgkin's lymphoma, ovarian cancer, colon cancer, multiple myeloma, renal cell carcinoma, Breast cancer, cervical cancer, endometrial cancer, glioma, head and neck cancer, liver cancer and lung cancer.

Provides constructs as growth factor trapping agents (GFT). The growth factor capture construct contains two different ectodomains (ECD) of the ligand and a multimerization domain as an activity modulator, where the multimerization domain is linked to the ECD directly or via a linker. One or both of the ECD and/or multimerization domains in the growth factor capture agent construct are modified in their primary amino acid sequence to alter binding of the ECD or multimerization domain. In some specific examples, in the growth factor capture constructs provided herein, the multimerization domain is a modified Fc. For example, in the growth factor capture constructs herein, the multimerization domain is a modified Fc or IgG Fc that includes one or more modifications, such as one that introduces binding; increases or enhances nascent Fc receptors Modifications of (FcRn) recycling; and modifications that reduce or eliminate immune effector functions. In some examples of growth factor capture constructs herein, the construct contains Fc, wherein Fc includes a pestle modification, wherein: According to the EU number, the pestle modification is selected from one or more of S354C, T366Y, T366W and T394W; and According to the EU number, the acetal modification is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V.

In some specific examples, the Fc in the growth factor capture construct herein includes one or more modifications that increase or enhance FcRn recycling, wherein the modifications are selected from one or more of the following: According to EU numbering, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436H, M2 52Y/T256Q, M252F/T256D, M252Y/ S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E294del/T307P/N4 34Y and T256N/A378V/S383N/N434Y.

In some embodiments, the Fc in the growth factor capture constructs herein includes an immune effector function selected from the group consisting of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cytotoxicity. One or more of sex cell-mediated phagocytosis (ADCP).

In some specific examples, the IgG1 and/or IgG4 in the growth factor capture agent constructs herein include one or more modifications that reduce or eliminate immune effector functions; the modifications in IgG1 can be selected from the group consisting of L235E, L234A according to EU numbering /L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P331S, G236R/L328R, G237A, E 318A, D265A, E233P, N297A, N297Q , N297D, N297G, N297G/D265A, A330L, D270A, P329A, P331A, K322A, V264A and F241A; modifications in IgG4 can be selected from the group consisting of L235E, F234A/L235A, S228P/L235E and S228P/F234A according to the EU number /L235A.

In some specific examples, the IgG Fc in the growth factor capture constructs herein includes one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector function is selected from one or more of CDC, ADCC and ADCP; and Modifications that increase or enhance immune effector functions are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan is introduced at residue N297; afucosylated glycan is introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y.

In any of the growth factor capture agents provided herein, the construct includes an IgGl Fc modified to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb. For example, in a specific example, the modification that increases binding to FcγRIIb is selected from the group consisting of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K according to EU numbering. one or more.

In some embodiments, the ECD in the growth factor trap construct includes one or more modifications. Exemplary ECDs in growth factor capture constructs herein include all or a portion of the extracellular domain (ECD) of a HER family member. Exemplary members of the HER family include EGFR/HER1, HER2, HER3, and HER4.

In some embodiments, the growth factor capture constructs herein include a linker connecting one or two ECDs to a multimerization domain. For example, linkers in the growth factor capture agent construct can provide flexibility, increase solubility, and/or alleviate or reduce steric hindrance or van der Waals interactions. Examples of such linkers include hinge regions or linkers containing G and S residues. Other linkers included in the growth factor capture constructs herein have the sequence shown in any of SEQ ID NOs: 812-834, or are PEG moiety linkers. In other examples, the linker is selected from: i) a GS linker selected from (GlySer) _n , where n = 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n = 1-10 ;(Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSGGSSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and/or ii) all or part of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26, or corresponding to the residues of SEQ ID NO: 29 All or part of the hinge sequence of nivolumab 212-223; and iii) IgG1 or IgG4 Fc, wherein: IgG1 Fc is selected from the IgG1 Fc of human IgG1 shown in SEQ ID NO: 10, or SEQ ID NO : The IgG1 Fc of trastuzumab shown in 27; and the IgG4 Fc is selected from the IgG4 Fc of human IgG4 shown in SEQ ID NO: 16, or nivolumab shown in SEQ ID NO: 30 of IgG4 Fc.

For example, in a growth factor capture construct containing a linker and an Fc, the Fc includes one or more introducers and/or increases or enhances nascent Fc receptor (FcRn) recycling and/or reduces or eliminates immune effects Modification of function. In some examples, where the growth factor capture construct contains a linker, the linker includes all or a portion of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29. For example, a construct containing a linker comprising all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29 can comprise an IgG1 or IgG4 Fc. In such examples, the IgG1 Fc is selected from the IgG1 Fc of human IgG1 set forth in SEQ ID NO: 10, or the IgG1 Fc of trastuzumab set forth in SEQ ID NO: 27; the IgG4 Fc is selected from The IgG4 Fc of human IgG4 shown in SEQ ID NO: 16, or the IgG4 Fc of nivolumab shown in SEQ ID NO: 30; and as appropriate, the Fc includes one or more introducing adapters and/or the addition of or Modifications that enhance recycling of nascent Fc receptors (FcRn) and/or reduce or eliminate immune effector functions.

In an exemplary growth factor capture construct containing a linker, the linker comprises all or a portion of the hinge sequence of trastuzumab, SCDKTH corresponding to residues 222-227 of SEQ ID NO: 26 or up to and including or The entire sequence of the hinge region of trastuzumab having the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26), or at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues thereof base, or residues ESKYGPPCPPCP of residues 212-223 of SEQ ID NO: 29, or a sequence having at least 98% or 99% sequence identity thereto as a linker. In constructs provided herein that are growth factor capture constructs and include a linker, the linker may include the sequence SCDKTH corresponding to residues 222-227 of SEQ ID NO: 26; and/or the linker may include a GS linker. and all or a portion of the hinge sequence of trastuzumab corresponding to residues EPKSCDKTHTCPPCP (219-233 of SEQ ID NO: 26); and/or the linker includes a GS linker and includes a linker corresponding to SEQ ID NO: 31 Sequence SCDKTH for residues 217-222.

In any of the linker-containing growth factor capture constructs provided herein, in some examples, the linker is selected from one or more of: comprising a GS linker and corresponding to SEQ ID NO. : A linker of all or part of the hinge sequence of nivolumab at residues 212-223 of 29; a linker containing (Gly ₄ Ser) ₃ ; a linker containing (Gly ₄ Ser) ₃ and SCDKTH (SEQ ID NO: 31 A linker comprising (Gly ₄ Ser) ₃ and a hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26; comprising (Gly ₄ Ser) ) ₃ and a linker corresponding to the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29.

In any of the growth factor capture constructs provided herein containing a GS linker, in some examples, the GS linker is (GGGGS) ₃ ; and the multimerization domain IgG Fc is that of trastuzumab Fc or Fc of nivolumab. Also provided herein are constructs that are growth factor capture constructs, comprising a GS linker selected from (GlySer) _n , where n = 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n = 1 -10; (Gly ₃ Ser) _n , where n = 1-5; (SerGly ₄ ) _n , where n = 1-5; (GlySerSerGly) _n , where n = 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and also contain a second linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab. In some such constructs containing a first GS linker and a second linker containing all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab, the constructs also include The half-life extending moiety, which is IgG Fc.

Any growth factor capture construct provided herein may also include a half-life extending moiety, such as an IgG Fc, a polyethylene glycol (PEG) molecule, or human serum albumin (HSA). In specific examples, where the growth factor capture construct includes a half-life extending moiety that is an IgG Fc, the IgG Fc can be selected from IgG1 and IgG4 Fc. In some examples, the IgG1 Fc is the Fc of trastuzumab set forth in SEQ ID NO: 27; or the IgG4 Fc is the Fc of nivolumab set forth in SEQ ID NO: 30. In some examples, where the construct includes one Fc or more than one Fc, the Fc is the Fc of human IgG1 set forth in SEQ ID NO: 10; and/or is the IgG4 Fc, i.e., SEQ ID NO: 16 The Fc of human IgG4 is shown in .

Provided constructs are multispecific heterodimeric constructs comprising a first ECD polypeptide and a second ECD polypeptide each linked directly or indirectly via a linker to a multimerization domain, wherein: The first ECD polypeptide and the second ECD polypeptide are different; and The first ECD polypeptide and the second ECD polypeptide are selected from ECDs, which include ECDs selected from: The ECD of HER1/EGFR corresponding to residues 1-621 of SEQ ID NO: 41 or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity with SEQ ID NO: 41; An ECD polypeptide comprising an ECD of HER2 corresponding to residues 1-628 of SEQ ID NO: 43, or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity with SEQ ID NO: 43; An ECD polypeptide comprising an ECD of HER3 corresponding to residues 1-621 of SEQ ID NO: 45, or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity to SEQ ID NO: 45; and An ECD polypeptide comprising an ECD of HER4 corresponding to residues 1-625 of SEQ ID NO: 47, or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity to SEQ ID NO: 47; and Parts or variants of each ECD may affect ligand binding and/or may dimerize with cell surface receptors. In particular examples where the construct is a bispecific heterodimeric construct, it includes a first ECD polypeptide and a second ECD polypeptide each linked directly or indirectly via a linker to a multimerization domain, wherein: The first ECD polypeptide comprises an ECD of HER1/EGFR corresponding to residues 1-621 of SEQ ID NO: 41, or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity with SEQ ID NO: 41; And the second ECD polypeptide comprises an ECD of HER2 corresponding to residues 1-628 of SEQ ID NO: 43, or a portion thereof, or a variant thereof that has at least 95% or 98% sequence identity to SEQ ID NO: 43; or The second ECD polypeptide comprises an ECD of HER3 corresponding to residues 1-621 of SEQ ID NO: 45, or a portion thereof, or a variant thereof that has at least 95% or 98% sequence identity to SEQ ID NO: 45; or The second ECD polypeptide comprises an ECD of HER4 corresponding to residues 1-625 of SEQ ID NO: 47, or a portion thereof, or a variant thereof that has at least 95% or 98% sequence identity to SEQ ID NO: 47; and Portions or variants of each ECD retain sufficient affinity for ligand binding and/or dimerization with cell surface receptors. For example, portions or variants of each ECD retain sufficient affinity for binding to the respective cell surface target or ligand, wherein the affinity is at least 10% of that of the full-length ECD. The construct may be a multimer, such as a dimer. The construct contains at least two different ECDs, such as heterodimers. For example, heterodimers include the ECD of EGFR and HER3.

One or both of the ECDs may contain amino acid modifications, such as insertions and/or deletions, to alter the properties of the ECD, such as increasing the affinity and/or receptor dimerization activity or other activities of the ECD. For example, the ECD may be an EGFR (HER1) ECD and comprise mutations T15S and G564S in EGFR ECD subdomains I and IV, respectively, with reference to the sequence of the mature EGFR protein shown in SEQ ID NO: 41 or an allelogenic variant thereof. , and with reference to the sequence of the mature HER3 protein shown in SEQ ID NO: 45 or its allelogenic variant Y246A in HER3 ECD subdomain II. The ligand capture agent construct may contain less than the full-length ECD of the HER protein and contain at least a sufficient portion of subdomains I, II, and III for ligand binding and receptor dimerization. The ECD may contain a sufficient portion of subdomains I and III for ligand binding, and/or a sufficient portion of the ECD to dimerize with a cell surface receptor, including a sufficient portion of subdomain II. For example, the ECD in the construct contains subdomains I, II, and III and at least module 1 of domain IV. Exemplary constructs include a first ECD containing all or a portion of an ECD of HER1/EGFR, HER2, HER3, or HER4, and a second ECD from a different cell surface receptor (CSR). For example, a construct is provided in which the second ECD is different from the first ECD and is derived from a CSR selected from: HER2, HER3, HER4, insulin growth factor 1 receptor (IGF1-R), vascular endothelial growth factor receptor ( VEGFR, such as VEGFR1), fibroblast growth factor receptor (FGFR, such as FGFR2 or FGFR4), TNFR, platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR), immunoglobulin-like and EGF-like domain 1 tyrosine kinase (TIE, such as TIE-1 or TEK (TIE-2)), receptor for advanced glycation end products (RAGE), Eph receptor, or T cell receptor. In some embodiments, the first ECD polypeptide comprises the full-length ECD of HER1/EGFR (corresponding to residues 1-621 of SEQ ID NO: 41), or a portion thereof, or is at least 95% or 98 identical to SEQ ID NO: 41 Allele gene variants that are % sequence identical and retain binding activity and/or dimerization activity. For example, the moiety may be residues 1-501 of SEQ ID NO: 41, which corresponds to module 1 of subdomains I-III and domain IV, or which is identical to residues 1-501 of SEQ ID NO: 41 Variants that have at least 95% or 98% sequence identity and retain binding and/or dimerization activity. In specific examples, the second ECD polypeptide can comprise a full-length ECD of HER3 corresponding to residues 1-621 of SEQ ID NO: 45, or a portion thereof, or it is at least 1-501 identical to residues 1-501 of SEQ ID NO: 45. Variants with 95% or 98% sequence identity that retain binding and/or dimerization activity. In other embodiments, the moiety has residues 1-500 of SEQ ID NO: 45, which correspond to subdomains I-III and module 1 of domain IV, or which are consistent with residues 1-500 of SEQ ID NO: 45. 500 A variant that has at least 95% or 98% sequence identity and retains binding and/or dimerization activity, or, for example, the ECD portion contains at least a sufficient portion of subdomains I and III to bind to a ligand of the HER receptor, and a sufficient portion of the ECD to dimerize with the cell surface receptor, including a sufficient portion of subdomain II.

Growth factor ligand capture agent constructs are provided, wherein at least one of the ECDs or the multimerization domain or the linker or a combination thereof is modified, wherein the first ECD polypeptide and the second ECD polypeptide form a multimer, the multimer Compared to the first or second chimeric polypeptide alone or a homodimer thereof bound to an additional ligand, and/or compared to the first or second chimeric polypeptide alone or a homodimer thereof bound to more Dimerization of cell surface receptors. For example, at least one of the ECD domains, or portions or variants thereof, include modifications that alter ligand binding, specificity, or other activities or properties compared to an unmodified ECD polypeptide, and generally, multimerization Domains and/or linkers are modified to alter properties (as described above and in the Examples). An example is a construct in which a first ECD polypeptide and a second ECD polypeptide form a heterodimer that binds a HER1 ligand and a HER3 ligand.

Modifications of an ECD include modifications that alter the ligand binding, specificity or other activities or properties of the ECD or full-length receptor containing such ECD as compared to an unmodified ECD or full-length receptor, whereby the heteromultimer behaves Altered activity or properties, such as ligand binding and/or specificity and/or dimerization activity. An example of such a construct is a construct comprising a HER1 ECD containing a mutation in subdomain III that increases its affinity for ligands other than EGF. Such affinity increases at least 2-fold, 10-fold, 100-fold, 1000-fold, 10 ⁴ -fold, 10 ⁵ -fold, 10 ⁶ -fold. Exemplary constructs provided herein are heterodimers containing a HER1 (EGFR) chimeric fusion polypeptide and a HER3 chimeric fusion polypeptide, wherein each chimeric fusion polypeptide includes an Fc receptor linked to human IgG1 optionally via a peptide linker. Body ECD. As noted above, constructs can also, and typically do, include modifications to the multimerization domain and/or linker to alter the properties of the resulting construct.

In these constructs, the C-terminus of the ECD polypeptide is linked to the N-terminus of the multimerization domain, which optionally is IgGl Fc or modified forms thereof, including any modifications described herein.

An example of a growth factor ligand capture agent construct is a construct comprising a HER1 ECD and/or a HER ECD modified to have increased or altered ligand binding and/or biological activity. For example, wherein HER1 includes S418F with reference to the sequence of the mature protein shown in SEQ ID NO: 41, whereby the HER3 ligand NRG2-β stimulates HER1, and the resulting ECD is combined with at least two ligands, that is, the EGF of HER1 and NRG2-β binding or interaction with HER3, such as constructs containing ECD HER1 (EGFR), and mutations T15S in EGFR/HER1 ECD subdomains I and IV, respectively, with reference to the sequence of the mature EGFR protein (SEQ ID NO: 41). and G564S, and Y246A in HER3 ECD subdomain II with reference to the sequence of the mature HER3 protein (SEQ ID NO: 45); and

The HER1 ECD contains additional mutations selected from the group consisting of E330D/G588S, S193N/E330D/G588S and T43K/S193N/E330D/G588S with reference to the sequence of the precursor HER1 (including signal peptide) shown in SEQ ID NO: 40 One or a combination, and with reference to the sequence of the mature HER1 polypeptide shown in SEQ ID NO: 41, corresponding to E306D/G564S, S169N/E306D/G564S and T19K/S169N/E306D/G564S, or the construct includes EGFR (HER1) : HER3 heterodimer, with reference to the sequence of mature EGFR protein (SEQ ID NO: 41 or the dual gene variant of SEQ ID NO: 41 with N516K) mutations T15S and G564S in EGFR ECD subdomains I and IV respectively, and Y246A in HER3 ECD subdomain II with reference to the sequence of the mature HER3 protein (SEQ ID NO: 45). Constructs may include Fc domains modified to enhance nascent Fc receptor (FcRn) recycling and/or effector function.

The claims set forth in this application are incorporated by reference into this disclosure.

summary A. definition B. Overview of constructs and methods C. tumor necrosis factor ( TNF ) and chronic inflammatory and autoimmune diseases and conditions 1. tumor necrosis factor ( TNF ) 2. tumor necrosis factor receptor ( TNFR ) a. TNFR1 b. TNFR2 3. Regulatory T cells ( Tregs ) and its role in the autoimmune microenvironment 4. Depend on TNF mediate or involve TNF autoimmunity / inflammatory disease a. Arthritis i. Rheumatoid arthritis and other types of arthritis b. inflammatory bowel disease ( IBD ) and uveitis c. fibrotic diseases d. Tumor necrosis factor receptor-associated periodic syndrome ( TRAPS ) / e. Depend on TNF mediate or involve TNF other diseases i. neurodegenerative diseases a ) Alzheimer's disease b ) Parkinson's disease c ) multiple sclerosis ( MS ) ii. endometriosis iii. Cardiovascular diseases iv. acute respiratory distress syndrome ( ARDS ) v. severe acute respiratory syndrome ( SARS ) and COVID-19 D. For rheumatoid arthritis and other chronic inflammatory and autoimmune diseases and conditions 1. synthesis of knowledge Disease-modifying antirheumatic drugs ( csDMARD ) 2. anti- TNF therapy /TNF blockers E. for targeting TNFR1/TNFR2 therapeutic agent 1. TNFR1 selective antagonist a. TNFR1 antagonist antibodies b. unit price TNFR1 antagonist antibodies / Antibody fragments i. Based on Fab and scFv Of TNFR1 Antagonist ii. domain-based antibodies ( dAb ) Of TNFR1 Antagonist a ) anti- TNFR1 dAb- anti-albumin dAb fusion construct b ) named GSK1995057 and GSK2862277 domain antibody fragment iii. Nanobodies ( Nb ) iv. anti- TNFR1 Nanobodies - Anti-albumin nanobody fusion construct c. TNF ( DN-TNF ) /TNF Dominant negative inhibitor of mutant protein 2. TNFR2 selective agonist a. TNFR2 agonist antibodies b. TNFR2 Selectivity TNF Mutated proteins and their fusions 3. anti- TNFR2 Antagonistic antibodies and small molecule inhibitors F. TNFR1 and / or TNFR2 Axis Selective Targeting 1. use TNFR1 antagonist selective blocking TNFR1 2. use TNFR2 Selective activation of agonists TNFR2 3. TNFR1 antagonist construct, TNFR2 agonist construct ; multispecific , Includes bispecific TNFR1 Antagonists and TNFR2 agonist construct 4. TNFR1 antagonist construct, TNFR2 Agonist constructs and multispecificity , Includes double specificity TNFR1 Antagonist /TNFR2 Components of Agonist Constructs a. TNFR1 Inhibitor part ( TNFR1 Antagonist ) b. TNFR2 Agonist constructs and TNFR2 antagonist construct c. Connector i. peptide linker a) flexible connector b) rigid connector ii. chemical linker d. active regulator i. right fc Modification of part a) Pestle and mortar ( K nobs-in-holes ) b) Enhance new life fc receptor ( ikB ) Recycling modifications c) Fc Enhancement or reduction of immune effector function / eliminate ii. fc Other modifications to the part iii. human serum albumin e. multispecific TNFR1 Antagonist /TNFR2 agonist construct For linking multispecific constructs ,by PEG as the center multispecific construct , such as bispecific TNFR1 Antagonist /TNFR2 of components of agonist constructs PEG change f. additional active regulator —— Fusion proteins including part or the entire polypeptide that increases serum half-life 5. Prediction and removal of immunogenicity in protein therapeutics a. B cells and T cellular epitope b. Computer Simulation Epitope Prediction Method i. B Computer simulation prediction of cellular epitopes ii. T Computer simulation prediction of cellular epitopes iii. peptide -MHCII class binding prediction c. In vitro epitope prediction method i. in test tube B Cellular epitope prediction method ii. in test tube T Cellular epitope prediction method MHC/HLA Combined analysis iii. in test tube T Cell analysis d. In vivo epitope prediction method e. Remove predicted B cells and T cellular epitope ( deimmunize ) G. Pan-growth factor capture peptide 1. receptor tyrosine kinase ( RTK ) a. human epidermal growth factor receptor ( HER ) family b. human epidermal growth factor receptor ( HER ) Family and ligand-related diseases 2. pan-growth factor inhibition a. RB242 ligand capture agent b. Used to treat autoimmune diseases RB200 and RB242 c. RB242 ligand capture agent 3. Optimized for multi-specificity , bispecific growth factor capture constructs such as a. extracellular domain ( ECD ) polypeptide b. Modification of the extracellular domain c. multimerization domain d. right fc domain modification i. Introduce pestle and mortar ii. Enhance new life fc receptor ( ikB ) Recycling modifications iii. effector function 4. Compositions, Therapeutic Uses and Methods of Treatment a. pharmaceutical composition b. Therapeutic Uses and Treatment Methods 5. combination therapy H. assess TNFR1 Antagonists and TNFR1 Antagonist /TNFR2 Agonist construct activity and efficacy 1. disease activity score ( DAS28 ) 2. ^SOMAscan® Proteosome analysis and other proteosome tools for quantifying analytes 3. Total transcript analysis to predict response to therapy and select individuals likely to benefit from treatment 4. L929 Cytotoxicity assay 5. HeLa IL-8 Analysis 6. HUVEC Analysis 7. Tregs Quantification and assessment of cell viability 8. TNFR1 Antagonist /TNFR2 Assessment of binding properties of agonist constructs 9. Antibody-dependent cytotoxicity ( ADCC ) and complement-dependent cytotoxicity ( CDC ) Analysis 10. disease model a. collagen-induced arthritis ( CIA ) b. Rheumatoid Arthritis Synovial Mononuclear Cell Culture c. of arthritis Tg197 mouse model d. Arthritis /IBD Of Δ ARE mouse model e. humanization TNF/TNFR2 mouse I. generate encoding TNFR1 antagonist constructs and TNFR1 Antagonist /TNFR2 Nucleic acid methods for agonist constructs 1. encoding TNFR1 Antagonists and TNFR2 Isolation or preparation of nucleic acids of agonist polypeptides 2. Generation of mutated or modified nucleic acids and encoded polypeptides 3. Vectors and cells 4. Performance a. prokaryotic cells b. yeast cells c. Insects and insect cells d. mammalian expression cells e. plant 5. Purification 6. Extra touch-ups a. PEGylation b. Albumination c. purification tag 7. Nucleic acid molecules and gene therapy J. Composition, preparation and dosage 1. Preparations 2. TNFR1 antagonist construct, TNFR2 Agonist constructs, multispecific ( such as bispecific ) Administration of constructs and nucleic acids 3. Administering nucleic acid-encoded polypeptides ( gene therapy ) K. Therapeutic Uses and Treatment Methods 1. chronic inflammatory / Treatment of autoimmune diseases and conditions 2. Treatment of neurodegenerative and demyelinating diseases and conditions 3. Treatment of cancer and other immunosuppressive diseases, disorders and conditions 4. combination therapy L. Example A. definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise indicated, all patents, patent applications, published applications and publications, GenBank sequences, databases, websites and other published materials mentioned throughout the disclosure herein are incorporated by reference in their entirety. . In the event there are multiple definitions for a term herein, the definitions in this section shall prevail. Where references are made to URLs or other such identifiers or addresses, it should be understood that although such identifiers may change and certain information on the Internet may come and go, it may be found by searching the Internet Equivalent information. References thereto confirm the availability and public dissemination of such information.

As used herein, a construct is a product containing one or more, typically at least two, components. Such components may be polypeptides, small molecules, aptamers, nucleic acids, and/or other such components as described herein or known to those of ordinary skill in the art. Various constructs are described and exemplified herein; the components and their types can be seen from the descriptions herein. A person of ordinary skill in the art may, in view of this specification, contemplate other constructs within the disclosure and patent scope of this document. The term construct is used because the product can include many different types of components.

As used herein, a construct that is a TNFR1 construct or a TNFR2 antagonist construct is a construct that contains a TNFR1 inhibitor moiety that is a moiety that inhibits or reduces TNFR1 activity, such as signaling.

As used herein, a construct that is a TNFR2 construct or a TNFR2 agonist construct is a construct that contains a TNFR2 agonist moiety that activates or induces the activity of TNFR2, such as signaling or activity that results in an increase in Treg cells. part.

As used herein, a construct that is a TNFR2 antagonist construct is a construct that includes a TNFR2 antagonist.

As used herein, a construct that is a multispecific construct is one that contains more than one antagonist or agonist, or both moieties, such as a construct that contains a TNFR1 inhibitor and a TNFR2 agonist; or that contains two. Constructs of TNFR1 antagonists, such as wherein each interacts with a different epitope on TNFR1 or each has a different TNFR1 antagonistic activity; or two TNFR2 agonists, such as where each interacts with a different TNFR2 epitope, or each Have different TNFR2 agonist activities.

As used herein, "tumor necrosis factor", "tumor necrosis factor alpha", "TNF", "TNF-alpha", "TNF-alpha" and " "TNFα" is used interchangeably to refer to a pleiotropic pro-inflammatory interleukin that is a member of the TNF superfamily and is associated with inflammatory and immunomodulatory activities, including regulation of tumorigenesis/cancer, host defense against pathogenic infections, apoptosis, and autoimmunity and septic shock. When other members of the TNF superfamily are intended to be used, they are identified by name. TNF is involved in the coordination of innate and adaptive immune responses and in organogenesis, especially that of lymphoid organs. TNF is produced as a homotrimeric membrane-bound protein containing 233 amino acids, which can be cleaved by the protease TACE (TNF alpha converting enzyme; also known as ADAM17) to release soluble TNF containing 157 amino acids (solTNF). ; Membrane-bound and soluble forms of TNF are biologically active. The homotrimer of TNF binds to two high-affinity, specific receptors, TNFR1 and TNFR2, and signals through these receptors; membrane-bound TNF mainly activates TNFR2, while soluble TNF mainly activates TNFR1. Uncontrolled or dysregulated production of TNF is associated with a number of chronic inflammatory and autoimmune diseases and conditions, including but not limited to septic shock, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile arthritis, Inflammatory arthritis and inflammatory bowel disease (IBD), as well as neurodegenerative and demyelinating diseases and conditions, including but not limited to Alzheimer's disease, Parkinson's disease, stroke and multiple Sclerosis.

As used herein, "TNF mutein" or "TNF-α mutein" or "modified TNF polypeptide" refers to the amine of TNF from a specific species. A polypeptide whose amino acid sequence differs from that of the corresponding wild-type TNF (TNFα) in one or more amino acids. Generally, such modified TNF polypeptides retain the ability to activate or inhibit TNFR1 and/or TNFR2. Specific mutations of TNF can make the resulting TNF mutant protein selective for binding to TNFR1 or TNFR2, and can make the TNF mutant protein have antagonistic or agonistic properties. For example, as described herein, there are TNFR1 selectively antagonistic TNF muteins and TNFR2 selectively agonistic TNF muteins.

As used herein, "dominant-negative inhibitor of TNF" or "DN-TNF" is a TNF mutein with one or more mutations that eliminate interaction with TNFR1 and/or Or binding of TNFR2 and signaling through it. DN-TNF selectively inhibits soluble TNF (sTNF or solTNF) by rapidly exchanging subunits with native TNF homotrimers, forming inactive mixed TNF heterotrimers with disrupted receptor binding surfaces, thereby preventing interaction with TNF receptor interactions. DN-TNF leaves transmembrane TNF (tmTNF) unaffected and maintains the protective effect of TNF signaling through TNFR2. An example of a DN-TNF is solTNF containing the substitutions L133Y, S162Q, Y163H, I173T, Y191Q and A221R with reference to the amino acid sequence set forth in SEQ ID NO: 1 (corresponding to solTNF as set forth with reference to SEQ ID NO: 2 TNF mutants of one or more of the sequence residues L57Y, S86Q, Y87H, I97T, Y115Q and A145R), which weaken the binding to TNFR.

As used herein, "modification" means modification of an amino acid sequence in a polypeptide or a nucleotide sequence in a nucleic acid molecule, and includes deletion, insertion, shift, substitution, and deletion of amino acids or nucleotides, respectively. its combination. Methods of modifying polypeptides or nucleic acids are routine to those of ordinary skill in the art, such as by using recombinant DNA methods.

As used herein, "deletion" when referring to a nucleic acid or polypeptide sequence refers to one or more nucleotides or amines as compared to a sequence, such as a polynucleotide or polypeptide of interest or a native or wild-type sequence. Missing amino acids.

As used herein, "insertion" when referring to a nucleic acid or amino acid sequence describes the inclusion of one or more additional nucleotides or amino acids within a target, native, wild-type, or other related sequence. Thus, a nucleic acid molecule containing one or more insertions contains one or more additional nucleotides within the linear length of the sequence compared to the wild-type sequence.

As used herein, "addition" when referring to a nucleic acid or amino acid sequence describes the addition of one or more nucleotides or amino acids to either terminus as compared to another sequence.

As used herein, "substitution" or "replacement" refers to one or more of the native, target, wild-type, or other nucleic acid or polypeptide sequences without changing the length of the molecule (e.g., described in terms of number of residues). A nucleotide or amino acid is replaced with an alternative nucleotide or amino acid. Thus, one or more substitutions in the molecule do not change the number of amino acid residues or nucleotides in the molecule. Amino acid substitutions can be expressed in terms of the number of amino acid residues along the length of the polypeptide sequence compared to a particular polypeptide. For example, a modified polypeptide having a modification in the amino acid at position 100 of the amino acid sequence, such as substitution/replacement of tyrosine (Tyr; Y) with glutamic acid (Glu; E), may express Is Y100E, Tyr100Glu or 100E. Y100 can be used to indicate that the modified amino acid at position 100 is tyrosine. For the purposes of this document, since the modification is in the heavy chain (HC) or light chain (LC) of the antibody, the modification may also be referred to as HC- or LC- to indicate the chain of the polypeptide.

As used herein, "at a position corresponding to" or reciting a nucleotide or amino acid position "corresponds to" in a disclosed sequence (such as that set forth in the Sequence Listing) A nucleotide or amino acid position refers to a nucleotide or amino acid position that is identified after alignment to a reference sequence to maximize agreement using standard alignment algorithms, such as the GAP algorithm. By aligning the sequences, one of ordinary skill in the art can identify corresponding residues, for example, using conserved and identical amino acid residues as guides. Generally, to identify corresponding positions, amino acid sequences are aligned for the highest order match (see, e.g., Computational Molecular Biology , Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects , Smith, DW, Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I , Griffin, AM and Griffin, HG, Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology , von Heinje, G., Academic Press, 1987; Sequence Analysis Primer , Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carrillo et al. (1988) SIAM J. Applied Math 48:1073).

As used herein, sequence alignment refers to the alignment of two or more nucleotide or amino acid sequences using homology. Typically, two or more related sequences with 50% or greater identity are aligned. A sequence alignment set refers to two or more sequences aligned at corresponding positions and may include aligned sequences derived from alignments of RNA (such as EST and other cDNA) and genomic DNA sequences. Related or variant polypeptides or nucleic acid molecules may be aligned by any method known to one of ordinary skill in the art. Such methods typically maximize matches, and include methods such as the use of manual alignment and by using the numerous alignment programs available (eg, BLASTP) and other methods known to those of ordinary skill in the art. By comparing the sequences of polypeptides or nucleic acids, one of ordinary skill in the art can identify similar portions or positions using conserved and identical amino acid residues as guides. In addition, one of ordinary skill in the art can also use conserved amino acids or nucleotide residues as guides to find corresponding amino acids or nucleotide residues between and within human and non-human sequences. Corresponding positions can also be based on structural alignment, for example by using computer simulations of protein structures. In other cases, corresponding regions can be identified. One of ordinary skill in the art can also use conserved amino acid residues as guides to find corresponding amino acid residues between and within human and non-human sequences.

As used herein, a statement that a protein is "compared under the same conditions" means that different proteins have been treated the same or substantially the same, such that any one or more conditions that may affect the activity or properties of the protein or agent are Do not vary or substantially vary between test reagents. For example, when the activity of an antibody is compared to that of another antibody, any one or more of the following conditions are consistent or substantially consistent between and within the polypeptides/antibodies being compared: such as the amount or concentration of the polypeptide; the addition of the active agent The presence (including amounts) of excipients, carriers or other ingredients in the formulation other than (e.g., antibodies); temperature; pH; storage time; storage container; storage characteristics (e.g., agitation); and/or association with exposure or use Other relevant conditions.

As used herein, "adverse effect" or "side effect" or "adverse event" or "adverse side effect" means a harmful, Adverse and/or unwanted effects. For example, side effects associated with administration of anti-TNF antibodies such as adalimumab (eg, sold under the trademark ^Humira® ) are known to those of ordinary skill in the art, and some are described herein. Such adverse side effects include, for example, serious infections, such as tuberculosis; and other infections caused by viruses, fungi, and bacteria, including upper respiratory tract infections; and dermatological/dermal toxicities, such as rashes, headaches, and nausea. Accordingly, "adverse effects" or "side effects" refer to harmful, adverse and/or undesirable effects of the administration of a therapeutic agent. Toxicity is used to grade side effects or adverse effects, and various toxicity scales exist to provide definitions for each level. Examples of such scales are the National Cancer Institute Common Toxicity Criteria version 2.0 toxicity scale and the World Health Organization or Common Terminology Criteria for Adverse Events (CTCAE) scale. . Assigning severity levels is within the skill of an experienced physician or other health care professional. Symptom severity can be quantified using the NCI Common Terminology Criteria for Adverse Events (CTCAE) grading system. CTCAE is a descriptive term used in adverse event (AE) reporting. A grading (severity) scale is provided for each AE item. CTCAE displays grades 1 to 5, in which the clinical description of the severity of each adverse event is based on the following general guidelines: Grade 1 (mild AE); Grade 2 (moderate AE); Grade 3 (serious AE); Grade 4 (critical AE). life or incapacitating AE); and Level 5 (death-related AE/fatal).

As used herein, a "property" of a polypeptide, such as an antibody, refers to any property exhibited by the polypeptide, including, but not limited to, binding specificity, structural configuration or conformation, protein stability, resistance to proteolysis, conformation Stability, heat resistance and tolerance to pH conditions. Changes in properties can alter the "activity" of a polypeptide. For example, changes in the binding specificity of an antibody polypeptide can alter the ability to bind the antigen and/or various binding activities, such as affinity or avidity, or the in vivo activity of the polypeptide.

As used herein, "activity" or "functional activity" of a polypeptide (such as an antibody) refers to any activity exhibited by the polypeptide. Such activities can be determined empirically. Exemplary activities include, but are not limited to, the ability to interact with biological molecules, such as via antigen binding, DNA binding, ligand binding, or dimerization; and enzymatic activities, such as kinase activity or proteolytic activity. For antibodies (including antibody fragments), activity includes, but is not limited to, the ability to specifically bind a specific antigen; the affinity of antigen binding (e.g., high affinity or low affinity); the affinity of antigen binding (e.g., high affinity or low affinity); Association rate; dissociation rate; effector functions, such as the ability to promote antigen neutralization or clearance; virus neutralization; and in vivo activity, such as preventing infection or invasion of pathogens, or promoting clearance of specific tissues or fluids or cells in the body, or The ability to penetrate specific tissues or fluids or cells in the body. Activity can be measured in vitro or in vivo using recognized assays such as ELISA, flow cytometry, surface plasmon resonance or to measure association or dissociation rates, immunohistochemistry and immunofluorescence histology, and Assessed by equivalent microscopy assays, cell-based assays, flow cytometry and combined assays (e.g. panning assays). For example, for antibody polypeptides, activity can be assessed by measuring binding affinity, avidity, and/or binding coefficient (e.g., for association/dissociation rates) in a test tube; and other activities, or by measuring various effects in vivo , such as immune effects, such as antigen clearance; antibody penetration or localization into tissue; prevention of disease, such as infection; serum or other fluid antibody titer; or other assays well known in the art. The results of such analyzes indicate that the polypeptide exhibits activity in vivo that can be correlated with the activity of the polypeptide, where the in vivo activity can be referred to as therapeutic activity or biological activity. Compared to the unmodified polypeptide, the activity of the modified polypeptide can be any level of activity percentage of the unmodified polypeptide, including but not limited to 1% activity, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% , 99%, 100%, 200%, 300%, 400%, 500% or greater activity. Assays for determining the functionality or activity of modified (or variant) antibodies are well known in the art.

As used herein, "bind/bound" and its grammatical variations refer to the participation of a molecule in any attractive interaction with another molecule, resulting in a stable association in which the two molecules are in close proximity to each other. Binding interactions include, but are not limited to, non-covalent bonds, covalent bonds (such as reversible and irreversible covalent bonds), and include interactions between molecules, such as, but not limited to, proteins, nucleic acids, carbohydrates, lipids, and small molecules, Such as chemical compounds, including drugs. Exemplary bonds are antibody-antigen interactions and receptor-ligand interactions. When an antibody "binds" to a specific antigen, "binding" refers to the specific recognition of the antigen by the antibody at the site of antibody combination via cognate antibody-antigen interactions. Binding may also involve the association of multiple chains of polypeptides, such as antibody chains, that interact via disulfide bonds.

As used herein, "binding activity" refers to a characteristic of a molecule (eg, a polypeptide) regarding whether and how it binds one or more binding partners. Binding activity includes the ability to bind a binding partner, the affinity to bind to the binding partner (e.g., high affinity), the affinity to bind to the binding partner, the strength of binding to the binding partner, and/or the specificity of binding to the binding partner. .

As used herein, "affinity" or "binding affinity" describes the strength of an interaction between two or more molecules, such as binding partners, and is typically the between two binding partners. the strength of non-covalent interactions between them. The affinity of an antibody or antigen-binding fragment thereof for an epitope of an antigen is a measure of the strength of the overall non-covalent interaction between a single antibody combination site and the epitope. Low-affinity antibody-antigen interactions are weak and the molecules tend to dissociate quickly, whereas high-affinity antibody-antigen binding is stronger and the molecules remain associated for a longer period of time. Binding affinity can be determined based on binding kinetics, such as by measuring association rates ( _ka or _kon ) and/or dissociation rates ( _kd or _koff ), half-maximal effective concentration ( _EC50 ) values, and/or thermodynamics Information (such as Gibbs free energy (ΔG), enthalpy (ΔH), entropy (-TΔS) and/or calculation of association (K _a ) or dissociation (K _d ) constants. EC ₅₀ , also known as is the apparent K _d , which is the concentration of antibody (e.g., ng/mL) at which 50% maximal binding is observed to achieve a fixed amount of antigen. Typically, the EC ₅₀ value is determined from a sigmoidal dose response curve, where EC ₅₀ is the recurve concentration at the point. High antibody affinity for its substrate is associated with lower EC ₅₀ values, and low affinity corresponds to high EC ₅₀ values. The affinity constant can be determined by standard kinetic methods for antibody reactions, such as immunoassays such as ELISA, Then curve fitting analysis was performed to determine.

As used herein, "affinity constant" refers to the association constant (K _a ) used to measure the affinity of an antibody for an antigen. The higher the affinity constant, the greater the affinity of the antibody for the antigen. Affinity constants are expressed in reciprocal molar concentration units (i.e., M ^-1 ) and can be calculated from the rate constants of association-dissociation reactions, such as by standard kinetic methods for antibody reactions (e.g., immunoassays, surface plasmons sub-resonance or other dynamic interaction analysis known in the art). The binding affinity of an antibody can also be expressed as a dissociation constant or K _d . The dissociation constant is the reciprocal of the association constant, that is, K _d =1/K _a . Therefore, the affinity constant can also be expressed by K _d . Affinity constants can be determined by standard kinetic methods for antibody reactions, such as immunoassays and surface plasmon resonance (SPR) (see, for example, Rich and Myszka (2000) Curr. Opin. Biotechnol 11:54; Englebienne (1998) Analyst. 123:1599), isothermal titration calorimetry (ITC), or other kinetic interaction analyzes known in the art (see, e.g., Paul, ed., Fundamental Immunology, 2nd ed., Raven Press, New York, pp. 332-336 (1989); see also U.S. Patent No. 7,229,619 for a description of exemplary SPR and ITC methods for calculating antibody binding affinity). Instruments and methods for real-time detection and monitoring of binding rates are known and commercially available (eg BIAcore 2000, BIAcore AB, Upsala, Sweden and GE Healthcare Life Sciences; Malmqvist (2000) Biochem. Soc. Trans. 27:335) .

Methods for calculating affinity are well known, such as methods for determining _EC50 values, or methods for determining association/dissociation constants. For example, in terms of EC ₅₀ , high binding affinity means that the antibody binds to less than about 10 ng/mL, 9 ng/mL, 8 ng/mL, 7 ng/mL, 6 ng/mL, 5 ng/mL, 3 Specific binding to the target protein with EC ₅₀ of ng/mL, 2 ng/mL, 1 ng/mL or less. High binding affinity can also be balanced by 10 ^-6 M or less, such as 10 ^-7 M, 10 ^-8 M, 10 ^-9 M, 10 ^-10 M, 10 ^-11 M or 10 ^-12 M or less Dissociation constant (K _d ) characterization. In terms of equilibrium association constant ( _Ka ), high binding affinity is generally associated with greater than or equal to about 10 ⁶ M ^-1 , greater than or equal to about 10 ⁷ M ^-1 , or greater than or equal to about 10 ⁸ M ^-1 , or greater than or is associated with a _Ka value equal to approximately 10 ⁹ M ^-1 , 10 ¹⁰ M ^-1 , 10 ¹¹ M ^-1 or 10 ¹² M ^-1 . Affinity can be estimated empirically, or affinity can be determined relatively, eg, by comparing the affinities of two or more antibodies for a particular antigen, eg, by calculating a pairwise ratio of the affinities of the antibodies tested. For example, such affinity can be readily determined using commonly known techniques, such as by ELISA; equilibrium dialysis; surface plasmon resonance; by radioimmunoassay, using radiolabeled target antigen; or by those skilled in the art. Another method known to those of ordinary knowledge. Affinity data can be analyzed, for example, by the method of Scatchard et al., (1949) Ann NY Acad. Sci., 51:660, or by curve fitting, for example using a 4-parameter logarithmic nonlinear regression model using the following equation: y = ((AD)/(1+((x/C)^B))))+ D, where A is the minimum asymptote, B is the slope factor, C is the inflection point (EC ₅₀ ), and D is the maximum asymptote .

As used herein, "antibody avidity" refers to the multiple relationships between a multivalent antibody and its cognate antigen (such as an antibody containing multiple binding sites and an antigen having a repeating epitope or array of epitopes). The strength of an interaction. High-affinity antibodies have a higher strength of such interactions than low-affinity antibodies.

As used herein, "specificity for a target," such as target TNFR1, refers to binding to a target with better, higher binding affinity compared to a non-target. Selective binding refers to binding to a target with ^an affinity typically of at least about ^{107-108M -1} . It may also refer to relative activity, where the affinity of a moiety or molecule for one target molecule is compared to its affinity for another molecule, and if the difference is of a specific magnitude, such as about 10-fold, then the moiety or molecule is relative to a second molecule. The target has greater specificity to the first target.

As used herein, with respect to an antibody or antigen-binding fragment thereof, "specifically binds" or "immunospecifically binds" are used interchangeably herein and means that the antibody or antigen-binding fragment thereof The ability to form one or more non-covalent bonds with a homologous antigen resulting from the non-covalent interaction between the antibody binding site of the antibody and the antigen. Typically, an antibody that immunospecifically binds (or specifically binds), for example, to TNFR1 is with an affinity constant (K _a ) of about or 1×10 ⁷ M ⁻¹ or 1×10 ⁸ M ⁻¹ or greater (or 1 Antibodies that bind to TNFR1 with a dissociation constant (K _d ) of ×10 ^-7 M or 1 × 10 ^-8 M or less. Antibodies or antigen-binding fragments that immunospecifically bind to specific antigens can be determined, for example, by immunoassays such as radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) or other technical identification known to those of ordinary skill in the art.

As used herein, "steric effects" refer to the effects of the size of atoms or groups on a molecule. Steric hindrance effects include, but are not limited to, steric hindrance and van der Waals repulsion. Steric hindrance is an effect caused by atoms taking up space; when atoms are close to each other, this generates energy because electrons close to the atoms repel each other.

As used herein, “exhibits at least one activity” or “retains at least one activity” means that an antibody exhibits less activity than a target or unmodified polypeptide that does not contain modifications. The activity exhibited by polypeptides, such as variant antibodies or other therapeutic peptides. Modified or variant polypeptides that maintain the activity of the polypeptide of interest may exhibit improved activity, decreased activity, or maintain the activity of the unmodified polypeptide. In some cases, a modified or variant polypeptide may retain increased activity compared to the target or unmodified polypeptide. In some cases, a modified or variant polypeptide may retain reduced activity compared to an unmodified or polypeptide of interest. Compared to the unmodified or target polypeptide, the activity of the modified or variant polypeptide may be any level of activity percentage of the unmodified or target polypeptide, including but not limited to 1% activity, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99%, 100%, 200%, 300%, 400%, 500% or greater activity. In other embodiments, the change in activity is at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold greater than the unmodified or target polypeptide. , 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 200 times, 300 times, 400 times, 500 times, 600 times, 700 times, 800 times, 900 times, 1000 times or more multiple times. The assay used to maintain activity depends on the activity to be maintained. Such analysis can be performed in vitro or in vivo. Activity can be measured, for example, using assays known in the art and described below for activity, such as, but not limited to, ELISA and panning assays. The activity of a modified or variant polypeptide can also be assessed based on in vivo therapeutic or biological activity or results following administration of the polypeptide as compared to an unmodified or target polypeptide.

As used herein, "surface plasmon resonance" refers to an optical phenomenon that allows the analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix. Commercial systems are available. For example, the BIAcore system (GE Healthcare Life Sciences) is an exemplary commercial system.

As used herein, "antibody" refers to immunoglobulins and immunoglobulin fragments that are natural or partially or completely synthetic, such as recombinantly produced, including immunoglobulin molecules that contain sufficient immunoglobulin molecules to form an antigen-binding site. At least a portion of the variable heavy chain and/or variable light chain region and any fragment thereof that when assembled specifically binds the antigen. Thus, an antibody includes any protein that has a binding domain that is homologous or substantially homologous to an immunoglobulin antigen-binding domain (antibody combination site). For example, an antibody refers to an antibody containing two heavy chains (which may be represented by H and H') and two light chains (which may be represented by L and L'), where each heavy chain may be sufficient to form antigen binding a full-length immunoglobulin heavy chain at the site, or a portion thereof (e.g., heavy chains include, but are not limited to, _VH chain, _VH - _CH1 chain, and _VH - _CH1 - _CH2 - _CH3 chain), and Each light chain may be a full-length light chain sufficient to form an antigen-binding site or a portion thereof ₍ eg, light chains include, but are not limited to, _VL chains and VL- _CL chains). Each heavy chain (H and H') is paired with a light chain (L and L'). Typically, an antibody will minimally include all or at least a portion of a variable heavy ( _VH ) chain and/or a variable light ( _VL ) chain. Antibodies may also include other regions, such as all or part of the constant region, and/or all or part of the hinge region (sufficient to provide flexibility).

For purposes herein, unless otherwise specified, the term "antibody" includes full-length antibodies and portions thereof, including antibody fragments, such as anti-TNFR1 antibody fragments. Antibody fragments include, but are not limited to, Fab fragments, Fab'fragments;F(ab') ₂ fragments, Fv fragments, disulfide-linked Fv (dsFv), Fd fragments, Fd' fragments, single-chain Fv (scFv), single-chain Fv Chain Fab (scFab), helix-stabilized Fv (hsFv), single domain antibody (dAb or sdAb), minibody, bifunctional antibody, anti-idiotypic (anti-Id) antibody, nanobody and camelid antibody, free light chains, _VHH antibodies (or nanobodies), or antigen-binding fragments of any of the above. Antibody fragments may also include combinations of any of the above fragments, such as tandem scFv, Fab-scFv (HC C-terminal or LC C-terminal), Fab-(scFv) ₂ (C-terminal), scFv-Fab-scFv, Fab _-CH 2-scFv, scFv fusion (C-terminal or N-terminal), Fab fusion (HC C-terminal or LC C-terminal), scFv-scFv-dAb, scFv-dAb-scFv, dAb-scFv-scFv and three Functional antibodies. The term "antibody" includes synthetic antibodies, recombinantly produced antibodies, multispecific and heterobinding antibodies (such as bispecific, trispecific and tetraspecific antibodies, bifunctional antibodies, trifunctional antibodies and tetrafunctional antibodies), Human antibodies, non-human antibodies, humanized antibodies, chimeric antibodies and intrabodies. Antibodies provided herein include members of any immunoglobulin class (eg, IgG, IgM, IgD, IgE, IgA, and IgY), any subclass (eg, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass ( Such as IgG2a and IgG2b).

As used herein, "form of an antibody" refers to the specific structure of an antibody. Antibodies as used herein include full-length antibodies and portions thereof, such as Fab fragments or other antibody fragments. Therefore, Fab is a specific form of antibody.

As used herein, reference to a "corresponding form" of an antibody means that when comparing the properties or activities of two antibodies, the same antibody form is used to compare that property. For example, if it is stated that the activity of an antibody is less than the activity of the corresponding form of the first antibody, this means that the specific form of the antibody, such as a Fab, is less active than the Fab form of the first antibody.

As used herein, a full-length antibody is one that has two full-length heavy chains (e.g., _VH - _CH1 - _CH2 - _CH3 or VH _{- CH1} - _CH2 - _CH3 - _CH4 ), Antibodies with two full-length light chains (VL- _CL ) and hinge regions, such _as human antibodies produced by antibody-secreting B cells and antibodies with the same domains produced synthetically.

As used herein, a "multi-specific construct" refers to a construct, such as an antibody or a construct containing portions of an antibody, that exhibits affinity for more than one target antigen such that it can specifically interact with the target. . The multispecific constructs herein may have a structure similar to that of a complete immunoglobulin molecule and include an Fc region, such as an IgG Fc region, and an antigen-binding region, such as a portion that specifically binds to TNFRl or TNFR2.

As used herein, "bispecific construct" refers to a multispecific construct with binding specificities for two different antigens. Bispecific constructs include, for example, monoclonal antibodies or antigen-binding fragments thereof linked to an active polypeptide region that modifies the construct, such as Fc or modified Fc. For human therapeutics, the construct is derived from a human source or humanized, and the construct has binding specificity for at least two different antigens. Bispecific constructs/molecules provided herein can have binding specificity for TNFRl and TNFR2. For example, bispecific constructs include TNFR1 antagonists and TNFR2 agonists. Bispecific antibodies or constructs include antibodies and their antigen-binding fragments that include two independent antigen-binding domains (eg, two scFv or two dAb or two Fab joined by a linker). Antigen binding domains can bind to the same antigen or different antigens.

As used herein, "antibody fragment" or "antibody portion" refers to any portion of a full-length antibody that is less than the full length but contains sufficient content to form an antigen-binding site (e.g., one or more complementarity determining sites). (complementarity-determining region (CDR)) of at least a portion of the variable region of an antibody and thus retains the binding specificity and/or activity of the full-length antibody; antibody fragments include antibody derivatives produced by enzymatic treatment of full-length antibodies, and Derivatives produced synthetically, for example recombinantly. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab) ₂ , single chain Fv (scFv), Fv, dsFv, diabodies, trifunctional antibodies, affinity antibodies, nanobodies, aptamers, dAb, Fd and Fd fragments (see, e.g., Methods in Molecular Biology , Volume 207: Recombinant Antibodies for Cancer Therapy Methods and Protocols (2003); Chapter 1; Pages 3-25, Kipriyanov). Fragments may include multiple chains linked together, such as by disulfide bridges and/or by peptide linkers. Antibody fragments generally contain at least about 50 amino acids, such as at least about or at least 100 amino acids, and typically at least about or at least 110, 120, 150, 170, 180, or 200 amino acids.

As used herein, a "Fv antibody fragment" consists of a variable heavy chain domain ( _VH ) and a variable light chain ( _VL ) domain linked by non-covalent interactions.

As used herein, a disulfide-linked Fv (dsFv) refers to an Fv that has engineered intermolecular disulfide bonds that stabilize the _VH - _VL pair.

As used herein, "scFv fragment" refers to an antibody fragment containing a variable light chain (V _L ) and a variable heavy chain (V _H ) covalently linked in any order by a polypeptide linker. The length of the linker allows the two variable domains to be bridged without substantial interference. An exemplary linker is a (Gly-Ser) _n residue, with some Glu or Lys residues scattered throughout to increase solubility.

As used herein, "diabodies" are dimeric scFv; diabodies typically have shorter peptide linkers than scFv and dimerize better.

As used herein, "triabodies" are trimeric scFv; they contain three peptide chains, each of which contains a _VH domain and a _VL domain, which are connected by a short linker (e.g., consisting of 1 -2 amino acid linkers) are joined to allow intramolecular association of _VH and _VL domains within the same peptide chain; trifunctional antibodies typically trimerize.

As used herein, a "Fab fragment" is an antibody fragment produced by digestion of a full-length immunoglobulin with papain, or a fragment of the same structure produced synthetically, such as by recombinant methods. The Fab fragment contains a light chain (containing _VL and _CL ) and another chain containing the variable domain ( _VH ) of the heavy chain and a constant region domain ( _CH1 ) of the heavy chain.

As used herein, "F(ab') ₂ fragment" is an antibody fragment _produced by digestion of an immunoglobulin with pepsin at pH 4.0-4.5, or synthetically, for example, by recombinant methods Produces fragments with the same structure. The F(ab') ₂ fragment consists essentially of two Fab fragments in which each heavy chain portion contains an additional few amino acids, such as all or a portion of the amino acids sufficient to provide flexibility in the hinge region, including the formation of a disulfide bond joining the two fragments of cysteine residues.

As used herein, a Fab' fragment is a fragment containing one-half of the F(ab') ₂ fragment (ie, one heavy chain and one light chain).

As used herein, an Fd fragment is an antibody fragment that contains the variable domain (V _H ) of the antibody heavy chain and one constant region domain ( _CH 1 ).

As used herein, an Fd' fragment is an antibody fragment containing one heavy chain portion of the F(ab') ₂ fragment.

As used herein, a Fv' fragment is a fragment containing only the _VH and _VL domains of an antibody molecule.

As used herein, a helix-stabilized Fv (hsFv) refers to an antibody fragment in which the constant domain typically found in Fab fragments has been replaced by a heterodimeric coiled-coil domain (see, e.g., Arndt et al. (2001) J. Mol. Biol. 7 : 312:221-228).

As used herein, "domain antibody", "single domain antibody", "sdAb" or "dAb" are used interchangeably and refer to the heavy chain (VH) or light chain ( _VH ) containing the antibody. _VL ) monomeric small antibody fragment of the variable domain. A dAb is the smallest antigen-binding fragment of an antibody; its size is approximately 11-15 kDa (approximately 100-150 amino acids), which is approximately one-tenth the size of a complete monoclonal antibody (mAb). There are three complementarity determining regions (CDRs) on each _VH and each _VL . Each dAb contains three of six CDRs, which are highly diverse loop regions that bind to the target antigen from the V _H -V _L pairs in the antibody.

As used herein, camelid antibodies (also known as nanobodies or VHHs) lack a light chain and are composed of two identical heavy chains. It occurs naturally in the camelid family, such as camels and alpacas.

As used herein, a polypeptide "domain" is a portion of a polypeptide (having 3 or more, typically 5, 10 or more amines) that is structurally and/or functionally distinguishable or definable. sequence of amino acids). An exemplary polypeptide domain is a portion of a polypeptide that may be composed of one or more structural motifs (eg, a combination of alpha helices and/or beta strands connected by loop regions) and/or consist of a specific functional activity (such as enzymatic activity, Dimerization or antigen binding) forms an independent folded structure within the polypeptide recognized. A polypeptide may have one or more, typically more than one, distinct domains. For example, a polypeptide can have one or more structural domains and one or more functional domains. Single polypeptide domains can be distinguished based on structure and function. A domain may encompass a contiguous linear sequence of amino acids. Alternatively, a domain may encompass a plurality of non-contiguous amino acid moieties that are not contiguous along the linear sequence of amino acids of the polypeptide. Typically, polypeptides contain multiple domains. For example, each heavy chain and each light chain of an antibody molecule contains a plurality of immunoglobulin (Ig) domains, each about 110 amino acids in length. One of ordinary skill in the art is familiar with polypeptide domains and can identify them by means of structural and/or functional homology with other such domains. Definitions are provided for purposes of illustration herein, with the understanding that identifying a particular domain by name is well within the skill of the art. If necessary, appropriate software can be used to identify domains.

As used herein, a "functional region" of a polypeptide is a region of the polypeptide that contains at least one functional domain that confers a specific function, such as the ability to interact with biological molecules, e.g., via antigen binding, DNA binding, ligand Binding or dimerization, or by enzymatic activity, such as kinase activity or proteolytic activity); Exemplary functional regions of polypeptides are antibody domains, such as _VH , _VL , _CH , _CL , and portions thereof, such as CDRs, Includes CDR1, CDR2 and CDR3, or antigen-binding portions, such as antibody combination sites.

As used herein, a "structural region" of a polypeptide is a region of the polypeptide that contains at least one structural domain.

As used herein, "Ig domain" is a domain that is recognized by those skilled in the art and is distinguished by a structure containing two beta-pleated sheets, known as the immunoglobulin (Ig) fold. The pleated sheets each contain antiparallel beta strands of amino acids linked by rings. The two β-sheets in the Ig fold are sandwiched together by hydrophobic interactions and conserved intrachain disulfide bonds. Individual immunoglobulin domains within antibody chains can further be differentiated based on function. For example, a light chain contains one variable domain (V _L ) and one constant domain ( _CL ), while a heavy chain contains one variable domain (V _H ) and three or four constant domains. ( _CH ). Each of the VL, _CL , _VH , and _CH domains are examples of immunoglobulin domains _.

As used herein, with reference to an antibody, a "variable domain" is a specific immunoglobulin (Ig) domain of an antibody heavy or light chain that contains amino acid sequences that differ in different antibodies. Each light chain and each heavy chain has a variable region domain (V _L and V _H respectively). The variable domains provide antigen specificity and are therefore responsible for antigen recognition. Each variable region contains a complementarity determining region (CDR), which is part of the antigen-binding site domain and the framework region (FR).

As used herein, "hypervariable region", "HV", "complementarity determining region", "CDR" and "antibody CDR" are used interchangeably to refer to the antigen-binding sites within each variable region that together form an antibody One of the plural parts of a point. Each variable region domain contains three CDRs, named CDR1, CDR2 and CDR3. The three CDRs are not contiguous along the linear amino acid sequence, but are close in the folded polypeptide. The CDRs are located within loops of parallel strands joining the beta sheets of the variable domains.

As used herein, "antigen-binding domain", "antigen-binding site", "antigen-binding fragment", "antigen combining site" )" and "antibody combining site" are used synonymously to refer to the domain within an antibody that recognizes and physically interacts with cognate antigens. Naturally known full-length antibody molecules have two known antigen-binding sites, each of which contains a portion of the heavy chain variable region and a portion of the light chain variable region. It is known that antigen binding sites contain loops connecting antiparallel beta strands within the variable region domain. The antigen combination site may contain other portions of the variable region domain. Each conventional antigen binding site contains three hypervariable regions from the heavy chain and three hypervariable regions from the light chain. Hypervariable regions are also called complementarity determining regions (CDRs).

As used herein, with reference to an antibody heavy or light chain or a variable heavy or light chain, "portion thereof" means a contiguous portion thereof sufficient to form an antigen-binding site such that when assembled into a structure containing a heavy chain and a light chain When the antibody is a chain, it contains at least 1 or 2, typically 3, 4, 5 or all 6 CDRs of the variable heavy chain ( _VH ) and the variable light chain (VL ₎ , sufficient to maintain the presence of all 6 CDRs. Each CDR corresponds to at least a portion of the binding specificity of the full-length antibody. In general, heavy chain CDR3 (CDRH3) is required for adequate antigen binding sites. It typically further requires CDR3 of the light chain (CDRL3). As described herein, CDRs are known to those of ordinary skill in the art and can be identified based on Kabat or Chothia numbering (see, e.g., Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest , 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol . 196:901-917).

As used herein, "framework regions" or "FR" are domains located within the antibody variable region domain within the beta sheet; FR regions are relatively more conserved with respect to their amino acid sequences than hypervariable regions . Each variable region contains four framework regions that separate three hypervariable regions.

As used herein, a "constant region" domain is a domain in an antibody heavy or light chain that contains an amino acid sequence that is more conserved among antibodies than the variable region domain. Each light chain has a single light chain constant region ( _CL ) domain, and each heavy chain contains one or more heavy chain constant region ( _CH ) domains, including _CH1 , _CH2 , _CH3 , and _CH 4. Full-length IgA, IgD and IgG isotypes contain CH ₁ , CH ₂ and _CH 3 domains and a hinge region, while IgE and IgM contain CH ₁ , _CH 2, _CH 3 and _CH 4 domains. The _CH1 and _CL domains extend the Fab arm of the antibody molecule, thus facilitating interaction with the antigen and rotation of the antibody arm. Antibody constant regions can provide effector functions such as, but not limited to, clearance of antigens, pathogens and toxins to which the antibody specifically binds, for example, via interactions with various cells, biomolecules and tissues.

As used herein, "antibody hinge region" or "hinge region" refers to the polypeptide region in the heavy chain of gamma, delta, and alpha antibody isotypes that is present between _CH 1 and _CH Between the 2 domains, the Fab and Fc regions are joined and have no homology with other antibody domains. This region is rich in proline residues and provides flexibility to IgG, IgD and IgA antibodies, allowing the two "arms" of the Fab portion (each containing an antibody combination site) to move and appear opposite each other when they bind to the antigen. from each other’s various angles. This flexibility allows the Fab arms to move to align antibody combination sites to interact with epitopes on the cell surface or other antigens. Two interchain disulfide bonds in the hinge region stabilize the interaction between the two heavy chains. In some embodiments provided herein, synthetically produced antibody fragments contain one or more hinge regions to promote stability, for example, via interactions between two antibody chains. The hinge region is an example part of the dimerization domain, and for purposes herein is part of the linker.

As used herein, "fragment crystallizable region" or "Fc region" or "Fc domain" refers to the constant region containing the antibody heavy chain, excluding the first constant region. Globulin domain polypeptides. Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG (CH ₂ and _CH 3, also known as Cγ2 and Cγ3), or the last three constant region immunoglobulin domains of IgE and IgM ( _CH 2, _CH 3 and _CH 4). If desired, the Fc domain may include all or a portion of the flexible hinge region, which is the N-terminus of such domains. For IgA and IgM, Fc may include the J chain. For an exemplary Fc domain of an IgG, the Fc contains the immunoglobulin domains _CH2 and _CH3 , and optionally all or part of the hinge between _CH1 and _CH2 (also known as Cγ1 and Cγ2). The boundaries of the Fc region can vary, but typically include at least a portion of the hinge region. For the purposes of this document, Fc also includes any allele or species variant, or any variant or modified form, such as an Fc whose binding to the Fc receptor (FcR) has altered or altered Fc-mediated effector functions any variant or modified form thereof. Mutations in the Fc region and their effects are well documented in the art.

As used herein, "Fc chimera" refers to a chimeric polypeptide in which one or more polypeptides are directly or indirectly linked to the Fc region or a derivative thereof. Typically, Fc chimeras combine the Fc region of an immunoglobulin with another polypeptide. Derivatives of modified Fc polypeptides are known to those of ordinary skill in the art.

As used herein, "Kabat numbering" refers to the index number of the IgG1 Kabat antibody (see, e.g., Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest , 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242); which allows simple comparisons among antibodies, similar to how chymotrypsin numbering allows comparisons among proteases. One of ordinary skill in the art can use Kabat numbering to identify regions of the constant region.

As used herein, "EU numbering" or "EU index" refers to the numbering scheme for EU antibodies as described in Edelman et al., (1969) Proc. Natl. Acad. Sci. USA 63: 78-85 in. "EU index as in Kabat" means Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest , 5th ed., US Department of Health and Human Services), EU index number for the human IgG1 Kabat antibody described in NIH Publication No. 91-3242. EU numbering, or EU numbering as in Kabat, is generally used by those of ordinary skill in the art to number the number of amino acid residues in the Fc region of light and heavy antibody chains. For example, one of ordinary skill in the art can use EU numbering to identify regions of the constant region. For example, the C _L domain of the Ig kappa light chain corresponds to residues R108-C214 according to Kabat and EU numbering (see, eg, Table 2 below). The _CH 1 domain of IgG1 corresponds to residues 118-215 (EU numbering) or 114-223 (Kabat numbering); _CH 2 corresponds to residues 231-340 (EU numbering) or 244-360 (Kabat numbering); C _H 3 corresponds to residues 341-447 (EU numbering) or 361-478 (Kabat numbering).

The table below defines the numbering by EU, Kabat and sequential numbering for the IgG1 and IgG4 heavy chain constant domains and the Igκ light chain constant domain. Table 1 shows the IgG1 heavy chain constant domains according to EU, Kabat and sequential numbering, where the sequential numbering refers to the amino acid sequence set forth in SEQ ID NO: 9 and identifies C _H1.C _H2&C _H3 domain and residues in the hinge region. Table 2 shows immunoglobulin (Ig) kappa light chain constant domains numbered by EU, Kabat and sequential numbering, wherein the sequential numbering refers to the amino acid sequence set forth in SEQ ID NO: 17. In Table 2, the top column (bold) illustrates the number of amino acid residues by sequential numbering (referring to SEQ ID NO: 17); the second column (bold) provides the positions indicated by the numbers in the top column the 1-letter code of the amino acid residue; the third column (in italics) indicates the corresponding Kabat number according to the Kabat number; and the fourth column indicates the corresponding EU index number according to the EU number. Table 3 shows the IgG4 heavy chain constant domains according to EU, Kabat and sequential numbering with respect to the amino acid sequence set forth in SEQ ID NO: 15 and identifying C _H1.C _H2&C _H3 domain and residues in the hinge region. Table 1. IgG1 heavy chain constant domains according to EU , Kabat and sequential numbering area Residue number area Residue number area Residue number EU index Kabat In order (SEQ ID NO: 9) IgG1 sequence EU index Kabat In order (SEQ ID NO: 9) IgG1 sequence EU index Kabat In order (SEQ ID NO:9) IgG1 sequence CH1 118 114 1 A CH2 231 244 114 A CH3 341 361 224 G CH1 119 115 2 S CH2 232 245 115 P CH3 342 363 225 Q CH1 120 116 3 T CH2 233 246 116 E CH3 343 364 226 P CH1 121 117 4 K CH2 234 247 117 L CH3 344 365 227 R CH1 122 118 5 G CH2 235 248 118 L CH3 345 366 228 E CH1 123 119 6 P CH2 236 249 119 G CH3 346 367 229 P CH1 124 120 7 S CH2 237 250 120 G CH3 347 368 230 Q CH1 125 121 8 V CH2 238 251 121 P CH3 348 369 231 V CH1 126 122 9 F CH2 239 252 122 S CH3 349 370 232 Y CH1 127 123 10 P CH2 240 253 123 V CH3 350 371 233 T CH1 128 124 11 L CH2 241 254 124 F CH3 351 372 234 L CH1 129 125 12 A CH2 242 255 125 L CH3 352 373 235 P CH1 130 126 13 P CH2 243 256 126 F CH3 353 374 236 P CH1 131 127 14 S CH2 244 257 127 P CH3 354 375 237 S CH1 132 128 15 S CH2 245 258 128 P CH3 355 376 238 R CH1 133 129 16 K CH2 246 259 129 K CH3 356 377 239 D CH1 134 130 17 S CH2 247 260 130 P CH3 357 378 240 E CH1 135 133 18 T CH2 248 261 131 K CH3 358 381 241 L CH1 136 134 19 S CH2 249 262 132 D CH3 359 382 242 T CH1 137 135 20 G CH2 250 263 133 T CH3 360 383 243 K CH1 138 136 twenty one G CH2 251 264 134 L CH3 361 384 244 N CH1 139 137 twenty two T CH2 252 265 135 M CH3 362 385 245 Q CH1 140 138 twenty three A CH2 253 266 136 I CH3 363 386 246 V CH1 141 139 twenty four A CH2 254 267 137 S CH3 364 387 247 S CH1 142 140 25 L CH2 255 268 138 R CH3 365 388 248 L CH1 143 141 26 G CH2 256 269 139 T CH3 366 389 249 T CH1 144 142 27 C CH2 257 270 140 P CH3 367 390 250 C CH1 145 143 28 L CH2 258 271 141 E CH3 368 391 251 L CH1 146 144 29 V CH2 259 272 142 V CH3 369 392 252 V CH1 147 145 30 K CH2 260 273 143 T CH3 370 393 253 K CH1 148 146 31 D CH2 261 274 144 C CH3 371 394 254 G CH1 149 147 32 Y CH2 262 275 145 V CH3 372 395 255 F CH1 150 148 33 F CH2 263 276 146 V CH3 373 396 256 Y CH1 151 149 34 P CH2 264 277 147 V CH3 374 397 257 P CH1 152 150 35 E CH2 265 278 148 D CH3 375 398 258 S CH1 153 151 36 P CH2 266 279 149 V CH3 376 399 259 D CH1 154 152 37 V CH2 267 280 150 S CH3 377 400 260 I CH1 155 153 38 T CH2 268 281 151 H CH3 378 401 261 A CH1 156 154 39 V CH2 269 282 152 E CH3 379 402 262 V CH1 157 156 40 S CH2 270 283 153 D CH3 380 405 263 E CH1 158 157 41 W CH2 271 284 154 P CH3 381 406 264 W CH1 159 162 42 N CH2 272 285 155 E CH3 382 407 265 E CH1 160 163 43 S CH2 273 286 156 V CH3 383 408 266 S CH1 161 164 44 G CH2 274 287 157 K CH3 384 410 267 N CH1 162 165 45 A CH2 275 288 158 F CH3 385 411 268 G CH1 163 166 46 L CH2 276 289 159 N CH3 386 414 269 Q CH1 164 167 47 T CH2 277 290 160 W CH3 387 415 270 P CH1 165 168 48 S CH2 278 291 161 Y CH3 388 416 271 E CH1 166 169 49 G CH2 279 292 162 V CH3 389 417 272 N CH1 167 171 50 V CH2 280 295 163 D CH3 390 418 273 N CH1 168 172 51 H CH2 281 296 164 G CH3 391 419 274 Y CH1 169 173 52 T CH2 282 299 165 V CH3 392 420 275 K CH1 170 174 53 F CH2 283 300 166 E CH3 393 421 276 T CH1 171 175 54 P CH2 284 301 167 V CH3 394 422 277 T CH1 172 176 55 A CH2 285 302 168 H CH3 395 423 278 P CH1 173 177 56 V CH2 286 303 169 N CH3 396 424 279 P CH1 174 178 57 L CH2 287 304 170 A CH3 397 425 280 V CH1 175 179 58 Q CH2 288 305 171 K CH3 398 426 281 L CH1 176 180 59 S CH2 289 306 172 T CH3 399 427 282 D CH1 177 182 60 S CH2 290 307 173 K CH3 400 428 283 S CH1 178 183 61 G CH2 291 308 174 P CH3 401 430 284 D CH1 179 184 62 L CH2 292 309 175 R CH3 402 433 285 G CH1 180 185 63 Y CH2 293 310 176 E CH3 403 434 286 S CH1 181 186 64 S CH2 294 311 177 E CH3 404 435 287 F CH1 182 187 65 L CH2 295 312 178 Q CH3 405 436 288 F CH1 183 188 66 S CH2 296 313 179 Y CH3 406 437 289 L CH1 184 189 67 S CH2 297 314 180 N CH3 407 438 290 Y CH1 185 190 68 V CH2 298 317 181 S CH3 408 439 291 S CH1 186 191 69 V CH2 299 318 182 T CH3 409 440 292 K CH1 187 192 70 T CH2 300 319 183 Y CH3 410 441 293 L CH1 188 193 71 V CH2 301 320 184 R CH3 411 442 294 T CH1 189 194 72 P CH2 302 321 185 V CH3 412 443 295 V CH1 190 195 73 S CH2 303 322 186 V CH3 413 444 296 D CH1 191 196 74 S CH2 304 323 187 S CH3 414 445 297 K CH1 192 197 75 S CH2 305 324 188 V CH3 415 446 298 S CH1 193 198 76 L CH2 306 325 189 L CH3 416 447 299 R CH1 194 199 77 G CH2 307 326 190 T CH3 417 448 300 W CH1 195 200 78 T CH2 308 327 191 V CH3 418 449 301 Q CH1 196 203 79 Q CH2 309 328 192 L CH3 419 450 302 Q CH1 197 205 80 T CH2 310 329 193 H CH3 420 451 303 G CH1 198 206 81 Y CH2 311 330 194 Q CH3 421 452 304 N CH1 199 207 82 I CH2 312 331 195 D CH3 422 453 305 V CH1 200 208 83 C CH2 313 332 196 W CH3 423 454 306 F CH1 201 209 84 N CH2 314 333 197 L CH3 424 455 307 S CH1 202 210 85 V CH2 315 334 198 N CH3 425 456 308 C CH1 203 211 86 N CH2 316 335 199 G CH3 426 457 309 S CH1 204 212 87 H CH2 317 336 200 K CH3 427 458 310 V CH1 205 213 88 K CH2 318 337 201 E CH3 428 459 311 M CH1 206 214 89 P CH2 319 338 202 Y CH3 429 460 312 H CH1 207 215 90 S CH2 320 339 203 K CH3 430 461 313 E CH1 208 216 91 N CH2 321 340 204 C CH3 431 462 314 A CH1 209 217 92 T CH2 322 341 205 K CH3 432 463 315 L CH1 210 218 93 K CH2 323 342 206 V CH3 433 464 316 H CH1 211 219 94 V CH2 324 343 207 S CH3 434 465 317 N CH1 212 220 95 D CH2 325 344 208 N CH3 435 466 318 H CH1 213 221 96 K CH2 326 345 209 K CH3 436 467 319 Y CH1 214 222 97 K CH2 327 346 210 A CH3 437 468 320 T CH1 215 223 98 V CH2 328 347 211 L CH3 438 469 321 Q hinge 216 226 99 E CH2 329 348 212 P CH3 439 470 322 K hinge 217 227 100 P CH2 330 349 213 A CH3 440 471 323 S hinge 218 228 101 K CH2 331 350 214 P CH3 441 472 324 L hinge 219 232 102 S CH2 332 351 215 I CH3 442 473 325 S hinge 220 233 103 C CH2 333 352 216 E CH3 443 474 326 L hinge 221 234 104 D CH2 334 353 217 K CH3 444 475 327 S hinge 222 235 105 K CH2 335 354 218 T CH3 445 476 328 P hinge 223 236 106 T CH2 336 355 219 I CH3 446 477 329 G hinge 224 237 107 H CH2 337 357 220 S CH3 447 478 330 K hinge 225 238 108 T CH2 338 358 221 K hinge 226 239 109 C CH2 339 359 222 A hinge 227 240 110 P CH2 340 360 223 K hinge 228 241 111 P hinge 229 242 112 C hinge 230 243 113 P surface 2. Igκ light chain constant domain Kabat and EU No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 R T V A A P S V F I F P P S D 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 E Q L K S G T A S V V C L L N 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 N F Y P R E A K V Q W K V D N 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 A L Q S G N S Q E S V T E Q D 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 S K D S T Y S L S S T L T L S 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 K A D Y E K H K V Y A C E V T 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 H Q G L S S P V T K S F N R G 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 106 107 E C 213 214 213 214 Table 3. IgG4 heavy chain constant domains according to EU , Kabat and sequential numbering area Residue number area Residue number area Residue number EU index Kabat In order (SEQ ID NO: 15) IgG4 sequence EU index Kabat In order (SEQ ID NO: 15) IgG4 sequence EU index Kabat In order (SEQ ID NO:15) IgG4 sequence CH1 118 114 1 A CH2 231 244 111 A CH3 341 361 221 G CH1 119 115 2 S CH2 232 245 112 P CH3 342 363 222 Q CH1 120 116 3 T CH2 233 246 113 E CH3 343 364 223 P CH1 121 117 4 K CH2 234 247 114 F CH3 344 365 224 R CH1 122 118 5 G CH2 235 248 115 L CH3 345 366 225 E CH1 123 119 6 P CH2 236 249 116 G CH3 346 367 226 P CH1 124 120 7 S CH2 237 250 117 G CH3 347 368 227 Q CH1 125 121 8 V CH2 238 251 118 P CH3 348 369 228 V CH1 126 122 9 F CH2 239 252 119 S CH3 349 370 229 Y CH1 127 123 10 P CH2 240 253 120 V CH3 350 371 230 T CH1 128 124 11 L CH2 241 254 121 F CH3 351 372 231 L CH1 129 125 12 A CH2 242 255 122 L CH3 352 373 232 P CH1 130 126 13 P CH2 243 256 123 F CH3 353 374 233 P CH1 131 127 14 C CH2 244 257 124 P CH3 354 375 234 S CH1 132 128 15 S CH2 245 258 125 P CH3 355 376 235 Q CH1 133 129 16 R CH2 246 259 126 K CH3 356 377 236 E CH1 134 130 17 S CH2 247 260 127 P CH3 357 378 237 E CH1 135 133 18 T CH2 248 261 128 K CH3 358 381 238 M CH1 136 134 19 S CH2 249 262 129 D CH3 359 382 239 T CH1 137 135 20 E CH2 250 263 130 T CH3 360 383 240 K CH1 138 136 twenty one S CH2 251 264 131 L CH3 361 384 241 N CH1 139 137 twenty two T CH2 252 265 132 M CH3 362 385 242 Q CH1 140 138 twenty three A CH2 253 266 133 I CH3 363 386 243 V CH1 141 139 twenty four A CH2 254 267 134 S CH3 364 387 244 S CH1 142 140 25 L CH2 255 268 135 R CH3 365 388 245 L CH1 143 141 26 G CH2 256 269 136 T CH3 366 389 246 T CH1 144 142 27 C CH2 257 270 137 P CH3 367 390 247 C CH1 145 143 28 L CH2 258 271 138 E CH3 368 391 248 L CH1 146 144 29 V CH2 259 272 139 V CH3 369 392 249 V CH1 147 145 30 K CH2 260 273 140 T CH3 370 393 250 K CH1 148 146 31 D CH2 261 274 141 C CH3 371 394 251 G CH1 149 147 32 Y CH2 262 275 142 V CH3 372 395 252 F CH1 150 148 33 F CH2 263 276 143 V CH3 373 396 253 Y CH1 151 149 34 P CH2 264 277 144 V CH3 374 397 254 P CH1 152 150 35 E CH2 265 278 145 D CH3 375 398 255 S CH1 153 151 36 P CH2 266 279 146 V CH3 376 399 256 D CH1 154 152 37 V CH2 267 280 147 S CH3 377 400 257 I CH1 155 153 38 T CH2 268 281 148 Q CH3 378 401 258 A CH1 156 154 39 V CH2 269 282 149 E CH3 379 402 259 V CH1 157 156 40 S CH2 270 283 150 D CH3 380 405 260 E CH1 158 157 41 W CH2 271 284 151 P CH3 381 406 261 W CH1 159 162 42 N CH2 272 285 152 E CH3 382 407 262 E CH1 160 163 43 S CH2 273 286 153 V CH3 383 408 263 S CH1 161 164 44 G CH2 274 287 154 Q CH3 384 410 264 N CH1 162 165 45 A CH2 275 288 155 F CH3 385 411 265 G CH1 163 166 46 L CH2 276 289 156 N CH3 386 414 266 Q CH1 164 167 47 T CH2 277 290 157 W CH3 387 415 267 P CH1 165 168 48 S CH2 278 291 158 Y CH3 388 416 268 E CH1 166 169 49 G CH2 279 292 159 V CH3 389 417 269 N CH1 167 171 50 V CH2 280 295 160 D CH3 390 418 270 N CH1 168 172 51 H CH2 281 296 161 G CH3 391 419 271 Y CH1 169 173 52 T CH2 282 299 162 V CH3 392 420 272 K CH1 170 174 53 F CH2 283 300 163 E CH3 393 421 273 T CH1 171 175 54 P CH2 284 301 164 V CH3 394 422 274 T CH1 172 176 55 A CH2 285 302 165 H CH3 395 423 275 P CH1 173 177 56 V CH2 286 303 166 N CH3 396 424 276 P CH1 174 178 57 L CH2 287 304 167 A CH3 397 425 277 V CH1 175 179 58 Q CH2 288 305 168 K CH3 398 426 278 L CH1 176 180 59 S CH2 289 306 169 T CH3 399 427 279 D CH1 177 182 60 S CH2 290 307 170 K CH3 400 428 280 S CH1 178 183 61 G CH2 291 308 171 P CH3 401 430 281 D CH1 179 184 62 L CH2 292 309 172 R CH3 402 433 282 G CH1 180 185 63 Y CH2 293 310 173 E CH3 403 434 283 S CH1 181 186 64 S CH2 294 311 174 E CH3 404 435 284 F CH1 182 187 65 L CH2 295 312 175 Q CH3 405 436 285 F CH1 183 188 66 S CH2 296 313 176 F CH3 406 437 286 L CH1 184 189 67 S CH2 297 314 177 N CH3 407 438 287 Y CH1 185 190 68 V CH2 298 317 178 S CH3 408 439 288 S CH1 186 191 69 V CH2 299 318 179 T CH3 409 440 289 R CH1 187 192 70 T CH2 300 319 180 Y CH3 410 441 290 L CH1 188 193 71 V CH2 301 320 181 R CH3 411 442 291 T CH1 189 194 72 P CH2 302 321 182 V CH3 412 443 292 V CH1 190 195 73 S CH2 303 322 183 V CH3 413 444 293 D CH1 191 196 74 S CH2 304 323 184 S CH3 414 445 294 K CH1 192 197 75 S CH2 305 324 185 V CH3 415 446 295 S CH1 193 198 76 L CH2 306 325 186 L CH3 416 447 296 R CH1 194 199 77 G CH2 307 326 187 T CH3 417 448 297 W CH1 195 200 78 T CH2 308 327 188 V CH3 418 449 298 Q CH1 196 203 79 K CH2 309 328 189 L CH3 419 450 299 E CH1 197 205 80 T CH2 310 329 190 H CH3 420 451 300 G CH1 198 206 81 Y CH2 311 330 191 Q CH3 421 452 301 N CH1 199 207 82 T CH2 312 331 192 D CH3 422 453 302 V CH1 200 208 83 C CH2 313 332 193 W CH3 423 454 303 F CH1 201 209 84 N CH2 314 333 194 L CH3 424 455 304 S CH1 202 210 85 V CH2 315 334 195 N CH3 425 456 305 C CH1 203 211 86 D CH2 316 335 196 G CH3 426 457 306 S CH1 204 212 87 H CH2 317 336 197 K CH3 427 458 307 V CH1 205 213 88 K CH2 318 337 198 E CH3 428 459 308 M CH1 206 214 89 P CH2 319 338 199 Y CH3 429 460 309 H CH1 207 215 90 S CH2 320 339 200 K CH3 430 461 310 E CH1 208 216 91 N CH2 321 340 201 C CH3 431 462 311 A CH1 209 217 92 T CH2 322 341 202 K CH3 432 463 312 L CH1 210 218 93 K CH2 323 342 203 V CH3 433 464 313 H CH1 211 219 94 V CH2 324 343 204 S CH3 434 465 314 N CH1 212 220 95 D CH2 325 344 205 N CH3 435 466 315 H CH1 213 221 96 K CH2 326 345 206 K CH3 436 467 316 Y CH1 214 222 97 R CH2 327 346 207 G CH3 437 468 317 T CH1 215 223 98 V CH2 328 347 208 L CH3 438 469 318 Q hinge 216 226 99 E CH2 329 348 209 P CH3 439 470 319 K hinge 217 227 100 S CH2 330 349 210 S CH3 440 471 320 S hinge 218 228 101 K CH2 331 350 211 S CH3 441 472 321 L hinge 219 229 102 Y CH2 332 351 212 I CH3 442 473 322 S hinge 220 230 103 G CH2 333 352 213 E CH3 443 474 323 L hinge 224 237 104 P CH2 334 353 214 K CH3 444 475 324 S hinge 225 238 105 P CH2 335 354 215 T CH3 445 476 325 L hinge 226 239 106 C CH2 336 355 216 I CH3 446 477 326 G hinge 227 240 107 P CH2 337 357 217 S CH3 447 478 327 K hinge 228 241 108 S CH2 338 358 218 K hinge 229 242 109 C CH2 339 359 219 A hinge 230 243 110 P CH2 340 360 220 K

As used herein, when referring to an antibody fragment derived from another antibody, such as a monoclonal antibody, the phrase "derived from" refers to an antibody fragment (e.g., Fab, F(ab'), F(ab ') _2. Single-chain Fv (scFv), Fv, dsFv, dAb, diabody, Fd and Fd' fragment) are engineered to maintain the binding specificity of the original antibody. Such fragments can be derived by a variety of methods known in the art, including but not limited to enzymatic cleavage, chemical cross-linking, recombinant means, or combinations thereof. Generally speaking, the derived antibody fragments share the same or substantially the same heavy chain variable region (V _H ) and light chain variable region (V _L ) as the parent antibody, such that the antibody fragment and the parent antibody bind to the same antigen. Determining base.

As used herein, "parent antibody" or "source antibody" refers to the antibody fragment from which it is derived (e.g., Fab, F(ab'), F(ab) ₂ , single chain Fv (scFv ), Fv, dsFv, dAb, diabody, Fd and Fd' fragment) antibodies.

As used herein, the term "epitope" refers to any epitope on an antigen or protein to which the paratope of an antibody can bind. Epitope determinants typically contain chemically active surface groups of molecules, such as amino acids or sugar side chains, and typically have specific three-dimensional structural properties as well as charge-to-mass ratio properties.

As used herein, "humanized antibodies" and human therapeutics refer to antibodies and other protein therapeutics that have been modified to include "human" sequences of amino acids such that administration to humans will not elicit an immune response. Humanized antibodies, for example, typically contain complementarity determining regions (CDRs or hypervariable loops) derived from immunoglobulins of non-human species, and the remainder of the antibody molecule derived primarily from human immunoglobulins. Methods for humanizing and producing proteins, including antibodies, are well known and readily available to those of ordinary skill in the art. For example, DNA encoding a monoclonal antibody can be altered by recombinant DNA technology to encode an antibody in which the amino acid composition of the non-variable region is based on that of a human antibody. Methods for identifying such regions are known and include computer programs designed to identify variable and non-variable regions of immunoglobulins. Thus, generally speaking, a humanized antibody contains substantially all of at least one, and typically two, variable domains, wherein all or substantially all of the hypervariable loops (e.g., CDRs) correspond to those of a non-human immunoglobulin, And all or substantially all framework regions (FRs) are FRs of human immunoglobulin sequences. Humanized antibodies optionally also contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

As used herein, "multimerization domain" refers to an amino acid sequence that facilitates the stable interaction of a polypeptide molecule with one or more additional polypeptide molecules, each of which contains a complementary polypeptide molecule. polymerization domain, which may be the same or different multimerization domains, to form stable multimers with the first domain. Generally, the polypeptide is linked to a multimerization domain, either directly or indirectly. Exemplary multimerization domains include immunoglobulin sequences or portions thereof, leucine zippers, hydrophobic regions, hydrophilic regions, and compatible protein-protein interaction domains. For example, the multimerization domain may be an immunoglobulin constant region or domain, such as an Fc domain from IgG (including IgG1, IgG2, IgG3 or IgG4 subtypes), IgA, IgE, IgD and IgM and modified forms thereof, or its part.

As used herein, "dimerization domains" are multimerization domains that facilitate interactions between two polypeptide sequences, such as, but not limited to, antibody chains. Dimerization domains include, but are not limited to, amino acid sequences containing cysteine residues that promote the formation of disulfide bonds between two polypeptide sequences, such as all or a portion of a full-length antibody hinge region, or one or more dimerization domains. Polymerization sequences, which are amino acid sequences known to promote interactions between polypeptides (eg, leucine zipper, GCN4 zipper).

As used herein, a "chimeric polypeptide" refers to a polypeptide that contains portions from at least two different polypeptides or two non-contiguous portions from a single polypeptide. Thus, chimeric polypeptides generally include a sequence of amino acid residues from all or a portion of one polypeptide and a sequence of amino acids from all or a portion of a different polypeptide. The two moieties may be linked directly or indirectly and may be via a peptide bond, other covalent bond, or have a strength sufficient to maintain the integrity of the substantial portion of the chimeric polypeptide under equilibrium and physiological conditions, such as in isotonic pH 7 buffered saline. other non-covalent interactions to connect.

As used herein, a "fusion protein" is, such as by expressing a fusion protein from a vector containing two nucleic acids, encoding two polypeptides that are in close proximity (eg, adjacent) to each other along the length of the vector that has been engineered to contain Polypeptides corresponding to the amino acid sequences of two different polypeptides. Thus, a fusion protein refers to a chimeric protein containing two proteins or peptides or portions of two or more proteins or peptides linked directly or indirectly via peptide bonds. Two molecules may be adjacent in a construct, or may be separated by a linker or spacer polypeptide.

As used herein, "linker," "linker unit," or "link" refers to a chain of atoms that covalently attaches an antibody or an antigen-binding fragment thereof to another therapeutic moiety or A peptide or chemical part of another antibody or fragment thereof. Linkers are included to, for example, increase flexibility, modify steric interactions (including steric hindrance), and increase solubility in aqueous media.

As used herein, a "linker peptide" or "spacer peptide" refers to a short sequence of amino acids (or nucleic acids encoding such amino acid sequences) that joins two polypeptide sequences. "Peptide linker" refers to a short sequence of amino acids that joins two polypeptide sequences. Exemplary polypeptide linkers are those that join a peptide transduction domain to an antibody, or that join two antibody chains in a synthetic antibody fragment, such as a scFv fragment. Linkers are well known and any known linker can be used in the provided methods. Exemplary polypeptide linkers include (Gly-Ser) _n amino acid sequences with some Glu or Lys residues dispersed throughout to increase solubility. Other exemplary linkers are described herein; any of these and other known linkers can be used with the polypeptides, antibodies, and other products and methods provided herein.

As used herein, "tag" or "epitope tag" refers to an amino acid that is typically added to the N- or C-terminus of the polypeptides provided herein, such as antibodies and antibody fragments/constructs. sequence. Including tags fused to the polypeptide may facilitate purification and/or detection of the polypeptide. Typically, a tag or tag polypeptide refers to a polypeptide that has sufficient residues to provide an epitope recognized by an antibody or that can be used for detection or purification, but is short enough that it does not interfere with the activity of the polypeptide to which it is linked. . Tag polypeptides are typically sufficiently unique that antibodies that specifically bind thereto do not substantially cross-react with epitopes in the polypeptide to which they are linked. Suitable tag polypeptides generally have at least 5 or 6 amino acid residues, and usually between about 8-50 amino acid residues, typically between 9-30 residues. The tag can be attached to one or more chimeric polypeptides in the multimer and allow detection of the multimer or allow its recovery from the sample or mixture. Such tags are well known and can be easily synthesized and designed. Exemplary tag polypeptides include those used for affinity purification and include, for example, a FLAG tag; a His tag; an influenza hemagglutinin (HA) tag polypeptide and its antibody 12CA5 (see, e.g., Field et al. (1988) Mol. Cell. Biol. 8 :2159-2165); the c-myc tag and its 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies (see, e.g., Evan et al. (1985) Molecular and Cellular Biology 5 :3610-3616); and herpes simplex Viral glycoprotein D (gD) tag and its antibodies (see, eg, Paborsky et al. (1990) Protein Engineering 3 :547-553). Antibodies used to detect epitope-tagged antibodies are typically referred to herein as secondary antibodies.

As used herein, "label" or "detectable moiety" refers to a detectable label (such as a fluorescent molecule, a chemiluminescent molecule, a bioluminescent molecule, a contrast agent (such as a metal), a radioactive nuclide, Chromophore, detectable peptide, or enzyme that catalyzes the formation of a detectable product), which may be directly or indirectly attached or linked to a molecule (e.g., an antibody or antigen-binding fragment thereof, such as an anti-TNFR1 antibody or an antigen thereof provided herein binding fragment), or associates with it, and can be detected in vivo and/or in vitro. The detection method can be any method known in the art, including known in vivo and/or in vitro detection methods (for example, by visual inspection, magnetic resonance (MR) spectroscopy, ultrasonic signals, X-ray rays, gamma-ray spectroscopy (such as positron emission tomography (PET) scans, single-photon emission computed tomography (SPECT)), fluorescence spectroscopy, or absorption). Indirect detection refers to the measurement of a physical phenomenon (such as energy or particle emission or absorption) that binds an atom, molecule, or composition directly or indirectly to a detectable moiety (e.g., detects binding to a primary antibody (e.g., as described herein) Labeled secondary antibodies or antigen-binding fragments thereof) of the provided anti-TNFR antibodies or antigen-binding fragments thereof).

As used herein, "nucleic acid" refers to at least two linked nucleotides or nucleotide derivatives, typically joined together by a phosphodiester bond, including deoxyribonucleic acid (DNA) and ribose. Nucleic acid (RNA). The term "nucleic acid" also includes nucleic acid analogs, such as peptide nucleic acid (PNA), phosphorothioate DNA, and other such analogs and their derivatives or combinations. Nucleic acids also include DNA and RNA derivatives that contain, for example, nucleotide analogs or "backbone" linkages other than phosphodiester linkages, such as phosphotriester linkages, aminophosphate linkages, phosphorothioate linkages, sulfide linkages, etc. Ester bonds or peptide bonds (i.e., peptide nucleic acids). The term also includes single-stranded (sense or antisense) and double-stranded nucleic acids, as equivalents, derivatives, variants and analogs of RNA or DNA made from nucleotide analogs. Deoxyribonucleotides include deoxyadenosine, deoxycytidine, deoxyguanosine and deoxythymidine. For RNA, the uracil base is uridine.

As used herein, an "isolated nucleic acid molecule" is a nucleic acid molecule that is separated from other nucleic acid molecules present in the natural source of the nucleic acid molecule. "Isolated" nucleic acid molecules, such as cDNA molecules, may be substantially free of other cellular material or culture media when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. Exemplary isolated nucleic acid molecules provided herein include isolated nucleic acid molecules encoding the provided antibodies or antigen-binding fragments.

As used herein, with reference to a nucleic acid sequence, region, element or domain, "operably linked" means that the nucleic acid regions are functionally related to each other. For example, a nucleic acid encoding a leader peptide is operably linked to a nucleic acid encoding a polypeptide, whereby the nucleic acid can be transcribed and translated to express a functional fusion protein, wherein the leader peptide enables secretion of the fusion polypeptide. In some cases, a nucleic acid encoding a first polypeptide (e.g., a leader peptide) is operably linked to a nucleic acid encoding a second polypeptide, and the nucleic acid is transcribed into a single mRNA transcript, but translation of the mRNA transcript can result in two One of the polypeptides is represented. For example, an amber stop codon can be located between a nucleic acid encoding a first polypeptide and a nucleic acid encoding a second polypeptide, such that when introduced into a subset of amber suppressor cells, the resulting single mRNA transcript can be translated to produce a nucleic acid containing the first polypeptide. Fusion proteins of one and a second polypeptide may be translated to produce only the first polypeptide. In another embodiment, a promoter can be operably linked to a nucleic acid encoding a polypeptide, whereby the promoter regulates or mediates transcription of the nucleic acid.

As used herein, with reference to, for example, a synthetic nucleic acid molecule or a synthetic gene or a synthetic peptide, "synthetic" refers to a nucleic acid molecule or a polypeptide molecule produced by recombinant methods and/or by chemical synthesis methods.

As used herein, the residues of a naturally occurring alpha-amino acid are those of the 20 alpha-amino acids found in nature and in humans through the passage of charged tRNA molecules through their homologs Specific recognition of source mRNA codons and incorporation into proteins.

As used herein, "polypeptide" refers to two or more amino acids covalently joined. The terms "polypeptide" and "protein" are used interchangeably herein.

As used herein, "peptide" refers to a polypeptide from 2 to about 40 amino acids in length.

As used herein, "amino acid" is an organic compound containing an amine group and a carboxylic acid group. Polypeptides contain two or more amino acids. For purposes herein, amino acids provided in polypeptides, such as antibodies, include twenty naturally occurring amino acids (Table 4), non-natural amino acids, and amino acid analogs (e.g., in which the α-carbon Amino acids with side chains). As used herein, amino acids present in the various amino acid sequences of the polypeptides presented herein are identified by their well-known three-letter or one-letter abbreviations (see Table 4). Nucleotides found in various nucleic acid molecules and fragments are named by standard one-letter names commonly used in the art.

As used herein, "amino acid residue" refers to the amino acid formed when a polypeptide is chemically digested (hydrolyzed) at its peptide bonds. The amino acid residues described herein are generally in the "L" isomeric form. Residues in the "D" isomer form may be substituted for any L-amino acid residue as long as the desired functional properties of the polypeptide are retained. NH ₂ refers to the free amine group present at the amino end of the polypeptide. COOH refers to the free carboxyl group present at the carboxyl terminus of a polypeptide. Consistent with standard polypeptide nomenclature as described in J. Biol. Chem. , 243:3557-59 (1968) and adopted at 37 CFR §§ 1.821 - 1.822, the abbreviations for amino acid residues are shown in Table 4: Table 4 - Correspondence table symbol 1- letter 3- letter amino acids Y Tyr tyrosine G Gly glycine F Phe Phenylalanine M Met methionine A Ala alanine S Ser Serine I Ile isoleucine L Leu Leucine T Thr threonine V Val Valine P Pro proline K Lys lysine H His Histidine Q gnc Glutamine E Glu glutamate Z gx Glutamic acid and/or glutamic acid W tp Tryptophan R Arg Arginine D Asp aspartic acid N Asn asparagine B Ax Aspartic acid and/or asparagine C Cys cysteine X Xaa unknown or other

All sequences of amino acid residues represented by formula herein have a left-to-right orientation in the conventional direction from the amine terminus to the carboxyl terminus. In addition, the phrase "amino acid residue" is defined to include the amino acids listed in the correspondence table (Table 4), modified non-natural and abnormal amino acids. Furthermore, a dash at the beginning or end of an amino acid residue sequence indicates a peptide with another sequence of one or more amino acid residues or with an amine terminus such as _NH2 or with a carboxyl terminus such as COOH key. Suitable conservative substitutions of amino acids in peptides or proteins are known to those of ordinary skill in the art and can generally be made without altering the biological activity of the resulting molecule. One of ordinary skill in the art recognizes that, in general, single amino acid substitutions in non-essential regions of polypeptides do not substantially alter biological activity (see, e.g., Watson et al., Molecular Biology of the Gene , 4th ed., 1987 , The Benjamin/Cummings Pub. Co., p. 224).

Such substitutions may be made according to the exemplary substitutions set forth in Table 5 below: Table 5. Exemplary Conservative Amino Acid Substitutions initial residue conservative substitution Ala(A) Gly; Ser Arg(R) Lys Asn(N) Gln;His Cys(C) Ser Gln(Q) Asn Glu（E） Asp Gly(G) Ala;Pro His(H) Asn;Gln Ile(I) Leu; Val Leu(L) Ile; Val Lys(K) Arg; Gln; Glu Met(M) Leu; Tyr; Ile Phe(F) Met; Leu; Tyr Ser(S) Thr Thr(T) Ser Trp(W) Tyr Tyr(Y) Trp; Phe Val(V) Ile;Leu

Other substitutions are also allowed and can be determined empirically or based on other known conservative or non-conservative substitutions.

As used herein, "naturally occurring amino acids" refers to the 20 L-amino acids present in polypeptides.

As used herein, "non-natural amino acid" refers to organic compounds that are structurally similar to natural amino acids but have been structurally modified to mimic the structure and reactivity of natural amino acids. Non-naturally occurring amino acids thus include, for example, amino acids or amino acid analogs other than the 20 naturally occurring amino acids and include, but are not limited to, D-stereoisomers of amino acids. Exemplary non-natural amino acids are known to those of ordinary skill in the art and include, but are not limited to, 2-aminoadipic acid (Aad), 3-aminoadipic acid (bAad), β-alanine /β-Amino-propionic acid (Bala), 2-aminobutyric acid (Abu), 4-aminobutyric acid/pipecolic acid (4Abu), 6-aminocaproic acid (Acp), 2-aminobutyric acid Heptanoic acid (Ahe), 2-aminoisobutyric acid (Aib), 3-aminoisobutyric acid (Baib), 2-aminopimelic acid (Apm), 2,4-diaminobutyric acid (Dbu) ), desmosin (Des), 2,2'-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), N-ethylglycine (EtGly), N-ethylglycine Asparagine (EtAsn), hydroxylysine (Hyl), allohydroxylysine (Ahyl), 3-hydroxyproline (3Hyp), 4-hydroxyproline (4Hyp), isodesmenin ( Ide), alloisoleucine (Aile), N-methylglycine, sarcosine (MeGly), N-methylisoleucine (MeIle), 6-N-methyllysine (MeLys) ), N-methylvaline (MeVal), norvaline (Nva), norleucine (Nle) and ornithine (Orn).

As used herein, a "DNA construct" is a single- or double-stranded, linear or circular DNA molecule containing DNA segments assembled and arranged in ways not found in nature. DNA constructs exist as a result of human manipulation and include pure strains and other copies of manipulated molecules.

As used herein, a "DNA segment" is a portion of a larger DNA molecule that has specified properties. For example, a DNA segment encoding a given polypeptide is a portion of a longer DNA molecule, such as a plasmid or plastid fragment, which when read from the 5' to 3' direction encodes the amino acid sequence of the given polypeptide.

As used herein, the term "polynucleotide" means a single- or double-stranded polymer of deoxyribonucleotide or ribonucleotide bases read from the 5' to the 3' end. Polynucleotides include RNA and DNA, and can be isolated from natural sources, synthesized in vitro, or prepared from a combination of natural and synthetic molecules. The length of a polynucleotide molecule is given herein in terms of nucleotides (abbreviated as "nt") or base pairs (abbreviated as "bp"). Where the context permits, the term nucleotide is used for both single- and double-stranded molecules. When this term is applied to a double-stranded molecule, it is used to indicate the total length and should be understood to be equivalent to the term base pairs. One of ordinary skill in the art will recognize that the two strands of a double-stranded polynucleotide can be slightly different in length and their ends can be staggered; therefore, all nucleotides within a double-stranded polynucleotide molecule cannot be paired. Such unpaired ends are generally no more than 20 nucleotides in length.

As used herein, produced by recombinant means by the use of recombinant DNA methods refers to the expression of the protein encoded by the cloned DNA using well-known molecular biology methods.

As used herein, "expression" refers to a method of producing a polypeptide by transcription and translation of a polynucleotide. The amount of polypeptide expressed can be assessed using any method known in the art, including, for example, methods that determine the amount of polypeptide produced by a host cell. Such methods may include, but are not limited to, analysis of cells by ELISA, Coomassie blue staining, followed by gel electrophoresis, Lowry protein assay, and Bradford protein assay. Peptides in the lysate were quantified.

As used herein, a "host cell" is a cell used to receive, maintain, regenerate and/or amplify a vector. Host cells can also be used to express the polypeptide encoded by the vector. As the host cell divides, the nucleic acid in the vector is replicated, thereby amplifying the nucleic acid.

As used herein, a "vector" is a replicable nucleic acid from which one or more heterologous proteins may be expressed when the vector is transformed into an appropriate host cell. References to vectors include those into which nucleic acids encoding polypeptides or fragments thereof can be introduced, typically by restriction digestion and ligation. References to a vector also include vectors containing nucleic acid encoding a polypeptide, such as a modified anti-TNFR1 antibody. Vectors are used to introduce a nucleic acid encoding a polypeptide into a host cell for amplification of the nucleic acid, or to express/display the polypeptide encoded by the nucleic acid. The vector typically remains episomal, but may be designed to achieve chromosomal integration of the gene or portion thereof into the genome. Also contemplated are vectors for artificial chromosomes such as yeast artificial chromosomes and mammalian artificial chromosomes. The selection and use of such vehicles is well known to those of ordinary skill in the art. Vectors also include "virus vectors/viral vectors". Viral vectors are engineered viruses that are operably linked to foreign genes to deliver the foreign genes (as a vector or shuttle) into cells.

As used herein, "expression vector" includes a vector capable of expressing DNA operably linked to regulatory sequences, such as a promoter region capable of effecting expression of such DNA fragments. Such other segments may include promoter and terminator sequences and, if appropriate, one or more origins of replication, one or more selectable markers, enhancers, polyadenylation signals, and the like. Expression vectors are generally derived from plasmid or viral DNA, or may contain elements of both. Thus, an expression vector refers to a recombinant DNA or RNA construct that expresses the cloned DNA when introduced into an appropriate host cell, such as a plastid, phage, recombinant virus, or other vector. Suitable expression vectors are well known to those of ordinary skill in the art, and include expression vectors that are replicable in eukaryotic cells and/or prokaryotic cells, expression vectors that remain episomal, or expression vectors that are integrated into the host cell genome. carrier.

As used herein, "primary sequence" refers to the sequence of amino acid residues in a polypeptide or the sequence of nucleotides in a nucleic acid molecule.

As used herein, "sequence identity" refers to the number of identical or similar amino acid or nucleotide bases in a comparison between a test and a reference polypeptide or polynucleotide. Sequence identity can be determined by sequence alignment of nucleic acid or protein sequences to identify regions of similarity or identity. For purposes herein, sequence identity is generally determined by alignment to identify identical residues. Alignments can be local or global. Matches, mismatches and gaps can be identified between compared sequences. Gaps are empty amino acids or nucleotides inserted between residues of the aligned sequences to align identical or similar characteristics. In general, internal and terminal gaps can exist. When gap penalties are used, sequence identity can be determined without penalty for terminal gaps (e.g., no penalty for terminal gaps). Alternatively, sequence identity can be determined without accounting for gaps as the number of identical positions/length of the total aligned sequences x 100.

As used herein, a "global alignment" is an alignment that aligns two sequences from beginning to end, aligning each letter in each sequence only once. Alignments are generated regardless of whether there is similarity or identity between sequences. For example, 50% sequence identity based on "global alignment" means that in an alignment of the complete sequences of two compared sequences, 50% of the residues are identical for every 100 nucleotides in length. It will be appreciated that global alignment can be used to determine sequence identity even when the aligned sequences are of different lengths. Unless "No penalty for terminal gaps" is selected, differences in sequence ends are considered when determining sequence identity. In general, global alignment is used for sequences that share significant similarity over most of their length. Exemplary algorithms for performing global alignments include the Needleman-Wunsch algorithm (Needleman et al. (1970) J. Mol. Biol. 48:443). Exemplary programs for performing global alignments are publicly available and include global sequence alignments available at the National Center for Biotechnology Information (NCBI) website (ncbi.nlm.nih.gov/) The method (Global Sequence Alignment Tool) and the program available at deepc2.psi.iastate.edu/aat/align/align.html.

As used herein, a "local alignment" is an alignment of two sequences, but only those portions of the sequences that share similarity or identity. Therefore, a local alignment is determined if a subsegment of one sequence is present in another sequence. If no similarity exists, no alignment will be returned. Local alignment algorithms include BLAST or the Smith-Waterman algorithm ( Adv. Appl. Math. 2:482 (1981)). For example, 50% sequence identity based on "local alignment" means that in an alignment of the complete sequences of two compared sequences of any length, a 100-nucleotide-long region of similarity is within the similarity range. have 50% identical residues in the sexual region.

For purposes herein, sequence identity may be determined by standard alignment algorithm programs used with preset gap penalties determined by each vendor. Default parameters for the GAP program may include: (1) a unary comparison matrix (containing the values 1 for identification and 0 for non-identification) and the weighting of Gribskov et al. Nucl. Acids Res. 14:6745 (1986) Comparison matrix, as described in Schwartz and Dayhoff, eds., Atlas of Protein Sequence and Structure , National Biomedical Research Foundation, pp. 353-358 (1979); (2) a penalty of 3.0 for each gap and a penalty of 3.0 for each gap An additional 0.10 penalty point for each symbol; and (3) no penalty for end gaps. Whether any two nucleic acid molecules have a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% "identical" or whether any two polypeptides have a nucleotide sequence consistent with such identity Amino acid sequences or other similar variations with the stated percentage identities can be determined using known computer algorithms based on local or global alignments (see, e.g., wikipedia.org/wiki/Sequence_alignment_software, which provides many known and published Links to available comparison databases and programs). Generally, for the purposes of this article, sequence identity is determined using global alignment-based computer algorithms, such as the Niedermann-Wonsch global sequence alignment tool available from NCBI/BLAST (blast.ncbi.nlm. nih.gov/Blast.cgi?CMD=Web&Page_TYPE =BlastHome); LAlign (William Pearson implements the Huang and Miller algorithm (Adv. Appl. Math. (1991) 12:337-357)); and programs from Xiaoqui Huang, available at deepc2.psi.iastate.edu/aat/align/align.html. Typically, the full-length sequences of each of the polypeptides or nucleotides being compared are aligned in a global alignment across the full length of each sequence. Local alignment can also be used when the compared sequences are substantially the same length.

As used herein, the term "identity" means a comparison or alignment between a test and a reference polypeptide or polynucleotide. In a non-limiting example, "at least 90% identical to" refers to a 90% to 100% identity relative to a reference polypeptide or polynucleotide. An indication of identity of 90% or greater assumes, for purposes of illustration, that when comparing test and reference polypeptides or polynucleotides that are 100 amino acids or nucleotides in length, no more than 10% (that is, 10 out of 100) of the amino acids or nucleotides are different from the amino acids or nucleotides in the reference polypeptide or polynucleotide. Similar comparisons can be made between test and reference polynucleotides. Such differences may be represented by point mutations randomly distributed over the entire length of the amino acid sequence, or they may be clustered in one or more positions of varying lengths, up to a permissible maximum of, for example, 10/100 amino acid differences. value (roughly 90% consistent). Differences may also be attributed to deletions or truncation of amino acid residues. Differences are defined as nucleic acid or amino acid substitutions, insertions, or deletions. Depending on the length of the compared sequences, at levels of homology or identity above about 85%-90%, the results can be independent of the program and the set gap parameters; such high levels of identity can be easily assessed and often do not need to be relied upon in software.

As used herein, a "disulfide bond" (also known as an S-S bond or a disulfide bridge) is a covalent single bond derived from the coupling of a thiol group. Disulfide bonds in proteins are formed between thiol groups of cysteine residues and stabilize interactions between polypeptide domains, such as antibody domains.

As used herein, "coupled" or "conjugated" means attached via covalent or non-covalent interactions.

As used herein, the phrase "conjugated to an antibody" or "linked to an antibody" refers to a moiety attached to an antibody or an antigen-binding fragment thereof, such as a diagnostic or therapeutic moiety. ” or its grammatical variation means that the portion is attached to the antibody or antigen-binding fragment thereof by any known means for linking peptides, such as by recombinantly producing a fusion protein, or by chemical translation. Conjugation can be accomplished using any of a variety of linkers, including, but not limited to, peptide or compound linkers or chemical cross-linkers.

As used herein, "antibody-dependent cell-mediated cytotoxicity", "antibody-dependent cellular cytotoxicity" and "ADCC" interchangeably refer to cell-mediated a reaction in which nonspecific cytotoxic cells (such as natural killer (NK) cells, neutrophils, and macrophages) expressing Fc receptors (FcR) recognize bound antibodies on target cells and subsequently elicit Lysis of cells. NK cells, the primary cells used to regulate ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch et al. (1991) Annu. Rev. Immunol , 9:457-492. To assess the ADCC activity of relevant molecules, an in vitro ADCC assay can be performed (see, eg, US Pat. Nos. 5,500,362 and 5,821,337). Exemplary effector cells in such analyzes include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of relevant molecules can be assessed in vivo (eg, in animal models such as those disclosed in Clynes et al. (1998) Proc. Natl. Acad. Sci. USA 95:652-656).

As used herein, complement-dependent cytotoxicity (CDC) is the effector function of IgG and IgM antibodies. When such antibodies bind to surface antigens on target cells, such as bacterial cells or virus-infected cells, the classical complement pathway is triggered by binding of protein C1q to these antibodies, allowing the formation of a membrane attack complex. MAC) and subsequent cell lysis.

As used herein, antibody-dependent cellular phagocytosis (ADCP) is a cellular process in which target cells are internalized by effector cells with phagocytic potential, such as monocytes and macrophages. Once engulfed, target cells reside in phagosomes, which fuse with lysosomes to degrade the target cells via oxygen-dependent or -independent mechanisms.

As used herein, "therapeutic activity" refers to the in vivo activity of a therapeutic polypeptide. Generally speaking, therapeutic activity is activity associated with the treatment of a disease or condition. The therapeutic activity of a modified polypeptide can be any level of a percentage of the therapeutic activity of an unmodified polypeptide compared to an unmodified polypeptide, including but not limited to 1% activity, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99%, 100%, 200%, 300%, 400%, 500% or greater therapeutic activity.

As used herein, the term "assessing" is intended to include obtaining absolute values of the activity of a protein (such as an antibody or antigen-binding fragment thereof) present in a sample as well as obtaining an index, ratio, percentage, visual or other value indicating the level of activity Quantitative and qualitative judgments in the sense. Assessment can be direct or indirect.

As used herein, "disease or disorder" means a pathological condition in an organism caused by a cause or condition including, but not limited to, infections, acquired conditions, and genetic conditions and characterized by identifiable symptoms.

As used herein, "treating" an individual suffering from a disease or condition means that the individual's symptoms are partially or completely relieved or remain static following treatment. Treatment therefore encompasses prevention, treatment and/or cure. Prevention means preventing underlying disease and/or preventing worsening of symptoms or progression of disease. Treatment also encompasses any medical use of any antibody or antigen-binding fragment or composition thereof provided herein.

As used herein, treating means ameliorating the symptoms or manifestations of a disease, disorder or condition.

As used herein, "prevention" or "prophylaxis" refers to methods of reducing the risk of developing a disease or condition. Preventing disease means reducing the risk of developing disease.

As used herein, "pharmaceutically effective agent" includes any therapeutic or bioactive agent, including but not limited to, for example, anesthetics, vasoconstrictors, dispersants and conventional therapeutic drugs, including small molecule drugs and therapeutics protein.

As used herein, "therapeutic effect" means an effect resulting from treating an individual that alters, typically ameliorates, or ameliorates the symptoms of a disease or condition or cures a disease or condition.

As used herein, "therapeutically effective amount" or "therapeutically effective dose" means an amount of an agent, compound, substance or composition containing at least a sufficient amount of the compound to produce a therapeutic effect upon administration to an individual . Therefore, it is the amount required to prevent, cure, ameliorate, arrest or partially arrest the symptoms of a disease or condition.

As used herein, "therapeutic efficacy" refers to the ability of an agent, compound, substance, or composition containing a compound to produce a therapeutic effect in an individual to whom the agent, compound, substance, or composition containing the compound is administered.

As used herein, "prophylactically effective amount" or "prophylactically effective dose" means an agent, compound, substance or composition containing a compound that will have the intended prophylactic effect when administered to an individual. For example, preventing or delaying the onset or recurrence of a disease or symptoms, reducing the possibility of the onset or recurrence of a disease or symptoms, or reducing the incidence of viral infection. Complete prophylaxis does not necessarily occur with the administration of a single dose and may occur only after a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.

As used herein, amelioration of symptoms of a particular disease or condition by treatment, such as by administration of a pharmaceutical composition or other therapeutic agent, means any alleviation of symptoms attributable to or associated with the administration of a composition or therapeutic agent, Whether permanent or temporary, lasting or fleeting.

As used herein, "prodrug" refers to a precursor or derivative form of a pharmaceutically active substance that is less cytotoxic to tumor cells than the parent drug and can be enzymatically activated or converted into a more active form. The parent form of (Eds.), pp. 247-267, Humana Press, 1985).

As used herein, "anti-cancer agent" refers to any agent that is destructive or toxic to malignant cells and tissues. For example, anti-cancer agents include agents that kill cancer cells or otherwise inhibit or weaken the growth of tumors or cancer cells. Exemplary anti-cancer agents are chemotherapeutic agents.

As used herein, "anti-angiogenic agent" or "angiogenesis inhibitor" is a compound that blocks or interferes with the production of blood vessels.

As used herein, a TNF-related or TNF-mediated disease refers to a disease, condition, or disorder in which TNFR1 or TNFR1 signaling contributes to the cause; including diseases, conditions, or disorders in which inhibition of TNFR1 signaling ameliorates symptoms of the disease, condition, or disorder and disease conditions.

As used herein, "TNFR2 agonist" or "anti-TNFR2 agonist" refers to initiating, promoting or enhancing the activation of TNFR2 and/or enhancing one or more signals mediated by TNFR2 Compounds of the transduction pathway include small molecules and TNFR2 antibodies or antigen-binding fragments thereof, as well as other polypeptides. For example, TNFR2 agonists can promote or enhance the proliferation of Treg cell populations. TNFR2 agonists can promote or enhance TNFR2 activation by binding to TNFR2, for example, to induce conformational changes that render the receptor biologically active. For example, TNFR2 agonists can nucleate TNFR2 trimerization in a manner similar to or mimic the interaction between TNFR2 and its cognate ligand TNF (TNFα), thereby inducing TNFR2-mediated signaling. . TNFR2 agonists can also induce the proliferation of CD4 ⁺ , CD25 ⁺ , and FOXP3 ⁺ Treg cells. TNFR2 agonists can also suppress cytotoxic T lymphocytes (e.g., CD8 ⁺ T cells), for example, by activating immune regulatory Treg cells or by directly binding to TNFR2 on the surface of autoreactive cytotoxic T cells and inducing apoptosis. of proliferation. TNFR2 agonist antibodies or fragments thereof for use in the methods herein can specifically bind to TNFR2, and are generally specific enough that they do not specifically bind to tumor necrosis factor receptor (TNFR). family member, another receptor such as TNFR1.

As used herein, a TNFR2 selective agonist is a TNFR2 agonist that does not produce, or does not produce substantially TNFR1 signaling activity.

As used herein, a Treg amplicon is a molecule, including small molecules and peptides, that increases regulatory T cells (Treg cells or Tregs), an immunosuppressive subset of T cells that possess immunosuppressive properties through the production of interleukins .

As used herein, the terms "pan-growth factor trap construct", "pan-EGFR ligand trap construct", "growth factor trap construct" (growth factor trap)", "multi-specific growth factor trap construct (multi-specific growth factor trap construct)", "bi-specific growth factor trap construct (bi-specific growth factor trap construct)", " "EGFR ligand trap construct", "pan-HER ligand trap construct", "pan-HER therapeutic" , "EGFR ligand trap construct", "HER ligand trap construct" and "growth factor trap construct" are used interchangeably to refer to the regulation of two or more Human epidermal growth factor receptor (EGFR), also known as HER or ErbB receptor, is an active panning cell surface receptor molecule, including peptide-based compounds. In general, panning growth factor capture agents target at least two different HER receptors, such as via ligand binding and/or interaction with the receptors.

As used herein, "extracellular domain" or "ECD" is the portion of a cell surface receptor that is present on the surface of the receptor and includes the ligand binding site. For the purposes herein, reference to an "ECD polypeptide" includes any molecule or portion thereof that contains ECD, so long as the ECD polypeptide does not contain another domain of the cognate receptor (e.g., a transmembrane domain, a protein kinase domain, or other domain) Any relevant continuous sequence will suffice.

As used herein, "knobs into holes" or "knobs-in-holes" (KIH) refers to a multimerization domain, such as an immunoglobulin Fc domain, that is engineered to Steric interactions between and/or within such domains promote stabilizing interactions and heterodimers (or heteromultimers) compared to homodimers (or homomultimers) from monomer mixtures. body) formed. This can be achieved, for example, by constructing pestles or protrusions and mortars or pockets in the complementary multimerization domain. Knobs can be constructed by replacing small amino acid side chains from the interface of the first multimerization domain polypeptide (e.g., the first Fc monomer) with large side chains (e.g., tyrosine or tryptophan) ”. Optionally produced at the interface of a second complementary multimerized polypeptide (e.g., a second Fc monomer) by replacing a large amino acid side chain with a small amino acid side chain (e.g., alanine or threonine). A complementary "mortar" of the same or similar size as the pestle.

As used herein, "tethering" refers to an interaction between two domains of a receptor monomer in which the monomer exists in a configuration that renders it less readily available for interaction. For example, subdomain II in HER1, HER3, and HER4 can interact with subdomain IV to form a tethered, inactive structure. When in the tethered state, the receptor or isomer thereof is not readily available or available for dimerization and/or ligand binding. The monomeric forms of ECD of HER1, HER3, and HER4 exist in a tethered form and exhibit lower ligand affinity than the untethered form. HER2 lacking certain residues in subdomain IV exists in an untethered form and is available for dimerization with HER1, HER3 and HER4. When the ligand binds to the tethered (monomeric) form, the tethered interaction is released and the ECD (or receptor) assumes a configuration available for dimerization involving domain II of the two ECDs. interactions between.

As used herein, HER (ErbB)-related disease, HER-associated disease, or HER-mediated disease is any disease in which the epidermal growth factor receptor (HER) and/or ligands are implicated in some aspect of its etiology, pathological development, or symptoms thereof. Disease, condition or disorder. Participation includes, for example, the expression, overexpression or activity of a HER family member or ligand. Diseases include, but are not limited to, proliferative diseases, including cancers such as, but not limited to, gliomas and pancreatic, gastric, head and neck, cervical, lung, colorectal, endometrial, prostate, esophageal, ovarian cancer, uterine cancer, bladder cancer or breast cancer. Other conditions include conditions involving cell proliferation and/or migration, including conditions involving pathological inflammation and/or autoimmune responses, such as rheumatoid arthritis (RA); non-malignant hyperproliferative diseases; ocular conditions ;Skin conditions (such as psoriasis); Conditions resulting from proliferation and/or migration of smooth muscle cells, such as stenosis (including restenosis), atherosclerosis, muscle thickening of the bladder, heart or other muscles, or endometriosis .

As used herein, the term "subject" refers to an animal, including mammals, such as humans.

As used herein, "patient" refers to a human individual.

As used herein, "animal" includes any animal, such as, but not limited to, primates, including humans, gorillas, and monkeys; rodents, such as mice and rats; poultry, such as chickens; ruminants, such as Goats, cattle, deer and sheep; pigs; and other animals. Non-human animals do not include animals covered by human actions. The polypeptides provided herein are derived from any source, animal, plant, prokaryotic and fungal. Most polypeptides are of animal origin, including mammalian origin, and generally for medical use, are human or humanized.

As used herein, "composition" refers to any mixture. It can be a solution, suspension, liquid, powder, paste, aqueous solution, non-aqueous solution or any combination thereof.

As used herein, "stabilizing agent" refers to a compound added to a formulation to protect an antibody or conjugate, such as under the conditions of storage or use (eg, temperature) of the formulation herein. Thus, agents that prevent protein degradation from other components in the composition are included. Exemplary such agents are amino acids, amino acid derivatives, amines, sugars, polyols, salts and buffers, surfactants, inhibitors or matrices and other agents as described herein.

As used herein, "combination" means any combination between or among two or more items. A combination may be two or more separate items, such as two compositions or two collections, a mixture thereof, such as a single mixture of two or more items, or any variation thereof. The elements of a combination are generally functionally related or associated, such as elements used in a method.

As used herein, "combination therapy" refers to the administration of two or more different therapies, such as an anti-TNFR construct provided herein or such as an antibody or antigen-binding fragment thereof, and one or more therapeutic agents or Other treatments, such as radiation and surgery. Multiple therapeutic agents can be provided and administered separately, sequentially, intermittently, simultaneously, or as a single composition.

As used herein, a "kit" is a packaged combination that may include other components, such as additional reagents and Instructions for using the combination or its components.

As used herein, "unit dosage form" refers to physically discrete units suitable for use in individual humans and animals and packaged individually, as is known in the art.

As used herein, "single dosage formulation" refers to a formulation for direct administration.

As used herein, "multi-dose formulation" refers to a formulation that contains multiple doses of a therapeutic agent and can be administered directly to provide several single doses of the therapeutic agent. Doses may be administered over the course of minutes, hours, weeks, days, or months. Multiple dose formulations may allow for dose adjustment, combined dose and/or split dose. Because multi-dose formulations are used over time, they typically contain one or more preservatives to prevent microbial growth.

As used herein, an "article of manufacture" is a product that is prepared and sold. As used throughout this application, this term is intended to encompass any of the compositions provided herein for inclusion in a packaged article or for use in packaging.

As used herein, "fluid" refers to any composition that can flow. Fluids thus encompass compositions in the form of semisolids, pastes, solutions, aqueous mixtures, gels, lotions, creams, and other such compositions.

As used herein, an isolated or purified polypeptide or protein (e.g., an isolated antibody or antigen-binding fragment thereof) or a biologically active portion thereof (e.g., an isolated antigen-binding fragment) is substantially free of cellular material or cells from which the protein was derived. or other contaminating proteins of the tissue, or are substantially free of chemical precursors or other chemicals when chemically synthesized. If the preparation is elucidated by standard analytical methods (such as thin layer chromatography (TLC), gel electrophoresis, and high performance liquid chromatography) as used by those of ordinary skill in the art to assess such purity, It can be determined that the substance appears to be free of readily detectable impurities, as determined by chromatography (HPLC), or is sufficiently pure that further purification will not detectably alter the physical and chemical properties, such as the enzymatic and biological activity of the substance. and other preparations are substantially pure. Methods for purifying compounds to produce substantially chemically pure compounds are known to those of ordinary skill in the art. However, substantially chemically pure compounds may be mixtures of stereoisomers. In such cases, further purification may increase the specific activity of the compound.

As used herein, "cellular extract" or "lysate" refers to a preparation or isolate made from lysed or disrupted cells.

As used herein, "control" means a sample that is substantially the same as the test sample, except that it is not manipulated by the test parameters or, if it is a plasma sample, it may be obtained from a sample that is not affected by the condition of concern. Normal volunteers. Controls can also be internal controls.

As used herein, the singular forms "a/an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a polypeptide containing an "immunoglobulin domain" includes polypeptides having one or more immunoglobulin domains.

As used herein, the term "or" is used to mean "and/or" unless it is expressly indicated that only alternatives are intended or alternatives are mutually exclusive.

As used herein, ranges and amounts may be expressed "about" a specific value or range. "About" also includes precise amounts. Therefore, "about 5 amino acids" means "about 5 amino acids" and "5 amino acids." For specific parameters, it is approximately the range of experimental error or, for specific parameters, it is the range acceptable to those with ordinary knowledge in the technical field.

As used herein, "optional/optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes circumstances in which the event or circumstance occurs and circumstances in which it does not occur. For example, optionally mutating a portion means that the portion is mutated or non-mutated.

Unless otherwise indicated, as used herein, abbreviations for any protecting groups, amino acids, and other compounds are consistent with common usage, accepted abbreviations, or the IUPAC-IUB Biochemical Nomenclature Committee (see Biochem . (1972) 11(9) ):1726-1732).

For clarity of disclosure, and not by way of limitation, the embodiments are divided into subsequent subsections. B. Overview of constructs and methods

Autoimmune diseases occur when the body's immune system attacks itself. The resulting inflammation and tissue destruction is triggered by an inflammatory hormone called tumor necrosis factor (TNF). There are more than 100 types of autoimmune diseases; overall, approximately 75% of patients with autoimmune diseases are women. Drugs previously used for autoimmune diseases have had adverse side effects, including infections, heart problems and other diseases and conditions.

TNF interacts with immune cells through two receptors. TNFR1 is overactivated in autoimmune diseases, while TNFR2 suppresses autoimmune diseases but is weakened when TNFR1 is overactivated. TNF blockers, such as infliximab (sold as Remicade®), adalimumab (sold as Humira®), and etanercept (sold as Enbrel®), block TNFR1 and TNFR2, causing unwanted side effects. The construct provided in this article solves this problem. The constructs provided herein turn off only TNFR1, allowing for increased TNFR2 activity, thereby not only treating autoimmune disease symptoms, but providing improved treatment with reduced or no adverse side effects because TNFR2 activity is not blocked. This article provides various constructs that solve the problems of prior art TNF blockers. The types of constructs identified by activity and detailed and provided herein are summarized in the table below: Type of structure disease to be treated effect TNFR1 antagonist Autoimmune diseases and acute inflammation Specifically blocks TNFR1; preserves TNFR2 growth factor capture agent Rheumatoid arthritis and cancer Captures 9 growth factors from the EGF family (EGFR and HER3; and dimerization-dependent HER2) TNFR2 antagonist cancer checkpoint inhibitors Tumor suppression suppresses Treg function, thereby increasing active immunity TNFR2 agonist Inflammation and fibrosis Induces Treg proliferation to reduce inflammation

Constructs are provided for the treatment of TNF-mediated diseases, disorders and conditions, or in which TNF plays a role in the cause or in which interfering with TNFRl signaling has an ameliorative effect. For example, TNFR1 antagonists may be used to treat a variety of conditions, including autoimmune disorders, as well as diseases and conditions such as endometriosis, brain fog such as from chemotherapy and COVID, Alzheimer's disease, such as Acute inflammation caused by influenza virus infection and SARS-CoV2, which leads to long-term or permanent damage to the lungs, kidneys and other tissues. Due to previous adverse effects and attendant safety concerns, TNF blockers cannot be used in most of these indications. The TNFR1 antagonist constructs provided herein can be used. Such constructs as described herein are monovalent in that they only inhibit TNFR1 without causing receptor aggregation, are specific, non-immunogenic, and have a half-life of at least about 3-4 weeks, allowing approximately Monthly dosing.

Thus, TNFR1 antagonist constructs, TNFR2 agonist constructs, and multispecific, such as bispecific constructs, including TNFR1 antagonist and TNFR2 agonist activities are provided. The construct includes at least one moiety that specifically interacts with TNFR1 or TNFR2, and another moiety that typically directly or indirectly modulates the interaction or provides pharmacological (pharmacodynamic or pharmacokinetic or both) properties to the construct. Thus, a construct as provided herein includes at least two moieties: a binding moiety that interacts with TNFR1 or TNFR2, and a second moiety that modulates or alters the pharmacological properties or activity of the construct or binding moiety.

Among the constructs provided herein are constructs that are antagonists of TNFR1 activity. TNFR1 antagonist constructs contain moieties that bind or interact with TNFR1 and inhibit TNFR1-mediated signaling, and confer additional properties (such as prolonged serum half-life, elimination of ADCC and/or CDC activity, and modulation of interactions with specific receptors) The second part of. TNFR1 antagonists and constructs also include modifications to render them non- or reduced immunogenic, particularly in humans, and may also include modifications to eliminate or reduce binding to pre-existing antibodies.

TNFR1 antagonist constructs are selected to specifically bind to TNFR1 and have minimal or no binding to TNFR2, or no TNFR2 antagonist activity. Therefore, the construct only regulates TNFR1. In some embodiments, a TNFRl antagonist construct is also selected to have or be linked to a second domain or portion having TNFR2 agonist activity. TNFR1 constructs, including those designed or selected to bind to TNFR1 with an affinity such as _Kd < 50 nM or < 10 nM or < 5 nM and especially with a higher affinity such as a K _d < 1 nM or < 0.1 nM or higher affinity ) interacts with and/or effectively inhibits TNFR1 signaling (e.g., IC ₅₀ 50 nM or < 10 nM or < 5 nM or < 3 nM or 1 nM or < 0.5 nM).

Multispecific, such as bispecific constructs containing a TNFRl antagonist moiety linked directly or via a linker to a TNFR2 agonist moiety are also provided. Linkers provide beneficial properties to the molecule, such as increased serum half-life, increased stability, appropriate three-dimensional structure and flexibility, and improved pharmacological properties. These constructs address issues associated with the administration of other therapies, such as anti-TNF therapies ("TNF blockers" (examples include etanercept, adalimumab ( ^Humira® ), infliximab)), because this Such constructs increase the specificity of TNFR1 inflammation blocking and retain or expand the function of TNFR2, a natural immunosuppressant, at least in part by upregulating immunosuppressive Tregs and inducing protective and anti-inflammatory signaling pathways. In addition, TNF Blockade leading to inhibition of TNFR2 function also reduces T cell-induced monocyte activation, leading to an increased likelihood of opportunistic infections (see, e.g., Rossel et al. (2007) J. Immunol. 179:4239-48).

There are many differences between the activity of the exemplary TNFR1 antagonist constructs provided herein and existing approved TNF blockers: TNF blockers, such as etanercept, adalimumab, and infliximab, for which TNFR1 is not specific. Other blockers, such as IL6, IL17, and IL23, block only part of their own interleukin cascade, but not all of it. Existing TNF blockers have the same mechanism of action on TNFR1 and TNFR2, thus blocking their activity. JAK inhibitors cause similar problems; they have both inflammatory and anti-inflammatory activities. For example, the inflammatory cytokine Il1 is not blocked by JAK inhibitors, the inflammatory cytokine IL6 is blocked by JAK inhibitors (a second-line use in rheumatoid arthritis treatment), and the anti-inflammatory IL10 is not blocked by JAK inhibitors agent blocking. In contrast, the constructs provided herein combine the effectiveness of TNFR1 and TNF inhibitor therapies with the benefits of TNFR2 agonists to eliminate or reduce the adverse effects of anti-TNFR1/anti-TNF therapies and also contribute additional treatment modality advantages. , including upregulating immunosuppressive Tregs and inducing protective and anti-inflammatory signaling pathways.

TNFR1 antagonist constructs contain one or more TNFR1 inhibitors, one or more linkers, and one or more activity modulators. For example, the structure of the TNFR1 antagonist construct provided herein can be represented by Formula 1: (TNFR1 inhibitor) _n - linker _p - (activity modulator) _q , Formula 1a, or (activity modulator) _q - linker _p - (TNFR1 inhibitor) _n , formula 1b, where: each of n and q is an integer, and each is independently 1, 2 or 3; p is 0, 1, 2 or 3; and the activity modulator A moiety that increases the serum half-life of a TNFR1 inhibitor, such as a polypeptide, such as albumin, or an Fc modified to have reduced or no ADCC activity; and a TNFR1 inhibitor that binds to TNFR1 and inhibits its activity, such as signaling activity Molecules, such as peptides or small drug molecules. The active modulator is not an antibody to human serum albumin or an unmodified single Fc. Modulators of activity include modified Fc regions, such as Fc, Fc dimers and other antibody domains modified to eliminate ADCC and/or CDC activity. Linkers include chemical linkers, and polypeptides such as GS linkers, and hinge regions such as those from antibodies, such that constructs include chemical conjugates, fusion proteins, and combinations of both.

Multispecific constructs are also provided. The structure of the multispecific, such as bispecific constructs provided herein is represented by the following formula (Formula 2): (TNFR1 inhibitor) _n ― (activity modulator) _r1 ― (linker (L) _p ― (activity modulator) ) _r2 - (TNFR2 antagonist) _q , where n = 1, 2 or 3, p = 1, 2 or 3, q = 0, 1 or 2, and each of r1 and r2 is independently 0, 1 Or 2. As with the construct of formula 1, the order of the components can vary and additional linkers may be present if desired. The construct may include additional linkers if desired to impart properties such as flexibility. Each linker may contain a plurality of Components. Formula 2 may also include activity modulators instead of or in addition to linkers. Activity modulators and linkers include Fc or Fc with a hinge region, or Fc with a GS linker, or components of Other combinations. The Fc in these constructs includes the unmodified Fc region; the linkers are as described above and detailed below.

Also provided are TNFR2 agonist constructs having Formula 3: (TNFR2 antagonist) _n - linker _p - (activity modulator) _q , Formula 3a, or (activity modulator) _q - linker _p - (TNFR2 antagonist ) _n , Formula 3b, wherein n, p, and q are as described for Formula 1, and the linker and activity modulator are as described for Formula 1.

The components of Formulas 1-3 (discussed in detail in the following sections) can be polypeptides or other molecules, such as small drugs that specifically bind or interact with the targeted receptor. Each component of the constructs/molecules provided herein is described sequentially in the following sections.

The properties of each component of the constructs provided herein are discussed in detail in the following sections. Therefore, the components of the construct include, but are not limited to, the following components, which are discussed in detail in subsequent chapters: 1. TNFR1 antagonist 2. TNFR2 agonist 3. Connector a. Glycine-serine linker b. Hinge area c. Chemical linker 4. Activity regulator a. Modified Fc b. Polypeptides and other moieties that confer improved or altered pharmacological properties, such as increased serum half-life, resistance to degradation by endogenous proteases, and other such properties.

Other constructs are also available, detailed in later chapters.

Constructs for use in methods of treating diseases, disorders, and conditions, wherein TNF is a pathological modulator of the disease, disorder, or condition, such that inhibition of TNFR1 signaling is reduced or inhibited, and/or wherein inhibition of TNF or TNFR1 signaling inhibits the disease, The disease or condition may cause the resolution of the disease, disease or condition, and/or inhibit the improvement of the symptoms of the disease, disease and/or condition. Such diseases, conditions and disorders, including inflammatory diseases, including autoimmune diseases, are discussed in subsequent chapters.

Pharmaceutical compositions for these methods and uses are also provided, as well as nucleic acids and vectors for generating constructs including polypeptides and constructs as fusion proteins. The following sections describe diseases, disorders, and conditions, TNFR1/TNFR2 activity and its role in diseases, disorders, and conditions, existing treatments for diseases, disorders, and conditions, constructs provided herein, and components thereof, resulting in such constructs Methods, pharmaceutical compositions and treatment methods containing such constructs and/or encoding nucleic acids. C. Tumor necrosis factor ( TNF ) and chronic inflammatory and autoimmune diseases and conditions

This section describes the role of tumor necrosis factor (TNF) and/or its receptors in inflammatory and autoimmune diseases, details of exemplified diseases and issues with existing therapies, and demonstrates how the constructs provided herein Solve these problems. 1. Tumor necrosis factor ( TNF )

Tumor necrosis factor (TNF; see, e.g., SEQ ID NO: 1; also known as TNF alpha, TNF-alpha, or TNF alpha) is a pleiotropic pro-inflammatory cytokine associated with inflammatory and immunomodulatory activities, including modulation of tumorigenesis/ Cancer, host defense against pathogenic infection, apoptosis, autoimmunity and septic shock, and plays an important role in the coordination of innate and adaptive immune responses and the organogenesis of lymphoid organs. In humans, TNF is mainly produced by macrophages, but can also be produced by monocytes, dendritic cells (DC), B cells, T cells, fibroblasts and other cell types. It is produced as a homotrimeric membrane-bound protein containing 233 amino acids (26 kDa), which is cleaved by the protease TACE (TNFα converting enzyme; also known as ADA17) to release a 157 amino acid (17 kDa ) of soluble TNF; membrane-bound and soluble forms of TNF are biologically active. Transmembrane human TNF contains 233 amino acids and contains a cytoplasmic domain corresponding to residues 1-35, a transmembrane domain corresponding to residues 36-56, and an extracellular domain corresponding to residues 57-233, refer to SEQ ID NO: 1. The soluble form of TNF corresponds to amino acid residues 77-233, as set forth in SEQ ID NO: 1 (for the amino acid residue sequence of soluble TNF, see SEQ ID NO: 2).

Uncontrolled production of TNF is associated with a number of inflammatory and autoimmune diseases and conditions, including, for example, septic shock, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis and inflammation Intestinal enteropathy (IBD). Excessive expression of TNF is also associated with neurodegenerative diseases and conditions, such as Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis. In addition, TNF promotes osteoclastogenesis, and excessive production of TNF is associated with bone loss. In rheumatoid arthritis (RA), TNF is overexpressed in synovial fluid and synovium, and expression of the TNF receptor (TNFR) is upregulated in the synovium. For example, overexpression of human TNF in mice causes spontaneous RA-like lesions in joints, with the formation of proliferative synovium and destruction of cartilage and bone (see e.g. Blüml et al. ( 2010) Arthritis & Rheumatism 62(6) ; _ _ ) International Immunology 24(5):275-281; Dong et al. (2016) Proc. Natl. Acad. Sci. USA 113(43):12304-12309).

As discussed further below, TNF signals through two high-affinity specific receptors, TNFR1 and TNFR2; TNFR1 is associated with adverse inflammatory processes, while TNFR2 is associated with beneficial immunomodulatory processes. Membrane-bound TNF has been shown to primarily activate TNFR2, whereas soluble TNF primarily activates TNFR1 (Blüml et al. (2010) Arthritis & Rheumatism 62(6):1608-1619). Soluble TNF (solTNF; corresponding to residues 77-233 of SEQ ID NO: 1; see also the sequence set forth in SEQ ID NO: 2), which is involved in paracrine signaling (mainly via TNFR1), is associated with chronic inflammation and The transmembrane TNF (tmTNF) lineage, which acts via cell-to-cell contact to induce juxtocrine signaling (primarily via TNFR2), is associated with resolution of inflammation and induction against pathogens such as Listeria monocytogenes and tuberculosis clade Immunity related to Mycobacterium tuberculosis (Zalevsky et al. (2007) J. Immunol. 179:1872-1883). Therefore, TNF signaling through TNFR1 and TNFR2 achieves different results depending on the receptor type.

Due to the correlation between excessive expression of TNF and the development of inflammatory and autoimmune diseases and conditions, blockade of TNF has been used to treat a variety of such diseases and conditions, including but not limited to rheumatoid arthritis (RA), psoriasis , psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis (JIA), and inflammatory bowel disease (IBD; such as Crohn's disease, ulcerative colitis). The use of TNF blockers, which block TNF and impede signaling through TNFR1 and TNFR2, is associated with an increased risk of serious infections such as tuberculosis and listeriosis due to immune suppression. TNF blockers not only block adverse inflammatory signaling via TNFR1 but also block beneficial immunomodulatory signaling via TNFR2. Therefore, the use of TNF blockers is limited especially in the setting of chronic diseases/conditions requiring long-term administration, such as arthritis or IBD. Approximately one-third of RA patients do not respond to anti-TNF therapy, or the benefits of treatment are not sustained. Therefore, there is a need for therapies with improved efficacy and safety, particularly therapies that block the inflammatory effects of TNFR1 signaling but maintain or enhance the beneficial anti-inflammatory effects of TNFR2 signaling. This article provides such treatments. 2. Tumor necrosis factor receptor ( TNFR )

Homotrimers of TNF bind to two specific high-affinity homotrimeric receptors, TNFR1 (TNF receptor type 1; also known as TNFRI, p55, p60, CD120a, TNF receptor superfamily member 1A, and TNFRSF1A) and and signaling through TNFR2 (TNF receptor type 2; also known as TNFRII, p75, p80, CD120b, TNF receptor superfamily member 1B, and TNFRSF1B). TNFR1 is expressed by all nucleated cell types; TNFR2 expression is limited to immune cells (such as monocytes, macrophages, activated T cells, regulatory T cells (Treg), B cells and natural killer (NK) cells), endothelial cells, Specific central nervous system (CNS) cells and specific heart cells. TNFR2 expression on Tregs is induced upon T cell receptor activation.

In vivo, after excretion from the cell surface, TNFR1 and TNFR2 exist as membrane-bound receptors and as soluble "decoy" (ie, non-signaling) receptors. Soluble TNF binds preferentially/selectively to TNFR1; however binding of membrane-bound and soluble forms of TNF activates TNFR1. The main ligand of TNFR2 is membrane-bound TNF. Soluble TNF does not fully activate TNFR2, but the soluble form of TNFR2 (after TNFR2 is excreted) has a high binding affinity for TNF, allowing its clearance and inhibition of TNF binding to membrane-bound signaling receptors, which contributes to the anti-inflammatory effects of TNFR2. Membrane-bound TNFR2 binds TNF with rapid association and dissociation kinetics, allowing TNFR2 to concentrate TNF on the cell surface and deliver the ligand to TNFR1, thereby mediating TNFR1 signaling. Each of TNFR1 and TNFR2 contains extracellular transmembrane and cytoplasmic domains. The extracellular domains of TNFR1 and TNFR2 contain four cysteine-rich domains (CRD) required for ligand binding. The intracellular domains of TNFR1 and TNFR2 initiate different signaling cascades in response to TNF ligand binding and mediate different effector functions.

Abnormal TNFR signaling is associated with several autoimmune diseases, and administration of TNF may be used as a therapeutic strategy for such diseases. For example, low-dose TNF selectively destroys autoreactive T cells in blood samples from patients with type I diabetes and scleroderma, and disrupts autoreactivity in animal models of Sjogren's syndrome. T cells. Administration of TNF can cause systemic toxicity, for example in cancer patients with high TNF levels. As described herein, toxicity results from the ubiquitous cellular expression of TNFR1; as described herein, agonist TNFR2 is a safer treatment option than administration of TNF due to its more restricted cellular expression. Promoting TNF signaling via TNFR2 can be achieved by administering TNFR1 antagonists (see, eg, Faustman et al. (2013) Front. Immunol. 4:478). a.TNFR1

Human TNFR1 (see SEQ ID NO: 3) is the major inflammatory receptor and is responsible for the pro-inflammatory cytotoxic and apoptotic effects of TNF. Human TNFR1 is a homotrimeric receptor, and its binding to TNF induces a pro-inflammatory response (for a description of TNFR1 signaling, see, e.g., Morton et al. (2019) Sci Signal. 12(592):eaaw2418). TNFR1 contains 455 amino acid residues; residues 1-29 correspond to the signal peptide, residues 30-211 correspond to the extracellular domain, residues 212-232 correspond to the transmembrane domain, and residues 233-455 correspond to the cytoplasmic domain area. Within the extracellular domain, TNFR1 contains cysteine-rich domains (CRD) 1-4, which correspond to amino acid residues 43-82, 83-125, 126-166 and 167- of SEQ ID NO: 3 respectively. 196. CRD 2 and 3 contact and bind TNF and CRD1, specifically with respect to amino acid residues 30-82 of SEQ ID NO: 3, forming a pre-ligand binding assembly domain (PLAD), a Haemophilic interaction motifs required for ligand binding and receptor function. The cytoplasmic domain contains a death domain (corresponding to residues 356-441 of SEQ ID NO: 3), which binds to the TNFR1-associated death domain (TRADD) and the Fas-associated death domain (Fas-associated death domain) after TNF binds to TNFR1 , FADD), a signaling pathway that produces activated apoptotic proteases and induces apoptosis. The binding of TNF to TNFR1 is also through mitogen-activated protein kinase (MAPK; such as p38, JNK, ERK) and the nuclear factor kappa-light-chain-enhancer of activated B cells (nuclear factor kappa-light-chain- enhancer, NF-κB) signaling pathway initiates the pro-inflammatory cascade. TNFR1 plays a role in lymphoid organogenesis and immune responses to pathogens, and is a major receptor associated with host antiviral defense mechanisms. It has been shown that mycobacterial inhibition is dependent on TNF-derived signaling and that patients treated with TNF blockers can suffer endogenous reactivation of latent tuberculosis.

TNFR1, which is mainly involved in pro-inflammatory signaling, is the driving force behind the development of arthritis. For example, genetic knockout of TNFR1 in mice and silencing of TNFR1 by RNA interference resulted in attenuation of collagen-induced arthritis (CIA), an animal model of arthritis. Prevent arthritis in TNFR1-deficient mice that overexpress TNF, and reintroduce TNFR1 on mesenchymal cells to cause TNF-dependent arthritis. In addition, TNFR1 promotes the generation of osteoclasts, which cause localized bone destruction, and it has been shown that deficiency of TNFR1 on hematopoietic cells attenuates bone destruction in models of erosive arthritis. TNFR1 has also been associated with cardiotoxic effects in TNF-induced heart failure and myocardial infarction models, and has been shown to promote neurodegeneration in animal models of retinal ischemia (see e.g. Schmidt et al. (2013) Arthritis & Rheumatism 65(9) ):2262-2273; Goodall et al. (2015) PLoS ONE 10(9):e0137065; McCann et al. (2014) Arthritis & Rheumatology 66(10):2728-2738; Ruspi et al. (2014) Cellular Signaling 26:683 -690; Faustman and Davis (2013) Front. Immunol. 4:478; Blüml et al. ( 2012) International Immunology 24(5):275-281; Dong et al. (2016) Proc. Natl. Acad. Sci. USA 113 (43:12304-12309). b.TNFR2

Human TNFR2 (see SEQ ID NO: 4) contains 461 amino acid residues; residues 1-22 correspond to the signal peptide, residues 23-257 correspond to the extracellular domain, and residues 258-287 correspond to the transmembrane domain, And residues 288-461 correspond to the cytoplasmic domain. Unlike TNFR1, TNFR2 lacks a death domain and has a TNF receptor-associated factor 2 (TRAF2) binding site. TNFR2 signaling via TRAF2 promotes cell survival and proliferation through NF-κB and activator protein 1 (AP1) activation, and is associated with PI3K-PKB/Akt-mediated repair and migration. As discussed elsewhere herein, TNF signaling through TNFR2 also promotes the expansion and activation of regulatory T cells (Tregs), which play an important role in curbing inflammatory and autoimmune diseases and conditions. TNFR2 signaling has been implicated in wound healing and repair and regeneration in models of myocardial infarction, and genetic deletion of TNFR2 in mouse models of erosive arthritis caused joint inflammation and bone destruction.

TNFR2, which is mainly involved in anti-inflammatory signaling, is related to nerve, heart, and bone protection. TNFR2 exhibits anti-inflammatory and protective effects; it has been reported, for example, in experimental autoimmune encephalomyelitis (EAE), experimental colitis, heart failure/heart disease, myocardial infarction, inflammatory arthritis, demyelination, and These effects have been demonstrated in neurodegenerative diseases and infectious diseases. For example, activation of TNFR2 by TNF inhibits epilepsy, attenuates cognitive dysfunction after brain injury, promotes survival in mice after myocardial infarction, prevents myocardial ischemia/reperfusion injury, and reduces remodeling and hypertrophy after heart failure. TNFR2 agonism is also associated with pancreatic regeneration, remyelination, survival of neuronal subtypes, and stem cell proliferation. TNFR2 agonism selectively destroys autoreactive T cells but not blood samples from patients with type 1 diabetes, multiple sclerosis, Graves' disease, and Sughren's syndrome of healthy cells. In animal models of type I diabetes, low-dose TNF was used to eliminate autoreactive T cells and allow pancreatic tissue regeneration. TNF signaling via TNFR2 has been shown to induce the regeneration of oligodendrocyte precursors in myelin and, therefore, may be used to treat demyelinating disorders such as multiple sclerosis (MS). TNFR2 has also been shown to promote neuroprotection in animal models of retinal ischemia.

TNFR2 also regulates osteoclastogenesis. Osteoclasts are a type of bone cell that breaks down bone tissue; regulation of osteoclast production is important for maintaining bone quality and preventing joint inflammation and erosive damage. Mice lacking TNFR2 display enhanced osteoclastogenesis, worsening TNF-driven arthritis, and localized bone destruction. Lack of TNFR2 in animal models of erosive arthritis causes disease progression, and TNFR2-deficient mice that overexpress TNF develop worsening arthritis and joint destruction compared with control mice. Expression of TNFR2 on hematopoietic cells attenuates TNF-driven arthritis, whereas loss of TNFR2 on hematopoietic cells increases the recruitment of inflammatory cells to the synovium. In experimental colitis, lack of TNFR2 on CD4 ⁺ T cells accelerates disease onset and increases inflammation severity, whereas in experimental autoimmune encephalitis (EAE), symptoms are exacerbated in TNFR2-deficient mice (see e.g. Schmidt et al. ( 2013) Arthritis & Rheumatism 65(9):2262-2273; Goodall et al. (2015) PLoS ONE 10(9):e0137065; McCann et al. (2014) Arthritis & Rheumatology 66(10):2728-2738 ; Ruspi et al. (2014) Cellular Signaling 26:683-690; Faustman and Davis (2013) Front. Immunol. 4:478; Blüml et al. ( 2012) International Immunology 24(5):275-281; Dong et al. ( 2016) Proc. Natl. Acad. Sci. USA 113(43):12304-12309). Polymorphism in the TNFR2 gene is associated with a variety of autoimmune diseases, including RA, Crohn's disease, systemic lupus erythematosus, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, and scleroderma. ; Pleomorphism prevents the binding of TNF to TNFR2, which limits the activation of NF-кB and hinders the TNFR2 signaling pathway in Tregs (see, e.g., Yang et al. (2018) Front. Immunol. 9:784).

TNFR1 contains an intracellular death domain and can activate apoptosis and/or inflammatory pathways, while TNFR2 binds TRAF and can activate canonical and atypical NF-кB pathways to control cell survival and proliferation. In general, cells expressing TNFR2 also express TNFR1 at varying rates depending on cell type and function. Since TNFR1 signaling normally induces cell death and TNFR2 signaling usually induces cell survival, the ratio of their co-expression on cells shifts the balance toward apoptosis or cell survival. As discussed above and elsewhere herein, TNFR1 has been shown to be the primary TNF receptor involved in the pathogenesis of RA, while TNFR2 plays an immunomodulatory role. However, both receptors are involved in mediating the antiviral activity of TNF. For example, animal disease models show that TNFR1 is associated with inflammatory neurodegeneration, while TNFR2 is associated with neuroprotection.

have been tested in mouse models of NMDA-induced acute neurodegeneration by administering ATROSAB (antagonistic TNF receptor monospecific antibody), TNFR1-selective IgG1 antibody, or EHD2-scTNF _R2 (a agonist TNFR2-selective TNF mutant protein). (i.e., mutant protein)) confirms the selective inhibition of TNFR1 or the selective activation of TNFR2. EHD2-scTNF _R2 contains a covalently stabilized human TNFR2-selective single-chain TNF trimer in which the mutations D143N/A145R (residue numbering refer to soluble TNF as set forth in SEQ ID NO: 2, and respectively correspond to those in SEQ ID NO. D219N and A221R of NO: 1; these mutations eliminate affinity for TNFR1) are fused to the dimerization domain EHD2 derived from the heavy chain _CH2 domain of IgE, resulting in a disulfide-bonded dimer containing a hexameric TNF domain . In an in vivo mouse model, simultaneous injection of NMDA and ATROSAB or NMDA and EHD2-scTNF _R2 into the nucleus basalis magnocellularis resulted in significant but incomplete neuroprotective efficacy compared with controls. The incomplete nature of these responses has been attributed to the agonist activity of ATROSAB, a by-product of the bivalent antibody that induces abnormal receptor clustering and activation (Richter et al. (2013) PLoS One 8(8):e72156. Similarly, EHD2 - scTNFR2 is immunogenic in humans due to its multiple fusion partners, and immune responses to IgE fragments caused autoimmune reactions in toxicological studies (see e.g. Weeratna et al. (2016) Immun. Inflamm. Dis. 4(2):135-147). Therefore, improved TNFR1 antagonists and improved TNFR2 agonists are needed to address these limitations. 3. Regulatory T cells ( Treg ) and their role in the autoimmune microenvironment

Regulatory T cells (Treg cells or Tregs) are an immunosuppressive subpopulation of T cells that have immunosuppressive properties through the production of interleukins. They include transforming growth factor beta, interleukin-35 and interleukin-10. Inducing Treg function can suppress several pathologies. Induction can increase transplant success rates, curb allergies, and control responses to infectious diseases and autoimmune reactions (such as severe acute respiratory syndrome). Tregs suppress and/or downregulate the induction and proliferation of effector T cells (Teff), regulate the immune system, maintain immune homeostasis and tolerance to self-antigens, and can prevent autoimmune diseases and tissue destruction. Tregs were expressed among other markers, CD4, CTLA-4, CD25 (also known as IL-2 receptor alpha chain or IL2RA) and FOXP3 (transcription factor forkhead box P3), and were ten times more expressed than TNFR1. Density represents TNFR2. TNFR2 is expressed only by the Treg subpopulation, which is the largest suppressive subpopulation; this subpopulation contains CD4 ⁺ FoxP3 ⁺ Tregs expressing TNFR2. TNF promotes Treg cell proliferation, up-regulation of FoxP3 expression, and Treg cell inhibitory activity/function via TNFR2 signaling. The autoimmune microenvironment contains more autoreactive CD8 ⁺ effector T cells than immunosuppressive CD4 ⁺ Tregs, leading to tissue destruction. Therefore, preservation of TNFR2 function or enhancement of TNFR2 function, which expands Tregs and eliminates autoreactive T cells, restores immune balance (see Sharma et al. (2018) Front Immunol. 9:883). For these reasons and others discussed below, pharmacological maintenance of Treg function by selective inhibition of TNFR1, possibly together with TNFR2 stimulation (agonism), would ameliorate many acute and chronic inflammatory conditions (severe acute respiratory syndrome, Autoimmune diseases).

In addition to up-regulating the expression of TNFR2 on Tregs, TNF also up-regulates the expression of other costimulatory members of the TNF receptor superfamily (TNFRSF) on Treg surfaces, such as 4-1BB and OX40, thereby causing optimal activation of Tregs and Proliferate and cause the weakening of excessive inflammatory responses. Neutralization of TNF (blocking TNFR2) blocks Treg expansion in vivo (e.g. Hamano et al. (2011) Eur. J. Immunol. 41:2010-2020).

Compared with CD4 ⁺ FoxP3 ^- conventional T cells, CD4 ⁺ FoxP3 ⁺ Tregs constitutively express TNFR2, promoting Treg cell activation, expansion and survival. TNF promotes Treg activation and expansion via TNFR2 signaling (i.e., TNFR2 agonism), while TNFR2 antagonism causes Treg contraction. For example, TNFR2 agonism selectively kills autoreactive T cells and expands suppressor Tregs in humans with autoimmune diseases and in autoimmune animal models. TNFR2 signaling promotes Treg cell expansion and suppressive activity in murine models of experimental autoimmune encephalomyelitis (EAE; an animal model of inflammatory CNS demyelinating diseases such as multiple sclerosis) and diabetes, and by Tolerogenic dendritic cells induce human antigen-specific Treg cells. TNFR2-deficient Tregs have reduced ability to prevent experimental colitis in vivo, and TNFR2 is required for sustained FoxP3 expression on Tregs. Therefore, in order to maintain the phenotypic and functional stability of Tregs, it is indicated that TNFR2 is required for the in vivo immunosuppressive function of Tregs. (See, e.g., McCann et al. ( 2014) Arthritis & Rheumatology 66(10):2728-2738; Faustman and Davis (2013) Front. Immunol . 4:478; Schmidt et al. ( 2013) Arthritis & Rheumatism 65(9):2262 -2273; Vanamee et al. (2017) Trends in Molecular Medicine 23(11):P1037-P1046; Chen et al. ( 2013) J. Immunol. 190(3):1076-1084). In one study, antigen-specific Tregs generated in vitro were shown to curb disease and reduce joint inflammation and bone destruction in a well-established model of antigen-induced arthritis (AIA), in which mice treated with methylation Bovine serum albumin (mBSA) immunization to induce T cell-mediated tissue damage (see, e.g., Wright et al. ( 2009) Proc. Natl. Acad. Sci. USA 106(45):19078-19083). The use of Tregs in cell therapy is needed and holds promise due to manufacturing and other complications where conventional biotherapeutics offer Treg advantages.

As described and provided herein, TNFR2 and its expression by Tregs are required to curb inflammatory and autoimmune diseases and conditions. For example, Mycobacterium bovis BCG (bacillus Calmetter-Guerin, BCG) induces transient expansion of Tregs. In clinical trials, BCG triggered Treg production in patients with type I diabetes, thereby curbing the disease and temporarily restoring islet cell function, indicating the use of Treg and/or modulators that enhance Treg function to treat type I diabetes (see, e.g., Spence et al. (2016) Curr Diab Rep 16 ( 11 ) :110. doi :10.1007/s11892-016-0807-6).

Described and identified herein, modulation of Treg function represents a therapeutic approach for preventing or treating inflammatory and autoimmune diseases and conditions. However, Tregs only account for about 1-5% of the total CD4+ T cells in the blood. Its low value hinders its clinical use. The in vitro production of Tregs and/or their in vivo production are factors that limit their therapeutic use. For example, in vivo stimulation with IL-2, anti-CD3, or anti-CD28 is too toxic, whereas in vitro stimulation with these agents generates a heterogeneous CD4 ⁺ population that releases pro-inflammatory cytokines and has antagonistic properties. Alternative approaches have used TL1A-Ig, naturally occurring TNF receptor superfamily agonists, or TNFR2 monoclonal antibody agonists to expand Tregs in vivo and ex vivo, respectively. The TNFR2 agonist constructs and multispecific constructs provided herein can preserve and/or expand Treg populations in vivo without interfering with therapeutic activity against TNFR1 activity. As described and provided herein, selective inhibition of inflammatory TNFR1 activity while maintaining or increasing TNFR2-associated Treg suppressive activity is beneficial in the treatment of inflammatory and autoimmune diseases and conditions. Such diseases and conditions include, but are not limited to, RA, Type I diabetes, heart failure, and multiple sclerosis (see, eg, Goodall et al. (2015) PLoS ONE 10(9):e0137065).

Compared to the autoimmune microenvironment in which the expansion of TNFR2+ Tregs prevents tissue destruction, in the tumor microenvironment (TME), tumors infiltrate through massive immunosuppressive TNFR2 ⁺ Tregs to prevent tumor killing of CD8 ⁺ cytotoxicity The proliferation of T lymphocytes (cytotoxic T lymphocytes, CTL), also known as effector T cells (Teff), allows tumor growth. Antagonism of TNFR2 on lymphocytes in the TME restores the balance between the two types of T cells by suppressing or eliminating Tregs and allowing effector T cell activation and expansion (conditions under which tumor growth can be controlled or reversed). To be useful as therapeutics, TNFR2 inhibitors must not have the ability to recruit immune cells via ADCC for two reasons: 1) transient aggregation leading to a “super-induction” of TNFR2-mediated immunosuppression; and 2) ultimately inducing Treg Systemic depletion would be detrimental to patients because basal levels of Treg activity must be maintained to maintain immune homeostasis. Tumor cells and myeloid-derived suppressor cells (MDSC) also express TNFR2 and inhibit TNFR2 in MDSC control of cancer metastasis, as shown in murine liver cancer models. Therefore, blocking TNFR2, such as through the use of non-antagonizing aggregation antibodies or other therapeutic agents as provided herein, presents a useful treatment for certain types of cancer via suppression of immunosuppressive Tregs. However, TNFR2 antagonists should only be administered to patients whose tumors exhibit overrepresentation of TNFR2 (as determined by immunohistochemistry compared to adjacent normal tissue). Therefore, such treatments should be accompanied by a diagnosis to confirm overexpression (for illustrative analyses, see e.g. Zhang et al. (2019) Thorac Cancer 10 ( 3 ) : 437-444. doi:10.1111/1759-7714.12948; Yang et al. ( 2017) Oncol Lett. 14 ( 2 ) :2393-2398. doi:10.3892/ol.2017.6410; and Yang et al. (2018) Oncol Lett. 16 ( 3 ) :2971-2978. doi:10.3892/ol.2018.8998) . 4. Autoimmune / inflammatory diseases mediated by or involving TNF

Higher levels or uncontrolled expression of TNF and dysregulation of TNF signaling can cause chronic inflammation, which can lead to the development of autoimmune diseases and tissue destruction. TNF-α is involved in a variety of diseases, disorders and conditions. The constructs provided herein can be used to treat such diseases, disorders and conditions. The following discussion describes some exemplary diseases, disorders, and conditions in which blocking TNF may be therapeutic. TNF blockers, such as etanercept, infliximab, adalimumab, certolizumab, and golimumab, have adverse side effects that may limit their use in treating such diseases, disorders, and conditions . Constructs provided herein that avoid some or all of these adverse effects can be used to treat such diseases, disorders and conditions (for a review of the role of TNF in disease and the use of TNF blockers in treating disease, see, e.g., Lis et al. Man (2014) Arch Med Sci. 10(6):1175-1185).

Inflammatory diseases include a range of diseases and conditions characterized by inflammation, and include autoimmune diseases. The immune system protects the body by producing antibodies and/or activating lymphocytes in response to invading microorganisms, such as viruses and bacteria. In healthy individuals, the immune system does not trigger a response against the body's own (also known as "autologous") cells; autoimmune diseases occur when the immune system attacks healthy, non-invasive autologous cells and tissues. Autoimmune/inflammatory diseases and conditions associated with higher TNF levels include, inter alia, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, spondyloarthritis), inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), uveitis, fibrotic diseases, endometriosis, lupus, ankylosing spondylitis, psoriasis, multiple sclerosis (MS), Parkinson's disease and Alzheimer’s disease, among others. Exemplary autoimmune and inflammatory diseases and conditions that may be treated with the constructs provided herein are discussed below. a. Arthritis , rheumatoid arthritis and other types of arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. The inflammation associated with rheumatoid arthritis affects the lining of joints (also known as the synovial lining) and also affects the membranes lining blood vessels, the heart, and can also become inflamed. RA is characterized by the infiltration of immune cells (such as activated B cells) into the synovium and the proliferation of synovial cells, causing thickening of the synovial lining. Proliferative material called pannus invades and destroys cartilage and bone, irreversibly destroying joint structure and function. This is mediated by induction of cytokines such as TNF, IL-1 and IL-6. Tumor necrosis factor alpha (TNFα) is a key mediator in the induction and perpetuation of pro-inflammatory activity associated with RA. TNF is overexpressed in synovial fluid and synovium, and TNFR is upregulated in synovium (see, e.g., Blüml et al. (2012) International Immunology 24(5):275-281; Schmidt et al. (2013) Arthritis & Rheumatism 65 (9):2262-2273; Keffer et al. (1991) EMBO J. 10(13):4025-4031). Other types of arthritis that may be treated with constructs herein include, for example, psoriatic arthritis, juvenile idiopathic arthritis, and spondyloarthritis. b. Inflammatory bowel disease ( IBD ) and uveitis

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is an inflammatory disease of the intestines and colon. Mice that overexpress TNF develop intestinal inflammation similar to Crohn's disease, while TNFR1 deficiency protects against Crohn's disease. (See e.g. Fischer et al. (2015) Antibodies 4:48-70).

Uveitis is a form of eye inflammation that affects the eye wall (uvea), the middle layer of the eye (white of the eye) between the retina and the sclera, and can lead to vision loss. TNF-α is involved in its pathophysiology, and TNF blockers have been used in treatment. c. Fibrotic diseases

The constructs herein may be used to treat fibrotic diseases. Dupuytren's disease is an example of such a disease. Dupuytren's disease (DD) is a common fibrotic condition of the hand, characterized by irreversible flexion contracture of the fingers. The condition is limited to the palm and causes irreversible warping of the fingers, seriously impairing hand function. There are no approved treatments for the early-stage disease, which presents as nodules that persist for a period of time and then become active and progress to flexion deformation of the spinal cord and fingers, resulting in loss of hand function. Treatment involves surgical removal of the diseased tissue or spinal cord (fasciotomy), or destruction of the spinal cord using collagenase or needle fasciotomy. Surgical and non-surgical treatments have higher recurrence rates and complications. Therapeutic intervention early in the disease to prevent progression to spinal cord development and subsequent digital flexion contractures would be advantageous (see, e.g., Nanchahal et al. (2018) EBioMedicine 33:282-288).

Myofibroblasts expressing the contractile protein α-smooth muscle actin (α-SMA) and accumulating in nodules deposit excessive collagen extracellular matrix and are responsible for its remodeling and contraction in all fibrotic conditions including DD. TNF converts palmar fibroblasts from DD patients into myofibroblasts through the Wnt signaling pathway, and DD myofibroblasts show a dose-dependent decrease in contractility and a decrease in α-SMA and procollagen after treatment with anti-TNF therapy. Reduction in performance. Treatments with fully humanized IgG mAbs adalimumab and golimumab have been the most effective. However, the use of anti-TNF therapies such as adalimumab is associated with an increased risk of infection, and in a phase 2a trial evaluating the efficacy of adalimumab in DD, 1 patient (out of 21 patients receiving adalimumab ) develops a wound infection requiring hospitalization (see e.g. Nanchahal et al. (2018) EBioMedicine 33:282-288). Therefore, other therapies are needed. d. Tumor necrosis factor receptor-associated periodic syndrome ( TRAPS )

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is the second most common inherited autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding TNFR1. TRAPS is characterized by unprovoked periodic persistent fever, systemic inflammation, abdominal pain, skin lesions, conjunctivitis, myalgia, and pericarditis, with inflammatory episodes lasting up to several weeks. A complication associated with the more severe clinical manifestations of TRAPS is type AA serum amyloidosis, which can lead to kidney damage and failure. Onset of the disease typically occurs in early childhood, but TRAPS can also occur in adults. Most TRAPS-related mutations occur in the extracellular domain of TNFR1, which is involved in ligand binding. High-penetrance mutations associated with the most severe clinical phenotypes occur in the extracellular cysteamine-rich domain (CRD). Mutations affect the folding and secondary structure of TNFR1, which can cause defective TNFR1 migration, changes in ligand binding affinity, reduced activation-induced excretion, and weakened cell signaling. For example, ligand-dependent enhancement of TNFR1 function induces TRAPS pathophysiology, and certain mutations result in constitutive activity of TNFR1, NF-кB, and apoptotic protease 1. Traditional anti-TNF therapies, including etanercept, infliximab, and others, are only partially effective in treating TRAPS (see, e.g., Greco et al. (2015) Arthritis Research & Therapy 17:93), and therefore additional therapies are needed. e. Other diseases mediated by or involving TNF i. Neurodegenerative diseases

Aging and several neurodegenerative diseases are associated with higher TNF levels in the central nervous system (CNS). TNF is involved in initiating and maintaining neuroinflammation and regulating other neural processes, such as synaptic function and plasticity. The TNFR1 content in the hippocampus of aged rats is approximately three times higher than the TNFR2 content. In animal models of disease, TNF has been implicated in chronic glial activation and attenuated neuronal survival through its effects on TNFR1. In aged animals, neural changes include synaptic dysfunction and Ca2 ⁺ dysregulation, which can be replicated in healthy young animals and neuronal cultures using artificial elevations in TNF. TNF also enhances the activity of L-type voltage-sensitive Ca ²⁺ channels (L-VSCC); similar effects have been observed in hippocampal neurons of aged rats with impaired memory. Studies in rats have shown that TNF blockade in the cerebellum accelerates learning of a delayed blink task. Using XPro1595, a soluble dominant negative TNF (DN-TNF) that better inhibits TNFR1 signaling, selectively blocks TNFR1 signaling, resulting in improved behavioral performance on the Morris swim task and decreased microglia. Activate and prevent hippocampal long-term depression (LTD) and reduce the activity of L-VSCC in CA1 neurons. These results indicate that TNF signaling through TNFR1 is involved in improving the neurological phenotype of aged animals and can cause pathological changes associated with neurological diseases. (See e.g. Sama et al. ( 2012) PLoS ONE 7(5):e38170). a ) Alzheimer’s disease

TNF is a central player in the inflammatory response; TNF protein levels are low in healthy brains but are chronically high in many neuroinflammatory diseases, including Alzheimer's disease (AD). In AD animal models, TNF promotes microglial activation, synaptic dysfunction, neuronal cell death, plaque accumulation and tangles, and cognitive decline. For example, in a triple transgenic AD mouse model (3xTg-Ad) with presenilin 1, amyloid precursor protein (APP), and tau mutations, TNF levels were higher in the entorhinal cortex. , consistent with the earliest manifestations of the lesion (see, e.g., McCoy et al. (2006) J. Neurosci. 26(37):9365-9375). TNF-driven processes are implicated in AD pathology and contribute to cognitive dysfunction and accelerated progression of AD. In several animal models of AD, the bacterial endotoxin lipopolysaccharide (LPS), which induces inflammation and produces TNF, accelerates the appearance and severity of AD lesions. When microglia, which are often tightly physically associated with amyloid plaques in AD brains, become chronically activated, overproduction of pro-inflammatory mediators including TNF occurs in the brain. Higher TNF levels inhibit the phagocytosis of amyloid beta (Aβ) in the brains of AD patients, which hinders effective plaque removal by microglia. Chronic inhibition of solTNF by administration of DN-TNF (such as XENP345) or lentivirus encoding DN-TNF prevents the acceleration of AD-like lesions induced by chronic systemic inflammation in an animal model of AD (3xTgAD mice), And reduce the accumulation of 6E10 immunoreactive proteins, especially C-terminal amyloid precursor protein (APP) fragment (β-CTF) in LPS-induced neurons in the hippocampus, cortex and amygdala. Genetic deletion of TNFR1 in 3xTgAD mice also prevents LPS-induced accumulation of neurotoxic β-CTF. Neuronal cells carrying familial AD (FAD) mutations accumulate β-CTF intracellularly, suggesting its involvement in the pathogenesis of AD. These results indicate that soluble TNF is a mediator of neuroinflammation in early pre-plaque lesions in 3xTgAD mice and that targeted inhibition of solTNF in the central nervous system (CNS) can attenuate amyloid-related pathology, cognitive deficits, and AD. the emergence of progressive neuronal loss in cerebrospinal fluid (see, e.g., McAlpine et al. (2009) Neurobiol. Dis. 34(1):163-177). b ) Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease in the United States, affecting 5% of individuals over the age of 65. The clinical manifestations of Parkinson's disease are caused by the selective loss of dopamine-stimulating neurons in the substantia nigra pars compacta (SNpc) of the ventral midbrain, which results in a decrease in striatal dopamine. The cerebrospinal fluid (CSF) and postmortem brains of patients with PD and PD animal models exhibit higher levels of TNF. The Japanese early-onset PD patient group showed an increased frequency of the polymorphic allele (-1031C) in the TNF gene promoter, resulting in higher transcriptional activity and higher TNF content. TNFR1 is highly expressed in nigrostriatal dopamine-stimulating neurons, thereby increasing susceptibility to TNF-induced neuroinflammation and dopamine-stimulating neuron toxicity. Soluble TNF (solTNF) is neuroprotective by in vivo neutralization of a dominant-negative TNF mutant protein (XENP345) and is induced by retrograde nigral injection of the oxidative neurotoxin 6-hydroxydopamine (6-OHDA). Degeneration was reduced by 50% and amphetamine-induced rotational behavior in rats was reduced, indicating preservation of striatal dopamine content. Delayed administration of XENP345 prevents dopamine-induced neuronal degeneration in embryonic rat midbrain neuron/glia cultures exposed to lipopolysaccharide (LPS), despite continued microglial activation and solTNF secretion. XENP345 also attenuated 6-OHDA-induced dopamine-stimulated neuronal toxicity in vitro. Thus, TNF is implicated in the development of Parkinson's disease, and it is possible that the progressive degeneration of the nigrostriatal pathway in humans may be delayed by the use of TNF-blocking therapeutics, especially in the early stages of Parkinson's disease. (See, eg, McCoy et al. (2006) J. Neurosci. 26(37):9365-9375). c ) Multiple sclerosis ( MS )

CNS-specific overexpression of TNF in transgenic mice results in spontaneous demyelination, indicating a role for TNF in multiple sclerosis (MS). Polymorphism in the gene encoding TNFR1 is associated with increased susceptibility to the development of MS. TNFR1 is required for disease induction in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and TNFR2 deficiency worsens the disease. Mice expressing non-cleavable membrane-bound TNF are protected from EAE, indicating that the interaction of soluble TNF with TNFR1 is relevant to disease pathology (see, eg, Fischer et al. (2015) Antibodies 4:48-70). ii. Endometriosis

TNF-α has been implicated in the pathophysiology of endometriosis. TNF-α levels are increased in the peritoneal fluid of women with endometriosis, and these levels correlate with disease severity (see, e.g., Koninckx (2008) Hum Reprod. 23: 2017-2023). Peritoneal fluid TNF-α is produced locally by activated peritoneal macrophages, and TNF-α induces IL-8 secretion by peritoneal mesothelial cells. The peritoneal fluid concentrations of TNF-α and IL-8 correlate with the size and the number of active peritoneal lesions (Bullimore, (2003) Med Hypotheses. 60 :84-88). Serum TNF-α levels are increased and are derived from intrauterine Monocytes from patients with membrane ectopia released more TNF-α in vitro than mononuclear spheres from controls. Peritoneal fluid MCP-1 levels are increased in patients with endometriosis. TNF-α, IL-8, and MCP-1 drive inflammatory Th-1-type responses in peritoneal fluid of patients with endometriosis. TNF-alpha-mediated inflammation may be the cause of pain associated with endometriosis. Blocking TNF-α appears to inhibit the development of the disease in animal models and may be effective in humans. Due to the adverse side effects of existing TNF blockers, their use in the treatment of endometriosis is not recommended (see Koninckx (2008) Hum Reprod. 23: 2017-2023). However, the constructs provided herein are designed to avoid adverse effects and may be considered for the treatment of TNF-alpha mediated inflammation in endometriosis. iii.Cardiovascular disease

TNFα is the first interleukin identified in atherosclerotic plaques; TNFα is involved in the activation of endothelium and the upregulation of adhesion molecules, which occurs in the early stages of atherosclerotic disease. TNF is also involved in the pathogenesis of atherosclerosis by affecting lipid metabolism and inducing vascular inflammation. Blocking TNFα by a TNF-binding protein or IL-1 by an IL-1 receptor antagonist partially prevented atherosclerosis in apoE knockout mice. Atherogenesis is primarily the result of TNFα production by bone marrow cells. The plaque area size in apoE ^-/- and TNF ^-/- mice fed a high-fat diet was half that of the plaque area in apoE ^-/- mice. Transplantation of bone marrow from apoE ^−/− and TNF ^−/− mice into apoE ^−/− mice reduced atherosclerotic lesion size by 83%. Atherosclerotic lesion size also decreased after treatment of apoE ^−/− mice with recombinant soluble p55 (TNFR1) TNF blocker, indicating a role for TNF in atherosclerosis. NF-кB signaling is involved in TNF-α production in human atherosclerotic plaques. Peripheral blood levels of TNFα are also associated with the development of myocardial infarction in patients with cardiovascular disease. Cardiotoxicity is mainly attributed to TNF-induced cardiomyocyte apoptosis. In clinical trials, the use of anti-TNF therapies, such as infliximab and etanercept, failed to treat heart failure and resulted in increased mortality; therefore anti-TNF therapies have not been tested for the treatment of cardiovascular disease (see e.g. Udalova et al. 2016) Microbial Spectrum 4(4):MCHD-0022-2015; Kalliolias and Ivashkiv (2016) Nat. Rev. Rheumatol. 12(1):49-62). Therefore, alternative treatments are needed. iv. Acute respiratory distress syndrome ( ARDS )

Acute respiratory distress syndrome (ARDS) affects approximately 190,000 patients in the United States each year and has a mortality rate of up to 40%. No effective therapeutic agents exist that target the underlying pathophysiological mechanisms of ARDS. ARDS is characterized by immune cell-mediated lung injury, which is associated with the release of inflammatory cytokines and proteases. The uncontrollable local inflammatory reaction in ARDS causes damage to the alveolar-capillary barrier and non-cardiogenic pulmonary edema. Pulmonary neutrophil recruitment, which is critical to the pathogenesis of ARDS, is mediated by the interaction of presensitized and activated neutrophils with pulmonary microvascular endothelium, and by the action of pro-inflammatory mediators on the alveolar-capillary Increased by the destruction of barriers. TNF-α has been identified as a key effector molecule in ARDS and in sepsis, a common cause of ARDS. For example, TNF-alpha promotes increased endothelial permeability. Clinical trials involving the administration of non-selective anti-TNF antibodies to treat sepsis failed to demonstrate any survival benefit, and one trial indicated that higher doses were harmful.

TNFR1-deficient mice are protected from lung injury, sepsis, and other acute organ injuries, whereas TNFR2-deficient mice are more susceptible to injury in these models, indicating that selective antagonism of TNFR1 may be therapeutically effective. GSK1995057, a short-acting fully human domain antibody (dAb) fragment that selectively antagonizes TNFR1 but not TNFR2, attenuates disease severity in a murine model of acute respiratory distress syndrome and attenuates inflammation of lung injury in non-human primates and signs. In a randomized placebo-controlled trial of nebulized GSK1995057 stimulated with low-dose inhaled endotoxin in 37 healthy humans, GSK1995057 treatment attenuated pulmonary neutrophilia, inflammatory cytokine release, and bronchoalveolar lavage and serum samples Signs of endothelial injury. These results indicate the possibility of pulmonary delivery of selective TNFR1 antagonists for the prevention and treatment of ARDS (see, eg, Proudfoot et al. (2018) Thorax 73:723-730). v. Severe acute respiratory syndrome ( SARS ) and COVID-19

Individuals infected with SARS-CoV present with fever and respiratory illness, general malaise, and lower respiratory symptoms, including cough and shortness of breath, with an overall mortality rate of approximately 10%. TNF signaling contributes to SARS pathogenesis by inducing excessive inflammation causing significant tissue damage. The development of cytokine release syndrome (CRS) plays a role in severe COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sustained viral stimulation in some individuals causes increased levels of circulating interleukins (such as IL-6 and TNFα), which decrease lymphocyte counts and trigger inflammatory organ damage, particularly lung and vascular damage. SARS-CoV-2 shares several similarities with SARS-CoV, the strain of coronavirus responsible for the 2002 SARS pandemic. SARS-CoV and SARS-CoV-2 use spike (S)-protein to access their cell receptor angiotensin-converting enzyme 2 (ACE2) to invade cells. The expression of ACE2 receptors is upregulated by SARS-CoV-2 infection and by stimulation of inflammatory cytokines. In SARS-CoV infection, S-protein induces TNF-α-converting enzyme (TACE)-dependent expulsion of the ACE2 extracellular domain, a process strictly linked to TNFα production. Loss of ACE2 activity due to excretion is associated with lung damage due to increased activity of the renin-angiotocin system. ACE2 knockout mice are susceptible to severe respiratory failure after chemical challenge, and ACE2 has demonstrated moderate ACE-induced intracellular inflammation. Downregulation of ACE2 is associated with severe respiratory distress associated with SARS-CoV infection. Thus, increased TNFα production may promote viral infection and cause organ damage, such as lung damage.

As discussed, regulatory T cells (Tregs) are a type of immunosuppressive cells that show diverse clinical applications in transplantation, allergy, infectious diseases, GVHD, autoimmunity, and cancer. Tregs co-expressed the characteristic inducible contents of CD4+ and interleukin-2 receptor α chain CD25 ^hi and the intracellular transcription factor forkhead box P3 (FOXP3). Naturally occurring Tregs express TNFR2 at a higher density than TNFR1. TNF promotes Treg activity through TNFR2 signaling: TNF-mediated TNFR2 activation and induction of Treg proliferation (100) and TNFR2 expression indicates maximal suppression of Tregs. When overproduced, Tregs prevent overreaction to inflammatory stimuli.

Anti-TNF can be a treatment for SARS and COVID-19. Adalimumab is being used to treat COVID-19 (Clinical trial in China in February 2020 (ChiCTR2000030089); see e.g. Lucchino et al (2020) Rheumatology ( Oxford ) 59 ( 6 ) :1200-1203; Haga et al ( 2008) Proc. Natl. Acad. Sci. USA 105 :7809-7814). Genetic deletion of TNFR2 in mice infected with SARS-CoV did not provide any protection; double gene deletion of TNFR1 and TNFR2 protected infected mice from infection-induced weight loss (see, e.g., McDermott et al. (2016) BMC Systems Biology 10:93 ). These results indicate that TNF signaling through TNFR1 mainly contributes to the pathogenesis of SARS-CoV infection by increasing pro-inflammatory processes, and that selective inhibition of TNFR1 rather than TNF inhibition is a better treatment. The constructs provided herein can be used to treat acute inflammatory forms of SARS and COVID-19. Constructs are used in combination with anti-infective agents; constructs are used to contain or ameliorate the acute effects of interleukin storms.

TNFα inhibition reduces the severity of virus-induced lung diseases, such as those caused by respiratory syncytial virus (RSV) or influenza virus, in mice. Depletion of TNF using anti-TNF antibodies in these mouse models reduced pulmonary recruitment of inflammatory cells, reduced production of pro-inflammatory interleukins (e.g., IFNγ, IL-4, IL-5, TNF) by T cells, and decreased disease severity without interfering with viral clearance (see, e.g., Hussell et al. ( 2001) Eur. J. Immunol. 31:2566-2573). These results indicate that TNF inhibitors and TNF receptor antagonists may be beneficial in the treatment of human viral lung diseases, such as those caused by SARS-CoV and SARS-CoV2, by preventing or reducing TNF-induced immune activation and lung injury. .

The emergence of non-infectious idiopathic pneumonia syndrome (IPS), an acute lung dysfunction similar to SARS pneumonia, complicates allogeneic hematopoietic stem cell transplantation. Higher TNFα levels have been found in the serum of patients who develop lung injury after allogeneic stem cell transplantation (SCT), and donor-derived alloreactive T cells have been shown to be involved in this process. In humans, anti-TNF therapy with etanercept is beneficial for the treatment of IPS after allogeneic stem cell transplantation. Due to the immunoablative effect of the SCT adjustment regimen, recipients of allogeneic stem cell transplantation are resistant to long-term use of immunosuppressive drugs to prevent or treat graft-vs-host disease (GvHD) and other diseases that can weaken the host. are at high risk of bacterial and fungal infections due to the need to prevent complications of SCT, including acute GvHD. (See, for example, Yanik et al. ( 2002) Biol. Blood Marrow Transplant. 8:395-400). Other indications that may be treated by the constructs provided herein include chemotherapy brain, a condition experienced during and after chemotherapy, particularly in women undergoing breast cancer treatment. Additionally, the treatments and constructs described herein may be used to treat long-term COVID.

Therefore, the use of selective TNFR1 antagonists, which preserve protective TNF signaling via TNFR2 and, unlike anti-TNF therapies, do not increase the risk of serious infection, may provide opportunities for the treatment, prevention, or amelioration of viral and non-viral induced lung injury. Safe and more effective treatment options. Therefore, the constructs provided herein are ideal therapeutics for these indications. D. Used for rheumatoid arthritis and other chronic inflammatory and autoimmune diseases and conditions

There is no cure for rheumatoid arthritis (RA), but treatments can improve symptoms and slow the progression of the disease, such as minimizing pain and swelling, preventing bone deformation, and maintaining daily functions. The main treatment for RA is disease-modifying anti-rheumatic drugs (DMARDs), which are also used to treat other chronic inflammatory and autoimmune diseases and conditions, such as psoriasis, plaque psoriasis, and psoriatic joints. arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Behçet's disease, inflammatory bowel disease (IBD; such as Crohn's disease and ulcerative colitis), multiple sclerosis, and lupus, and used to treat some cancers.

DMARD is an immunosuppressive and immunomodulatory agent, which is divided into conventional synthetic DMARD (conventional synthetic DMARD, csDMARD) or biological DMARD (biological DMARD, bDMARD; such as antibodies and fusion proteins). Commonly known synthetic DMARDs include, for example, methotrexate (MTX), chemotherapeutic agents and immunosuppressive agents; hydroxychloroquine (HCQ; Plaquenil®), an anti-malarial agent; Azulfidine (Azulfidine®), an anti-inflammatory agent medicine; and leflunomide (Arava®), an immunosuppressant that inhibits dihydroorotate dehydrogenase. Biological DMARDs include, for example, abatacept (Orencia®), which prevents T cell activation and a fusion protein containing the Fc region of IgG1 fused to the extracellular domain of CTLA-4; anakinra (e.g., sold under the trademark Kineret® ), a recombinant human IL-1 receptor antagonist; rituximab (sold under the trademarks including: Rituxan®, Truxima®, MabThera®), a chimeric monoclonal antibody against CD20 that induces CD20 ⁺ cells, such as B-cell apoptosis; tocilizumab (atlizumab, Actemra®, RoActemra®), a humanized monoclonal antibody against the IL-6 receptor (IL-6R); cortex Steroids; tofacitinib (Xeljanz®), a small molecule inhibitor of Janus kinase (JAK), a protein tyrosine kinase involved in mediating interleukin signaling; and TNF inhibitor/ Anti-TNF agents, such as pegylated certolizumab (Cimzia®), infliximab (Remicade®), adalimumab (Humira®), golimumab (Simponi®), and etanercept Enbrel®. Combination therapy, especially the combination of methotrexate and biologic DMARDs, is more effective than either therapy alone. Combination therapy may also include multiple csDMARDs and multiple csDMARDs with a biologic DMARD. Due to the risk of serious side effects, including serious infections, multiple biologic DMARDs, especially anti-TNF DMARDs, are typically not used in combination therapy approaches.

The following section describes existing treatments and related issues to highlight how the treatments presented here address these issues. 1. Commonly known synthetic disease-modifying antirheumatic drugs ( csDMARDs )

Synthetic disease-modifying antirheumatic drugs (csDMARDs) are typically known as first-line treatments for RA and other autoimmune and chronic inflammatory diseases and conditions. csDMARDS include drugs such as methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. Methotrexate is the most commonly used agent for initial treatment and its mechanism of action involves stimulation of adenosine from fibroblasts. Release, reduce neutrophil adhesion, inhibit leukotriene B4 synthesis of neutrophils, inhibit local IL-1 production, reduce IL-6 and IL-8 content, suppress cell-mediated immunity and inhibit synovial collagenase Gene expression. Other conventional synthetic DMARDs act by inhibiting lymphocyte proliferation or causing lymphocyte dysfunction. For example, leflunomide inhibits dihydroorotate dehydrogenase, thereby inhibiting pyrimidine synthesis and blocking lymphocyte proliferation. Sulfasalazine mediates its anti-inflammatory effect by preventing oxidation, nitration, and nitrosation damage, and hydroxychloroquine is a mild immunomodulator that inhibits intracellular toll-like receptor 9 (TLR9).

Hydroxychloroquine has the best safety profile of known DMARDs, does not increase the risk of infection, and does not cause liver toxicity or renal dysfunction; common side effects of hydroxychloroquine include rash and diarrhea. Retinopathy/maculopathy is a rare but serious side effect of hydroxychloroquine therapy that is associated with doses above 5 mg/kg/day, long-term use (more than 5 years of therapy), older age, and chronic kidney disease. Other rare adverse effects of hydroxychloroquine include anemia, leukopenia, myopathy, and cardiomyopathy. Therapy with methotrexate, leflunomide, and sulfasalazine is associated with higher rates of nausea, abdominal pain, diarrhea, rash/anaphylaxis, myelosuppression, hepatotoxicity, and common and sometimes serious infections. Methotrexate and leflunomide also cause baldness. Other side effects associated with methotrexate therapy include interstitial lung disease, folate deficiency, and cirrhosis. Leflunomide has also been associated with hypertension, peripheral neuropathy, and weight loss. Sulfasalazine carries a high risk of gastrointestinal upset and can rarely cause DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) (see e.g. Benjamin et al. Disease Modifying Anti-Rheumatic Drugs (DMARD) [2020 Updated February 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2020. Available from: URL: ncbi.nlm.nih.gov/books/NBK507863/). These drugs are effective due to their immunosuppressive properties. The constructs provided herein as selective anti-TNFR1 antagonists that retain TNFR2 immunosuppressive activity may advantageously avoid the need for such immunosuppressive drugs. 2. Anti- TNF therapy /TNF blocker

Anti-TNF therapy/TNF blockers (a type of biologic DMARD) are typically prescribed after failure of conventional DMARDs and include monoclonal antibodies (mAbs), such as the chimeric mAb infliximab ( ^Remicade® ); containing mouse like variable region and human IgG1 constant region); and fully humanized mAbs (IgG1) adalimumab (Humira®) and golimumab ( ^Simponi® ); pegylated humanization of mAbs targeting TNF Fab'fragments; pegylated certolizumab ( ^Cimzia® ); and TNFR2 fusion proteins, such as the TNFR2-Fc fusion protein etanercept ( ^Enbrel® ), which contains an extracellular receptor region that contains Binding site for human TNFR2 Fc fusion of human IgG1. ^Remsima® and ^Inflectra® are biosimilars of infliximab, which are approved in the EU for the treatment of various autoimmune and chronic inflammatory diseases and conditions. These TNF inhibitors, which chelate TNF, are useful in the treatment of various diseases and conditions, including, for example, RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis (JIA), and/or inflammatory bowel disease. (IBD; such as Crohn's disease and ulcerative colitis).

Due to the immunosuppressive effects of TNF-targeting therapies, such therapies are associated with serious side effects, including, for example, an increased risk of sepsis and serious infections such as listeriosis, tuberculosis reactivation, hepatitis B/C reactivation, and Herpes zoster reactivation and invasive fungi and other opportunistic infections. TNF is a key interleukin in the inflammatory and immune response to infection, and the use of drugs that remove TNF weakens the host's immunity to microorganisms and increases the risk of infection. For example, TNF blockers have been associated with reactivation of Mycobacterium tuberculosis infection. TNF plays an important role in fighting Mycobacterium tuberculosis, and adalimumab therapy significantly reduces reactivity to Mycobacterium tuberculosis in RA patients. As described herein, reduced immune reactivity can be associated with activation of Tregs and induction of apoptosis in effector lymphocytes. Anti-TNF therapy has been shown to induce macrophage apoptosis in rheumatoid synovium. Infliximab is associated with increased apoptosis of inflammatory cell infiltrates in the intestine of patients with Crohn's disease. Other antirheumatic drugs, such as methotrexate and glucocorticoids, can also induce immune cell apoptosis (see, eg, Vigna-Pérez et al. (2005) Clin. Exp. Immunol. 141(2):372-380). Adalimumab and infliximab, but not etanercept (a TNFR2-Fc fusion protein), induce apoptotic protease-dependent apoptosis in cultured monocytes and downregulate IL production by monocytes -10 and IL-12 (see, eg, Shen et al. (2005) Ailment Pharmacol. Ther. 21:251-258). The most common fungal infections associated with TNF blockers are histoplasmosis, candidiasis, and zoomycosis. Anti-TNF agents can also cause severe congestive heart failure, drug-induced lupus and demyelinating central nervous system (CNS) disease, and exacerbation of lymphoma and non-melanoma skin cancers (see, e.g., Benjamin et al. Disease Modifying Anti-Rheumatic Drugs (DMARD) [Updated February 27, 2020]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2020. Available from: ncbi.nlm.nih.gov/books/NBK507863 /).

Infliximab has also been associated with leukopenia, neutropenia, thrombocytopenia, and total cytopenias (some fatal). Etanercept is associated with an increased incidence of opportunistic bacterial and viral infections in patients with RA. Etanercept is also used to treat severe refractory graft-versus-host disease (GvHD). Individuals with severe GvHD treated with etanercept were at very high risk of developing invasive aspergillosis (IA) (100% risk in one study, see Zoran et al. (2019) Sci. Rep. 9:17231), invasive koji mycosis is a life-threatening mold (also known as fungus) infection caused by Aspergillus fumigatus . Treatment with etanercept causes downregulation of genes involved in immune responses and TNF signaling, including genes involved in NF-кB signaling, antimicrobial humoral responses and apoptotic processes, as well as secretion of chemokines from immune cells, such as CXCL10 decrease (see e.g. Zoran et al. (2019) Sci. Rep. 9:17231).

Other side effects associated with the use of TNF-blocking therapy include congestive heart failure, liver damage, demyelinating diseases/CNS disorders, lupus, psoriasis, sarcoidosis, and the development of additional autoimmune diseases including lymphoma and solid malignancies. Increased susceptibility to cancer (see, e.g., Dong et al. (2016) Proc. Natl. Acad. Sci. USA 113(43):12304-12309; Zalevsky et al. (2007) J. Immunol. 179:1872-1883; Zoran et al. (2019) Sci. Rep. 9:17231). Therefore, eliminating all TNF-mediated signaling by chelating TNF is not an ideal therapeutic strategy because it produces severe immunosuppression that can lead to severe, sometimes fatal infections and other dangerous side effects.

Anti-TNF therapy improves RA but is not curative and requires years of continuous and expensive therapy. TNF inhibition/blockade in RA reduces inflammation and joint destruction but, as discussed above, is associated with an increased risk of serious infections due to immunosuppression, such as tuberculosis and listeriosis. Therefore, the use of TNF blockers is limited especially in the setting of chronic diseases/conditions that require long-term administration, such as arthritis and IBD. With anti-TNF therapy, approximately 30% of RA patients do not respond, or the treatment benefit is not sustained (see, e.g., McCann et al. (2014) Arthritis & Rheumatology 66(10):2728-2738). Anergy also occurs in non-RA patients receiving anti-TNF therapeutics. Depending on the anti-TNF agent, 13-33% of treated patients do not respond to treatment, and up to 46% of treated patients cease responding, leading to discontinuation or dose increase (see e.g. Richter et al. (2019) MABS 11(4) ):653-665). Therefore, there is a need for therapies with improved efficacy and safety.

Anti-TNF therapeutics block/chelate TNF and inhibit soluble TNF (solTNF) and transmembrane TNF (tmTNF) signaling via TNFR1 and TNFR2, respectively; solTNF signaling is associated with chronic inflammation, while tmTNF signaling is associated with resolution of inflammation and targeting Immunity induction by pathogens such as Listeria monocytogenes and Mycobacterium tuberculosis. The main anti-inflammatory effect of anti-TNF therapy is achieved by blocking TNFR1, while blocking TNFR2 inhibits Treg cell activity. As discussed elsewhere herein, TNFR1 signaling is primarily inflammatory and is involved in the pathogenesis of inflammatory and autoimmune diseases and conditions, such as RA, psoriasis, IBD, and neurodegenerative disorders, such as MS; whereas TNFR2 signaling is involved in the pathogenesis of inflammatory and autoimmune diseases and conditions, including neurological, It has anti-inflammatory and protective effects in various cells and organ types in the heart, intestines, and bone tissue, and is also involved in host defense mechanisms against pathogenic infections. Therefore, as described herein, selective blockade of TNFR1 improves efficacy compared to anti-TNF therapies and eliminates unwanted pro-inflammatory signaling associated with RA and other autoimmune and inflammatory diseases and conditions while preserving TNFR2 Beneficial effects of signaling (see, e.g., McCann et al. (2014) Arthritis & Rheumatology 66(10):2728-2738; Schmidt et al. (2013) Arthritis & Rheumatism 65(9):2262-2273; Blüml et al. (2012) International Immunology 24(5):275-281; Zalevsky et al. (2007) J. Immunol. 179:1872-1883).

Anti-TNF therapies have failed in treating neurodegenerative diseases associated with overexpression of TNF, such as Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis (MS). For example, in a phase II trial for the treatment of relapsing-remitting MS, the TNFR1 receptor anti-Fc IgG1 fusion protein anti-TNF treatment lenercept (Ro 45-2081) compared with patients receiving placebo. Ineffective, with increased/worsened symptoms and more severe neurological deficits in lenaccept-treated patients. These results indicate that anti-TNF therapy may exacerbate demyelinating disease. Although TNFR1 has been shown to mediate inflammatory neurodegeneration, TNFR2 induces neuroprotection, therefore, anti-TNF therapy blocking signaling through both receptors eliminates the neuroprotective effects of TNFR2 signaling. In a mouse model of NMDA-induced acute neurodegeneration, TNFR1 was blocked with ATROSAB, a humanized monoclonal antibody that blocks TNFR1, or TNFR2 was activated with EHD2-scTNF _R2 , a agonist TNFR2-selective TNF mutein. , causing choline-induced neuronal protection against cell death and recovery of memory impairment associated with neurodegeneration. This may be immunogenic. ATROSAB is a partial TNFR1 agonist; one of ordinary skill in the art would not advise administration of TNFR1 agonists. However, blockade of TNFR1 and TNFR2 abolished efficacy, indicating that TNFR2 plays an important role in neuroprotection and that selective blockade of TNFR1 could be used to treat neurodegenerative diseases when anti-TNF therapy has failed (see e.g. Dong et al. (2016) ) Proc. Natl. Acad. Sci. USA 113(43):12304-12309).

Due to adverse effects associated with the use of anti-TNF agents, unresponsiveness in some patients, lack of sustained response in patients with initial responses, and treatment failure and/or worsening of neurodegenerative diseases such as MS, additional therapies are needed. This article provides such treatments. E. Therapeutic agents for targeting TNFR1/TNFR2

The following sections discuss exemplary therapies targeting TNFR1/TNFR2 and describe some of the issues and limitations of such therapies. Existing therapeutic agents can be modified as described in Section F and the Examples, or used in whole or in part, or modified to improve their properties for use in the constructs provided herein. 1. TNFR1 selective antagonist

As discussed and provided herein, therapy with TNF blockers (such as etanercept, infliximab, adalimumab, and others) abolishes TNF signaling through TNFRl and TNFR2. While TNFR1 signaling causes inflammation, cytotoxicity, and apoptosis, TNFR2 signaling is protective and anti-inflammatory, in part due to its expansion and activation of immunosuppressive Tregs that disrupt autoimmunity Effector T cells in the environment prevent tissue destruction and disease progression. Therapy with TNF blockers, through their inhibition of TNFR2 signaling and consequent depletion of immunosuppressive Tregs that induce a pro-inflammatory microenvironment, may not treat autoimmune and inflammatory diseases and conditions and/or may Exacerbating autoimmune and inflammatory diseases and conditions. Dual blockade of TNFR1 and TNFR2 can also cause opportunistic infections and cancer.

As provided herein, specific inhibition of TNFR1 signaling maintains normal TNFR2 function through the generation of regulatory T cells and a subset of cytotoxic T cells, which is required to maintain the balance between pro-inflammatory and anti-inflammatory activities. Selective TNFR1 inhibition preserves the potent anti-inflammatory activity of TNFR2 signaling, reducing the risk of opportunistic infections and cancer, and preserves TNF-induced Treg function. a. TNFR1 antagonist antibody

Among the TNFR1 antagonist antibodies is ATROSAB (antagonistic TNF receptor monospecific antibody). The first TNFR1 blocking antibody, ATROSAB, is a full-length IgG1 that is a humanized version of the neutralizing mouse anti-human TNFR1 monoclonal antibody H398. It was discarded as a therapeutic because it has partial agonist activity that activates TNFR1, thereby mimicking TNF activity (a toxicity pathway). ATROSAB maintains the conformation of TNFR1 in the inactive state and blocks TNF binding. The Fc region in ATROSAB is mutated to eliminate FCγR receptor binding and complement fixation, thereby avoiding unwanted immune system activation (see, e.g., Kalliolias and Ivashkiv (2016) Nat. Rev. Rheumatol. 12(1):49-62).

Full-length antibodies have the advantage of extended in vivo half-life, but as discussed elsewhere in this article, are not feasible for the development of TNFR1 antagonists due to receptor cross-linking that tends to agonize TNFR1 rather than antagonize it. This is not caused by Fc cross-linking, as the FcR interacting portion of the antibody is removed by mutation. For example, IgG ATROSAB exhibits some TNFR1 agonist activity in the absence of TNF, which is observed to a limited extent in a narrow concentration range due to its bivalent molecular structure. Cross-linking of TNFR1 can also occur due to secondary events, such as interactions with FcγR or anti-drug antibodies (ADA), and these secondary events must be avoided to maintain the antagonistic properties of TNFR1 inhibitors. ADA has been observed in 50% and 31% of patients treated with infliximab or adalimumab, respectively (see e.g. Richter et al. (2019) mAbs 11(4):653-665; Richter et al. , (2019) mAbs 11(1):166-177). b. Monovalent TNFR1 antagonist antibody / antibody fragment

Small antibody fragments, such as domain antibodies and their derivatives and modified forms, have been developed, and exemplary antibody fragments and modified forms are discussed in the following sections. However, small antibody fragments have not been successfully developed into pharmaceuticals. It has limitations in its use as a therapeutic agent; due to its small size, it has a short serum half-life and rapid peripheral clearance. For example, molecules with a size of 50-60 kDa or smaller undergo renal filtration; dAbs and other antibody fragments with a size smaller than 50-60 kDa are rapidly cleared by the kidneys. For example, a dAb named DMS5541 and similar molecules demonstrate selectivity for TNFR1 and can potentially inhibit adverse effects of TNFR1 signaling. DMS5541, formed from two dAbs (anti-TNFR1 and anti-human serum albumin), is only approximately 25 kDa in size and is too small for therapeutic purposes without the desired pharmacokinetics. Its association with HSA (which means stabilizing its half-life) is only 34 nM, which means it is often in a dissociated state relative to HSA. The single domain antibodies (sdAb) tested so far express themselves in E. coli and tend to aggregate (unfold) during production. In addition, sdAbs prepared in a cytoplasmic manner (from direct expression in E. coli) often lack the conserved disulfide bonds found in the variable heavy chain domain, which lower their melting point and may reduce their refolding ability. The rapid clearance and short elimination half-life of small antibody fragments, which can be less than a few hours, reduces in vivo efficacy and requires frequent administration and/or continuous infusion, which can reduce patient compliance. Because these molecules (see e.g. Holland et al. (2013) J Clin Immunol 33(7):1192-203) are produced in E. coli and often do not fold correctly, resulting in poor solubility and immunogenicity, thereby causing their clinical failure (See e.g. adisinsight.springer.com/drugs/800037882).

Constructs provided herein, such as TNFR1 antagonist constructs, address this issue as well as other issues, such as immunogenicity and reactivity with pre-existing antibodies. Provided herein are constructs containing small antibody fragments, such as dAbs, specific for TNFR1 and/or TNFR2, which exhibit improved pharmacology, such as pharmacokinetic properties, including longer serum half-life, compared to prior art dAbs. Increased stability, reduced/slower peripheral clearance and lower immunogenicity.

Therapeutic antibodies of various structures can be potent and well-tolerated therapeutics. Antibodies are used to treat a variety of diseases and conditions, including, for example, rheumatoid arthritis (e.g., adalimumab sold under the trademark Humira®); cancer, such as non-Hodgkin's lymphoma (e.g., rituximab and ibritumomab tiuxetan, sold under the trademarks Rituxan® and ^Zevalin®, respectively) and breast and gastric cancers (e.g., trastuzumab, sold under the trademark ^Herceptin® ); and respiratory tract contagious viral infections (e.g., palivizumab , sold under the trademark ^Synagis® ). The production of complete antibodies has several limitations, such as reliance on mammalian cell expression. Therefore, antigen-binding fragments of antibodies have been developed, such as Fab (approximately 57 kDa) and single-chain Fv fragments (scFv, approximately 27 kDa) and other structures, which can be selected in vitro, such as by phage display (to circumvent animal immunity). inoculum) and can be produced in large quantities using bacterial or yeast cell cultures. Fab fragments contain a VH- _CH1 polypeptide linked to a VL _{- CL} polypeptide via a disulfide bond _; scFv is a fusion protein containing a _VH domain and a _VL domain linked by a short polypeptide linker. Another class of therapeutic small antibody fragments are domain antibodies (dAb; also known as single domain antibodies, or sdAb), which are monomeric and contain the variable domain of the heavy ( _VH ) or light chain ( _VL ) of the antibody. A dAb is the smallest antigen-binding fragment of an antibody; its size is approximately 11-15 kDa, approximately one-tenth the size of an intact monoclonal antibody (mAb) (see, e.g., Holt et al. (2003) Trends in Biotechnology 21 (11) :484-490). Similar to dAbs, nanobodies (Nbs) are small antigen-binding fragments derived from camelid heavy chain antibodies that do not contain a light chain. Nanobodies are small (approximately 15 kDa), have low immunogenicity and high affinity, are soluble and stable, and are encoded by a single gene/exon (VHH), making them modular and allowing high-level production in bacteria and yeast. Yield production (see, e.g., Steeland et al. (2015) J. Biol. Chem. 290(7):4022-4037; Steeland et al. ( 2017) Sci. Reports 7:13646). i. Fab- and scFv - based TNFR1 antagonists

As discussed above, the humanized semi-agonist/antagonist TNFR1-specific antibody ATROSAB inhibits TNFR1-mediated cellular responses. ATROSAB may exhibit some TNFR1 agonist activity due to its bivalent molecular structure or by virtue of its binding to TNFR1 in the absence of TNF. The stronger inhibitory potential of the parent mouse antibody H398 is attributed to the faster dissociation of ATROSAB compared to H398 (i.e. higher k _off value). This was measured using a quartz crystal microbalance (QCM) measurement, in which the antigen density on the chip was reduced to promote monovalent interactions; the slower dissociation of monovalently bound H398 from TNFR1 and the resulting longer receptor occupancy Helps improve TNFR1 blockade. Therefore, in order to eliminate the TNFR1 agonist activity of ATROSAB and to improve its TNFR1 antagonistic activity, monovalent derivatives of ATROSAB were developed.

To increase the affinity and antagonistic activity of ATROSAB, the single-chain variable fragment (scFv) of ATROSAB undergoes a first affinity maturation induced by site-directed mutagenesis of exposed residues within individual CDRs or combinations of CDRs and by targeting human TNFR1- Fc phage display and selection. The scFv of ATROSAB contains a _VH domain corresponding to residues 1-115 of the ATROSAB heavy chain (see SEQ ID NO: 31), linked to residues 1-113 of the ATROSAB light chain (see SEQ ID NO: 31) via a short peptide linker ID NO: 32) V _L domain. Clone scFv IG11 (see SEQ ID NO: 674) with 6 mutations Y52V, Y54T, S55Q, H57E, Y59K and E62D (see SEQ ID NO: 31) within the CDR-H2 of the ATROSAB heavy chain exhibits a slower acceptor Dissociation and improved balanced binding to human TNFR1-Fc, and improved inhibition of TNF-induced TNFR1 activation. This pure line was further subjected to random mutation induction to produce pure scFv T12B (see SEQ ID NO: 675), which contains mutations Q1H, Y52V, Y54S, S55Q, H57E, Y59K and E62D in the V _H domain (see SEQ ID NO: 31) and S96G in the V _L domain (refer to SEQ ID NO: 32). The scFv T12B has reduced dissociation from immobilized TNFR1-Fc and increased TNFR1 inhibitory activity compared to the scFv of ATROSAB and compared to scFv IG11 (see, e.g., Richter et al. (2019) mAbs 11(1):166-177; see also Richter, F . Thesis, titled "Evolution of the Antagonistic Tumor Necrosis Factor Receptor One-Specific Antibody ATROSAB" Universität Stuttgart, 2015; available at pdfs.semanticscholar.org/d8e7/8b87d76dce36225c1d497939ef37445cfa8a.pdf).

Humanization of H398 was reengineered by exchanging the VH and VL framework regions of H398 with alternative germline genes to optimize the CDR arrangement. scFv 13.7 containing the VH domain of scFV T12B linked to the novel humanized VL domain of H398 via a short peptide linker, binds similarly to human TNFR1-Fc in ELISA and QCM, improves inhibition of TNF-induced TNFR1 activity and Improved thermal stability with melting temperature 10 degrees Celsius higher than scFv T12B. Based on scFv 13.7, IgG and Fab (IgG 13.7 and Fab 13.7, respectively) with constant regions consistent with ATROSAB were generated, and their binding to TNFR1 was compared to ATROSAB (1.4 times) and ATROSAB's Fab (Fab ATR; 8.7 times) increase respectively. Compared with Fab ATR, Fab 13.7 also reduces the dissociation of self-immobilized TNFR1-Fc, with the monovalent affinity improved by 18.8 times. Thus, affinity maturation and framework replacement resulted in improved binding to TNFR1 for Fab 13.7. Fab 13.7 and IgG 13.7 showed selectivity for TNFR1-Fc and did not bind to TNFR2-Fc fusion protein; Fab 13.7 bound to human and rhesus monkey TNFR1-Fc but not to mouse and rat TNFR1-Fc, showing that ATROSAB is similar to the binding mode. In vitro, monovalent Fab ATR and Fab 13.7 did not activate TNFR1, while ATROSAB showed marginal activation of TNFR1 activity and IgG 13.7 strongly activated TNFR1. The agonist activity of IgG 13.7 can be attributed to improved affinity and slower dissociation from TNFR1, allowing the formation of stable signaling-competent receptor-antibody complexes. Fab 13.7 showed improved inhibition of TNFR1 activity compared to Fab ATR and ATROSAB and lacked any agonist activity. Incubation of Fab 13.7 or ATROSAB with cross-linked anti-human Fab serum revealed that Fab 13.7 does not activate TNFR-1, but ATROSAB does (see, e.g., Richter et al. (2019) mAbs 11(1):166-177).

Compared to ATROSAB with an initial half-life of 0.44 hours, the terminal half-life was 32.1 hours and the area under the curve (AUC) was 181 µg/ml xh for Fab 13.7 (molecular weight approximately 47 kDa). Fab 13.7 showed an initial half-life of 0.08 hours, a terminal half-life of 1.4 hours, and an AUC of 4.2 µg/ml xh, which is similar to the values obtained for Fab ATR. To extend half-life, a Fab' fragment, Fab' 13.7, was generated by introducing a free cysteine residue at the C-terminus of the CH1 domain, which was chemically linked to a branched PEG _{40 kDa} moiety, resulting in Fab 13.7PEG . Fab 13.7 is also fused to the N-terminus of mouse serum albumin (MSA) via its Fd and short flexible linker to produce Fab13.7-MSA. Monovalent Fab-Fc fusion proteins were generated by fusing Fab 13.7 to a modified Fc lacking a cysteine residue and capable of dimerization via the CH3 domain, thereby generating a single-arm half IgG molecule (IgG1 _half 13.7). Monovalent Fv-Fc molecules are also generated by fusing the VH and VL domains to a heterodimeric kih Fc chain lacking a cysteine residue in the hinge region (Fv13.7-Fc _kih ). None of the derivatives exhibited any agonist TNFR1 activity, and slightly reduced binding to human TNFR1-Fc was observed for Fab13.7PEG, Fab13.7-MSA and IgG1 _half 13.7 compared to Fab 13.7; Fv13.7-Fc _kih The combination is not affected. Compared with Fab 13.7, TNF-mediated inhibition of TNFR1 activity was reduced by 1.5-3.3 times; Fab13.7PEG showed the most severe functional impairment, and Fv13.7-Fc _kih showed the lowest change in biological activity. IgG _half 13.7 has a similar half-life to Fab 13.7, and the AUC value is increased by 7.1 times. Fab13.7PEG, Fab13.7-MSA and Fv13.7-Fc _kih have extended terminal half-lives with values of 14.4 h, 9.7 h and 10.5 h respectively and increased AUC values. Therefore, the fusion protein Fv13.7-Fc _kih, engineered for heterodimer assembly of the two peptide chains by using the pestle-in-mortar technique, showed an optimal combination of improved pharmacokinetic properties and TNFR1 antagonistic activity ( See, e.g., Richter et al. (2019) mAbs 11(1):166-177; see also Richter, F. Thesis, “Evolution of the Antagonistic Tumor Necrosis Factor Receptor One-Specific Antibody ATROSAB” Universität Stuttgart, 2015; available From pdfs.semanticscholar.org/d8e7/8b87d76dce36225c1d497939ef37445cfa8a.pdf).

In another study, to improve the pharmacokinetic properties of Fab 13.7, such as serum half-life, an IgG-like Fc was incorporated into the molecule while maintaining Fab-like heterodimerization of the polypeptide chain. To accomplish this, the variable domains of the heavy and light chains of Fab 13.7 were fused to the N-terminus of a newly generated heterodimeric Fc chain, termed Fc-/κ (Fc1κ). The Fc heterodimerization approach is based on interspersed Ig domains derived from the heterodimeric IgG1 constant heavy chain domain, CH1 and kappa light chain constant domain, CLκ, and containing a segment of the IgG1 CH3 sequence to mediate FcRn binding and enable FcRn-mediated drugs can be recycled in vivo. Interspersed Ig domains include "CH31", which contains the amino acid sequence fragment of CH1 and CH3, and "CH3kappa" (CH3κ), which contains the amino acid sequence fragment of CLκ and CH3. The IgG1 CH2 domain is also fused to the N-terminus of the CH31 and CH3κ domains to include the entire FcRn binding region of the IgG molecule. The addition of the IgG1 hinge region to the N-terminus of the CH2 domain creates a covalently linked heterodimeric Fc moiety, termed Fc1κ. Fc heterodimerization In contrast to other Fc heterodimerization techniques involving the replacement of one or more amino acids at the CH3-CH3 interface, such as PEST, by exchanging larger amine groups obtained from human antibody sequences Acid sequence extension is achieved. Asymmetric scFv-Fc1κ fusion proteins were prepared and compared to scFv fusions with Fc-containing pestle-in-a-mortar technology, and heterodimer formation was similar or improved compared to fusions containing a pestle-in-a-mortar technology (see, e.g., Richter et al. Human (2019) mAbs 11(4):653–665).

The variable domain of the TNFR1-specific Fab 13.7 molecule uses a short peptide linker, by fusing VH to the CH2-CH3κ chain and VL to the CH2-CH31 chain (VL13.7-CH2-CH31/VH13.7-CH2-CH3κ ; VL1C/VHκC) and fused to the N-terminus of the CH2 domain of the Fc chain containing CH31 or CH3κ, producing a monovalent TNFR1-specific antagonist antibody derivative molecule (Fv-Fc1κ fusion protein), known as atosimab (Atrosimab) (size 72 kDa). Atocilimab lacks the ability to mediate Fc effector functions due to mutations introduced into Fc1κ; lack of binding to effector molecules of the immune system prevents TNFR1 due to secondary cross-linking of atocilimab binding to cells expressing FcγR activation. Atocilimab binds to TNFR1 with high affinity (K _D 2.7 nM) and inhibits TNF induction with IC ₅₀ values of 16-55 nM in various in vitro assays and in the presence of anti-human IgG antibodies (i.e., cross-linking antibodies). Activation of TNFR1 and showed improved pharmacokinetic properties. Compared to the parent Fab 13.7 molecule, TNFR1 binding and inhibition were slightly reduced, which can be attributed to changes in VH and VL pairing after fusion with the CH2 domain. The initial and terminal half-lives of atocilimab were determined to be 2.2 +/- 1.2 hours and 41.7 +/- 18.1 hours, respectively, and the AUC was 5856 +/- 1369.9 µg/ml xh. The terminal half-life of atocimab is almost 40-fold longer compared to the terminal half-life of Fab 13.7 and 1.3-fold longer compared to ATROSAB; however, these values may not be accurate because of the lower injection doses of Fab 13.7 and ATROSAB. This may affect pharmacokinetic properties (see e.g. Richter et al. (2019) mAbs 11(4):653-665). ii. Domain antibody ( dAb ) -based TNFR1 antagonists

Another class of therapeutic agents, small fragments of antibodies, are domain antibodies (dAb; also known as single domain antibodies, or sdAb), which are monomers and contain either the heavy chain (V _H ) or the light chain (V _L ) of the antibody. Change domain. A dAb is the smallest antigen-binding fragment of an antibody; its size is approximately 11-15 kDa, which is one-tenth the size of a complete monoclonal antibody (mAb). Similar to dAbs are nanobodies found in the camelid family, producing antibodies containing only heavy chains, in which the antigen-binding site is a single unpaired variable domain, called _VHH . In a dAb, there are three complementarity determining regions (CDRs) on each _VH and each _VL ; therefore, each dAb contains three of the six CDRs from the _VH - _VL pair in the antibody, which are Highly diverse loop regions that bind target antigens.

Due to their smaller size, dAbs are produced in higher yields from bacterial cultures and are more suitable for phage display since only a single polypeptide chain is produced. Specific dAbs with high affinity and potency can be produced by protein engineering. The small size of dAbs also allows for increased tissue penetration, stability and delivery formulation options. Due to their smaller size, it is possible to generate molecules containing linked dAbs specific for different antigens/targets, which is not possible with conventional antibodies and difficult to achieve with other antibody fragments such as Fabs and scFvs. Due to the monomeric and monovalent binding mode of dAb, it is suitable for use in situations where the target cannot interfere with the monoclonal antibody. TNFR1 is one such target; TNFR1 is activated/activated by antibody-induced receptor cross-linking (see, e.g., Holt et al. (2003) Trends in Biotechnology 21(11):484-490; Schmidt et al. ( 2013) Arthritis & Rheumatism 65(9):2262-2273; Goodall et al. (2015) PLoS ONE 10(9):e0137065).

Small-sized antibody fragments, such as dAb, scFv, Fv, disulfide-bonded Fv, and Fab, are easier to produce and process than larger molecules, and are rapidly distributed throughout the body; however, they have shorter in vivo half-lives limit its efficacy. As with other antibody fragments, increasing the serum half-life of a dAb increases efficacy and reduces dosing frequency, especially in applications where binding to antigen in the bloodstream is required, such as in the treatment of rheumatoid arthritis or cancer. This can be achieved by pegylation, binding to serum albumin, fusion to a second dAb that specifically binds to serum albumin, or fusion to an Fc fragment or complete antibody constant region. Fusion to the Fc region also allows recruitment of Fc effector functions, including complement activation, antibody-dependent cytotoxicity, or FcR-mediated clearance of immune complexes (see, e.g., Holt et al. (2003) Trends in Biotechnology 21(11):484-490; Goodall et al. (2015) PLoS ONE 10(9):e0137065). a ) Anti- TNFR1 dAb- anti-albumin dAb fusion construct

DMS5540 is a 25 kDa mouse TNFR1 antagonist, a bispecific single variable domain antibody containing a non-competitive (does not interfere with TNF binding) anti-TNFR1 dAb fused to an albumin-binding dAb (AlbudAb; extends serum half-life). DMS5540, which does not bind human TNFR1, was found to inhibit TNFα-mediated cytotoxicity in the mouse fibroblast cell line L929, which is highly sensitive to TNFα-mediated cytotoxicity. DMS5540 was administered intravenously to mice, followed by an intravenous bolus injection of TNFα four hours later, and serum IL-6 levels were assessed. DMS5540 demonstrates TNFα-mediated signaling in vivo as measured by reduced IL-6 response when compared to mice administered a control dAb lacking specific antigen binding but fused to AlbudAb (DMS5538) or no dAb Dose-dependent inhibition of conduction effects (see e.g. Goodall et al. (2015) PLoS ONE 10(9):e0137065).

In another study, starting on the day of arthritis onset, DMS5540, an isotype (negative) control dAb (DMS5538), or murine TNFR2 genetically fused to the mouse IgG1 Fc domain (mTNFRII-Fc; mTNFR2.Fc) (which blocks Mice with collagen-induced arthritis (CIA) were treated for 10 days by blocking two receptors (TNFR1 and TNFR2) and inhibiting TNF in mice, and the disease progression was monitored. Systemic interleukin concentrations are measured, the number of T cell subsets in lymph nodes and spleen is assessed, and intrinsic Treg cell function is assessed. Compared with negative controls, disease progression was similarly inhibited by blocking TNFR1 with DMS5540 and TNFR1/2 with mTNFRII-Fc, indicating that blocking TNFR1 or TNF protects joints from inflammatory mediators that cause joint damage in arthritis. body impact. Increased effector T cell activity as measured by expression of pro-inflammatory cytokines (e.g., IFNγ, IL10, and RANTES) following blockade of TNFR1/2 with mTNFRII-Fc, but not after selective blockade of TNFR1 with DMS5540, indicated Immunomodulatory effects of TNFR2 signaling (e.g. suppression of T cell effector functions). In addition, blocking TNFR1 but not TNFR1/2 caused the expansion and activation of Treg cells, and increased expression of FoxP3 and TNFR2, both expressed by Treg, was observed in joints experiencing remission, indicating their role in the resolution of inflammation. These results indicate that inhibition of TNFR1 but not TNFR2 signaling suppresses inflammation and promotes Treg cell suppressive activity, resulting in enhanced efficacy compared with traditional approaches of TNF inhibition (see, e.g., McCann et al. (2014) Arthritis & Rheumatology 66 (10):2728-2738).

In an in vivo mouse model of lipopolysaccharide (LPS)-induced osteolysis, DMS5540 also prevented inflammation-induced osteoclast formation and bone loss more effectively than mTNFR2.Fc (anti-TNF). TNFR2-deficient mice display increased LPS-induced bone destruction. In vitro, the human equivalent of DMS5541, containing the anti-human TNFR1 dAb, DMS5541, was more effective than etanercept in reducing human osteoclastogenesis in the presence and absence of low doses of TNF. These results indicate an osteoprotective role of TNFR2 signaling. Therefore, selective inhibition of TNFR1 may also be useful for therapeutic intervention in inflammatory bone loss disorders, such as osteomyelitis and periprosthetic osteolysis and aseptic relaxation (see, e.g., Esperito Santo et al. Biochem. Biophys. Res. Commun. 464: 1145-1150).

DMS5541 containing a non-competitive human TNFR1-specific dAb fused to AlbudAb was evaluated for selective blocking of TNF signaling through TNFR1 in cultured human rheumatoid arthritis (RA) synovial mononuclear cells (MNC) in vitro (also known as TNFRI-AlbudAb), these synovial monocytes express TNFR1 and TNFR2 and spontaneously produce inflammatory cytokines and chemokines in the absence of exogenous stimulation. DMS5541 inhibits the pro-inflammatory cytokines GM-CSF, IL-10, IL-1β, and IL-6 as well as the chemokines IL-8, RANTES ( CCL5) and MCP-1 (CCL2) production. This inhibition was not due to cytotoxicity, as DMS5541 inhibited TNFα-induced cytotoxicity in human rhabdomyosarcoma KYM-1D4 cells in a dose-dependent manner similar to TNF blockade with etanercept. In addition, DMS5541 inhibited the production of soluble TNFR1, but not the production of soluble TNFR2, confirming its selectivity for TNFR1. These results indicate that the TNFR1 pathway is the primary inflammatory pathway responsible for the TNF response observed in an in vitro cultured RA synovial MNC disease model (see, e.g., Schmidt et al. (2013) Arthritis & Rheumatism 65(9): 2262-2273). b ) Domain antibody fragments named GSK1995057 and GSK2862277

The domain antibody fragment designated GSK1995057 (see SEQ ID NO: 55) is a short-acting fully human domain antibody (dAb) fragment (containing a _VH chain) that selectively antagonizes TNF signaling through TNFR1 but not through TNFR2. Due to its small size, GSK1995057 can be aerosolized directly into the lungs and has been studied in animal and human acute respiratory distress syndrome (ARDS) models via inhalation therapy. GSK1995057 reduces lung inflammation in non-human primate (cynomolgus macaque) and human ARDS models. Pulmonary neutrophil infiltration is central to the pathogenesis of ARDS and is increased by disruption of the alveolar-capillary barrier resulting from the action of pro-inflammatory mediators. TNF-α promotes an increase in endothelial permeability, and GSK1995057 prevents this increase, indicating that TNFR1 signaling mediates TNF-induced endothelial permeability (see, e.g., Proudfoot et al. (2018) Thorax 73:723-730). The trial failed due to its inherently short half-life and neutralization by autoantibodies. The immunogenicity of GSK1995057 is more attributable to improper folding of the protein in E. coli than to a failure to properly humanize the dAb; it is derived from a human antibody fragment and only the hypervariable sequence is altered to accommodate targeting of TNFR1 Specificity (see, for example, International PCT Publication No. WO2008/149148A2).

Pretreatment with GSK1995057 reduced pulmonary neutropenia in a dose-dependent manner in monkeys exposed to a single inhaled lipopolysaccharide (LPS) challenge, a well-established model for triggering clinically relevant inflammatory responses and modeling subclinical tissue damage. Globular infiltration, pro-inflammatory chemokines content, endothelial damage markers and alveolar-capillary leakage. The results indicate that inhalation of GSK1995057 can affect the same results as higher doses of parenterally administered antibodies. In clinical trials in which healthy human subjects were pretreated with a single aerosolized dose of GSK1995057 and subsequently exposed to low doses of inhaled LPS, the pretreated individuals experienced fewer symptoms in response to LPS challenge compared with individuals who received placebo. Systemic inflammation, as well as signs of neutrophilic pulmonary inflammation and endothelial injury. Regardless of these results, they are unlikely to be translated into the clinic. In trial GSK1995057, it was administered before the LPS challenge, but patients with ARDS generally require treatment after the initial injury (see, e.g., Proudfoot et al. (2018) Thorax 73:723-730), rather than before.

Another difficulty is the adverse effect of anti-drug antibodies (ADA) observed in the clinical phase I study of GSK1995057 with anti-TNFR1 agents due to high levels of pre-existing naturally occurring ADA present in approximately 50% of the drug in healthy individuals. For anti-immunoglobulin autoantibodies (also known as ADA), interleukin release infusion reactions have been observed at doses of 2-10 µg/kg. Specifically, ADA is a human anti- _VH (HAVH) autoantibody, and a complex of HAVH autoantibodies with the framework sequence of GSK1995057 causes activation of TNFR1 signaling, and in individuals with high HAVH autoantibody titers Mild to moderate infusion reactions have occurred (see, e.g., Cordy et al. (2015) Clin. Exp. Immunol. 182:139-148).

Binding of HAVH autoantibodies to the framework region of dAb GSK1995057 induces interleukin release in vitro. Characterization of epitopes on GSK1995057 of autoantibodies. Pre-existing anti-drug antibodies (ADA) bind to epitopes close to the C-terminal region of _VH dAbs, including dAb GSK1995057. To combat this, a modified dAb was generated by adding a single alanine residue at the C-terminus of the modified dAb, named GSK2862277 (see SEQ ID NO: 56). This modification reduces binding to HAVH autoantibodies. In serum samples from healthy individuals who screened positive for HAVH autoantibodies binding to GSK1995057, the frequency of preexisting autoantibodies decreased from 51% for GSK1995057-specific HAVH autoantibodies to 51% for GSK2862277-specific autoantibodies. 7%. Human in vitro system and in vivo animal experiments show that GSK2862277 does not induce TNFR1 activation even in the presence of GSK2862277-specific autoantibodies, and the pharmacological and biophysical properties of GSK2862277, including target affinity, in vitro potency, and in vivo drug The kinetics and pharmacodynamics are comparable to the pharmacological and biophysical properties of the parent dAb (GSK1995057).

A Phase I clinical trial investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeated doses of inhaled (ih) and intravenous (iv) GSK2862277 found that when administered via inhalation or intravenously, GSK2862277 Generally well tolerated. However, one individual had a mild infusion reaction with interleukin release following repeated IV dosing; this individual had high serum levels of pre-existing antibodies to GSK2862277, and serum antibodies from this individual demonstrated in the in vitro assay Activates TNFR1 signaling. The interaction between GSK2862277 and autoantibodies causes antibody-mediated GSK2862277-dependent cross-linking of cellular TNFR1, agonizing the receptor and causing cytokine release. Therefore, although binding of GSK2862277 to pre-existing HAVH autoantibodies is reduced, adverse effects are still associated with the presence of new pre-existing antibody responses specific to the modified dAb framework. These results highlight the challenges in developing biological antagonists against TNFR1 (see, eg, Cordy et al. (2015) Clin. Exp. Immunol. 182:139-148). Therefore, improved TNFR1 antagonists are still needed. iii. Nanobody ( Nb )

Similar to dAbs, nanobodies (Nbs) are small antigen-binding fragments derived from camelid heavy chain antibodies that do not contain a light chain. It is small (15 kDa), has low immunogenicity and high affinity, is soluble and stable, and is encoded by a single gene/exon (VHH), making it modular and allowing high-yield production in bacteria or yeast. iv. Anti -TNFR1 nanobody - anti-albumin nanobody fusion construct

TNF Receptor One-Silencer (TROS; also known as Nb Alb-70-96) is a trivalent high-affinity nanobody-based selective inhibitor of human TNFR1 that competes with TNF for binding to TNFR1 . To generate TROS, two anti-human TNFR1 nanobodies (Nb 70 and Nb 96; see SEQ ID NO: 683 and 684, respectively) that had been generated from the VHH library by immunizing sheep with recombinant human soluble TNFR1 were ligated Constructed from camels, these nanobodies were linked to anti-albumin nanobodies (Nb Alb) via a (Gly ₄ Ser) ₃ linker to increase serum half-life to produce trivalent TROS. The serum half-life of TROS is about 24 hours; the serum half-life of monovalent Nb is only about 1.5 hours. Treatment with TROS delays the onset of experimental autoimmune encephalomyelitis (EAE; MS model) in mice and prevents established disease; efficacy is attributed to the redirection of TNF signaling through TNFR2 and the role of this signaling. TROS also inhibits inflammation in cultured colon biopsies from Crohn's disease patients and antagonizes inflammation in an acute TNF-induced hepatitis model in liver chimeric humanized mice (see, e.g., Steeland et al. (2015) J . Biol. Chem. 290(7):4022-4037; Steeland et al. (2017) Sci. Reports 7:13646). c. Dominant negative inhibitor of TNF ( DN-TNF ) /TNF mutant protein

Another class of TNF inhibitors is the incompetent dominant negative inhibitor of TNF (DN-TNF) signaling, also known as TNF mutant protein. DN-TNF is an engineered variant of TNF with mutations that eliminate binding to and signaling through TNFR1 and TNFR2. DN-TNF selectively inhibits soluble TNF (sTNF or solTNF) by rapidly exchanging subunits with native TNF homotrimers, forming inactive mixed TNF heterotrimers with disrupted receptor binding surfaces, thereby preventing interaction with TNF receptor interactions. DN-TNF leaves transmembrane TNF (tmTNF) unaffected, maintaining the protective effect of TNF signaling via TNFR2. DN-TNF inhibits TNF-induced NF-кB activity and apoptotic protease-mediated apoptosis, and reduces disease severity in animal models of arthritis and Parkinson's disease. Such molecules may be immunogenic because of their structure.

As a selective inhibitor of soluble TNF, DNA-TNF, unlike anti-TNF therapies that bind to solTNF and tmTNF, does not inhibit tmTNF signaling and does not suppress resistance to Listeria monocytogenes infection in mice. An example of a DN-TNF is solTNF containing the substitutions L133Y, S162Q, Y163H, I173T, Y191Q and A221R with reference to the amino acid sequence set forth in SEQ ID NO: 1 (corresponding to solTNF as set forth with reference to SEQ ID NO: 2 TNF mutants of one or more of the sequence residues L57Y, S86Q, Y87H, I97T, Y115Q and A145R), which weaken the binding to TNFR. Additional modifications may also be included, for example to improve performance and allow site-specific pegylation (see, eg, Zalevsky et al. (2007) J. Immunol. 179:1872-1883).

For example, the TNF mutations R32 and S86T of SEQ ID NO: 2 cause a hundreds-fold loss of affinity to TNFR2, but do not affect binding to TNFR1. The R32W/S86T double mutant eliminates all binding to TNFR2 and has no loss in binding to TNFR1. Refer to the mutations of SEQ ID NO: 2 L29S, L29G, L29Y, R31E, R31N, R32Y, R32W, S86T, L29S/R32W, L29S/S86T, R32W/S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T and E146R also confer selectivity for TNFR1. The mutations D143N, D143Y, A145R and D143N/A145R of SEQ ID NO: 2 render the TNF variant selective for TNFR2 (see, for example, Loetscher et al. (1993) J. Biol. Chem. 268(35):26350-26357 ; U.S. Patent No. 5,422,104).

The modified TNF (INmuneBio; see SEQ ID NO: 701) named C69V, Y87H, C101A and A1456R (see, for example, U.S. Publication No. 2015/0239951). XPro1595 reduces neuroinflammation and is being studied to treat Alzheimer's disease (see, for example, Clinical Trial Identifier No. NCT03943264). XPro1595 blocks the occurrence of amyloid pathology in a mouse model of Alzheimer's disease (3xTgAD), prevents the loss of neuronal communication and cognitive impairment in a different (tgCRND8) mouse model of Alzheimer's disease, and attenuates normal aging Dysfunction of neuronal communication and cognitive deficits in rats, and prevent amyloid pathology, cognitive impairment and neuronal communication dysfunction in young mice in the third model of Alzheimer's disease (5xFAD). In aged mice with Alzheimer's-like lesions, XPro1595 reduced amyloid, improved cognition, restored neuronal communication, and normalized innate and adaptive immune responses.

Levels of TNFR1 compared with TNFR2 were higher in the hippocampus in old (22 months) but not young adult (6 months) Fischer 344 rats. When treated with XPro1595, aged rats showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to long-term hippocampal depression, and increased GluR1-type glutamate receptors. The body content and lower L-type voltage-sensitive Ca ²⁺ channel (L-VSCC) activity in hippocampal CA1 neurons indicate that selective changes in TNF signaling may produce functional changes related to brain aging. XPro1595 inhibits neuroinflammation and microglial activation in animal models of Parkinson's disease and aging. In EAE (MS model), XPro1595 ameliorates disease, improves remyelination and reduces CNS pathology and neuroinflammation. XPro1595 also improves inflammatory arthritis and reduces susceptibility in treated animals. Compared with etanercept, which has no efficacy, treatment with XPro1595 is more effective in delaying the onset of EAE and improving symptoms. XPro1595 administration increased TNFR2 expression in EAE lesion areas, indicating that tmTNF signaling via TNFR2 is involved in neuroregeneration (see, e.g., Yang et al. (2018) Front. Immunol. 9:784; Sama et al. (2012) PLoS ONE 7 ( 5):e38170). Since XPro1595 does not inhibit the activity of transmembrane TNF (which activates TNFR1 and TNFR2), it cannot block the inflammatory effect of TNFR1. This also applies to other dominant negative TNF agents described below.

XENP345 (see SEQ ID NO: 702) is a pegylated DN-TNF mutein containing the mutation I97T/A145R of reference SEQ ID NO: 2. In animal models of Parkinson's disease and Alzheimer's disease, XENP345 neutralizes soluble TNF (solTNF) in vivo and is neuroprotective, reducing neuronal degeneration and cognitive dysfunction, and slowing the progression of neurodegenerative diseases ( See, eg, McCoy et al. (2006) J. Neurosci. 26(37):9365-9375; McAlpine et al. (2009) Neurobiol. Dis. 34(1):163-177).

R1antTNF (see SEQ ID NO: 703) is a TNFR1-selective antagonistic mutant TNF identified from a phage library showing structural human TNF variants in which the receptor binding site corresponds to residues 84-89 of SEQ ID NO: 2 Each of the six amino acid residues was mutated. R1antTNF containing mutations A84S, V85T, S86T, Y87H, Q88N and T89Q has similar affinity to TNFR1 as wild-type human TNF and does not interfere with TNFR2 activity. R1antTNF ameliorated liver injury, as demonstrated by reduced serum levels of alanine aminotransferase and the pro-inflammatory cytokines IL-2 and IL-6 in two models of acute hepatitis. However, R1antTNF, like wild-type TNF, has an extremely short plasma half-life (12 minutes). To extend the in vivo half-life of R1antTNF, a pegylated version, PEG-R1antTNF, was generated in which PEG was bound to the N-terminal site of R1antTNF. PEG-R1antTNF reduces the incidence, improves disease symptoms, improves myelin loss in EAE mouse models, and inhibits Th1 and Th17 cell activation and inflammatory T cell infiltration in the spinal cord. PEG-R1antTNF also inhibits NF-κB in IL-1 receptor antagonist-deficient mice, inhibits smooth muscle cell proliferation, and reduces the expression of chemokines and adhesion molecules, thereby inducing femoral artery injury in the external vascular cuff model. It then reduces intimal hyperplasia and arterial inflammation. When recombinant adenoviral vectors were used to compare the antiviral immunity effects of PEG-R1antTNF and etanercept, PEG-R1antTMF did not reactivate viral infection and did not affect the clearance of injected adenovirus. At the same time, the viral load increased with etanercept. Increased after general treatment. PEG-R1antTNF treatment also delayed and improved CIA symptoms in both preventive and therapeutic settings and was more effective than etanercept when used to treat established CIA (see e.g. Yang et al. ( 2018) Front. Immunol. 9:784; Shibata et al. (2008) J. Biol. Chem. 283(2):998-1007; Kitagaki et al. (2012) J. Atheroscler. Thromb . 19(1):36-46; Fischer et al. Humans (2015) Antibodies 4:48-70; Horiuchi et al. (2010) Rheumatology ( Oxford ) 49 :1215-1228).

Soluble TNFR1 is also associated with an increased risk of developing MS; therefore, neutralization of soluble TNFR1 that is not achieved by DN-TNF/TNF mutant proteins may be beneficial. In contrast to solTNF inhibitors such as DN-TNF, TNFR1 antagonists block the binding of lymphotoxicity-α (LT-α), another member of the TNF superfamily, to TNFR1. LT-α can have pro-inflammatory effects in RA and animal disease models such as CIA and EAE; therefore, in acute and chronic inflammatory diseases and conditions, TNF and LT-α are simultaneously blocked by TNFR1 antagonists binding to TNFR1 TNF inhibition may have additional benefits compared to sol (see e.g. Fischer et al. (2015) Antibodies 4:48-70). 2. TNFR2 selective agonists

CD4 ⁺ FoxP3 ⁺ regulatory T cells (Treg) maintain immune homeostasis and suppress autoimmune responses; Tregs also regulate anti-tumor immune responses and allow tumor immune evasion. Therefore, Tregs are therapeutic targets in the treatment of, for example, autoimmune and chronic inflammatory diseases and conditions, graft versus host disease (GvHD), transplant rejection, and cancer. TNF regulates the function and activity of Tregs through TNFR2 signaling. TNFR2 agonists upregulate Treg activity, while TNFR2 antagonists downregulate Treg activity. Treg stimulation of the TNF-TNFR2 signaling pathway can be used to treat several human diseases and conditions via agonist effects, including autoimmune and chronic inflammatory diseases, and cancer via antagonism (see, e.g., Zou et al. (2018) Front. Immunol. 9:594).

TNFR2 agonists include antibodies, such as monoclonal TNFR2 agonist antibodies and antigen-binding fragments thereof, peptides and proteins, such as TNFR2-selective TNF muteins, fusion proteins and small molecules. As provided herein, the specific agonistic effects of TNFR2 induce the expansion and activation of Tregs that regulate the immune system, reduce the activity of autoreactive CD8 ⁺ T cells in damaged tissue, and induce anti-inflammatory and cell survival, regeneration and protection Its effects include signal transduction pathways for neuroprotection, cardioprotection, intestinal protection and bone protection. Therefore, enhancing TNFR2 signaling with TNFR2-selective agonists may be used to enhance the efficacy of TNFR1-specific antagonism, especially in the treatment of autoimmune and chronic inflammatory diseases and conditions, including those in which anti-TNF therapy/TNF blockade has failed. Neurodegenerative diseases. a. TNFR2 agonist antibody

Human TNFR2-selective agonist antibodies include commercially available MR2-1 (monoclonal mouse IgG1 that binds human, cynomolgus monkey, and rhesus monkey TNFR2; Hycult Biotech) and pure line MAB2261 (monoclonal mouse that binds human TNFR2 IgG2A; R&D Systems). TNFR2 agonists, such as antibodies, effectively stimulate the expansion of a homogeneous population of FoxP3 ⁺ Tregs in CD4 cell cultures and upregulate the expression of TNF, TRAF2, TRAF3, BIRC3 (cIAP2) and FoxP3 mRNA. When expanded in the presence of TNFR2 agonist antibodies, compared to in the absence of TNFR2 agonists, using standard in vitro human Treg expansion protocols (i.e., with anti-CD3 antibodies, anti-CD28 antibodies, IL Magnetic-activated cell sorting (MACS) purified CD4 ⁺ CD25 ⁺ cells cultured with -2 and rapamycin), resulting in higher levels of FoxP3 (and other characteristic Treg markers) Expanded Tregs and more effective suppression capabilities. Tregs isolated from patients with type 1 diabetes (displaying a dormant phenotype) were activated and expanded after in vitro treatment with TNFR2 agonist antibodies; these Tregs are more potent in suppressing autologous CD8 ⁺ T cells (see For example Zou et al. (2018) Front. Immunol. 9:594).

Treatment of isolated Tregs expanded using standard in vitro protocols with MR2-1, a commercially available agonist human TNFR2 monoclonal antibody (mAb) containing mouse IgG1, generated a homogeneous population of FoxP3 ⁺ Helios ⁺ CD127 ^low Tregs; this Tregs maintained their phenotype and high suppressor activity in humanized mouse models. Therefore, TNFR2 agonists can enhance the ex vivo expansion of Treg cells from impure cell populations for Treg-based immunotherapy (see, e.g., Zou et al. (2018) Front. Immunol. 9:594). b. TNFR2- selective TNF mutant protein and its fusion

As described herein, TNF can be engineered to selectively bind TNFR1 or TNFR2; for example, a TNFR2-selective TNF mutein is one that contains one or more proteins that increase binding to TNFR2 and/or reduce or eliminate binding to TNFR1. Mutated TNF variants. TNFR2 selective mutations include non-conservative substitutions of the Asp residue at position 143 of soluble TNF (see SEQ ID NO: 2), such as D143Y, D143F, or D143N, or non-conservative substitutions of the Ala residue at position 145 of soluble TNF, such as A145R (see, eg, U.S. Patent No. 9,081,017). Other mutations in TNF that confer selectivity for TNFR2 include, but are not limited to, for example, K65W, D143E, D143W, D143V, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N /T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145 T/E146S/S147D, A145Q/E146D /S147D、A145T/E146D/S147D、A145D/E146G/S147D、A145D/S147D、A145K/E146D/S147T、A145R/E146T/S147D、A145R/S147T、E146D/S147D、D143V/F 144L/A145S and D143V/A145S, reference SEQ ID NO: 2, (see, eg, U.S. Patent Publication No. 2020/0102362).

TNF ligand trimerization is required for signaling through TNFR. At low concentrations, such as in serum, the trimer dissociates, causing its degradation. To generate functionally active receptor-specific TNF muteins, stable trimers must be generated. TNF07 is a soluble TNF (sTNF or solTNF) mutein that contains the mutations S95C/G148C (see the residue sequence set forth in SEQ ID NO: 2) that form a stable TNF trimer and acts as a TNFR2 agonist. The S95C/G148C mutation causes the formation of intermolecular Cys-Cys covalent bonds; thus a stable trimer is formed due to covalent internal disulfide cross-linking of sTNF at strategic positions between TNF monomers. TNF07 acts as a TNFR2 agonist despite lacking TNFR2-selective mutations. TNF07 induces potent TNFR2 signaling, expands FoxP3 ⁺ Treg cells, and selectively induces death of autoreactive CD8 ⁺ T cells isolated from patients with type 1 diabetes (see e.g. Ban et al. (2015) Molecular and Cellular Therapies 3:7; Zou et al. (2018) Front. Immunol. 9:594).

Several TNFR2 agonists have been generated containing fusions of single-chain TNFR2-selective TNF mutein trimers and multimerization domains. As described herein, the primary ligand of TNFR2 is membrane-bound TNF (memTNF; also referred to herein as transmembrane TNF or tmTNF). The addition of multimerization domains, such as dimerization or trimerization domains, generates hexameric or nonameric molecules, respectively, relative to TNF subunits; these hexamers and nonamers of TNF mimic membrane-bound TNF trimers , and therefore can effectively activate TNFR2 signaling. Commonly used dimerization domains include EHD2, which is derived from the heavy chain _CH2 domain of IgE, and MHD2, which is derived from the heavy chain _CH2 domain of IgM. Dimerization domains may also include Fc domains, such as those derived from IgG1 and IgG4, optionally including modifications that alter immune effector function. Commonly used trimerization domains include chicken tenascin C (TNC) and human TNC. Dimerization and trimerization enhance TNFR2 signaling and improve the half-life of the fusion protein, for example by increasing the molecular weight of the molecule and/or by introducing FcRn recycling, for example when the dimerization domain is Fc.

STAR2 (also known as TNC-sc-mTNF (221N/223R)) is a nine-mer agonist TNFR2-specific mouse TNF variant that does not bind TNFR1 and is a single-chain mouse TNF trimer in which each TNF subunit Residues 91-235 of SEQ ID NO: 5 fused to the trimerization domain of chicken tenascin C (cTNC) corresponding to residues 110-139 of SEQ ID NO: 804 (see also SEQ ID NO: 805) . Three single-chain mouse TNF subunits are linked via two (GGGS) _4- peptide linkers (see, e.g., SEQ ID NO:707. Residues 116-120), and the TNC trimerization domain is linked in the single-chain trimer The N terminal of the first TNF subunit. The specificity of STAR2 for TNFR2 results from mutations D221N and A223R within individual TNF subunits (referring to the sequence of mouse TNF set forth in SEQ ID NO: 5), which create steric hindrance between STAR2 and mouse TNFR1. Fusion with the TNC trimerization domain causes spontaneous oligomer formation, producing three covalently linked TNF trimers and mimicking membrane-bound TNF. STAR2 stimulates Treg proliferation in vitro and in vivo in a TNFR2-dependent and IL-2-dependent mechanism. Pretreating allogeneic hematopoietic stem cells with STAR2 in mice before transplantation prolonged survival and reduced the severity of GvHD in a TNFR-2 and Treg-dependent manner. Human equivalents of the TNFR2-specific STAR2 agonist TNC-scTNF (143N/145R), consisting of residues 9-157 of soluble TNF containing the mutation D143N/A145R (solTNF) referenced to SEQ ID NO: 2 (see SEQ ID NO: 2) constitutes a potent in vitro stimulation of CD4 ⁺ FoxP3 ⁺ Treg expansion from CD4 ⁺ T cells isolated from healthy donors (see, e.g., Chopra et al. (2016) J. Exp. Med. 213(9):1881-1900 ; Zou et al. (2018) Front. Immunol. 9:594).

TNC-scTNF _R2 is a soluble human TNFR2 agonist that is a fusion of the trimerization domain of human tenascin C (hTNC) and the N-terminus of a TNFR2-selective single-chain TNF variant (scTNF _R2 ; SEQ ID NO:803) , the human tenascin C contains residues 110-139 of SEQ ID NO: 806 (see also SEQ ID NO: 807), this variant contains three TNF domains connected by two short peptide linkers (GGGGS). The TNFR2-selective TNF molecule scTNF _R2 is similar to soluble trimeric TNF, and each TNF subunit includes amino acids 80-233 of the full-length TNF set forth in SEQ ID NO: 1 (corresponding to residue 4 of SEQ ID NO: 2 -157), this TNF has the mutation D143N/A145R of reference SEQ ID NO: 2, which eliminates the binding to TNFR1. Since TNFR2 is fully activated only by membrane-bound TNF and not soluble TNF trimers, the trimerization domain of TNC was fused to the N-terminus of scTNF _R2 , resulting in TNC-scTNF _R2 . TNC-scTNF _R2 exists in trimeric assemblies of single-stranded fusion proteins and resembles non-polymeric TNF molecules; this oligomeric TNF mutant protein mimics membrane-bound TNF (memTNF) activity due to its increased affinity, inducing TNFR2 clustering chemical and TNFR2 signaling complexes are formed, effectively activating TNFR2. TNC-scTNF _R2 exhibits neuroprotective properties; it protects neurons from peroxidative cell death and repairs neurons from catecholamine-sensitive cell death. In an in vitro model of Parkinson's disease, TNC-scTNF _R2 repaired neurons following 6-OHDA-induced cell death. These results indicate that TNC-scTNF _R2 may improve neurodegenerative processes (see, eg, Fischer et al. (2011) PLoS ONE 6(11):e27621).

EHD2-scTNF _R2 (see SEQ ID NO: 810) is a potent TNFR2-selective TNF mutein fusion protein containing a covalently stabilized human TNFR2-selective single-chain TNF trimer (scTNF _R2 ; SEQ ID NO: 803). This trimer has the mutations D143N/A145R (residue numbers refer to soluble TNF as set forth in SEQ ID NO: 2), which eliminate binding to TNFR1, fused to the heavy chain _CH 2 domain derived from IgE Dimerizes domain EHD2 (SEQ ID NO: 808) and produces a disulfide-bonded dimer containing a hexameric TNF domain. Each TNF subunit within scTNF _R2 contains residues 4-157 of SEQ ID NO: 2. EHD2 was fused to the N-terminus of trivalent human single-chain scTNF _R2 via a peptide linker (GGGSGGGSGGGSGGGSGGGSGGSEFLA; SEQ ID NO:809), and the three TNF domains of scTNF _R2 were connected via two GGGGS peptide linkers. EHD2-scTNF _R2 exhibits neuroprotective properties in a mouse model of NMDA-induced acute neurodegeneration (see, e.g., Dong et al. (2016) Proc. Natl. Acad. Sci. USA 113(43):12304-12309; and U.S. Patent Public Case No. 2020/0102362).

TNFR2 agonist fusion proteins also include single-chain TNFR2 agonist (scTNF _R2 ), which contains three TNF mutant proteins with mutations D143N/A145R (reference SEQ ID NO: 2), which eliminates binding to TNFR1 and acts as The Fc dimerization domain is fused to produce a protein that is hexameric with respect to the TNF domain (scTNF _R2 -Fc). The Fc can be an IgG4 or IgG1 Fc, optionally containing mutations that eliminate Fc effector functions, such as ADCC and CDC. Three TNF muteins containing residues 12-157 of SEQ ID NO: 2 are linked together by two short peptide linkers, and the dimerization domain is linked to a single-chain triplet by a third short peptide linker. The N-terminus or C-terminus of poly-TNF molecule (scTNF _R2 ). The three linkers may all be the same or may be different, and may include a GS linker such as (GGGGS) _n residues 116-121 of SEQ ID NO: 707, and/or other combinations of Gly and Ser), where n=1 -5, or may include all or part of the stem region of TNF-α, at least 10, 15, or 20 contiguous residues (GPQREEFPRDLSLISPLAQAVRSSSRTPSDK (SEQ ID NO:812), corresponding to residue 57- of SEQ ID NO:1 87). Dimerization enhances signaling by TNFR2 agonists and also improves the half-life of the fusion protein. Alternative dimerization domains that can be used in fusion proteins include Fc fusion proteins derived from other dimeric molecules, such as IgE heavy chain domain 2 (EHD2; see SEQ ID NO: 808) and IgM heavy chain domain 2 (MHD2; see SEQ ID NO: 811) (see, for example, International Application Publication No. WO 2019/226750). 3. Anti- TNFR2 antagonist antibodies and small molecule inhibitors

TNFR2 antagonists inhibit the proliferation of Treg and induce their death, and can also inhibit the proliferation and induce the death of tumor cells expressing TNFR2. TNFR2 antagonists can reduce or inhibit the proliferation of myeloid-derived suppressor cells (MDSCs) and/or induce apoptosis within MDSCs by binding to TNFR2 expressed on the surface of MDSCs present in the tumor microenvironment. TNFR2 antagonists also induce the expansion of T effector cells, including cytotoxic CD8 ⁺ T cells, by inhibiting Treg expansion and activity. Therefore, TNFR2 antagonists may be suitable for the treatment of infectious diseases and certain cancers expressing TNFR2, such as T-cell lymphoma (such as Hodgkin's lymphoma and cutaneous non-Hodgkin's lymphoma), ovarian cancer, colon cancer, Multiple myeloma, renal cell carcinoma, breast cancer, cervical cancer, endometrial cancer, glioma, head and neck cancer, liver cancer and lung cancer. (See, e.g., U.S. Patent Publication No. 2019/0144556; Torrey et al. (2017) Sci. Signal. 10:eaaf8608).

As discussed herein, the expression of TNFR2 is restricted to specific immune cells, including Tregs and MDSCs; endothelial cells; and specific neuronal and cardiac cells. The restricted expression of TNFR2 makes it an ideal drug target because systemic toxicity from anti-TNFR2 therapeutics is unlikely to occur.

TNFR2 antagonist antibodies and antigen-binding fragments thereof bind to epitopes in human TNFR2 containing one or more of the residues KCRPG (corresponding to residues 142-146 of SEQ ID NO: 4), or containing residues 130-149 , 137-144 or 142-149, or at least 5 contiguous or discontinuous residues within such epitopes, and do not bind to residues containing residues KCSPG (corresponding to residues SEQ ID NO. : 4 of 56-60) epitope. TNFR2 antagonists can also bind to the TNFR2 epitopes PECLSCGS (corresponding to residues 91-98 of SEQ ID NO: 4), RICTCRPG (corresponding to residues 116-123 of SEQ ID NO: 4), CAPLRKCR (corresponding to residues 116-123 of SEQ ID NO: 4) NO: 4 (residues 137-144), LRKCRPGFGVA (corresponding to SEQ ID NO: 4 residues 140-150) and VVCKPCAPGTFSN (corresponding to SEQ ID NO: 4 residues 159-171) and/or contained in SEQ An epitope of at least 5 consecutive or non-consecutive residues within residues 75-128, 86-103, 111-128 or 150-190 of ID NO: 4 (see, e.g., U.S. Patent Publication No. 2019/0144556) .

In general, antagonistic TNFR2 antibodies or antigen-binding fragments thereof bind to an epitope containing one or more residues of the KCRPG sequence (SEQ ID NO: 840) with greater affinity than the same antibody or antigen-binding fragment containing human TNFR2. The affinity of the peptide of the KCSPG sequence (SEQ ID NO: 839) is at least 10 times greater. An antibody or antibody fragment that binds an epitope containing one or more residues of the KCRPG sequence and an epitope containing a KCSPG motif with similar affinity (e.g., less than a 10-fold difference in affinity) is not an antagonistic TNFR2 antibody. Antagonistic TNFR2 antibodies include TNFRAB1 (for the sequences of the heavy and light chains of TNFRAB1, see SEQ ID NO: 1213 and 1213, respectively), TNFRAB2 and TNFR2A3 (for a description of these antibodies, see, for example, U.S. Patent Publication No. 2019/0144556 ). TNFR2 antagonists also include CDR-H3 containing TNFRAB1 (QRVDGYSSYWYFDV; corresponding to residues 99-112 of SEQ ID NO: 1212), TNFRAB2 (ARDDGSYSPFDYWG; SEQ ID NO: 1217) or TNFR2A3 (ARDDGSYSPFDYFG; SEQ ID NO: 1223) Sequence or CDR-H3 sequence having at least about 85% sequence identity thereto and antibodies and antibody fragments thereof. TNFRAB1, for example, specifically binds to residues 130-149 of TNFR2-containing residues KCRPG with a 40-fold higher affinity than residues 48-67 of TNFR2-containing residues KCSPG (see, eg, U.S. Patent Publication No. 2019/0144556) .

TNFRAB1 (see SEQ ID NO: 1212 and 1213 for heavy and light chains, respectively) is a murine antibody that antagonizes the TNF-TNFR2 interaction and, in addition to binding to the KCRPG sequence of TNFR2, also binds to TNFR2 (SEQ ID NO: 4). Epitope within residues 161-169 (CKPCAPGTF; SEQ ID NO: 1258). TNFRAB2, another antagonistic TNFR2 antibody, binds to an epitope containing residues 137-144 (CAPLRKCR; SEQ ID NO: 851) and including positions 80-86 (DSTYTQL; SEQ ID NO: 1247), 91-98 of human TNFR2 An epitope of one or more residues within (PECLSCGS; SEQ ID NO: 1248) and 116-123 (RICTCRPG; SEQ ID NO: 1249). TNFR2A3 is a murine antagonistic human TNFR2 antibody that was discovered by immunizing mice with human TNFR2 and subsequent CDR mutation induction, in which the CDR-H3 of the resulting precursor antibody was modified by the CDR-H3 sequence ARDDGSYSPFDYFG (SEQ ID NO: 1223) replacement. TNFR2A3 binds to two different epitopes within human TNFR2; the first epitope includes residues 140-150 of human TNFR2 (LRKCRPGFGVA; SEQ ID NO: 1463) and contains the KCRPG motif, and the second epitope is Contains the downstream sequence of residues 159-171 of human TNFR2 (VVCKPCAPGTFSN; SEQ ID NO: 1464). These data indicate that the CDR-H3 sequences of antagonistic TNFR2 antibodies are largely indicative of antigen-binding properties and that the CDR-H3 motif is a modular domain that can be substituted into anti-TNFR2 antibodies that do not exhibit antagonistic activity in order to confer such antibodies with Or its antigen-binding fragment TNFR2 dominant antagonistic characteristics. For example, the CDR-H3 sequence of a neutral anti-TNFR2 antibody (i.e., an antibody that is neither antagonistic nor agonistic) is modified by the CDR-H3 sequence of an antagonistic TNFR2 antibody (such as TNFRAB1, TNFRAB2, or TNFR2A3). ) substitution, e.g., converting a phenotypically neutral antibody into an antagonistic TNFR2 antibody, such as a dominant antagonist TNFR2 antibody, which is an antagonist that inhibits TNFR2 activation even in the presence of a TNFR2 agonist, such as TNF or IL-2 (see e.g. U.S. Patent Publication No. 2019/0144556).

The TNFR2 antagonist antibody or antigen-binding fragment thereof may contain the CDR-H1 sequence set forth in any of SEQ ID NOs: 1214, 1215, and 1231-1233; any of SEQ ID NOs: 1216, 1224, and 1230 The CDR-H2 sequence set forth in any of SEQ ID NO: 1217, 1223 and 1225-1229; or the CDR-H3 of TNFRAB1 corresponding to the residue of SEQ ID NO: 1212 Bases 99-112; the CDR-L1 sequence set forth in any one of SEQ ID NO: 1218 and 1234-1236; or the CDR-L1 sequence of TNFRAB1 corresponding to residues 24-33 of SEQ ID NO: 1213; The CDR-L2 sequence set forth in any one of SEQ ID NO: 1219, 1220, 1237 and 1238; or the CDR-L2 sequence of TNFRAB1 corresponding to residues 49-55 of SEQ ID NO: 1213; or SEQ ID The CDR-L3 sequence set forth in any of NO: 1221, 1222, and 1241-1244; or the CDR-L3 sequence of TNFRAB1 corresponding to residues 88-96 of SEQ ID NO: 1213. Exemplary framework regions that can be used to develop humanized anti-TNFR2 antibodies containing one or more of the above CDRs include, but are not limited to, U.S. Patent Nos. 7,732,578 and 8,093,068 and International Application Publication No. WO 2003/105782. Another approach to engineering humanized anti-TNFR2 antagonist antibodies is to align the heavy and light chain variable regions of an antagonist TNFR2 antibody, such as TNFRAB1, TNFRAB2, or TNFR2A3, with the heavy chain variable region of a common human antibody. and light chain variable region alignment. Common human antibody heavy and light chain sequences are known in the art (see, e.g., "VBASE" Human Germline Sequence Database; see also Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Department of Human Services, NIH Publication No. 91-3242, (1991); Tomlinson et al., (1992) J. Mol. Biol. 227:776-798; and Cox et al., (1994) Eur. J. Immunol. 24 :827-836). In this manner, variable domain framework residues and CDRs can be identified by sequence alignment. One can, for example, replace the CDR-H3 of a common human antibody with the CDR-H3 of an antagonistic TNFR2 antibody, such as TNFRABl, TNFRAB2, or TNFR2A3, to generate humanized TNFR2 antagonist antibodies. Exemplary variable domains of common human antibodies include the heavy chain variable domain set forth in SEQ ID NO: 1245 and the light chain variable domain set forth in SEQ ID NO: 1246, identified in U.S. Patent No. 6,054,297 (see For example, U.S. Patent Publication No. 2019/0144556). The CDR-H1 and CDR-H2 sequences of the exemplary consensus sequence of the human antibody heavy chain variable domain of SEQ ID NO: 1245 may, for example, be replaced by the corresponding CDR sequence of a phenotypically neutral TNFR2-specific antibody, and SEQ ID NO: 1246 The CDR-L1, CDR-L2 and CDR-L3 sequences of the exemplary consensus sequence of the human antibody light chain variable domain can be replaced with the corresponding CDR sequences of a phenotypically neutral TNFR2-specific antibody to generate a humanized antagonist TNFR2 antibody.

Other TNFR2 antagonists can be produced by using techniques known in the art, such as phage display, bacterial display, yeast display, mammalian display, ribosome display, mRNA display and cDNA display, or any other method known in the art. , such as methods described in U.S. Patent Publication No. 2019/0144556, screening for peptides that bind epitopes within TNFR2, such as those set forth in any of SEQ ID NOs: 1247-1464 identification.

When added to standard Treg expansion culture conditions, human TNFR2 antagonist mAb inhibits Treg expansion and reduces their inhibitory activity (see, e.g., Zou et al. (2018) Front. Immunol. 9:594). Two potent dominant anti-human TNFR2 antagonist antibodies that outperform TNF, the natural agonist of TNFR2, inhibit TNF-induced in vitro expansion of human Tregs and induce Treg death in vitro. TNFR2 antagonists specifically bind to TNFR2 through cross-linking of the F(ab) region or antibody independent of the Fc region, and block the binding of TNF to TNFR2 by binding to antiparallel dimers of TNFR2. Therefore, TNF-induced activation of the NF-κB pathway in Tregs is inhibited, and the conversion of transmembrane TNFR2 (tmTNFR2) to soluble TNFR2 (sTNFR2) is inhibited. Tregs isolated from ovarian cancer tissue were found to be more sensitive to cell death induced by TNFR2 antagonist mAbs because of higher TNFR2 expression on tumor-infiltrating Tregs. TNFR2 antagonists also induce death in TNFR2 ⁺ OVCAR3 (ovarian cancer) tumor cells, which also express TNFR2. These results indicate the therapeutic potential of TNFR2 antagonists in tumors by targeting tumor-infiltrating Tregs as well as tumor cells (see, e.g., Zou et al. ( 2018) Front. Immunol. 9:594; Torrey et al. ( 2017) Sci. Signal . 10:eaaf8608).

In addition to anti-TNFR2 antagonist mAbs, small molecules can inhibit TNFR2. For example, thalidomide is a small molecule synthetic glutamic acid derivative with immunomodulatory and anti-inflammatory properties; thalidomide and its structural analogs, lenalidomide and polydomide are classified as immunomodulators Drugs. Thalidomide and its analogues inhibit TNF synthesis by downregulating NF-кB, destroying TNF mRNA and targeting reactive oxygen species and α1 acid glycoprotein, and also inhibit TNF by inhibiting intracellular TNFR2 transport to the cell surface. Surface expression of TNFR2 on cells. Thalidomide has been shown to reduce the number and function of Tregs in patients with chronic lymphocytic leukemia, and in patients with acute myeloid leukemia, combination therapy with lenalidomide and azacytidine downregulates TNFR2 expression on CD4 ⁺ T cells and Reduce the number of TNFR2 ⁺ Treg, thereby enhancing effector immune function. However, in patients with multiple myeloma, treatment with thalidomide and its analogs increased the number of Treg, which may be attributed to the increase in serum levels of TNF after treatment, indicating that the effect of thalidomide on TNFR2 ⁺ Tregs is Disease specific (see e.g. Zou et al. ( 2018) Front. Immunol. 9:594).

Another small molecule inhibitor of TNFR2 is pabinostat, a histone deacetylase inhibitor that can reduce FoxP3 expression and inhibit the suppressive activity of Treg. Combination therapy with pabinostat and azacytidine reduces the number of TNFR2 ⁺ Tregs in the blood and bone marrow of patients with acute myeloid leukemia, and increases IFNγ and IL-2 production by effector T cells. efficacy in patients (see, e.g., Zou et al. (2018) Front. Immunol. 9:594). Cyclophosphamide, a DNA alkylating agent commonly used as a cytotoxic chemotherapeutic agent in cancer therapy, inhibits the immunosuppressive effects of Tregs at low doses and depletes PROb-bearing colon cancer cells after a single dose. Maximally suppressive Tregs in mice, causing activation of anti-tumor immune responses. Depletion of TNFR2 ^hi Tregs in a mesothelioma, cyclophosphamide-treated mouse model. The combination of cyclophosphamide and etanercept inhibits the growth of established CT26 tumors in mice by blocking TNF-TNFR2 interactions and eliminating TNFR2-expressing Treg activity (see, e.g., Zou et al. (2018) Front. Immunol. 9:594). Triptolide, an immunosuppressive molecule isolated from the Chinese herb Tripterygium wilfordii , inhibits the expression of TNF and TNFR2 in the colon of a mouse colitis model, and also reduces the number of Treg and inhibits the development of melanoma. tumor growth in mice (see e.g. Zou et al. (2018) Front. Immunol. 9:594). F. Selective targeting of the TNFR1 and / or TNFR2 axis

As described herein, existing anti-TNF therapies that block TNF and inhibit its signaling through TNFR1 and TNFR2 are limited in their therapeutic efficacy, tolerability, and safety. Anti-TNF therapy improves RA and other autoimmune and inflammatory diseases and conditions by preventing TNF signaling through TNFR1 and eliminating apoptotic and inflammatory pathways. However, these anti-TNF therapies also block the beneficial effects of TNFR2 signaling, including protective, pro-survival, pro-regenerative, and anti-inflammatory signaling pathways, as well as TNFR2-associated expansion of immunosuppressive Tregs, leading to severe, sometimes Fatal side effects, including serious infection. Other side effects associated with the use of TNF-blocking therapy include congestive heart failure, liver damage, demyelinating diseases/CNS disorders, lupus, psoriasis, sarcoidosis and increased susceptibility to other autoimmune diseases, and cancer, including Lymphoma and solid malignancies. Anti-TNF therapies have failed in treating demyelinating and neurodegenerative diseases and can worsen disease symptoms.

Provided herein are constructs for selectively inhibiting TNF signaling via TNFR1, including TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs and nucleic acids and methods (see, eg, Figure 2, which depicts exemplary bispecific constructs). Constructs and methods for selectively inhibiting TNF signaling through TNFR1, including while maintaining or enhancing TNFR2 signaling, are also provided. These constructs and methods provide improved treatments for diseases and disorders of the TNF/TNFR1 axis. Such treatments include, but are not limited to, the treatment of autoimmune, chronic inflammatory, neurodegenerative and demyelinating diseases, disorders and conditions, as well as cancers that also have an inflammatory component. As described herein, simultaneous or sequential selective agonism of TNFR2 and antagonism of TNFR1 has therapeutic effects through activation of required signaling pathways, such as anti-inflammatory pathways and NF-кB that controls cell survival and proliferation. pathway, and increase the therapeutic index of selective TNFR1 antagonists by inducing the expansion of immunosuppressive Tregs that remove excess autoreactive/effector T cells from the autoimmune microenvironment leading to tissue destruction.

Sections 1 and 2 describe methods to target each of TNFR1 and TNFR2; Section 3 provides an overview of constructs provided herein that address issues with previous approaches, particularly those targeting TNFR1; And Section 4 describes the structure and components of the construct provided in this article. 1. Selective blocking of TNFR1 with TNFR1 antagonists

However, the use of multivalent agents, such as antibodies against TNFR1, is not feasible. The TNF trimer binds to three TNFR1 chains as a preligand assembly complex, mediated by the preligand assembly domain (plad) of each monomeric TNFR. This differs from most receptor systems that require ligand binding to form clusters on the cell surface. TNF receptors are single transmembrane glycoproteins with approximately 28% homology mainly in their extracellular domains. Both receptors contain four tandem repeats of a cysteine-rich motif. Their intracellular sequences are essentially unrelated, with little homology to each other, and early studies suggested compartmentalization of their signaling functions (Grell et al. (1994) J. Immol. 153(5):1963-72). It contains several motifs with known functional significance. Each of TNFR1 and TNFR2 contains an extracellular proligand-binding assembly domain (PLAD), which (different from the ligand-binding region) pre-complexes the receptor. When the trimeric TNF ligand binds to the TNFR trimer in the cell membrane, it induces conformational changes, resulting in signaling activation (MacEwan (2002) Br J Pharmacol. 135(4) :855-875; and Lo et al. (2019) ) Sci Signal. 12(592) :eaav5637).

Therefore, antibodies and other multivalent agents that bind TNFR1 may not be suitable for use as antagonists because they can cause hyperaggregation, leading to activation of TNFR signaling. On the other hand, monovalent antagonists such as single domain antibodies (dAb or sdAb), nanobodies (Nb; camelid single domain antibodies), scFv fragments, and Fab fragments bind to a TNFR1 molecule and do not induce the receptor on the cell surface. cross-link or aggregate, thereby eliminating any activation of TNFR1 signaling. Monovalent antagonists can bind to domains 1, 2, 3, or 4 of the TNFR1 extracellular domain or to epitopes spanning multiple domains (see, e.g., U.S. Pat. Nos. 9,028,817 and 9,028,822), but these existing antagonists are ineffective treatments. agent. Various issues include short serum half-life and immunogenicity, among other issues. Selective blockade of TNFR1 can be achieved using TNFR1 antagonists having properties described and provided herein. 2. Selective activation of TNFR2 with TNFR2 agonists

As described herein, selective activation of TNFR2 can be achieved using TNFR2-specific agonists, which can include, for example, TNFR2 agonist antibodies and antigen-binding fragments thereof, and TNFR2-selective TNF muteins and fusions thereof protein. Antigen-binding fragments of antibodies that bind to the first and/or second epitope of human TNFR2 can be used. The first epitope of TNFR2 includes amino acid residues 48-67 of SEQ ID NO: 4, and the second epitope includes position 135 of SEQ ID NO: 4, including, for example, residue 128 of SEQ ID NO: 4. -147, 130-149, 135-147 or 135-153 (see, eg, International Application Publication No. WO 2014/124134; and US Patent No. 9,821,010). Other epitopes on TNFR2 have been identified and can be used to design antigen-binding fragments with TNFR2 selectivity, as discussed below.

In contrast to the antagonism of TNFR1, in order to promote TNFR2, dimer and trimer molecules are used to simulate the effects of membrane-bound TNF, which is the main ligand for activating TNFR2. Therefore, TNFR2 agonists include TNFR2-selective TNF muteins and antibody fragments. Examples are TNF muteins and antibody fragments fused to a multimerization domain, especially a dimerization or trimerization domain, as discussed below. To extend the half-life of these molecules, they can be associated or coupled with polyethylene glycol with or without cleavable linkers (see e.g. Santi et al. (2012) Proc. Natl. Acad. Sci. USA 109 :6211-6216), or with half-life extending proteins or peptides such as human serum albumin (with or without FcRn optimization, and itself with or without PEGylation); and inactivation of ADCC with or without PEGylation /FcRn optimizes antibody Fc domain fusion or binding (reviewed in, eg, Strohl (2015) BioDrugs 29(4):215-239). Half-life extenders include, for example, PEGylation, glycosylation modification, sialylation, PASylation (PAS amino acid polymer, approximately 100-200 residues in length), ELPylation (see, e.g., Floss et al. (2010) J. Trends Biotechnol.28(1): 37-45), HAPylation (glycine homopolymer), fusion with human serum albumin, fusion with GLK, fusion with CTP, fusion with GLP, fusion with human immunoglobulin (IgG) Constant fragment (Fc) domain fusions, fusions to transferrin, fusions to unstructured peptides such as XTEN (also known as rPEG, genetic fusions of non-exact repeating peptide sequences containing A, E, G, P, S and T, See, e.g., Schellenberger et al. (2009) Nat Biotechnol. 27(12):1186-90) and other such modifications and fusions that increase size, increase hydrodynamic radius, change charge, or target the receptor for recycling rather than clearance, and combinations of such modifications. Specific examples of half-life extending agents are discussed in detail and exemplified below. 3. TNFR1 antagonist constructs, TNFR2 agonist constructs ; multispecific , including bispecific TNFR1 antagonists and TNFR2 agonist constructs

Accordingly, provided herein are constructs for inhibiting TNFRl signaling/activity and/or for stimulating TNFR2. Included among the constructs provided herein are the multispecific constructs discussed below, such as bispecific constructs that inhibit TNFRl signaling and enhance TNFR2. Care is taken when designing such constructs because bispecific antagonists TNFR1 or TNFR2 may inhibit the ability of TNF to induce activating changes in the conformation of resting trimeric TNFR, thus preventing its signaling. Other multimeric molecules risk receptor aggregation, forcing TNFR to signal cellular inflammation and apoptosis. Multispecific constructs herein generally target different receptors, such as each of TNFR1 and TNFR2. By inhibiting TNFR1 signaling and favorably stimulating TNFR2 activity, this provides improved treatment of diseases, conditions and disorders involving TNF.

Among the constructs provided herein are TNFR1 antagonist constructs. These include fusion protein constructs, such as TNFR1 antagonist-Fc fusion constructs. As described herein and exemplified in the Examples, TNFR1 antagonists can be selected, generated or designed that specifically target TNFR1 without antagonizing or substantially antagonizing TNFR2, or that include or exhibit TNFR2 agonist activity. TNFR1 antagonist constructs improve upon the therapeutic efficacy and safety of previous TNFR1 antagonists, including monovalent antagonists such as dAb, scFv and Fab.

Selective TNFR2 agonist constructs, such as TNFR2-Fc fusion constructs, are also provided, which improve upon the therapeutic efficacy of previous TNFR2 agonists. For example, as shown herein, the half-life of an Fc fusion construct increases the half-life of a prior TNFR1 antagonist or TNFR2 agonist, which, for example, reduces dosing frequency, increases patient compliance, and increases the therapeutic index. Selective TNFR2 agonist constructs, such as TNFR2-Fc fusion constructs, are also provided, which improve upon the therapeutic efficacy of previous TNFR2 agonists. For example, as shown herein, the half-life of an Fc fusion construct increases the half-life of a prior TNFR1 antagonist or TNFR2 agonist, which, for example, reduces dosing frequency, increases patient compliance, and increases the therapeutic index. Alternative candidate half-life extenders including PEGylation and fusion to peptides are discussed above, and exemplary extenders are detailed below (reviewed in Strohl (2015) BioDrugs 29(4) :215-239, see also Tan et al. ( 2018) Current Pharmaceutical Design 24 :4932-4946), and also includes PEGylation using linear or branched PEG (see, e.g., Swierczewska et al. (2015) Expert Opin Emerg Drugs 20(4) :531-536).

TNFR1 agonist constructs include an optional linker and an optional activity modulator. They can be assembled in any order. The structure of the TNFR1 antagonist construct can be represented by Formula 1: (TNFR1 inhibitor) _n ― linker _p ― (activity modulator) _q , Formula 1a, or (activity modulator) _q ― linker _p ― (TNFR1 inhibitor) _n , Formula 1b, wherein: each of n and q is an integer, and each is independently 1, 2 or 3; p is 0, 1, 2 or 3; and the activity modulator is the serum that increases the TNFR1 inhibitor A portion of the half-life, such as a polypeptide, such as albumin, or Fc modified to have reduced or no ADCC activity; and a TNFR1 inhibitor is a molecule that binds to TNFR1 and inhibits its activity, such as a polypeptide or a small drug molecule. The active modulator is not an antibody to human serum albumin or unmodified Fc. Also provided are TNFR2 agonists of Formula 3: (TNFR2 agonist) _n - linker _p - (activity modulator) _q , wherein n, p and q, the linker and the activity modulator are as set forth for Formula 1.

Multispecific, including bispecific constructs containing a TNFR1 antagonist (TNFR1 inhibitor) and a TNFR2 agonist linked directly or via a linker are also provided. Such constructs may include a TNFR1 antagonist of the formula above or may have a structure as shown in Formula 2 below. Bispecific and multispecific constructs selectively inhibit inflammatory and harmful TNFR1 signaling and enhance protective and anti-inflammatory TNFR2 signaling. It includes those that provide favorable pharmacokinetic properties, including increased serum half-life and stability and reduced peripheral clearance compared to previous TNFR1 antagonists and TNFR2 agonists.

The structure of the multispecific, such as bispecific molecules/constructs provided herein is represented by the following formula (Formula 2): (TNFR1 inhibitor) _n - (activity modulator) _r1 - linker (L) _p - (activity modulator agent) _r2 - (TNFR2 antagonist) _q , where n = 1, 2 or 3, p = 1, 2 or 3, r1 and r2 independently = 0, 1, 2, and q = 0, 1 or 2. As with Formula 1, the order of the components can vary. The linker may contain multiple components, such as a GS linker, a polymeric moiety such as PEG, or other such linkers, or a hinge region, or other combinations of components, and the activity modulator is a moiety that modulates the activity of the construct, Such as Fc regions or modified Fc regions or polypeptides that increase half-life or resistance to endogenous inhibitors. The components of Formula 1 and Formula 2 may be polypeptides, or may contain other molecules, such as small drugs or chemical linkers that specifically bind, or non-peptide activity modulators. Examples of each component are described below.

Also provided are constructs containing (Formula 5): (TNFR2 antagonist) _n ― linker _p ― (activity modulator) _q , Formula 5a, or (activity modulator) _q ― linker _p ― (TNFR2 antagonist) _n , Formula 5b, wherein each component is as defined in Formula 1 above, and the TNFR2 agonist can be a small molecule or polypeptide, such as a TNFR2 single chain antibody agonist or a portion thereof. 4. TNFR1 antagonist constructs, TNFR2 agonist constructs and components of multispecific , including bispecific TNFR1 antagonist /TNFR2 agonist constructs

Descriptions and examples of constructs and components of the constructs provided herein are described in the following sections. Exemplary forms of each construct are depicted and described by Formulas 1 and 2 above, and Formulas 3 and 4 below. a. TNFR1 inhibitor part ( TNFR1 antagonist )

The TNFR1 inhibitor moiety in Formula 1 above and the multispecific molecules/constructs provided herein (Formula 2 above) is any molecule, including polypeptides or small molecules, that inhibits TNFR1 signaling. This includes TNFR1 inhibitors that selectively inhibit TNFR1 signaling without inhibiting TNFR2 signaling.

In order to avoid aggregation of agonist TNFR1 receptors, TNFR1 antagonist constructs are generally monomeric/monovalent. The TNFR1 antagonist inhibitor component of the construct may be a component known to have TNFR1 antagonist activity, or may be identified, such as by selection from a library, such as a phage library, an antibody library, or an aptamer library. There are TNFR1 inhibitors in the class that have been modified or selected to have increased specificity or affinity for TNFR1 and have no or few adverse side effects for TNFR1 such that such activity has adverse side effects based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) grading system. Less than level 2, and generally level 1 or less) agonist activity, and optionally also a portion that has agonist activity for TNFR2. In such cases, the TNFR1 inhibitor moiety may be provided as a single chain antibody or in any other form described herein, including, for example, linked to a half-life extender, such as any of the half-life extenders described above and below, such as modified The Fc region or Fc dimer, or linked to one or more other moieties that increase serum half-life.

For example, as provided herein, the TNFR1 inhibitor component of a TNFR1 antagonist construct can be or can include a human domain antibody (dAb) that specifically binds to TNFR1. dAbs may contain variable heavy ( _VH ) or light ( _VL ) domains. As used herein, dAbs include, for example, those designated DOM1h-574-208 (SEQ ID NO: 54) (from DMS5541; see SEQ ID NO: 38), GSK1995057 (see SEQ ID NO: 55), and GSK2862277 (see SEQ ID NO: 56 ), and the dAb shown in any of SEQ ID NOs: 57-672; see, for example: U.S. Patent Nos. 9,028,817 and 9,028,822; U.S. Publication Nos. 2006/0083747, 2010/0034831 and No. 2012/0107330; and International Application Publication Nos. WO 2004/058820, WO 2004/081026, WO 2005/035572, WO 2006/038027, WO 2007/049017, WO 2008 /No.149144, No. WO 2008/149148, No. WO 2010/094720, No. WO 2011/051217, No. WO 2011/006914, No. WO 2012/172070, No. WO 2012/104322 and No. WO 2015/ 104322 and other related family member applications and patents; see also Enever et al., (2015) Protein Engineering, Design & Selection 28(3) :59-66, which provides sequences and discussion of various dAbs). Vhh dAbs containing heavy chains are provided. These dAbs may be linked directly or indirectly to moieties such as Fc or HSA that increase serum half-life and may also confer other properties or activities to the construct.

The anti-TNFR1 inhibitor component may be or include a Nanobody. Examples of these are (Nb)Nb 70 and/or Nb 96 (see SEQ ID NO: 683 and 684 respectively). The immunogenicity of these dAbs and Nbs is investigated and, if necessary, modified using molecular modeling and mutagenesis to remove predicted immunogenic sequences. Immunogenic sequences can be eliminated by standard methods known in the art. For example, potential antigenic peptides are identified and conservative substitutions of each amino acid are made to identify peptides that are non-antigenic and retain activity. Other methods are known (see, eg, Schubert et al. (2018) PLoS Comput Biol. 14(3) :e1005983), which describes a method of deimmunizing proteins).

Thus, for example, a TNFRl antagonist dAb moiety may be a dAb set forth in any of SEQ ID NOs: 54-672, or have a similar affinity to a dAb set forth in any of SEQ ID NOs: 54-672. or a dAb with at least about 85%, 90%, 95%, 98%, 99% or greater sequence identity, or a TNFRl antagonist dAb known to one of ordinary skill in the art.

Other TNFRl antagonists include, for example, antigen-binding antibody fragments. For example, TNFR1 antagonists can be Fab fragments, Fab' fragments, single-chain Fv (scFv), disulfide-linked Fv (dsFv), Fd fragments, Fd' fragments, single-chain Fab (scFab), hsFv (helical Stable Fv), free light chain, or antigen-binding fragment of any of the above. It may also include linkers, such as GS linkers, within the construct, for example to increase flexibility.

For example, the TNFR1 inhibitor portion of the antagonist may contain an antigen-binding fragment from a TNFR1 antagonist antibody designated ATROSAB. Such fragments include one or more (or all) of the heavy or light chain CDRs of ATROSAB, or exhibit at least 85%, 90%, 95% or greater sequence identity thereto (e.g., 85%, 90%, 95% , 96%, 97%, 98%, 99% or greater sequence identity) CDRs. The TNFR1 antagonist may contain _VH (residues 1-115 of SEQ ID NO: 31) and/or _VL (residues 1-113 of SEQ ID NO: 32) of ATROSAB, or with _VH or _VL of ATROSAB _VH or _VL containing at least 85%, 90%, 95% or greater sequence identity. For example, it may contain a dAb derived from ATROSAB. TNFR1 antagonists may contain other monovalent antibody fragments of ATROSAB, including, for example, Fab or scFv fragments, such as the ATROSAB Fab (FabATR) light and heavy chains shown in SEQ ID NO: 679 and 680, respectively, or SEQ ID NO: 673 ATROSAB scFv shown (scFv IZI06.1). For example, an scFv contains a _VH domain corresponding to residues 1-115 of the ATROSAB heavy chain (see SEQ ID NO: 31), via a short peptide linker (e.g., GGGGSGGGGSGGSAQ, as in SEQ ID NO: 673, or The linker shown in any of SEQ ID NO: 813-834) is linked to the V _L domain corresponding to residues 1-113 of the ATROSAB light chain (see SEQ ID NO: 32). TNFR1 antagonists may contain variants of the ATROSAB scFV that have increased affinity or selectivity for TNFR1 or both, including scFv IG11, which includes or has the sequence set forth in SEQ ID NO: 674; scFv T12B, which contains The sequence shown in SEQ ID NO: 675; or scFv 13.7, which contains the sequence shown in SEQ ID NO: 676; or a variant containing at least 90% sequence identity with the sequences of scFv IG11, scFv T12B and scFv 13.7 . TNFR1 antagonists may also include the amino acid residue sequences of the Fab 13.7 light chain and heavy chain (derived from scFV 13.7) as shown in SEQ ID NO: 681 and 682, respectively.

TNFR1 inhibitors within the TNFR1 antagonist construct also include TNF variants (mutated proteins) that bind to TNFR1 to reduce or inhibit signaling. These include, for example, TNF variants (mutated proteins) such as, but not limited to, reference to SEQ ID NO: 2 containing mutations L29S, L29G, L29Y, R31E, R31N, R32Y, R32W, S86T, L29S/R32W, L29S/S86T, R32W/ TNF variants of one or more of S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T and E146R. These mutations confer selectivity for TNFR1. The TNFR1 antagonist may comprise, for example, a TNFR1 -selective antagonistic TNF mutein derived from the mutein designated XPro1595 (see SEQ ID NO: 701). Referring to SEQ ID NO: 2, XPro1595 contains mutations V1M, R31C, C69V, Y87H, C101A and A1456R. Other exemplary TNFR1-selective antagonistic TNF muteins are derived from XENP345 (see SEQ ID NO: 702), which contains mutation I97T/A145R with reference to SEQ ID NO: 2; and the TNFR1-selective antagonistic TNF mutein designated R1antTNF (see SEQ ID NO: 702). See SEQ ID NO: 703), which contains mutations A84S, V85T, S86T, Y87H, Q88N and T89Q with reference to SEQ ID NO: 2. TNFR1 inhibitors used in TNFR1 antagonists also include small molecule inhibitors that can be chemically coupled to a linker.

As described herein, see for example the Examples, a TNFR1 inhibitor (antagonist) moiety can be modified to increase its specificity/selectivity for TNFR1 and can also be modified to have TNFR2 agonist activity if desired. TNF binds to TNFR1 with low pM affinity (K _d 19 pM); in general, antagonists in this context have at least the same affinity as TNF unless their activity is due to "locking" the receptor in an inactive conformation , it is undesirable because the receptor will be locked. TNFR1 antagonist constructs provided herein include those that specifically bind to TNFR1 with a _KD value of less than or less than about 100 nM (e.g., less than or equal to: 95 nM, 90 nM, 85 nM, 80 nM, 75 nM, 70 nM, 65 nM , 60 nM, 55 nM, 50 nM, 45 nM, 40 nM, 35 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM) construct. In some specific examples, the K _D value of the TNFR1 antagonist that specifically binds to TNFR1 is less than 1 nM (for example, less than or equal to: 990 pM, 980 pM, 970 pM, 960 pM, 950 pM, 940 pM, 930 pM, 920 pM, 910 pM, 900 pM, 890 pM, 880 pM, 870 pM, 860 pM, 850 pM, 840 pM, 830 pM, 820 pM, 810 pM, 800 pM, 790 pM, 780 pM, 770 pM, 760 pM, 750 pM, 740 pM, 730 pM, 720 pM, 710 pM, 700 pM, 690 pM, 680 pM, 670 pM, 660 pM, 650 pM, 640 pM, 630 pM, 620 pM, 610 pM, 600 pM, 590 pM , 580 pM, 570 pM, 560 pM, 550 pM, 540 pM, 530 pM, 520 pM, 510 pM, 500 pM, 490 pM, 480 pM, 470 pM, 460 pM, 450 pM, 440 pM, 430 pM, 420 pM, 410 pM, 400 pM, 390 pM, 380 pM, 370 pM, 360 pM, 350 pM, 340 pM, 330 pM, 320 pM, 310 pM, 300 pM, 290 pM, 280 pM, 270 pM, 260 pM, 250 pM, 240 pM, 230 pM, 220 pM, 210 pM, 200 pM, 190 pM, 180 pM, 170 pM, 160 pM, 150 pM, 140 pM, 130 pM, 120 pM, 110 pM, 100 pM, 90 pM , 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 5 pM or 1 pM).

The TNFR1 antagonist constructs provided herein are also selected or designed to lack or reduce binding to other TNFR superfamily members. For example, they are assessed using any suitable in vitro binding assay to identify constructs that do not specifically bind to another TNFR superfamily member, such as TNFR2. Analytical methods include, for example, ELISA-based methods. For example, a TNFRl antagonist construct can specifically bind to human TNFRl or a TNFRl-derived peptide with greater affinity than to another family member or its corresponding peptide. The increased affinity is, for example, at least or at least about 5 times greater (e.g., at least or equal to 5 times greater, 6 times greater, 7 times greater, 8 times greater, 7 times greater, 8 times greater, than the affinity of a TNFR1 antagonist for another TNFR superfamily member, such as TNFR2). 9 times bigger, 10 times bigger, 20 times bigger, 30 times bigger, 40 times bigger, 50 times bigger, 60 times bigger, 70 times bigger, 80 times bigger, 90 times bigger, 100 times bigger, 200 times bigger, 300 times bigger Big, 400 times bigger, 500 times bigger, 600 times bigger, 700 times bigger, 800 times bigger, 900 times bigger, 1,000 times bigger, 2,000 times bigger, 3,000 times bigger, 4,000 times bigger, 5,000 times bigger, 6,000 times bigger, 7,000 times larger, 8,000 times larger, 9,000 times larger, 10,000 times larger or larger).

Among the TNFR1 antagonist constructs provided herein, there are constructs that exhibit high k _on and low k _off values upon interaction with TNFR1, consistent with binding to the high-affinity receptor. For example, TNFR1 antagonist constructs provided herein can exhibit a k _on value in the presence of TNFR1 of greater than or equal to, or greater than about 10 ⁴ M ⁻¹ s ⁻¹ (e.g., greater than or equal to 1.0 x 10 ⁴ M ⁻¹ s ^-1 , 1.5 x 10 ⁴ M ^-1 s ^-1 , 2.0 x 10 ⁴ M ^-1 s ^-1 , 2.5 x 10 ⁴ M ^-1 s ^-1 , 3.0 x 10 ⁴ M -1 s ^{-1 ,} 3.5 x 10 ⁴ M ^-1 s ^-1 , 4.0 x 10 ⁴ M ^-1 s ^-1 , 4.5 x 10 ⁴ M ^-1 s ^-1 , 5.0 x 10 ⁴ M ^-1 s ^-1 _, 5.5 x 10 ⁴ M ^-1 s ^{-1 , 6.0 _ _ _ _ _ _ _ _ _ _ 4} M ^-1 s ^-1 , 8.5 x 10 ⁴ M ^-1 s ^-1 , 9.0 x 10 ⁴ M ^-1 s ^-1 , 9.5 x 10 ⁴ M ^-1 s ^-1 , 1.0 x 10 ⁵ M ^-1 s ^{- 1} , 1.5 x 10 ⁵ M ^-1 s ^-1 , 2.0 x 10 ⁵ M ^-1 s ^-1 , 2.5 x 10 ⁵ M ^-1 s ^-1 , 3.0 x 10 ⁵ M ^-1 s ^-1 , 3.5 x 10 ⁵ M ^-1 s ^-1 , 4.0 x 10 ⁵ M ^-1 s ^-1 , 4.5 x 10 ⁵ M ^-1 s ^-1 , 5.0 x 10 5 M ^-1 s ^-1 , 5.5 x ^{10 5} M ^-1 s ^-1 , 6.0 x 10 ⁵ M ^-1 s ^-1 , 6.5 x 10 ⁵ M ^-1 s ^-1 , 7.0 x 10 ⁵ M ^-1 s ^-1 , 7.5 x 10 ⁵ M ^-1 s ^-1 , 8.0 x 10 ⁵ M ^-1 s ^-1 , 8.5 x 10 ⁵ M ^-1 s ^-1 , 9.0 x 10 ⁵ M ^-1 s ^-1 , 9.5 x 10 ⁵ M ^-1 s ^-1 , 1.0 x 10 ⁶ M ^-1 s ^-1 ) . For example, TNFR1 antagonists provided herein can exhibit a k _off value of less than or equal to, or less than about 10 ^-3 s ^-1 (e.g., less than or less than about 1.0 x 10 ^-3 s ^-1 , when complexed with TNFR1 9.5 x 10 ^-4 s ^-1 , 9.0 x 10 ^-4 s ^-1 , 8.5 x 10 ^-4 s ^-1 , 8.0 x 10 ^-4 s ^-1 , 7.5 x 10 ^-4 s ^-1 , 7.0 x 10 ^-4 s ^-1 , 6.5 x 10 ^-4 s ^-1 , 6.0 x 10 ^-4 s ^-1 , 5.5 x 10 ^-4 s ^-1 , 5.0 x 10 ^-4 s ^-1 , 4.5 x 10 ^-4 s ^-1 , 4.0 x 10 ^-4 s ^-1 , 3.5 x 10 ^-4 s ^-1 , 3.0 x 10 ^-4 s ^-1 , 2.5 x 10 ^-4 s ^-1 , 2.0 x 10 ^-4 s ^-1 , 1.5 x 10 ^-4 s ^{-1 , 1.0 _ _ _ _ _ _ _ _} 10 ^-5 s ^-1 , 7.0 x 10 ^-5 s ^-1 , 6.5 x 10 ^-5 s ^-1 , 6.0 x 10 ^-5 s ^-1 , 5.5 x 10 ^-5 s ^-1 , 5.0 x 10 ^-5 s ^{- 1} , 4.5 x 10 ^-5 s ^-1 , 4.0 x ^{10 -5} s ^-1 , 3.5 x 10 -5 s ^-1 , 3.0 x 10 ^-5 s ^-1 , 2.5 x 10 ^-5 s ^-1 , 2.0 x 10 ^-5 s ^-1 , 1.5 x 10 ^-5 s ^-1 or 1.0 x 10 ^-5 s ^-1 ).

TNFR1 antagonists (the TNFR1 inhibitor portion of the constructs of Formula 1 and Formula 2), such as the C-terminus of any of the TNFR1 antagonist constructs described herein may be directly or more generally via a linker or linker element The combination is linked to the activity modulator or fused to the N-terminus of a TNFR2 agonist (or a small molecule TNFR2 agonist) via one or more linkers, as discussed below and elsewhere herein. Alternatively, the N-terminus of the TNFR1 inhibitor moiety can be fused to the C-terminus of the TNFR2 agonist, or the C-terminus of the TNFR1 inhibitor moiety (or small molecule TNFR2 agonist) can be fused directly or via a linker to an activity modulator or linker. Fusion.

Linker (L), discussed in more detail below, is any linker that improves pharmacological properties, including increasing stability and flexibility and reducing steric hindrance, and optionally confer additional properties to the construct. A linker may include more than one component, with each component conferring specific properties. For example, a TNFR1 antagonist may include any one or more of an IgFc region and/or an antibody hinge region and/or a short peptide linker (such as a glycine-serine linker). The Fc region is modified, for example, to eliminate or reduce ADCC activity, and/or to alter receptor binding, and/or for other such activities and properties. As discussed below, linkers also include chemical linkers. For example, in some embodiments, the linker is a poly(ethylene glycol) (PEG) molecule or a branched PEG molecule, such as a PEG molecule with a molecular mass of about 30 kDa or greater. b. TNFR2 agonist construct and TNFR2 antagonist construct

TNFR2 agonist (regulatory T cell generating agent) constructs may be used to treat inflammatory and autoimmune diseases and solid tumors, among other diseases, disorders and conditions. Regulatory T cells (Tregs) suppress autoimmunity and have immunosuppressive effects, such as in the tumor microenvironment. The proliferation of Treg is positively regulated by TNFR2, and the deficiency of TNFR2 is related to the reduction of Treg number and the worsening of experimental arthritis. Therefore, TNFR2 agonist constructs can be used to treat many autoimmune diseases, other chronic inflammations, and other acute inflammatory conditions (e.g., SARS, COVID-19).

TNFR2 antagonist constructs inhibit regulatory T cells and are used to treat cancer and other hyperproliferative diseases (TNFR2 is a "checkpoint receptor"). Regulatory T cells accumulate in the tumor microenvironment and complexly suppress anti-tumor immune responses. TNFR2 antagonist constructs are used to treat cancer and other hyperproliferative diseases such as Dupuytren's Contracture and idiopathic pulmonary fibrosis.

As discussed above, TNFR2 agonist constructs containing TNFR2 agonists are also provided. These include TNFR2 agonists linked directly or via a linker to an activity modulator, and also include multispecific constructs such as those containing a TNFR1 antagonist and a TNFR2 agonist in various forms with a linker of appropriate structure and properties. Configuration of bispecific constructs. In some embodiments, the TNFR2 agonist is in a bispecific construct. TNFR2 agonists, particularly among the multispecific, such as bispecific molecules/constructs provided herein, selectively activate or agonize TNFR2 without activating or substantially activating TNFR1 and/or do not interfere with the multispecific Sexually, TNFR1 antagonists such as bispecific molecules partially inhibit TNFR1 signaling.

TNFR2 agonists can be any agonists known to those of ordinary skill in the art, including agonist antibodies and their antigen-binding portions, as well as single-chain and other configuration derivatives of antibodies, and can also be small molecules. Agonist. TNFR2 agonists can also be generated, such as by in silico design and/or by preparing candidates and screening libraries. For example, a phage library or an antibody library or an aptamer library can be screened to identify TNFR2 agonists. TNFR2 agonist antibodies or antigen-binding fragments thereof can be generated by screening libraries of antibodies and antigen-binding fragments thereof for functional molecules that bind to epitopes within TNFR2 and selectively promote receptor activation. Examples of such methods and molecules are those described in International Application Publication No. WO 2017/040312.

The development of TNFR2-selective agonists may include elucidation of epitopes within TNFR2 that promote agonist receptor binding. Epitope mapping analysis using linear peptides derived from different regions of TNFR2 and constrained cyclic and bicyclic peptides showed that agonistic TNFR2 antibodies bind to epitopes in different regions of the TNFR2 polypeptide in a conformation-dependent manner. For example, one identified epitope of TNFR2 includes residues 56-60 of SEQ ID NO: 4 (KCSPG). The agonist TNFR2 antibody MR2-1 binds to this epitope; it does not bind to the epitope containing residues 142-146 of SEQ ID NO: 4 (KCRPG). Human TNFR2 can be selected to bind to an epitope such as residues 56-60 including SEQ ID NO: 4. Generally speaking, human TNFR2 agonists can be selected or designed to interact with at least five discontinuous or contiguous residues within human TNFR2 containing residues 96-154 of SEQ ID NO: 4 (CGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPGT; SEQ ID NO: 841) The epitope binds, and/or can bind to the epitope within residues 111-150 of SEQ ID NO: 4 (TREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVA; SEQ ID NO: 842), to which MR2-1 additionally binds. Human TNFR2 agonists can also bind to residues 115-142 of SEQ ID NO: 4 (NRICTCRPGWYCALSKQEGCRLCAPLRK; SEQ ID NO: 843) and/or residues 122-136 of SEQ ID NO: 4 (PGWYCALSKQEGCRL; SEQ ID NO: 844 ) and/or the epitope within residues 96-122 (CGSRCSSDQVETQACTR; SEQ ID NO: 845) of SEQ ID NO: 4, and/or residues 101-107 (SSDQVET; SEQ ID NO. : 846; MR2-1 additionally binds to), and/or the epitopes within amino acids 48-67 (QTAQMCCSKCSPGQHAKVFC; SEQ ID NO: 847) of SEQ ID NO: 4, and/or An epitope containing residues 130-149 of SEQ ID NO: 4 (KQEGCRLCAPLRKCRPGFGV; SEQ ID NO: 848) and/or residues 110-147 of SEQ ID NO: 4 (CTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGF; SEQ ID NO: 849), and /or contains at least five consecutive or discontinuous residues of positions 106-155 of SEQ ID NO: 4 (ETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPGTE; SEQ ID NO: 850) and/or residues 137-144 of SEQ ID NO: 4 (CAPLRKCR; SEQ ID NO: 4 ID NO: 851) and/or the epitope of residues 141-149 of SEQ ID NO: 4 (RKCRPGFGV; SEQ ID NO: 852).

In another aspect, TNFR2 agonist antibodies and antigen-binding fragments thereof are within or contain an epitope of an amino acid residue in any of SEQ ID NO: 853-1211 Specific binding whereby the antibody or antigen-binding fragment specifically binds human TNFR2 but not another TNFR superfamily member, especially TNFR1. Human TNFR2 agonist antibodies or antigen-binding fragments thereof do not bind or have weak/reduced binding to other members of the TNFR superfamily, including TNFR1 (see, eg, International Application Publication No. WO 2017/040312).

Epitopes within TNFR2 that may be used to screen for TNFR2 agonists include peptides whose sequences are set forth in any of SEQ ID NOs: 853-1211. These peptides can be converted into cyclic and polycyclic forms (e.g., by incorporating cysteine residues into the N- and C-terminal positions or various internal positions within the peptide chain) to restrict the peptide fragments to different The three-dimensional configuration simulates the structural rigidity of TNFR2 and the configuration constraints of the peptide fragment within TNFR2. Cyclic and polycyclic peptide fragments can then be immobilized on solid surfaces and ELISA used to screen for molecules that bind, for example, the TNFR2 agonist antibody MR2-1. Using this assay, peptides containing residues within the TNFR2 epitope that promote receptor activation can structurally preorganize these amino acids to resemble the conformation of the corresponding peptide in the native protein. Cyclic and polycyclic peptides thus obtained (e.g., peptides having the sequence of any one of SEQ ID NOs: 853-1194, and especially containing KCSPG as in SEQ ID NOs: 905, 921, 927, 970 and 1085 Motif peptides) can be used to screen libraries of antibodies and their antigen-binding fragments to identify TNFR2 agonists for use herein. The constrained peptide serves as a surrogate for an epitope within TNFR2 that promotes receptor activation, and therefore, antibodies or antigen-binding fragments generated using this screening technology bind to the corresponding epitope in TNFR2 and have a stimulating effect on receptor activity. effectiveness (see, for example, International Application Publication No. WO 2017/040312). To generate TNFR2 agonists, phage display was used. The phage display library is contacted under conditions under which specific binding occurs. A TNFR2-derived peptide (eg, the peptide of any of SEQ ID NO: 853-1194) is immobilized on a solid support or in a phage. The phage containing the TNFR2 binding moiety forms a complex with the target on the solid support, and unbound phage is washed away. Bound phage are then released from the target by changing the buffer to extreme pH (pH 2 or 10), changing the ionic strength of the buffer, adding denaturants, or by other known means. To isolate bound phage, protein elution can be performed (see, eg, International Application Publication No. WO 2017/040312).

MR2-1 is an exemplary agonist TNFR2 antibody that binds TNFR2 and enhances TNFR2-mediated Treg cell proliferation. MR2-1 binds osteoprotegerin, however, the heavy chain and/or light chain variable regions of this antibody, or specifically the heavy chain and/or light chain CDRs of MR2-1, can be modified to eliminate the resulting antibody or its The ability of the fragment to bind to TNFR superfamily members other than TNFR2, resulting in agonistic TNFR2 antibodies or antigen-binding fragments thereof. This can be achieved using genetic engineering and/or antibody library screening techniques, for example, as described in International Application Publication No. WO 2017/040312.

As provided herein, TNFR2 agonists may contain antigen-binding fragments of agonistic human anti-TNFR2 antibodies, such as MR2-1 and MAB2261, such as the commercially available MR2-1 from Hycult Biotech; and MAB2261 from R&D Systems. For example, one or more of the _VH and VL _domains of MR2-1 or MAB2261 or the CDRs contained therein are used to generate TNFR2 agonists. Such agonists may contain human domain antibodies (dAb) specific for TNFR2; the dAb may contain the variable heavy ( _VH ) or light ( _VL ) domain of MR2-1 or MAB2261, or may be associated with The _VH or VL of MR2-1 or MAB2261 has a _VH or _VL of at least or at least about 85 _% , 90%, 95% or greater sequence identity _, with the proviso that the resulting TNFR2 retains TNFR2 agonist activity. TNFR2 agonists may also contain other antigen-binding fragments derived from the MR2-1 or MAB2261 antibodies, or having amino acid sequences with at least or at least about 85%, 90%, 95% or greater sequence identity, such as Fab Fragment, Fab' fragment, F(ab') ₂ fragment, Fv fragment, disulfide-linked Fv (dsFv), Fd fragment, Fd' fragment, single-chain Fv (scFv), single-chain Fab (scFab), hsFv ( Helix-stabilized Fv), minibodies, diabodies, anti-genetic (anti-Id) antibodies, free light chains, or antigen-binding fragments of any of the above. Antibody fragments include combinations of any of the above fragments, such as tandem scFv, Fab-scFv (HC C-terminal or LC C-terminal), Fab-(scFv) ₂ (C-terminal), scFv-Fab-scFv, Fab-C _H 2-scFv, scFv fusion (C-terminal or N-terminal), Fab fusion (HC C-terminal or LC C-terminal), scFv-scFv-dAb, scFv-dAb-scFv, dAb-scFv-scFv and trifunctional antibodies . TNFR2 agonists include dAbs having a sequence provided herein or known in the art, having about or at least about 85%, 90%, 95% or greater sequence identity thereto and TNFR2 agonist activity. Either.

In some specific examples, the TNFR2 agonist can be an scFv of a TNFR2 agonist monoclonal antibody, including any scFv known in the art, or has about or at least about 85%, 90%, 95% affinity to such scFv. % or more than 95% sequence identity of the scFv, with the proviso that the resulting construct retains TNFR2 agonist activity. In some specific examples, the TNFR2 agonist can be a TNFR2 agonist monoclonal antibody or a Fab thereof or a Fab having about or at least about 85%, 90%, 95% or greater sequence identity and TNFR2 agonist activity. Fab fragment.

TNFR2 agonists may also be or include TNF muteins modified to bind to TNFR2 and have agonist activity (see, eg, SEQ ID NO: 765-800). An example of such a specific example is a TNFR2 agonist containing a TNFR2-selective TNF mutein, such as with reference to SEQ ID NO: 2, having the TNFR2-selective mutations K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H , A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A14 5H/E146S/S147D, A145H/S147D , L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S 147D, A145K/E146D/S147T, A145R /TNF variants of one or more of E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S and D143V/A145S and combinations thereof, such as the combination of D143V/A145S and S95C/G148C. For example, a TNF variant with mutations D143N/A145R (SEQ ID NO: 781) binds and potentiates TNFR2 and can be used in the constructs provided herein. With reference to SEQ ID NO: 2, TNF muteins with combinations of mutations S95C/G148C and any other mutations listed or known or identified are also TNFR2 selective agonists and may be included in the constructs provided herein.

The TNFR2 agonist may contain a fusion of a single-chain TNFR2-selective TNF mutein trimer and a multimerization domain. As described herein, the primary ligand of TNFR2 is membrane-bound TNF (memTNF; also referred to herein as transmembrane TNF or tmTNF). The addition of multimerization domains, such as dimerization or trimerization domains, generates hexameric or nonameric molecules, respectively, relative to TNF subunits; these hexamers and nonamers of TNF mimic membrane-bound TNF trimers , and thus activates TNFR2 signaling. Dimerization domains include, for example, EHD2 (SEQ ID NO: 808) discussed above. EHD2 is derived from the heavy chain _CH2 domain of IgE, and MHD2 (SEQ ID NO:811) is derived from the heavy chain _CH2 domain of IgM. Dimerization domains also include Fc domains, such as those derived from IgGl (see SEQ ID NO: 10) and IgG4 (see SEQ ID NO: 16), optionally including modifications such as altering immune effector function and/or enhancing FcRn Recycling modifications. Trimerization domains include, for example, the trimerization domain of chicken tenascin C (TNC) (SEQ ID NO: 805) and the trimerization domain of human TNC (SEQ ID NO: 807). Dimerization and trimerization enhance TNFR2 signaling and improve the pharmacological properties of the construct. For example, the half-life of the fusion protein is increased by increasing the molecular weight of the molecule and/or by introducing FcRn recycling, for example when the dimerization domain is Fc.

As provided herein, a TNFR2 agonist may comprise a TNF mutein (TNFmut) trimer chain, with any of the mutations described herein that confer selectivity for TNFR2 and/or reduce or eliminate binding to TNFR1. An example of such a mutation is the substitution D143N/A145R with reference to SEQ ID NO: 2, which is fused to a multimerization domain (MD), such as a dimerization or trimerization domain. The multimerization domain can be fused to the N-terminus or C-terminus of the TNF mutant protein trimer chain, and the linker is included between each TNF mutant protein and between the TNF mutant protein trimer chain and the multimerization domain. Such TNFR2 agonists have Formula 4 and Formula 5: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Equation 4) or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula 5), wherein MD is the multimerization domain (activity modulator); TNFmut is a TNFR2-selective TNF mutein, such as a mutein with mutations D143N/A145R; and L1, L2, and L3 are the linkers described below, such as Gly-Ser Connectors can be the same or different.

In certain embodiments, the multimerization domain is EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO: 811), chicken TNC trimerization domain (SEQ ID NO: 805), human TNC trimerization domain domain (SEQ ID NO: 807), IgG1 Fc or IgG4 Fc. When the dimerization domain is an IgG1 Fc or an IgG4 Fc, it is the same Fc used to link the TNFR1 antagonist to the TNFR2 agonist, not an additional Fc. The IgGl or IgG4 Fc can be modified to enhance or eliminate immune effector functions, such as ADCC, ADCP and/or CDC activity, and/or to enhance FcRn binding. Multimerization domains, such as the Fc region, increase the in vivo stability and serum half-life of the construct. For purposes herein, the Fc region in the constructs of Formulas 1-5, or variations thereof, is generally modified to alter or modulate the pharmacological properties or activity of the construct. Fc modifications are discussed in more detail below. Any multimerization domain known in the art is also contemplated for use in the TNFR2 agonists herein.

A TNF mutein can be a TNF variant with any one or more of the mutations that confer selectivity for TNFR2. Referring to SEQ ID NO: 2, mutations include, for example, K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A1 45R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/ D1 43V/F144L/A145S and D143V/A145S. TNF variants with mutations D143N/A145R are considered for use herein. Any other mutations known in the art that confer selectivity for TNFR2 are also contemplated for use herein. The TNF mutein may contain the entire sequence of soluble TNF (i.e., residues 1-157 of SEQ ID NO: 2), or may contain part of the sequence of soluble TNF, such as residues 4-157, 9- of SEQ ID NO: 2 157 or 12-157, which is long enough to bind and/or catalyze TNFR2.

The L1, L2 or L3 linkers can be the same or different. In particular, the linker may contain a short peptide linker, such as a GS linker. For example, the linker may contain (GGGGS) _n , where n = 1-5 (SEQ ID NO: 1471). The linker may also contain all or part (at least 10, 15 or 20 contiguous residues) of the stem region of TNF-α, which region contains the amino acid sequence GPQREEFPRDLSLISPLAQAVRSSSRTPSDK (SEQ ID NO: 812), which corresponds to SEQ ID NO : Residues 57-87 of the full-length sequence of TNF (transmembrane TNF) shown in 1. For example, a linker containing all or part of a stem region (containing at least 10, 15 or 20 contiguous amino acid residues) can be between the N-terminal or C-terminal TNF mutein and the multimerization domain. All three linkers may be (GGGGS) _n , where n is typically 1-10 (SEQ ID NO: 1472), or other combinations of Gly-Ser, or may contain Gly-Ser residues such as (GGGGS) _n and TNF A mixture of all or part of the stem region (containing at least 10, 15 or 20 consecutive amino acid residues). Exemplary linkers are shown in SEQ ID NOs: 813-834, 1471 and 1472.

TNFR2 agonists provided herein include those that specifically bind to TNFR2 with a _KD value of less than or equal to, or less than about 100 nM (e.g., 95 nM, 90 nM, 85 nM, 80 nM, 75 nM, 70 nM, 65 nM, 60 nM, 55 nM, 50 nM, 45 nM, 40 nM, 35 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM) agent. In some cases, TNFR2 agonists specifically bind to TNFR2 with a _KD value of less than 1 nM (e.g., 990 pM, 980 pM, 970 pM, 960 pM, 950 pM, 940 pM, 930 pM, 920 pM, 910 pM , 900 pM, 890 pM, 880 pM, 870 pM, 860 pM, 850 pM, 840 pM, 830 pM, 820 pM, 810 pM, 800 pM, 790 pM, 780 pM, 770 pM, 760 pM, 750 pM, 740 pM, 730 pM, 720 pM, 710 pM, 700 pM, 690 pM, 680 pM, 670 pM, 660 pM, 650 pM, 640 pM, 630 pM, 620 pM, 610 pM, 600 pM, 590 pM, 580 pM, 570 pM, 560 pM, 550 pM, 540 pM, 530 pM, 520 pM, 510 pM, 500 pM, 490 pM, 480 pM, 470 pM, 460 pM, 450 pM, 440 pM, 430 pM, 420 pM, 410 pM , 400 pM, 390 pM, 380 pM, 370 pM, 360 pM, 350 pM, 340 pM, 330 pM, 320 pM, 310 pM, 300 pM, 290 pM, 280 pM, 270 pM, 260 pM, 250 pM, 240 pM, 230 pM, 220 pM, 210 pM, 200 pM, 190 pM, 180 pM, 170 pM, 160 pM, 150 pM, 140 pM, 130 pM, 120 pM, 110 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 5 pM or 1 pM).

A TNFR2 agonist is one that can induce Tregs (e.g., CD4 ⁺ , CD25 ⁺ FOXP3 ⁺ Treg) proliferation agonist. Treg proliferation can be induced, e.g., at or about 0.00001% to 100.0% (e.g., 0.00001%, 0.00002%), as measured, e.g., by FACS analysis, relative to an individual or sample containing a cell population not treated with a TNFR2 agonist ,0.00003%, 0.00004%, 0.00005%, 0.00006%, 0.00007%, 0.00008%, 0.00009%, 0.0001%, 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%, 0 .0008%, 0.0009%, 0.001 %, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0% , 8.0%, 9.0%, 10.0%, 20.0%, 30.0%, 40.0%, 50.0%, 60.0%, 70.0%, 80.0%, 90.0% or 100%).

Accordingly, TNFR2 agonists can be used to promote Treg cell proliferation and can be administered to mammalian subjects, such as human patients, suffering from autoimmune or chronic inflammatory diseases or conditions to attenuate the extent and duration of the patient's immune response (e.g., The number of CD8 ⁺ cytotoxic T lymphocytes produced in vivo in response to self or non-threatening foreign antigens). For example, administration of TNFR2 agonists to human patients, or by treating ex vivo expanded Treg cell populations with TNFR2 agonists, can result in secreted immunoglobulins that cross-react with self or non-threatening antigens ( for example, IgG), e.g., a decrease or a decrease of about 0.00001 mg/mL to 10.0 mg/mL relative to an individual not treated with a TNFR2 agonist (e.g., 0.00001 mg/mL, 0.0001 mg/mL, 0.001 mg/mL, 0.01 mg/mL, 0.1 mg/mL, 1.0 mg/mL, or 10.0 mg/mL), or reduced by 0.001 to 1.0 mg/mL (e.g., 0.001 mg/mL, 0.005 mg/mL, 0.010 mg/mL, 0.050 mg/mL, 0.10 mg/mL, 0.20 mg/mL, 0.30 mg/mL, 0.40 mg/mL, 0.50 mg/mL, 0.60 mg/mL, 0.70 mg/mL, 0.80 mg/mL, 0.90 mg/mL or 1.0 mg/mL) . Additionally or alternatively, a TNFR2 agonist may reduce cytotoxic T cell counts (e.g., CD8 ⁺ T cell content) in an individual, as measured, e.g., by FACS analysis, relative to individuals not treated with a TNFR2 agonist, e.g. Reduce or decrease by approximately 0.00001 to 100.0% (e.g. 0.00001%, 0.00002%, 0.00003%, 0.00004%, 0.00005%, 0.00006%, 0.00007%, 0.00008%, 0.00009%, 0.0001%, 0.0002%, 0. 0003%, 0.0004%, 0.0005 %, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0% , 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 20.0%, 30.0%, 40.0%, 50.0%, 60.0%, 70.0%, 80.0%, 90.0% or 100 %). For example, a TNFR2 agonist can be administered to an individual (eg, a mammalian individual, such as a human) to treat an autoimmune or chronic inflammatory disease or disorder, such as those described herein. Treating an individual in this manner reduces the number of autoreactive CD8 ⁺ T cells in the individual.

The TNFR2 agonists provided herein can be evaluated to identify agonists that lack specific binding to another TNFR superfamily member, particularly TNFR1. This can be accomplished using any of a variety of in vitro binding assays known to those of ordinary skill in the art, such as ELISA-based methods. For example, TNFR2 agonists include agonists that specifically bind to human TNFR2 or TNFR2-derived peptides, such as a peptide fragment within human TNFR2 containing residues 48-67 of SEQ ID NO: 4 (QTAQMCCSKCSPGQHAKVFC, SEQ ID NO: 847). An agonist with an affinity that is at least or at least about 2, 3, 4, or 5 times greater (e.g., 5 times greater, 6 times greater, 7 times greater, 8 times bigger, 9 times bigger, 10 times bigger, 20 times bigger, 30 times bigger, 40 times bigger, 50 times bigger, 60 times bigger, 70 times bigger, 80 times bigger, 90 times bigger, 100 times bigger, 200 times bigger Big, 300 times bigger, 400 times bigger, 500 times bigger, 600 times bigger, 700 times bigger, 800 times bigger, 900 times bigger, 1,000 times bigger, 2,000 times bigger, 3,000 times bigger, 4,000 times bigger, 5,000 times bigger, 6,000 times larger, 7,000 times larger, 8,000 times larger, 9,000 times larger, 10,000 times larger or greater).

TNFR2 agonists provided herein include agonists that exhibit high k _on and low k _off values upon interaction with TNFR2, consistent with binding to high affinity receptors. For example, TNFR2 agonists provided herein can exhibit a _kon value in the presence of TNFR2 that is greater than or equal to, or greater than about 10 ⁴ M ⁻¹ s ⁻¹ (e.g., greater than or greater than about 1.0 x 10 ⁴ M ⁻¹ s ^-1 , 1.5 x 10 ⁴ M ^-1 s ^-1 , 2.0 x 10 ⁴ M ^-1 s ^-1 , 2.5 x 10 ⁴ M ^-1 s ^-1 , 3.0 x 10 ⁴ M -1 s ^{-1 ,} 3.5 x 10 ⁴ M ^-1 s ^-1 , 4.0 x 10 ⁴ M ^-1 s ^-1 , 4.5 x 10 ⁴ M ^-1 s ^-1 , 5.0 x 10 ⁴ M ^-1 s ^-1 _, 5.5 x 10 ⁴ M ^-1 s ^{-1 , 6.0 _ _ _ _ _ _ _ _ _ _ 4} M ^-1 s ^-1 , 8.5 x 10 ⁴ M ^-1 s ^-1 , 9.0 x 10 ⁴ M ^-1 s ^-1 , 9.5 x 10 ⁴ M ^-1 s ^-1 , 1.0 x 10 ⁵ M ^-1 s ^{- 1} , 1.5 x 10 ⁵ M ^-1 s ^-1 , 2.0 x 10 ⁵ M ^-1 s ^-1 , 2.5 x 10 ⁵ M ^-1 s ^-1 , 3.0 x 10 ⁵ M ^-1 s ^-1 , 3.5 x 10 ⁵ M ^-1 s ^-1 , 4.0 x 10 ⁵ M ^-1 s ^-1 , 4.5 x 10 ⁵ M ^-1 s ^-1 , 5.0 x 10 5 M ^-1 s ^-1 , 5.5 x ^{10 5} M ^-1 s ^-1 , 6.0 x 10 ⁵ M ^-1 s ^-1 , 6.5 x 10 ⁵ M ^-1 s ^-1 , 7.0 x 10 ⁵ M ^-1 s ^-1 , 7.5 x 10 ⁵ M ^-1 s ^-1 , 8.0 x 10 ⁵ M ^-1 s ^-1 , 8.5 x 10 ⁵ M ^-1 s ^-1 , 9.0 x 10 ⁵ M ^-1 s ^-1 , 9.5 x 10 ⁵ M ^-1 s ^-1 or 1.0 x 10 ⁶ M ^-1 s ^-1 ) . For example, TNFR2 agonists provided herein can exhibit k _off values of less than or less than about 10 ^-3 s ^-1 (e.g., less than or less than about 1.0 x 10 ^-3 s ^-1 , 9.5 x 10 ^-4 s ^-1 , 9.0 x 10 ^-4 s ^-1 , 8.5 x 10 ^-4 s ^-1 , 8.0 x 10 ^-4 s ^-1 , 7.5 x 10 ^-4 s ^-1 , 7.0 x 10 ^-4 s ^{- 1} , 6.5 x 10 ^-4 s ^-1 , 6.0 x 10 ^-4 s ^-1 , 5.5 x ^{10 -4} s ^-1 , 5.0 x 10 ^-4 s ^-1 , 4.5 x 10 ^-4 s ^-1 , 4.0 x 10 ^-4 s ^-1 , 3.5 x 10 ^-4 s ^-1 , 3.0 x 10 ^-4 s ^-1 , 2.5 x 10 ^-4 s ^-1 , 2.0 x 10 ^-4 s ^-1 , 1.5 x 10 ^-4 s ^-1 , 1.0 x 10 ^-4 s ^-1 , 9.5 x 10 ^-5 s ^-1 , 9.0 x 10 ^-5 s ^-1 , 8.5 x 10 ^-5 s ^-1 , 8.0 x 10 ^-5 s ^-1 , 7.5 x 10 ^{- 5} s ^-1 , 7.0 x 10 ^-5 s ^-1 , 6.5 x 10 ^-5 s ^-1 , 6.0 x 10 ^-5 s ^-1 , 5.5 x 10 ^-5 s ^-1 , 5.0 x 10 ^-5 s ^-1 , 4.5 x 10 ^-5 s ^-1 , 4.0 x 10 ^-5 s ^-1 , 3.5 x 10 ^-5 s ^-1 , 3.0 x 10 ^-5 s ^-1 , 2.5 x 10 ^-5 s ^-1 , 2.0 x 10 ^-5 s ^-1 , 1.5 x 10 ^-5 s ^-1 or 1.0 x 10 ^-5 s ^-1 ).

As provided herein, a TNFR2 agonist is linked to a TNFR1 antagonist, such as any of the above, directly or indirectly via a linker, in any order or suitable configuration. For example, the N-terminus of a TNFR2 agonist (such as any of the TNFR2 agonists described herein) is fused to the C-terminus of a TNFR1 antagonist via one or more linkers, as discussed below and elsewhere herein . Alternatively, the C-terminus of a TNFR2 agonist can be fused to the N-terminus of a TNFR1 antagonist. When the TNFR2 agonist has the structure shown in Formula 3, the N-terminus of the multimerization domain is connected to the C-terminus of the TNFR1 antagonist, and when the TNFR2 agonist has the structure shown in Formula 4, the multimerization domain The C-terminus of the domain is linked to the N-terminus of the anti-TNFR1 antagonist. The linker (L) between the TNFR1 antagonist and the TNFR2 agonist may include any suitable linker and combinations thereof, such as Ig Fc region and/or antibody hinge region and/or short peptide linker such as glycine- one or more of serine linkers). In some embodiments, the linker is a 30 kDa or larger poly(ethylene glycol) (PEG) molecule or a branched chain PEG molecule. As discussed above, when the TNFR2 agonist has the structure shown in Formula 3 or 4, if the multimerization domain is an Fc, then it is the same Fc used to link the TNFR1 antagonist to the TNFR2 agonist. c. Connector

The above-described TNFR1 antagonist constructs (such as Formula 1), multispecific TNFR1 antagonist-TNFR2 agonist constructs (such as Formula 2), and TNFR2 agonist constructs (such as Formulas 3-5) optionally include linkers and Activity modulator. Linkers serve a variety of functions, including providing additional or improved biological and pharmacological properties, as well as serving structural purposes to join different molecules. Exemplary linkers are Gly-Ser polypeptides, hinge regions (see, eg, Tables 1-4 above, which show various hinge region sequences and combinations thereof).

Includes polypeptide linkers as well as chemical linkers for chemical coupling. Linker peptides are included as spacers between polypeptides and may promote proper protein folding and stability of the polypeptides, improve protein performance, and enhance the biological activity of the construct components. Peptide linkers are mainly designed as unstructured flexible peptides. Linkers may be included as shown in Exemplary Formulas 1-4 above. For example, in provided bispecific constructs, the components are fused via a linker (L) in an N-to-C-terminal or C-terminal to N-terminal configuration. The linker is generally a peptide linker alone, including a polypeptide, such as an Fc region, or in combination with one or more other linkers, including, for example, short peptide linkers, such as a glycine-serine (GS) linker and/or Hinge region of immunoglobulin (Ig). In specific examples herein, for example, the C-terminus of the TNFR1 antagonist is fused to the N-terminus of the peptide linker, and the C-terminus of the peptide linker is fused to the N-terminus of the TNFR2 agonist. In other embodiments, the C-terminus of a TNFR2 agonist is fused to the N-terminus of a peptide linker, and the C-terminus of the peptide linker is fused to the N-terminus of a TNFR1 antagonist. Linkers provide increased molecular weight, increase stability and serum half-life, enhance tissue retention, and reduce or reduce peripheral elimination, thereby increasing the therapeutic index of the molecule. Linkers also increase the flexibility of the molecule, allowing each part of the molecule to interact with its target antigen/epitope (such as TNFR1 and TNFR2 provided herein). As discussed below and elsewhere herein, in specific examples where the linker contains an immunoglobulin Fc region (generally a modified Fc region), additional properties may be conferred, including, for example, nascent Fc receptor (FcRn) recycling, which further Increase serum stability and half-life, and/or enhance or eliminate immune effector functions. i. Peptide linker

Linkers for fusion proteins are well known to those of ordinary skill in the art. See, for example, Chen et al. (2013) Adv. Drug. Deliv. Rev. 65 :1357-1369, entitled " Fusion Protein Linkers: Property, Design and Functionality ". Linkers may be designed, or may be derived from or based on linkers of naturally occurring multidomain proteins. Empirical linkers designed by researchers are generally divided into three categories based on their structure: flexible linkers, rigid linkers, and in vivo cleavable linkers, which are used, for example, to deliver prodrugs activated by in situ cleavage of the linker.

In addition to their role in joining functional domains together (as in flexible and rigid linkers) or releasing free domains in vivo (as in in vivo cleavable linkers), linkers can also modify the properties of the linker moiety. . These include, for example, improved biological activity, increased performance, and achieving a desired pharmacokinetic profile. Databases and methods for selecting linkers are known to those of ordinary skill in the art (see, e.g., George et al. (2002) " An analysis of protein domain linkers: their classification and role in protein folding ," Protein Eng. 15 :871-879). a) Flexible connector

Flexible linkers are often used when the junction domain requires some degree of movement or interaction. Flexible linkers are generally rich in small or polar amino acids, such as Gly and Ser, to provide good flexibility and solubility. It is a suitable choice when certain movements or interactions are required for the fusion protein domain (eg in scFv). In addition, although flexible linkers do not have a rigid structure, they can act as passive linkers to maintain the distance between functional domains. The length of the flexible linker can be adjusted to allow for proper folding or to obtain optimal biological activity of the fusion protein.

As suggested by Argos (1990) J. Mol. Biol. 211(4):943-958, flexible linkers are generally composed of small non-polar (eg Gly) or polar (eg Ser or Thr) amino acids. The small size of these amino acids provides flexibility and allows movement of linked functional domains. The incorporation of Ser or Thr can maintain the stability of the linker in aqueous solution by forming hydrogen bonds with water molecules, and thus reduce adverse interactions between the linker and protein moieties.

Exemplary flexible linkers are linkers containing primarily or exclusively segments of Gly and Ser residues ("GS" linkers). An example is a flexible linker with the sequence (Gly-Gly-Gly-Gly-Ser) _n . By adjusting the number of copies "n", the length of the GS linker can be selected to achieve appropriate separation of functional domains, or to maintain necessary inter-domain interactions. Flexible linkers are also rich in small or polar amino acids, such as Gly and Ser, and may also contain additional amino acids, such as Thr and Ala, to maintain flexibility, as well as polar amino acids, such as Lys and Glu , to improve solubility.

In order to confer protease resistance and increase the flexibility of the fusion protein, the SCDKTH hinge sequence and other hinge sequences can be replaced by or preceded by a short polypeptide linker. An example of a polypeptide linker is the (Gly-Ser) _n amino acid sequence (GS linker), in which some Glu or Lys residues are dispersed throughout to increase solubility. For example, polypeptide linkers include, but are not limited to, (GlySer) _n , where n=1-10; ( _GlySer2 ); ( _Gly4Ser ) _n , where n=1-10; ( _Gly3Ser ) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSSGSGSGSSG; GSSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; linker, see SEQ ID NO: 816-827). The linker can be a polyGly peptide of at least 2-18 residues in length or longer, or a similar linker of the same length and flexibility. Exemplary polypeptide linkers in molecules provided herein include, but are not limited to (for Gly-Ser linkers, see SEQ ID NO: 816-827): for example, GSGS, GGGGS, or GGGGSGGGGSGGGGS. Another linker that provides similar performance is the (GGGGS) ₄ (SEQ ID NO: 819) linker. Another Gly- and Ser-rich flexible linker is GSAGSAAGSGEF (SEQ ID NO: 828). This linker has been shown to maintain good solubility in aqueous solutions. Linkers containing only glycine can be used. For example, the (Gly) ₆ (SEQ ID NO: 1473) and (Gly) ₈ (SEQ ID NO: 1474) linkers are known and have been shown to respond to proteolytic digestion during purification of proteins from expressing organisms as Stable.

Several other types of flexible linkers include KESGSSVSSEQLAQFRSLD (SEQ ID NO: 829) and EGKSSGSGSESKST (SEQ ID NO: 830). Gly and Ser residues in the linker provide flexibility, and Glu and Lys improve solubility. b) Rigid connector

While flexible linkers have the advantage of passively connecting functional domains and allowing a degree of movement, the lack of rigidity of these linkers can be limiting. Rigid linkers are chosen when spatial separation of domains is required to maintain stability or biological activity of the fusion protein. Rigid linkers exhibit relatively strong structures by adopting an α-helical structure or by containing multiple Pro residues. The length of the linker can be easily adjusted by changing the number of replicas to achieve an optimal distance between domains.

The linker formed by the α-helix with the sequence (EAAAK) _n (SEQ ID NO: 831) has been used in the construction of many recombinant fusion proteins. The α-helical structure is rigid and stable, with intra-segment hydrogen bonds and a tightly packed backbone. Strong α-helical linkers act as rigid spacers between protein domains. An example of a rigid linker is: A(EAAAK) _n A (SEQ ID NO: 832), where n = 2-5. This linker exhibits an α-helical conformation, which is stabilized by Glu−Lys ⁺ salt bridges within the segment. Another type of rigid linker has a Pro-rich sequence (XP) _n , where X represents any amino acid, and is typically Ala, Lys, or Glu. The presence of Pro in non-helical linkers increases stiffness and allows efficient separation of protein domains. An example of such a linker is a peptide containing 33 residues of -Glu-Pro- and -Lys-Pro- repeated.

A person of ordinary skill in the art may choose from known linkers or designed linkers. The desired properties and their necessary conditions are known. The following discussion summarizes some exemplary linkers (see Chen et al. (2013) Adv. Drug. Deliv. Rev. 65 :1357-1369), which provides details of flexible and rigid and cleavable linkers that can be used). Flexible linkers are rich in small and/or hydrophilic amino acids, such as Gly or Ser, to provide structural flexibility and have been used to connect functional domains that facilitate interdomain interactions or movement. Rigid linkers can be used where adequate separation of protein domains is required. Rigid linkers are designed or selected to adopt an alpha-helical structure or to incorporate proline. Rigid linkers keep protein parts at a distance. Flexible and rigid linkers are stable in vivo and do not allow separation of the joined proteins. Cleavable linkers allow the release of free functional domains via reductive or proteolytic cleavage in vivo. They are generally used to deliver prodrugs to target sites.

In formula 2 above, additional linkers may be included, such as between the TNFR1 antagonist and/or TNFR2 agonist moiety and the activity modulating moiety such as the Fc moiety; such linkers may contain, for example, the hinge sequence of trastuzumab All or a portion of the hinge region of nivolumab that is sufficient to provide flexibility, including at least residues SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), or all or a portion of the hinge region of nivolumab that is sufficient to provide Flexible, having the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29) or a sequence having at least 98% or 99% sequence identity thereto, or any other suitable antibody known in the art Hinge region or sequence.

In some specific examples, only the GS linker is included. Other short peptide linkers known in the art are also contemplated for use in the bispecific molecules provided herein. For example, the N-terminal or C-terminal extension of Fc can be used as a linker. The C-terminal extension of human IgG ELQLEESSAEAQDGELDG (SEQ ID NO: 833) or a sequence having at least 98% or 99% sequence identity thereto, or containing the sequence ELQLEESSAEAQGG (SEQ ID NO: 834) or having at least 98% or 99% sequence identity thereto Variants of the sequence identity can also be used as linkers.

A second Fc subunit may be included, which may or may not be a fusion protein (see, eg, Figure 2), and may be modified to contain a pestle (see discussion below). It will assemble within a mammalian cell expression system to form a pestle-mediated Fc dimer, thereby producing an Fc dimer, which further increases the serum half-life and stability of the molecule. In certain embodiments, a second Fc subunit is fused to a second TNFR2 agonist, producing a bivalent antibody-like structure .In other embodiments, only one Fc subunit (Fc monomer) is included. ii. Chemical linker

In some embodiments, the linker is a chemical linker. These include linkers such as polymer molecules, including PEGylated moieties, as non-cleavable moieties, chemical cross-linking reagents and polypeptide modulators. Chemical linkers are more suitable for generating branched chain constructs and other structures that cannot be achieved with peptide linkers.

Exemplary linkers include non-cleavable linkers. Non-cleavable linkers include, for example, amide linkers and amide and ester linkages with succinate spacers (see, eg, Dosio et al., (2010) Toxins 3:848-883). Exemplary chemical cross-linking linkers include, but are not limited to, SMCC (succinimidyl-4-( N -maleimidomethyl)cyclohexane-1-carboxylate) and SIAB (( 4-iodoacetyl)aminobenzoic acid succinimidyl ester). SMCC is an amine-thiol crosslinker containing NHS-ester and maleimide reactive groups at opposite ends of the intermediate length cyclohexane stabilizing spacer arms. SIAB is a short NHS-ester and iodoacetyl cross-linker for amine-sulfhydryl coupling. Other exemplary cross-linking reagents include, but are not limited to, thioether linkers, chemically unstable hydrazone linkers, 4-mercaptopentanoic acid, BMPEO, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SMPB, SMPH, Sulfo-EMCS, Sulfo-GMBS, Sulfo-KMUS, Sulfo-MBS, Sulfo-SIAB, Sulfo-SMCC and Sulfo-SMPB and SVSB (succinimide-(4 -ethylenesulfonyl)benzoate) and bismaleimide reagents such as DTME, BMB, BMDB, BMH, BMOE, BM(PEO) ₃ and BM(PEO) ₄ , which are commercially available (Pierce Biotechnology, Inc.). Bismaleimide reagents allow free thiol groups of cysteine residues of an antibody to be linked to thiol-containing targeting agents or linker intermediates in a sequential or simultaneous manner. In addition to maleimide, other thiol-reactive functional groups include iodoacetamide, bromoacetamide, vinylpyridine, disulfide, pyridine disulfide, isocyanate, and isothiocyanate. Other exemplary linkers and methods of use are well known to those of ordinary skill in the art, for example, as described in U.S. Patent Publication No. 2005/0276812 and Ducry et al. (2010) Bioconjug. Chem. 21:5-13 connectors and methods.

Linkers may optionally be substituted with groups that modulate properties such as solubility and reactivity. For example, sulfonate substituents may increase the water solubility of the reagent and facilitate coupling of the linker reagent to the antibody or drug moiety, and/or facilitate coupling reactions. Linker reagents are also available from commercial sources such as Molecular Biosciences Inc. (Boulder, CO.) or according to Toki et al. (2002) J. Org. Chem. 67:1866-1872; U.S. Patent No. 6,214,345; U.S. Publication Nos. 2003/130189 and 2003/096743; and International Application Publication Nos. WO 02/088172, WO 03/026577, WO 03/043583 and WO 04/032828 Procedural synthesis. For example, linker reagents such as DOTA-maleimide (4-maleimidebutylamidobenzyl-DOTA) can be prepared according to Axworthy et al. (2000) Proc. Natl. Acad Sci. USA 97(4):1802-1807 Procedure by aminobenzyl-DOTA and 4-maleimide butyric acid (Fluka) activated with isopropyl chloroformate (Aldrich) prepared by reaction. The DOTA-maleimide reagent reacts with the free cysteine amino acid of the cysteine-engineered antibody and provides a metal complex ligand on the antibody (Lewis et al. (1998) Bioconj. Chem. 9:72-86). Chelate linker labeling reagents such as DOTA-NHS (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(N-hydroxysuccinimide ester) It is commercially available (Macrocyclics, Dallas, TX.).

The linker can be a dendritic type linker for covalent attachment of more than one moiety to the antibody via a branched chain multifunctional linker moiety (see, eg, Sun et al. (2002) Bioorganic & Medicinal Chemistry Letters 12:2213-2215; Sun et al. (2003) Bioorganic & Medicinal Chemistry 11:1761-1768; King et al. (2002) Tetrahedron Letters 43:1987-1990). If the antibody carries only one reactive cysteine thiol group, many other moieties can be connected via dendritic linkers. Exemplary dendritic linker reagents are known (see, eg, US Patent Publication No. 2005/0276812).

Another example of a chemical linker (which may also be an activity modulator for use in the constructs herein) is PEG molecules and branched chain PEG molecules, especially those with a molecular weight of 30 kDa or greater. The PEG linker provides the introduction of multispecificity and bivalency (receptor aggregation enhances signaling in the case of TNFR2 agonists) and increases the molecular weight of the molecule, thereby increasing serum half-life in vivo. PEG linkers also alleviate difficulties in antibody re-engineering, for example by avoiding the introduction of non-native structures that are rapidly degraded and cleared and/or cause immunogenicity. d.Activity regulator

There are parts or regions in the construct components that modulate or change the activity and/or pharmacological properties of the construct (see Formula 1 and Formula 2 above). Examples of such are Fc regions, modified Fc regions, other multimerization domains, dimers and other portions of Fc and modified Fc, such as polymeric portions, including polypeptides, such as half-life extending polypeptides; albumins, such as Human serum albumin (HSA); and transferrin; and polymers that increase serum half-life, such as PEG, as discussed elsewhere herein. Activity modulators may confer properties such as, but are not limited to, prolonged plasma half-life by reducing access to proteases, reducing renal filtration, and/or altering intracellular pathways via receptor-mediated recycling; by being associated with endocytic transport Receptor binding provides for absorption across epithelial bilayers; targeting of sites in vivo where specific receptors or antigens are overexpressed or uniquely expressed; and other properties as exemplified in the discussion below and known in the art.

As provided herein, the construct may include as an activity modulator the Fc region of a human immunoglobulin such as an IgG, e.g., IgGl Fc (SEQ ID NO: 10), IgG2 Fc (SEQ ID NO: 12), IgG3 Fc (SEQ ID NO: 14) or IgG4 Fc (SEQ ID NO: 16). In particular, the Fc is derived from an IgGl or IgG4 antibody. For example, the linker may include an IgG1 kappa Fc region, such as an IgG1 Fc derived from trastuzumab, which contains the _CH2 and _CH3 domains of the trastuzumab heavy chain (see, e.g., SEQ ID NO: Residues 234-450 of 26; see also SEQ ID NO: 27). The Fc subunit in the bispecific molecules provided herein may also be an IgG4 Fc, such as an IgG4 Fc derived from nivolumab (Opdivo®), which contains the _CH 2 and _CH 3 domains of the nivolumab heavy chain (See, eg, residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30).

As discussed below, the Fc region can be mutated or modified to eliminate, reduce, or enhance immune effector functions, including, for example, antibody-dependent cellular cytotoxicity (ADCC; also known as antibody-dependent cell-mediated cytotoxicity), antibody-dependent cellular cytotoxicity Any one or more of mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). In some embodiments herein, for example, when the construct is a bispecific molecule for the treatment of inflammatory and autoimmune diseases and conditions, the immune effector function is eliminated or reduced. When therapeutic agents are used to treat tumors or cancers, immune effector functions can be enhanced to improve anti-tumor immune responses and therapeutic efficacy. Additionally or alternatively, the Fc region is modified to enhance FcRn recycling to increase the in vivo serum stability and half-life of the molecules provided herein.

For the purposes herein, the Fc region or domain is modified, particularly to reduce or eliminate ADCC. Small molecule therapeutics such as antibody fragments (eg Fab, scFv, dAb) are advantageous. It can be produced in high yields and has other advantageous properties. Compared with monoclonal antibodies (mAbs), they exhibit enhanced tissue penetration and target accessibility, and they prevent the adverse effects of mAbs, such as receptor aggregation, activation of immune effector functions, poor tissue penetration, and vasculature Poorly transformed areas cannot approach the target. However, small antibody fragments have poor pharmacokinetic properties. For example, due to their small size, dAbs and other antibody fragments are rapidly cleared by the kidneys, as molecules of 50-60 kDa or smaller undergo renal filtration. The rapid clearance and short elimination half-life of small antibody fragments, which may be less than a few hours, reduces in vivo efficacy and requires frequent administration and/or continuous infusion.

Several methods are available to increase the retention and in vivo half-life of small antibody fragments such as dAbs. For example, as provided herein, TNFR1 antagonists, TNFR2 agonists, and dAbs in combination/multispecific constructs are fused to a linker that is or includes a half-life extender, such as an IgG (such as IgG1 or IgG4 ) of the Fc area. Fc can be a monomer or dimer. The fusion of small antibody fragments (such as dAb) to the Fc region of IgG molecules increases the size of the molecule, thereby protecting it from clearance/excretion from the body, and mediates binding to nascent Fc receptors (FcRn) expressed on endothelial cells, protecting Antibodies are not degraded by lysosomes and have a prolonged half-life in vivo. However, the addition of Fc can introduce undesirable properties, such as the induction of immune effector functions that can lead to complement activation, release of proinflammatory cytokines, and cytotoxicity. Because TNFR1 is almost universally expressed and TNFR2 is expressed by many tissues, it is generally undesirable to use ADCC-enhancing antibodies and instead rely on the antagonist activity of the antibody for efficacy.

As described herein, the Fc region in TNFR1 antagonists, TNFR2 agonists, and multispecific (such as bispecific) constructs is modified to improve pharmacokinetic and pharmacodynamic (i.e., pharmacological) properties and eliminate incompatibility required characteristics. For example, the Fc region is modified to utilize/enhance nascent FcR recycling to increase half-life in vivo, and/or is mutated to eliminate Fc-related immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC; also known as antibody-dependent sex cell-mediated cytotoxicity), antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). Additionally, in embodiments where the construct is multispecific, such as bispecific (such as the embodiment containing a TNFR1 antagonist and a TNFR2 agonist) and contains an Fc dimer, the dimer is mutated to introduce Pestle and mortar to prevent homodimerization. Many modifications to the Fc portion (or region) are known to those of ordinary skill in the art (see, eg, Li et al., (2014) Expert Opin Ther Targets 18 :335-350). i. Modification of Fc part a) Pestle and mortar

Bispecific antibodies (bsAbs) include two distinct antigen-binding sites, allowing for an alternative treatment approach to conventional therapeutic monoclonal antibodies (mAbs), thereby avoiding limitations associated with mAbs, such as receptor coaggregation . Although small antibody fragments are easier and cheaper to produce in high yields and can easily penetrate tissue, they also have limitations such as poor stability, solubility, and pharmacokinetic properties. For example, its small size results in a short serum half-life, reduced tissue retention, and rapid clearance from the blood via the kidneys. Therefore, IgG-like bispecific (bs) Abs that do not share the same limitations would be advantageous. For example, a bsAb can include an Fc region to increase serum half-life and also allow effector functions to be exerted where needed. However, producing high yields of purified bsAb can be challenging because homodimerization of the heavy chain must be prevented. The "knobs-in-holes"(KiH; also known as "knobs-in-holes") method provides a solution to this problem. The _CH3 domain of the antibody (IgG) heavy chain is engineered for heterodimerization, allowing the construction of Fc-containing bifunctional therapeutic molecules that do not self-associate.

The pestle-and-mortar approach involves asymmetrically mutating interface residues in the _CH3 domains of the two parental heavy chains in a complementary manner. "Pestle" is produced by replacing an amino acid with a small side chain at the interface between _CH3 domains with an amino acid with a larger side chain, such as tyrosine or tryptophan, and " Acetaminophen is produced by replacing an amino acid with a large side chain with an amino acid with a smaller side chain, such as alanine or threonine. The pestle and mortar variants heterodimerize by inserting the pestle into a correspondingly designed mortar on the _CH3 domain. Pstle-pestle association is prevented due to steric repulsion, and the mortar-mortar homodimer is unstable. For example, the hammer mutation can be S354C, T366Y, T366W or T394W, and the hammer mutation can be Y349C, T366S, L368A, F405A, Y407T, Y407A or Y407V (all according to EU numbering). It has been shown that pestles generated toward the center of the dimer interface, such as at residue T366, are more disruptive to homodimer formation than pestles located near the edges of the dimer interface. Residue T366 on the first _CH3 domain is within hydrogen bonding distance of residue Y407 on the second or collocated _CH3 domain. Therefore, T366Y and Y407T represent a common pestle and mortar pair; this pair has been shown to interact with more than 90% of yields heterodimers (see, eg, Ridgway et al. (1996) Protein Eng. 9(7):617-621).

For example, the IgG Fc region in the bispecific TNFR1 antagonist/TNFR2 agonist constructs provided herein can be modified using the pestle and mortar method to produce heterodimeric molecules in high yields. Table 6 below shows the corresponding pestle and mortar mutations according to Kabat numbering and sequence numbering with reference to the IgG1 heavy chain constant domain sequence shown in SEQ ID NO: 9. Any mutation known to one of ordinary skill in the art to introduce a pestle can be employed in the constructs herein. Table 6 : Introducing IgG1 Fc modification into pestle and mortar modification type Modification according to EU number Modification based on Kabat number Modification according to sequence number (SEQ ID NO:9 ) pestle S354C S375C S237C pestle T366Y T389Y T249Y pestle T366W T389W T249W pestle T394W T422W T277W mortar Y349C Y370C Y232C mortar T366S T389S T249S mortar L368A L391A L251A mortar F405A F436A F288A mortar Y407T Y438T Y290T mortar Y407A Y438A Y290A mortar Y407V Y438V Y290V Ligand capture agent construct

As mentioned above, Fc modified to have "pestles" can also be used with other bispecific molecules to generate heterodimers. For example, U.S. Patent Publication No. 2010/0055093 and Jin et al. (2009 ) Mol. Med. 15 :11-20 describes bispecific "ligand" capture constructs targeting EGF receptor family ligands, including one designated RB200 and another designated RB242. The problem with these constructs is that they are heterogeneous and contain both homodimers and heterodimers, the latter being the intended therapeutic agent. RB200 and RB242 are examples of ligand capture agents that can be modified by replacing the Fc portion with a modified Fc region with complementary pestles and mortars, such that the resulting dimers are both heterodimers. RB242 targets HER1 (EGFR), HER2 and HER3 ligands as well as some HER4 ligands. It is designed so that it does not capture HER4-specific ligands because HER4 plays a role in neuronal development that other members of the EGFR family do not possess. RB242 consists of the extracellular domain (ECD) of HER1/ErbB1 (amino acids 1 to 621 of SEQ ID NO: 41) and HER3/ErbB3 (amino acids 1 to 621 of SEQ ID NO: 45) and human immunoglobulin G1 ( The Fc domain of IgG1) is composed of a fusion (HER1-HER3/Fc) and acts as a chimeric dual-specific ligand capture agent. The HER3/Fc component of RB242 contains a 6×histidine tag at the COOH terminus (see, e.g., Jin et al. (2009) Mol. Med. 15 :11-20). RB200 binds to HER1/ErbB1 ligands (EGF, TGF-α, HB-EGF, AR, BTC, EPR and EPG) and HER3/ErbB3 ligands (NRG1-α and NRG1-β3) with high affinity. RB242 inhibits EGF-stimulated and NRG1-β1-stimulated tyrosine phosphorylation of HER family proteins (HER1, HER2, and HER3) and has shown efficacy in a variety of cell proliferation assays. RB200 inhibits tumor growth in in vivo animal models.

The epidermal growth factor (EGF) ligand/receptor family plays a role in a variety of diseases, disorders and conditions, including rheumatoid arthritis (RA). The EGF family of cell surface receptors (ErbB and human epidermal growth factor receptor (HER)) belong to the receptor tyrosine kinase (RTK) superfamily and contain an extracellular domain (ECD) and an intracellular tyrosine kinase signaling domain. . The EGF family has four members: EGF receptor (EGFR)/HER1/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4, which are activated by large family ligands, including EGF, transforming growth factor α (TGF-α ), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), beta-cell protein (BTC), epiregulin (EPR), epithelial mitogen (EPG) and neuregulin (NRG). Within EGFR, there are four ECDs; domains I and III are ligand-binding domains, and domains II and IV mediate binding to each other and other members of this receptor family. Ligand binding induces the formation of homo- or heterodimers between receptors. For example, TGF-α and EGF bind to EGFR/HER1/ErbB1, while NRG4 binds to HER4/ErbB4. Depending on the dimer formed, the intracellular domain undergoes transphosphorylation, leading to the activation of many downstream signaling pathways, leading to cell proliferation, survival and differentiation (see e.g. Jin et al. (2009) Mol. Med. 15 : 11-20).

The epidermal growth factor receptor family consists of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2 (Erb-B2), HER3 (ErbB-3), and HER4 (ErbB-4). In many cancer types, mutations or amplifications in a family member are associated with worse survival in cancer patients. In autoimmune diseases, TNF signaling transactivates the EGFR signaling pathway by inducing the synthesis of Epiregulin and heparin-binding EGF (HB-EGF), two growth factors that activate EGFR, on macrophages.

EGFR and HER2 are upregulated on synovial fibroblasts in a complementary manner, thereby driving their proliferation. EGFR, HER2 (ErbB2) and EGF-like growth factors are overexpressed in, for example, RA synovial fibroblasts and macrophages. Thus, the TNF and EGFR pathways cooperate in the progression of lupus and rheumatoid arthritis, as well as other autoimmune diseases. Among the constructs provided herein are constructs called "ligand capture agents." The ligand trap construct intercepts most inflammatory growth factors of the EGFR family, thereby inhibiting the growth of rapidly growing synovial fibroblasts in affected RA joints. These ligand capture agents are intended to be administered in combination therapy regimens with TNF blocker constructs, which are the TNFR1 and/or TNFR2 targeting constructs provided herein. Such combination therapies, such as for rheumatoid arthritis, may be combined synergistically to achieve disease regression.

The EGFR family of growth factors is overrepresented in hyperproliferative/inflammatory diseases such as RA, and is also overrepresented in ovarian and other cancers. Elevated levels of the EGFR family and/or its homologs are a common component of many types of cancer. When overexpressed (or sometimes mutated), these receptors are causally linked to shorter survival in a variety of malignancies. Examples of targeted therapeutics that act through the EGFR family are (listed by common name and exemplary trademark providing the source) cetuximab (Erbitux®), panitumumab (Vectibix®), Trastuzumab (Herceptin®) and pertuzumab (Perjeta®). Small molecule inhibitors also target the intracellular tyrosine kinase activity of the EGFR family. Examples of small molecules include lapatinib (Tykerb®), erlotinib (Iressa®), and neratinib (Nerlynx®). These drugs target only one member of the EGFR family, with the result that other members of the family can be upregulated and compensate for tumor growth. Similarly, antibodies directed against a single growth factor (eg, TGF-α, EGF, HB-EGF, and others) inhibit only that growth factor, and tumor cells will compensate by upregulating other growth factors. The ligand capture constructs provided here solve this problem by blocking HER1, HER2, and HER3 simultaneously. This results in pan-inhibition of cancer cells by the EGFR family. Ovarian cancer is one of the cancers that undergoes treatment.

The ligand capturer constructs provided herein are modified by optimizing heterodimer production and FcRn recycling using a modified Fc region as described below for the TNFR1/TNFR2 construct. Ligand capture agent constructs and TNFR1 antagonist constructs, and/or TNFR2 agonist constructs, and/or multispecific TNFR1 antagonist/bispecific constructs, and/or provided herein for use in treating as herein The TNF acts and/or any other construct for diseases, disorders and conditions known to those of ordinary skill in the art is administered together in a combination therapy regimen. b) Modification to enhance recycling of nascent Fc receptor ( FcRn )

Many methods exist to increase the short serum half-life of small peptide or protein therapeutics. PEGylation increases the serum half-life of small protein therapeutics, but has a drawback. PEGylation can reduce the potency or activity of protein therapeutics, can lead to heterogeneity, and can lead to immunoreactivity of the protein. Other approaches involve fusion with albumin, which improves protein circulation by increasing molecular weight and reducing renal clearance.

Serum half-life can also be increased by fusion with the Fc portion of IgG. The long circulating half-life and slow clearance of IgG of approximately 2-3 weeks are due at least in part to its interaction with the nascent Fc receptor (FcRn), which binds IgG with high affinity at acidic pH and at neutral or Release at higher pH. FcRn binds to the Fc portion (within the _CH 2- _CH 3 domain) of pinocytotic IgG in acidic (~pH 6) endosomes in a 2:1 FcRn:IgG configuration (bivalent interaction), autolyzing it It is transferred to the cell surface during the enzymatic degradation pathway and is recycled into the circulation after exposure to extracellular physiological pH (~7.4), where the Fc-FcRn complex dissociates. Binds poorly to FcRn at acidic pH, resulting in antibody transport to lysosomes where they are degraded. Recycling receptors, such as FcRn, also provide pathways for transepithelial (endocytic transport) transport of IgG into the bloodstream. Exploiting interactions with FcRn can improve protein transport across epithelial barriers, such as in the gut and lungs, allowing for non-invasive delivery. Residues in the Fc _CH2 and _CH3 domains are involved in FcRn binding, and their mutations in mAbs have been shown to affect serum half-life in vivo. Circulation and delivery of small protein therapeutics can be improved by fusing them to the Fc domain of IgG so that the resulting fusion protein binds FcRn and exploits the IgG serum stabilization pathway. Fusion to the Fc domain also increases the molecular weight of the therapeutic and reduces renal clearance, but may be undesirable as the tissue permeability and specific activity of the fusion protein may be reduced. Alternatively, studies have shown that short FcRn-binding peptides (FcRnBPs) allow interaction of small proteins with FcRn, avoiding the need for fusion with high molecular weight Fc domains. For example, fusion to FcRnBP increases molecular weight by approximately 3 kDa compared to fusion to Fc or albumin which increases molecular weight by approximately 50-70 kDa (see e.g. Datta-Mannan et al. (2019) Biotechnol. J. 14: 1800007; Sockolosky et al. (2012) Proc. Natl. Acad. Sci. USA 109(40):16095-16100).

For example, short (16 residues) linear and cyclic FcRnBPs (see, e.g., SEQ ID NO: 48-51) have been fused to the C-terminus, N-terminus, or both of Fab heavy and light chains (FcRnBP-Fab constructs body), each Fab has 1-4 FcRnBPs. Pharmacokinetic studies in cynomolgus monkeys showed that FcRn binding of the FcRnBP-Fab construct increased with the number of peptides fused to the Fab. This is due to increased affinity, as shown in the pharmacokinetics of a construct containing four linear FcRnBPs fused to the N- and C-termini of the heavy and light chains of the Fab in cynomolgus monkeys relative to the parental Fab. Maximum improvement. For example, the half-life is increased from 3.7 hours for the parent Fab to 15-60 hours for various FcRnBP-Fab constructs (see, eg, Datta-Mannan et al. (2019) Biotechnol. J. 14:1800007). Although these results indicate an improvement in serum half-life, they are still well below the half-life of IgG of approximately 2-3 weeks. Administration of FcRnBP also does not decrease renal clearance because it does not significantly increase the molecular weight of the therapeutic.

As discussed above, fusion to IgG Fc increases the half-life of a small protein therapeutic by utilizing FcRn binding and also by increasing the molecular weight of the therapeutic so that it is cleared from the body less rapidly, for example, by the kidneys. In order to improve pharmacokinetics and overall pharmacology, residues within the Fc region can be mutated to increase the affinity for FcRn, typically by more than 30-fold, further increasing in vivo half-life. The Fc region spanning the interface of _CH2 and _CH3 domains interacts with FcRn. Human Fc residues identified to play a role in FcRn binding include, for example, L251, M252, I253, S254, L309, H310, Q311, L314, E380, N434, H435 and Y436 (based on EU numbering, see Table 1). Mutations of residues located at the Fc-FcRn interface, including M252, S254, T256, H433, N434 and Y436 (according to EU numbering), improve the stability of the human FcRn-IgG1 complex. For example, substitutions M252Y/S254T/T256E and H433K/N434F/Y436H increase the binding to human FcRn at pH 6.0 by 11-fold and 6.5-fold, respectively, relative to wild-type IgG1, and enable efficient release at pH 7.4. The combination of these substitutions resulted in a 57-fold increase in binding affinity to FcRn. Additional mutations in the IgG1 Fc showing improved binding to FcRn include, for example, M252W, M252Y, M252Y/T256Q, M252F/T256D, E380A and N434F/Y436H (see, e.g., Dall'Acqua et al. (2002) J. Immunol. 169: 5171-5180).

The triple substitution M252Y/S254T/T256E, when introduced into the _CH2 domain of MEDI-524, a humanized anti-respiratory syncytial virus (RSV) mAb, improved the mAb's performance in cynomolgus macaques compared with unmodified MEDI-524. The serum half-life in vivo increases approximately 4-fold. When introduced into the Fc portion of MEDI-522, a humanized, affinity-optimized mAb against the human αvβ3 integrin complex, substitution M252Y/S254T/T256E (YTE) reduces its ADCC activity and its interaction with human FcγRIIIA (F158 isotype ) combination. The ADCC activity of MEDI-522-YTE can be restored and increased by the introduction of ADCC-enhancing substitution S239D/A330L/I332E (according to EU numbering) compared with unmodified MEDI-522, indicating that the substitution of YTE provides a reversible mechanism. Modulates the ADCC function of human IgG1 (see, eg, Dall'Acqua et al. (2006) J. Biol. Chem. 281(33):23514-23524).

Residues at positions 250, 314 and 428 (according to EU numbering) of the human IgG heavy chain are conserved in all four human IgG subtypes and are also located near the Fc-FcRn interface. Mutations T250Q, M428L, and T250Q/M428L, when introduced into the Fc of a human IgG2 mAb, increased binding to FcRn at pH 6.0 by approximately 3-fold, 7-fold, and 28-fold, respectively, with no binding observed at pH 7.5. When the pharmacokinetics of the mutants were evaluated in rhesus monkeys, it was found that the average clearance rate, that is, the volume of serum antibody cleared per unit time, was approximately 1.8-fold lower for the M428L mutant compared with the unmodified antibody, and for T250Q /M428L mutant decreased by approximately 2.8-fold, while the elimination half-life of the M428L mutant was increased by approximately 1.8-fold and the T250Q/M428L mutant was increased by approximately 1.9-fold. Since these residues are conserved among IgG subtypes, mutations M428L and T250Q/M428L are expected to have similar effects in human IgG1, IgG3 and IgG4 antibodies (see, e.g., Hinton et al. (2004) J. Biol. Chem. 279 (8):6213-6216). Modification T250R/M428L was shown to result in selective binding to FcRn at pH 6.0 and a 2.8-fold reduction in degradation of IgG2 and IgG1 in rhesus monkey serum (see, e.g., Saxena et al. (2016) Front. Immunol. 7:580).

Mutation N434A (according to EU numbering), when introduced into human anti-HER2 IgG1 trastuzumab, resulted in approximately 4-fold higher affinity for human FcRn at pH 6 than the unmodified antibody, but binding at pH 7.4 was neglect. When tested in vivo in cynomolgus macaques, the N434A variant showed increased exposure, reduced clearance (approximately 2-fold) and increased half-life (approximately 2-fold) compared to the wild-type antibody. In contrast, the mutation N434W increased the binding to FcRn by about 80-fold at pH 6, showing a similar clearance rate to the wild type; this mutant also showed significant binding to FcRn at pH 7.4, indicating that it maintains The pH-dependent binding of Fc mutants to FcRn is key to improving pharmacokinetics in vivo (Yeung et al. (2009) J. Immunol. 182:7663-7671). The N434A mutation also counteracts the poor FcRn affinity that may result from the introduction of mutations that increase binding to FcγR; N434A is typically added to mutations S298A/E333A/K333A to create variants with enhanced FcγR binding and normal or improved FcRn binding body. Fc mutations that improve FcRn binding also include N434Y, E294del/T307P/N434Y, and T256N/A378V/S383N/N434Y. Deletion of E294 results in greater sialylation of the N297 glycan on the Fc, thereby increasing antibody half-life in vivo. It has been shown that sialylation also plays a role in regulating serum half-life (see, e.g., Saunders, KO (2019) Front. Immunol . 10:1296).

Substitution M428L/N434S (according to EU numbering), when introduced into the humanized anti-VEGF IgG1 antibody bevacizumab (Avastin®), resulted in an 11-fold increase in affinity for FcRn at pH 6.0 and in vivo serum from cynomolgus monkeys The half-life was extended from 9.7 days to 31.1 days, which is equivalent to a 3.2-fold increase. The M428L/N434S modification caused a similar increase in FcRn binding and prolonged half-life when introduced into the anti-EGFR antibody cetuximab, which is rapidly cleared due to receptor-mediated internalization. The extended half-life of these anti-tumor antibodies correlates with enhanced in vivo tumor reduction in mouse models, suggesting that the in vivo therapeutic efficacy of the antibodies increases when pharmacokinetics (such as clearance) are improved. Other mutations engineered into the Fc of bevacizumab include (according to EU numbering): N434S, which increases FcRn binding approximately 3-fold and serum half-life in mice by approximately 2.8-fold; V259I/V308F, which increases FcRn binding approximately 6-fold and The serum half-life of mice and crab-eating macaques increased by approximately 3 times and approximately 2-fold respectively; M252Y/S254T/T256E, FcRn binding increased by approximately 7-fold and the serum half-lives of mice and crab-eating macaques increased by approximately 4 and 2.5 times respectively; and V259I/V308F/M428L, FcRn binding was increased approximately 20-fold and the serum half-life in mice and cynomolgus macaques was increased approximately 4-5 times and 2.6-fold, respectively (Zalevsky et al. (2010) Nat. Biotechnol. 28(2):157 -159).

The mutations identified above, and other such mutations, can be introduced into the IgG Fc region of the constructs provided herein. These include constructs such as Formula 1 and Formula 2, where the linker includes Fc or an Fc dimer, depending on the structure of the construct.

In some specific examples, the IgGFC region in constructs herein, such as the bispecific TNFR1 antagonist/TNFR2 agonist constructs and TNFR1 antagonist constructs provided herein, is modified to enhance nascent FcR recycling, thereby increasing in vivo half life. This can be achieved by mutating residues at the interface of the _CH2 and _CH3 domains of the IgG Fc that are responsible for binding to FcRn. These include, but are not limited to, residues T250, L251, M252, I253, S254, T256, V259, T307, V308, L309, H310, L314, Q311, A378, E380, S383, M428, H433, N434, according to EU numbering. H435 and Y436. Exemplary Fc modifications that increase binding to FcRn include, but are not limited to, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, according to EU numbering. N434W, N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M4 28L/N434S, V259I/V308F, V259I/ One or more of V308F/M428L, E294del/T307P/N434Y, T256N/A378V/S383N/N434Y and their combinations. Table 7 below shows the corresponding mutations according to Kabat numbering and sequence numbering with reference to the IgG1 heavy chain constant domain sequence shown in SEQ ID NO: 9. Other modifications known in the art that confer enhanced or increased FcRn binding are also contemplated for use herein. Table 7 : IgG1 Fc modification to enhance FcRn binding Modification according to EU number Modification based on Kabat number Modification according to sequence number ( SEQ ID NO:9 ) T250Q T263Q T133Q T250R T263R T133R M252F M265F M135F M252W M265W M135W M252Y M265Y M135Y S254T S267T S137T T256D T269D T139D T256E T269E T139E T256Q T269Q T139Q V259I V272I V142I V308F V327F V191F E380A E405A E263A M428L M459L M311L H433K H464K H316K N434F N465F N317F N434A N465A N317A N434W N465W N317W N434S N465S N317S N434Y N465Y N317Y Y436H Y467H Y319H M252Y/T256Q M265Y/T269Q M135Y/ T139Q M252F/T256D M265F/T269D M135F/T139D M252Y/S254T/T256E M265Y/S267T/T269E M135Y/S137T/T139E H433K/N434F/Y436H H464K/N465F/Y467H H316K/N317F/Y319H N434F/Y436H N465F/Y467H N317F/Y319H T250Q/M428L T263Q/M459L T133Q/M311L T250R/M428L T263R/M459L T133R/M311L M428L/N434S M459L/N465S M311L/N317S V259I/V308F V272I/V327F V142I/ V191F V259I/V308F/M428L V272I/V327F/M459L V142I/V191F/M311L E294del/T307P/N434Y E311del/T326P/N465Y E177del/T190P/N317Y T256N/A378V/S383N/N434Y T269N/A401V/S408N/N465Y T139N/A261V/S266N/N317Y c) Enhancement or reduction / elimination of Fc immune effector function

There are four human IgG subclasses that differ in effector function, circulating half-life, and stability. IgG1 has Fc effector function, is the most abundant IgG subclass, and is the most commonly used subclass in FDA-approved therapeutic proteins. IgG2 lacks Fc effector function but dimerizes with other IgG2 molecules and is unstable due to scrambling of disulfide bonds in the hinge region. IgG3 has Fc effector function and a very long rigid hinge region. IgG4 lacks Fc effector function, has a shorter circulating half-life than other subclasses, and the IgG4 dimer is biochemically unstable due to the presence of a single disulfide bond in the hinge region, leading to H-chain exchange between different IgG4 molecules. Therefore, the Fc regions of IgG2 and IgG4 do not have effector functions and can be used in situations where effector functions are not required or would be detrimental, such as in the context of autoimmune and inflammatory diseases and disorders.

Most approved therapeutic mAbs belong to the human IgG1 subclass and interact with humoral and cellular components of the immune system. For example, antibodies participate in the humoral immune response via interaction with the complement protein C1q (which initiates the complement cascade), leading to the formation of membrane attack complexes that induce cytolysis of target cells (i.e., complement-dependent cytotoxicity (CDC)). , and participates in cellular immune responses through interaction with Fcγ receptors (FcγR). FcγR includes FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) classes, which differ in cell surface expression and Fc binding affinity. The five activated FcγRs include the high-affinity FcγRI, which binds monovalent antibodies, and the lower-affinity FcγRIIa, FcγRIIc, FcγRIIIa, and FcγRIIIb, which require affinity-based interactions. FcγRIIb is the only inhibitory receptor. After Fc binds to activating receptors, effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC; Also known as antibody-dependent cellular phagocytosis) and antibody-dependent cell-mediated phagocytosis (ADCP; also known as antibody-dependent cellular phagocytosis) and inflammation due to induction of interleukin secretion. Signaling via inhibitory FcγRIIb, regulated by phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM), recruits phosphatases to counteract activating signaling pathways (see e.g. Wang et al. (2018) Protein Cell 9(1):63-73).

The hinge and proximal CH ₂ amino acid sequences (lower hinge-upper _CH 2 domain region) and the conserved N297 residue in the Asn-X-Ser/Thr glycosylation motif of the _CH 2 domain of the Fc region (according to EU No.) glycosylation mediates the interaction of the antibody with FcγR and complement protein C1q. Antibody/Fc engineering has been used to modulate the immune effector functions of antibodies by altering their binding to C1q and various Fcγ receptors. The CDC, ADCC and ADCP activities of therapeutic mAbs can therefore be increased or decreased, depending on the application. For example, the efficacy of anti-cancer mAbs depends in part on their induction of FcyR effector functions. Effector functions include activation of natural killer (NK) cells via FcγRIIIa and subsequent ADCC activity and release of inflammatory cytokines, induction of macrophage-mediated ADCP via interactions with multiple FcγRs, and recruitment and activation of other immune cells. Such as neutrophils, the main receptors for NK cell-mediated ADCC. FcγRIIIa has two polymorphic variants: one with V158, which has a higher affinity for IgG1, and one with F158, which has a lower affinity for IgG1. Cancer patients with high-affinity V158 polymorphism may have better outcomes after treatment with cetuximab, trastuzumab, and rituximab compared with patients with low-affinity F158 polymorphism . Results such as these highlight the role played by FcγR-mediated immune effector functions in therapy and suggest that engineering antibodies and related molecules to increase affinity for FcγR may enhance therapeutic efficacy (see, e.g., Wang et al. (2018) Protein Cell 9 (1):63-73).

Residues in the lower hinge and proximal _CH2 region of IgG have been identified as critical for binding to FcγR. For FcγRI, FcγRIIa, FcγRIIb and FcγRIIIb, residues within 5 Å of the FcγR:Fc interface include residues (according to EU numbering) P232, E233, L234, L235, G236, G237, P238, S239 (refer to SEQ ID NO: 9 , corresponding to residues P115-S122), D265, V266, S267, H268, E269, D270 (refer to SEQ ID NO: 9, corresponding to residues D148-D153), Y296, N297, S298, T299 (refer to SEQ ID NO: : 9, corresponding to residues Y179-T182) and N325, K326, A327, L328, P329, A330, P331 and I332 (referring to SEQ ID NO: 9, corresponding to residues N208-I215) (see e.g. Wang et al. ( 2018) Protein Cell 9(1):63-73).

Fc modifications that enhance or reduce ADCC activity and/or enhance affinity/binding to the receptor are known to those of ordinary skill in the art. For example, Fc modifications that increase the affinity and binding of IgG1 to FcγRIIIa and/or enhance ADCC function include substitutions (according to EU numbering): F243L/R292P/Y300L/V305I/P396L, L235V/F243L/R292P/Y300L/P396L, F243L /R292P/Y300L, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A, and L234Y/L235Q/G236W/S239M/H268D/ D270E/S298A and the corresponding ones in one heavy chain heavy chain The combination of D270E/K326D/A330M/K334E, and the combination of L234Y/G236W/S298A in one heavy chain and S239D/A330L/I332E in the opposite heavy chain. In addition, mutations A327Q/P329A (interacts with FcγRI), D265A/S267A/H268A/D270A/K326A/S337A (interacts with FcγRIIa), G236A (interacts with FcγRIIa), and T256A/K290A/S298A/E333A/K334A (interacts with FcγRIIa) FcγRIIIa interaction) results in high affinity interaction with FcγR.

Fc modifications that increase binding to FcγRIIa and FcγRIIIa and enhance ADCC and ADCP include (according to EU numbering) G236A/I332E, G236A/S239D/I332E (also increase binding to FcγRI), and G236A/S239D/A330L/I332E (see e.g. Wang (2018) Protein Cell 9(1):63-73; Saxena et al. (2016) Front. Immunol. 7:580; and Saunders, KO (2019) Front. Immunol . 10:1296).

Glycosyl engineering of IgG contains a conserved N-linked glycosylation site at residue N297 in the _CH2 domain, which can enhance Fc effector function. Glycosylation of N297 is critical for maintaining Fc conformation and mediating its interaction with FcγR (and C1q). The glycan present at residue N297 typically has two N-acetylglucosamine (GlcNAc), three mannose, and two additional GlcNAcs linked to the mannose to form a biantennary complex glycan. Other fucose, galactose, sialic acid and GlcNAc can be added to the decorin structure. IgG circulating in human serum is found to be generally fucosylated, but recombinant IgG production can be achieved by expressing antibodies in plant cells, knocking in or knocking out specific glycosidases, or in vitro enzymatic digestion of glycosylated IgG. Sugar composition; Because both heavy chains are glycosylated, individual IgG molecules can have glycan heterogeneity. Glycans directly affect FcγR binding. For example, the N297 glycan on the Fc can conflict with the glycan on the FcγRIII protein, leading to poor engagement of effector cells that mediate ADCC. Fc regions containing different glycans at N297 adopt different hinge region configurations, which can affect the ability of Fc to interact with FcγRs. When expressing IgG, expressing β(1,4)-N-acetamidoglucose transferase III will produce antibodies that are glycosylated with biantennary glycans at position N297; this antibody has increased binding to FcγRIIIa and enhanced ADCC activity . It has been demonstrated that IgG1 lacking fucose (afucosylated/nonfucosylated) exhibits up to 50-fold increased binding to FcγRIIIa and enhanced ADCC activity. Two glycoengineered (afucosylated) mAbs, obinutuzumab (anti-CD20) and mogamulizumab (anti-CCR4), have been approved for clinical use, indicating that Glycoengineering has the potential to enhance effector functions and convert them into clinically approved therapeutics (see, e.g., Wang et al. (2018) Protein Cell 9(1):63-73; Saxena et al. (2016) Front. Immunol. 7:580; and Saunders, KO (2019) Front. Immunol . 10:1296).

Fc can also be modified to bind to a wider range of Fc receptors. Fc receptors of isotypes other than gamma (i.e., IgA, IgM, and IgE) exist on some leukocytes, and by modifying the Fc region to engage multiple Fc receptors, antibodies with expanded ability to engage effector cells are produced . Neutrophils are the most abundant white blood cells in the body and bind the Fc of IgA antibodies through the FcαRI receptor. For example, to join FcγR and FcαRI, a single domain of IgA2 is added to the end of the IgG1 constant region, forming a four-domain constant region CH1g-CH2g-CH3g-CH3a. The _CH1 domain of IgG1 is replaced by the α1 constant region, resulting in a constant region (CH1a-CH2g-CH3g-CH3a) that is structurally closer to the α constant region. These four-domain cross-isotype IgGA chimeric antibodies bind to the J chain similarly to natural IgA2, reduce the transport of aggregated Ig receptors, reduce FcγRI affinity by 3-5 times, and have the short serum half-life of IgA2 rather than the long serum circulation of IgG1. However, the four-domain cross-isotype IgGA chimeric antibody has the ability to mediate complement-dependent lysis of sheep red blood cells and is more pH resistant than IgG1. Another cross-isotype Fc is generated by fusing the γ1 and α constant regions together to form a tandem G1-A Fc region, in which the hinge, _CH2 and _CH3 domains of IgA2 are fused to the C-terminus of IgG1. This tandem cross-isotype IgG/IgA fusion shows similar expression, antigen binding and thermal stability to IgG1, and binds to FcαRI and FcγRI, FcγRII, FcγRIIIa and FcRn in vitro, with affinities similar to wild-type IgA and IgG respectively. . Binding to various FcRs results in ADCC activity in polymorphonuclear cells and NK cells; however, C1q binding is reduced 3-fold compared to IgG1. The in vivo half-life of tandem IgG/IgA in BALB/c mice is similar to that of IgG1. The alternative cross-isotype antibody system was developed by combining the _CH 3 domain of the IgG1 constant region and residues 245-258 of the _CH 2 α1 loop (corresponding to the sequence PKPKDTLMISRTPE according to EU numbering; (residues 128-141 of SEQ ID NO: 9) ) by replacing it with a structurally similar region of the IgA constant region. This chimeric Fc can bind to FcγRI, FcγRIIa and FcαRI, and the antibody containing the chimeric Fc mediates ADCC of polymorphonuclear cells and ADCP of macrophages, and activates complement, but lacks binding to FcRn that regulates the half-life of the antibody; therefore, , requiring further optimization for effective use in vivo (see e.g. Saunders, KO (2019) Front. Immunol . 10:1296).

Another method to enhance FcγR binding is the multimerization of IgG, which has shown promise in the treatment of autoimmune diseases. IgG multimerization systems are developed, for example, by adding a heterologous multimerization domain such as an isoleucine zipper, or by adding another hinge region at the N-terminus of the native hinge, or by adding another hinge region at the C-terminus of the _CH3 domain. Hinge area to produce. The IgG hexameric system is generated by appending an IgM tail to the C-terminus of the IgG1 Fc and forming a cysteine bond at position 309; this multimeric IgG binds strongly to FcγRI, FcγRIIa and FcγRIIIa and weakly to FcγRIIb and FcγRIIIb combine. Various multimeric IgGs have increased binding to FcγRI, FcγRIIb, and FcγRIII compared to monomeric IgG and have shown promise in preclinical models of arthritis, neuropathy, and autoimmune myasthenia gravis. This multimeric IgG design was further optimized to fine-tune which immune receptors, including FcRn, can bind to the multimer (see, e.g., Saunders, KO (2019) Front. Immunol . 10:1296).

Residues in the Fc region of IgG involved in interaction and binding to C1q (and therefore CDC) include (according to EU numbering) S267, D270, K322, K326, P329, P331 and E333. Fc modifications that have been shown to enhance CDC by increasing C1q binding include, for example, K326A, E333A, K326A/E333A, K326W, K326W/E333S, K326M/E333S, C220D/D221C, H268F/S324T, S267E, H268F, S324T, S267E/H 268F /S324T and G236A/I332E/S267E/H268F/S324T (all according to EU numbers). In the hinge region above the IgG1 Fc, replacing Trp in various combinations at positions 222, 223 and 224 (i.e. K222W, T223W and H224W, according to EU numbering) increases C1q binding and CDC activity relative to wild-type IgG1 without affecting FcγRIIIa binding and ADCC activity. Specifically, the mutations include K222W/T223W, K222W/T223W/H224W and D221W/K222W. Mutations C220D/D221C and C220D/D221C/K222W/T223W also increase C1q binding and CDC activity (see, e.g., Wang et al. (2018) Protein Cell 9(1):63-73; Saxen et al. (2016) Front. Immunol. 7 :580; Saunders, KO (2019) Front. Immunol . 10:1296; and Dall'Acqua et al. (2006) J. Immunol. 177:1129-1138).

The best in vitro combination between IgG3 and C1q is to combine the CH ₁ and hinge regions of IgG1 with the _CH 2 and _CH 3 regions of IgG3 (to retain the ADCC activity of IgG1 and the CDC activity of IgG3) to produce an IgG1/IgG3 crossover. Subtype antibodies that also increase C1q binding and enhance CDC activity. Another type of IgG1/IgG3 cross-subtype antibody with increased C1q binding and enhanced CDC activity includes CH ₁ , hinge, and _CH 3 of IgG1 and _CH 2 of IgG3; these modifications increase Cq1 binding because C1q binds _CH 2 domain, as well as ease of purification because Protein A binds the _CH3 domain. In addition, modification E345R/E430G/S440Y leads to the formation of IgG hexamers, in which K322 is oriented to a position that favorably interacts with the hexameric C1q head, enhancing CDC activity. Mutation E345R alone also results in IgG hexamer formation with increased C1q binding and enhanced CDC activity (see e.g. Wang et al. (2018) Protein Cell 9(1):63-73; Saxena et al. (2016) Front. Immunol. 7:580; Saunders, KO (2019) Front. Immunol . 10:1296).

Glycoengineering can also be used to improve complement fixation; the N297 glycan within the _CH2 domain of the Fc can be modified to improve CDC activity. For example, excess galactosylation in IgG1 Fc increases C1q binding and CDC activity and also improves thermal stability compared to the unmodified glycoform of IgG1. Therefore, Fc galactosylation can be used to generate stable biologics with enhanced CDC activity (see, eg, Saunders (2019) Front. Immunol . 10:1296).

Table 8 below summarizes Fc modifications that increase binding to FcγR or C1q and thus enhance immune effector functions (including ADCC, ADCP, and CDC), and provides the IgG1 complex according to Kabat numbering and sequence numbering as shown in SEQ ID NO: 9 Corresponding modifications to the chain constant domain sequence. Any one or more of these modifications may be introduced into the IgG1 Fc portion of the constructs provided herein, alone or in various combinations. Other modifications known in the art that confer enhanced or increased immune effector functions are also contemplated for use herein. Table 8 : IgG1 Fc modification to enhance immune effector function Modification according to EU number Modification based on Kabat number Modification according to sequence number (SEQ ID NO:9 ) effect S239D S252D S122D Increase binding to FcγRIIIa; enhance ADCC I332E I351E I215E Increase binding to FcγRIIIa; enhance ADCC S239D/I332E S252D/I351E S122D/ I215E Increase binding to FcγRIIIa; enhance ADCC S239D/A330L/I332E S252D/A349L/I351E S122D/A213L/I215E Increase binding to FcγRIIIa; enhance ADCC S298A/E333A/K334A S317A/E352A/K353A S181A/E216A/K217A Increase binding to FcγRIIIa; enhance ADCC F243L/R292P/Y300L/V305I/P396L F256L/R309P/Y319L/V324I/P424L F126L/R175P/Y183L/V188I/P279L Increase binding to FcγRIIIa and FcγRIIa; enhance ADCC L235V/F243L/R292P/Y300L/P396L L248V/F256L/R309P/Y319L/P424L L118V/F126L/R175P/Y183L/P279L Increase binding to FcγRIIIa; enhance ADCC F243L/R292P/Y300L F256L/R309P/Y319L F126L/R175P/Y183L Increase binding to FcγRIIIa; enhance ADCC L234Y/G236W/S298A (1st heavy chain) and S239D/A330L/I332E (2nd heavy chain) L247Y/G249W/S317A (1st heavy chain) and S252D/A349L/I351E (2nd heavy chain) L117Y/G119A/S181A (1st heavy chain) and S122D/A213L/I215E (2nd heavy chain) Increase binding to FcγRIIIa; enhance ADCC L234Y/L235Q/G236W/S239M/H268D/D270E/S298A (1st heavy chain) and D270E/K326D/A330M/K334E (2nd heavy chain) L247Y/L248Q/G249W/S252M/H281D/D283E/S317A (1st heavy chain) and D283E/K345D/A349M/K353E (2nd heavy chain) L117Y/L118Q/G119W/S122M/H151D/D153E/S181A (1st heavy chain) and D153E/K209D/A213M/K217E (2nd heavy chain) Increase binding to FcγRIIIa; enhance ADCC A327Q/P329A A346Q/P348A A210Q/P212A Increased binding to FcγRI D265A/S267A/H268A/D270A/K326A/S337A D278A/S280A/H281A/D283A/K345A/S357A D148A/S150A/H151A/D153A/K345A/S220A Increased binding to FcγRIIa T256A/K290A/S298A/E333A/K334A T269A/K307A/S317A/E352A/K353A T139A/K173A/S181A/E216A/K217A Increased binding to FcγRIIIa G236A G249A G119A Increase binding to FcγRIIa; enhance ADCP G236A/I332E G249A/I351E G119A/I215E Increase binding to FcγRIIa and FcγRIIIa; enhance ADCC and ADCP G236A/S239D/I332E G249A/S252D/I351E G119A/S122D/I215E Increase binding to FcγRI, FcγRIIa and FcγRIIIa; enhance ADCC and ADCP G236A/S239D/A330L/I332E G249A/S252D/A349L/I351E G119A/S122D/A213L/I215E Increase binding to FcγRIIa and FcγRIIIa; enhance ADCC and ADCP Biantennary glycan at N297 Biantennary glycan at N314 Biantennary glycan at N180 Increase binding to FcγRIIIa; enhance ADCC Afucosylated glycan at N297 Afucosylated glycan at N314 Afucosylated glycan at N180 Increase binding to FcγRIIIa; enhance ADCC K326W K345W K209W Increase binding to C1q; enhance CDC K326A K345A K209A Increase binding to C1q; enhance CDC E333A E352A E216A Increase binding to C1q; enhance CDC K326A/E333A K345A/E352A K209A/E216A Increase binding to C1q; enhance CDC and retain ADCC activity K326W/E333S K345W/E352S K209W/E216S Increase binding to C1q; enhance CDC K326M/E333S K345M/E352S K209M/E216S Increase binding to C1q; enhance CDC and retain ADCC activity K222W/T223W K235W/T236W K105W/T106W Increase binding to C1q; enhance CDC K222W/T223W/ H224W K235W/T236W/ H237W K105W/T106W/ H107W Increase binding to C1q; enhance CDC D221W/K222W D234W/K235W D104W/K105K Increase binding to C1q; enhance CDC C220D/D221C C233D/D234C C103D/D104C Increase binding to C1q; enhance CDC and retain ADCC activity C220D/D221C/K222W/T223W C233D/D234C/K235W/T236W C103D/D104C/K105W/T106W Increase binding to C1q; enhance CDC H268F/S324T H281F/S343T H151F/S207T Increase binding to C1q; enhance CDC S267E S280E S150E Increase binding to C1q; enhance CDC H268F H281F H151F Increase binding to C1q; enhance CDC S324T S343T S207T Increase binding to C1q; enhance CDC S267E/H268F/S324T S280E/H281F/S343T S150E/H151F/S207T Increase binding to C1q; enhance CDC G236A/I332E/S267E/ H268F/S324T G249A/I351E/S280E/ H281F/S343T G119A/I215E/S150E/ H151F/S207T Increase binding to C1q; enhance CDC E345R E366R E228R Increase binding to C1q; enhance CDC; form IgG1 hexamers E345R/E430G/S440Y E366R/E461G/S471Y E228R/E313G/S323Y Increase binding to C1q; enhance CDC; form IgG1 hexamers

Therapeutic antibodies can also be engineered to reduce or eliminate immune effector functions. For the purposes herein, there are specific examples where it may be of interest, for example, to reduce or eliminate ADCC activity. Constructs including Fc herein are generally modified to reduce or eliminate ADCC activity.

It makes sense to reduce or eliminate immune effector functions, for example where: therapeutic antibodies are antagonistic to prevent receptor-ligand interactions and signaling; antibodies are receptor agonists to cross-link receptors and induce signaling Transduction; antibodies are drug delivery vehicles that deliver drugs to antigen-expressing target cells; and wherein reduction or elimination of effector functions prevents target cell death or unwanted interleukin secretion. Reduced effector function also prevents antibody drug conjugates from interacting with FcγR, thereby reducing off-target cellular toxicity. The importance of reducing or eliminating effector function became apparent following adverse events associated with administration of the first approved mAb, muromonab, which was designed to prevent recipients of donor kidneys, lungs, or T cell activation in heart transplant patients. Patients administered morotumumab experience dangerous induction of pro-inflammatory cytokines (i.e., interleukin storm); this is due in part to the interaction of morotumumab with FcγR (see, e.g., Wang et al. (2018) Protein Cell 9(1):63-73; and Saunders, KO (2019) Front. Immunol . 10:1296).

There are many known mutations that reduce or eliminate receptor function. For example, substitutions L235E and F234A/L235A in human IgG4 and L235E and L234A/L235A in human IgG1 (all according to EU numbering) reduce FcγR and C1q binding and reduce effector functions such as inflammatory cytokine release. The release of inflammatory cytokines from therapeutic antibodies can lead to adverse effects. When the substitution S228P/L235E is introduced into IgG4, it also reduces the binding to FcγR; the S228P mutation improves the stability of IgG4. The mutations S228P/F234A/L235A in the IgG4 Fc reduce binding to FcγRI, IIa and IIIa, and reduce ADCC and CDC. The triple mutation L234E/L235F/P331S in IgG1 Fc reduces the binding to FcγRI, FcγRII, FcγRIII and C1q and reduces CDC, and the mutation L234A/L235A/P329G in IgG1 Fc eliminates the binding of FcγRI, FcγRII, FcγRIII and C1q and reduces ADCP. Mutation L234F/L235E/P331S also reduces binding to FcγR and C1q, and reduces the effector function of IgG1 Fc. Mutations G237A and E318A in IgG1 Fc each reduce binding to FcγRII and reduce ADCP; mutations D265A and E233P reduce binding to FcγRI, FcγRII and FcγRIII and reduce ADCC and ADCP, and mutations G236R/L328R reduce binding to all FcγRs and reduce ADCC. Crystal structure data show that the conformational change at residue P329 between the two conserved tryptophans present in all FcγRs forms a "proline sandwich", which may be detrimental to the interaction with FcγRs, and that at residue D270 Modifications may have a negative impact on the interaction with C1q (see, for example, Wang et al. (2018) Protein Cell 9(1):63-73; Saunders, KO (2019) Front. Immunol . 10:1296; International Application Publication No. WO 2019/226750).

Induction of the complement cascade is associated with adverse reactions at the site of antibody injection and eliminates C1q binding to Fc, which is even primary in the activation of CDC. Modifications of the Fc region that eliminate C1q binding can be used to eliminate CDC of constructs containing the Fc region. Many mutations that eliminate FcγR binding also eliminate C1q binding, as shown above. For example, mutation A330L disrupts C1q binding and reduces CDC, and also eliminates FcγRIIb binding. Mutations D270A, P329A, K322A, and P331A also lead to reduced C1q binding and reduced CDC activity (see, e.g., Saunders, KO (2019) Front. Immunol . 10:1296).

Glycoengineering can be used to eliminate FcγR and C1q binding. As discussed elsewhere herein, the glycan at residue N297 is a complex biantennary glycan. Modification of this glycan to a high mannose glycan (i.e., high mannose glycosylation) reduces the affinity of the IgG1 Fc for C1q and reduces CDC activity. Mutations in Fc that reduce or eliminate C1q and FcγRI binding can also result in increased galactosylation and sialylation of the N297 glycan; such mutations include, for example, F241A, V264A, and D265A. According to EU numbering, mutations N297A, N297Q, N297D and N297G remove the glycosylation site at N297 and reduce effector functions, such as CDC and ADCC, by eliminating the interaction of Fc with C1q and FcγR respectively. Combination N297G/D265A almost completely eliminated binding to FcγR and C1q. The binding of IgG3 Fc (aglycone Fc) that lacks glycosylation to FcγRI and C1q is reduced. (See, e.g., Wang et al. (2018) Protein Cell 9(1):63-73; Saunders, KO (2019) Front. Immunol . 10:1296).

To reduce or eliminate Fc effector function, large portions of Fc regions from different subclasses lacking opposite functions can be exchanged to create cross-subclass Fc regions. For example, IgG2 has poor FcγR binding but binds C1q, and IgG4 lacks C1q binding but reacts with FcγR; therefore, a combination of IgG2 and IgG4 CH domains without C1q and FcγR binding can be constructed. Generally, in an IgG1/IgG4 chimera, the hinge and _CH 1 domains are from IgG2, and the CH ₂ and _CH 3 domains are from IgG4. Because IgG1 and IgG3 recruit complement more efficiently than IgG2 and IgG4, and because IgG2 and IgG4 have limited ability to induce ADCC, a cross-subclass approach may reduce effector function. For example, the anti-C5 mAb eculizumab contains IgG2 residues 118-260 (according to EU numbering; corresponding to residues 114-273 according to Kabat numbering, and reference to residues 1- of SEQ ID NO: 11 139), and IgG4 residues 261-447 (according to EU numbering; corresponding to residues 274-478 according to Kabat numbering, and reference to residues 141-327 of SEQ ID NO: 15), and have limited or or undetectable effect function. Similarly, with the point mutation H268Q/V309L/A330S/P331S from IgG4 (according to EU numbering; corresponding to H281Q/V328L/A349S/P350S according to Kabat numbering, and referring to H147Q/V188L/A209S/P210S of SEQ ID NO: 11) The IgG2 variant (IgG2m4) lacks binding to all FcγRs and C1q and exhibits reduced effector function. Contains the IgG2 to IgG4 cross-subclass mutation V309L/A330S/P331S (according to EU number; corresponds to V328L/A349S/P350S according to Kabat number, and refers to V188L/A209S/P210S of SEQ ID NO: 11) and the non-germline mutation V234A/ The variant (called IgG2σ) of G237A/P238S/H268A (according to EU numbering; corresponding to V247A/G250A/P251S/H281A according to Kabat numbering, and referring to V114A/G116A/P117S/H147A of SEQ ID NO: 11) and FcγR and C1q and showed undetectable CDC, ADCC and ADCP activities. The IgG1/IgG4 cross-subclass variant IgG1σ, including mutations L234A/L235A/G237A/P238S/H268A/A330S/P331S, lacks binding to FcγRI and IIIa, and the binding to FcγRIIa and IIb is very weak at high concentrations of antibodies, resulting in ADCC and CDC activities are reduced (see, e.g., Wang et al. (2018) Protein Cell 9(1):63-73; Saunders, KO (2019) Front. Immunol . 10:1296).

Tables 9 and 10 below summarize some IgG1 and IgG4 Fc modifications that reduce or eliminate binding to FcγR and/or C1q, and therefore reduce or eliminate immune effector functions, including ADCC, ADCP, and CDC, which modifications can be incorporated into the constructs herein In the Fc region of the body. The tables provide corresponding modifications according to Kabat numbering and according to sequence numbering, with reference to the sequence of the IgG1 heavy chain constant domain shown in SEQ ID NO: 9 or the IgG4 heavy chain constant domain shown in SEQ ID NO: 15. Any one or more of these modifications may be introduced into the IgG1 Fc portion of the constructs provided herein, alone or in various combinations. Other modifications known in the art that reduce or eliminate immune effector functions are also contemplated for use herein. Table 9 : IgG1 Fc modification that reduces or eliminates immune effector function Modification according to EU number Modification based on Kabat number Modification according to sequence number (SEQ ID NO:9 ) effect L235E L248E L118E Reduce FcγR binding; reduce ADCC L234A/L235A L247A/L248A L117A/L118A Reduce FcγR and C1q binding; reduce ADCC, ADCP and CDC L234E/L235F/P331S L247E/L248F/P350S L117E/L118F/P214S Reduce FcγR and C1q binding; reduce CDC L234F/L235E/P331S L247F/L248E/P350S L117F/L118E/P214S Reduce FcγR and C1q binding; reduce effector function L234A/L235A/P329G L247A/L248A/P348G L117A/L118A/P212G Eliminate FcγR and C1q binding; reduce ADCP and CDC L234A/L235A/G237A/P238S/H268A/A330S/P331S L247A/L248A/G250A/P251S/H281A/A349S/P350S L117A/L118A/G120A/P121S/H151A/A213S/P214S Reduce binding to FcγR1, IIa, IIb and IIIa; reduce ADCC and CDC G236R/L328R G249R/L347R G119R/L211R Reduce binding to FcγR; reduce ADCC G237A G250A G120A Reduce binding to FcγRII; reduce ADCP E318A E337A E201A Reduce binding to FcγRII; reduce ADCP D265A D278A D148A Reduce binding to FcγRI, II, and III; reduce ADCC and ADCP E233P E246P E116P Reduce binding to FcγRI, II, and III; reduce ADCC and ADCP N297A N314A N180A Remove glycosylation sites; reduce interaction with FcγR; reduce effector functions (CDC, ADCC, ADCP) N297Q N314Q N180Q Remove glycosylation sites; reduce interaction with FcγR; reduce effector functions (CDC, ADCC, ADCP) N297D N314D N180D Remove glycosylation sites; reduce interaction with FcγR; reduce effector functions (CDC, ADCC, ADCP) N297G N314G N180G Remove glycosylation sites; reduce interaction with FcγR; reduce effector functions (CDC, ADCC, ADCP) N297G/D265A N314G/D278A N180G/D148A Reduce binding to FcγR and C1q; reduce effector function A330L A349L A213L Reduce C1q binding; reduce CDC D270A D283A D153A Reduce C1q binding; reduce CDC P329A P348A P212A Reduce C1q binding; reduce CDC P331A P350A P214A Reduce C1q binding; reduce CDC K322A K341A K205A Reduce C1q binding; reduce CDC V264A V277A V147A Reduce C1q binding; reduce CDC F241A F254A F124A Reduce C1q binding; reduce CDC Table 10 : IgG4 Fc modification that reduces or eliminates immune effector function Modification according to EU number Modification based on Kabat number Modification according to sequence number (SEQ ID NO:15 ) effect L235E L248E L115E Reduce FcγR binding; reduce ADCC F234A/L235A F247A/L248A F114A/L115A Reduce FcγR and C1q binding; reduce ADCC, ADCP and CDC S228P/L235E S241P/L248E S108P/L115E Reduced FcγR binding; reduced effector function S228P/F234A/L235A S241P/F247A/L248A S108P/F114A/L115A Reduce binding to FcγRI, IIa and IIIa; reduce ADCC and CDC ii. Other modifications to the Fc part

The Fc portion can also be modified to increase binding to inhibitory FcγRs, thereby causing suppression of the immune response. Therapeutic antibodies with immunosuppressive Fc modifications would be advantageous for treating inflammatory diseases. Such mutations may be incorporated into the Fc portion of constructs herein intended for use in the treatment of diseases and conditions that have an inflammatory component or etiology or involvement. For example, an immunosuppressive anti-CD19 antibody (XmAb5871 ^; B cells. The same mutation, when introduced into a humanized anti-IgE antibody (XmAb7195; Xencor), prevents IgE from binding to its high-affinity receptor (FcεRI) present on basophils and mast cells, increasing affinity for FcγRIIb approximately 430-fold. And used to treat allergies, including allergic asthma. The anti-CD3 antibody TRX4 (Tolerx) containing the aglycosylated Fc mutation N297A (according to EU numbering) suppresses pathogenic T cells and restores normal Treg cell activity in patients with type 1 diabetes (autoimmune) (see e.g. Saxena et al. (2016) Front. Immunol. 7:580).

Another example is a monomeric IgG1 Fc (mFc) containing the mutations L351S/T366R/L368H/P395K (according to EU numbering), which binds FcRn and exhibits a similar in vivo half-life as the dimeric Fc, selectively with high Affinity binds to FcγRI but not FcγRIIIa, thereby eliminating Fc-mediated cytotoxicity, including ADCC and CDC. FcγRI is expressed on inflammation-related cells, such as inflammatory macrophages. Targeting this receptor could be used to treat chronic inflammatory diseases such as arthritis, multiple sclerosis and cancer. The mutant mFc kills FcγRI ⁺ macrophage-like U937 cells when fused to Pseudomonas aeruginosa exotoxin A fragment (PE38). Neither the mutant mFc nor the fusion protein showed any cytotoxicity (ADCC or CDC) in vitro (see, e.g., Ying et al. (2014) mAbs 6(5):1201-1210).

Modifications that increase binding or confer selective binding to inhibitory FcγRIIb and/or FcγRI instead of FcγRIIIa can be engineered into the IgG Fc region of the TNFR1 antagonist and TNFR1 antagonist/TNFR2 agonist constructs provided herein. Such modifications include, but are not limited to, one or more of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F, L351S/T366R/L368H/P395K and combinations thereof according to EU numbering. Table 11 below shows the corresponding substitutions according to Kabat numbering and according to sequence numbering with reference to the IgG heavy chain constant domain sequence shown in SEQ ID NO: 9. Table 11 : IgG1 Fc modifications that increase binding to inhibitory FcγRIIb Modification according to EU number Modification based on Kabat number Modification according to sequence number (SEQ ID NO:9 ) S267E S280E S150E N297A N314A N180A L328F L347F L211F L351S L372S L234S T366R T389R T249R L368H L391H L251H P395K P423K P278K S267E/L328F S280E/L347F S150E/L211F L351S/T366R/L368H/P395K L372S/T389R/L391H/ P423K L234S/T249R/L251H/P278K iii. Human serum albumin ( HSA )

A problem with dAbs as previously provided (see, eg, International PCT Application No. 2008/149144) is that their serum half-life is insufficient for use as therapeutic agents. It is linked to anti-HSA antibodies to bind HSA; has insufficient half-life. Here, dAb or Vhh antibodies are linked to HSA. HSA has 33 cysteines; Cys34 is the only cysteine with a free sulfhydryl group that does not participate in a disulfide bond. HSA can be linked to the dAb via its N- or C-terminus directly or via a linker (such as a Gly-Ser linker) to extend the serum half-life of the dAb. It can also be linked via free cysteine. Example 6 illustrates a construct containing a dAb linked to the N-terminus of HSA via a Gly-Ser linker. e. Multispecific TNFR1 antagonist /TNFR2 agonist constructs

To selectively inhibit TNFR1 signaling while enhancing the beneficial effects of TNFR2 signaling, multispecific, such as bispecific constructs containing TNFR1 antagonists and TNFR2 agonists are provided (see, eg, Formula 2 above). Such multispecific constructs may include linkers and activity modulators to optionally confer advantageous properties, as discussed above.

The TNFR1 inhibitor and TNFR2 agonist portions of the constructs provided herein can be polypeptides or small molecules or combinations thereof; they can be in any order, directly or via a linker, such as a Gly-Ser linker, including any linker described herein. ) and/or the hinge region are connected indirectly, or they can be connected via a chemical linker. The construct may contain activity modulators, such as an Fc region or modified Fc, and/or other activity modulators, such as half-life extending polypeptides, such as HSA, and may be polymers, such as PEG or polymeric moieties.

A human TNFRl antagonist, such as a TNFRl antagonist set forth in any of SEQ ID NOs: 54-703 or having an affinity of about or at least The C-terminus of a TNFR1 antagonist with approximately 95% sequence identity is fused to the N-terminus of a first IgG1 Fc, such as an IgG1 Fc derived from trastuzumab. The order can be reversed.

The Fc region contains the _CH2 and _CH3 domains of the trastuzumab heavy chain (see, eg, residues 234-450 of SEQ ID NO: 26). In some embodiments, the linker between the TNFRl antagonist and the first Fc subunit contains all or part of the hinge sequence of an antibody such as trastuzumab (SCDKTH; corresponding to residue 222 of SEQ ID NO: 26 -227). To confer protease resistance and increase the flexibility of the fusion protein, the SCDKTH hinge sequence or protease cleavage site or both can be replaced with a Gly-Ser short peptide linker, such as GSGS, GGGGS or GGGGSGGGGSGGGGS and those described and/or associated herein. Other linkers known in the art. In other specific examples, only the GS linker is included. In another embodiment, the linker contains PEG or branched PEG with a molecular weight of 30 kDa or greater.

In some embodiments, Fc subunits (also referred to as regions or domains) can be multimerized. The first Fc subunit is attached to the second Fc subunit via a disulfide bond. For bispecific constructs, the C-terminus of the second Fc subunit is linked to a TNFR2 agonist, such as a TNFR2 agonist of any of SEQ ID NOs: 765-801, 803, and 810 or to SEQ ID NO: The TNFR2 agonist of any one of 765-801, 803, and 810 has about or at least about 95% sequence identity to the N-terminus of the TNFR2 agonist, or is linked to a small molecule TNFR2 agonist. The second Fc subunit and the TNFR2 agonist are linked via a linker, such as the SCDKTH hinge sequence of trastuzumab alone or in combination with a short GS linker, as described above. In other specific examples, only the GS linker is included. In alternative embodiments, a single chain Fv fragment (scFv) or Fab region or other antigen-binding fragment of a TNFR2 agonist monoclonal antibody may be used; the scFv or Fab is dimerized by fusion of the N-terminus to the C-terminus of the Fc . As provided herein, antigen-binding fragments can be derived from TNFR2 agonist mAbs MR2-1 and MAB226.

The Fc subunit can be modified to alter its activity. For example, dimers are modified to prevent homodimerization, and/or eliminate immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and/or complement dependent cytotoxicity (CDC), and/or enhanced recycling of nascent FcR (FcRn) to increase the in vivo half-life and stability of the recombinant construct, as described below.

In specific examples where the construct is used to treat inflammatory diseases, the Fc portion is modified to have reduced or eliminated effector function. In specific examples such as where the construct is used to treat cancer, the Fc dimer is modified to enhance immune effector functions, such as ADCC, ADCP and/or CDC. The specific Fc modification depends on the intended disease target.

In some specific examples, the Fc subunit may contain an IgG4 Fc region, such as an IgG4 Fc derived from nivolumab (Opdivo®), which contains the _CH 2 and _CH 3 domains of the nivolumab heavy chain (see e.g. Residues 224-440 of SEQ ID NO: 29). A short peptide linker containing the nivolumab hinge sequence ESKYGPPCPPCP sufficient to provide flexibility can be included between the nivolumab Fc region and the TNFR1 antagonist and/or TNFR2 agonist (see, e.g., SEQ ID NO: 29 all or part of residues 212-223). Optionally or alternatively, a GS linker may also be included.

In an illustrative embodiment, since TNFR2 may require receptor aggregation/clustering for signaling, bivalent antibody-like structures can be generated to achieve superior agonism. In this specific example, the C-termini of the first and second Fc subunits are each fused to the N-terminus of the TNFR2 agonist, as described above. The Fc dimer is modified to prevent homodimerization, eliminate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and enhance nascent FcR recycling to increase the in vivo half-life of the recombinant construct, as described here Described elsewhere. PEGylation of components used to link multispecific constructs, PEG - centered multispecific constructs , such as bispecific TNFR1 antagonist /TNFR2 agonist constructs

PEGylation refers to the covalent attachment of the biocompatible and bioinert polymer poly(ethylene glycol) (PEG) to molecules such as proteins, peptides, drugs, and other molecules and is another modulator of construct activity. It can increase the water solubility of molecules, increase the molecular weight of molecules, prolong in vivo circulation time, reduce peripheral clearance, minimize non-specific absorption and target tumors through the enhanced penetration and retention (EPR) effect. PEGylation of therapeutics, including protein therapeutics, can mask undesirable antigen surface markers, protect the therapeutics from antibodies and antigen-processing cells, and reduce degradation by proteolytic enzymes and other inactivation processes. PEGylation also increases the molecular weight of protein therapeutics, prolongs half-life in vivo and reduces peripheral clearance, and allows for less frequent dosing.

Chemical coupling of therapeutic molecules to polymers such as PEG can form stable ester or amide linkages as well as disulfide bonds. Conjugation of PEG to related molecules, such as the TNFR1 antagonists and TNFR2 agonists provided herein, can be achieved, for example, by using coupling agents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3- Dimethylaminopropyl)carbodiimide (EDC), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] Pyridinium 3-oxide hexafluorophosphate) or other coupling agents known in the art, or by using N-hydroxysuccinimide (NHS) esters, such as PEG NHS ester. Other methods include the use of PEG maleimide, which reacts with sulfhydryl groups on proteins or peptides; PEG pentafluorophenyl (PFP) ester, which reacts with primary and secondary amines; thiol PEG, which reacts with cysteine Thiol reactions on the side chains of amino acid residues; and click chemistry technology. PEG azide, propargyl PEG, amineoxy PEG, hydroxy PEG, amine PEG, PEG acid, biotin PEG, PEG tosylate and PEG with other functional groups are also commercially available and can be used Conjugated to peptides and other therapeutic molecules.

A common method for preparing PEG-protein conjugates is by coupling the -NH ₂ group on the protein and monomethoxyPEG (mPEG) with an electrophilic functional group; this method results in a covalent attachment of the core to the globular protein. of polymer chains. This property is exploited herein to provide PEG-centric constructs in which the PEG or chemically similar or suitable moiety exhibits multiple moieties that bind or interact with one or more different targets. To increase drug (binding moiety) loading, multi-arm or branched PEG (or similar moieties or branched moieties) can be used. Alternatively, the drug can be conjugated to small PEG dendrites (see, e.g., the PEG conjugation protocol on the BROADPHARM® website, available at broadpharm.com/web/protocols.php; see also Banerjee et al. (2012) Journal of Drug Delivery , Article ID 103973). To attach a plurality of (such as two) different therapeutic moieties, heteropolyfunctional (such as heterobifunctional) PEG moieties such as having different reactive groups at each end can be used. The PEG moiety can have two, three or more different reactive groups. Such molecules may be used to deliver two or more different ligands, targeting two different receptors on the same cell or on different cells, such as TNFR1 and TNFR2 as described herein, or to deliver two ligands on the same receptor. Targeting agents that bind at different sites either aggregate the receptor, for example to activate or inhibit the receptor, or cross-link two different receptors, for example to inhibit receptor activity. Identical bifunctional PEG molecules with identical reactive groups at each end can be used to aggregate the same receptor on the same cell or (if the PEG chain length permits) on different cells. Such constructs can be used to capture circulating soluble receptors or ligands, such as TNF. Figure 3 herein provides an exemplary construct using a PEG moiety to present a drug (binding reactive moiety).

In order to improve reactivity and flexibility, enhance ligand-protein binding and reduce steric hindrance, the construct may include a linker molecule or a plurality of linker molecules as described herein as spacer molecules. Such spacers include, for example, amino acid spacers such as alanine, glycine and small peptides. Any linker described herein, including GS linkers and other flexible linkers as well as rigid linkers, can be used to combine reactive moieties, such as the TNFR1 inhibitor moiety described herein and/or the TNFR2 agonist moiety described herein. agent coupled with multifunctional PEG molecules. These constructs may also include activity modulators, such as Fc regions.

The use of branched chain PEG moieties or multi-arm PEG moieties as described herein (see, eg, Figure 5) with or without linkers is not limited to use with TNFR1 inhibitor moieties or TNFR2 agonists, or a combination of both. construct, but can be used to present other inhibitors and/or agonist moieties of any relevant receptors and/or also generate immunotoxins and other toxic conjugates. Methods for synthesizing a variety of PEG moieties and variations thereof are known (see, eg, U.S. Patent Publication No. 2010/0221213; Han et al., (2014) Sci Rep 4 :4387.

For example, in some embodiments containing a TNFR1 inhibitor and a TNFR2 agonist moiety, the construct includes a bifunctional PEG moiety, and also includes between the PEG moiety and each of the TNFR1 antagonist and TNFR2 agonist connector. The multispecific construct contains a branched PEG polymer with a linker attached and one or both of the TNFR1 inhibitor moiety and the TNFR2 moiety attached. Suitable PEG moieties may have a molecular weight of 30 kDa or greater, such as 30-40 kDa or greater. An exemplary branched PEG molecule can be, for example, a 3-arm heterobifunctional PEG molecule containing one arm with one type of reactive group (RG1; e.g., _-NH2 ) attached to a TNFR1 inhibitor moiety; and two arms , with different types of reactive groups (RG2; e.g. -COOH), each linked to a TNFR2 agonist. Such 3-arm heterobifunctional branched PEG molecules are commercially available (e.g. from BROADPHARM®). The first PEG arm can be linked to the N-terminus or C-terminus of the TNFR1 inhibitor moiety, and the other two arms can be linked to the N-terminus or C-terminus of the TNFR2 agonist or to the TNFR2 agonist if it is a small molecule. . In some embodiments, the construct may also include optional linkers, as described herein. Such linkers may be included between the PEG arm and the TNFR1 inhibitor moiety and/or TNFR2 agonist. Such PEG-centered bispecific constructs provide monovalency for TNFR1 antagonist activity, which prevents TNFR1 receptor aggregation leading to unwanted agonism, and bivalency for TNFR2 receptor aggregation, which enhances TNFR2 signaling. Exemplary structures of the PEG-centered bispecific TNFRl antagonist/TNFR2 agonist constructs described herein are among those depicted in Figure 3.

In another specific example, the linker between the TNFR1 antagonist and the TNFR2 agonist contains branched PEG with a molecular weight of 30 kDa or greater. The branched chain PEG molecule contains one branch chain connected to the N-terminus of the TNFR1 antagonist and two branch chains each connected to the TNFR2 agonist, providing bivalence for TNFR2 receptor aggregation, thereby enhancing TNFR2 signaling.

Figures 3A-D depict various configurations of multispecific constructs in which the PEG moiety is linked to the functional moiety. The PEGylation component and PEGylation procedure are discussed in more detail in Section H below. Methods for preparing various PEG linkers and configurations are well known to those of ordinary skill in the art (see, eg, creativepegworks.com/pegylation_literature.php; and broadpharm.com/web/protocols.php). In Figure 3, each n can independently be 1-10, such as 1-7, 1-5 and 1-3, 1 or 2. In Figure 3A, each n typically ranges from 1 to 3, depending on the specific ligand shown. In others in Figure 3, n is generally 1 to 5. In all specific examples, n may be 1. One of ordinary skill in the art will recognize other conventional variations of the PEG moiety that serves as the central linker; similar moieties may be used in place of the PEG.

In Figure 3A: R ¹ is H or a lower alkyl group (C1 to C5, or C1 or C2), such as CH ₃ , and n is generally 1 to 5, such as 1 or 2. The figure depicts a ligand or epitope that binds to multiple targets (i.e., epitopes on a receptor), such as targets (circles) 1 a, b, c represent different epitopes on the same receptor. Target 2 can be an epitope on a different receptor. In Figures 3B and 3C, the circles represent the ligands of the target epitopes or receptors, and n is generally 1-5. Typically, n is 1 or 2, and is generally 1. Figure 3D depicts a homobifunctional construct; n is typically 1-3, typically 1 or 2, such as 1. Activity modulators, such as Fc or others as described herein or known to those of ordinary skill in the art, are optional. In all such constructs, the PEG moiety is generally "inactive" except to provide activity modulating activities such as half-life extension and/or steric linkage to the intended target (peptides, small molecules, aptamers, and others). pieces.

Figure 3A depicts an exemplary bivalent construct with PEG as the central moiety. A circle is, for example, a polypeptide agonist, antagonist or binding protein, such as an antibody or antigen-binding fragment thereof, or an aptamer (nucleic acid or peptide). Another circle represents a different moiety, such as a polysaccharide or a receptor ligand. The bivalent structure provides target aggregation for receptor activation. In some specific examples provided herein, targets include TNFR1 and TNFR2, and circles represent TNFR1 inhibitors and TNFR2 agonists as described throughout the disclosure herein. Figure 3B depicts a monovalent single ligand, such as CD3+, linked via a PEG moiety to an agonist, antagonist or binding protein (which is bivalent for receptor aggregation) that prevents interleukin release syndrome. Figure 3C depicts a different method for cross-linking two different cell-targeting agents or two agents that bind to the same receptor or to different sites on two receptors, such as trastuzumab and pertuzumab. Bifunctional PEG (or other such carrier). The constructs in Figures 3B and 3C can be used, for example, to aggregate checkpoint control receptors to stimulate or inhibit immune responses, or to cross-link two different receptors to achieve inhibition of receptor activity (i.e., CD3 and CD450), or to combine two different receptors to achieve inhibition of receptor activity. Delivery of different ligands, such as stimulatory and costimulatory ligands, to two different receptors on the same cell. These constructs can also act as prodrugs that are directed or accumulated in hypoxic regions of lower pH where the linker can be chemically released by protonation. For example, in the case of tumors, this could be a toxin, or it could be a locally released TNF inactivator (ie, an aptamer or a peptide).

Figure 3D depicts homobifunctional PEG used to aggregate the same receptor on the same or different cells depending on chain length, or to capture circulating disease targets such as soluble receptors or ligands such as TNF. Additionally, in all such embodiments, additional PEG side chains may be included in such constructs, optionally linked to another reactive group or functional group, such as a serum half-life extending moiety, such as HSA, or an FcRn polypeptide.

Other structures are also considered, where X and Y refer to reactive groups, such as binding moieties, molecules that interact with the target (see Figure 4):

Other examples (see e.g. Figure 5) are as follows, X and Y as above can be any targeting moiety or binding moiety or drug that interacts with the target: f. Additional activity modulators - including fusion proteins of part or the entire polypeptide that increase serum half-life

The properties of the construct can be altered by adding full-length polypeptides or portions thereof that increase serum half-life but do not substantially or alter the interaction of the construct with TNFR1 and/or TNFR2. This includes albumination and other such modifications (see discussion above on half-life extenders; reviewed in Strohl (2015) BioDrugs 29(4) :215-239, see also Tan et al. (2018) Current Pharmaceutical Design 24 :4932-4946). 5. Prediction and removal of immunogenicity in protein therapeutics

Many protein therapeutics, including those containing human germline sequences, such as recombinant human interleukins and human antibodies, are immunogenic and induce a host immune response to the therapeutic. As described herein, the constructs provided herein, including TNFR1 antagonist molecules and TNFR2 agonists, as well as the multispecific constructs described and provided herein, may be modified, if desired, such as by amino acid substitutions, to remove or eliminate epitopes that are immunogenic or interact with pre-existing antibodies.

Prediction, identification and removal of immunogenic B cell and/or T cell epitopes in constructs, thereby reducing or eliminating any potential immunogenicity and increasing the safety, tolerability and efficacy of therapeutic molecules . The molecules were tested in in vitro assays and in vivo animal models to determine immunogenicity before and after removal of the immunogenic sequence.

As discussed in greater detail below, protein therapeutics may contain immunogenic B cell and/or T cell epitopes. When the immune system recognizes a protein therapeutic as a foreign substance, a coordinated, undesired immune response against the therapeutic is induced. This reaction can lead to clinical complications including, for example, rapid drug clearance, reduced drug function and efficacy, delayed infusion-like anaphylaxis, severe anaphylaxis, and in some cases life-threatening autoimmunity. Immune responses to protein therapeutics occur via two different mechanisms; classical immune responses and tolerance breaking. The immune distinction between self and non-self proteins determines the mechanism of the immune response, and recognition of proteins as foreign induces a classical immune response, which is characterized by administration, usually days to weeks after a single injection of a protein therapeutic Antibodies are formed within. This response is long-lasting and difficult to reverse once memory B cells are formed. Subsequent exposure to the protein induces a secondary reaction, primarily characterized by large amounts of IgG that negatively impact the therapy. Therapeutic proteins that induce classical immune responses include replacement therapies such as rhGAA (recombinant human acid alpha-glucosidase) and FVIII, as well as monoclonal antibody (mAb) therapeutics in which the complementarity determining regions (CDRs) are highly immunogenic and The lack of tolerance to the center of the CDR region leads to the production of anti-genetic alloantibodies. Therapeutic proteins that are homologous to endogenous proteins typically do not cause an immune response due to established immune tolerance, however, they can become immunogenic upon repeated administration by breaking B cell tolerance, such as IFN- γ, IFN-β and erythropoietin (EPO) (see e.g. Baker et al. (2010) Self/Nonself 1(4):314-322; Choi et al. (2017) Methods Mol. Biol. 1529:375- 398; Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654).

Factors affecting the immunogenicity of protein therapeutics include, for example, the duration of treatment and the route and frequency of administration; subcutaneous administration of protein therapeutics is more immunogenic than intravenous administration, and long-term, frequent administration of therapy is more immunogenic sex. Patient-related factors, such as the patient's immune status and the polymorphism of MHC (or human HLA) molecules also affect protein immunogenicity. For example, MHC molecules are highly polymorphic, and there are several different alleles of MHC II, including different subunits such as DP, DM, DOA, DOB, DQ, and DR; these receptor subtypes Binding affinities for epitopes vary, and therefore, differences in MHC subtypes between patients can affect the immune response to protein therapeutics. The patient's immune status may also influence immunogenicity, as autoimmune patients respond more strongly to protein therapeutics than immunocompromised patients. Other factors that influence immunogenicity include the characteristics of the protein product, including the presence of immunogenic epitopes such as MHC II recognition, the formation of aggregates in the final product, oxidation of the protein, aggregates in the formulation, and post-translational modifications. , such as glycosylation. Recombinant proteins can be produced in several different cell types, including, for example, bacterial cells, such as E. coli, and mammalian cells, such as CHO cells. Proteins expressed in bacteria do not undergo post-translational modifications, such as glycosylation, but proteins produced in mammalian cells do, which can lead to differential immunogenicity. For example, the interferon (interferon beta-1b) sold under the trademark Betaseron® is produced in E. coli cells and is not glycosylated, while the later product sold under the trademark Avonex® (interferon beta-1a ) line was produced in CHO cells using recombinant DNA technology. The immunogenicity of Betaseron is much higher than that of Avonex® interferon, 35% and 5% respectively. This difference may be partially attributed to differences in glycosylation patterns, which can lead to aggregation (see, e.g., Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654).

The effect of administration of a protein therapeutic is the production of high-affinity anti-therapeutic antibodies, also known as anti-drug antibodies or ADA. The generation of ADA involves the stimulation of adaptive and non-adaptive immune responses, which are predominantly multistrainy and can have both neutralizing and non-neutralizing effects on protein therapeutics. ADA may contain heavy chain constant regions of multiple isotypes (e.g., IgM, IgE, and IgG) and subclasses (e.g., IgG1-4) and contain variable regions that bind with high affinity to protein therapeutics and, therefore, undergo variable region Somatic hypermutation of genes. Immune responses are induced by recognition of immunogenic peptide fragments, such as B-cell and T-cell epitopes, in protein therapeutics. Therefore, many protein therapeutics need to be deimmunized before clinical application while retaining the desired therapeutic activity (see e.g. Baker et al. (2010) Self/Nonself 1(4):314-322; Choi et al. (2017) Methods Mol . Biol. 1529:375-398).

The formation of anti-drug antibodies (ADA) against protein therapeutics is mediated by antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, as well as by B and T lymphocytes. The presence of MHC class II-restricted T cell epitopes in the sequence of a protein therapeutic may result in the development of a humoral response to the protein therapeutic. For example, DCs stimulated via pattern recognition receptors (PRRs) stimulate T cells and induce T cell-dependent high-affinity ADA responses. In the first step of the T cell-dependent antibody response, APC engulfs the protein therapeutic, processes the antigen into peptide epitopes, and binds to major histocompatibility complex (MHC) class II molecules on the APC cell surface. Present the epitope to naive T cells. For full T cell activation, which is required for B cell activation, the T cell receptor (TCR) must interact with the MHC II-epitope complex, and this must be accompanied by co-stimulatory molecules from costimulatory molecules such as CD80 and CD86 For additional signals, these molecules are provided by APC. Naive B cell lines are activated by interaction between IgM and IgD receptors on the B cell surface and its cognate antigen. Antigen-specific T cells then secrete interleukins, which stimulate B cells to proliferate and mature into plasma cells, leading to the participation of CD40 and CD40 ligands, providing further signals, allowing pure B cells to expand to produce antibodies and differentiate into antibody-secreting cells. Plasma cells and memory B cells. Memory B cells remain dormant until subsequent exposure to the therapeutic protein, while plasma cells secrete antibodies that recognize specific epitopes on the therapeutic protein presented by the APC MHC receptor. Many protein therapeutics, including recombinant human proteins, contain potent T cell epitopes. For example, the immunogenicity of IFNβ1b was improved after localization and removal of individual immunodominant (but not subdominant) T cell epitopes via amino acid mutation.

Immunogenicity can also occur in a T cell-independent process whereby the antigen directly engages B cells. High molecular weight aggregates of protein therapeutics can induce T cell-dependent and -independent anti-drug antibody responses by stimulating DCs or cross-linking B cell receptors. For example, if a protein therapeutic forms a multimeric structure that cross-links the B cell receptor (BCR) sufficiently effectively to obviate the need for T cell costimulation, T-independent stimulation of B cells can occur, resulting in ADA response. There is an association between enhanced immunogenicity and aggregated or multimeric proteins. For example, aggregated but not monomeric recombinant human interferon (IFN) α resulted in the production of IFNα-specific antibodies in human IFNα transgenic mice. The formation of aggregates depends on drug solubility and manufacturing process (see, e.g., Baker et al. (2010) Self/Nonself 1(4):314-322; Dingman et al. (2019) J. Pharm. Sci. 108(5):1637 -1654; De Groot, AS and Moise (2007) Curr. Opin. Drug Discov. Devel. 10(3):332-340).

ADA responses to protein therapeutics can be in the form of neutralizing or binding antibodies. Neutralizing antibodies recognize regions of a protein therapeutic that are necessary for biological activity and directly eliminate its activity. The humoral response is directed against B cell epitopes within the protein therapeutic, resulting in the ability to neutralize the protein therapeutic. For example, ontogenetic human anti-mouse (HAMA) or human anti-human (HAHA) responses to antibody therapies are neutralizing and can be generated against humanized and fully human antibodies. For example, in 30% of patients with hemophilia A, neutralizing ADA is produced in response to administered recombinant FVIII, eliminating its hemostatic effect, and in 89-100% of Pompe disease patients who receive rhGAA, Anti-rhGAA neutralizing antibodies undermine therapeutic efficacy. Binding antibodies alters the pharmacokinetic properties of protein therapeutics and indirectly affects their efficacy by reducing systemic exposure, for example by promoting rapid clearance of the protein. For example, long-term use of adalimumab results in the development of ADA in approximately 28% of patients, resulting in lower adalimumab concentrations and poorer clinical effects (see, e.g., Baker et al. (2010) Self/Nonself 1(4):314 -322; Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654).

ADA levels can be assessed and monitored before, during and after treatment. Various analytical methods can be used. Such assays include bridging immunoassays, which involve labeling a drug and detecting ADA forming a bridge between two labeled drug molecules. Bridging assays can be used with all antibody classes and any type of sample. Ligand binding assays (LBA) are used to detect binding to targets, including surface plasmon resonance (SPR), electrochemiluminescence and biolayer interferometry, and can also be used to detect ADA. Protein-specific assays can be used, such as the Bethesda assay, which has been used to measure the concentration of neutralizing anti-FVIII antibodies. Anti-PEG antibodies can also be measured in an assay in which biotin-PEG is coupled to magnetic beads, and a sensor that detects changes in complex size is used to measure the amount of anti-PEG antibody bound to the beads. Drug tolerance assays overcome limitations caused by the presence of drugs in samples and improve ADA quantification. Such assays include, for example, pH shift ontogenetic antigen binding assays, acid dissociation assays, temperature change assays, and electrochemiluminescence assays. Enzyme-linked immunosorbent assay (ELISA) can be used to detect ADA; the protein therapeutic is coated on a plate and incubated with the sample to measure bound ADA. Due to the lack of ADA standards, ELISAs for detecting ADA may be limited. Other methods include immuno-PCR, which is an extension of the bridging assay in which complexes are labeled with biotin and detected using anti-biotin antibodies conjugated to DNA. DNA was subsequently amplified using PCR and quantified to assess ADA content. Immuno-LC/MS can be used to detect ADA in plasma samples; the sample must be enriched by labeling the drug with biotin or by spiking excess drug into the sample to saturate ADA binding (see e.g. Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654).

Predicting and removing immunogenic epitopes (i.e., deimmunization) in protein therapeutics can increase the efficacy and safety of therapeutics and prevent adverse effects that may lead to drug failure in clinical trials. For example, protein therapeutics, particularly antibodies, have been successfully advanced into clinical trials by deimmunizing their T cell epitopes. These results demonstrate the importance of T cell epitopes in generating ADA responses and that deimmunization provides safer, less immunogenic therapeutics (see e.g. Baker et al. (2010) Self/Nonself 1(4): 314-322). Such methods can be used to detect or identify or predict the immunogenicity of the constructs provided herein, and can be used to identify amino acid mutations that eliminate or reduce immunogenicity or an individual's immune response. Constructs are provided that have been modified to reduce or eliminate immunogenicity. Deimmunization of protein therapeutics involves identification of highly immunogenic B cell and/or T cell epitopes and deletion of the identified epitopes through mutation-induced substitutions of key amino acid residues. As discussed below, preclinical prediction and assessment of immunogenic regions within protein therapeutic sequences include the use of in silico tools focused on epitope mapping, in vitro methods such as epitope mapping, MHC/HLA affinity analysis method and T cell proliferation assay) and in vivo testing in animal models. To improve the efficiency of deimmunization of protein therapeutics, computational epitope prediction tools are used. Computer simulation tools include databases and algorithms to quickly predict immunogenic sequences in peptide libraries. The results can then be confirmed and the specific immunogenic effect of the epitope on B cells or T cells can be further assessed using in vitro assays. The effects on the immune response to protein therapeutics can be assessed using in vivo assays in animal models such as transgenic mice and non-human primates.

Once an immunogenic epitope is identified, the amino acid sequence of the therapeutic agent can be modified to remove the epitope. Removal methods include random or site-directed mutagenesis to remove immunogenic sequences (ie, epitope deimmunization). After mutation induction, immunogenic sequences are re-evaluated to confirm that they are no longer immunogenic. Computer simulation tools exist to simplify this process; for example, each amino acid in the immunogenic sequence can be programmed to be replaced by one of the other 19 naturally occurring amino acids (especially alanine), and then re-evaluated. Immunogenicity of sequences. In this way, non-immunogenic sequences can be efficiently narrowed down to the most promising candidates before peptide synthesis and re-evaluation of immunogenicity in vitro and/or in vivo. However, the predicted and mutation-induced deletion of immunogenic epitopes is not necessarily sufficient to deimmunize a protein, as the protein must maintain its folded, stable and active structure to maintain its therapeutic efficacy. Therefore, epitope deletion mutations that are compatible with the structure and function of the protein must be selected.

The methods discussed below were used to predict, identify and eliminate epitopes of the constructs provided herein. a. B cell and T cell epitopes

Interactions between antigens and antibodies are important in inducing humoral immune responses against invading pathogens. Specific antibodies recognize discrete regions of a specific antigen called epitopes or B-cell epitopes. B-cell epitopes contain solvent-exposed and surface-accessible amino acid clusters that are recognized and bound by secreted antibodies or B-cell receptors (BCRs), which contain membrane-bound receptors that induce cellular or humoral immune responses. Immunoglobulin.

Identification of B cell epitopes is part of the development of antibodies and other protein-based therapeutics. B cell epitopes are classified based on spatial structure into continuous (also called linear) epitopes, which contain contiguous residues; and discontinuous (also called conformational) epitopes, which are nonlinear and conformational. Discontinuous B cell epitopes contain groups of solvent-exposed amino acid residues that are not completely contiguous but are packed tightly together when the protein/antigen folds into its three-dimensional configuration. Approximately 90% of B cell epitopes are conformational. Linear B cell epitopes can be recognized by antibodies after the antigen is denatured, but if the antigen is denatured, the conformational epitopes are no longer recognized. The minimum amino acid sequence or contact residue span required for correct folding of a discontinuous B cell epitope ranges from approximately 20 to 400 residues in native proteins. Most of the identified linear B cell epitopes are believed to be components of conformational B cell epitopes, and it has been shown that more than 70% of discontinuous B cell epitopes contain 1 to 5 linear segments, each of which Segment length is 1-6 amino acids (see, eg, Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830; Sanchez-Trincado et al. (2017) Journal of Immunology Research , Article ID 2680160).

T cell epitopes are linear and bind to major histocompatibility complex (MHC) molecules through the interaction of amino acid side chains with binding pockets in the MHC epitope binding groove. The presence or absence of specific side chains determines whether and how tightly the epitope binds to the MHC (see, e.g., De Groot, AS and Moise, L. (2007) Curr. Opin. Drug Discov. Devel. 10(3):332 -340). T cells have T cell receptors (TCRs) that recognize antigens displayed on the surface of antigen-presenting cells (APCs) and bound to MHC molecules. T cell epitopes are presented by MHC class I (MHC I) and class II (MHC II) molecules and are recognized by CD8 ⁺ and CD4 ⁺ T cells respectively; therefore, CD8 ⁺ and CD4 ⁺ T cell epitopes exist. CD8 ⁺ T cells form cytotoxic T lymphocytes (CTL) after recognizing CD8 ⁺ T cell epitopes, while presensitized CD4 ⁺ T cells form helper T (Th) cells, which amplify immune responses, or form regulatory T (Treg) cells, which are immunosuppressive (see, eg, Sanchez-Trinchado et al. (2017) Journal of Immunology Research , Article ID 2680160). b. Computer simulation epitope prediction method

Experimental studies and computer simulation analysis show that most epitopes span 15-25 residues, have an area of 600-1000 Å ² , are organized into rings, and the epitope sequences are rich in tyrosine, tryptophan, and have exposure Charged and polar amino acids and specific amino acid pairs in the side chains. However, it has been demonstrated that the differences between epitope and non-epitope residues are not significant and amino acid composition alone is insufficient to distinguish epitopes from non-epitope. The combination of epitope mapping technology and bioinformatics enables the development of immunoinformatics, which involves the use of computational methods in immunology to identify the structure of antibodies, B cells, T cells and allergens, predict MHC binding, and epitope models Analysis of chemical and immune networks (see, for example, Potocnakova et al. (2016) Journal of Immunology Research , article ID 6760830). i. Computer simulation prediction of B cell epitopes

B cell epitope prediction identifies immunogenic epitopes so that they can be displaced/deimmunized, for example for therapeutic protein production. Databases of known B cell epitopes have been developed and include multifaceted databases such as the Immune Epitope Database (IEDB) and IEDB-3D (available at iedb.org) and AntiJen (available at ddg -pharmfac.net/antijen/AntiJen/ antijenhomepage.htm); B cell-oriented libraries such as BciPep (available at imtech.res.in/raghava/bcipep/info.html), Epitome (available at rostlab.org /services/epitome/) and the Structural Database of Allergen Proteins (SDAP; available at fermi.utmb.edu/); and databases for single pathogenic organisms, such as the HIV Molecular Immunology Database (available at hiv.lanl .gov/content/immunology/index.html), FLAVIdB (available at cvc.dfci.harvard.edu/flavi/), and the Influenza Sequence and Epitope Database (ISED; available at influenza.cdc.go.kr obtained). Other B cell epitope databases include the Conformational Epitope Database (CED; available at immunenet.cn/ced/), the Protein Data Bank (PDB; available at rcsb.org), and the Structural Epitope Data library (SEDB; available at sedb.bicpu.edu.in) (see e.g. Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830).

Several algorithms are available for predicting B cell epitopes from sequence or structure. These algorithms have been developed which initially relied on the identification of linear epitopes via propensity scaling, but have been developed by machine learning based methods such as Hidden Markov Models (HMM), Recurrent Neural Networks (RNN) and Improved by support vector machine (SVM). In silico B cell epitope prediction tools include tools for predicting continuous/linear B cell epitopes and tools for predicting discontinuous/configurational B cell epitopes. Prediction of discontinuous B cell epitopes requires information on amino acid statistics, spatial information, and surface exposure. Web-available tools for continuous/linear B cell epitope prediction include, for example, ABCPred (available at crdd.osdd.net/raghava/abcpred/), APCPred (available at omictools.com/apcpred-tool), BCPREDs (BCPred and FBCPred, available at ailab.ist.psu.edu/bcpred/), BepiPred (available at cbs.dtu.dk/services/BepiPred/), LBtope (available at crdd.osdd.net/raghava/lbtope /obtained), BcePred (available at crdd.osdd.net/raghava/bcepred/), EPMLR (available at bioinfo.tsinghua.edu.cn/epitope/EPMLR/), BEST (B cells using support vector machine tools Epitope prediction; available at biomine.cs.vcu.edu/datasets/BEST/), COBEpro (available at scratch.proteomics.ics.uci.edu/), PEOPLE (available at iedb.org/), and SVMTrip (available at sysbio.unl.edu/SVMTrip/). Web-available tools for discontinuous/configured B cell epitope prediction include, for example, CEP (available at bioinfo.ernet.in/cep.htm), DiscoTope (available at cbs.dtu.dk/services/DiscoTope- 2.0/available), BEpro (formerly PEPITO; available at pepito.proteomics.ics.uci.edu/), ElliPro (available at tools.immuneepitope.org/ellipro/), SEPPA (Space for Improvement of Protein Antigens Epitope prediction server; available at badd.tongji.edu.cn/seppa/), EPITOPIA (available at epitopia.tau.ac.il/), CBTOPE (available at crdd.osdd.net/raghava/ cbtope /obtained), EPCES (available at sysbio.unl.edu/EPCES/), EPSVR (Antigenic epitope prediction server using support vector regression; available at sysbio.unl.edu/EPSVR/), EPMeta ( Available at sysbio.unl.edu/EPMeta/), PEASE (Prediction of epitopes using antibody sequences; available at ofranlab.org/PEASE), EpiPred (available at opig.stats.ox.ac.uk/webapps/sabdab -sabpred/EpiPred.php), 3DEX (3D epitope detector; not available online), PEPOP (available at pepop.sys2diag.cnrs.fr/), PEPOP 2.0 (available at sys2diag.cnrs.fr/ index .php?page=pepop) and EpiSearch (available at curie.utmb.edu/episearch.html) (see, e.g., Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830; Sanchez-Trincado et al. (2017) Journal of Immunology Research , article ID 2680160; Sun et al. (2013) Comput. Math Method M. , article ID 943636).

Sequence-based prediction methods and binding site prediction methods can also be used to predict B cell epitopes. Sequence-based prediction tools rely on the primary sequence of the antigen and use a propensity scale to measure the probability of each residue being part of an epitope. Sequence-based prediction tools include BEST, which predicts conformational B cell epitopes. Binding site prediction tools designed to identify binding sites on antibodies that conform B cell epitopes include, for example, ProMate, ConSurf, PINUP, and PIER (see, e.g., Sun et al. (2013) Comput. Math Method M. , Article ID 943636 ).

Conformational B cell epitopes in proteins or antigens with known 3D structures can be identified using epitope prediction methods based on simulated epitopes. Mimetic epitopes are peptides selected from a random peptide library that are capable of binding to antibodies raised against the native antigen. Methods based on simulated epitopes require the input of peptides selected by antibody affinity (i.e., simulated epitopes) and the 3D structure of the selected antigen. Epitope prediction methods are available based on simulated epitopes derived from phage display experiments, and use the statistical characteristics of the simulated epitopes to locate the simulated epitopes to overlapping position patches on the antigen surface, or through alignment The mock epitope is used to map back to the antigen sequence, which can indicate the location of the B cell epitope. To identify affinity-selected peptides or mock epitopes, random peptides are displayed on the surface of filamentous phage, and peptides that bind to the monoclonal antibody with a certain degree of affinity are screened, eluted, and amplified. This selection process is repeated a total of 3-5 times to narrow down the peptides to those with the highest affinity. Mimic epitopes and epitopes can combine the same paratope of monoclonal antibodies and elicit an immune response, and therefore have similar functions. The selected simulated epitopes have a high degree of sequence similarity, indicating the existence of certain key binding motifs and physicochemical preferences during interaction with the antibody. Therefore, mapping the simulated epitope back to the source antigen can help to find the true epitope more accurately. Mimetic epitopes have similar physicochemical properties and spatial organization, but rarely show sequence similarity to native antigens. Databases providing information on simulated epitopes include, for example, ASPD (available at mgs.bionet.nsc.ru/mgs/gnw/aspd), RELIC Peptides (available upon application), PepBank (available at pepbank.mgh .harvard.edu) and MimoDB (available at immune.cn/mimodb). In silico prediction tools based on simulated epitopes are critical to localize the simulated epitopes back to the surface of the source antigen in order to locate optimally aligned sequences and predict likely epitope regions. In silico B cell epitope prediction tools based on simulated epitope analysis include, for example, MIMOX (available at immune.cn/mimox/), MimoPro (available at informatics.nenu.edu.cn/MimoPro), and Pep-3D -Search (available at kyc.nenu.edu.cn/Pep3DSearch), MIMOP/MimCons (available after application), LocaPep (available at atenea.monstes.upm.es/#soft), EpiSearch (available at curie .utmb.edu/episearch.html), Pepitope/PepSurf (available at pepitope.tau.ac.il/sources.html), PepMapper (available at informatics.nenu.edu.cn/PepMapper/), FINDMAP ( Not available online), EPIMAP (not available online), MEPS (available at capsur.it/meps), 3DEX (3D epitope detector; not available online), Mapitope (available at pepitope.tau.ac.il ) and SiteLight (not available online) (see e.g. Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830; Sanchez-Trincado et al. (2017) Journal of Immunology Research , Article ID 2680160; Sun et al. (2013) Comput . Math Method M ., Article ID 943636). ii. Computer simulation prediction of T cell epitopes

Linear T cell epitopes bind to MHC through the interaction of their amino acid side chains with the binding pocket in the MHC epitope binding groove, and the presence or absence of specific side chains determines whether the T cell epitopes bind to MHC. and the tightness of the bond. For in silico predictions, there are databases that provide existing epitope libraries, such as IEDB, Epitome and SEDB, which provide information on two-dimensional T cell epitopes. Other in silico T cell epitope databases include CED, AntiJen, Bcipep and HLA Epitope Registry. There are several web pages and programs available that can be used to analyze sequences and predict immunogenic epitopes on protein therapeutic candidates. For example, a number of MHC binding motif-based tools are available that scan protein sequences for potential T cell epitopes. Such T cell epitope mapping tools include, for example, EpiMatrix, IEDB, SYFPEITHI, MHC Thread, MHCPred, MHCPred 2.0, EpiJen, NetMHC, NetCTL, nHLAPred, SVMHC and Bimas (see, e.g., De Groot, AS and Moise, L. (2007) ) Curr. Opin. Drug Discov. Devel. 10(3):332-340). For example, the MHCPred algorithm provides information on the MHC binding potential of amino acid sequences to various alleles, and EpiMatrix/JanusMatrix predicts the allele-specific binding of protein therapeutics to MHC class II receptors and can assess the Binding at the T cell receptor interface. Other algorithms and programs for epitope prediction include, for example, ProPred, MMBPred, and Protean 3D. Epitope prediction should be combined with in vitro methods and activity assessment to ensure that any modifications that remove immunogenic sequences retain the activity of the therapeutic protein (see, e.g., Dingman et al. (2019) J. Pharm. Sci. 108(5) :1637-1654). iii. Peptide -MHC class II binding prediction

Structure-based approaches to identify T cell epitopes rely on modeling peptide-MHC structures and evaluating interactions using, for example, molecular dynamics simulations. Structure-based methods are computationally intensive and have lower predictive performance than data-driven methods. Structure-based T cell epitope prediction tools include EpiDOCK (available at epidock.ddg-pharmfac.net). Data-driven methods for peptide-MHC binding prediction are based on peptide sequences known to bind to MHC molecules; peptide sequences are available in epitope databases such as IEDB, EPIMHC, AntiJen and those described herein and in the art. Other databases known in . Peptide-MHC binding predictions can be based on sequence motifs (SMs), which include frequently occurring amino acids (anchor residues) at specific positions known to bind MHC molecules. The motif matrix (MM) evaluates the contribution of each residue (including non-anchor residues) to MHC molecule binding, but does not consider binding affinity. Quantitative affinity matrix (QAM) predicts peptide-MHC binding and binding affinity. The quantitative structure-activity relationship (QSAR) additivity model predicts that the binding affinity of a peptide to the MHC is the sum of the amino acid contributions at each position, plus the contribution of adjacent side chain interactions. Machine learning (ML) is the most popular and robust method, using algorithms trained on data sets consisting of peptides bound or not bound to MHC molecules, and examples of ML-based discrimination models include those based on artificial neural networks ( ANN), support vector machine (SVM), decision tree (DT) and hidden Markov model (HMM) models (see, for example, Sanchez-Trinchado et al. (2017) Journal of Immunology Research , article ID 2680160).

Models for predicting the immunogenicity of protein therapeutics include in silico peptide-MHC class II algorithms, which predict the ability of a peptide sequence to bind to MHC class II with reasonable accuracy. Such algorithms allow rapid screening of sequence libraries. However, in silico and in vitro MHC class II binding assays result in high levels of false positives, in which the identified immunogenic peptides fail to stimulate T cell responses in vitro and in vivo. Such analyzes do not take into account other factors that influence epitope formation, such as protein processing, T cell receptor (TCR) recognition, and T cell tolerance to peptides. To address this issue, in vitro T cell assays are used. A combination of in silico and in vitro assays is very useful for identifying epitopes and designing peptide variants with epitope-depleted protein sequences that have reduced MHC binding capacity (see e.g. Baker et al. ( 2010) Self/Nonself 1(4):314-322).

Prediction of T cell epitopes via peptide-MHC binding models is also complicated by MHC polymorphism; in humans, MHC molecules are called human leukocyte antigens (HLAs), and hundreds of class I and class II HLAs exist Allelic variants of molecules that bind different peptides and require specific models to predict peptide-MHC binding (see, e.g., Sanchez-Trinchado et al. (2017) Journal of Immunology Research , Article ID 2680160). T cell epitope prediction tools based on peptide-MHC binding models include, for example, EpiDOCK, MotifScan, Rankpep, SYFPEITHI, MAPPP, PREDIVAC, PEPVAC, EPISOPT, Vaxign, MHCPred, EpiTOP, BIMAS, TEPITOPE, Propred, Propred-1, EpiJen, IEDB-MHCI, IEDB-MHCII, IL4pred, MULTIPRED2, MHC2PRED, NetMHC, NetMHCII, NetMHCpan, NetMCHIIpan, nHLAPred, SVMHC, SVRMHC, NetCTL and WAPP (see e.g. Sanchez-Trincado et al. (2017) Journal of Immunology Research , Article ID 2680160 ).

EpiSweep is a set of protein design algorithms that integrates computational prediction of immunogenic T cell epitopes with sequence-based or structure-based assessment of the impact of epitope deletion mutations on protein stability, structure, and function, allowing selection Optimizing combinations of mutations for protein therapeutics to achieve low immunogenicity and high activity and stability (for a step-by-step guide to applying the EpiSweep deimmunization algorithm suite, see, e.g., Choi et al. (2017) Methods Mol. Biol. 1529:375 -398). c. In vitro epitope prediction method

In vitro methods can be used to determine the cellular mechanisms of immune responses, identify immunogenic epitopes, and assess MHC affinity, T cell proliferation, and the immunogenic effects of whole protein therapeutics. For example, epitope mapping identifies immunogenic epitopes by analyzing peptide fragments individually. Peptide fragments are exposed to immune cells, and immunogenicity is determined by measuring interleukins and surface markers that indicate an inflammatory immune response. Epitope mapping of intact proteins is labor intensive, and computer simulation programs are used in conjunction with mapping to identify potentially immunogenic regions and narrow down epitope candidates. In vitro epitope prediction methods include, for example, structural epitope mapping methods such as X-ray crystallography, nuclear magnetic resonance and electron microscopy methods, as well as functional epitope mapping methods such as antigen fragmentation/antigen binding assays, competitive Combining assays, modification testing/mutation induction, display technologies such as phage display and yeast display, and simulated epitope analysis. i. Method for predicting B cell epitopes in vitro

Experimental methods used to identify B cell epitopes include, for example, solving the 3D structure of the antigen-antibody complex, screening peptide libraries for antibody binding, or performing functional assays in which the antigen is mutated and the effect on the antigen-antibody interaction is analyzed. . Antibody-producing B cells recognize structural epitopes, which are about 16-22 residues in size and contain amino acids that contact the antibody; and functional epitopes, which are about 3-5 residues in size and Affects the affinity between protein and antibody. The most accurate method for identifying structural epitopes is through X-ray crystallography of antigen-antibody complexes. This identification of the sequence bound to the antibody can be used to locate the precise position of the epitope within the protein structure, and can identify continuous and Discontinuous epitopes and provide information on binding strength. Structural epitope mapping identifies residues that are in direct contact with the antibody but does not always provide information on which residues contribute to binding strength. The free-to-use FTProd program can be used as a computational alternative to X-ray crystallography. Nuclear magnetic resonance (NMR) can be used to identify structural epitopes without generating crystals, but its use is limited to small proteins and peptides less than 25 kDa in size. NMR provides information on the structure, kinetics, and binding energy of antigen-antibody complexes and is performed in solution, avoiding the need for crystallization. Two other methods for epitope localization at moderate resolution include saturation transfer differential NMR and antibody inhibition of hydrogen-deuterium exchange in the antigen. Electron microscopy can also be used for epitope mapping, but it is a low-resolution structural method and is typically used for larger antigens, such as whole virions or viral capsids. Electron microscopy cannot detect contact residues but can be used to confirm surface accessibility of epitopes. Cryo-electron microscopy is an alternative method in which rapidly frozen antigen-antibody complexes are observed in physiological buffer, avoiding the need for stains and fixatives (see e.g. Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654; Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830).

Functional epitopes can be identified by a variety of methods, including antigen fragmentation, competitive binding and modification tests. For example, functional B cell epitope mapping methods typically involve screening antigen-derived proteolytic fragments or peptides for antibody binding and testing the antigen-antibody reactivity of mutated proteins that have undergone site-directed or random mutagenesis. Therefore, functional epitope mapping tools are used to identify and characterize residues within an epitope that are important for antibody binding. Most functional methods detect the binding of antibodies to antigen fragments, synthetic peptides, or recombinant antigens such as mutant variants, antigens arranged by in situ cell-free translation, and/or antigens expressed using selectable systems such as phage display. . For example, antigen fragmentation and binding assays involve immobilizing a peptide on a solid support and using Western blotting, dot blotting, and/or ELISA to determine whether the epitope fragment binds the antibody; binding indicates that the peptide Fragments may be immunogenic. Competitive binding assays provide low-resolution localization of potentially immunogenic antigens on a protein by assessing whether multiple antibodies can bind to an epitope on a protein simultaneously or whether they compete with each other for binding to the same epitope. Information that determines the number of bases (see, e.g., Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654; Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830).

Modification testing or mutagenesis is a method of epitope mapping in which individual residues (called hot spots) in functional epitopes are substituted and the effect of the modifications on antibody binding to immunogenic sequences is assessed. Hotspots, most commonly including Tyr, Arg, and Trp residues, are energetically important residues that comprise part of the intact protein-protein interface region. Mutation of individual residues allows the identification of unfavorable residues that can be replaced, with the constraint that the protein retains its structure and activity. For epitope mapping via mutagenesis, peptide libraries are generated through random or site-directed mutagenesis; the combination of mutation induction and display technology allows screening of large numbers of mutated proteins. Saturation mutagenesis is another method for epitope mapping in which amino acid residues at specific positions within the epitope are replaced with all 20 naturally occurring amino acids and the loss of antibody binding is monitored. The disadvantage of this method is that the loss of immunoreactivity may be attributed to the destruction of the antigen structure, making the interpretation of the results difficult. The majority of contacts between epitopes and antibodies occur via amino acid side chains, and alanine scanning mutagenesis can be used to define the contribution of each residue side chain to antibody binding. This is done by sequentially alanine substitution of each non-alanine residue, one at a time, which truncates the side chain to the β-carbon without increasing the flexibility of the protein backbone. This method identifies key residues whose side chains contribute the highest energy to the paratope-epitope interaction. Computational alanine scans can also be used to quickly determine the effect of alanine mutations on binding free energies in protein-protein complexes by using simple free energy functions. Combinatorial mutagenesis is based on combinatorial randomization of discrete antigenic regions and grouping of mutated residues (primary sequence proximity) to maximize the chance of identifying combinatorial effects mediated by adjacent residues; this allows identification of binding effects that are not Residues that are critical but contribute to the formation of an epitope, or that form multiple individually weak interactions with the paratope. Shotgun mutagenesis is a high-throughput method based on large-scale mutagenesis in which each clone has a defined amino acid mutation (e.g., alanine substitution) and involves direct cellular testing of mAb reactivity to natively folded proteins. Shotgun mutagenesis allows the identification of linear and conformational epitopes with localization rates exceeding 20 epitopes/month (see, e.g., Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830).

Other techniques for epitope mapping include display technology and simulated epitope analysis, which are inexpensive, flexible and fast technologies. Display technologies, such as phage display and yeast display, are based on testing various peptides displayed on display platforms via affinity selection methods through biopanning (e.g. peptides tethered to ribosome-mRNA complexes, or phage, bacteria, mammalian , insect or yeast cell surface) and the binding ability of related mAbs (see, for example, Potocnakova et al. (2016) Journal of Immunology Research , article ID 6760830). ii. Method for predicting T cell epitopes in vitro

In vitro methods, such as MHC or HLA binding assays and T cell assays, can be used to predict T cell epitopes and assess T cell responses to protein therapeutic antigens. The synthesis of hundreds or thousands of overlapping peptides for in vitro assays is a limiting factor that can be overcome by using in silico epitope prediction tools that can accurately model the MHC:epitope interface and Predicting immunogenic peptide sequences (see, eg, De Groot, AS and Moise, L. (2007) Curr. Opin. Drug Discov. Devel. 10(3):332-340). MHC/HLA binding assay

T cell epitope predictions identify the shortest peptide sequence within the antigen that stimulates CD8 ⁺ or CD4 ⁺ T cells and is therefore immunogenic. The immunogenicity of T cell epitopes depends on antigen processing, the binding of peptides to MHC molecules, and the recognition of homologous TCRs; MHC-peptide binding is the most selective process and the main basis for predicting T cell epitopes. MHC binding assays can be used to detect high-affinity peptides and are often used in conjunction with epitope mapping to identify regions of a protein that may be immunogenic. In vitro MHC class II binding assays include cell-based binding assays and soluble HLA binding assays. High-throughput MHC binding assays involve incubating different doses of relevant peptides with control peptides and soluble MHC proteins to assess binding affinity; high-affinity peptides bind to MHC more strongly and the epitopes are more likely to be recognized by T cells. For example, MHC II:epitope binding can be assessed by measuring the ability of exogenously added peptides to bind to the surface of B cells of lymphoblastoid lines expressing MHC class II alleles and based on competing HLA The assay may be suitable for high-throughput screening. MHC binding assays to identify potentially immunogenic epitopes are commercially available, e.g. from ProImmune (see e.g. Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654; De Groot, AS and Moise, L. (2007) Curr. Opin. Drug Discov. Devel. 10(3):332-340; Sanchez-Trincado et al. (2017) Journal of Immunology Research , Article ID 2680160). iii. In vitro T cell analysis

The presence of T cell epitopes in protein therapeutics can be detected by in vitro assessment of T cell responses in a T cell assay. T cells proliferate and release interleukins when stimulated by immunogenic proteins. T cell epitopes induce effector T cells to secrete interleukins, such as IL-2, IL-4, IL-5 and IFNγ, and induce regulatory T cells (Treg) to secrete the interleukins TGFβ and TNFα and chemokines. , such as MIP1α/1β. Proliferation of T cells in response to an immunogenic peptide/epitope can be measured by radiolabeling with thymidine or by labeling with a fluorescent dye such as carboxyfluorescein succinimidyl ester (CFSE). ELISA or ELISpot methods and flow cytometry can be used to measure the levels of interleukins (such as IL-2 and IFN-γ) secreted by T cells to determine immunogenicity. The ELISpot method is highly sensitive and can detect individual T cells directly from spleen cells or peripheral blood, and measure the number of antigen-specific T cells that secrete specific interleukins. ELISpot assays for measuring, for example, IL-2 and IL-4 are commercially available. Flow cytometry can also be used to measure T cell responses, where T cells responding to specific epitopes can be directly labeled using tetramers (MHC class II: epitope complexes). T cell proliferation and interleukin release assays can be combined with T cell phenotyping to classify the type of T cell response that occurs. The number and phenotype of T cells responding to an antigen can be determined using methods such as flow cytometry, by identifying cell surface markers such as CD25 for effector T cells and FoxP3 for Tregs, and/or by identifying intracellular To determine the expression of cytokines. Therefore, identification of T cell epitopes can be combined with phenotypic studies to assess whether the immune response will be inflammatory or suppressive. Peripheral blood mononuclear cell (PBMC) assays use PBMC preparations that include several types of immune cells, such as CD4 ⁺ and CD8 ⁺ T cells, to better simulate the in vivo immune system and can be used to assess the immunogenicity of proteins and potential immune responses without testing in humans. In in vitro culture, PBMCs are stimulated with whole therapeutic proteins or peptides derived from the therapeutic proteins. Innate immune screens using innate cell systems, such as PBMC preparations lacking CD8 ⁺ reactive T cells, or innate lymphocytes (ILCs), can be used to differentiate between innate and adaptive immune responses to immunogenic proteins. To be useful, in vitro T cell assays should test peptides on PBMC from a large population of donors with a broad range of MHC class II allotypes. In vitro T cell assays provide information on the number and potency of T cell epitopes, which can be used to determine immunogenicity risk during preclinical development and guide removal of such epitopes by targeted amino acid substitutions Epitope (see, e.g., Baker et al. (2010) Self/Nonself 1(4):314-322; Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654; De Groot, AS and Moise, L. (2007) Curr. Opin. Drug Discov. Devel. 10(3):332-340). d. In vivo epitope prediction method

In vivo assessment of the immunogenicity of protein therapeutics in humans uses animal models, such as mice. In general, any human or humanized protein therapeutic may be immunogenic when administered to non-human animals. However, animal models can be used to predict immunogenicity, compare the relative immunogenicity between products, pharmaceutical formulations, or routes of administration, determine the immunogenicity of aggregates, and elucidate immune mechanisms. Studies of receptive transfer and T cell proliferation in animal models can be used to determine the role of T cells and B cells in protein immunogenicity. The immunogenicity of human protein therapeutics may be difficult to assess in animals because animal MHC receptors do not directly mimic human HLA receptors and because HLA and MHC genes are highly polymorphic and there is inter-individual variability in HLA/MHC performance. high. To overcome these limitations, HLA transgenic mice have been generated that mimic human individuals and are tolerant to specific proteins; the mice will tolerate the protein therapeutics evaluated and any immunogenicity developed is attributable to the autologous The breakdown of tolerance is not attributable to the classical immune response to foreign antigens. In vivo methods for determining the immunogenicity of protein therapeutics include exposing HLA transgenic mice to whole proteins or epitope peptides. Several lines of transgenic mice expressing common HLA gene products, such as HLA-A, HLA-B, and HLA-DR molecules, have been generated and can be used to measure T cell responses by ELISA and neutralizing antibody assays. and antibodies induced by exposure to protein therapeutics. B cell epitopes in protein therapeutics can also be identified by immunizing HLA transgenic mice with the protein (see, for example, Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654; De Groot, AS and Moise, L. (2007) Curr. Opin. Drug Discov. Devel. 10(3):332-340).

NOD scid gamma (NSG) mice are highly immunocompromised and lack most immune cells as well as complement and interleukin signaling and can be transfected to study the human immune system in an in vivo model. For example, a CD34 ⁺ humanized NSG mouse model was transplanted with umbilical cord blood-derived hematopoietic stem cells to generate a functional immune system with normal T cell and inflammatory functions. Animal models also include non-human primates, such as rhesus monkeys and chimpanzees, which are more useful in predicting protein immunogenicity because their proteins exhibit a higher degree of homology with human proteins and because of their immune mechanisms Similar to the immune mechanism of humans (see, for example, Dingman et al. (2019) J. Pharm. Sci. 108(5):1637-1654). e. Remove predicted B cell and T cell epitopes ( deimmunization )

As described herein, predicting and removing immunogenic epitopes (i.e., deimmunization) in protein therapeutics can increase the efficacy and safety of the constructs provided herein and reduce the potential for or prevent adverse effects. . For example, removal of identified epitopes, such as B cell epitopes, can prevent the formation of ADA by reducing the administration of the protein therapeutic by neutralizing the therapeutic and/or inducing its rapid elimination from the body. effect.

Deimmunization of protein therapeutics involves identification of highly immunogenic B cell and/or T cell epitopes and deletion of the identified epitopes through mutation-induced substitutions of key amino acid residues. As discussed above, predicting and assessing immunogenic regions within protein therapeutic sequences involves the use of a variety of in silico, in vitro and in vivo methods. After the immunogenic epitope is identified, the amino acid sequence of the epitope is modified by random or site-directed mutagenesis to remove the immunogenic sequence and deimmunize the epitope. For example, the majority of contacts between epitopes and antibodies occur via amino acid side chains, and alanine scanning mutagenesis can be used to define the contribution of each residue side chain to antibody binding. This is performed by sequentially substituting alanine substitutions on each non-alanine residue, one at a time, to identify key residues whose side chains make the highest energetic contribution to the paratope-epitope interaction. However, prediction of immunogenic epitopes and mutation-induced deletion are not enough to achieve protein deimmunization, because the protein must maintain its folded, stable and active structure to maintain its therapeutic efficacy; it must be selected to be compatible with the structure and function of the protein Epitope deletion mutations.

Computer simulation tools exist to improve the efficiency of this process. For example, a program can be used to sequentially replace each amino acid in an immunogenic sequence with one of the other 19 naturally occurring amino acids, and then reassess the immunogenicity of the new sequence. For example, OptiMatrix is a tool that iteratively substitutes all 20 amino acids at any given position in a peptide sequence and subsequently reanalyzes the predicted immunogenicity of the modified sequence (see, e.g., De Groot, AS and Moise , L. (2007) Curr. Opin. Drug Discov. Devel. 10(3):332-340). EpiSweep is a set of protein design algorithms that integrates computational prediction of immunogenic T cell epitopes with sequence-based or structure-based assessment of the impact of epitope deletion mutations on protein stability, structure, and function, allowing selection Optimizing combinations of mutations for protein therapeutics to achieve low immunogenicity and high activity and stability (for a step-by-step guide to applying the EpiSweep deimmunization algorithm suite, see, e.g., Choi et al. (2017) Methods Mol. Biol. 1529:375 -398). Computational alanine scans can also be used to quickly determine the effect of alanine mutations on binding free energy in protein-protein complexes by using a simple free energy function (see e.g. Potocnakova et al. (2016) Journal of Immunology Research , Article ID 6760830) . G. Pan-Growth Factor Trapper Construct 1. Receptor Tyrosine Kinase ( RTK )

Receptor tyrosine kinase (RTK) is a high-affinity cell surface receptor for many polypeptide growth factors, interleukins, and hormones. RTKs participate in many signal transduction pathways and play a role in a variety of cellular processes, including cell division, proliferation, differentiation, migration, and metabolism. RTKs can be activated by specific binding of ligands to their cognate receptors. Such activation in turn activates events in signal transduction pathways, such as by triggering autocrine or paracrine cell signaling pathways, such as activation of second messengers, thereby producing specific biological effects. Approximately 20 different classes of RTKs have been identified, including, for example, the epidermal growth factor receptor (EGFR) family (class I, also known as the ErbB family); the insulin receptor family (class II); the platelet-derived growth factor receptor (PDGFR) ) family (class III); vascular endothelial growth factor receptor (VEGFR) family (class IV); fibroblast growth factor receptor (FGFR) family (class V); hepatocyte growth factor receptor (HGFR) family (VIII class); and the Eph receptor family (Ephs, after the human hepatocyte receptor that produces erythropoietin, class IX), etc.

RTKs are related to regulatory pathways involved in angiogenesis (including physiological and tumor blood vessel formation) and are involved in the regulation of cell proliferation, migration and survival. RTK has been implicated in a variety of diseases, including autoimmune diseases and cancers such as breast and colorectal cancers, gastric cancers, gliomas, and mesoderm-derived tumors. Dysregulation of RTK has been associated with several cancers. For example, breast cancer has been associated with amplification of p185-HER2. RTKs are also associated with eye diseases, including diabetic retinopathy and macular degeneration. In addition, members of the epidermal growth factor receptor (EGFR) family and EGF-like growth factors (ligands) have been shown to be overexpressed in synovial fibroblasts and macrophages in patients with rheumatoid arthritis (RA). a. Human epidermal growth factor receptor ( HER ) family

Disease-related RTKs include class I human EGFR (HER; also known as ErbB) family receptors, which include HER1/EGFR (ErbB1), HER2 (ErbB2/Neu), HER3 (ErbB3), and HER4 (ErbB4). HER1, HER3 and HER4 jointly bind more than 11 typical ligands, including epidermal growth factor (EGF), transforming growth factor (TGF)-α, heparin-binding (HB)-EGF, amphiregulin, beta-cell protein (BTC) ), epiregulin, epithelial mitogen and neuregulin (NRG) 1-4. HER2 does not bind any of these ligands, but acts as a signal amplifier by heterodimerization with other HER family members such as HER3 and HER4 (see, e.g., Jin et al. (2009) Mol. Med. 15(1-2):11-20). HER1, HER2 and HER4 are active as tyrosine kinases, whereas HER3 is inactive as a kinase (despite having a kinase domain) and signals via the phosphoinositide 3-kinase pathway.

All members of the HER family have an extracellular ligand-binding domain, a single transmembrane domain, and a cytoplasmic tyrosine kinase domain. The extracellular region of each HER family member contains four subdomains L1, CR1, L2 and CR2, where "L" refers to the leucine-rich repeat domain and "CR" refers to the cysteine-rich region/domain (Also known as Flynn-like repeat domain); the four subdomains are also known as domains I-IV. Domains I and III are ligand-binding domains, and domains II and IV mediate binding to each other and to other members of the receptor family. Domain II contains the sequences required for dimerization, termed the dimerization arm, and domain IV contains sequences that allow domain II/IV tethering, with the exception of HER2, which does not undergo a tethered conformation. In the absence of ligand, EGFR, HER3 and HER4 subdomains II and IV form intramolecular autoinhibitory tethers. Upon ligand binding, the subdomains undergo conformational changes that allow subdomains I and III to form high-affinity ligand binding pockets. It has been shown that mutation-induced disruption of the tether formed by subdomains II and IV or C-terminal deletion of subdomain IV increases ligand binding affinity by up to 15-fold (see e.g. Jin et al. (2009) Mol. Med. 15(1) -2):11-20).

HER family members are expressed in various tissues of epithelial, mesenchymal and neuronal origin. Under normal physiological conditions, the activation of HER is controlled by the spatial and temporal expression of its ligands, which are members of the EGF family of growth factors. Ligand binding induces the formation of receptor homodimers and multiple heterodimer combinations, leading to activation of the intrinsic kinase domain, autophosphorylation of specific tyrosine residues in the cytoplasmic tail, and the activation of several intracellular proteins. Recruitment and phosphorylation and coupling to multiple downstream signaling cascades. Activated signaling pathways include the Ras-Raf-mitogen-activated protein kinase cell division pathway, the phosphatidylinositol 3-kinase-AKT cell survival pathway, and the stress-activated protein kinase C and Jak/Stat pathways. The induced signaling pathways lead to a variety of cellular responses, including, for example, cell migration, invasion, proliferation, survival and differentiation (see, eg, Sarup et al. (2008) Mol. Cancer Ther. 7(10):3223-3236). b. Diseases related to the human epidermal growth factor receptor ( HER ) family and its ligands

Dysregulation of HER family members and their ligands, either through overexpression or through mutations, has been shown to play a role in cancer and other diseases. For example, HER1 and HER2 are involved in the development and pathology of many human cancers, and alterations in these receptors are associated with more aggressive disease and poor clinical outcomes. Overexpression of TGF-α is associated with prostate, pancreatic, lung, ovarian, and colon cancers, while overexpression of NRG1 is associated with breast cancer. Overexpression of HER1 is associated with gliomas and cancers of the head and neck, breast, bladder, prostate, kidney, and non-small cell lung cancer, and mutations in HER1 are associated with gliomas and cancers of the lung, breast, and ovary. HER2 overexpression is associated with breast, lung, pancreatic, colon, esophageal, endometrial, and cervical cancers; HER3 is associated with breast, colon, gastric, prostate, and oral squamous cell carcinoma; and HER4 is associated with Breast and prostate cancer, and medulloblastoma in children (see, eg, Yarden et al. (2001) Nat. Rev. Mol. Cell Biol. 2:127-137).

Ligands and receptors of the EGF family have been shown to play a role in the development of inflammatory arthritis. For example, expression of HER2 and the presence of the EGFR ligands EGF, amphiregulin and TGF-α have been detected in RA synovium. Adenoviral delivery of the human EGFR family inhibitor herstatin (an alternative splicing variant of HER2) has been shown to eliminate all clinical symptoms of collagen-induced arthritis (CIA) in mice. Herstatin disrupts dimerization and acts as a natural inhibitor of native HER1, HER2 and HER3. Patients with long-term RA, previously treated with rituximab and adalimumab, experienced significant reductions in joint pain after treatment of head and neck cancer with the anti-EGFR/HER1 antibody cetuximab. These results suggest that HER-targeted therapies may be therapeutically useful in treating autoimmune inflammatory conditions such as rheumatoid arthritis (RA) (see, e.g., Gompels et al. (2011) Arthritis Research & Therapy 13: R161).

Macrophages are the source of TNF in chronically inflamed RA joint tissue. Phenotypic analysis of macrophages in synovial tissue from RA patients revealed abundant HBEGF ⁺ (heparin-binding EGF-like growth factor ⁺ ), which overexpresses the pro-inflammatory gene NR43A (nuclear receptor subfamily 4 group A member 3) , PLAUR (plasminogen activator, urokinase receptor) and CXCL2 , as well as the growth factors HB-EGF and Epiregulin (EGFR family ligand). HBEGF ⁺ inflammatory macrophages also produce the proinflammatory cytokine IL-1 and promote synovial fibroblast invasion in an epidermal growth factor receptor-dependent manner. Most drugs used to treat RA have been shown to target HBEGF ⁺ macrophages in ex vivo synovial tissue assays, and EGFR inhibitors effectively block macrophage induction in RA tissues in ex vivo assays. fibroblastic response, suggesting that blocking EGFR responses may provide a non-immunosuppressive treatment for RA (see, e.g., Kuo et al. (2019) Sci. Transl. Med. 11(491)). Such an approach is superior to the use of traditional anti-TNF therapies, which are immunosuppressive and often associated with the development of serious infections such as tuberculosis.

HER family signaling is also associated with coronary atherosclerosis, which involves the migration of vascular smooth muscle cells in the arterial intima. Activation of the thrombin receptor is required for smooth muscle cell migration and proliferation, and activation of this G protein-coupled receptor depends on transcriptional activation of HER1/EGFR in response to HB-EGF. EGFR expression is also associated with psoriasis; in normal skin, EGFR expression is restricted to the basal layer, whereas in psoriasis patients, EGFR and its ligand amphiregulin are highly expressed throughout the epidermis (see, e.g., Yarden et al. (2001) Nat . Rev. Mol. Cell Biol. 2:127-137).

Other HER-mediated diseases and conditions include neurodegenerative diseases and conditions, such as multiple sclerosis, Parkinson's disease, schizophrenia and Alzheimer's disease. For example, certain diseases and conditions are associated with exposure to one or more neuregulin (NRG) ligands, such as NRG1, including types I, II and III, NRG2, NRG3 and/or NRG4, e.g. Caused or aggravated by ligands. Examples of NRG-related diseases include neurological or neuromuscular diseases, including schizophrenia and Alzheimer's disease (see, eg, US Publication No. 2010/0055093).

Due to its role in cancer and other proliferative diseases, rheumatoid arthritis, neurodegenerative diseases, and autoimmune diseases, HER is a target for therapeutic intervention. Anti-HER therapeutics include antibodies targeting the extracellular domain (referred to herein as ECD) and small molecule tyrosine kinase inhibitors. Therapeutics approved to treat cancers driven by the HER protein family include monoclonal antibodies such as trastuzumab (for HER2), pertuzumab (for HER2), panitumumab (for HER1/EGFR ) and cetuximab (targeting HER1/EGFR), and small molecule tyrosine kinase inhibitors, such as HER1 kinase inhibitors gefitinib and erlotinib, and HER2 kinase and HER1 kinase dual inhibitor lapa Tinib. For example, trastuzumab is used to treat HER2-overexpressing node-positive or node-negative breast cancer; cetuximab is used to treat metastatic colorectal cancer and head and neck cancer; and panitumumab is used to treat metastatic colon cancer. Rectal cancer; lapatinib as first-line therapy for triple-positive breast cancer and adjuvant therapy in patients with progression on trastuzumab; and erlotinib for the treatment of non-small cell lung cancer and pancreatic cancer.

Anti-HER therapeutics exhibit limited efficacy and limited duration of response. Trastuzumab (eg, sold as Herceptin®) is a humanized version of a murine monoclonal antibody that targets the extracellular domain of HER2. However, the effectiveness of trastuzumab requires high expression of HER2 (at least 3- to 5-fold overexpression), and therefore less than 25% of breast cancer patients are eligible for treatment. In this group, a larger proportion fail to respond to treatment. Furthermore, small molecule tyrosine kinase inhibitors often lack specificity. Except for patients with high HER2 expression and treated with trastuzumab in combination with chemotherapy, the efficacy observed with single-targeted anti-HER antibodies or small molecule tyrosine kinase inhibitors was in the range of 10-15%. Treatments, especially those targeting only one HER family member, also suffer from intrinsic or acquired resistance, which is associated with co-expression and ligand activation of other RTKs, especially other HER family members. For example, drug resistance is often associated with upregulation or compensation of other HER family members, such as HER3 and HER4, or with increased expression of HER1 or HER3 ligands by tumor cells. Homodimerization and heterodimerization among HER family receptor members also have implications for therapies targeting single HER family receptors. Due to the limited effectiveness of available therapies, alternative anti-HER therapies are needed. This article provides more effective alternative therapies targeting HER family RTKs and their ligands. 2. Pan-growth factor inhibition

As described herein, resistance to single-targeted anti-HER therapies (such as trastuzumab, cetuximab, gefitinib, and erlotinib) is often co-expressed with other HER family members and/ or related to upregulation and/or overexpression of its ligands. One strategy to reduce or overcome this resistance and improve the efficacy of HER-targeted therapies is to inhibit multiple ligand-induced HER family members simultaneously. This can be achieved, for example, by chimeric HER ligand-binding molecules that behave like receptor decoys and sequester multiple HER family ligands, thereby preventing ligand-dependent receptor activation and downregulating aberrant HER family activity. a. RB242 ligand capture agent

The antagonist, named RB242, is a chimeric dual-specific ligand capture agent that is an Fc-mediated heterodimer of the EGFR (HER1) and HER3 ligand-binding domains, targeting all four members of the EGFR/HER family. members. The EGFR and HER3 ligand-binding domains dimerize by fusing each ligand-binding domain with the Fc domain of human IgG1. In RB200, EGFR (corresponding to residues 1-621 of the mature EGFR protein shown in SEQ ID NO: 41) and HER3 (corresponding to residues 1-621 of the mature HER3 protein shown in SEQ ID NO: 45 ) are each fused to the N-terminus of the Fc fragment of human IgG1 (corresponding to residues P100-K330 of SEQ ID NO: 9), and Gly-Arg-Met- is added to the N-terminus of the Fc fragment Asp (GRMD) linker. The HER3/Fc component of RB200 contains a 6×His tag at the COOH end for purification.

RB200 has been shown to interact with EGFR and HER3 ligands (including EGF, TGF-α, HB-EGF, amphiregulin, β-cell protein, Epiregulin, and epithelial mitogen, respectively), as well as NRG1-α, NRG1-β1, and NRG1- β3) binds with high affinity, inhibits ligand-induced tyrosine phosphorylation of HER family members (HER1, HER2 and HER3), inhibits the proliferation of various tumor cells in vitro, and inhibits tumor xenografts (epidermis) in nude mouse models. cancer and non-small cell lung cancer). RB200 also shows synergy with tyrosine kinase inhibitors targeting EGFR/HER1 and HER2 kinases, such as AG-825, erlotinib, gefitinib or lapatinib, in inhibiting tumor cell proliferation in vitro. RB200 inhibits ligand-stimulated phosphorylation of HER1, HER2 and HER3 more effectively than monoclonal antibodies targeting HER1 (C225) or HER2 (trastuzumab and 2C4) (see e.g. Sarup et al. ( 2008) Mol. Cancer Ther. 7(10):3223-3236; Gompels et al. (2011) Arthritis Research & Therapy 13:R161).

The ligand capture agent named RB242 is derived from RB200 and is an affinity-optimized Fc-mediated triple mutant EGFR:HER3 heterodimer that contains the sequence referenced to the mature EGFR protein (SEQ ID NO: 41). Mutations T15S and G564S in EGFR ECD subdomains I and IV, and mutation Y246A in HER3 ECD subdomain II with reference to the sequence of the mature HER3 protein (SEQ ID NO: 45). HER1 (EGFR) allele variants also contain the substitution N516K, so RB242 can have this substitution without changing its properties. RB242 may also have a modified Fc domain in place of the anchor to alter other properties, such as modifications that enhance nascent Fc receptor (FcRn) recycling and/or effector function, as described and detailed in the following sections.

To express the RB200 and RB242 heterodimeric chimeric fusion proteins, vectors encoding HER1/Fc and HER3/Fc constructs were co-transfected into HEK293T cells at a ratio of 1:3 (HER1/Fc:HER3/Fc). In addition to the related HER1/Fc:HER3/Fc heterodimers, this also causes the manifestation of HER1/Fc and HER3/Fc homodimers. The expressed protein was purified by a combination of Protein-A, Ni-Sepharose and EGFR-affinity antibody column chromatography. Analytical reversed-phase high-performance liquid chromatography (HPLC) showed that the RB242 heterodimer contained approximately 10% contamination from the combined combination of the two homodimers (see, e.g., Sarup et al. (2008) Mol. Cancer Ther. 7(10) ):3223-3236). Therefore, improved methods are needed to increase the yield and purity of heterodimers. b. RB200 and RB242 for the treatment of autoimmune diseases

As discussed elsewhere herein, a significant proportion of RA patients do not respond or cease to respond to treatment with anti-TNF therapies (such as anti-TNF antibodies), which is associated with an increased risk of serious infections, including tuberculosis. Therefore, alternative treatments are needed. Increased expression of EGF ligand and receptor (HER) has been documented in the synovium and synovial fluid of patients with rheumatoid arthritis (RA), suggesting that EGFR-targeted therapies may be useful in the treatment of RA and other autoimmune and Inflammatory diseases and conditions.

The bispecific EGFR ligand capture agent RB200 (and its derivative RB242) shows a dose-dependent reduction in disease severity in collagen-induced arthritis (CIA). Mice with CIA were treated with RB200 (or RB242) at a dose of 0.1 mg/kg, 1 mg/kg or 10 mg/kg on the day of disease onset (day 1) and on days 4 and 7 of the disease. Intraperitoneal treatment. Treatment with 1 mg/kg or 10 mg/kg RB200 inhibited the increase in clinical scores and paw swelling in a dose-dependent manner. EGF has been shown to promote angiogenesis, and RB200-treated mice showed reduced CD31 immunopositive staining, reflecting a reduction in synovial vasculature and inhibition of synovial angiogenesis. Joint sections from mice treated with PBS control showed large numbers of infiltrating cells in the inflamed synovium, and synovial invasion and erosion of bone correlated with significant CD31 expression. The joints of mice treated with 1 mg/kg or 10 mg/kg RB200 were protected, normal in appearance, with well-preserved joint structures and few CD31-positive blood vessels. These results suggest that inhibition of EGFR-mediated responses may have therapeutic use in the treatment of RA (see, eg, Gompels et al. (2011) Arthritis Research & Therapy 13:R161).

Combination of TNF inhibition with inhibitors of EGFR-mediated signaling may increase the therapeutic efficacy of anti-TNF therapy and may be used to treat RA. It has been shown that the combination of a low dose of RB200 (0.5 mg/kg) and a suboptimal dose of etanercept (1 mg/kg) suppresses increases in clinical scores and paw swelling and completely eliminates CIA. Similar to that observed with the optimal dose of etanercept (5 mg/kg) administered alone. In contrast, low-dose RB200 alone or low-dose etanercept alone were ineffective. Fluorescently labeled monoclonal antibodies against E-selectin can be used to localize endothelial activation in inflamed tissue in vivo and are a sensitive, specific, and quantifiable molecular imaging technique for assessing CIA. The combination of low-dose RB200 and low-dose etanercept reduced the amount of E-selectin detected in the paws to levels seen in healthy animals, compared with low-dose RB200 alone or low-dose etanercept alone. E-selectin was detected in the paws of CIA mice. Although RB200 alone and etanercept alone had a dose-dependent effect on joint structure, with the number of severely damaged joints gradually decreasing and the number of mildly or moderately damaged joints increasing, the most obvious effect was observed with the combination treatment, 64% joints appeared normal, compared to 0% in mice treated with low-dose RB200 alone or low-dose etanercept alone. The combination treatment was also more effective than high-dose etanercept alone, demonstrating the effectiveness of combining pan-EGFR and TNF-targeted therapies in promoting joint protection (see, e.g., Gompels et al. (2011) Arthritis Research & Therapy 13:R161). c. RB242 ligand capture agent

The ligand capture agent named RB242 is derived from RB200 and is an affinity-optimized Fc-mediated triple mutant EGFR:HER3 heterodimer, which contains the sequence referenced to the mature EGFR protein (SEQ ID NO: 41). Mutations T15S and G564S in EGFR ECD subdomains I and IV, and mutation Y246A in HER3 ECD subdomain II with reference to the sequence of the mature HER3 protein (SEQ ID NO: 45). Compared with the parent molecule RB200, RB242 has an average 22-fold increase in affinity for various ligands (including EGF, TGF-α, HB-EGF, and NRG1-β), and is highly effective on cultured monolayer BxPC3 pancreatic cancer cells and human non-cancer cells. Demonstrated improved antiproliferative activity in mouse models of small cell lung cancer. RB242 also exhibits a 10- to 60-fold improvement in inhibiting ligand-induced HER phosphorylation compared to RB200 (see, eg, Jin et al. (2009) Mol. Med. 15(1-2):11-20). 3. Optimized multispecificity , such as bispecific growth factor capture constructs

Provided herein are multispecific, such as bispecific growth factor capture constructs designed to specifically target more than one cell surface receptor, such as by binding to a ligand for one or more receptors and / Or interact with one or more cell surface receptors to become a pan-cell surface receptor therapeutic agent, as long as it modulates the activity of more than one cell surface receptor. Such constructs include constructs that target more than one HER family member as well as constructs that target one or more HERs and additional receptors, such as HERs that contribute to or participate in the development of resistance to anti-HER therapies. Growth factor capture constructs provided herein contain multiple, particularly two, chimeric fusion polypeptides, each containing an extracellular domain (ECD) of a receptor, particularly a HER family member, such as EGFR/HER1, HER2, HER3 or HER4. All or a portion of a protein is fused to a multimerization domain, such as the Fc of a human immunoglobulin (Ig), such as the Fc of a human IgG. The ECD or portion thereof in the chimeric fusion polypeptide can be linked to the Fc directly or indirectly via a linker, such as a peptide linker. Typically, the C-terminus of an ECD polypeptide is linked to the N-terminus of a multimerization domain (such as IgG Fc).

Growth factor capture constructs in this article are, for example, Sarup et al. (2008) Mol. Cancer Ther. 7(10):3223-3236; Gompels et al. (2011) Arthritis Research & Therapy 13:R161; Jin et al. (2009) ) Mol. Med. 15(1-2):11-20; and the performance and purification described in U.S. Patent Publication No. 2010/0055093. The following sections describe each part of the multispecific growth factor capture agent constructs provided herein. a. Extracellular domain ( ECD ) polypeptide

Provided herein are multispecific, such as bispecific growth factor capture constructs that comprise the extracellular domains (ECDs) of two or more cell surface receptors (CSRs), or portions thereof. In certain embodiments, the construct is a bispecific heterodimeric construct that contains two different cell surface receptors. The constructs include a first ECD polypeptide and a second ECD polypeptide, each linked directly or indirectly via a linker to a multimerization domain. In some specific examples, the first ECD polypeptide comprises the ECD of HER1/EGFR (corresponding to residues 1-621 of SEQ ID NO: 41) or a portion thereof, and the second ECD polypeptide comprises HER2 (corresponding to SEQ ID NO: 43 ECD or part thereof, especially HER3 or HER4 ECD or part thereof. In specific examples where the ECD polypeptide contains less than the full-length ECD of the HER protein, it contains at least a sufficient portion of subdomains I, II, and III for ligand binding and receptor dimerization. For example, the ECD may contain a sufficient portion of subdomains I and III for ligand binding, and/or a sufficient portion of the ECD to dimerize with a cell surface receptor, including a sufficient portion of subdomain II. In some embodiments, the ECD contains subdomains I, II, and III and at least Module 1 of domain IV.

In some examples, a multispecific, such as a bispecific growth factor capture construct contains a first ECD polypeptide that contains all or a portion of the ECD of HER1/EGFR, HER2, HER3, or HER4 (especially EGFR/HER1); and A second chimeric polypeptide containing an ECD from a different CSR such as HER2, HER3, HER4, insulin growth factor-1 receptor (IGF1-R), vascular endothelial growth factor receptor (VEGFR, e.g., VEGFR1), fibroblast Cellular growth factor receptor (FGFR, such as FGFR2 or FGFR4), TNFR, platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR), tyrosine with immunoglobulin-like and EGF-like domains 1 Kinase (TIE, such as TIE-1 or TEK (TIE-2)), receptor for advanced glycation end products (RAGE), Eph receptor, or T cell receptor.

In a specific embodiment, the first ECD polypeptide comprises the full-length ECD of HER1/EGFR (corresponding to residues 1-621 of SEQ ID NO: 41) or a portion thereof (e.g., residues 1-501 of SEQ ID NO: 41, It corresponds to module 1 of subdomains I-III and domain IV), and the second ECD polypeptide comprises the full-length ECD of HER3 (corresponding to residues 1-621 of SEQ ID NO: 45) or a portion thereof (e.g., SEQ ID NO. : Residues 1-500 of 45, which correspond to module 1 of subdomains I-III and domain IV), wherein the ECD portion contains at least a sufficient portion of subdomains I and III to bind a ligand of the HER receptor, and A sufficient portion of the ECD to dimerize with the cell surface receptor includes a sufficient portion of subdomain II. The first and second ECD polypeptides form multimers, such as dimers, through the interaction of their multimerization domains. The resulting multimeric constructs provided herein are combined with additional ligands compared to the first or second chimeric polypeptide alone or homodimers thereof, and/or are combined with the first or second chimeric polypeptide alone or homodimers thereof. Dimerizes with more cell surface receptors than homodimers. For example, the first and second ECD polypeptides form a heterodimer that binds a HER1 ligand and a HER3 ligand. b. Modification of extracellular domain

In some embodiments, at least one of the ECD domains, or a portion thereof, includes modifications that alter ligand binding, specificity, or other activities or properties compared to an unmodified ECD polypeptide. In such multimeric constructs, the second ECD moiety can be the same ECD domain, wild type or mutant, or can be an ECD from any other cell surface receptor. The ECD of each monomer, or a portion thereof, is linked directly or via a linker to the multimerization domain, or to a second ECD or portion thereof, directly or via a linker. For example, the modification alters ligand binding, specificity or another activity or property of the ECD or full-length receptor containing such ECD as compared to an unmodified ECD or full-length receptor, whereby the heteromultimer behaves Altered activity or properties, such as altered ligand binding or specificity. Such modifications include any modification that eliminates or adds or enhances activity, such as binding to additional ligands. An example of such a multimeric construct is a construct containing at least one HER1 ECD containing a mutation in subdomain III that increases its affinity for ligands other than EGF. Such affinity is increased by at least 2 to 10-fold, typically 100, 1000, 10 ⁴ , 10 ⁵ , 10 ⁶ -fold or more.

In certain embodiments, the growth factor capture agent construct is a heterodimer containing a HER1 (EGFR) chimeric fusion polypeptide and a HER3 chimeric fusion polypeptide, wherein each chimeric fusion polypeptide comprises a human peptide, optionally linked to a human via a peptide linker ECD of the Fc receptor of IgG1. Such chimeric fusion polypeptides are referred to herein as HER1/Fc and HER3/Fc. Typically, the C-terminus of an ECD polypeptide is linked to the N-terminus of a multimerization domain (such as IgGl Fc).

In some examples, the ligand binding and/or biological activity of the HER1 portion is enhanced. In other examples, the ligand binding and/or biological activity of the HER3 portion is enhanced. In another example, the ligand binding and/or biological activity of both HER1 and HER3 portions is enhanced.

Exemplary modifications include, for example, S418F in HER1 (referring to the sequence of the mature protein shown in SEQ ID NO: 41), which allows stimulation of HER1 by the HER3 ligand NRG2-β. The resulting ECD binds or interacts with at least two ligands, one a ligand for HER1, such as EGF, and another a ligand for HER3, such as NRG2-β. Other modifications include, for example, the mutations T15S and G564S in the EGFR/HER1 ECD subdomains I and IV, respectively, with reference to the sequence of the mature EGFR protein (SEQ ID NO: 41), and to the sequence of the mature HER3 protein (SEQ ID NO: 45) in Y246A in HER3 ECD subdomain II, these mutations, when combined, increase the affinity to various ligands (including EGF, TGF-α, HB-EGF and NRG1-β) by an average of 22 times. Additional mutations in the HER1 ECD include E330D/G588S, S193N/E330D/G588S and T43K/S193N/E330D/G588S with reference to the sequence of precursor HER1 (including signal peptide) shown in SEQ ID NO: 40 and correspond to the reference E306D/G564S, S169N/E306D/G564S and T19K/S169N/E306D/G564S of the mature HER1 polypeptide sequences shown in SEQ ID NO: 41. These mutations increase the binding affinity of HER1 to the ligands EGF, HB-EGF, and TGF-α (see, eg, US Patent Publication No. 2010/0055093). c. Multimerization domain

In certain embodiments, the multimerization domain is an Fc domain or a variant thereof that achieves multimerization. The Fc domain can be derived from any immunoglobulin (Ig) molecule, including from IgG, IgM or IgE. For example, the Fc domain can be from IgGl, IgG2, IgG3 or IgG4 and includes all or part of the _CH2 and _CH3 domains and optionally the hinge region. In certain examples, the Fc portion is that of a human IgGl, optionally including all or part of the hinge region, and corresponds to, for example, residues 99-330, 100-330, 104-330, 109- of SEQ ID NO: 9 330, 111-330, 113-330 or 114-330. Also included are modified Fc domains as described in the section above that are modified to have modified and altered properties.

Each ECD polypeptide in the multispecific growth factor capture agent construct is linked to Fc directly or indirectly via a linker (such as a chemical or peptide linker) to form a chimeric fusion polypeptide (i.e., ECD/Fc fusion polypeptide). The multimerization domains (such as the Fc domain) of each chimeric fusion polypeptide interact (via disulfide bonds in the case of the Fc domain) to form heteromultimers, such as heterodimers.

The linker between the ECD and Fc portions of each chimeric fusion polypeptide can be a flexible peptide linker, such as the hinge region of IgG, or can be composed of various lengths and combinations of small amino acids (such as glycine, serine , threonine and/or alanine). For example, the linker can be (Gly) _n , (GGGGS) _n , (SSSSSG) _n , or (AlaAlaProAla) _n , where n is 1-6, or can be GKSSGGSESKS, GGSTSGSGKSSEGKG, GSTSGSGKSSSEGSGSTKG, GSTGSSGKPGSGEGSTKG, EGKSSGSGSESKEF, Gly- Arg-Met-Asp (GRMD), Ser-Cys-Asp-Lys-Thr (SCDKT) or Glu-Lys-Thr-Ile-Ser (EKTIS) (see SEQ ID NO: 816-834) or described elsewhere herein or Any other linkers suitable for such purposes are known in the art. d. Modification of Fc domain

The Fc domains in the growth factor capture constructs provided herein are modified to improve or enhance protein performance and purity, as well as to improve pharmacodynamic and pharmacokinetic properties, including, for example, by extending half-life in vivo and/or altering immune effector functions. , as described below, and results in the production of heterodimers as the major or sole product. i.Introduce pestle and mortar

The Fc domain in the growth factor capture agent constructs provided herein can be engineered such that steric interactions promote stable interactions and promote the formation of heterodimers rather than homodimers from mixtures of chimeric ECD polypeptide monomers. As discussed elsewhere herein, "knobs-in-holes"(KiH; also known as "knobs-into-holes") are introduced into the _CH3 domain of the heavy chain of an antibody (e.g., IgG) to allow heterogeneity. Optimization of dimer production. The pestle and mortar approach involves asymmetrically mutating interface residues in the _CH3 domains of two Fc monomers in a complementary manner. Generally speaking, the "pestle" or protrusion is formed by replacing an amine group with a small side chain at the interface between _CH3 domains with an amino acid with a larger side chain, such as tyrosine or tryptophan. acid, and a compensating "mortar," or cavity of the same or similar size as the pestle, is produced by replacing the amine group with the large side chain with an amino acid with a smaller side chain, such as alanine or threonine. Produced by acid. The pestle and mortar variants of the Fc monomer heterodimerize by inserting the pestle into a correspondingly designed mortar on the _CH3 domain. Pstle-pestle association is prevented due to steric repulsion, and the mortar-mortar homodimer is unstable.

In some embodiments, the Fc portion of the heterodimeric growth factor capture constructs provided herein is engineered to contain a pestle. The mutation may be, for example, S354C, T366Y, T366W or T394W according to EU numbering, which refers to the sequence of the human IgG1 heavy chain constant domain shown in SEQ ID NO: 9, corresponding to S237C, T249Y, T249W or T277W respectively. The mutation can be Y349C, T366S, L368A, F405A, Y407T, Y407A or Y407V according to EU numbering, which refers to the sequence of the human IgG1 heavy chain constant domain shown in SEQ ID NO: 9, corresponding to Y232C, T249S, L251A respectively. , F288A, Y290T, Y290A or Y290V. For example, when compared to RB200 and RB242, the introduction of pestle and mortar increases the yield of related heterodimers, reduces the amount of homodimer impurities, and promotes the bispecific heterodimeric growth factor capture constructs provided herein. Protein purification process. ii. Modification to enhance recycling of nascent Fc receptor ( FcRn )

As described elsewhere herein, fusion to IgG Fc binds by utilizing nascent Fc receptors (FcRn) and also increases the half-life of small protein therapeutics by increasing the molecular weight of the therapeutic, allowing it to be eliminated from the body, e.g., by the kidneys The speed is reduced. In order to improve pharmacokinetics and overall pharmacology, residues within the Fc region of the growth factor capture agent constructs provided herein can be mutated to increase the affinity for FcRn, typically more than 30-fold, further increasing the in vivo half-life.

In some embodiments, the Fc portion of the growth factor capture constructs herein is modified to enhance nascent FcRn recycling, thereby increasing half-life in vivo. This can be achieved by mutating residues at the interface of the _CH2 and _CH3 domains of the IgG Fc that are responsible for binding to FcRn. Exemplary Fc modifications that increase binding to FcRn and may be incorporated into the Fc portion of the growth factor capture constructs herein include, but are not limited to, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N4 34F/Y436H, T250Q/M428L, T250R/ One or more of M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E294del/T307P/N434Y and T256N/A378V/S383N/N434Y and their combination (according to EU number). With reference to the sequence of the IgG1 heavy chain constant domain shown in SEQ ID NO: 9, the corresponding mutations according to Kabat numbering and sequence numbering are listed in Table 7 of the section describing Fc modifications (IgG1 Fc modifications that enhance FcRn binding). Other modifications known in the art that confer enhanced or increased FcRn binding are also contemplated for use herein.

Compared to RB200 and RB242, modifications to the Fc portion of the growth factor capture constructs provided herein that enhance FcRn binding and recycling increase the in vivo half-life of the therapeutic, thereby requiring lower doses and/or less frequent administration. administration and improve therapeutic efficacy. iii. Effect function

As described herein, immune effector functions mediated by IgG Fc include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC; also known as antibody-dependent cytotoxicity), and antibody-dependent cellular cytotoxicity. mediated phagocytosis (ADCP; also known as antibody-dependent cellular phagocytosis). The Fc region of the growth factor capture constructs herein may be mutated or modified, as discussed below and elsewhere herein, to eliminate, reduce, or enhance immune effector functions, including, for example, any one or more of CDC, ADCC, and ADCP .

Since the growth factor targeted by the growth factor capture construct exists in the form of a membrane protein and a free (ie, soluble) ligand, in some specific examples, the immune effector function of the Fc portion of the ECD/Fc fusion polypeptide (especially ADCC ) is retained. In alternative embodiments, other Fc regions in addition to the human IgGl Fc may be included in the ECD/Fc chimeric fusion polypeptides provided herein. For example, when effector function mediated by Fc/FcγR interactions is minimized, consider fusion with an IgG isotype that recruits complement or effector cells poorly and does not exhibit effector function, such as the Fc of IgG2 or IgG4. This approach may be used in situations where effector functions are not required or are detrimental, such as in the context of autoimmune and inflammatory diseases and conditions.

In certain examples the Fc portion can be modified to enhance or increase immune effector functions. This can be achieved, for example, by modifications that increase binding to Clq (for CDC) and/or certain activating FcγRs (eg, FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and FcγRIIIb). Fc regions modified to increase binding to Fc receptors may more effectively promote the destruction of cancer cells in patients, even when linked to ECD polypeptides. Antibodies destroy tumor cells through a variety of possible mechanisms, including, for example, anti-proliferation by blocking growth pathways, intracellular signaling leading to apoptosis, enhancing receptor down-regulation and/or turnover, ADCC, ADCP, CDC, and promoting adaptability immune response. Thus, in specific examples where the growth factor capture constructs herein are used to treat cancer, the Fc portion of the construct can be modified to enhance or increase immune effector functions. Table 8 (IgG1 Fc Modifications to Enhance Immune Effector Functions) in Section F.4.d.i.c) (Enhancement or Reduction/Elimination of Fc Immune Effector Functions) summarizes factors that increase binding to FcγR or C1q and thus enhance immune effector functions (including ADCC , ADCP and CDC), and provide corresponding modifications according to the sequence of the IgG1 heavy chain constant domain shown in SEQ ID NO: 9, according to Kabat numbering and sequence numbering. Any one or more of these modifications may be introduced into the IgGl Fc portion of the growth factor capture constructs provided herein, alone or in various combinations. Other modifications known in the art that confer enhanced or increased immune effector functions are also contemplated for use herein. The lists in the above sections describe IgG1 Fc modifications that enhance immune effector functions.

In alternative embodiments, the Fc portion of the growth factor capture constructs provided herein is modified to reduce or eliminate immune effector function. This can be achieved, for example, by modifications that reduce or eliminate binding to Clq (for CDC) and/or certain activating FcγRs (eg, FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and FcγRIIIb). This may be desirable, for example, where antagonism rather than killing of cells bearing the target antigen is desired, or where it is necessary to reduce undesirable or harmful immune effector functions, such as unwanted pro-inflammatory cytokine release and off-target In case of cytotoxicity. Thus, in specific examples where the growth factor capture constructs provided herein are used to treat chronic inflammatory and autoimmune diseases and disorders, such as RA, the Fc portion of the construct can be modified to reduce or eliminate immune effector functions. .

Table 9 (IgG1 Fc modifications that reduce or eliminate immune effector functions) in Section F.4.d.i.c) (Enhancement or reduction/elimination of Fc immune effector functions) summarizes the factors that reduce or eliminate binding to activating FcγR and/or C1q and therefore Immune effector functions (including ADCC, ADCP, and CDC) are reduced or eliminated, and exemplary IgG1 Fc modifications can be introduced in the Fc region of the growth factor capture constructs herein. This table provides reference to the sequence of the IgG1 heavy chain constant domain shown in SEQ ID NO: 9, with corresponding modifications according to Kabat numbering and sequence numbering. Any one or more of these modifications may be introduced into the IgGl Fc portion of the growth factor capture constructs provided herein, alone or in various combinations. Other modifications known in the art that reduce or eliminate immune effector functions are also contemplated for use herein.

The Fc portion of the growth factor capture constructs provided herein can also be modified to increase binding to inhibitory FcγRs, resulting in suppression of immune responses. Therapeutic antibodies with immunosuppressive Fc modifications would be advantageous for treating inflammatory diseases. Such mutations may be incorporated into the Fc portion of the growth factor capture constructs herein intended for use in the treatment of diseases and conditions that have an inflammatory component or cause or involvement, such as RA, as well as other inflammatory and Autoimmune diseases.

Modifications that increase binding to, or confer selective binding to, inhibitory FcγRIIb and/or FcγRI instead of FcγRIIIa can be engineered into the IgG1 Fc region of the growth factor capture constructs provided herein. Such modifications include, but are not limited to, one or more of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F, L351S/T366R/L368H/P395K and combinations thereof according to EU numbering. Table 11 in Section F.4.dii (IgG1 Fc Modifications to Increase Binding to Inhibitory FcγRIIb) shows the sequence of the IgG1 heavy chain constant domain with reference to that shown in SEQ ID NO: 9, corresponding to Kabat numbering and sequence numbering Displacement. These modifications are summarized above in the section describing IgG1 Fc modifications that increase binding to inhibitory FcγRIIb. 4. Compositions, therapeutic uses and treatment methods

Provide nucleic acid molecules encoding chimeric fusion polypeptides (ie, ECD/Fc) and growth factor capture agent constructs, and vectors containing these nucleic acid molecules. Also provided are cells containing vectors as described herein, and pharmaceutical compositions containing any of the growth factor capture agent constructs, encoding nucleic acid molecules, vectors, or cells described herein. The growth factor capture constructs herein are as described previously, for example, Sarup et al. (2008) Mol. Cancer Ther. 7(10):3223-3236; Gompels et al. (2011) Arthritis Research & Therapy 13:R161; Jin et al. 2009) Mol. Med. 15(1-2):11-20; and production and purification as described in U.S. Patent Publication No. 2010/0055093.

The multispecific (including bispecific) growth factor capture constructs herein contain two or more, especially two chimeric proteins, by combining two or more, especially two identical or different ECD polypeptides are produced by direct or indirect linkage to a multimerization domain. In some examples, where the multimerization domain is a polypeptide, such as an immunoglobulin Fc, the gene fusion encoding the ECD-multimerization domain chimeric polypeptide is inserted into an appropriate expression vector. The resulting ECD-multimerization domain chimeric proteins can be expressed in host cells transformed with recombinant expression vectors, particularly mammalian cells (e.g., HEK293T or CHO cells, or any other suitable mammalian cells described herein or known in the art). expressed in animal cells) and assemble into multimers, such as dimers, in which the multimerization domains interact to form multivalent polypeptides. The resulting chimeric polypeptide and the multimers formed therefrom may be purified by any suitable method known in the art, such as by affinity chromatography on a protein A or protein G column. Additionally or alternatively, other protein purification techniques may be used, including, for example, gel electrophoresis, dialysis, ion exchange chromatography, ethanol precipitation, HPLC (such as reverse phase HPLC), silica gel chromatography, heparin agarose chromatography, chromatofocusing, SDS-PAGE and ammonium sulfate precipitation. When two nucleic acid molecules encoding different ECD chimeric polypeptides are transformed into cells (such as HER1/Fc and HER3/Fc), the formation of homodimers and heterodimers will occur. Performance conditions can be adjusted so that heterodimer formation is more favorable than homodimer formation. For example, the ratio of nucleic acid molecules encoding different ECD chimeric polypeptides can be adjusted so that an excess of one nucleic acid molecule results in the formation of less homodimers. In addition, as mentioned above, the introduction of the pestle and mortar into the Fc monomer facilitates the formation of heterodimers rather than homodimers.

ECD chimeric polypeptides containing the Fc region can also be engineered to include tags with metal chelates or other epitopes, such as 6×His tag, c-myc tag, FLAG tag, maltose binding protein (MBP), gluten thione-S-transferase (GST) or thioredoxin (TRX). Tagged domains can be used for rapid purification by metal chelation chromatography and/or by antibodies and allow detection in activity depletion/blocking in Western blotting, immunoprecipitation or bioassays. a.Pharmaceutical composition

Provided herein are pharmaceutical compositions containing multiple specificities provided herein, such as bispecific growth factor capture constructs or encoding nucleic acid molecules. Pharmaceutical compositions containing isolated cells containing the nucleic acid molecules or vectors provided herein are also provided. Such compositions contain a therapeutically effective amount of a growth factor capture agent construct. Pharmaceutical compositions may be formulated in any conventional manner by mixing a selected amount of a growth factor capture construct or nucleic acid molecule with one or more physiologically acceptable carriers or excipients. Pharmaceutical compositions can be used in therapeutic, prophylactic and/or diagnostic applications. The concentration of active compound in the composition will depend on the rate of absorption, inactivation and excretion of the active compound, the schedule and amount of administration, and other factors known to those of ordinary skill in the art.

Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carrier known to one of ordinary skill in the art to be suitable for a particular mode of administration. The selection of the carrier or excipient is within the skill of the pharmaceutical professional and may depend on a number of parameters. Such parameters include, for example, the mode of administration (as well as systemic, oral, nasal, pulmonary, topical, topical, or any other mode) and the condition being treated. Pharmaceutical compositions including a therapeutically effective amount of a multispecific, such as bispecific growth factor capture construct or nucleic acid molecule described herein may also be provided in the form of a lyophilized powder that is reconstituted immediately prior to administration, such as with sterile water. .

The pharmaceutical compositions provided herein may be in various forms, such as solid, semi-solid, liquid, powder, aqueous solution or lyophilized form. The pharmaceutical compositions provided herein may be formulated for single dose (direct) administration, or for dilution or other modification. The concentration of compound in the formulation is effective to deliver an amount effective for the intended treatment when administered. Typically, the compositions are formulated for single dose administration. The compounds may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product. The form of the resulting mixture will depend on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. Effective concentrations are sufficient to improve the target condition and can be determined empirically. In order to formulate the composition, a certain weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in the selected vehicle at an effective concentration to alleviate or improve the target condition.

Methods for generating nucleic acids encoding growth factor capture agent constructs provided herein include those described in Section H. Section H also describes vectors and cells that can be used, as well as methods for protein expression and purification. The compositions, formulations, dosages, and methods of administration described in Section I can be adapted to produce compositions and formulations including the growth factor capture agent constructs and encoding nucleic acid molecules described herein. Dosages and methods of administration can be determined by the dosing practitioner and are known in the art and described elsewhere herein. b. Therapeutic uses and treatment methods

The multispecific (including bispecific) growth factor capture constructs provided herein may be used for any purpose known to one of ordinary skill in the art to use such molecules. For example, the growth factor capture constructs provided herein may be used for one or more of therapeutic, diagnostic, industrial and/or research purposes. In particular, the multispecific growth factor capture constructs provided herein may be used to treat various diseases and conditions involving CSR, including RTKs, particularly proteins of the HER family, including proteins described herein. HER signaling is implicated in the cause of various diseases and disorders, and any such disease or disorder is contemplated for treatment with the growth factor capture constructs provided herein.

The growth factor capture constructs and encoding nucleic acid molecules and pharmaceutical compositions provided herein can be used to treat anti-HER therapies (such as trastuzumab, cetuximab, gefitinib, erlotinib, and lappa). (as well as others described herein and/or known in the art), including but not limited to cancer and other proliferative diseases and conditions, angiogenesis-related diseases and conditions, rheumatoid arthritis and others Chronic inflammatory and autoimmune diseases and conditions, and neurodegenerative diseases and conditions of the central nervous system (CNS). By way of example, treatments using the growth factor capture constructs provided herein include, but are not limited to, treatment of angiogenesis-related diseases and conditions, inflammatory diseases and conditions, autoimmune diseases and conditions, neurodegenerative diseases, and cell proliferation. Related medical conditions. Such diseases and conditions include, for example, eye disease, atherosclerosis, vascular damage, Alzheimer's disease, cancer, smooth muscle cell-related conditions, rheumatoid arthritis (RA), and various autoimmune diseases.

Dosage levels and regimens can be determined based on known dosages and regimens, and if necessary, can be extrapolated based on changes in properties of the polypeptides and constructs provided herein, and/or can be determined empirically based on a variety of factors. Such factors include, for example, the individual's weight and general health, age, sex, and diet, as well as the activity of the specific compound used, time of administration, excretion rate, drug combination, severity and duration of the disease, and the patient's response to the disease. treatment and the judgment of the treating physician. The active ingredients are typically combined with a pharmaceutically effective carrier. The amount of active ingredient that can be combined with the carrier materials to produce single or multiple dosage forms will vary depending on the host treated and the particular mode of administration.

Dosage will depend on the specific disorder, disease, or condition being treated and on the particular individual. Typical dosages are similar to those of known anti-HER therapies, such as antibodies, including trastuzumab, cetuximab, pertuzumab, and panitumumab, and small molecule tyrosine kinase inhibitors, such as Gefitinib, erlotinib and lapatinib. For individuals, including humans and other animals, exemplary dosages range from about or 0.1 to 100 mg/kg, such as 1 mg/kg to about or 30 mg/kg, such as 5 mg/kg to 25 mg/kg. The dose can be determined based on the assumption that the average person has a mass of approximately 75 kg. Dosage may be adjusted for children, infants, and smaller adults.

After the patient's condition improves, if necessary, a maintenance dose of the compound or composition may be administered; and the dose, dosage form, or frequency of administration, or combination thereof, may be modified. In some cases, individuals may require long-term intermittent treatment upon recurrence of any disease symptoms or on a predetermined dose basis.

Treatment of diseases and conditions with the multispecific growth factor capture constructs provided herein may be accomplished by any suitable route of administration using suitable formulations as described herein, including but not limited to infusion, subcutaneous injection, and inhalation, or Intramuscular, intradermal, oral, topical, and transdermal administration.

Provided herein is a method of treating a HER-mediated or HER-related disease or condition, comprising testing an individual with the disease to identify which HER receptors are expressed or overexpressed, and selecting to target at least one, typically two HERs based on the results Receptor multispecific growth factor capture constructs. In a specific example, the disease is cancer. Examples of cancers for treatment herein include gliomas and cancers of the pancreas, stomach, head and neck, cervix, lung, colorectum, endometrial, prostate, esophagus, ovary, uterus, Bladder or breast cancer. Cancers that may be treated with the growth factor (HER ligand) capture constructs herein are generally those that express at least one HER receptor, and typically more than one HER receptor. Such cancers can be identified by any means known in the art for detecting HER manifestations. For example, HER2 performance can be assessed using commercially available diagnostic/prognostic assays, such as HercepTest™ (Dako). Immunohistochemistry (IHC) analysis was performed on paraffin-embedded tissue sections from tumor biopsies and met the HER2 protein staining intensity guidelines. Tumors that meet a score less than the threshold are characterized as not overexpressing HER2, while those that meet a score greater than or equal to the threshold are characterized as overexpressing HER2. In one example of treatment, tumors that overexpress HER2 are assessed as candidates for treatment with a multispecific growth factor capture agent construct, such as any provided herein.

In another specific example, the HER-mediated or HER-related disease or condition is an inflammatory or autoimmune disorder, particularly rheumatoid arthritis. Animal models of arthritis, such as the collagen-induced arthritis (CIA) mouse model, can be used to test the growth factor capture constructs provided herein. For example, reduced arthritis symptoms, including paw swelling, erythema, and joint stiffness, were observed in mice treated with the growth factor capture constructs herein (such as by local injection of the protein). Reductions in synovial angiogenesis and synovial inflammation were also observed.

The multispecific (including bispecific) growth factor capture constructs, encoding nucleic acid molecules and pharmaceutical compositions provided herein can be used to treat HER (ErbB)-related diseases or HER receptor-mediated diseases, which are HER receptors and or any disease, condition or disorder in which the ligand is associated with the cause, pathology or some aspect of its development. HER-related diseases for treatment include cancers such as glioma or pancreatic, gastric, head and neck, cervical, lung, colorectal, endometrial, prostate, esophageal, ovarian, uterine cancer , bladder cancer, kidney cancer or breast cancer. Other treatable diseases include noncancerous proliferative diseases, such as those involving proliferation and/or migration of smooth muscle cells, inflammatory or autoimmune diseases, skin conditions, and ophthalmic conditions. Diseases and conditions used to treat include, for example, rheumatoid arthritis, diabetic retinopathy, anterior eye disease, psoriasis, restenosis, stenosis, atherosclerosis, hypertension due to thickening of blood vessels, bladder, heart or other muscle enlargements. Thickness, bladder disease, endometriosis, and obstructive airway disease, as well as exposure to one or more neuregulin (NRG) ligands, such as NRG1 (including types I, II, and III), NRG2, and NRG3 and/or NRG4, or other HER family ligand-related (e.g., causes or aggravates) diseases or conditions. Examples of NRG-related diseases and diseases associated with other HER family ligands include neurological or neuromuscular diseases, including schizophrenia, Parkinson's disease and Alzheimer's disease, cardiomyopathies, preeclampsia, neurological diseases and cardiac disease Exhaustion.

Examples of treatable cancers include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies, such as squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non- Small cell lung cancer, lung adenocarcinoma and lung squamous carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, Liver cancer, breast cancer, colon cancer, rectal cancer, renal cell cancer, esophageal cancer, glioma, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, thyroid cancer, liver cancer, and head and neck cancer cancer.

With single-targeted anti-HER therapies, such as trastuzumab, cetuximab, and other antibodies described herein or known in the art, and small molecule tyrosine kinase inhibitors, such as gefitinib When administered, the multispecific growth factor capture agent constructs provided herein generally increase therapeutic efficacy and reduce drug resistance compared to erlotinib, lapatinib, and lapatinib. As described herein, resistance to single-targeted anti-HER therapies is associated with co-expression and/or up-regulation of other HER family members and over-expression of their ligands. The HER-ligand binding construct provided herein acts as a receptor decoy and sequesters multiple HER family ligands, preventing ligand-dependent receptor activation and downregulating abnormal HER family activity, thereby simultaneously inhibiting multiple ligand-induced HER family members. . This increases treatment efficacy and reduces the chance of drug resistance developing. 5. Combination therapy

Combination therapies may be used. Combination therapies include administration of the multispecific (including bispecific) growth factor capture constructs, nucleic acid molecules, and pharmaceutical compositions provided herein in combination with another agent or treatment, including radiation and surgery. Another agent or therapy can be administered concurrently with, before, after, or intermittently with the treatment provided herein. They can be separate compositions or co-formulations.

The multispecific, such as bispecific heteromultimeric growth factor capture constructs, nucleic acid molecules, and pharmaceutical compositions provided herein may be administered before, after, intermittently, or concurrently with one or more other treatment regimens or agents, including but not limited to Not limited to TNF antagonists/blockers, chemotherapeutic agents, single-targeted anti-HER therapies (including antibodies and tyrosine kinase inhibitors), anti-angiogenic agents, antibodies, cytotoxic agents, anti-inflammatory agents, interleukins, Growth inhibitors, antihormonal agents, cardioprotective agents, steroids, immunostimulants, immunosuppressants, biological or nonbiological disease-modifying antirheumatic drugs (DMARDs), treatments for infectious diseases (including antibodies), or other therapeutic agents. Specifically, the growth factor capture agent construct is administered together with the TNFR1/TNFR2 axis construct provided herein. It may also be administered with other anti-TNF therapies, including any of those described in the above sections or known to those of ordinary skill in the art.

The TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific constructs, nucleic acids, and other constructs provided herein can be administered in regimens with other anti-TNF therapies. Examples of anti-TNF therapies that may be used in combination therapies herein include, for example, conventional synthetic DMARDs such as methotrexate (MTX), hydroxychloroquine (HCQ; Plaquenil®), sulfasalazine (Azulfidine®), and leflunomide (Arava®); biologic DMARDs such as abatacept (Orencia®), anakinra (Kineret®), rituximab (Rituxan®, Truxima®, MabThera®), tocilizumab (Ali TNF Inhibitors/anti-TNF agents such as pegylated certolizumab (Cimzia®), infliximab (Remicade®), adalimumab (Humira®), golimumab (Simponi®) and Etanercept (Enbrel®). Combination therapy may also include immunotherapeutic drugs such as cyclosporine, methotrexate, adelithromycin or cisplatin and immunotoxins.

In specific examples, a growth factor capture construct provided herein is combined with a TNFR1 antagonist construct, a TNFR2 agonist construct, or a multispecific, such as a bispecific TNFR1 antagonist/TNFR2 agonist construct provided herein. for the treatment of any of the chronic inflammatory, autoimmune and/or neurodegenerative/demyelinating diseases and conditions described herein, particularly rheumatoid arthritis (RA) ).

In some examples, the growth factor capture constructs provided herein are administered with one or more anti-angiogenic agents. For example, anti-angiogenic factors can be small molecules or proteins (eg, antibodies, Fc fusions, or interleukins) that bind to growth factors or growth factor receptors involved in promoting angiogenesis. Examples of anti-angiogenic agents include, but are not limited to, antibodies that bind to vascular endothelial growth factor (VEGF) or to VEGF-R, RNA-based therapeutics that reduce the amount of VEGF or VEGF-R expressed, VEGF-toxin fusions, Regeneron VEGF Trap, Angiostatin (Plasminogen Fragment), Antithrombin III, Vasozyme, ABT-627, Bay 12-9566, BeneFin, Bevacizumab, Bisphosphonate, BMS-275291 , cartilage-derived inhibitor (CDI), CAI, CD59 complement fragment, CEP-7055, Col 3, combretastatin A-4, endostatin (collagen XVIII fragment), farnesyl transferase inhibitor, fibronectin Fragment, GRO-β, halofuginone, heparinase, heparin hexasaccharide fragment, HMV833, human chorionic gonadotropin (hCG), IM-862, interferon alpha, interferon beta, interferon gamma, interferon induction Protein 10 (IP-10), interleukin-12, kringle 5 (plasminogen fragment), marimastat, metalloproteinase inhibitors (e.g. TIMP), 2-methoxyestradiol, MMI 270 (CGS 27023A), plasminogen activator inhibitor (PAI), platelet factor-4 (PF4), prolinostat, prolactin 16 kDa fragment, proliferin-related protein (PRP), PTK 787/ZK 222594, retinoids, solistat, squalamine, SS3304, SU5416, SU6668, SU11248, tetrahydrocortisol-S, tetrathiomolybdate, thalidomide, thrombospondin-1 (TSP-1 ), TNP470, transforming growth factor beta (TGF-β), angiostatin, angiostatin (calreticulin chaperone fragment), ZS6126 and ZD6474.

In some examples, a growth factor capture agent construct provided herein is administered with one or more tyrosine kinase inhibitors and, optionally, a TNFR1/TNFR2 axis construct provided herein. Examples of tyrosine kinase inhibitors include, but are not limited to, quinazolines, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; Pyrazolopyrimidine; 4-(anilino)-7H-pyrrolo(2,3-d)pyrimidine; Curcumin (difertioylmethane, 4,5-bis(4-fluoroanilino) phthalimide); Tyfostin containing a nitrothiophene moiety; PD-0183805 (Warner-Lambert); antisense molecules (e.g., antisense molecules that bind to ErbB-encoding nucleic acids); quinine Phenolines (see, e.g., U.S. Patent No. 5,804,396); Tyfostin (see, e.g., U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-ErbB inhibitors such as C1-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); Imatinib mesylate (STI571, Gleevec®; Novartis); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); C1-1033 (Pfizer); EKB- 569 (Wyeth); semacenib (Sugen); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1 C11 (ImClone); gefitinib (Iressa®, ZD1839, AstraZeneca); and OSI -774 (sold under the trademark Tarceva®, OSI Pharmaceuticals/Genentech) or as described in any of the following patent publications: U.S. Patent No. 5,804,396 and International Application Publication Nos. WO 99/09016, WO 98/ No. 43960, No. WO 97/38983, No. WO 99/06378, No. WO 99/06396, No. WO 96/30347, No. WO 96/33978, No. WO 96/33979 and No. WO 96/33980 No.

Other compounds that may be used in combination therapy include steroids, such as angiogenic 4,9(11)-steroids and C21 oxidative steroids, angiostatin, endostatin, angiostatin, angiostatin and mammastatin, Angiopoietins, bacterial polysaccharide CM101 and antibody LM609 (see, e.g., U.S. Patent No. 5,753,230), thrombospondin (TSP-1), platelet factor 4 (PF4), interferons, metalloproteinase inhibitors, pharmacological agents, including AGM -1470/TNP-470, thalidomide and carboxylaminotriazole (CAI), corticosterone, such as in the presence of heparin or heparin fragments, anti-invasive factors, retinoic acid and paclitaxel, shark cartilage extract, anionic polyamides Or polyurea oligomers, oxindole derivatives, estradiol derivatives and thiazolopyrimidine derivatives.

Examples of anti-cancer antibodies that may be co-administered with the growth factor capture constructs provided herein include, but are not limited to, anti-17-IA cell surface antigen antibodies, such as edronocumab (sold under the trademark (Panorex®)); 4-1BB antibodies; anti-4Dc antibodies; anti-A33 antibodies, such as A33 and CDP-833; anti-α1 integrin antibodies, such as natalizumab; anti-α4β7 integrin antibodies, such as LDP-02; anti-αVβ1 integrin antibodies, Such as F-200, M-200 and SJ-749; anti-αVβ3 integrin antibodies such as abciximab, CNTO-95, Mab-17E6 and Medi-523 (sold under the trade name Vitaxin); anti-complement factor 5 (C5 ) antibodies, such as 5G1.1; anti-CA125 antibodies, such as ogovumab (sold under the trademark OvaRex®); anti-CD3 antibodies, such as vecilizumab (Nuvion®) and Rexomab; anti-CD4 antibodies, such as IDEC- 151. MDX-CD4 and OKT4A; anti-CD6 antibodies, such as Oncolysin B and Oncolysin CD6; anti-CD7 antibodies, such as HB2; anti-CD19 antibodies, such as B43, MT-103 and Oncolysin B; anti-CD20 antibodies, such as 2H7, 2H7.v16 , 2H7.v114, 2H7.v115, tositumomab (Bexxar®), rituximab (Rituxan®), and itumomab (Zevalin®); anti-CD22 antibodies such as epratizumab ( Lymphocide®); anti-CD23 antibodies, such as IDEC-152; anti-CD25 antibodies, such as basiliximab and Zenapax® (dalizumab); anti-CD30 antibodies, such as AC10, MDX-060 and SGN-30; anti-CD33 Antibodies, such as gemtuzumab ozogamicin (Mylotarg®), Oncolysin M, and Smart Ml 95; anti-CD38 antibodies; anti-CD40 antibodies, such as SGN-40 and tocilizumab; anti-CD40L antibodies, such as 5c8, Lulizumab monoclonal antibody (Antova) and IDEC-131; anti-CD44 antibody, such as bivacizumab; anti-CD46 antibody; anti-CD52 antibody, such as Campath® (alemtuzumab); anti-CD55 antibody, such as SC-1; anti-CD56 Antibodies, such as huN901-DM1; anti-CD64 antibodies, such as MDX-33; anti-CD66e antibodies, such as XR-303; anti-CD74 antibodies, such as IMMU-110; anti-CD80 antibodies, such as galiximab and IDEC-114; anti- CD89 antibodies, such as MDX-214; anti-CD123 antibodies; anti-CD138 antibodies, such as B-B4-DM1; anti-CD146 antibodies, such as AA-98; anti-CD148 antibodies; anti-CEA antibodies, such as cT84.66, labezumab and Pentacea®; anti-CTLA-4 antibodies, such as MDX-101; anti-CXCR4 antibodies; anti-EGFR antibodies, such as ABX-EGF, Erbitux® (cetuximab), panitumumab, IMC-C225, and Merck Mab 425 ; anti-EpCAM antibodies, such as Crucell's anti-EpCAM, ING-1 and IS-IL-2; anti-ephrin B2/EphB4 antibodies; anti-HER2 antibodies, such as Herceptin® (trastuzumab), pertuzumab and MDX -210; anti-FAP (fibroblast-activating protein) antibodies, such as cilozumab; anti-ferritin antibodies, such as NXT-211; anti-FGF-1 antibody; anti-FGF-3 antibody; anti-FGF-8 antibody; anti- FGFR antibodies; anti-fibrin antibodies; anti-G250 antibodies, such as WX-G250 and gereliximab (Rencarex®); anti-GD2 ganglioside antibodies, such as EMD-273063 and TriGem; anti-GD3 ganglioside antibodies, Such as BEC2, KW-2871 and Mitumomab; anti-gpIIb/IIIa antibodies, such as ReoPro; anti-heparinase antibodies; anti-HLA antibodies, such as Oncolym and Smart 1D10; anti-HM1.24 antibodies; anti-ICAM antibodies, such as ICM3 ; Anti-IgA receptor antibodies; anti-IGF-1 antibodies, such as CP-751871 and EM-164; anti-IGF-1R antibodies, such as IMC-A12; anti-IL-6 antibodies, such as CNTO-328 and isomumab; Anti-IL-15 antibodies, such as HuMax®-IL15 antibodies; anti-KDR antibodies; anti-laminin 5 antibodies; anti-Lewis Y antigen antibodies, such as Hu3S193 and IGN-311; anti-MCAM antibodies; anti-Muc1 antibodies, such as BravaRex and TriAb Anti-NCAM antibodies, such as ERIC-1 and ICRT; Anti-PEM antigen antibodies, such as Theragyn and Therex; Anti-PSA antibodies; Anti-PSCA antibodies, such as IG8; Anti-Ptk antibodies; Anti-PTN antibodies; Anti-RANKL antibodies, such as AMG-162; Anti-RLIP76 antibodies; anti-SK-1 antigen antibodies, such as Monopharm C; anti-STEAP antibodies; anti-TAG72 antibodies, such as CC49-SCA and MDX-220; anti-TGF-β antibodies, such as CAT-152; anti-TNF-α antibodies, such as CDP571, CDP870, D2E7, adalimumab (Humira®) and infliximab (Remicade®); anti-TRAIL-R1 and TRAIL-R2 antibodies; anti-VE-cadherin 2 antibody; and anti-VLA-4 antibody, Such as Antegren® antibodies. Anti-idiotypic antibodies may be used, including, but not limited to, GD3 epitope antibody BEC2 and gp72 epitope antibody 105AD7. Bispecific antibodies may also be used, including but not limited to the anti-CD3/CD20 antibody Bi20.

Examples of antibodies that may be co-administered with the growth factor capture constructs provided herein include, but are not limited to, anti-α4β7 integrin antibodies, such as LDP- 02; Anti-β2 integrin antibodies, such as LDP-01; Anti-complement (C5) antibodies, such as 5G1.1; Anti-CD2 antibodies, such as BTI-322 and MEDI-507; Anti-CD3 antibodies, such as OKT3 and SMART Anti-CD3; Anti-CD3 CD4 antibodies, such as IDEC-151, MDX-CD4, and OKT4A; anti-CD11a antibodies; anti-CD14 antibodies, such as IC14; anti-CD18 antibodies; anti-CD23 antibodies, such as IDEC-152; anti-CD25 antibodies, such as Zenapax; anti-CD40L antibodies, such as 5c8, Antova, and IDEC-131; anti-CD64 antibodies, such as MDX-33; anti-CD80 antibodies, such as IDEC-114; anti-CD147 antibodies, such as ABX-CBL; anti-E-selectin antibodies, such as CDP850; anti-gpIIb/IIIa antibodies , such as ReoPro®/Abcixima; anti-ICAM-3 antibody, such as ICM3; anti-ICE antibody, such as VX-740; anti-FcγR1 antibody, such as MDX-33; anti-IgE antibody, such as rhuMAb-E25; anti-IL-4 antibody, such as SB-240683; anti-IL-5 antibodies, such as SB-240563 and SCH55700; anti-IL-8 antibodies, such as ABX-IL8; anti-interferon gamma antibodies; anti-TNFα antibodies, such as CDP571, CDP870, D2E7, adalimumab, Infliximab and MAK-195F; and anti-VLA-4 antibodies such as Antegren. Examples of other Fc-containing molecules that may be co-administered to treat autoimmune or inflammatory diseases, transplant rejection, and GvHD include, but are not limited to, the TNFRI receptor/Fc fusion Enbrel® (etanercept) and Regeneron's IL- 1 capture agent.

Examples of antibodies that may be co-administered to treat infectious diseases include, but are not limited to, anti-anthrax antibodies, such as ABthrax; anti-CMV antibodies, such as CytoGam and sevelumab; anti-Cryptosporidium antibodies, such as CryptoGAM and Sporidin-G; anti-Helix bacillus antibodies, such as Pyloran; anti-hepatitis B antibodies, such as HepeX-B and Nabi-HB; anti-HIV antibodies, such as HRG-214; anti-RSV antibodies, such as panvelizumab, HNK-20, palivizumab and RespiGam; and anti-staphylococcal antibodies such as Aurexis, Aurograb, BSYX-A110 and SE-Mab.

In some examples, a growth factor capture construct described herein is administered with one or more chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piperosulfan; Hormones, such as carotesterone, drostanolone propionate, cyclothiandrostenol, mestandrostane, and testolactone; anti-adrenergics, such as amineglutethimide, mitotane, and trolostane; anti-androgens, such as Flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; antibiotics such as aclarithromycin, actinomycin, azomycin, azoserine, and bleomycin , actinomycin C, calicheamicin, carrubicin, erythromycin, carcinogen, chromomycin, dactinomycin, daunorubicin, ditobicin, 6-diazo-5- Side-oxygen-L-norleucine, doxorubicin, epirubicin, esopubicin, idarubicin, masiciromycin, mitomycin, mycophenolic acid, nogaramycin, olive Mycomycin, pelomycin, pofilomycin, puromycin, quinamycin, rhodobicin, streptozotocin, streptozocin, tuberculin, ubenimex, netinostat and levorubicin; antiestrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trovoxifen, raloxifene Fen, LY 117018, onapristone and toremifene (Fareston); antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as dinotrin, methotrexate aziridines, such as benzotepa, carboquinone, metotepa and uretipa; ethyleneimines and methylmelamines, including hexamelamine and triptamide , triethylphosphatide, triethylthiophosphatamide, and trimethylolmelamine; folic acid supplements, such as aldehyde folic acid; nitrogen mustards, such as chlorambucil, naphthyl mustard, and chlorambucil. Amine, estramustine, ifosfamide, dichloromethyldiethylamine, dichloromethyldiethylamine oxide hydrochloride, melphalan, nitrogen mustard, mustard cholesterol, prednimol Stetine, trofosfamide, and uracil mustine; nitrosoureas such as carmustine, chlortrimethrin, formostine, lomustine, nimustine, and ramomustine; platinum analogs substances, such as cisplatin and carboplatin; vinblastine; platinum; proteins, such as arginine deiminase and aspartase; purine analogs, such as fludarabine, 6-mercaptopurine, thiomidine and thioguanine; pyrimidine analogs, such as amcitabine, azacitidine, 6-azuridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enoxitabine , floxuridine, and 5-FU; taxanes, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); topology Isomerase inhibitors, such as RFS 2000; thymidylate synthase inhibitors, such as Tomudex; additional chemotherapeutic agents, including acetate glucuronide; aldehyde phosphatide glycosides; aminoacetate; amsacridine; Besbucil; Bisantrene; Edatroxate; Desfosamide; Demecocin; Diaquinone; Difluoromethylornithine (DMFO); Eflornithine; Eriacetonium; Etogle Lu; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguanhydrazone; mitoxantrone; mopandol; nitroacridine; pentostatin; belamet; pirarubicin; Podophyllic acid; 2-ethyl hydrazine; procarbazine; PSK®; Razoxane; Cizoran; Spirogermanium; Alternaria; Triiminoquinone; 2,2',2"-Trichloro Triethylamine; urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcolol; piperobromide; garcitocin; arabinoside ("Ara-C"); Cyclophosphamide; thiotepa; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunorubicin; Aminopterin; Xeloda; Ibandronate; CPT-11; Retinoic acid; Espelamycin; capecitabine; and topoisomerase inhibitors, such as irinotecan. Pharmaceutically acceptable salts, acids or derivatives of any of the above may also be used.

Chemotherapeutic agents can be administered as prodrugs. Examples of prodrugs that may be administered with the growth factor capture agent constructs described herein include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-containing prodrugs, -Amino acid modified prodrugs, glycosylated prodrugs, beta-lactam containing prodrugs, optionally substituted phenoxyacetamide containing prodrugs or optionally substituted phenylacetamide containing prodrugs drugs as well as 5-fluorocytosine and other 5-fluorouridine prodrugs, which can be converted into more active non-cytotoxic drugs.

In some examples, the multispecific growth factor capture constructs described herein are administered with one or more immunomodulators. Such agents may increase or decrease the production of one or more interleukins, up-regulate or down-regulate self-antigen presentation, mask MHC antigens, or promote proliferation, differentiation, migration or activation of one or more types of immune cells. Examples of immunomodulators include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, celecoxib, diclofenac, etodolac, fenoprofen, indomethacin, ketorolac, oroxygen. Shaprozine, nabumetone, sulindac, tolmetin, rofecoxib, naproxen, ketoprofen, and nabumetone; steroids, such as glucocorticoids, dexamethasone, corticosterone, hydroxy Corticosterone, methylpresomethonium, prexamethonone, premisoside, and triamcinolone; eicosanoids, such as prostaglandins, thromboxane, and leukotrienes; topical steroids, such as anthratriol, calcipotriol , becloxazone and tazarotene; interleukins, such as TGFβ, IFNα, IFNβ, IFNγ, IL-2, IL-4, IL-10; interleukins, chemokines or receptor antagonists, including For BAFF, B7, CCR2, CCR5, CD2, CD3, CD4, CD6, CD7, CD8, CD11, CD14, CD15, CD17, CD18, CD20, CD23, CD28, CD40, CD40L, CD44, CD45, CD52, CD64, CD80 , CD86, CD147, CD152, complement factors (C5, D) CTLA-4, eosin, Fas, ICAM, ICOS, IFNα, IFNβ, IFNγ, IFNAR, IgE, IL-1, IL-2, IL-2R , IL-4, IL-5R, IL-6, IL-8, IL-9 IL-12, IL-13, IL-13R1, IL-15, IL-18R, IL-23, integrin, LFA-1 , LFA-3, MHC, selectins, TGFβ, TNFα, TNFβ, TNFR1, TNFR2 and T cell receptor antibodies, soluble receptors and receptor-Fc fusions, including etanercept (Enbrel®), adalimumab monoclonal antibodies (Humira®) and infliximab (Remicade®); allogeneic anti-lymphocyte globulin; and other immunomodulatory molecules, such as 2-amino-6-aryl-5 substituted pyrimidines, MHC-binding peptides and Anti-idiotypic antibodies against MHC fragments, azathioprine, buquinar, bromocriptine, cyclophosphamide, cyclosporine A, D-penicillamine, desoxyspignatin, FK506, glutaraldehyde, gold , hydroxychloroquine, leflunomide, malonitramide (such as leflunomide), methotrexate, minocycline, mizoribine, mycophenolate mofetil, rapamycin, and Azasulfapyridine.

In some examples, the multispecific growth factor capture constructs described herein are administered with one or more interleukins. Examples of interleukins include, but are not limited to, lymphoid mediators, monokines, and traditional polypeptide hormones. Interleukins include interferons, such as interferon alpha, beta, and gamma; community stimulating factors (CSF), such as macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), and Granule-CSF (G-CSF); interleukins (IL), such as IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, and IL-15; tumor necrosis factors, such as TNF-α or TNF-β; and other peptide factors, including LIF and kit ligand (KL ).

In some examples, the multispecific growth factor capture constructs described herein are administered with one or more interleukins or other agents that stimulate immune system cells and enhance desired effector functions. For example, agents that stimulate natural killer (NK) cells, including but not limited to IL-2, can be administered with the multispecific growth factor capture constructs described herein. In another specific example, agents that stimulate macrophages include, but are not limited to, C5a and formyl peptides, such as N-formyl-methionyl-methionyl-phenylalanine (see, e.g., Beigier-Bompadre (2003) Scand. J. Immunol . 57:221-228), can be administered with the multispecific growth factor capture agent constructs described herein. Agents that stimulate neutrophils include, but are not limited to, G-CSF and GM-CSF, and may also be administered with the multispecific growth factor capture constructs described herein. Agents that promote the migration of such immunostimulatory interleukins can be administered with the multispecific growth factor capture constructs described herein. Additional agents include, but are not limited to, interferon gamma, IL-3, and IL-7, which may promote one or more effector functions. In some examples, the multispecific growth factor capture constructs described herein are administered with one or more interleukins or other agents that inhibit effector cell function.

In some examples, the multispecific growth factor capture constructs described herein are administered with one or more antibiotics, including but not limited to: aminoglycoside antibiotics (e.g., apramycin, arbekacin, Bamber (mycin, buteroxin, dibekacin, gentamicin, conmycin, neomycin, netimycin, paromomycin, ribomycin, sisomicin and spectinomycin), amines cycloalcohols (such as spectinomycin), aminoacyl antibiotics (such as chloramphenicol azide, chloramphenicol, florfenicol and tomacin), ansamycin antibiotics (such as riformide and rifamycin). Fupin), carbapenems (such as imipenem, meropenem and panipenem), cephalosporins (such as cefaclor, cefadroxylin, cefamandole, ceftriazin, cefoxidone, Cefazolin, ceftizole, cefpiramide, cefpirome, cefprozil, cefuroxime, cefixime, cephalexin and cefradine), cephalosporins (such as cefprazone, cefoxitin, cefminox, cefmetazole and cefotetan), lincosamides (such as clindamycin and lincomycin), macrolides (such as azithromycin, brefeldin A, clarithromycin, erythromycin , roxithromycin and tobramycin), monomycins (such as antronam, carumonan, and tigemonan), mupirocin, oxycephems (such as flurocephalosporin, laoxycephalosporin and laoxycephalosporin), penicillins (such as amdenocillin, amdenocillin bislipid, amoxicillin, bampicillin, benzylpenicillic acid, benzylpenicillin sodium, epipicillin, phenylin Becillin, flucloxacillin, penacillin, pensacillin hydriodate, benzethylamine penicillin, penicillin O, penicillin V, penicillin benzoate V, hydampenicillin V, penicillin and phenoxyethyl Penicillin potassium), peptides (such as subtilisin, colistin, polymyxin B, teicoplanin and vancomycin), quinolinones (such as amloxacin, cinofloxacin, ciprofloxacin , enoxacin, enrofloxacin, flerofloxacin, flumequine, gatifloxacin, gemifloxacin, gpafloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin , ofloxacin, oxorinic acid, pefloxacin, piperamic acid, roxoxacin, rofloxacin, sparfloxacin, temafloxacin, tosufloxacin and trovafloxacin) , rifampicin, streptozotocins (such as quinupristin and dalfopristin), sulfonamides (such as p-aminobenzenesulfonamide and sulfamethoxazole) azoles) and tetracyclines (such as chlortetracycline, demeclocycline hydrochloride, demeclocycline, doxycycline, duramycin, minocycline, neomycin, oxytetracycline, streptomycin, tetracycline and vancomycin).

In some examples, the multispecific growth factor capture constructs provided herein are administered with one or more antifungal agents, including, but not limited to, amphotericin B, ciclopirox, clotrimazole, econazole, Fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, nystatin, terbinafine, terconazole and tioconazole.

In some examples, the multispecific growth factor capture constructs described herein are administered with one or more antiviral agents, including, but not limited to, protease inhibitors, reverse transcriptase inhibitors, and others, including type I interferons. , viral fusion inhibitor, neuraminidase inhibitor, acyclovir, adefovir, amantadine, amprenavir, clevudine, enfuvirtide, entecavir, foscarnet, ganci Lovir, iodine glycoside, indinavir, lopinavir, praconali, ribavirin, amantadine, ritonavir, saquinavir, trifluridine, vidarabine and zidovudine.

The multispecific growth factor capture constructs provided herein can be combined with other treatment options. For example, in one specific example, a patient to be treated with the multispecific growth factor capture constructs provided herein may receive radiation therapy. Radiation therapy may be administered according to protocols commonly used in the art and known to those of ordinary skill in the art. Such therapies include, but are not limited to, cesium, iridium, iodine or cobalt radiation. Radiation therapy may be total body irradiation, or may be directed locally to specific areas or tissues in or on the body, such as the lungs, bladder, or prostate. Radiation therapy may also include treatment with isotope-labeled molecules, such as antibodies. Examples of radioimmunotherapeutic agents include those sold under the trademarks Zevalin® (Y-90-labeled anti-CD20), LymphoCide® (Y-90-labeled anti-CD22), and Bexxar® (I-131-labeled anti-CD20).

Typically, radiation therapy is administered in pulses over a period of about 1 to 2 weeks. However, radiation therapy can be given over a longer period of time. For example, radiation therapy may be administered to a patient with head and neck cancer for about 6 to about 7 weeks. Radiation therapy may be given as a single dose or as multiple consecutive doses, as needed. The skilled practitioner can empirically determine the appropriate dose or doses for use in the radiation therapy herein. In some examples, multispecific growth factor capture agent constructs and optionally one or more other anti-cancer therapies are used to treat cancer cells in vitro. Such ex vivo treatments are contemplated for use in bone marrow transplantation, and particularly autologous bone marrow transplantation. For example, treatment of cancer cell-containing cells or tissues with a multispecific growth factor capture agent construct and one or more anti-cancer therapies, such as described herein, can be used to deplete or substantially deplete the recipient patient prior to transplantation cancer cells.

Additionally, it is contemplated that the multispecific growth factor capture constructs provided herein may be administered to a patient or individual in combination with other treatment techniques, such as surgery or phototherapy.

For example, provided herein is a method of treating cancer by administering any of the multispecific growth factor capture constructs, nucleic acid molecules, or pharmaceutical compositions provided herein in combination with another anti-cancer agent. . Anti-cancer agents may include radiation and/or chemotherapeutic agents. For example, the anti-cancer agent can be a tyrosine kinase inhibitor or an antibody. Exemplary anti-cancer agents include quinazoline kinase inhibitors, antisense or siRNA or other double-stranded RNA molecules, antibodies that interact with HER family receptors, and antibodies conjugated to radionuclides or cytotoxins. Other exemplary anti-cancer agents include gefitinib, lapatinib, erlotinib, panitumumab, cetuximab, trastuzumab, imatinib, platinum complexes, or nucleosides Analogues. Examples of cytotoxic or chemotherapeutic agents include, for example, taxanes (such as paclitaxel and docetaxel) and anthracycline antibiotics, doxorubicin/adelinomycin, erythromycin, daunorubicin, Aminopterin, methotrexate, methotrexate, methotrexate, mitomycin C, pofiromycin, 5-fluorouracil, 6-mercaptopurine, A Glycocytidine, podophyllotoxin or podophyllotoxin derivatives such as etoposide or etoposide phosphate, melphalan, vinblastine, vincristine, isovincristine, vindesine, epoxyvinblastine, vinblastine Dentinol, epothilone A or B, paclitaxel, estramustine, cisplatin, combretastatin and analogs and cyclophosphamide. Any of the other anti-cancer antibodies and chemotherapeutic agents described elsewhere herein or known in the art are also contemplated for use in combination with the multispecific growth factor capture constructs, nucleic acid molecules, or pharmaceutical compositions provided herein. Treat cancer.

In another example, provided herein is a method of treating rheumatoid arthritis (RA) by combining any of the multispecific growth factor capture constructs, nucleic acid molecules, or pharmaceutical compositions provided herein Administer in combination with another antirheumatic drug (such as anti-TNF therapy). Examples of anti-TNF therapies that may be used in combination with the multispecific growth factor capture constructs, nucleic acid molecules, or pharmaceutical compositions provided herein include conventional synthetic DMARDs such as methotrexate (MTX), hydroxychloroquine (HCQ; Plaquenil ®), sulfasalazine (Azulfidine®), and leflunomide (Arava®); biologic DMARDs such as abatacept (Orencia®), anakinra (Kineret®), rituximab (Rituxan or Triamcinolone), tofacitinib (Xeljanz®), and TNF inhibitors/anti-TNF agents such as pegylated certolizumab (Cimzia®), infliximab (Remicade®), adalimumab (Humira®), golimumab (Simponi®), and etanercept (Enbrel®). Combination therapy may also include immunotherapeutic drugs such as cyclosporine, methotrexate, adelithromycin or cisplatin and immunotoxins.

Also provided herein is a method for treating chronic inflammatory, autoimmune, neurodegenerative and/or demyelinating diseases described elsewhere herein, particularly RA, by administering multiple specific Any of the sexual growth factor capture constructs and any of the TNFR1 antagonist, TNFR2 agonist, or bispecific TNFR1 antagonist/TNFR2 agonist constructs provided herein. If necessary, additional anti-TNF therapy may also be administered, such as methotrexate, or any of those described above or elsewhere herein or known in the art, and may be administered for use in the treatment of chronic inflammatory, autoimmune, or chronic inflammatory disease. Any other therapy for immune, neurodegenerative and/or demyelinating diseases, such as immunosuppressants, anti-angiogenic agents, cardioprotective agents, antibodies, cytotoxic agents, anti-inflammatory agents, interleukins, growth inhibitors, Chemotherapeutic agents, biological or nonbiological disease-modifying antirheumatic drugs (DMARDs), treatments for infectious diseases (including antibodies), or other suitable therapeutic agents described herein or known in the art.

Angiogenesis plays a key role in the formation and maintenance of pannus in RA. The multispecific growth factor capture constructs provided herein can be used in combination with other treatments to modulate angiogenesis. For example, angiogenesis inhibitors can be used in combination with the multispecific growth factor capture agent constructs provided herein to treat RA. Exemplary angiogenesis inhibitors include, but are not limited to, angiostatin, anti-angiogenic antithrombin III, angiostatin, cartilage-derived inhibitors, fibronectin fragments, IL-12, angiostatin, and those skilled in the art. Other angiogenesis inhibitors are known and described elsewhere herein.

In some specific examples, the growth factor trap constructs provided herein are used in combination with TNF blockers and/or other DMARDs, such as methotrexate, and compared to standard of care RA therapy. For example, the growth factor capture constructs provided herein can be combined with etanercept and/or methotrexate, such as suboptimal doses of etanercept and/or methotrexate. To assess effectiveness, the combination may be a separate regimen of etanercept and/or methotrexate, including optimal and suboptimal doses of etanercept and/or methotrexate. Growth factor capture constructs allow lower doses of other treatments, thereby reducing undesirable or undesirable side effects. In other embodiments, the growth factor trap constructs provided herein can be combined with other anti-TNF therapies, such as adalimumab or infliximab, with or without methotrexate (including sub-optimal doses of methotrexate). combinations of monoclonal antibodies (including the next best dose) and therapeutic efficacy compared with treatment with anti-TNF therapy alone with or without methotrexate. In another specific example, a growth factor capture construct provided herein can be combined with a TNFR1 antagonist, TNFR2 agonist, or multispecific, such as a bispecific TNFR1 antagonist/TNFR2 agonist construct provided herein. Either were combined and compared to standard of care RA therapies such as etanercept, adalimumab or infliximab with or without methotrexate. H. Assessment of TNFR1 Antagonist and TNFR1 Antagonist /TNFR2 Agonist Construct Activity and Efficacy

If desired or necessary, the activity and efficacy of the constructs provided herein can be assessed using any in vivo and/or in vitro assay known to one of ordinary skill in the art to assess the properties and/or therapeutic specificity of the construct. Suitability for a disease, disease or condition. Such assays may also be used to monitor treatment and/or predict response or select individuals for treatment. Exemplary analytical methods are described in the following sections.

Generally speaking, antagonist constructs as used herein are non-competitive constructs; they are generally constructs that lock the receptor in an inactive configuration, which, as discussed above, means selecting for high affinity versus selecting for antagonists Activity is less important. 1. Disease Activity Score ( DAS28 )

The Disease Activity Score at 28 joints (DAS28; or Disease Activity Score at 28 joints) is a measure of disease activity in rheumatoid arthritis (RA) and is a simplification of the original DAS score that required counting 44 joints. The 28 joints counted included proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10 joints), wrist (2), elbow (2), shoulder (2), and knee ( 2). DAS28 is indicative of RA disease activity and response to treatment, and is therefore used in clinical trials evaluating RA therapeutics. DAS28 is based on counting 28 swollen and tender joints and is scored on a scale of 0-10, with higher values indicating greater disease activity. In addition to counting the number of swollen and tender joints (28 in total), DAS28 includes measurements of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), which are acute phase reactants/blood markers of inflammation, as well as general health status (GH) rating, which represents the patient's self-assessment of disease activity, is scored on a 100 mm visual analog scale (VAS), with a value of 0 meaning "no activity" and a value of 100 meaning "highest possible activity." The DAS28 is often combined with other measures of disease severity, such as pain and grip strength, and uses the Health Assessment Questionnaire (HAQ) to assess physical function.

To calculate the DAS28 value using ESR or CRP levels, use the following formula respectively : DAS28(ESR) = 0.56 x √(TJC28) + 0.28 x √(SJC28) + 0.014 x GH + 0.70 x ln(ESR); DAS28 (CRP) = 0.56 x √(TJC28) + 0.28 x √(SJC28) + 0.014 x GH + 0.36 x ln(CRP+1) + 0.96; where TJC = tender joint count and SJC = swollen joint count.

A value < 2.6 indicates remission, a value ≤ 3.2 (> 2.6 but ≤ 3.2) indicates low disease activity, a value > 3.2 but ≤ 5.1 indicates moderate disease activity, and a value greater than 5.1 indicates high disease activity (i.e., active disease). Improvement (ie, decrease in DAS28 score/value) >1.2 indicates good response/improvement; improvement >0.6 to ≤1.2 indicates moderate response; and decrease in DAS28 ≤0.6 indicates no improvement (see e.g. Prevoo et al. (1995) Arthritis & Rheumatism 38( 1):44-48; Wells et al. (2009) Ann. Rheum. Dis. 68:954-960).

The therapeutic efficacy of the selective TNFR1 antagonists, TNFR2 agonists and/or bispecific constructs containing combinations thereof provided herein can be assessed by calculating DAS28 (ESR) or DAS28 (CRP) before, during and after treatment. . 2. ^SOMAscan® proteosome analysis and other proteosome tools for quantifying analytes

The ^SOMAscan® proteosome analysis method (SomaLogic, Inc.; Boulder, CO.) is a versatile, sensitive, quantitative and reproducible aptamer-based proteosome analysis tool that can simultaneously measure samples as small as 150 µL ( The number of over 5,000 protein analytes in such products as serum, plasma or cerebrospinal fluid). Other biological matrices may also be used, such as cell culture supernatants, cell and tissue lysates, synovial fluid, and bronchoalveolar and nasal lavage fluids. With the ability to simultaneously quantify a broad range of protein targets, the SOMAscan® assay is optimized for protein biomarker discovery and has been used to identify biomarker signatures associated with several diseases, including, for example, non-small cell Lung cancer, Alzheimer's disease, cardiovascular disease and inflammatory bowel disease. The SOMAscan® assay can be used to determine, for example, protein signatures in RA patients by analyzing samples taken before and after initiation of treatment with the TNFR1 antagonists, TNFR2 agonists and bispecific constructs provided herein. In this way, patient response can be monitored at early treatment time points and throughout the course of treatment.

The SOMAscan® assay uses protein capture reagents called slow off-rate modified aptamers (sold as SOMAmer® aptamers) reagents, which are short, single-stranded DNA-based protein affinity reagents composed of molecules that mimic amino acid side chains. Chemically modified nucleotide constructs that have slow dissociation rates and allow specific, high-affinity binding to protein targets. The assay measures proteins in their native, folded configuration (i.e., tertiary structure) but does not detect unfolded and denatured (i.e., inactivated) proteins. For the SOMAscan® assay, the SOMAmer®-protein binding step is followed by a series of partitioning and washing steps, whereby each individual protein concentration is converted into the corresponding SOMAmer® reagent concentration (based on the DNA signal of the SOMAmer®), which is then Standard DNA detection techniques such as microarrays or qPCR are used to quantify proteins in biological samples. This assay exploits the dual nature of the SOMAmer reagent, which acts as an affinity-binding reagent for proteins with a well-defined three-dimensional structure and contains a unique nucleotide sequence that can be recognized by a specific DNA hybrid probe.

SOMAmer® reagents are prepared with three tags and contain a fluorophore linked to biotin via a photocleavable linker. Briefly, for the assay, relevant biological samples were diluted and subsequently incubated with the corresponding SOMAmer® reagent mixture pre-immobilized on avidin (SA)-coated beads. SOMAmer® reagents bind to proteins in biological samples, and the beads are washed to remove unbound proteins. Any nonspecific complexes formed have a rapid dissociation rate. Proteins still bound to the cognate SOMAmer® reagent are tagged using NHS-Biotin Reagent, and a polyanionic competitor solution is added to resolve any non-specific complexes. The protein-SOMAmer® complex and unbound (free) SOMAmer® reagent are released from the avidin beads by cleaving the photocleavable linker using UV light. The photocleaved eluate containing all SOMAmer® reagents (some bound to the biotinylated protein and some free) is then incubated with a second avidin-coated bead, which binds the biotinylated protein and biotin The protein-SOMAmer® complex is oxidized and unbound material is removed by subsequent washing steps. In the final elution step, denaturing conditions are used to release the protein-bound SOMAmer® reagent from its cognate protein and by standard DNA quantification techniques, such as by hybridization to a custom DNA microarray and measurement of fluorescence Group labels to quantify SOMAmer® reagents. Data are reported in relative fluorescence units (RFU) after normalization and calibration, and the measured SOMAmer® reagent signal is related to the protein levels found in the biological sample (see e.g. Gold et al. (2010) PLoS ONE 5(12): e15004; Candia et al. (2017) Sci. Reports 7:14248; Tanaka et al. (2018) Aging Cell. 17:e12799). 3. Total transcript analysis to predict response to therapy and select individuals who may benefit from treatment

Traditional anti-TNF therapies, namely TNF blockers, such as etanercept, infliximab and others are associated with approximately 30% unresponsiveness in RA patients. However, there are clinical markers that predict the efficacy of these anti-TNF therapies. Genes differentially expressed following anti-TNF therapy with etanercept have been analyzed using global total transcript profiling that characterizes RNA expression in peripheral blood mononuclear cells (PBMCs). Similar total transcript analysis can be performed to assess the efficacy of, and/or assess patient responsiveness to, the TNFR1 antagonists and TNFR1 antagonist/TNFR2 agonist constructs herein.

In an exemplary protocol, blood samples are obtained from patients before and after treatment, and PBMCs are isolated using Ficoll density gradients, followed by assessment of CD3 ⁺ , CD14 ⁺ , CD19 ⁺ , and CD56 ⁺ cell populations using flow cytometry. Total RNA is then extracted, for example using the Qiagen ^RNeasy® kit, and the expression profile of tens of thousands of known genes in the PBMC is analyzed using microarray analysis (for example using Affymetric® microarray technology) to identify responder/non-responder profiles. Gene expression profiles can be determined in the early stages of treatment to rapidly identify non-responders. For example, by using this method to identify reliable biomarkers for predicting the therapeutic efficacy of etanercept in RA patients, gene pairs with prediction accuracy > 89% and genes with prediction accuracy > 95% were identified triplet. Such genes include, for example, genes involved in TNF signaling via the NF-кB pathway, genes involved in NF-кB-independent signaling, and genes involved in regulating cellular and oxidative stress responses. For example, the gene triplets identified include TNFAIP3 , which encodes TNFα-induced protein 3, a zinc finger protein shown to inhibit NF-кB activation; PDE4B , which encodes a protein involved in NF-кB-independent signaling ( cAMP)-specific cyclic nucleotide phosphodiesterase; and RAPGEF1 , which encodes Rap guanine nucleotide exchange factor 1, an activator of RAS signaling. Expression of all three of these genes was downregulated 3 days after administration of etanercept to responders compared with non-responders. Other genes evaluated included CCL4 , CXCR4 , CCL3 , PIGO , FSD1 , RUNX1 , LGALS13 , PTPRD , IL1B , ADAM12 and HCG4P6 (see, eg, Koczan et al. (2008) Arthritis Research & Therapy 10:R50).

The expression of a subset of relevant genes can be measured by quantitative real-time PCR (RT-PCR) using pre-designed primers and probes to verify the results obtained by microarray analysis. To calculate changes in gene expression for selected genes, the ΔΔC _T method can be used, whereby the critical cycle (C _T ) value for a specific mRNA expression in a sample is normalized to the C _T value for, for example, GAPDH mRNA in the sample, and the gene expression change ( ΔΔC _T ) is defined by the difference in C _T values after treatment and before treatment (see, eg, Koczan et al. (2008) Arthritis Research & Therapy 10:R50). 4. L929 Cytotoxicity Assay

TNFRl -mediated processes and cellular responses can be determined, for example, by assessing TNF-induced cell death using the L929 cytotoxicity assay, where TNFRl antagonists inhibit TNF-induced cytotoxicity. Briefly, L929 mouse fibroblasts were seeded in microtiter plates and incubated overnight with TNFR1 antagonist, 100 pg/ml TNF, and 1 mg/ml actinomycin D. Cell viability is enhanced by binding to 3-(4,5-dimethylthiazol-2-yl)-5-(3-hydroxymethoxyphenyl)-2-(4-sulfophenyl)-2H- After incubation with tetrazolium (MTS), the absorbance was measured at 490 nm. TNFR1 antagonists reduce TNF-mediated cytotoxicity, resulting in increased absorbance compared to TNF-only controls. 5. HeLa IL-8 Assay

The activity of TNFR1 antagonists can be determined using the HeLa IL-8 assay, in which the ability of the antagonist to neutralize TNF-induced IL-8 secretion in HeLa cells is assessed. Briefly, HeLa cells were seeded in microtiter plates overnight in the presence of different concentrations of TNFR1 antagonist and 300 pg/ml TNF. The supernatant was then aspirated and the concentration of IL-8 was measured using a sandwich ELISA. TNFR1 antagonist activity reduced IL-8 secretion into the supernatant compared to the TNF-only control. 6. HUVEC analysis method

Human umbilical vein endothelial cells (HUVEC) assays can be used to determine the activity of the TNFR1 antagonists described herein. Treatment of HUVECs with TNF upregulates the expression of VCAM-1 on the cells, which can be determined, for example, by ELISA. Since TNFR1 antagonists inhibit the effects of TNF, the expression of VCAM-1 in HUVEC is reduced in the presence of the antagonist. The extent of inhibition of TNF-induced VCAM-1 expression by TNFR1 antagonists was then determined by plotting antagonist concentration versus percent inhibition of VCAM-1 expression.

According to the protocol of this assay, HUVEC were cultured overnight and subsequently incubated with TNFR1 antagonist for 1 hour, followed by stimulation with TNF (1 ng/mL) for 23 hours. Cells cultured with culture medium alone served as a negative control group, and cells cultured with TNF alone served as a positive control group. The cell culture supernatant was then aspirated, and the cells were washed three times with ice-cold PBS and lysed by adding ice-cold Tris-glycerol lysis buffer (40 mM Tris, 274 mM NaCl, 2% Triton-X-100, 20% glycerol , 50 mM NaF, 1 mM Na ₃ VO ₄ , 1× protease inhibitor tablets per 10 mL) and then incubated on ice for 15 minutes. Cell lysates were subsequently used in a VCAM-1 sandwich ELISA. To calculate the rate of inhibition of TNF-induced VCAM-1 expression, % inhibition of maximal VCAM-1 expression (i.e., as measured in the positive control group) = {100 - [( OD value at antagonist concentration ) / ( OD value of positive control group )]} x 100 .

The _EC50 value is then determined by plotting antagonist concentration versus percent inhibition, for example using available software such as GraphPad Prism software. 7. Quantification and evaluation of Treg cell activity

To determine the effects of TNFR1 antagonists and TNFR1 antagonist/TNFR2 agonist constructs on Tregs, peripheral blood mononuclear cells (PBMCs) can be isolated from blood samples, such as by using the Ficoll-Paque method, followed by CD4 ⁺ CD25 ⁺ Treg and CD4 ⁺ CD25 ^- non-regulatory T cells are isolated using strain antibodies (mAb) and paramagnetic beads or other similar methods known in the art to quantify the number of Treg before, after and during treatment. The number of each cell type can be quantified using flow cytometry and immunostaining with mAbs against CD4 and CD25 (for Tregs) or CD4 and CTLA-4 (for non-regulatory T cells) (see e.g. Vigna-Pérez et al. Human (2005) Clin. Exp. Immunol. 141(2):372-380).

CD4 ⁺ CD25 ⁺ Tregs inhibit the proliferation of CD4 ⁺ CD25 ^- T cells. To test the activity of Tregs from treated patients, a cell proliferation assay can be used, in which Tregs and T cells are cultured together with phytohemagglutinin (PHA, which stimulates T cells) for 48 hours. ^3H -TdR (tritiated thymidine) was added during the last 12 hours of culture, after which cells were harvested and proliferation determined using a liquid scintillation counter. CD4 ⁺ CD25 ⁻ T cells cultured alone were used as controls, and the results were expressed as stimulation index (SI) of cell proliferation, which was calculated using the following formula: SI = ( cpm of cells cultured with PHA ) ÷ ( medium only cpm) of cultured cells , where cpm is counts per minute, as determined by counting radioactivity (see, eg, Vigna-Pérez et al. (2005) Clin. Exp. Immunol. 141(2):372-380).

To test immunoreactivity against Mycobacterium tuberculosis, PBMC were cultured in complete medium in the presence of whole protein extracts of the bacteria for 72 hours. ³ H-TdR (tritiated thymidine) was added during the last 12 hours of culture, after which cells were harvested and proliferation determined using a liquid scintillation counter. Results are expressed as stimulation index, as described above. For in vivo reactivity against Mycobacterium tuberculosis, the standard PPD (Purified Protein Derivative) skin test can be used (see e.g. Vigna-Pérez et al. (2005) Clin. Exp. Immunol. 141(2):372-380) . 8. Evaluation of Binding Properties of TNFR1 Antagonist /TNFR2 Agonist Constructs

Specific binding of an antibody or antibody fragment or multispecific construct (such as the constructs provided herein) to TNFR1 and/or TNFR2 (e.g., human TNFR1 and/or TNFR2) can be achieved by any of a variety of known methods. assessment. Affinity can be quantified by various measures, including the concentration required to achieve half-maximal enhancement of TNFR1 and/or TNFR2 signaling in vitro ( _EC50 ) and antagonist- The equilibrium constant (K _D ) for the dissociation of TNFR1 and/or agonist-TNFR2 complexes. The equilibrium constant _K describing the interaction of TNFR1 or TNFR2 with a binding agent, such as a construct (binder) provided herein, is a TNFR1-Binder Construct Complex or a TNFR2-Binder Complex Dissociation Reaction is Solvent Isolated TNFR1 or Chemical equilibrium constants for TNFR2 and non-interacting binder molecules.

TNFR1 antagonists, TNFR2 agonists and multispecific constructs can also be characterized by a variety of in vitro binding assays. Examples of experiments that can be used to determine _KD or _EC50 include, for example, surface plasmon resonance (SPR, such as BIAcore™ analysis), isothermal titration calorimetry, fluorescence anisotropy, and ELISA-based assays. ELISA is a particularly useful method for analyzing antibody activity because such assays typically require minimal concentrations of antibody. A common signal analyzed in a typical ELISA assay is luminescence, which is typically a secondary antibody that specifically binds a primary antibody, such as a TNFR1 antagonist or TNR1 antagonist-TNFR2 agonist bispecific construct provided herein. Result of activity of antibody-conjugated peroxidase.

The kinetics of association and dissociation of TNFR1 antagonists with TNFR1 or TNFR2 agonists with TNFR2 can be quantitatively characterized, for example, by monitoring the rate of formation of antibody-antigen complexes according to established procedures. For example, one can use surface plasmon resonance (SPR) to determine the rate constants for the formation ( _kon ) and dissociation ( _koff ) of antagonist-TNFR1 or agonist-TNFR2 complexes. The equilibrium constant (K _D ) can be determined from this data because the equilibrium constant for single-molecule dissociation can be expressed as the ratio of the k _off and _kon values. SPR is a technique that is useful for determining the kinetic and thermodynamic parameters of receptor-antibody (or other binding agent) interactions because the experiment does not require modification of a component by attaching a chemical label. Instead, receptors are typically immobilized on a solid metal surface and pulsed with solutions of increasing concentrations of antibody or binding agent (i.e., TNFR1 antagonist or TNFR2 agonist, or bispecific constructs thereof). Antibody-receptor binding induces a distortion in the reflection angle of incident light on the metal surface, and when the antibody is introduced into the system, this change in refractive index over time can be fit to established regression models known in the art to Calculation of association and dissociation rate constants for antibody-receptor interactions. 9. Antibody-dependent cytotoxicity ( ADCC ) and complement-dependent cytotoxicity ( CDC ) assays

Antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays can be used to evaluate the immunity of TNFR1 antagonists, TNFR2 agonists and multispecific constructs containing Fc monomers or dimers provided herein. Effector function/cytotoxicity. Generally, the Fc portion is modified to eliminate or substantially reduce (to eliminate or reduce adverse side effects to tolerable levels) ADCC or ADCC and CDC effector functions. Such assays are well known in the art (see, eg, Ying et al. (2014) mAbs 6(5):1201-1210). For example, for an exemplary ADCC assay, mesothelin-negative A431 or mesothelin-positive H9 cells are incubated with a TNFRl antagonist, TNFR2 agonist, or multispecific construct provided herein for 30 minutes, followed by targeting Cells are added to wells containing effector cells (e.g., PBMC) at a ratio of 50:1 effector cells to target cells. After 24 hours of incubation, lysis of target cells was measured using the CytoTox-ONE Homogenous Membrane Integrity Assay (Promega) according to the manufacturer's protocol.

For the exemplary CDC assay, A431 and H9 cells were washed in serum-free RPMI, and the density was adjusted to 1 million/ml in serum-free RPMI. 50 µL of the cell suspension was then incubated with 50 µL of a dilution of TNFR1 antagonist, TNFR2 agonist, or multispecific construct in RPMI. The negative control group contained 50 µL of cell suspension and 50 µL of RPMI, and the positive control group contained target cells lysed with 1% Triton X-100 to a final volume of 150 µL. Fresh human plasma was diluted (1:4) in PBS and clarified by centrifugation, then 50 µL of diluted plasma was added to each cell/construct mixture and incubated in 96-well plates at 37°C to allow complement Mediated cell lysis. After 3 hours of incubation, 100 µL of the supernatant was transferred to a white plate, and 100 µL of substrate from CytoTox-ONE Homogenous Membrane Integrity Assay Kit (Promega) was added. The plate was then incubated at room temperature for 10 minutes and the fluorescence signal was read using a fluorometer with an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The CDC of target cells is expressed as the percentage of experimental sample and positive control. 10. Disease Model

The selective TNFRl antagonists, TNFR2 agonists, and multispecific constructs provided herein can be evaluated in any clinically relevant disease model known to one of ordinary skill in the art to determine their effect on the cause of disease mediated by TNF or Autoimmune and inflammatory and other diseases or conditions involving TNF. Exemplary disease models include, but are not limited to, collagen-induced arthritis (CIA), rheumatoid arthritis synovial mononuclear cell culture, Tg197 mouse model of arthritis, ΔARE mouse model of arthritis/IBD, small DSS-induced IBD model and multiple sclerosis experimental autoimmune encephalomyelitis (EAE) model. Other models are known to those of ordinary skill in the art. See, for example, Malaviya et al. (2017) Pharmacol Ther. 180 :90-98, which provides a number of models for testing constructs for treating inflammatory lung diseases; Feldmann et al. (2020) Lancet 395 :1407-1409, which deals with anti- The use of TNF therapy and the model and treatment of COVID-19; Shi et al. (2013) Crit. Care 17(6) : R301, which uses anti-TNF therapy to treat H1N1 and viral infection models; and Orti-Casan et al. (2019 ) Front. Neurosci. 13:49, which describes that activating TNFR2 is advantageous for treating Alzheimer's disease, demonstrates that the approach of this article, namely TNF blockers that inhibit TNFR1 and TNFR2, is problematic. The following is a non-exhaustive discussion of diseases, disorders, and conditions that may be treated with the constructs provided herein, as well as illustrative models of each. These are illustrative; one of ordinary skill in the art can select an appropriate model for a particular construct and target disease, disorder or condition. Because the anti-TNFR1 and TNFR2 antagonist/agonist constructs provided herein are intended for targeting human TNFR1/TNFR2, they are expected to perform better when reacting/interacting with TNFR1/TNFR2 from non-human, especially non-primate species. not effectively. For testing, human TNFR1 and human TNFR2 are transgenic in non-human models, such as rodent models, such as mouse models. It can be used in in vivo models of inflammatory and autoimmune diseases in the context of murine TNFR1/2 knockout mice. Alternatively, severely immunocompromised mice (such as NOD/NSG mice) transplanted with human CD34+ stem cells can be used for this purpose. Alternatively, human rheumatoid arthritis synoviocytes can be transplanted into immunodeficient mice, resulting in RA-like inflammation (for a description of such models, see, e.g., Schinnerling et al. (2019) Front Immunol. 10 :203). a. Collagen-induced arthritis ( CIA )

Type II collagen-induced arthritis (CIA) can be induced in mice as a model of autoimmune inflammatory joint disease that is histologically similar to RA and is characterized by inflammatory synovitis, pannus formation, and Erosion of cartilage and bone. To induce CIA, bovine type II collagen (B-CII) was injected intradermally at the base of the tail in the presence of complete Freund's adjuvant. After 21 days, mice can be re-immunized using the same regimen. To study the effects of the selective TNFR1 antagonists, TNFR2 agonists, and multispecific constructs provided herein, intraperitoneal administration was performed twice weekly 3 weeks after the initial challenge with B-CII or at the onset of arthritis symptoms. Selective TNFR1 antagonist, TNFR2 agonist or multispecific construct or control for 3 weeks. Mice can be sacrificed 7 weeks after primary immunization for histological analysis.

To assess the therapeutic efficacy of the constructs in established disease, the constructs may be administered daily for a total of 10 days after the development of clinical arthritis in one or more limbs. The initial degree of swelling in the affected joint can be monitored by measuring the thickness of the paw using calipers. Serum can be drawn from mice to measure pro-inflammatory cytokines and chemokines, such as granulosa macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), IL-1β , IL-6, IL-8, RANTES (CCL5) and monocyte chemoattractant protein 1 (MCP-1; also known as CCL2).

In another example, primate models can be used for RA treatment. Individuals treated with a recombinant therapeutic TNFR1 antagonist, TNFR2 agonist or bispecific construct and a control may be monitored for tender and swollen joint responses (e.g., as measured by clinical arthritis scores) to assess treatment efficacy and treatment. b. Rheumatoid arthritis synovial mononuclear cell culture

Human rheumatoid arthritis (RA) synovial mononuclear cells (MNC) expressing TNFR1 and TNFR2 can also be used to test the therapeutic efficacy of the constructs provided herein. RA synovial MNCs can be obtained from RA patients undergoing joint replacement surgery and cultured in vitro to assess the production and regulation of interleukin by RA synovial cells. RA synovial MNC cultures spontaneously produce inflammatory cytokines and chemokines in the absence of exogenous stimulation; antibody-mediated TNF neutralization and TNFR1 selectivity in these cultures Blocking (such as by constructs provided herein) inhibits the production of pro-inflammatory cytokines and chemokines, such as GM-CSF, IL-10, IL-1β, IL-6, IL-8, RANTES ( CCL5) and MCP-1 (CCL2).

In an exemplary assay, to prepare RA synovial MNCs, RA synovial tissue was dissected into small pieces and incubated in RPMI 1640 with 5 mg/ml collagenase A and 0.15 mg/ml DNase for 1 hour at 37°C. The digested tissue was then passed through a 170 µm filter and washed three times with RPMI 1640 containing 100 units/ml streptomycin, 100 µg penicillin, and 10% FCS. Subsequently, heterogeneous RA synovial MNCs can be used without passage. For in vitro cell culture, single-cell suspensions of RA synovial MNCs were cultured in 96-well flat plates (2 × ¹⁰ cells/well) in RPMI 1640 medium with 5% FCS at 37 °C and 5% CO ₂ Cultures were performed for 2-5 days in the presence or absence of TNFR1 antagonist, TNFR2 agonist or bispecific constructs or controls. The supernatant is then collected and used immediately or stored at -20°C for analysis by cytokine and chemokine ELISA (see e.g. Schmidt et al. (2013) Arthritis & Rheumatism 65(9):2262 -2273). Alternatively, interleukins in culture supernatants can be quantified by interleukin bead array analysis. c. Tg197 mouse model of arthritis

The Tg197 transgenic mouse strain, a mouse model of erosive arthritis, is a recognized animal model of RA. Tg197 mice are human TNF transgenic C57BL/6 mice that overexpress human TNF and suffer from symmetric polyarthritis with pannus formation, bone destruction, and cartilage damage that are characteristic of human RA. In addition to displaying features of chronic destructive joint disease, this model exhibits symptoms such as enthesitis or bilateral sacroiliitis that are characteristic of other inflammatory diseases such as spondyloarthritis (Blüml et al. (2010) Arthritis & Rheumatism 62(6):1608-1619). Tg197 mice develop arthritis with 100% penetrance and provide a rapid in vivo model for evaluating human therapeutics targeting RA. For example, the Tg197 mouse model was used to evaluate the therapeutic efficacy of infliximab (originally sold as Remicade®), the first anti-TNF therapeutic successfully used in the clinic and recommended by the FDA for screening potential anti-RA treatments. agent.

Tg197 mice carry five copies of the human TNF gene construct in which the 3' region containing the 3' untranslated and 3' flanking sequences is exchanged with the 3' region of the human β-globin gene. This gene construct was microinjected into mouse zygotes to produce an in vivo model of dysregulated TNF gene expression, because a set of highly conserved UA-rich sequences in the 3' untranslated region of TNF mRNA is important for regulating mRNA stability and translation. Efficiency is critical (see, eg, Keffer et al. (1991) EMBO J. 10(13):4025-4031). d. Δ ARE mouse model of arthritis /IBD

Mice lacking the 3' AU-rich element ( ^ARE ) of TNF mRNA ( ^TnfΔARE ) overproduce TNF and develop an inflammatory disease histopathologically similar to Crohn's disease at 4-8 weeks of age. Enteropathy. Mice also developed clinical symptoms of RA. The efficacy of the TNFR1 antagonists, TNFR2 agonists and bispecific constructs provided herein can be assessed by assessing the inhibitory effect on Crohn's disease-like pathology and arthritis in ^TnfΔARE mice following intraperitoneal injection ( See, for example, U.S. Patent No. 9,028,822). e. Humanized TNF/TNFR2 mice

One limitation in developing therapeutics targeting the TNF/TNFR2 signaling pathway is the lack of preclinical animal models, because many human anti-TNF therapeutics do not interact with murine TNF or TNFR2, and human TNF binds to and engages murine TNFR1. But does not bind and engage TNFNR2. Humanized TNF/TNFR2 mice carrying a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module can be used to evaluate therapeutics in various autoimmune models, such as agonist and antagonist antibody constructs human TNF or Human TNFR2. Such TNF/TNFR2 dual humanized mice can be used, for example, to evaluate the TNFR2 agonist constructs provided herein.

Humanized TNF/TNFR2 mice can be generated as described in Atretkhany et al. (2018) Proc. Natl. Acad. Sci. USA 115(51):13051-13056. Briefly, human TNFR2 knock-in (hTNFR2KI) and human TNF knock-in (hTNFKI) mouse lines were generated using standard genetic engineering techniques. hTNFKI mice in which the mouse TNF gene has been replaced with the human TNF gene are then crossed with hTNFR2KI mice containing the humanized TNFR2 ligand-binding portion, and then with each other to generate doubly humanized double homozygous hTNFKI x hTNFR2KI mice. To assess the role of TNFR2 signaling in specific cells, such as Tregs, two LoxP sites were inserted into the hTNFR2 locus to allow conditional Cre-mediated ablation of the extracellular portion of TNFR2. For Treg-specific deletion of TNFR2, these mice were crossed with FoxP3-Cre transgenic mice (see, e.g., Atretkhany et al. (2018) Proc. Natl. Acad. Sci. USA 115(51):13051-13056). I. Methods of producing nucleic acids encoding TNFR1 antagonist constructs and TNFR1 antagonist /TNFR2 agonist constructs

The TNFR1 antagonist polypeptides, TNFR2 agonist polypeptides and TNFR1 antagonist/TNFR2 agonist polypeptide constructs provided herein are polypeptides that can be used for protein purification and recombinant protein expression and for recombinant antibodies by methods well known in the art. Obtained by preparation method. Constructs provided herein that include non-polypeptide moieties such as linkers can optionally be prepared by chemical coupling methods. The polypeptide portion may be produced by standard recombinant techniques, such as by growing in a suitable host (in bacteria if glycosylation is not required, or in eukaryotic cells such as HEK293 and CHO cells if glycosylation is desired). Medium) performance. Active antibodies and antibody fragments have been produced in E. coli , but due to improper folding, these antibodies and antibody fragments often suffer from aggregation and solubility problems, which can be remedied by further mutagenesis of the coding sequence (see e.g. Kunz et al. ( 2018) Sci Rep. 8(1) :7934).

Peptides can also be synthesized chemically. Fusion polypeptides can be synthesized by standard methods of recombinant production. The components of the various constructs discussed above can be synthesized separately and combined using standard methods to produce the construct.

Nucleic acids encoding polypeptide constructs or polypeptide portions thereof, including modified or variant, including truncated forms, can be prepared from nucleic acids. Modified or variant polypeptides can be engineered from nucleic acids encoding wild-type polypeptides using standard recombinant DNA methods. For example, modified TNF polypeptides, such as TNF muteins, that selectively bind TNFR1 or TNFR2 and/or selectively antagonize TNFR1 or selectively agonize TNFR2 can be engineered from wild-type TNF, such as by encoding DNA. Site-directed mutagenesis. Any method known to a person of ordinary skill in the art may be used. The descriptions in the following discussion and examples are illustrative. 1. Isolation or preparation of nucleic acids encoding TNFR1 antagonist and TNFR2 agonist polypeptides

Nucleic acids encoding TNFR1 antagonist polypeptides, TNFR2 agonist polypeptides, and TNFR1 antagonist/TNFR2 agonist polypeptide constructs can be cloned or isolated using any available method for selecting and isolating nucleic acid molecules known in the art. . Such methods include polymerase chain reaction (PCR) amplification of nucleic acids and screening of libraries, including nucleic acid hybrid screening, antibody-based screening and activity-based screening. For example, when the polypeptide is produced recombinantly, any method known to one of ordinary skill in the art for identifying nucleic acids encoding the desired polypeptide may be used.

Nucleic acid molecules encoding the polypeptides herein may be produced synthetically or, if appropriate, using conventional procedures (e.g., by using heavy chains and/or heavy chains encoding antibody fragments such as single domain antibodies (dAb), scFv fragments, and Fab antibody fragments). Or light chain gene-specific binding oligonucleotide probes) can be easily isolated and sequenced. For example, any cell source known to produce or express TNFRl antagonist or TNFR2 agonist antibodies or fragments thereof may serve as a source of such DNA. In another example, once the sequence of DNA encoding a TNFRl antagonist or TNFR2 agonist antibody or fragment thereof is determined, gene synthesis techniques can be used to construct the nucleic acid sequence.

Methods for amplifying nucleic acids can be used to isolate nucleic acid molecules encoding the desired polypeptide, including, for example, polymerase chain reaction (PCR) methods. Examples of such methods include the use of a Perkin-Elmer Cetus thermal cycler and Taq polymerase (Gene Amp). Nucleic acid-containing materials can be used as starting materials from which nucleic acid molecules encoding the desired polypeptide can be isolated. For example, DNA and mRNA preparations, cell extracts, tissue extracts, liquid samples (such as blood, serum, and saliva), and samples from healthy and/or diseased individuals can be used in amplification methods. The source, generally will be from human sources and, where appropriate, from any eukaryotic species, including but not limited to vertebrate, mammalian, human, porcine, bovine, feline, avian, equine, canine and other primate sources. Nucleic acid libraries can also be used as a source of starting material. Primers can be designed to amplify the desired polypeptide. For example, primers can be designed based on expression sequences that produce the desired polypeptide. Primers can be designed based on back-translation of polypeptide amino acid sequences. If necessary, degenerate primers can be used for amplification. Oligonucleotide primers hybridized to sequences at the 3' and 5' ends of the desired sequence can be used as primers for amplifying sequences from nucleic acid samples by PCR. Primers can be used to amplify entire full-length polypeptides or truncated sequences thereof, such as nucleic acids encoding any of the TNFR1 antagonist and TNFR1 agonist polypeptides and TNFR1 antagonist/TNFR2 agonist polypeptide constructs provided herein. Nucleic acid molecules produced by amplification can be sequenced and confirmed to encode the desired polypeptide or construct.

Mutagenesis techniques can be used to generate other modified forms of TNFRl antagonist or TNFR2 agonist antibodies or fragments thereof, and to generate modified forms of activity modulators, such as the Fc and hinge region and linker portions. DNA can also be modified. For example, gene synthesis and conventional molecular biology techniques can be used to achieve insertion, deletion, addition or substitution/substitution of nucleotides. Additional nucleotide sequences can be ligated to the nucleic acid molecule encoding the polypeptide, including linker sequences containing restriction endonuclease sites for cloning the synthetic gene into a vector, such as a protein expression vector or one designed to amplify A vector that increases the DNA sequence encoding the core polypeptide. Additional nucleotide sequences specifying functional DNA elements (such as promoters, enhancers, and IRES sequences) are operably linked to the nucleic acid molecule encoding the polypeptide. Examples of such sequences include, but are not limited to, promoter sequences designed to promote intracellular protein expression, and secretion sequences designed to promote protein secretion, such as heterologous signal sequences. Such sequences are known to those of ordinary skill in the art. Additional nucleotide sequences, such as those specifying protein binding regions, can also be linked to nucleic acid molecules encoding polypeptides. Such regions include, but are not limited to, sequences that facilitate uptake of the polypeptide into specific target cells or otherwise alter or enhance the pharmacokinetics of the synthetic gene product.

Tags and/or other moieties may be added, for example, to facilitate detection or affinity purification of the polypeptide. For example, additional nucleotide sequences, such as base sequences specifying epitope tags or other detectable labels, can also be linked to a nucleic acid molecule encoding a polypeptide. Examples of such sequences include nucleic acid sequences encoding SUMO tags or His tags or Flag tags.

It will be understood that any of the amino acid sequences provided herein can be reverse-translated (also referred to as back-translation) using standard methods commonly used by those of ordinary skill in the art to generate the corresponding coding nucleic acid sequence, which can Selected into vectors and expressed to produce constructs provided herein, including polypeptides, antibodies and antibody fragments. For example, there are several online tools that can be used to convert protein sequences into coding DNA sequences, such as bioinformatics.org/sms2/rev_trans.html; biophp.org/minitools/protein_to _dna/demo.php; vivo.colostate.edu/ molkit/rtranslate/; ebi.ac.uk/Tools/st/emboss_backtranseq/; molbiol.ru/eng/scripts/01_19.html; and geneinfinity.org/sms/sms_backtranslation.html. Such reverse-translated sequences may be inserted into any of the expression vectors provided herein to express and produce the antibodies or fragments provided. Anti-TFR1 and anti-TNFR2 antibodies, such as TNFR1 antagonists and TNFR2 agonist constructs may appear as full-length proteins or less than full-length proteins. For example, antibody fragments may be expressed, such as, but not limited to, single domain antibodies (dAb), scFv fragments, and Fab fragments.

The identified and isolated nucleic acids can then be inserted into appropriate selection vectors. A large number of vector-host systems known in the art can be used. Possible vectors include, but are not limited to, plasmids or modified viruses, but the vector system must be compatible with the host cell used. Such vectors include, but are not limited to, phage, such as lambda derivatives; or plasmids, such as pCMV4, pBR322 or pUC plasmid derivatives or the pBluescript vector (Stratagene, La Jolla, CA). Insertion into a selection vector can be achieved, for example, by ligating the DNA fragment into a selection vector with complementary sticky ends. Insertion can be achieved using TOPO selection vectors (Invitrogen, Carlsbad, CA).

If complementary restriction sites for DNA fragmentation are not present in the selection vector, the ends of the DNA molecules can be enzymatically modified. Alternatively, any desired site can be created by ligating nucleotide sequences (linkers) to the DNA termini; these ligated linkers can contain specifically chemically synthesized oligos encoding restriction endonuclease recognition sequences. glycosides. In an alternative approach, the cleavage vector and polypeptide genes can be modified by homopolymeric tailing.

Recombinant molecules can be introduced into host cells via, for example, transformation, transfection, infection, electroporation, and sonoporation, thereby producing many copies of the genetic sequence. In certain embodiments, transforming a host cell with a recombinant DNA molecule that incorporates an isolated polypeptide gene, cDNA, or synthetic DNA sequence can produce multiple copies of the gene. Therefore, genes can be obtained in large quantities by growing transformants, isolating recombinant DNA molecules from the transformants, and, if necessary, extracting the inserted genes from the isolated recombinant DNA.

To express antibodies and fragments thereof, generally, nucleic acid molecules encoding the antibody heavy chain are cloned into a vector, and nucleic acid molecules encoding the antibody light chain are cloned into the vector. Methods for producing antibodies and portions thereof are well known (see, eg, U.S. Patent Nos. 4,816,567, 6,331,415, and 7,923,221, as well as many other seminal patents). Genes can be cloned into a single vector for their dual expression, or into separate vectors. If desired, the vector may also contain other sequences encoding additional constant or hinge regions to generate other antibody formats. Vectors can be transfected and expressed in host cells. Expression can be performed in any cell expression system known to those of ordinary skill in the art. For example, host cells include cells that do not otherwise produce immunoglobulins to obtain synthesis of antibodies in recombinant host cells. For example, host cells include, but are not limited to, simian COS cells; Chinese hamster ovary (CHO) cells, such as CHO-DG44 (DHFR ^- ) and FreeStyle™ CHO-S cells (Invitrogen); 293FS cells; HEK293 cells; NSO cells, or Other myeloma cells. Other expression vectors and host cells are described herein.

Constructs provided herein, including TNFRl antagonists, TNFR2 agonists, and TNFRl antagonist/TNFR2 agonist constructs, may be generated or expressed as full-length constructs or less than full-length, including but not limited to antigen-binding fragments, such as single domains Antibody (dAb), Fab, Fab', Fab hinge, F(ab') ₂ , single chain Fv (scFv), scFv tandem, Fv, dsFv, scFv hinge, scFv hinge (ΔE), diabody, Fd and Fd 'fragment. Various techniques exist for producing antibody fragments. For example, fragments can be obtained by proteolytic digestion of intact antibodies (see, eg, Morimoto and Inouye (1992) Journal of Biochemical and Biophysical Methods 24:107-117; Brennan et al. (1985) Science 229:81-83). Fragments can also be produced directly by recombinant host cells. For example, dAb, Fab, Fv and scFv antibody fragments can be expressed and secreted in host cells, such as E. coli, CHO cells or HEK293 cells, thereby facilitating the production of large amounts of such fragments. F(ab') ₂ fragments can be produced by chemical coupling of Fab'-SH fragments (see, eg, Carter et al. (1992) Bio/Technology , 10:163-167), or they can be isolated directly from recombinant host cell culture. In some examples, TNFR1 antagonist constructs include single domain antibodies (dAb; described in, for example, International Application Publication Nos. WO 2004/058820, WO 2004/081026, WO 2005/035572, WO 2006/038027 No., WO 2007/049017, WO 2008/149144, WO 2008/149148, WO 2010/094720, WO 2011/006914, WO 2011/051217, WO 2012/172070 , No. WO 2012/104322 and No. WO 2015/104322; Enever et al., (2015) Protein Engineering, Design & Selection 28(3) :59-66); U.S. Application Publication No. 2006/0083747, No. 2010 /0034831 and 2012/0107330; and U.S. Patent Nos. 9,028,817 and 9,028,822), single-chain Fv fragments (scFv) (see, for example, International Application Publication Nos. WO 2017/174586 and WO 2008/113515 ; See also Richter, F. Thesis, "Evolution of the Antagonistic Tumor Necrosis Factor Receptor One-Specific Antibody ATROSAB," Universität Stuttgart, 2015; available at pdfs.semanticscholar.org/d8e7/8b87d76dce36225c1d497939ef37445cfa8a.pdf) or Fab fragment (See, for example, International Application Publication Nos. WO 2017/174586 and WO 2008/113515; see also Richter, F. Thesis, entitled “Evolution of the Antagonistic Tumor Necrosis Factor Receptor One-Specific Antibody ATROSAB,” Universität Stuttgart, 2015; available at pdfs.semanticscholar.org/d8e7/8b87d76dce36225c1d497939ef37445cfa8a.pdf). dAb, Fv and scFv fragments have intact combination sites but no constant regions; therefore, they are suitable for reducing non-specific binding during in vivo use. dAb and scFv fusion proteins can be constructed to attach an effector protein (eg, IgG Fc) at the amino or carboxyl terminus of the dAb or scFv. Antibody fragments can also be linear antibodies (see, eg, US Pat. No. 5,641,870). Such linear antibody fragments can be monospecific or bispecific. Other techniques for producing antibody fragments are known to those of ordinary skill in the art.

Upon expression, the antibody heavy and light chains or fragments thereof are paired via inter-chain disulfide bonds to form a full-length antibody or fragments thereof. For example, to express _{full-length Ig, the sequence encoding VH-CH1-hinge-CH2-CH3 can be cloned into the first expression vector, and the sequence encoding the VL-CL domain can be cloned into} the first expression vector. The sequence is cloned into a second expression vector. During co-expression, the full-length heavy and light chains are linked to each other by disulfide bonds to produce full-length antibodies. In another example, to generate a Fab, a sequence encoding a fragment containing the _VH and _CH1 regions can be cloned into a first expression vector, and a sequence encoding a VL _{- CL} domain can be cloned into a first expression vector. Two expression carriers. Upon co-expression, the heavy chain pairs with the light chain to create Fab monomers. The sequences of the _CH1 , hinge, _CH2 and/or _CH3 regions of the various IgG subtypes are known to those of ordinary skill in the art (see, eg, US Publication No. 2008/0248028; see also SEQ ID NO: 9, 11, 13 and 15). Likewise, the sequences of CL, λ, or κ are also known (see, eg, US Publication No. 2008/0248028; see also SEQ ID NO: 17-22).

In addition to recombinant production, the TNFRl antagonist polypeptides, TNFR2 agonist polypeptides and TNFRl antagonist/TNFR2 agonist polypeptide constructs provided herein can be produced by direct peptide synthesis using well-known solid phase techniques. In vitro protein synthesis can be performed using manual techniques or by automation. Automated synthesis can be accomplished, for example, using Applied Biosystems 431A Peptide Synthesizer (Perkin Elmer; Foster City, CA) according to the instructions provided by the manufacturer. Various fragments of polypeptides can be chemically synthesized separately and combined using chemical methods. 2. Generation of mutated or modified nucleic acids and encoded polypeptides

Modifications provided herein can be performed by standard recombinant DNA techniques routinely used by those of ordinary skill in the art. Any method known in the art can be used to achieve mutation of any one or more amino acids in the target protein or polypeptide. Methods include standard site-directed mutagenesis of encoding nucleic acid molecules (using, for example, a kit such as the QuikChange kit available from Stratagene) or solid-phase polypeptide synthesis methods. 3. Vectors and cells

For recombinant expression of one or more of the desired polypeptides described herein, such as any TNFR1 antagonist or TNFR2 agonist polypeptide or TNFR1 antagonist/TNFR2 agonist polypeptide construct, contain all or a portion of the nucleotide sequence encoding the polypeptide The nucleic acid molecule can be inserted into an appropriate expression vector, that is, a vector containing the elements required for the transcription and translation of the inserted polypeptide coding sequence. Vectors containing nucleic acid molecules encoding polypeptides are also provided. Following insertion of the nucleic acid molecule, the vector is typically used to transform the host cell, eg, to amplify the nucleic acid for replication and/or expression. In these examples, vehicles suitable for high content expression are used. In other cases, a vector is selected that is compatible with display of the polypeptide on the cell surface. The choice of carrier can depend on the desired application. A variety of expression vectors are available and known to those of ordinary skill in the art for expressing anti-TNFR1 and anti-TNFR2 antibodies or portions thereof, such as antigen-binding fragments. Such choices are well within the skill of a person with ordinary knowledge in the art. Generally speaking, expression vectors may include a transcriptional promoter and optionally an enhancer, a translational signal and a transcriptional and translational termination signal. Expression vectors used for stable transformation typically have a selectable marker that allows selection and maintenance of transformed cells. In some cases, a higher replica number origin of replication can be used to amplify the replica number of the vector in the cell. The vector may also typically contain additional nucleotide sequences (eg, His tag, Flag tag) operably linked to the conjugated nucleic acid molecule. For applications with antibodies, the vector usually includes sequences encoding constant regions. Thus, antibodies or portions thereof can also be expressed as protein fusions. For example, fusion proteins can be produced to add additional functionality to a polypeptide. Examples of fusion proteins include, but are not limited to, fusions of signal sequences, epitope tags (such as for localization, eg, a His6 tag or a myc tag) or tags for purification (such as a GST tag) and/or for directing protein secretion and/or membrane-associated sequences. Fusion proteins herein also include fusions of TNFR1 antagonists and/or TNFR2 agonists with modified Fc regions, hinge regions of IgG, and/or peptide linkers (such as GS linkers).

A variety of host-vector systems are available for expressing protein coding sequences. Such systems include, but are not limited to, mammalian cell lines infected with viruses (such as vaccinia virus, adenovirus, and other viruses); insect cell lines infected with viruses (such as baculovirus); microorganisms, such as those containing yeast vectors Yeast; and bacteria transformed by phage, DNA, plastid DNA or myxoplast DNA. The choice between eukaryotic expression systems and bacterial systems depends on the desired post-translational modifications, such as glycosylation. The expressive elements of a carrier vary in their intensity and specificity. Depending on the host-vector system used, any of a variety of suitable transcription and translation elements may be used.

Any method known to one of ordinary skill in the art for inserting a DNA fragment into a vector may be used to construct a vector containing a polypeptide encoding a polypeptide provided herein (such as an antibody fragment or a TNFR1 antagonist or a TNFR2 agonist) and appropriate transcription/translation Expression vector of nucleic acid molecules that control signals. These methods may include in vitro recombinant DNA and synthesis techniques and in vivo recombinants (genetic recombination). Insertion into a selection vector can be achieved, for example, by ligating the DNA fragment into a selection vector with complementary cohesive ends. If complementary restriction sites for DNA fragmentation are not present in the selection vector, the ends of the DNA molecules can be enzymatically modified. Alternatively, any desired site can be created by joining nucleotide sequences (linkers) to the DNA termini; these linked linkers can contain specifically chemically synthesized nucleic acids encoding restriction endonuclease recognition sequences. .

For example, the expression of construct polypeptides (such as the TNFR1 antagonists, TNFR2 agonists, and TNFR1 antagonist/TNFR2 agonist constructs herein) can be controlled by any promoter/enhancer known in the art. . Suitable bacterial promoters are well known in the art and are described below. Other promoters suitable for use in mammalian cells, yeast cells, and insect cells are well known in the art and some are exemplified below. The choice of promoter used to direct the expression of heterologous nucleic acids depends on the specific application. Promoters that can be used include, but are not limited to, eukaryotic expression vectors containing the SV40 early promoter (see, for example, Benoist and Chambon (1981) Nature 290:304-310), the 3' long end of Rous sarcoma virus Promoters contained in repeat sequences (see, for example, Yamamoto et al. (1980) Cell 22 :787-797), herpes thymidine kinase promoter (see, for example, Wagner et al. (1981) Proc. Natl. Acad. Sci. USA 78 :1441-1445), regulatory sequences of metallothionein genes (see, e.g., Brinster et al. (1982) Nature 296 :39-42) and cytomegalovirus (CMV) promoter; prokaryotic expression vectors, such as β-lactamase promoter (see, e.g., Jay et al. (1981) Proc. Natl. Acad. Sci. USA 78 :5543) or the tac promoter (see, e.g., DeBoer et al. (1983) Proc. Natl. Acad. Sci. USA 80 :21- 25); see also "Useful Proteins from Recombinant Bacteria": in Scientific American 242 :79-94 (1980)); plant expression vector containing nopaline synthase promoter (see, for example, Herrara-Estrella et al. (1984) Nature 303 :209-213), the cauliflower mosaic virus 35S RNA promoter (see, e.g., Gardner et al. (1981) Nucleic Acids Res. 9(12):2871-2888) and the photosynthetic enzyme ribulose diphosphate carboxylic acid promoters of enzymes (see, e.g., Herrera-Estrella et al. (1984) Nature 310 :115-120) promoter elements from yeast and other fungi, such as Gal4 promoter, alcohol dehydrogenase promoter, phosphoglycerol kinase promoter , the alkaline phosphatase promoter, and the following animal transcriptional control regions that exhibit tissue specificity and have been used in transgenic animals: the elastase gene control region that is active in pancreatic gland cells (see, e.g., Swift et al. (1984) ) Cell 38 :639-646; Ornitz et al. (1986) Cold Spring Harbor Symp. Quant. Biol. 50 :399-409; MacDonald (1987) Hepatology 7 :425-515), active in pancreatic beta cells Insulin gene control region (see, for example, Hanahan et al. (1985) Nature 315 :115-122), immunoglobulin gene control region active in lymphocytes (see, for example, Grosschedl et al. (1984) Cell 38 :647-658; Adams et al. (1985) Nature 318 :533-538; Alexander et al. (1987) Mol. Cell Biol. 7 :1436-1444), control of mouse mammary tumor viruses active in testicle, breast, lymphoid and mast cells region (see, e.g., Leder et al. (1986) Cell 45 :485-495), the albumin gene control region active in the liver (see, e.g., Pinkert et al. (1987) Genes and Devel. 1 :268-276), in The α-fetoprotein gene control region that is active in the liver (see, e.g., Krumlauf et al. (1985) Mol. Cell. Biol. 5 :1639-1648; Hammer et al. (1987) Science 235 :53-58), has Active α-1 antitrypsin gene control region (see, e.g., Kelsey et al. (1987) Genes and Devel. 1 :161-171), β-hemoglobulin gene control region active in bone marrow cells (see, e.g., Magram et al. Man (1985) Nature 315 :338-340; Kollias et al. (1986) Cell 46 :89-94), the myelin basic protein gene control region active in oligodendritic glial cells of the brain (see e.g. Readhead (1987) Cell 48 :703-712), the myosin light chain-2 gene control region active in skeletal muscle (see e.g. Shani (1985) Nature 314 :283-286) and in the hypothalamus The gonadotropin-releasing hormone gene control region active in gonadotroph cells (see, eg, Mason et al. (1986) Science 234 :1372-1378).

Expression vectors typically contain a transcription unit or expression cassette containing all additional elements required to express the construct or parts thereof in the host cell. A A representative expression cassette contains a promoter operably linked to a nucleic acid encoding a construct, such as an antibody fragment, domain, derivative or homolog thereof, or other polypeptide as described herein (e.g., TNF muteins and fusion proteins), and signals required for efficient polyadenylation of transcripts, ribosome binding sites, and translational termination. Additional elements of the cassette may include enhancers. In addition, the cassette typically contains a transcription termination region downstream of the structural gene to provide efficient termination. The termination region may be obtained from the same gene as the promoter sequence, or may be obtained from a different gene. For example, a vector includes a promoter or domain, fragment, derivative or homologue thereof operably linked to a nucleic acid encoding a desired polypeptide, one or more origins of replication, and optionally one or more selectable markers. (e.g. antibiotic resistance genes).

Expression systems can have markers that provide for gene amplification, such as thymidine kinase and dihydrofolate reductase. Expression systems that do not involve gene amplification are also suitable, such as the use of baculovirus vectors in insect cells, in which the nucleic acid sequence encodes the polypeptide under the direction of a polyhedral promoter or other strong baculovirus promoter.

For the purposes herein, there is provided a vector containing a nucleotide sequence encoding the Fc region of an IgG antibody, typically a modified Fc, operably linked to a nucleic acid encoding a TNFR1 antagonist or TNFR2 agonist polypeptide, and encoded in proteins such as IgG hinge sequences and/or short peptide linkers such as GS linkers, including glycine-rich flexible linkers such as (Gly ₄ Ser) _n as described herein, where n is positive integers, such as 1-5 or greater), as well as other linkers as described herein or known to those of ordinary skill in the art. The vector may include the sequence of one or all of _CH1 , _CH2 , hinge, _CH3 or _CH4 and/or _CL . Generally, such as for the expression of Fab, the vector contains the sequence of _CH 1 or _CL (kappa or lambda light chain). For example _{, VH-CH1 and VL-CL sequences can be} inserted into suitable expression vectors for expression of Fab molecules. The sequences of the constant or hinge regions are known to those of ordinary skill in the art (eg, US Publication No. 2008/0248028). This article provides examples of such sequences.

Typically, the vector may be a plasmid, viral vector, or other vector known in the art for expressing polypeptides in vivo or in vitro. For example, the constructs provided herein, such nucleic acids encoding TNFR1 antagonists and TNFR2 agonist polypeptide constructs, are expressed in mammalian cells, including, for example, Chinese Hamster Ovary (CHO) cells.

Exemplary eukaryotic vectors include, for example, well-known readily available vectors such as pCMV (Agilent Technologies), pCDNA3.1 (Invitrogen (Thermo Fisher Scientific)), pCBL (from Creative BioLabs, see, eg, Figure 1). Other eukaryotic vectors, such as any eukaryotic vector containing regulatory elements from eukaryotic viruses, may be used as eukaryotic expression vectors. This includes, for example, SV40 vectors, papilloma virus vectors, and vectors derived from Epstein-Bar virus. Exemplary eukaryotic vectors include, for example, pMSG, pAV009/A+, pMT010/A+, pMAMneo-5, baculovirus pDSCE, and proteins that allow expression in the CMV promoter, SV40 early promoter, SV40 late promoter, metallothionein promoter, mouse A mammary tumor virus promoter, a Rous sarcoma virus promoter, a polyhedral promoter, or any other vector that exhibits expression under the direction of other promoters that are efficiently expressed in eukaryotes.

Viral vectors may be used, such as adenovirus, retrovirus or vaccinia virus vectors. In some examples, the vector is a defective or attenuated retrovirus or other viral vector (see, eg, U.S. Patent No. 4,980,286). For example, retroviral vectors can be used (see, eg, Miller et al. (1993) Meth. Enzymol. 217:581-599). These retroviral vectors have been modified to remove retroviral sequences that are not required for viral genome packaging and integration into host cell DNA. In some examples, viruses formed with nucleic acids encoding polypeptides herein can promote their replication and spread within target tissues. Viruses can also be cleaved viruses or non-lytic viruses, where the virus selectively replicates under tissue-specific promoters. When the virus replicates, the co-expression of polypeptides and viral genes will promote the spread of the virus in the living body.

For bacterial expression, vectors include the well-known and widely disseminated vectors pBR322, pUC, pSKF, pET23D and fusion vectors such as MBP (Sigma-Aldrich), GST (Sigma-Aldrich) and LacZ-containing vectors. Exemplary plastid vectors for transformation of E. coli cells include, for example, the pQE expression vector (available from Qiagen®, Valencia, Calif.; see also the literature published by Qiagen® describing this system). The pQE vector features a phage T5 promoter (recognized by E. coli ribonucleic acid polymerase) and a dual lac operator repression module to provide high-level performance of tightly regulated recombinant proteins in E. coli; synthetic ribosome binding for efficient translation site (RBS II); 6XHis tag coding sequence; t0 and T1 transcription terminators; ColE1 origin of replication; and β-lactamase gene used to confer ampicillin resistance. The pQE vector allows the 6xHis tag to be placed at the N or C terminus of the recombinant protein. Such plasmids include pQE 32, pQE 30 and pQE 31, which provide multiple selection sites for all three reading frames and provide expression of N-terminal 6xHis-tagged proteins. Other exemplary plastid vectors for transformation of E. coli cells include, for example, the pET expression vector (see, eg, U.S. Patent 4,952,496; available from NOVAGEN, Madison, WI; see also the literature published by NOVAGEN describing this system). Such plasmids include pET 11a, which contains the T7lac promoter, T7 terminator, inducible E. coli lac operator and lac repressor genes; pET 12a-c, which contains the T7 promoter, T7 terminator and E. coli ompT secretion signal ; and pET 15b and pET19b (NOVAGEN, Madison, WI), which contain the His-TagTM leader sequence for purification of the His line and a thrombin cleavage site that allows post-purification cleavage on the line, the T7-lac promoter region, and T7 terminator.

Cells containing the vector are provided. In general, any cell type that can be engineered to express heterologous DNA and has a secretion pathway is suitable. Cells include eukaryotic and prokaryotic cells, and vectors are suitable for use in either. Generally speaking, a cell is one capable of glycosylation of the encoded protein. Prokaryotic and eukaryotic cells containing vectors are provided. Such cells include bacterial cells, yeast cells, fungal cells, Archaea, plant cells, insect cells and animal, especially mammalian cells. Cells are used to produce polypeptides by growing the cells under conditions encoding the polypeptide to be expressed by the cell and recovering the expressed polypeptide. For purposes herein, for example, the polypeptide may be secreted into the culture medium.

The host cell strain can be selected for its ability to modulate the expression of the inserted sequence or to process the expressed protein in a desired manner. Such modifications of polypeptides include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation. Post-translational processing can affect polypeptide folding and/or function. Different host cells, such as but not limited to Chinese Hamster Ovary (CHO) cells, such as DG44, FreeStyle™ CHO-S cells (Invitrogen), DXB11, CHO-K1), HeLa, MCDK, HEK293 and WI38 cells, have such post-translational Specific cellular mechanisms and characteristic mechanisms of activity, and can be selected to ensure correct modification and processing of the introduced protein. In general, cells are selected that are capable of introducing N-linked glycosylation into the expressed polypeptide. Thus, eukaryotic cells containing vectors are provided. An example of a eukaryotic cell is a mammalian Chinese hamster ovary (CHO) cell. For example, polypeptides provided herein are produced using CHO cells, such as DG44 cells, that lack dihydrofolate reductase (DHFR ⁻ ). 4.Performance _

The polypeptide constructs provided herein, including TNFR1 antagonist constructs, TNFR2 agonist constructs, TNFR1 antagonist/TNFR2 agonist multispecific constructs and parts thereof, can be obtained by those with ordinary knowledge in the art. Produced by any method known for protein production, including in vivo and in vitro methods, recombinant and synthetic and chemical methods. The desired protein may be expressed in any organism suitable for producing the protein in the required amounts and forms, such as those required for administration and treatment. Expression hosts include prokaryotic and eukaryotic organisms, such as E. coli, yeast, plants, insect cells, mammalian cells, including human cell strains and transgenic animals. Expression hosts may differ in their level of protein production, as well as in the types of post-translational modifications present on the expressed proteins. The choice of expression host can be based on these and other factors known to those of ordinary skill in the art; such factors include regulatory and safety considerations, production costs, and purification needs and methods. Purification methods and assembly of components are well known to those of ordinary skill in the art.

Representation in eukaryotic hosts may include yeast (such as Saccharomyces cerevisiae and Saccharomyces cerevisiae), insect cells (such as Drosophila cells and Lepidoptera cells), plants and plant cells (such as tobacco, corn, rice, algae and duckweed). Performance. Eukaryotic cells used for expression also include mammalian cell lines, such as Chinese hamster ovary (CHO) cells, human embryonic kidney (HEK293) cells, or baby hamster kidney (BHK) cells. Eukaryotic expression hosts also include production in transgenic animals, including, for example, production in serum, milk, and eggs.

Many expression vectors are available and known to those of ordinary skill in the art and can be used to express proteins. The choice of expression vehicle will be affected by the choice of host presentation system. Generally speaking, expression vectors may include a transcriptional promoter and optionally an enhancer, a translational signal and a transcriptional and translational termination signal. Expression vectors used for stable transformation typically have selectable markers that allow selection and maintenance of transformed cells. In some cases, origins of replication can be used to amplify the number of copies of the vector in a cell.

TNFR1 antagonists, TNFR2 agonists, and the bispecific TNFR1 antagonist/TNFR2 agonist constructs herein may also be expressed as protein fusions. For example, fusion proteins can be produced to add additional functionality to a polypeptide. Examples of fusion proteins include, but are not limited to, fusions of signal sequences, such as tags for localization (e.g., his6 tag or myc tag) or tags for purification (e.g., GST fusions) and for directing protein secretion and/or membrane The sequence of associations. Fusion proteins also include fusions with the Fc region of IgG and linkers, such as the hinge sequence of IgG and/or the glycine-serine (GS) peptide linker. Alternatively, in some embodiments, TNFR1 antagonists, TNFR2 agonists, and the bispecific TNFR1 antagonist/TNFR2 agonist constructs herein can also be fused to serum albumin.

For long-term high-yield production of recombinant proteins, stable performance is desired. For example, cell lines that stably express polypeptides can be transformed using expression vectors containing viral origins of replication or endogenous expression elements and selectable marker genes. After introduction of the vector, the cells can be allowed to grow in rich medium for 1-2 days before the rich medium is exchanged for selective medium. The purpose of the selectable marker is to confer resistance to selection, and its presence allows for the growth and recovery of cells that successfully express the introduced sequence. Resistant cells of stably transformed cells can be propagated using tissue culture techniques appropriate to the cell type.

Many selection systems are available for recovery of transformed cell lines. Such features include, but are not limited to, herpes simplex virus (HSV) thymidine kinase (TK) (see, e.g., Wigler et al., (1977) Cell 11:223-232) and adenine phosphoribosyltransferase (APRT) (see, e.g., Lowy , I. et al. (1980) Cell , 22:817-23) genes, which can be used in TK ^- or APRT ^- cells, respectively. Additionally, antimetabolite, antibiotic or herbicide resistance can be used as a basis for selection. For example, dihydrofolate reductase (DHFR), which confers resistance to methotrexate (see, e.g., Wigler et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-70), can be used respectively; npt that confers resistance to the aminoglycosides neomycin and G-418 (see, e.g., Colbere-Garapin et al. (1981) J. Mol. Biol. 150:1-14); and confers resistance to chlorsulfuron and glufosinate Dyltransferase-resistant als or pat. Additional selectable genes have been described, such as trpB, which enables cells to utilize indole instead of tryptophan; or hisD, which allows cells to utilize histidinol instead of histidine (see, e.g., Hartman, SC and RC Mulligan (1988) Proc. Natl. Acad. Sci. USA 85:8047-8051). Visible markers such as, but not limited to, anthocyanins, beta-glucuronidase and its substrate GUS, and luciferase and its substrate luciferin can also be used to identify transformants and are also quantitatively attributable. The amount of transient or stable protein expression in a specific vector system (see, e.g., Rhodes et al. (1995) Methods Mol. Biol. 55:121-131). a. Prokaryotic cells

Prokaryotes, especially E. coli, provide a system for producing large amounts of proteins. Prokaryotic expression systems are generally used to produce products that are not glycosylated. Transformation of E. coli protocols is well known to those of ordinary skill in the art. E. coli expression vectors may contain inducible promoters; such promoters are suitable for inducing the expression of high levels of proteins and for the expression of proteins that exhibit some toxicity to the host cell. Examples of inducible promoters include, for example, the lac promoter, the trp promoter, the hybrid tac promoter, the T7 and SP6 RNA promoters, and the temperature-regulated lambda PL promoter.

Polypeptides and fusion protein constructs provided herein, such as any polypeptide and fusion protein constructs provided herein, can be expressed in the cytoplasmic environment of E. coli. The cytoplasm is a reducing environment, and for some molecules this can lead to the formation of insoluble inclusion bodies. Reducing agents (such as dithiothreitol and β-mercaptoethanol) and denaturing agents (such as guanidine-HCl and urea) can be used to resolubilize proteins. An alternative approach is to express the protein in the periplasmic space of bacteria providing an oxidative environment and chaperone protein-like and disulfide isomerase enzymes, and allowing the production of soluble proteins. Typically, a leader sequence is fused to the protein to be expressed, which directs the protein to the periplasm. The leader sequence is then removed by signal peptidase within the periplasm. Exemplary pathways that express protein translocation into the periplasm are the Sec pathway, the SRP pathway, and the TAT pathway. Examples of periplasmic targeting leaders include the pelB leader, StII leader, and DsbA leader from the pectin disintegrase gene and the leader derived from the alkaline phosphatase gene. In some cases, periplasmic expression allows leakage of the expressed protein into the culture medium. Secretion of proteins allows rapid and simple purification from culture supernatants. Unsecreted proteins can be obtained from the periplasm by osmotic solubilization. Similar to cytoplasmic behavior, in some cases proteins can become insoluble, and denaturants and reducing agents can be used to promote solubilization and refolding. The temperature of induction and growth can also affect expression and solubility; temperatures between 25°C and 37°C are typically used. Typically, bacteria produce glycosylated proteins. Thus, if glycosylation is required for protein function, glycosylation can be added in vitro after purification from the host cell. b. Yeast cells

Yeasts such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Yarrowia lipolytica, Kluyveromyces lactis, and Saccharomyces methanolica are well-known performance hosts that can be used to produce proteins, such as any of the proteins described herein. Yeast can be transformed via episomal replicating vectors or via stable chromosomal integration via homologous recombination. Typically, inducible promoters are used to regulate gene expression. Examples of such promoters include GAL1, GAL7 and GAL5, as well as metallothionein promoters such as CUP1, AOX1 or other Pichia or other yeast promoters. Expression vectors typically include selectable markers for selection and maintenance of transformed DNA, such as LEU2, TRP1, HIS3 and URA3. Proteins expressed in yeast are often soluble. Co-expression of chaperones such as Bip and protein disulfide isomerase can increase expression and solubility. Additionally, proteins expressed in yeast may be directed toward the use of secretion signal peptide fusions (such as the yeast-matched alpha-factor secretion signal from Saccharomyces cerevisiae) and fusions to yeast cell surface proteins (such as Aga2p-matched adhesion receptors or Arxula adeninivorans amylase) secretion. Protease cleavage sites, such as those used for Kex-2 protease, can be engineered to remove fusion sequences from expressed polypeptides as they exit the secretory pathway. Yeast is also able to glycosylate on the Asn-X-Ser/Thr motif. c. Insects and insect cells

Insect cells, especially expressed using baculovirus, are suitable for expressing polypeptides, including antibodies or fragments thereof. Insect cells express high levels of proteins and are capable of carrying out most of the post-translational modifications used by higher eukaryotes. Baculoviruses have a restricted host range, which improves safety and reduces regulatory issues for eukaryotic expression. Typically, expression vectors use promoters for high-content expression, such as the baculovirus polyhedrin promoter and the p10 promoter. Baculovirus systems include baculoviruses, such as Alfalfa Spodoptera, California nuclear polyhedrosis virus (AcNPV) and Bombyx mori nuclear polyhedrosis virus (BmNPV); and insect cell lines, such as Sf9, TN derived from Trichopodia exigua, A7S derived from the armyworm and DpN1 derived from the monarch butterfly. For high-level expression, the nucleotide sequence of the molecule to be expressed is fused immediately downstream of the start codon of the polyhedrin protein of the virus. To generate baculovirus recombinants capable of expressing human antibodies, dual expression transfers such as pAcUW51 (PharMingen) can be used. Mammalian secretion signals are precisely processed in insect cells and can be used to secrete expressed proteins into the culture medium. The cell lines A7S and DpN1 produce proteins with glycosylation patterns similar to mammalian cell lines. Exemplary insect cells are insect cells that have been altered to reduce immunogenicity, including insect cells with "mammalian" baculovirus expression vectors and insect cells lacking the enzyme FT3.

An alternative expression system in insect cells is the use of stably transformed cells. Cell lines such as Schneider 2 (S2) and Kc cells (Drosophila melanogaster) and C7 cells (Aedes albopictus) can be used for expression. The Drosophila metallothionein promoter can be used to induce high levels of expression in the presence of heavy metal induction with cadmium or copper. The baculovirus immediate early gene promoter IE1 can be used to induce consistent expression amounts. Typical expression vectors include pIE1-3 and pI31-4 transfer vectors (Novagen). Expression vectors are typically maintained through the use of selectable markers such as neomycin and hygromycin. d. Mammalian expression cells

Mammalian expression systems can be used to express polypeptides, including constructs herein, including TNFR1 antagonists, TNFR2 agonists, bispecific TNFR1 antagonist/TNFR2 agonist constructs, and fusions thereof, provided herein. Constructs can be expressed by viral infection (such as with adenovirus) or by direct DNA transfer (such as by using liposomes, calcium phosphate and DEAE-polydextrose) and by physical means (such as electroporation and microinjection) transferred to mammalian cells. Expression vectors for use in mammalian cells typically include an mRNA capping site, a TATA box, a translation initiation sequence (Kozak consensus sequence), and a polyadenylation element. Internal ribosome entry site (IRES) elements can also be added to allow bicistronic expression with another gene (such as a selectable marker). Such vectors often include transcriptional promoter-enhancers for high-level performance, such as the SV40 promoter-enhancer, the human cytomegalovirus (CMV) promoter, and the long terminal repeats of Roussema virus (RSV). These promoter-enhancers are active in a variety of cell types. Tissue- and cellular-type promoter and enhancer regions can also be used for expression. Exemplary promoter/enhancer regions include, but are not limited to, genes derived from proteins such as elastase I, insulin, immunoglobulins, mouse mammary tumor virus, albumin, alpha fetoprotein, alpha-1 antitrypsin, beta hemoglobulin, myeloid Promoter/enhancer regions of genes controlled by sphingomyelin, myosin light chain 2 and gonadotropin-releasing hormone genes.

Selectable markers can be used to select and maintain cells with expression constructs. Examples of selectable marker genes include, but are not limited to, hygromycin B phosphotransferase, adenosine deaminase, xanthine-guanine phosphoribosyltransferase, aminoglycoside phosphotransferase, and dihydrofolate reductase (DHFR) and thymidine kinase (TK). For example, expression can be performed in the presence of methotrexate to select only those cells that express the DHFR gene. Modified anti-TNFR antibodies and antigen-binding fragments thereof can be produced, for example, using the NEOR/G418 system, the dihydrofolate reductase (DHFR) system, or the glutamine synthetase (GS) system. The GS system uses combined expression vectors, such as pE12/pEE6, to express heavy and light chains. Fusions to cell surface signaling molecules such as TCR-ζ and Fc _ε RI-γ direct the expression of proteins in an active state on the cell surface.

Many cell lines are available for mammalian expression, including mouse, rat, human, monkey, chicken, and hamster cells. Exemplary cell lines include, but are not limited to, BHK (e.g., BHK-21 cells), 293-F, CHO, CHO expression (CHOX; ExcellGene), Balb/3T3, HeLa, MT2, mouse NS0 (non-secreting), and other myeloma Cell lines, fusion tumor and xenogeneic fusion tumor cell lines, lymphocytes, fibroblasts, Sp2/0, COS, NIH3T3, HEK293, 293S, 2B8 and HKB cells. Cell lines suitable for serum-free media are also available, which facilitates purification of secreted proteins from the cell culture medium. Examples include CHO-S cells (Invitrogen®, Carlsbad, CA, catalog number 11619-012) and the serum-free EBNA-1 cell line (see, eg, Pham et al. (2003) Biotechnol. Bioeng. 84:332-342). Cell lines suitable for growth in special media optimized for maximum performance are also available. For example, DG44 CHO cells are suitable for growth in suspension culture in chemically defined animal product-free media. e. Plants

Transgenic plant cells and plants can be used to express polypeptides and proteins, such as any described herein. Expression constructs are typically delivered to plants using direct DNA delivery (such as by microprojectile bombardment) and PEG-mediated delivery to protoplasts and Agrobacterium-mediated transformation. Expression vectors may include promoter and enhancer sequences, transcription termination elements, and translation control elements. Expression vectors and transformation technologies are generally divided between dicot hosts (such as Arabidopsis and tobacco) and monocot hosts (such as maize and rice). Examples of plant promoters for expression include, for example, the cauliflower mosaic virus promoter (CaMV 35S), the nopaline synthase promoter, the ribose bisphosphate carboxylase promoter, and ubiquitin (e.g., maize ubiquitin 1 ( ubi- 1) )) and UBQ3 promoter. Selectable markers, such as hygromycin, phosphomannose isomerase, and neomycin phosphotransferase, are often used to facilitate the selection and maintenance of transformed cells. Transformed plant cells can be maintained as cells, aggregates (callus) in culture, or regenerated into whole plants. Transgenic plant cells may also include algae engineered to produce polypeptides. Because plants have different glycosylation patterns than mammalian cells, this can affect the selection of proteins produced in these hosts. 5. Purification

Host cells transformed with nucleic acids encoding polypeptide constructs provided herein can be cultured under conditions suitable for expression and recovery of the encoded protein from cell culture. Proteins produced by recombinant cells are generally secreted but may be contained within the cell, depending on the sequence and/or vector used. As is understood by those of ordinary skill in the art, expression vectors containing nucleic acid molecules encoding polypeptides provided herein can be designed to have signal sequences that facilitate direct secretion of the expressed polypeptides through prokaryotic or eukaryotic cell membranes.

The method used to purify polypeptides from host cells depends on the host cell and expression system chosen. For secreted molecules, the protein is typically purified from the culture medium after removal of the cells. For intracellular expression, cells can be lysed and proteins can be purified from the extracts. When transgenic organisms such as transgenic plants and animals are used for expression, tissues or organs can be used as starting material to prepare lysate cell extracts. In addition, the production of transgenic animals can include the production of polypeptides in milk or eggs that can be collected, and if necessary, the proteins can be extracted and further purified using standard methods in the art.

Polypeptides, such as TNFR1 antagonist constructs, TNFR2 agonist constructs, TNFR1 antagonist/TNFR2 agonist bispecific constructs, and other constructs provided herein and their components may be used by those of ordinary skill in the art. Purification using known protein purification techniques. This includes, but is not limited to: SDS-PAGE, particle size screening and size exclusion chromatography, ammonium sulfate precipitation, chelating agent chromatography, column chromatography, HPLC, dialysis and ion exchange chromatography, such as anion exchange and combinations thereof . Affinity purification techniques can also be used. The constructs herein may be purified using methods developed for the purification of antibodies and antibody fragments. Examples of methods for purifying antibodies and antibody fragments are methods involving column chromatography, in which a solid support column material is linked to protein G, a cell surface-associated protein from Streptococcus that binds immunoglobulins with high affinity. Antibodies and antibody fragments can also be purified by methods including protein A chromatography, where protein A is a cell surface-associated protein from Staphylococcus aureus that binds immunoglobulins, such as IgG, with high affinity to a solid support column . Other immunoglobulin-binding bacterial proteins that can be used to purify antibodies and antibody fragments include Protein A/G, a recombinant fusion protein combining the IgG binding domains of Protein A and Protein G; and Protein L, a surface protein from Peptostreptococcus. ( See, e.g., Bjorck (1988) J. Immunol. 140(4):1194-1197; Kastern et al. (1992) J. Biol. Chem . 267(18):12820-12825; Eliasson et al. (1988) J. Biol . Chem. 263:4323-4327). The construct is substantially pure, typically at or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure. Purity can be assessed by standard methods, such as by SDS-PAGE and Coomassie blue staining.

When antibodies and their fragments and related polypeptides are expressed from large numbers of transformed bacteria, typically after promoter induction, the polypeptides can form insoluble aggregates, although expression can be constitutive. Protocols for purifying polypeptide inclusion bodies are known to those of ordinary skill in the art. For example, in one method, the cell suspension is centrifuged to assemble the inclusion bodies, and the aggregated pellets containing the inclusion bodies are resuspended in a buffer, such as 20 mM Tris-HCL (pH 7.2), 1 mM EDTA, 150 mM NaCl and 2% Triton-X 100 (non-ionic detergent, does not damage inclusion bodies but dissolves contaminants). Washing steps can be repeated to remove as much cell debris as possible. The remaining aggregates of inclusion bodies are resuspended in an appropriate buffer (such as 20 mM sodium phosphate, pH 6.8, 150 mM NaCl). Other suitable buffers as well as alternative purification schemes are known or can be developed by one of ordinary skill in the art.

Other methods, antibodies and fragments thereof, and constructs provided herein may be used or developed for purification. It can be purified from the bacterial periplasm. For deriving polypeptides from the bacterial periplasm in which they are produced, the periplasmic portion of the bacteria can also be isolated by cryo-osmotic shock, in addition to other methods known to those of ordinary skill in the art. For example, in one method, recombinant polypeptides are isolated from the periplasm and bacterial cells are centrifuged to form aggregates. The aggregated pellets were resuspended in buffer containing 20% sucrose. To lyse the cells, the bacteria were centrifuged and the pellet resuspended in _ice -cold 5 mM MgSO and kept in an ice bath for approximately 10 minutes. The cell suspension was centrifuged and decanted and the supernatant was saved. Recombinant polypeptides present in the supernatant can be separated from host proteins by standard separation techniques well known to those of ordinary skill in the art. Such methods include, but are not limited to, the following steps: particle size screening, size difference filtration, and column chromatography.

Expression constructs may also be engineered to include nucleic acids encoding affinity tags, for example, for detection or purification of expression products operably linked to the encoded polypeptide upon expression. Affinity tags include, for example, small ubiquitin modifier (SUMO) tags, myc epitopes, GST fusions, or His6, which are affinity purified using SUMO, myc antibodies, glutathione resin, and Ni resin, respectively. Nucleic acids encoding such tags can be ligated to nucleic acids encoding the polypeptide constructs provided herein. Tags can facilitate purification and/or detection of soluble proteins. For example, a TNFRl antagonist polypeptide construct, or portion thereof, may be represented by a recombinant protein with the addition of one or more other polypeptide domains to facilitate protein purification. Purification of facilitating domains includes, but is not limited to, metal-chelating peptides such as histidine-tryptophan modules that allow purification on immobilized metals, protein A domains that allow purification on immobilized immunoglobulins, and for FLAGS extension/affinity purification system (Immunex Corp., Seattle, WA). Encoding a cleavable linker sequence is included between the purification domain and the encoded expression polypeptide, such as a Factor Xa cleavable recognition site (Ile-Glu-Gly-Arg, engineered to include an Nru I restriction site, see e.g. EP 92115607A ) or enterokinase (Invitrogen (Thermo Fisher Scientific), San Diego, CA) to facilitate purification. Exemplary expression vectors encode expression of a fusion protein containing a TNFR1 antagonist and/or TNFR2 agonist polypeptide and an enterokinase cleavage site. The small ubiquitination modifier (SUMO) tag facilitates purification by immobilized metal ion affinity chromatography (IMIAC), and the enterokinase cleavage site provides cleavage sites for purified peptides from the fusion protein.

Purity can be assessed by any method known in the art, including gel electrophoresis, orthogonal HPLC methods, staining, and spectrophotometric techniques. Expressed and purified polypeptides may be analyzed using any assay or method known to one of ordinary skill in the art, such as any method described herein. Such analysis includes analysis based on the physical and/or functional properties of the polypeptide, including but not limited to analysis by gel electrophoresis analysis, immunoassays, binding assays and TNF-mediated TNFR1 and/or TNFR2 activity. 6. Additional modifications

Provided modified TNFR1 antagonist constructs, TNFR2 agonist constructs, bispecific TNFR1 antagonist/TNFR2 agonist constructs, and other constructs as described above, as well as components thereof including altered pharmacological properties , including components with pharmacokinetic and pharmacodynamic properties (activity modulators). Portions of constructs such as TNFR1 inhibitor polypeptides and small molecules and TNFR2 agonist polypeptides and small molecules can be conjugated to polymers or polymeric moieties, such as, but not limited to, polyethylene glycol (PEG) moieties or polydextrose, or to Human serum albumin (HSA) may be sialylated to reduce immunogenicity and/or increase half-life in serum and other body fluids. Polypeptides can also be linked to purification tags, such as His tags or SUMO sequences. Other modifications include, for example, glycosylation, carboxylation, hydroxylation, phosphorylation or other known modifications. Glycosylation can be incorporated in vitro using appropriate expression systems, such as mammalian expression systems, or via a combination of in vivo and in vitro methods, where for example the polypeptide is expressed in prokaryotic cells and glycosylated in vitro using enzymatic cleavage Further embellishments. Other modifications can be performed in vitro or, for example, by producing the modified polypeptide in a host suitable for producing such modifications.

Modulators and modifications effect and select such modifications or activities such that the modified polypeptide has the modified functionality compared to the non-fused or unmodified polypeptide and retains the functionality compared to the non-fused or unmodified polypeptide. At least a portion, generally at least 50%, 60%, 70%, 80%, 90% or 95% active, including 96%, 97%, 98%, 99% or higher active. For example, a TNFR1 antagonist construct retains the ability to inhibit TNF-mediated signaling via TNFR1.

The linkage of a polypeptide, such as a TNFR1 antagonist or a TNFR2 agonist, to another polypeptide can be accomplished directly or indirectly via a linker. In one example, attachment may be by chemical linkage, such as via a heterobifunctional agent, or a thiol linkage, or other such linkage. Fusion can also be achieved by recombining performance. Fusions of a polypeptide, such as a TNFR1 antagonist or TNFR2 agonist, and another polypeptide can be at the N-terminus or C-terminus of the TNFR1 antagonist or TNFR2 agonist polypeptide. Non-limiting examples of polypeptides that may be used in fusion proteins with the TNFR1 antagonist or TNFR2 agonist polypeptides provided herein include, for example, GST (glutathione S-transferase) polypeptides, Fc from immunoglobulin G Domains, albumins, heterologous signal sequences, and combinations thereof.

The encoded constructs can be produced by standard recombination techniques. For example, DNA fragments encoding different polypeptide moieties are ligated in frame according to conventional techniques, such as by using blunt or staggered ends for ligation, restriction enzyme digestion to provide appropriate ends, filling of sticky ends as needed, Avoid alkaline phosphatase treatment and enzymatic ligation that is not required for ligation. Fusion genes can be synthesized by conventional techniques, including automatic DNA synthesizers. Alternatively, PCR amplification of gene fragments can be performed using anchor primers that generate complementary overhangs between two contiguous gene fragments, which can subsequently be ligated and reamplified to create chimeric genes. Many expression vectors (eg, GST polypeptides) that already encode fusion moieties are commercially available. Polypeptide-encoding nucleic acids can be cloned into such expression vectors such that the fusion moieties are linked in-frame to TNFRl antagonist, TNFR2 agonist, and multispecific (such as bispecific as provided herein) constructs. a.PEGylation _

Polyethylene glycol (PEG) is used in biomaterials, biotechnology and medicine; it is a biocompatible, non-toxic, water-soluble polymer that is generally non-immunogenic. In the field of drug delivery, PEG derivatives are used to covalently attach to proteins (i.e., "PEGylation") to reduce immunogenicity, proteolysis, and renal clearance, increase serum half-life, and enhance solubility. (See, eg, Zalipsky (1995) Adv. Drug Del. Rev. 16:157-182). PEG has been attached to low molecular weight, relatively hydrophobic drugs to enhance solubility, reduce toxicity, and alter biodistribution. Binding to linear or branched PEG moieties increases the molecular weight and hydrodynamic radius of the polypeptide and decreases the glomerular filtration rate by the kidneys. Typically, pegylated drugs are administered in solution, such as by injection. In the constructs herein, the PEGylated moiety and other such polymers may be part of the linker moiety of the construct.

A related application is the synthesis of cross-linked degradable PEG networks or formulations for drug delivery, since many of the same chemistries used in the design of degradable, soluble drug carriers can also be used in the design of degradable gels ( See, for example, Sawhney et al. (1993) Macromolecules 26:581-587). Intermolecular complexes can be formed by mixing solutions of two complementary polymers. Such complexes are formed by electrostatic interactions (polyanions-polycations) and/or hydrogen bonds (polyacids-polybases) between the polymers involved and/or by hydrophobicity between polymers in the culture medium. interaction to stabilize. (See, eg, Krupers et al. (1996) Eur. Polym. J. 32:785-790). For example, mixing solutions of polyacrylic acid (PAAc) and polyethylene oxide (PEO) under appropriate conditions results in the formation of mostly hydrogen bond-based complexes. The breakdown of these complexes under physiological conditions has been used to deliver drugs ( i.e. non-PEGylated) drugs. Compounds of complementary polymers have been formed from homopolymers and copolymers.

Many reagents for pegylation are known, as do pegylated therapeutic proteins. Such reagents include, but are not limited to, N-hydroxysuccinimide (NHS) activated PEG, succinimide mPEG, mPEG2-N-hydroxysuccinimide, mPEG succinimide alpha. -Methyl butyrate, mPEG succinimide propionate, mPEG succinimide butyrate, mPEG carboxymethyl 3-hydroxybutyrate succinimide, homobifunctional PEG-succinimidyl propionate, homologous bifunctional PEG propionaldehyde, homologous bifunctional PEG butyraldehyde, PEG maleimide, PEG hydrazine, p-nitrophenyl-carbonate PEG , mPEG-benzotriazole carbonate, propionaldehyde PEG, mPEG butyraldehyde, branched chain mPEG2 butyraldehyde, mPEG acetyl, mPEG piperidone, mPEG methyl ketone, mPEG "linker-less" maleic acid Imine, mPEG vinyl sulfide, mPEG thiol, mPEG o-pyridyl thioester, mPEG o-pyridyl disulfide, Fmoc-PEG-NHS, Boc-PEG-NHS, vinyl styrene PEG-NHS, acrylate PEG- NHS, luciferin PEG-NHS and biotin PEG-NHS (see, eg, Veronese et al. (1997) J. Bioactive Compatible Polymers 12:197-207; and numerous US and world patents). In one example, polyethylene glycol has a molecular weight in the range of about 3 kDa to about 50 kDa, and typically about 5 kDa to about 30 kDa. Covalent attachment of PEG to a drug (called "PEGylation") can be accomplished by known chemical synthesis techniques. For example, PEGylation of a protein can be achieved by reacting NHS-activated PEG with the protein under suitable reaction conditions.

Although many reactions have been described for PEGylation, reactions that are generally most applicable to proteins impart directionality, utilize mild reaction conditions, and do not require extensive subsequent processing to remove toxic catalysts or by-products. For example, monomethoxyPEG (MPEG) has only one reactive terminal hydroxyl group, and its use therefore limits the resulting PEG-protein product mixture to a certain heterogeneity. Activation of the hydroxyl group at the polymer terminus opposite the terminal methoxy group is generally required to achieve efficient protein PEGylation, with the goal of making the derivatized PEG more susceptible to nucleophilic attack. The attacking nucleophile is usually the ε-amine group of the amine acyl residue, but if local conditions are favorable, other amines can also react (such as the N-terminal α-amine of histidine or cyclic amines). More directed attachment is possible in proteins containing a single lysine or cysteine. This latter residue can be targeted for thiol-specific modification by PEG-maleimide. Alternatively, PEG hydrazine can be reacted with iodate-oxidized proteins and reduced in the presence of _NaCNBH . More specifically, PEGylated CMP sugars can react with proteins in the presence of appropriate glycosyltransferases. One technique is "PEGylation" in which multiple polymer molecules are coupled to the polypeptide in question. When this technology is used, the immune system has difficulty recognizing epitopes on the surface of the polypeptide responsible for the formation of antibodies, thereby reducing the immune response. For polypeptides (i.e., drugs) that are directly introduced into the human circulation system to produce specific physiological effects, typical potential immune responses are IgG and/or IgM reactions, while polypeptides inhaled through the respiratory system (i.e., industrial peptides) may cause IgE reactions. (i.e. allergic reaction). One theory to explain the reduced immune response is that polymer molecules shield epitopes on the surface of the polypeptide responsible for the immune response that leads to antibody formation. Another theory, at least in part, is that the heavier the conjugate, the more the immune response is reduced.

For example, the PEG ester polypeptide constructs and polypeptide components provided herein are associated with the polypeptide via covalent linkage. Techniques for PEGylation include, but are not limited to, the use of specialized linkers and coupling chemistries (see, e.g., Harris (2002) Adv. Drug Deliv. Rev. 54:459-476), attachment of multiple PEG moieties to a single binding site (such as via the use of branched PEG; see, eg, Veronese et al., (2002) Bioorg. Med. Chem. Lett . 12:177-180), site-specific PEGylation, and/or monoPEGylation (See, eg, Chapman et al. (1999) Nature Biotech . 17:780-783) and site-directed enzymatic pegylation (see, eg, Sato (2002) Adv. Drug Deliv. Rev. 54:487-504). Methods and techniques described in the art can produce proteins with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 PEGs or PEG derivatives attached to a single protein molecule ( See, for example, U.S. Patent Publication No. 2006/0104968). b.Albuminization _

The polypeptides provided herein, such as TNFR1 antagonist constructs, TNFR2 agonist constructs, and multispecific TNFR1 antagonist/TNFR2 agonist constructs, can be fused (i.e., "albuminated") to albumin, For use in human therapeutics, fused to human serum albumin (HSA) to increase the half-life, stability, bioavailability and distribution of the polypeptide and/or improve pharmacological properties, such as pharmacokinetics. A number of products related to human serum albumin (HSA) are approved for use as therapeutic agents, including as cancer therapeutics, and for the treatment of type 2 diabetes (see e.g. AlQahtani et al. (2019) Biomed and Pharmacotherapy 113:108750; Roscoe et al. Man (2018) Mol. Pharmaceutics 151:15046-5047; Strohl, WR (2015) BioDrugs 4:215-239). In some embodiments, mature HSA proteins lacking signal and activation sequences are fused to related proteins. In some examples, serum albumin, such as human serum albumin (HSA), is conjugated to the polypeptide. An exemplary HSA protein is set forth in SEQ ID NO: 35.

This article provides integration with HSA. These include fusion of HSA to the N- or C-terminus of a TNFR1 antagonist (such as a dAb, scFv, Fab or other antigen-binding fragment as provided herein) or a TNFR2 agonist (such as a TNF mutein), typically via a short peptide Linkers such as, but not limited to, glycine-serine (GS) linkers, such as (GSGS) _n or (GGGGS) _n , where n=1-5 or 6. Exemplary TNFR1 antagonist-HSA fusions are set forth in SEQ ID NOs: 709, 713, 717, 721, and 725. c.Purification tag

In some examples, the TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, and fusion proteins provided herein can be used to purify the product. label. Exemplary tags for purification are described elsewhere herein. For example, the exemplary polypeptides herein may contain SUMO or His sequences for purification. Typically, the tag is a cleavable tag.

Polypeptide constructs provided herein, including fusion proteins, may include a His purification tag, such as a 6xHis tag. His-tagged polypeptides may optionally contain fusion partners and/or signals for expression and secretion. For example, an exemplary His polypeptide fusion protein may contain a human immunoglobulin light chain kappa (κ) leader signal peptide sequence (SEQ ID NO: 835), a 6xHis tag (SEQ ID NO: 836), a SUMO sequence (SEQ ID NO: 837) and one or more of HSA (SEQ ID NO: 35). In another example, an exemplary His-tagged polypeptide fusion protein may contain a human immunoglobulin light chain kappa (κ) leader signal peptide sequence (SEQ ID NO: 835), a 6xHis tag (SEQ ID NO: 836), a SUMO sequence (SEQ ID NO: 837) and IgG Fc (see, eg, SEQ ID NO: 10, 12, 14, 16, 27 and 30).

In some embodiments, the polypeptides and fusion proteins provided herein may include His tags and/or SUMO sequences for accumulation in inclusion bodies. For example, the His-SUMO sequence set forth in SEQ ID NO: 838 can be linked to any of the polypeptides or fusion proteins provided herein. His-SUMO tagged polypeptides may optionally contain fusion partners and/or signals for expression and secretion. For example, the His-SUMO-polypeptide fusion protein may contain a human immunoglobulin light chain kappa (κ) leader signal peptide sequence (SEQ ID NO: 835), a 6xHis tag (SEQ ID NO: 836), a SUMO sequence (SEQ ID NO: 837) and HSA (SEQ ID NO: 35). In another example, an exemplary His-SUMO-polypeptide fusion protein may contain a human immunoglobulin light chain kappa (κ) leader signal peptide sequence (SEQ ID NO: 835), a 6xHis tag (SEQ ID NO: 836), SUMO sequence (SEQ ID NO: 837) and IgG Fc (see, eg, SEQ ID NO: 10, 12, 14, 16, 27 and 30). 7. Nucleic acid molecules and gene therapy

Nucleic acid molecules encoding polypeptide constructs that are fusion proteins provided herein may be used in gene therapy, such as for expression in a gene therapy vector or for administration as a DNA or RNA construct. Among them, some TNFR1 antagonists, TNFR2 agonists and bispecific TNFR1 antagonist/TNFR2 agonist constructs provided herein are provided as fusion proteins. Provided herein are nucleic acid molecules encoding such constructs as well as vectors and other delivery vehicles. A nucleic acid molecule may encode a nucleic acid molecule that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any polypeptide or construct provided herein. % sequence identity of the peptide. In another specific example, a nucleic acid molecule may include a nucleic acid molecule having a degenerate codon sequence encoding any of the polypeptides or constructs provided herein.

Nucleic acid molecules used in gene therapy are optionally operably linked to regulatory sequences of the nucleic acid. Such regulatory sequences include promoters, enhancers, signal sequences and other transport sequences, and other such regulatory sequences that are well known to those of ordinary skill in the art. For vectors with tropism for a particular tissue, the regulatory sequences may be specific for such tissue (for long-term gene expression, such as the liver, or for any ophthalmic application, the eye). Exemplary promoters include inducible and constitutive promoters for expression in mammalian cells. Such promoters, as those recognized in eukaryotic (such as mammalian) individuals, include, but are not limited to, CMV and SV40 promoters; adenovirus promoters, such as the E2 gene promoter, which responds to the E7 oncoprotein ; PV promoters, such as the BPV p89 promoter, which is responsive to the PV E2 protein; and other suitable promoters.

The polypeptides provided herein can also be delivered to cells in gene transfer vectors. The transfer vector may also encode additional therapeutic agents for the treatment of diseases or conditions described herein or known in the art, such as rheumatoid arthritis or any other chronic inflammatory, autoimmune, neurodegenerative or demyelogenous disease A sheath disease or condition for which a polypeptide is administered. Transfer vectors encoding polypeptides provided herein can be administered systemically by administering nucleic acid molecules to an individual. For example, the transfer vector can be a viral vector, such as an adenoviral vector. Vectors encoding polypeptides or constructs herein can also be incorporated into stem cells, and such stem cells can be administered to an individual, such as by transplanting or transplanting the stem cells at the site for therapy. For example, mesenchymal stem cells (MSCs) can be engineered to express therapeutic polypeptides, and such MSCs can be transplanted at the transplantation site for treatment.

The nucleic acid may be administered in vivo, such as systemically or by any other route, or in vitro, such as by removing cells (including lymphocytes), introducing the nucleic acid therein, and reintroducing it into a host or compatible recipient, and Non-delivery protein.

Polypeptides can be delivered to cells and tissues through the expression of nucleic acid molecules. Polypeptides can be administered as nucleic acid molecules encoding the polypeptide, including in vitro techniques and direct in vivo expression. Nucleic acids can be delivered to cells and tissues by any method known to those of ordinary skill in the art. Isolated nucleic acid sequences can be incorporated into vectors for further manipulation. Methods of administering polypeptides through expression of encoding nucleic acid molecules include administration of recombinant vectors. The vector may be designed to remain episomal, such as by including an origin of replication, or may be designed to integrate into the chromosome of the cell. Nucleic acid molecules encoding the polypeptides provided herein may also be used in in vitro gene expression therapy using non-viral vectors. For example, a cell can be engineered to express a polypeptide operably linked to a regulatory sequence or positioned so that it is operably linked to a regulatory sequence in a location within the genome. Such cells can then be administered locally or systemically to an individual, such as a patient in need of treatment.

Gene therapy vectors may remain episomal or may be integrated into the chromosomes of the treated individual. The polypeptide can be expressed by a virus that is administered to an individual in need of treatment. Viral vectors suitable for gene therapy include adenovirus, adeno-associated virus (AAV), retrovirus, lentivirus, vaccinia virus and other viruses mentioned above. Viral vectors including, for example, adenovirus, adeno-associated virus (AAV), poxvirus, herpesvirus, retrovirus, and other viral vectors designed for gene therapy may be used. AAV vectors are available with altered tropism, such as against hepatocytes. AAV vectors consist of a tropism-conferring capsid and nucleic acid encoding a polypeptide flanked by an ITR.

For example, adenovirus expression technology is well known in the art, and methods of adenovirus production and administration are also well known. Adenovirus serotypes can be obtained, for example, from the American Type Culture Collection (ATCC, Rockville, MD). Adenoviral vectors can be used in vitro, eg, cells isolated from a patient in need of treatment and transduced with polypeptide-expressing adenoviral vectors. After a suitable culture period, the transduced cells are administered to the individual locally and/or systemically. Alternatively, the polypeptide adenoviral particles are isolated and formulated in a pharmaceutically acceptable carrier for delivery of a therapeutically effective amount to prevent, treat, or ameliorate a disease or condition in an individual. Typically, adenoviral particles are delivered at a dose ranging from 1 particle to 10 ¹⁴ particles per kilogram of subject body weight, generally between 10 ⁶ or 10 ⁸ particles to 10 ¹² particles per kilogram of subject body weight. In some cases, it is desirable to provide the nucleic acid source with a cell-targeting agent, such as an antibody specific for a cell surface membrane protein or the target cell, or a ligand for a receptor on the target cell. The polypeptides or constructs provided herein can also be targeted for delivery to specific cell types. For example, adenoviral vectors encoding polypeptides or constructs provided herein can be used for stable expression in non-dividing cells, such as liver cells (see, eg, Margaritis et al. (2004) J. Clin. Invest . 113:1025-1031 ). In another example, viral or non-viral vectors encoding polypeptides or constructs herein can be transduced into isolated cells for subsequent delivery. Additional cell types for expression and delivery include, but are not limited to, fibroblasts and endothelial cells.

Nucleic acid molecules can be introduced into artificial chromosomes and other non-viral vectors. Artificial chromosomes, such as ACES (see Lindenbaum et al., (2004) Nucleic Acids Res. 32(21):e172), can be engineered to encode and express isomers. Briefly, mammalian artificial chromosomes (MACs) provide a way to introduce larger payloads of genetic information into cells in an autonomously replicating, non-integrating form. Unique among MACs, mammalian satellite DNA-based artificial chromosomal expression (ACE) can be reproducibly regenerated in cell lines of different species and easily purified from host cell chromosomes. Purified mammalian ACE can then be reintroduced into a variety of recipient cell lines that have been stably maintained for extended periods of time in the absence of selective pressure using the ACE system. Using this method, specific loading of one or two gene targets has been achieved in LMTK(-) and CHO cells.

Another method for introducing nucleic acids encoding polypeptides is the two-step gene replacement technique in yeast, starting with the selection of complete adenoviral genomes (Ad2; Ketner et al. (1994) Proc . Natl. Acad. Sci. USA 91: 6186-6190) and plasmids containing adenoviral sequences to target specific regions in YAC clones, expression cassettes for relevant genes, and positive and negative selectable markers. YAC is of great interest because it allows the incorporation of larger genes. This method can be used to construct adenovirus-based vectors carrying nucleic acids encoding any of the polypeptides or constructs described herein for gene transfer into mammalian cells or whole animals.

The nucleic acid may be encapsulated in a vehicle, such as a liposome, or introduced into a cell, such as a bacterial cell, especially an attenuated bacterium, or into a viral vector. For example, when liposomes are used, proteins bound to cell surface membrane proteins involved in endocytosis can be used to target and/or promote absorption, such as capsid proteins or fragments thereof, targeting specific cell types. Antibodies to proteins that undergo internalization in the circulation and proteins that target intracellular locations and enhance intracellular half-life.

For in vitro and in vivo methods, a nucleic acid molecule encoding a polypeptide or construct herein is introduced into cells from a suitable donor or individual to be treated. Cells into which nucleic acids may be introduced for therapeutic purposes include, for example, any desired available cell type appropriate for the disease or condition to be treated, including, but not limited to, epithelial cells; endothelial cells; keratinocytes; fibroblasts; myocytes; Liver cells; blood cells, such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes and granulocytes; and various stem cells or precursor cells, especially hematopoietic stem cells or precursor cells , such as stem cells obtained from bone marrow, umbilical cord blood, peripheral blood, embryonic liver and other sources.

For ex vivo treatment, cells from a donor compatible with the individual to be treated or cells from the individual to be treated are removed, nucleic acids are introduced into the isolated cells, and the modified cells are administered to the individual. Treatment includes direct administration, such as encapsulation within a porous membrane and implantation into a patient (see, eg, U.S. Patent Nos. 4,892,538 and 5,283,187, each of which is incorporated herein by reference in its entirety). Techniques suitable for in vitro transfer of nucleic acids into mammalian cells include electroporation using liposomes and cationic lipids (such as DOTMA, DOPE, and DC-cholesterol), microinjection, cell fusion, DEAE-polydextrose, and calcium phosphate precipitation. method. DNA delivery methods can be used to express the polypeptides or constructs provided herein in vivo. Such methods include liposome delivery of nucleic acids and naked DNA delivery, including local and systemic delivery, such as using electroporation, ultrasound, and calcium phosphate delivery. Other techniques include microinjection, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, and spherical plastid fusion.

The in vivo performance of the polypeptides or constructs herein may be related to the performance of other molecules. For example, the expression of a polypeptide can be associated with the expression of a cytotoxic product, such as in an engineered virus, or in a cytotoxic virus. Such viruses can target specific cell types that are targeted for therapeutic efficacy.

In vivo expression of a polypeptide or construct provided herein may involve operably linking a nucleic acid molecule encoding the polypeptide to a specific regulatory sequence, such as a cell-specific or tissue-specific promoter. Polypeptides can also be expressed from vectors that specifically infect and/or replicate in target cell types and/or tissues. Inducible promoters can be used to selectively regulate polypeptide or construct expression.

Nucleic acid molecules, such as naked nucleic acids, or vectors, artificial chromosomes, liposomes, and other vehicles can be administered to individuals via systemic, topical, topical, and other routes of administration. Nucleic acid molecules or vehicles containing nucleic acid molecules can target cells when administered systemically and in vivo. Administration may include intravenous administration and direct injection into tissue, such as direct injection into the liver, including methods of direct injection into compartmental organs or portions thereof, such as the liver (see, eg, U.S. Patent No. 9,821,114).

Administration can also be direct, such as by administration of vectors or cells that typically target cells or tissues. Cells used for in vivo expression of the polypeptides or constructs herein also include cells autologous to the patient. Such cells can be removed from the patient, nucleic acid expressing the polypeptide introduced, and then administered to the patient, such as by injection or transplantation. J. Compositions, Preparations and Dosages

Pharmaceutical compositions are provided that contain any of the polypeptides and constructs provided herein, including TNFR1 antagonist constructs, TNFR2 agonist constructs and multispecifics, in a pharmaceutically acceptable vehicle, such as Bispecific TNFR1 antagonist/TNFR2 agonist constructs include fusion proteins or nucleic acid molecules encoding polypeptides or constructs. Such compositions contain an amount of polypeptide, construct or nucleic acid that can be diluted to a therapeutically effective amount or formulated for direct administration without dilution. The specific concentration of the construct or nucleic acid will depend on a variety of parameters that are within the skill of one of ordinary skill in the art, including, for example, the indication being treated, the construct or nucleic acid, route of administration, and regimen. Routes of administration include systemic and local routes, oral, transrectal, intravenous, intramuscular, subcutaneous, transmucosal, peritoneal, and any suitable route known to one of ordinary skill in the art.

As discussed above, depending on the various parameters of the constructs provided herein (including TNFR1 antagonist constructs, TNFR2 agonist constructs, and multispecific, such as bispecific TNFR1 antagonist/TNFR2 agonist constructs, including fusion proteins or nucleic acid molecules encoding such constructs) in a selected amount (such as a therapeutically effective amount) formulated in a suitable vehicle for administration. Pharmaceutical compositions may be formulated in any conventional manner by mixing a selected amount of a construct or mixture thereof with one or more physiologically acceptable carriers or excipients or vehicles. Pharmaceutical compositions can be used in therapeutic, prophylactic and/or diagnostic applications. The concentration of the active compound (i.e., construct or nucleic acid) in the composition depends on a variety of factors, including those mentioned above, as well as the absorption, inactivation, and excretion rates of the active compound; the schedule of administration; and the administration the amount given; the age and size of the individual; and other factors known to those of ordinary skill in the art.

Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carrier known to one of ordinary skill in the art to be suitable for the particular mode of administration. Pharmaceutical compositions including a therapeutically effective amount of a construct or nucleic acid molecule described herein may also be provided in the form of a lyophilized powder, such as reconstituted with sterile water immediately prior to administration. 1. Preparations

Pharmaceutical compositions containing any of the constructs and nucleic acids provided herein may be formulated in any conventional manner by mixing selected amounts of the active compound with one or more physiologically acceptable carriers or excipients. The selection of the carrier or excipient is within the skill of the pharmaceutical professional and will depend on a variety of parameters. Such parameters include, for example, the mode of administration (as well as systemic, oral, nasal, pulmonary, topical, topical, or any other mode) and the condition being treated. Generally speaking, pharmaceutical compositions include components that do not significantly impair the biological properties of the construct or nucleic acid or encoded polypeptide or enhance or improve its pharmacological properties. The formulations may also be co-formulated with other active agents for combination therapy.

The pharmaceutical compositions provided herein may be in a variety of forms, such as, but limited to, solid, semi-solid, liquid, emulsion, powder, aqueous solution, and lyophilized forms. The pharmaceutical compositions provided herein may be formulated for single dose (direct) administration or for dilution or other regimens. The concentration of the compound in the formulation is effective after dilution or mixing with another composition, or for direct administration, to deliver, upon administration, an amount effective for the treatment contemplated. The composition may be formulated for direct administration in a single dose or in multiple doses. The compounds may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product. The form of the resulting mixture will depend on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The resulting mixtures are solutions, suspensions, emulsions and other such mixtures, and may be formulated as non-aqueous or aqueous mixtures, creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes , foams, aerosols, rinses, sprays, suppositories, bandages, or any other formulation suitable for systemic, topical or topical administration. For local internal administration, such as intramuscular, parenteral, or intra-articular administration, the constructs and nucleic acids may be formulated as a solution suspension in an aqueous medium such as isotonic buffered saline, or as intended for internal administration. Provide a biocompatible carrier or bioadhesive combination. Effective concentrations are sufficient to improve the target condition and can be determined empirically. In order to formulate the composition, a certain weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in the selected vehicle at an effective concentration to alleviate or improve the target condition.

Generally speaking, pharmaceutically acceptable compositions are prepared in accordance with approval from regulatory or other agencies and/or in accordance with generally recognized pharmacopoeias for use in animals and humans. Pharmaceutical compositions may include a carrier, such as a diluent, adjuvant, excipient, or vehicle, with which the polypeptide is administered. Such pharmaceutical carriers can be sterile liquids such as water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil and sesame oil. When pharmaceutical compositions are administered intravenously, water is a typical carrier. Physiological saline and aqueous dextrose and glycerol solutions can be used as liquid carriers, especially for injectable solutions. In addition to the active ingredient, the composition may contain diluents such as lactose, sucrose, dicalcium phosphate and carboxymethylcellulose; lubricants such as magnesium stearate, calcium stearate and talc; and binders such as starch, Natural gums, such as acacia gelatin, glucose, molasses, polyvinylpyrrolidone, cellulose and its derivatives, povidone, crospovidone, and those with ordinary knowledge in the art Other such adhesives are known. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicone, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin , propylene glycol, water and ethanol. When necessary, the composition may also contain a small amount of wetting agent or emulsifier, or pH buffering agent, such as acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine sodium acetate, etc. Ethanolamine oleate and other such reagents. Such compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, granules and sustained release formulations. Capsules and cartridges for use in inhalers or insufflators (e.g., composed of gelatin) may be formulated to contain a powder mixture of the compound and a suitable powder base (such as lactose or starch). The compositions may be formulated as suppositories, with traditional binders and carriers, such as triglycerides. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and other such agents. Formulations for oral administration may also suitably be formulated with protease inhibitors, such as Bowman-Birk inhibitors, conjugated Bowman-Birk inhibitors, aprotinin, and camostat. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, generally in purified form, and a suitable amount of carrier so as to provide for appropriate administration to the individual or patient.

The pharmaceutical compositions provided herein may contain other additives, including, inter alia, antioxidants, preservatives, antimicrobial agents, analgesics, binders, disintegrants, colorants, diluents, excipients, extenders, glide agents, etc. Agents, solubilizers, stabilizers, tonicity agents, vehicles, viscosity agents, flavoring agents; emulsions, such as water-in-oil or water-in-oil emulsions; emulsifying and suspending agents, such as gum arabic, agar, alginic acid, sodium alginate, Bentonite, carbomer, carrageenan, carboxymethylcellulose, cellulose, cholesterol, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose Vitamin C, stearyl alcohol-9, oleyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, sorbitan ester, stearyl alcohol, gum tragacanth, gum trixanthemum and its derivatives; Solvents and miscellaneous ingredients such as crystalline cellulose, microcrystalline cellulose, citric acid, dextrin, dextrose, liquid glucose, lactic acid, lactose, magnesium chloride, potassium metaphosphate, and starch (see generally Alfonso R. Gennaro (2000) Remington : The Science and Practice of Pharmacy , 20th ed. Baltimore, MD: Lippincott Williams & Wilkins). Such carriers and/or additives can be formulated by conventional methods and can be administered to the individual at a suitable dosage. Stabilizers such as lipids, nuclease inhibitors, polymers and chelating agents prevent degradation of the composition in the body.

The formulation should meet the requirements of the mode of administration. For example, the active compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,4-butanediol. It is common practice to use sterile fixed oil as the solvent or suspension medium. For this purpose any bland fixed oil may be employed including, but not limited to, synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, and other oils) or synthetic fatty vehicles (such as ethyl oleate). Buffers, preservatives, antioxidants, and suitable ingredients may be incorporated, if desired, or alternatively may constitute the formulation.

Active compounds, such as the constructs and nucleic acids provided herein, can be formulated as the sole pharmaceutically active ingredient in the compositions, or can be combined with other active ingredients. Active compounds can be delivered targeted, such as by conjugation to a targeting agent, such as an antibody. Liposome suspensions, including tissue-targeted liposomes, are also suitable as pharmaceutically acceptable carriers. Such carriers may be prepared according to methods known to those of ordinary skill in the art. For example, liposome formulations can be prepared by methods well known to those of ordinary skill in the art, such as those described in U.S. Patent No. 4,522,811. Liposome delivery may also include slow release formulations including pharmaceutical matrices such as collagen gels and fibronectin-modified liposomes (see, eg, Weiner et al. (1985) J. Pharm. Sci . 74(9):922- 925). The compositions provided herein may additionally contain one or more adjuvants to enhance delivery, such as, but not limited to, inert carriers or colloidal dispersion systems. Representative and non-limiting examples of such inert carriers may be selected from the group consisting of water, isopropyl alcohol, gaseous fluorocarbons, ethanol, polyvinylpyrrolidone, propylene glycol, gel making materials, stearyl alcohol, stearic acid, Spermatous wax, sorbitan monooleate, methylcellulose, and suitable combinations of two or more of them.

The active compound is included in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without causing unwanted side effects to the individual treated. Therapeutically effective concentrations can be determined empirically by testing the compounds in known in vitro and in vivo systems, such as the assays described herein. Determination of a therapeutically effective amount is well within the ability of one of ordinary skill in the art. Therapeutically effective doses can be determined using in vitro and in vivo methods as described herein. Thus, when in pharmaceutical preparations, the active compounds provided herein, or mixtures thereof, may be presented in unit dosage form for administration. 2. Administration of TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific ( such as bispecific ) constructs and nucleic acids

Active compounds (including constructs provided herein, including TNFR1 antagonist constructs, TNFR2 agonist constructs, and multispecific, such as bispecific TNFR1 antagonist/TNFR2 agonist constructs, including fusion proteins and those encoding the Nucleic acid molecules of such constructs) may be administered by any suitable route. Such routes include in vitro, in vitro, or in vivo administration by contacting a mixture, such as a body fluid or other tissue sample, with an active compound provided herein. For example, when administering a compound ex vivo, a body fluid or tissue sample from an individual can be contacted with a polypeptide coated on a tube or filter, such as in a bypass machine. For in vivo administration, the active compounds may be administered in liquid, semi-liquid or solid form by any appropriate route, such as orally, nasally, pulmonary, intravenously, intradermally, intravitreally, intraretinally, subretinally, periocularly. , subcutaneous, intraarticular, intracisternal, intraocular, intracerebroventricular, intrathecal, intramuscular, intraperitoneal, intratracheal, transrectal or local, or by direct injection into an organ, and by two or more of these Any combination of a variety of drugs can be administered in a manner suitable for each route of administration.

The route of administration is according to known methods, for example by intravenous, intraperitoneal, intracerebral, intramuscular, subcutaneous, intraocular, intraarterial, intrathecal, inhalation or intralesional route, locally or by injection with a sustained release system or infusion. Antibodies or fragments thereof are typically administered continuously by infusion or by bolus injection. The active compounds provided herein may be prepared in admixture with pharmaceutically acceptable carriers, as discussed above. Techniques for formulating and administering compounds are known to those of ordinary skill in the art. The therapeutic composition may be administered intravenously or via the nose or lungs, such as in liquid or powder aerosol (lyophilized) form. The composition may also be administered parenterally or subcutaneously if necessary. When administered systemically, the therapeutic composition should be sterile, pyrogen-free and in a parenterally acceptable solution, taking into account pH, isotonicity and stability and other factors known to those of ordinary skill in the art. condition.

Therapeutic formulations can be administered in a number of conventional dosage formulations. Dosage formulations of the active compounds provided herein are prepared for storage or administration by mixing the compound with the desired purity and a physiologically acceptable carrier, excipient, or stabilizer. Such materials are non-toxic to the recipient at the doses and concentrations used and may include buffers such as TRIS hydrochlorides, phosphates, citrates, acetates and other organic acid salts; antioxidants such as ascorbic acid; low molecular weight ( less than about ten residues) peptides, such as polyarginine; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, gluten Amino acids, aspartic acid or arginine; monosaccharides, disaccharides and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols such as mannose alcohol or sorbitol; counterions such as sodium and/or non-ionic surfactants such as those sold under the trademarks TWEEN and PLURONICS and polyethylene glycol (PEG).

Pharmaceutical compositions may contain stabilizers. Stabilizers can be amino acids, amino acid derivatives, amines, sugars, polyols, salts or surfactants. In some examples, stable co-formulations contain a single stabilizer. In other examples, stable co-formulations contain 2, 3, 4, 5 or 6 different stabilizers. For example, the stabilizer may be a sugar or a polyol such as glycerol, sorbitol, mannitol, myo-inositol, sucrose or trehalose. In a specific example, the stabilizer is sucrose. In other examples, the stabilizer is trehalose. The concentration of sugar or polyol is or is about 100 mM to 500 mM, 100 mM to 400 mM, 100 mM to 300 mM, 100 mM to 200 mM, 200 mM to 500 mM, 200 mM to 400 mM, 200 mM to 300 mM, 250 mM to 500mM, 250mM to 400mM, 250mM to 300mM, 300mM to 500mM, 300mM to 400mM, or 400mM to 500mM, each including the endpoints.

In examples, the stabilizers may be surfactants, which are polypropylene glycol, polyethylene glycol, glycerin, sorbitol, poloxamer and polysorbates. For example, the surfactant may be polypropylene glycol, polyethylene glycol, glycerin, sorbitol, poloxamer or polysorbate, such as poloxamer 188, polysorbate 20 and polysorbate 80. In a specific example, the stabilizer is polysorbate 80. The concentration of surfactant (as % mass concentration (w/v) in the formulation) is at or about 0.005% to 1.0%, 0.01% to 0.5%, 0.01% to 0.1%, 0.01% to 0.05%, or 0.01 % to 0.02%, each inclusive.

For in vivo administration, the formulation should be sterile. This is easily accomplished, such as by filtration through a sterile filtration membrane before or after lyophilization and reconstitution. Formulations can be stored in lyophilized form or in solution. Other vehicles may be used, such as naturally occurring vegetable oils, such as sesame oil, peanut oil, or cottonseed oil; or synthetic fatty vehicles, such as ethyl oleate or the like. Buffers, preservatives, antioxidants and the like may be incorporated in accordance with accepted pharmaceutical practice.

Dosage determination is within the skill of the physician and may be a function of the specific condition, route of administration, and individual individual. Exemplary dosages include, for example, 0.1 to 100 mg/kg, such as 1 to 10 mg/kg, or an appropriate amount based on the mass of the subject being treated; the average human subject has a mass of about 70-75 kg. The polypeptide may be administered once or more than once, such as two, three, four, or any number of times necessary to achieve a therapeutic effect. Multiple administrations may be by any route or combination of routes, and may be administered every hour, every two hours, every three hours, every four hours, or more hours.

The active compound may be provided in the composition at a concentration of, for example, 0.1 to 10 mg/mL or about 0.1 to 10 mg/mL, such as a concentration of at least or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 , 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10 mg/mL or greater. The solution volume may be from or about 0.1 to 100 mL or greater, such as at or about at least 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 , 60, 65, 70, 75, 80, 85, 90, 95 or 100 mL or larger. In some examples, the active compound is supplied in phosphate buffered saline. For example, the compositions may be supplied as 50 mL vials or other containers containing 100 mg of the polypeptide or fusion protein at a concentration of 2 mg/mL in phosphate buffered saline.

The active compounds provided herein can be lyophilized for storage and reconstituted in a suitable vehicle before use. This technique has been shown to be effective with conventional immunoglobulin and protein preparations, and lyophilization and reconstitution techniques known in the art can be used.

The active compounds provided herein may be provided in controlled release or sustained release compositions. Polymeric materials are known in the art for use in formulating pills and capsules to achieve controlled or sustained release (see, e.g., Controlled Drug Bioavailability, Drug Product Design and Performance , Smolen and Ball (eds.), Wiley, New York (1984); See also Levy et al. (1985) Science 228:190; During et al. (1989) Ann. Neurol. 25:351; Howard et al. (1989) J. Neurosurg . 71:105; U.S. Patent Nos. 5,679,377, 5,916,597 , No. 5,912,015, No. 5,989,463 and No. 5,128,326; and International Application Publication No. WO 99/015154 and No. WO 99/020253). Examples of polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate) ester), poly(methacrylic acid), polyglycolide (PLG), polyanhydride, poly(N-vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), poly Lactide (PLA), poly(lactide-co-glycolide) (PLGA) and polyorthoesters. Generally speaking, polymers used in sustained release formulations are inert, free of leachable impurities, storage stable, sterile, and biodegradable. Any technique known in the art for producing sustained release formulations may be used to produce sustained release formulations.

Constructs and nucleic acids, and their salts and solvates in physiologically acceptable forms, may be formulated for administration by inhalation (via the mouth or nose) or other routes of administration, including, for example, oral, transdermal, pulmonary , parenteral or rectal administration. For administration by inhalation, the active compound may be presented as an aerosol spray from a pressurized pack or nebulizer, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other Suitable for gas delivery. In the case of pressurized aerosols, the dosage unit may be measured by providing a valve that delivers a metered amount. Capsules and cartridges for use in inhalers or insufflators (e.g., composed of gelatin) may be formulated to contain a powder mixture of the compound and a suitable powder base (such as lactose or starch).

For pulmonary administration, the construct may be delivered as an aerosol spray from a nebulizer, turbonebulizer, or microprocessor-controlled metered dose oral inhaler using a suitable propellant. Typically, aerosols have smaller particle sizes, such as in the range of 0.5 microns to 5 microns. In the case of pharmaceutical compositions formulated for pulmonary administration, detergent surfactants are typically not used. Transpulmonary drug delivery is a promising non-invasive systemic delivery method. The lungs represent an attractive route for drug delivery primarily due to higher absorptive surface area, thin alveolar epithelium, extensive vascularization, absence of first-pass hepatic metabolism, and relatively low metabolic activity.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, pills, liquid suspensions or capsules prepared by conventional methods using pharmaceutically acceptable excipients such as binding agents (e.g. , pregelatinized cornstarch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, Talc or silica); a disintegrant (e.g., potato starch or sodium starch glycolate); or a wetting agent (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Oral liquid preparations may take the form of, for example, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared in a conventional manner using pharmaceutically acceptable additives, such as suspending agents (such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (such as lecithin or acacia); non-aqueous vehicles (such as almond oil, oil esters, ethanol, or fractionated vegetable oils); and preservatives (such as methyl or propylparaben, or sorbic acid). Such preparations may contain buffer salts, flavoring agents, coloring agents and sweetening agents as desired.

Formulations for oral administration may be formulated for controlled release of the active compound. For buccal administration, the composition may take the form of a lozenge or buccal lozenge formulated in a conventional manner. The active compounds can be formulated in the form of depot formulations. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, the therapeutic compounds may be formulated, for example, with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).

The active compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form (for example, in ampoules or in multi-dose containers) with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder lyophilized form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

Pharmaceutical compositions may be formulated in the form of gels, creams and lotions for topical or topical administration, such as topical application to the skin and mucous membranes, such as the eye, and for administration to the eye or intracisternal or intraspinal administration. Such solutions, especially those intended for ophthalmic use, may be formulated with appropriate salts as 0.01% to 10% isotonic solutions and have a pH of about 5% to 7. The compounds may be formulated into aerosols for topical administration (such as by inhalation) (see, for example, U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which references describe applications for delivery of compounds suitable for the treatment of inflammatory diseases, particularly asthma) aerosols of steroids).

The concentration of the active compound in the pharmaceutical composition depends on the absorption, inactivation and excretion rates of the active compound, the duration and amount of administration, and other factors known to those of ordinary skill in the art. As further described herein, dosages can be determined empirically using comparisons of properties and activities. For example, inhibition of TNF-mediated inflammatory signaling via TNFR1 by constructs provided herein is comparable to traditional anti-TNF therapies such as adalimumab.

Where appropriate, the compositions may be presented in packages, kits and dispenser devices which may contain one or more unit dosage forms containing the active ingredient. In some embodiments, the composition may be coated on a device, such as on a pipe or filter of a bypass machine, for example. For example, packaging contains metal or plastic foil, such as blister packaging. The packaging or dispenser device may be accompanied by instructions for administration. Compositions containing active agents can be packaged into articles containing packaging materials, an agent provided herein, and a label indicating the condition for which the agent is provided. The pharmaceutical composition may be packaged in a unit dosage form containing a certain amount of the pharmaceutical composition for a single dose or multiple doses. The encapsulated composition may contain a lyophilized powder of a pharmaceutical composition containing the constructs provided herein, including TNFR1 antagonist constructs, TNFR2 agonist constructs, and multispecific, such as bispecific TNFR1 antagonists. /TNFR2 agonist constructs, including fusion proteins and nucleic acid molecules encoding the constructs provided herein, the lyophilized powder can be reconstituted (e.g., with water or saline) prior to administration.

The articles provided herein contain encapsulating materials. Packaging materials for packaging pharmaceutical products are well known to those of ordinary skill in the art (see, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252). Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers (e.g., pressurized metered dose inhalers (MDI), dry powder inhalers (DPI)), nebulizers (e.g., jet or ultrasonic nebulizers), and others single respiratory liquid system), pumps, bags, vials, containers, syringes, bottles and any packaging material suitable for the selected formulation and the intended mode of administration and treatment.

Active compounds, including constructs provided herein, including TNFR1 antagonist constructs, TNFR2 agonist constructs, and multispecific, such as bispecific TNFR1 antagonist/TNFR2 agonist constructs, including fusion proteins and encoding the same The combination of nucleic acid molecules, pharmaceutical compositions and active agents and other components (including other therapeutic agents) of such constructs can be provided in the form of a set. The kit may optionally include one or more components, such as instructions for use, equipment, additional reagents (e.g., sterile water or saline solutions for diluting the composition and/or reconstituting the lyophilized protein), and components for practicing the method, such as tubing. , containers and syringes. Exemplary kits can include the constructs and encoding nucleic acids provided herein, and optionally can include instructions for use, a device for administering the compound to an individual, a device for detecting the compound in the individual, a device for detecting the compound obtained from A device for extracting compounds or metabolites thereof from a sample of an individual and a device for administering other therapeutic agents to an individual. The kit may include an instruction manual if required. Instructions typically include tangible statements describing the active compound and, if necessary, other components included in the kit, and methods of administration, including methods for determining the appropriate state of an individual, appropriate dosage, administration Plans and investment methods. Instructions may also include instructions for monitoring the individual during the duration of the treatment session.

Kits may also include pharmaceutical compositions and diagnostic items described herein. For example, such kits may include articles for measuring the concentration, amount, or activity of an active compound administered in an individual. Kits provided herein may also include a device for administering the compound. Any of a variety of devices known in the art for administering drugs to individuals may be included in the kits provided herein. Exemplary devices include, but are not limited to, hypodermic needles, intravenous needles, and catheters. Typically, the device used for administration is compatible with the method by which the active agent is to be administered. 3. Administering nucleic acid-encoded polypeptides (gene therapy)

Among the pharmaceutical compositions are those containing nucleic acid molecules encoding the polypeptide constructs provided herein. Instead of delivering proteins, nucleic acid molecules can be administered in vivo or ex vivo, such as systemically or by other routes, such as by removing cells (including lymphocytes), introducing the nucleic acid molecules therein and reintroducing them into the host or compatible recipient. among those.

The polypeptide constructs provided herein include TNFR1 antagonist constructs, TNFR2 agonist constructs, and multispecific, such as bispecific TNFR1 antagonist/TNFR2 agonist constructs, including fusion proteins, which can be expressed through nucleic acid molecules. The performance is delivered to cells and tissues. Nucleic acids can be delivered to cells and tissues by any method known to those of ordinary skill in the art. Isolated nucleic acids can be incorporated into vectors for further manipulation. As discussed above, methods of administering a polypeptide by expression of an encoding nucleic acid molecule include administration of a recombinant vector. The vector may be designed to remain episomal, such as by including an origin of replication, or may be designed to integrate into the chromosome of the cell. Polypeptides can also be used in in vitro gene expression therapy using non-viral vectors. Suitable gene therapy vectors and delivery methods are known to those of ordinary skill in the art and are discussed in the section above. K. Therapeutic Uses and Treatment Methods

A pharmaceutical composition, such as the one described above, is prepared and administered to an individual suffering from a disease, disorder or condition suitable for treatment with a construct that inhibits and/or agonizes TNFR1 and TNFR2, respectively. Dosage will depend on the specific disorder, disease, or condition being treated and on the particular individual. Typical dosages are similar to known TNF blockers, such as etanercept. For individuals, including humans and other animals, exemplary dosages range from about or 0.1 to 100 mg/kg, such as 1 mg/kg to about or 30 mg/kg, such as 5 mg/kg to 25 mg/kg. The dose can be determined based on the assumption that the average person has a mass of approximately 75 kg. Dosage may be adjusted for children, infants, and smaller adults.

The TNFR1 antagonists, TNFR2 agonists, bispecific TNFR1 antagonist/TNFR2 agonist constructs and fusion proteins provided herein may be used for any purpose known to those skilled in the art to use such molecules, including In the treatment of any diseases, illnesses and conditions described herein. For example, the TNFR1 antagonists, TNFR2 agonists, multispecific TNFR1 antagonist/TNFR2 agonist constructs and fusion proteins provided herein can be used for one or more of therapeutic, diagnostic, industrial and/or research purposes. . The therapeutic methods provided herein include methods for the therapeutic use of the TNFRl antagonists, TNFR2 agonists, multispecific TNFRl antagonist/TNFR2 agonist constructs and fusion proteins provided herein. For example, TNFR1 antagonists described herein can be used to antagonize TNFR1, and/or inhibit the binding of TNF to TNFR1, and/or inhibit TNF-mediated pro-inflammatory signaling via TNFR1. TNFR2 agonists can be used to potentiate TNFR2 to induce protective/anti-inflammatory TNFR2 signaling, and/or to induce the expansion, proliferation and activation of immunosuppressive TNFR2 ⁺ regulatory T cells (Tregs). In some embodiments, a combination of a TNFR1 antagonist and a TNFR2 agonist, as described herein, or using a bispecific TNFR1 antagonist/TNFR2 agonist construct provided herein provides selective inhibition of pro-inflammatory TNFR1 activity. , while maintaining or increasing TNFR2-related protective signaling and Treg immunosuppressive activity, which is beneficial in the treatment of chronic inflammatory and autoimmune diseases and the treatment of neurodegenerative and demyelinating diseases and conditions.

The TNFR1 antagonists, TNFR2 agonists, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs and fusion proteins provided herein may have therapeutic activity alone or in combination with other agents. The TNFR1 antagonists, TNFR2 agonists, bispecific TNFR1 antagonist/TNFR2 agonist constructs and fusion proteins and encoding nucleic acid molecules provided herein can be used to treat anti-TNF therapies (such as adalimumab, infliximab , etanercept, and others described herein and/or known in the art) or other disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, abatacept, anakinra, rituximab, tocilizumab, tofacitinib and others described herein and/or known in the art), including but not limited to Chronic inflammatory and autoimmune diseases and conditions, as well as neurodegenerative and demyelinating diseases and conditions. For example, individuals administered therapeutic molecules provided herein exhibit acute or chronic inflammation of the joints, skin, lungs, and/or intestines, and/or suffer from autoimmune diseases, rheumatoid arthritis (RA), Psoriasis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), spondyloarthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), uveitis, fibrosis Chemical diseases, endometriosis, lupus, multiple sclerosis (MS), congestive heart failure, cardiovascular disease, myocardial infarction (MI), atherosclerosis, metabolic disease, interleukin release syndrome, sepsis Hemorrhagic shock, sepsis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), COVID-19, influenza, acute and chronic neurodegenerative diseases, demyelinating diseases and conditions, stroke, Alzheimer's disease , Parkinson's disease, Behcet's disease, Dupuytren's disease, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), pancreatitis, type I diabetes, chronic obstructive pulmonary disease (COPD), chronic bronchitis , emphysema, graft rejection, graft-versus-host disease (GvHD), respiratory diseases, lung inflammation, lung diseases and conditions, asthma, cystic fibrosis, idiopathic pulmonary fibrosis, acute fulminant viruses Or bacterial infections, pneumonia, genetic diseases with TNF/TNFR1 as the pathogenic pathological mediator, periodic fever syndrome and cancer.

The constructs provided herein, when administered, generally cause a subject to exhibit reduced or mitigated side effects compared to those that may be observed following administration of anti-TNF therapy. Treatment of diseases and conditions with the polypeptides provided herein, such as TNFR1 antagonists, TNFR2 agonists, and bispecific constructs and fusion proteins thereof, may be accomplished by any suitable route of administration, using suitable formulations as described herein , including but not limited to infusion, subcutaneous injection and inhalation, or intramuscular, intradermal, oral, topical and transdermal administration.

As discussed elsewhere herein, existing anti-TNF therapies, such as adalimumab, are immunosuppressive due to blocking TNF signaling via TNFR1 and TNFR2, and are associated with the risk of adverse side effects, including, for example, sepsis and serious infections such as Listeria. Increased risk of idiopathic diseases, reactivation of tuberculosis, reactivation of hepatitis B/C, reactivation of herpes zoster, and invasive fungi and other opportunistic infections. Anti-TNF agents can also cause exacerbation of severe congestive heart failure and can cause drug-induced lupus, liver damage, psoriasis, sarcoidosis, and demyelinating central nervous system (CNS) disease, and predispose to other autoimmune diseases. Increased susceptibility, as well as lymphoma and solid malignancies such as non-melanoma skin cancer. Depending on the anti-TNF agent, approximately 3-33% of treated patients do not respond to treatment, and up to 46% of treated patients cease responding, leading to discontinuation or dose increase. Anti-TNF therapies have failed in treating neurodegenerative diseases and CNS conditions, such as Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis (MS), which are associated with excessive expression of TNF. Due to adverse effects associated with the use of anti-TNF agents, unresponsiveness in some patients, lack of sustained response in patients with initial responses, and treatment failure and/or worsening of neurodegenerative diseases such as MS, additional therapies are needed. This article provides such treatments.

As described herein, selective inhibition of TNFR1 retains the potent anti-inflammatory and protective activities of TNFR2 signaling, leading to fewer opportunistic infections and cancers, and preserves TNF-induced Treg function. Previous selective TNFR1 antagonists have immunogenicity, including the formation of anti-drug antibodies (ADA), poor pharmacokinetics and pharmacodynamics, including, for example, short serum half-life, rapid renal clearance, and/or poor binding affinity and potency. The therapies provided herein overcome limitations associated with previous selective TNFR1 antagonists. Examples of therapeutic modifications using the polypeptides provided herein, such as TNFRl antagonists, include, but are not limited to, lower doses, fewer and/or less frequent administrations, reduced side effects, and increased therapeutic efficacy.

Accordingly, the selective TNFR1 antagonists, TNFR2 agonists, and multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs and fusion proteins provided herein are associated with reduced side effects and, if necessary, higher doses. regimen, and may have improved efficacy and safety. Side effects that may be reduced, mitigated, or eliminated compared to those observed with existing anti-TNF therapeutics, such as adalimumab and other therapeutics described herein and/or known in the art, include those described herein or any adverse non-therapeutic effects known in the art, such as, but not limited to, sepsis, severe infection, congestive heart failure/cardiotoxicity, antibody production and cancer, autoimmune disease and/or demyelination of the central nervous system ( CNS) disease onset or worsening. In some examples, administration of a TNFR1 antagonist, bispecific construct, or fusion protein provided herein results in one or more side effects being more severe than the side effects caused by administration of existing anti-TNF therapeutics, such as adalimumab. At least or about 99%, at least or about 95%, at least or about 90%, at least or about 85%, at least or about 80%, at least or about 75% relative to the severity of one or more side effects of anti-TNF therapy , at least or about 70%, at least or about 65%, at least or about 60%, at least or about 55%, at least or about 50%, at least or about 45%, at least or about 40%, at least or about 35%, at least or about 30%, at least or about 25%, at least or about 20%, at least or about 15% or at least or about 10%.

Dosage levels and regimens can be determined based on known dosages and regimens, and if necessary, can be extrapolated based on changes in properties of the polypeptides and constructs provided herein, and/or can be determined empirically based on a variety of factors. Such factors include, for example, the individual's weight and general health, age, sex, and diet, as well as the activity of the specific compound used, time of administration, excretion rate, drug combination, severity and duration of the disease, and the patient's response to the disease. treatment and the judgment of the treating physician. The active ingredients are typically combined with a pharmaceutically effective carrier. The amount of active ingredient that can be combined with the carrier materials to produce single or multiple dosage forms will vary depending on the host treated and the particular mode of administration.

After the patient's condition improves, if necessary, a maintenance dose of the compound or composition may be administered; and the dose, dosage form, or frequency of administration, or combination thereof, may be modified. In some cases, individuals may require long-term intermittent treatment upon recurrence of any disease symptoms or on a predetermined dose basis.

This section provides exemplary uses and methods of administration of the constructs provided herein, including polypeptides and encoding nucleic acid molecules. The therapies described are illustrative only and do not limit the applications of the molecules/constructs provided herein. It is within the skill of the treating physician to identify diseases or conditions that may be treated using the TNFR1 antagonists, TNFR2 agonists, bispecific TNFR1 antagonist/TNFR2 agonist constructs and fusion proteins and encoding nucleic acid molecules provided herein. 1. Treatment of chronic inflammatory / autoimmune diseases and conditions

As described herein, elevated or uncontrolled levels of TNF and dysregulation of TNF signaling can cause chronic inflammation, which can lead to autoimmune disease and tissue damage. TNF signaling via TNFR1 is primarily pro-inflammatory and drives the development of chronic inflammatory and autoimmune diseases and conditions. For example, TNFR1 signaling is associated with the development of arthritis, inflammatory bowel disease (IBD), and respiratory diseases, as well as the production of osteoclasts that lead to local bone destruction and TNF-induced heart failure and myocardial infarction models. Related to cardiotoxic effects. Therefore, selective blockade of TNFR1 may be used to treat chronic inflammatory and autoimmune diseases and conditions. TNF signaling via TNFR2 is primarily anti-inflammatory and has been associated with neurological, cardiac, intestinal and bone protective effects. The anti-inflammatory and protective effects of TNFR2 signaling have been demonstrated in experimental colitis, heart failure/heart disease, myocardial infarction, inflammatory arthritis, infectious diseases, pancreatic regeneration, stem cell proliferation, autoreactive T cells It has been demonstrated in the destruction of bone and the regulation of osteoclast production that maintains bone mass and protects against joint inflammation and erosive damage. TNFR2 agonism also leads to the proliferation and expansion of immunosuppressive TNFR2 ⁺ Tregs and promotes Treg cell suppressive activity, thereby eliminating autoreactive/effector T cells, preventing tissue destruction and suppressing inflammatory and autoimmune diseases. and disease conditions. Therefore, TNFR2 agonism may also be used to treat or alleviate symptoms of chronic inflammatory and autoimmune diseases and conditions.

The TNFR1 antagonists, TNFR2 agonists, multispecific TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and encoding nucleic acids provided herein can be used to treat or alleviate autologous diseases associated with elevated TNF levels and dysregulation of TNF signaling. Symptoms of immune/inflammatory diseases and conditions. The constructs, fusion proteins and nucleic acids provided herein may be used to treat diseases, disorders and conditions, including but not limited to, for example, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, spondyloarthritis) , inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), uveitis, fibrotic diseases (such as Dupuytren's disease), Behcet's disease, endometriosis, lupus, Ankylosing spondylitis, psoriasis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cardiovascular disease, congestive heart failure, myocardial infarction (MI), atherosclerosis, respiratory disease, asthma, cystic fibrosis, Chronic obstructive pulmonary disease (COPD), pancreatitis, type I diabetes, metabolic diseases, interleukin release syndrome, septic shock, sepsis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), COVID-19 , influenza, chronic bronchitis, emphysema, pulmonary inflammation, idiopathic pulmonary fibrosis, graft rejection, graft-versus-host disease (GvHD), acute fulminant viral or bacterial infection, pneumonia, TNF/TNFR1 Genetic diseases and periodic fever syndrome as pathogenic pathological mediators.

TNF blockade can also reduce the interleukin storm observed in some viral infections, such as SARS virus and infection with COVID-19. This prevents ventilator dependence, multi-organ damage and death in patients with severe acute respiratory syndrome (SARS), such as caused by SARS-CoV-2 and other SARS viruses/coronaviruses. TNF-induced viral syndrome (TIVS) is induced by a TNF-driven cytokine storm and involves not only lung damage but also multi-organ failure. TIVS is similar to SIRS (severe inflammatory respiratory syndrome), SARS (severe acute respiratory syndrome) and sepsis (caused by bacteria). These conditions affect lung function and also affect many other organs. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, which causes COVID-19) enters host cells via angiotensin-converting enzyme, which is expressed in alveolar cells of the lungs that secrete type II surfactant. Severe COVID-19 is associated with a major immune-inflammatory response with large numbers of neutrophils, lymphocytes, macrophages, and immune mediators. Death from COVID-19 is mainly caused by diffuse alveolar damage with pulmonary edema, hyaline membrane formation, and interstitial mononuclear inflammatory infiltrate compatible with early adult respiratory distress syndrome (ARDS). TNF is present in the blood and disease tissues of COVID-19 patients; TNF is involved in almost all acute inflammatory responses and acts as an inflammation amplifying agent. Accordingly, treatment with the constructs herein is provided. 2. Treatment of neurodegenerative and demyelinating diseases and conditions

As discussed elsewhere herein, several neurodegenerative and demyelinating diseases and conditions are associated with chronic elevations in TNF levels in the central nervous system (CNS). Elevated levels of TNF and TNF signaling via TNFR1 are associated with initiating and maintaining neuroinflammation and promoting neuronal cell death, demyelination, and cognitive decline. For example, in patients with Alzheimer's disease (AD), TNF promotes microglial activation, synaptic dysfunction, neuronal cell death, and accumulation of plaques and tangles, and elevated TNF levels inhibit AD. Phagocytosis of amyloid beta (Aβ) in the patient's brain prevents microglia from effectively removing plaques. In patients with Parkinson's disease (PD), elevated TNF levels lead to neuroinflammation and dopamine-induced neuronal toxicity. Elevated levels of TNF and polymorphisms in the gene encoding TNFR1 are associated with demyelination and the development of demyelinating disorders, such as multiple sclerosis (MS). Accordingly, selective blocking of TNF signaling through TNFRl may be used to treat or alleviate neurodegenerative and demyelinating diseases and disorders, as well as other conditions of the CNS.

TNF signaling via TNFR2 is associated with anti-inflammatory and neuroprotective effects. For example, activation of TNFR2 by TNF inhibits epileptic seizures, alleviates cognitive dysfunction after brain injury, and promotes remyelination and neuronal survival. After the agonistic effect of TNFR2, the proliferation, expansion and activation of immunosuppressive Tregs also have neuroprotective effects. For example, in experimental autoimmune encephalomyelitis (EAE), an animal model of inflammatory CNS demyelinating diseases such as multiple sclerosis, TNFR2 signaling promotes Treg cell expansion and suppresses activity. Therefore, TNFR2 agonism may also be used to treat or alleviate neurodegenerative and demyelinating diseases and disorders, as well as other conditions of the CNS.

The TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids provided herein may be used to treat or ameliorate neurodegeneration and degeneration. Symptoms of myelin diseases and other CNS disorders and conditions, including but not limited to Alzheimer's disease, Parkinson's disease, multiple sclerosis and stroke. 3. Treatment of cancer and other immunosuppressive diseases, diseases and conditions

As described here, tumors are infiltrated by large numbers of immunosuppressive TNFR2 ⁺ Tregs, which prevent the proliferation of tumor-killing CD8 ⁺ cytotoxic T lymphocytes (CTL), also known as effector T cells (Teff), thereby allowing tumor growth. Antagonism of TNFR2 on lymphocytes in the tumor microenvironment (TME) restores the balance between the two types of T cells by eliminating Tregs and allows activation and expansion of effector T cells, resulting in tumor cell lysis (see e.g. Vanamee et al. (2017) Trends in Molecular Medicine 23(11):P1037-P1046).

TNFR2 is abundantly expressed on the cell surface of many types of human cancers, including, for example, renal cell carcinoma, colon cancer, Hodgkin's lymphoma, multiple myeloma, cutaneous non-Hodgkin's lymphoma, and ovarian cancer. TNFR2 mutations in cancer are associated with gene duplication and constitutive activation. Murine myeloid-derived suppressor cells (MDSC) also express TNFR2, and its inhibitory effect has been demonstrated to control metastasis in murine liver cancer models. In addition, immune checkpoint inhibitors lead to the upregulation of TNFR2 on tumor-infiltrating Tregs, thereby leading to tumor immune evasion and drug resistance. Not all patients respond to immune checkpoint inhibitor therapy, patients may relapse, and severe autoimmune side effects have been observed with checkpoint inhibitor therapy (see e.g. Vanamee et al. (2017) Trends in Molecular Medicine 23(11) :P1037-P1046). Therefore, blocking TNFR2 can be used to treat certain types of cancer by directly killing tumor cells by suppressing immunosuppressive Tregs, allowing effector T cells to proliferate, and by inhibiting MDSCs, which can prevent metastasis formation. Because TNFR2 is also expressed on normal tissues (especially macrophages; see, e.g., proteinatlas.org/ensg00000028137-tnfrsf1b/tissue), TNFR2 antagonists do not have ADCC activity but do have FcRn activity (or enhanced FcRn activity). Administration is personalized because, as described in this article, to be eligible for treatment, a patient's tumor must have significantly higher TNFR2 content than adjacent normal tissue. To this end, TNFR2 antagonists will be used together with other therapies, especially immunomodulatory therapies that otherwise cause the accumulation of regulatory T cells in tumors.

Therefore, the TNFR2 agonists, bispecific TNFR1 antagonist/TNFR2 agonist constructs and fusion proteins provided herein can also be used to treat solid cancers, hematological malignancies and other hyperproliferative diseases and disorders, including but not limited to, for example, Renal cell carcinoma, colon cancer, Hodgkin's lymphoma, multiple myeloma, cutaneous non-Hodgkin's lymphoma, and ovarian cancer. 4. Combination therapy

Combination therapies include combining the TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids provided herein with another agent or treatment (including radiation and surgery) combined administration. Another agent or therapy can be administered concurrently with, before, after, or intermittently with the treatment provided herein. They can be in separate compositions or in co-formulations.

Provided herein are TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids in one or more other treatment regimens or therapeutic agents Before, after, intermittent or concurrent administration, including but not limited to TNF antagonists/blockers, antibodies, cytotoxic agents, anti-inflammatory agents, interleukins, growth factors, growth inhibitors, cardioprotective agents, immunosuppressive agents agents, chemotherapeutics, biological or nonbiological disease-modifying antirheumatic drugs (DMARDs), treatments for infectious diseases (including antibodies), or other therapeutic agents. The TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs and nucleic acids provided herein may be used as first-line treatments, or as anti-TNF therapeutics that are ineffective. Second-line therapy, given to patients as acute or chronic treatment. Examples of anti-TNF therapies that may be used in combination therapies herein include, for example, conventional synthetic DMARDs such as (common name and exemplary trademark): methotrexate (MTX), hydroxychloroquine (HCQ; Plaquenil®), sulfasalazine Pyridines (Azulfidine®) and leflunomide (Arava®); biologic DMARDs such as abatacept (Orencia®), anakinra (Kineret®), rituximab (Rituxan®, Truxima®, MabThera ®), tocilizumab (alizumab, Actemra®, RoActemra®), corticosteroids (e.g., dexamethasone, methylprexamethasone, prexamethasone, prexamethasone, or triamcinolone), Fatinib (Xeljanz®) and TNF inhibitors/anti-TNF agents such as pegylated certolizumab (Cimzia®), infliximab (Remicade®), adalimumab (Humira®), Gor Limumab (Simponi®) and etanercept (Enbrel®). Combination therapy may also include immunotherapeutic drugs such as cyclosporine, methotrexate, adlinomycin or cisplatin and immunotoxins.

Examples of anti-inflammatory drugs and anti-inflammatory agents that may be used in combination therapy include non-steroidal anti-inflammatory drugs (NSAIDs), including salicylates, such as aspirin; traditional NSAIDs, such as ibuprofen, naproxen, ketoprofen, nabumetone , piroxicam, diclofenac, or indomethacin; and Cox-2 selective inhibitors such as celecoxib (sold under the trademark Celebrex®) or roticosin (sold under the trademark Vioxx®). Other compounds that may be used in combination therapy include antimetabolites, such as methotrexate and leflunomide; corticosteroids or other steroids, such as corticosterone, dexamethasone, or prexamethasone; analgesics, such as acetaminophen; amine-based waters Cylates, such as meseramine; and cytotoxic agents, such as azathioprine (sold under the trademark Imuran®), cyclophosphamide (sold under the trademark Cytoxan®), and cyclosporine A.

Additional agents that may be used in combination therapy include biological response modifiers, including, for example, anti-inflammatory cytokines such as IL-10; B cell targeting agents such as anti-CD20 antibodies (such as rituximab); targeted T antigens compounds; adhesion molecule blockers; chemokine receptor antagonists; kinase inhibitors, such as inhibitors of mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK), or NFκB; and peroxidation Proliferator-activated receptor-γ (PPAR-γ) ligand. Additional agents that may be used in combination therapy include immunosuppressive agents. Immunosuppressive agents may include, for example, tacrolimus or FK-506; mycophenolic acid; calcineurin inhibitor (CNI); CsA; and sirolimus, or other agents known to suppress the immune system.

The polypeptides and constructs provided herein may also be used in combination with agents administered to treat cardiovascular disease and/or during procedures to treat cardiovascular disease, such as anticoagulants. Exemplary anticoagulants include, but are not limited to, heparin, warfarin, acenocoumarol, phenylindione, EDTA, citrates, oxalates, and direct thrombin inhibitors such as argatroban, lecithin, Pirudin, bivalirudin and ximelagatran.

The polypeptides and constructs provided herein can be administered with antibodies to treat autoimmune or inflammatory diseases, transplant rejection, or GvHD. Examples of such antibodies include, but are not limited to, anti-α4β7 integrin antibodies, such as LDP-02; anti-β2 integrin antibodies, such as LDP-01; anti-complement (C5) antibodies, such as 5G1.1; anti-CD2 antibodies, such as BTI- 322 and MEDI-507; anti-CD3 antibodies, such as OKT3 and SMART anti-CD3; anti-CD4 antibodies, such as IDEC-151, MDX-CD4, and OKT4A; anti-CD11a antibodies; anti-CD14 antibodies, such as IC14; anti-CD18 antibodies; anti-CD23 antibodies , such as IDEC 152; anti-CD25 antibodies, such as daclizumab; anti-CD40L antibodies, such as 5c8, lulizumab, and IDEC-131; anti-CD64 antibodies, such as MDX-33; anti-CD80 antibodies, such as IDEC-114; anti-CD147 Antibodies, such as ABX-CBL; anti-E-selectin antibodies, such as CDP850; anti-gpIIb/IIIa antibodies, such as ReoPro®/Abcixima; anti-ICAM-3 antibodies, such as ICM3; anti-ICE antibodies, such as VX-740; anti-FcγR1 antibodies , such as MDX-33; anti-IgE antibodies, such as rhuMAb-E25; anti-IL-4 antibodies, such as SB-240683; anti-IL-5 antibodies, such as SB-240563 and SCH55700; anti-IL-8 antibodies, such as ABX-IL8; Anti-interferon gamma antibodies; anti-TNFα antibodies, such as CDP571, CDP870, D2E7, infliximab, and MAK-195F; and anti-VLA-4 antibodies, such as Antegren®. Examples of other Fc-containing molecules that may be co-administered to treat autoimmune or inflammatory diseases, transplant rejection, and GvHD include, but are not limited to, the TNFR2-Fc fusion protein Enbrel® (etanercept) and Regeneron's IL-1 capture agent.

Examples of antibodies that may be co-administered to treat infectious diseases include, but are not limited to, anti-anthrax antibodies, such as ABthrax; anti-CMV antibodies, such as CytoGam and sevelumab; anti-Cryptosporidium antibodies, such as CryptoGAM and Sporidin-G; anti-Helix bacilli antibodies, such as Pyloran; anti-hepatitis B antibodies, such as HepeX-B and Nabi-HB; anti-HIV antibodies, such as HRG-214; anti-RSV antibodies, such as panvelizumab, HNK-20, palivizumab and RespiGam; and anti-staphylococcal antibodies such as Aurexis, Aurograb, BSYX-A110 and SE-Mab.

In some examples, the TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids provided herein are combined with one or more chemical Therapeutic agents are administered together. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piperosulfan; Hormones, such as carotesterone, drostanolone propionate, cyclothiandrostenol, mestandrostane, and testolactone; anti-adrenergics, such as amineglutethimide, mitotane, and trolostane; anti-androgens, such as Flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; antibiotics such as aclarithromycin, actinomycin, azomycin, azoserine, and bleomycin , actinomycin C, calicheamicin, carrubicin, erythromycin, carcinogen, chromomycin, dactinomycin, daunorubicin, ditobicin, 6-diazo-5- Side-oxygen-L-norleucine, doxorubicin, epirubicin, esopubicin, idarubicin, masiciromycin, mitomycin, mycophenolic acid, nogaramycin, olive Mycomycin, pelomycin, pofilomycin, puromycin, quinamycin, rhodobicin, streptozotocin, streptozocin, tuberculin, ubenimex, netinostat and levorubicin; antiestrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trovoxifene, raloxifene Fen, LY 117018, onapristone and toremifene (Fareston); antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as dinotrin, methotrexate aziridines, such as benzotepa, carboquinone, metotepa and uretipa; ethyleneimines and methylmelamines, including hexamelamine and triptamide , triethylphosphatide, trisethylthiophosphatamide, and trimethylolmelamine; folic acid supplements, such as aldehyde folic acid; nitrogen mustards, such as chlorambucil, naphthyl mustard, and chlorambucil. Amine, estramustine, ifosfamide, dichloromethyldiethylamine, dichloromethyldiethylamine oxide hydrochloride, melphalan, nitrogen mustard, mustard cholesterol, prednimol Stestin, trofosfamide, and uracil mustine; nitrosoureas, such as carmustine, chlortrimethrin, formostine, lomustine, nimustine, and ramomustine; platinum analogs substances, such as cisplatin and carboplatin; vinblastine; platinum; proteins, such as arginine deiminase and aspartase; purine analogs, such as fludarabine, 6-mercaptopurine, thiomidine and thioguanine; pyrimidine analogs, such as amcitabine, azacitidine, 6-azuridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enoxitabine , floxuridine, and 5-FU; taxanes, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); topology Isomerase inhibitors, such as RFS 2000; thymidylate synthase inhibitors, such as Tomudex; additional chemotherapeutic agents, including acetate glucuronide; aldehyde phosphatide glycosides; aminoacetate; amsacridine; Besbucil; Bisantrene; Edatroxate; Desfosamide; Demecocin; Diaquinone; Difluoromethylornithine (DMFO); Eflornithine; Eriacetonium; Etogle Lu; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguanhydrazone; mitoxantrone; mopandol; nitroacridine; pentostatin; belamet; pirarubicin; Podophyllic acid; 2-ethyl hydrazine; procarbazine; polysaccharide K (PSK, Krestin); Razoxane; Sizoran; Spirogermanium; Alternaria; Triiminoquinone; 2,2', 2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; piperobromide; garcitocin; arabinoside ("Ara -C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide ; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunorubicin; Aminopterin; Xeloda; Ibandronate; CPT-11 ; Retinoic acid; esperamycin; capecitabine; and topoisomerase inhibitors, such as irinotecan. Pharmaceutically acceptable salts, acids or derivatives of any of the above may also be used.

Chemotherapeutic agents can be administered as prodrugs. Examples of prodrugs that may be administered with the TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins, and nucleic acids provided herein include But are not limited to, for example, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactone-containing prodrugs Amine prodrugs, prodrugs containing optionally substituted phenoxyacetamide or prodrugs containing optionally substituted phenoxyacetamide, and 5-fluorocytosine and other 5-fluorouridine prodrugs, which may Converted into more active non-cytotoxic drugs. TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs can be provided as prodrugs, for example by using them with an in vivo cleavable linker Attached to a targeting agent that targets a specific tissue or disease site, thereby releasing the active form of the construct.

In some examples, the TNFRl antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFRl antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids provided herein are combined with one or more antibiotics Administered together, including but not limited to: aminoglycoside antibiotics (e.g., apramycin, arbekacin, bambomycin, buteroxin, dibekacin, gentamicin, conmycin, neomycin antibiotics (such as spectinomycin), netilmycin, paromomycin, ribomycin, sisomicin and spectinomycin), aminocycloalcohols (such as spectinomycin), aminoacyl antibiotics (such as chloramphenicol azide, chloramphenicol, florfenicol and tomacin), ansamycin antibiotics (such as rifamidate and rifampicin), carbapenems (such as imipenem, meropenem and panipenem) , cephalosporins (such as cefaclor, cefadroxylin, cefamandole, ceftriazin, cefoxidrone, cefazoline, cefametazole, cefpiramide, cefpirome, cefprozil, cefuroxime, cephalosporins oxime, cephalexin and cefradine), cephalomycins (such as cefrazone, cefoxitin, cefminox, cefmetazole and cefotetan), lincosamides (such as clindamycin and lincosamides) commycin), macrolides (such as azithromycin, brefeldin A, clarithromycin, erythromycin, roxithromycin and tobramycin), monomycins (such as antronam , carumonan and tigemonan), mupirocin, oxycephems (such as flurocephalosporin, laoxycephalosporin and laoxycephalosporin), penicillins (such as amdenoxicillin, amdenol Amoxicillin, Bamicillin, Benzyl Penicillin, Benzyl Penicillin Sodium, Epicillin, Fenbecillin, Flucloxacillin, Penacillin, Pensacillin Hydroiodide, O-Benzyl Ethylamine Penicillin , penicillin O, penicillin V, penicillin benzoate V, hydramidine V, penicillin and phenoxyethyl penicillin potassium), polypeptides (such as subtilisin, colistin, polymyxin B, ticolin Lanine and vancomycin), quinolinones (such as amloxacin, cinofloxacin, ciprofloxacin, enoxacin, enrofloxacin, fleroxacin, flumequine, gatixacin Star, gemifloxacin, gpafloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxalinic acid, pefloxacin, pipemidic acid, rozoxacin new, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin and trovafloxacin), rifampicin, streptozotocins (such as quinupristin and dalfopristin ), sulfonamides (such as p-aminobenzene sulfonamide and sulfamethyl isopropyl azoles) and tetracyclines (such as chlortetracycline, demeclocycline hydrochloride, demeclocycline, doxycycline, duramycin, minocycline, neomycin, oxytetracycline, streptomycin, tetracycline and vancomycin).

In some examples, TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins, and nucleic acids provided herein can be combined with one or more Antifungals administered together include, but are not limited to, amphotericin B, ciclopirox, clotrimazole, econazole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, Nystatin, terbinafine, terconazole and tioconazole. In some examples, the TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs and nucleic acids provided herein are together with one or more antiviral agents. Administration, including but not limited to protease inhibitors, reverse transcriptase inhibitors and others, including type I interferons, viral fusion inhibitors, neuraminidase inhibitors, acyclovir, adefovir, adamantane Amprenavir, clevudine, enfuvirtide, entecavir, foscarnet, ganciclovir, iodine glycoside, indinavir, lopinavir, praconarib, ribavirin, Amantadine, ritonavir, saquinavir, trifluridine, vidarabine, and zidovudine.

The TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids provided herein can be combined with the growth factor capture agents described below The constructs are administered in combination and are also used in combination therapy with the growth factor capture agent construct with any of the therapeutic anti-TNF agents and treatments described below. Combination therapies may also include growth factor capture agent constructs provided herein.

Pharmaceutical compositions containing the TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids provided herein can be used to treat the diseases described herein. Any diseases, illnesses and conditions known to those with ordinary skill in the art. Diseases, disorders and conditions include one or more chronic inflammatory, autoimmune, neurodegenerative or demyelinating diseases or conditions. Also provided are combinations of the polypeptides and constructs provided herein with another treatment or compound for the treatment of chronic inflammatory, autoimmune, neurodegenerative or demyelinating diseases or conditions. The TNFR1 antagonist constructs, TNFR2 agonist constructs, multispecific (such as bispecific) TNFR1 antagonist/TNFR2 agonist constructs, fusion proteins and nucleic acids provided herein, and additional agents can be packaged as separate compositions Things intended to be administered together or sequentially or intermittently. Alternatively, it may be provided as a single composition for administration, or as two compositions for administration as a single composition. Combinations can be packaged as kits, with additional reagents, instructions for use, vials and other containers, syringes and other items for treatment as needed. L. EXAMPLES The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1 Performance and Evaluation of Candidate Monovalent TNFR1 Antagonist Molecules Performance and Purification of Anti -TNFR1 Molecules

Candidate monovalent TNFR1 antagonist molecules are expressed in mammalian cells under the control of the CMV promoter using the expression plasmid depicted in Figure 1 (in which TE19080L is the insert). To express protein therapeutics, such as constructs herein, mammalian cells are used, such as Chinese Hamster Ovary (CHO) or Human Embryonic Kidney 293 (HEK293) cells, to provide post-translational modifications, including glycosylation, that are required for appropriate Protein structure, function and activity can be important. Expression in bacterial, yeast, or insect cells results in no glycosylation (for bacterial cells), or results in a different glycosylation pattern (in the case of yeast or insect cells) compared to expression in mammalian cells. Performance in bacteria can also lead to contamination of protein therapeutics with bacterial endotoxins, which may activate innate immune cells, complicate analysis by cell-based assays, and cause pyrogenic effects after in vivo administration.

Expression plastid construction and transient and stable cell line expression were performed using methods such as those described in Vazquez-Lombardi et al. (2018) Nat. Protoc. 13(1):99-117. Five exemplary TNFR1 antagonist molecules were generated for preliminary evaluation. TNFR1 antagonist molecules include H398-derived scFv (SEQ ID NO: 678), which contains a V _L and a V _H domain of H398, linked together by a (GGGGS) ₃ peptide linker; TNFR1 antagonist domain antibody (dAb ) DOM1h-574-16 (SEQ ID NO: 57); the TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58); a fusion protein (SEQ ID NO: 704) containing peptides from DMS5541 (described elsewhere herein) TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54), anti-serum albumin dAb (albudAb) via (GGGGS) ₃ peptide linker to DMS5541 (DOM7h-11-3; SEQ ID NO: 52) Fusion; and a fusion protein (SEQ ID NO: 705) containing the anti-TNFR1 dAb designated DOM1h-131-206 (SEQ ID NO: 59) via a (GGGGS) ₃ peptide linker and the anti-serum albumin of DMS5541 dAb (albudAb or DOM7h-11-3; SEQ ID NO: 52) fusion. Insert (GGGGS) ₃ linkers into H398 scFv and DOM1h-574-208 and DOM1h-131-206 fusion proteins to provide more flexibility between the V _H and V _L domains and between the two dAbs respectively, and Increase the stability and resistance to denaturation of molecules, thereby improving the manufacturing process. The sequence of each of these TNFR1 antagonist molecules is provided in Table 12 below, some with various linker sequences (see also Enever et al., (2015) Protein Engineering, Design & Selection 28(3) :59- 66, which describes dAbs and their modifications that can be used for further modification and addition of linkers and modulators). Table 12 : TNFR1 antagonist molecules sequence SEQ ID NO. H398 derived scFv QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGSGT DFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKR 678 DOMlh-574-16 EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS 57 DOMlh-549 EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSS 58 DOM1h-574-208 – albudAb fusion protein EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAPKLLILWNSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCAQAGTHPTTFGQGTKVEIKR 704 DOM1h-131-206 dAb – albudAb fusion protein EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAPKLLILWNSRLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCAQAGTHPTTFGQGTKVEIKR 705

Nanobodies and Nanobody-containing constructs are also provided, which include two DNA sequences selected from any one of SEQ ID NOs: 53-83 and 503-671 (such as SEQ ID NOs: 57-59). Heavy chain, and variants thereof having at least 95%, 96%, 97%, 98%, or 99% sequence identity therewith. Provides constructs containing consistent heavy chains. An example of this is the TNFR1 dAb designated DOM1h-131-206. Constructs containing any of these dAbs, such as linked to human serum albumin directly or more generally via a linker such as a GS linker, or provided as an Fc fusion, or as described herein, are also provided. dAb in any of the other constructs.

These and other such dAbs and TNFR1 binding molecules may be modified to increase specificity for TNFR1 by eliminating any antagonistic activity for TNFR2, and/or to increase or add TNFR2 agonist activity, and/or may be modified To reduce or eliminate immunogenic epitopes, and/or can be linked to activity modulators, such as Fc units and modified Fc units/modified Fc dimers, and/or serum half-life extending moieties.

The HEK293 cell line is used for transient expression and in vitro evaluation of antagonists expressed and identification of agents with desirable properties, such as high affinity for TNFR1 (e.g., _Kd < 50 nM or < 10 nM or < 5 nM) and potent inhibition Stable cell lines are prepared in derivatives of CHO cells following the detection of molecules that induce TNFR1 signaling (e.g. IC ₅₀ <50 nM or <10 nM or <5 nM). Generally, this is a picomolar (pM) affinity, such as about or about 19 pM affinity or 20 pM, 15 pM, 10 pM, 5 pM, 2 pM or 1 pM affinity.

Transient performance is optimized in CHO DG44 cells (e.g., CHO-DG44 (DHFR ^- ) and FreeStyle™ CHO-S cells, Invitrogen) to generate transfection pools that are screened to identify or select high-performing pure lines. No polyhistidine or other purification tags are used. In practice, proteins used for screening are purified from serum-free media by HPLC in combination with other well-known methods. The matrix used for HPLC is Amsphere™ A3 Protein A chromatography resin (JSR Life Sciences) or other similar resins, following the manufacturer's protocol. If the protein is not at least 95% pure, as judged by size exclusion HPLC, further purification (such as ion exchange or hydrophobic chromatography) is performed.

Removal of endotoxin (for an exemplary protocol, see e.g. Vazquez-Lombardi et al. (2018)). After protein purification, endotoxin content is determined using an assay kit such as the QCL-1000 Endpoint Chromogenic LAL Assay Kit (Lonza). To remove endotoxin, the theoretical pI of the purified protein is determined using a sequence analysis tool (eg, ExPASy ProtParam) and the low pH endotoxin PBS buffer is adjusted to a pH lower than but close to the theoretical pI of the purified protein. The protein sample is then dialyzed against at least 30 volumes of pH-adjusted PBS for at least 2 hours at 4°C. An additional dialysis step was performed overnight and then dialyzed again the next day for at least 2 hours. The sample is then purified using anion exchange affinity chromatography, retested to determine endotoxin content, and the process is repeated until acceptable endotoxin levels are achieved. The size and purity of the protein product are determined by SDS-PAGE analysis or other suitable methods. Alternatively, other methods may be used, such as a Proteus Endotoxin Removal Kit and accompanying manufacturer's manual (BIORAD, see bio-rad-antibodies.com/static/uploads/ifu/pur030.pdf). This step can be repeated until the desired level of endotoxin is reached, typically >0.5 endotoxin units/ml (less than or equal to 0.5 endotoxin units/ml). Screening of purified proteins

Use the methods described in the above embodiments or methods known in the art, such as immunoassays (eg ELISA), surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) or methods known in the art. Purified TNFR1 antagonist molecular candidates are screened to measure binding affinity to the extracellular domain of TNFR1 using other kinetic interaction assays known in . SPR can be performed using several commercially available platforms, such as the BIAcore system (GE Healthcare Life Sciences). Exemplary assays are described, for example, in Lang et al. (2015) J. Biol Chem 291 :5022-5037, which describes and compares various assays for assessing binding affinity. Selected candidates include those with _Kd values <5 nM.

TNFRl antagonists are also screened using methods known in the art, such as SPR, to determine whether binding to TNFRl is competitive or non-competitive with respect to TNF. If an inhibitor binds to a receptor (e.g. TNFR1) and blocks the binding of a ligand (e.g. TNF), e.g. by attaching to the active site, this is competitive inhibition because the inhibitor "competes" with the substrate for the enzyme ; that is, only inhibitors or substrates can be bound at a time. In noncompetitive inhibition, the inhibitor does not block the binding of the ligand to the ligand-binding site on the receptor. In effect, it attaches to another site and blocks the receptor's response to the bound ligand. This inhibition is called "noncompetitive" because the inhibitor and substrate can bind simultaneously. Therefore, if a ligand is added to a receptor binding assay at a saturating concentration and it does not inhibit antibody binding, the two molecules are independent and non-competitive. vice versa. If the two are competitive, increasing the concentration of the antibody will prevent TNF from binding to the receptor. This is valid whether the binding assay is performed on cells or with receptors or ligands bound to the surface. For exemplary assays, see, for example, Frey et al. (2001) Current Protocols in Neuroscience , "Receptor Binding Techniques", available at doi.org/10.1002/0471142301.ns0104s00.

For example, the ability of TNF to bind to human TNFR1 coated on BIAcore wafers was first determined. The TNFR1 surface is then saturated with TNFR1 antagonist molecules, followed by injection of TNF, and TNF binding to TNFR1 is re-evaluated. If the binding is non-competitive, they both bind to TNFR1; if the binding is competitive, they will interfere with each other. The antagonist's binding to TNFR1 is considered non-competitive with respect to TNF if TNF binding is unaffected or only slightly reduced, and if TNF binding is eliminated or significantly reduced, the antagonist's binding is deemed to be competitive with TNF. sexual. For the purposes of this article, competitive binders were selected.

Using methods known in the art, such as those described by McFarlane et al. (2002) FEBS Lett. 515(1-3):119-126, which results in activation of NFκB-luciferase expression (i.e., gene Reporter assay) to further screen TNFR1 antagonist molecules for their ability to inhibit TNFR1 signaling in the presence of TNF on cells. Cells used in these experiments do not express TNFR1 or TNFR2 (e.g., the myeloma cell lines AMO1, U266, and L363; see, e.g., Rauert et al. (2011) Cell Death Dis. 2(8):e194) unless expressed TNFR1 or TNFR2 of plasmid transfection. Alternatively, human cell lines in which the TNFR1 and/or TNFR2 genes are inactivated or genetically deleted using CRISPR vectors, antisense RNA expression, or other methods known in the art can be used. TNFR1 ^- and/or TNFR2 ^- cell lines available from commercial sources such as Genoway and Synthego can also be used. These cell lines can then be specifically transfected with TNFR1 and/or TNFR2 expression cassettes. For example, cells expressing TNFR1, TNFR2, or TNFR1 and TNFR2 can be used to assess the selectivity of antagonists for TNFR1 and determine the efficacy of inhibiting TNF signaling through TNFR1.

To determine the inhibition of TNFR1 signaling by TNFR1 antagonists, cells expressing human TNFR1 were transiently transfected with an NF-κB-luciferase reporter construct using lipofectamine, and receptors were measured 48 hours after transfection. Stimulated luciferase transcription. Cells stably expressing TNFR1 and NF-κB-luciferase were seeded in a 24-well plate at a density of 1×10 ⁵ cells/ml of culture medium, and cultured until they reached 80% confluence (approximately 24 hours). Cells were then incubated with 50 ng/ml TNF and various concentrations of TNFR1 antagonist for 6 hours. NF-κB stimulated luciferase activity by washing cells twice with ice-cold PBS and adding 200 µl of ice-cold lysis buffer (25 mM Tris-phosphate pH 7.8, 8 mM MgCl ₂ , 1 mM DTT, 1 % Triton X-100, 15% glycerol) and incubate on ice for 5 minutes. The cell extract was then scraped into a 1.5 ml Eppendorf tube, centrifuged to collect cell debris, and 100 µl of the supernatant was used to measure luciferase induction photometrically. _IC50 is then calculated by plotting relative luminescence units (RLU) versus TNFRl antagonist concentration and using curve fitting software, such as GraphPad Prism. Other similar assays for assessing inhibition of TNFR1 signaling include assays that measure the induction of phosphorylated-IκBα in TNFR1-expressing cells treated with TNF (see, e.g., Rauert et al. (2011 ) Cell Death Dis. 2(8):e194).

TNFR1 antagonist candidates that exhibit at least 80% inhibition of TNFR1 signaling as determined above and have an _IC50 value approximately equal to _Kd (ie, <5 nM) are selected for further optimization. Example 2 Optimization of selected candidate monovalent TNFR1 antagonist molecules for TNFR1 affinity and TNFR1 signaling inhibitory potency

Candidate TNFR1 antagonist molecules that meet the above selection criteria (i.e., high affinity for TNFR1 and effective inhibition of TNFR1 signaling, Kd _{and IC50} values < 5 nM) are optimized to increase affinity for TNFR1 and TNFR1 signaling. The effectiveness of conduction inhibition. This is accomplished by methods including one or more of random mutagenesis, site-directed mutagenesis, molecular modeling, and/or error-prone PCR to achieve _Kd and _IC50 values as low as <1 nM, typically at least equal to or < 100 nM, < 50 nM, < 10 nM or < 5 nM. For example, this can be achieved by a method (see Tiller et al. (2017) Frontiers Immunol. 8 :986) in which the amino acids most critical for binding are retained and the remaining amino acids of the _VH domain are subjected to Mutation is induced, a phage library is prepared, and high-affinity binding variants to TNFR1 are screened and selected. According to this method, a phage display library is generated to select such variants. In a first step, computational and experimental alanine scans induce mutagenesis to identify sites in complementarity-determining regions (CDRs) that allow mutagenesis while maintaining antigen binding. Next, based on natural antibody diversity, most allowed CDR positions are mutated at each CDR position using degenerate codons encoding wild-type residues and a few of the most frequently occurring residues. This mutagenesis method results in variants in antibody libraries with a wide range of CDR mutation numbers, including antibody domains with a single mutation and other antibody domains with dozens of mutations. In the final step, the library (approximately 10 million variants) displayed on the yeast surface is sorted to identify the CDR mutations with the greatest increase in affinity. half-life extension

The optimized molecule is then linked to a half-life extending moiety, for example by fusion to an IgG Fc domain, especially a modified Fc domain or human serum albumin (HSA), or by PEGylation, as described in the embodiments above , to achieve an in vivo serum half-life of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days, such as 10-12 days in SCID mice. The modified molecules were then retested in the in vitro assay described above to ensure retention of high affinity binding to TNFR1 and effective inhibition of TNFR1 signaling. Scale up production of successful candidates for further in vitro and in vivo assays. In vitro assay Phagocytosis assay

As discussed and described in the Examples, existing TNF blockers that inhibit TNFR1 activity also inhibit TNFR2. TNF blockers carry two types of black box warnings from regulatory agencies. The first is the susceptibility to infection in patients treated with anti-TNF (TNF blockers). These infections can involve a variety of organ systems and sites and are caused by bacteria, mycobacteria (e.g. tuberculosis), fungi (e.g. histoplasmosis, mongomycosis, candidiasis, coccidiosis, blastomycosis and pneumocystis). ), viruses (such as hepatitis B), and other opportunistic pathogens (organisms that usually do not cause illness in healthy people but can cause serious illness when a person's immune system (resistance) is weakened). Another black box warning issued relates to pediatric malignancies (see, e.g., online.epocrates.com/u/10b3301/Humira/Black+Box+Warnings). As discussed in the Examples, this vulnerability is caused by the complete blockage of signaling by TNFR1 and TNFR2 when their ligand TNF is blocked. This inhibition of the innate immune effects of TNF is mediated by TNFR2 (see, e.g., Ahmad et al. (2018) Front. Immunol. 9 :2572) and primarily by the transmembrane form of TNF, which preferentially activates TNFR2 (see For example, Miller et al. (2015) Journal of Immunology 195(6) :2633-2647).

Anti-TNF therapeutics such as adalimumab, infliximab, and etanercept have been shown to affect IFN-γ-induced phagosome maturation in phorbol myristate acetate-differentiated human THP-1 cells. Has an inhibitory effect. Adalimumab and infliximab, but not etanercept, inhibit phagosome maturation in primary human peripheral blood monocyte-derived macrophages in the presence or absence of IFN-γ (see e.g. Harris et al. (2008) J. Infect. Dis. 198 :1842-1850). In summary, one advantage of specific TNFR1 inhibitor constructs is that they preserve TNFR2 function and therefore macrophage function; macrophages are very important in expelling opportunistic infections from organisms. Opportunistic infectious agents include mycobacteria that cause tuberculosis (see, eg, Fraga et al. (2018) Curr. Issues Mol. Biol. 25: 169-198). Macrophage function is disrupted in autoimmune diseases in patients treated with TNF blockers. TNFR1-specific antagonists inhibit only TNFR1 function, thereby avoiding disruption of TNFR2 function required for normal macrophage function. Such TNFR1-specific antagonists can be identified by assaying the anti-TNF effect on macrophage phagocytosis. Among the identified TNFR1-specific antagonists are those that also stimulate TNFR2 function, thereby increasing macrophage activity (TNFR1 antagonists and TNFR2 agonists). Assay to determine the effect of TNFR1 antagonists on macrophage responses to Mycobacterium tuberculosis infection

TNF plays an important role in mediating host inflammatory responses to various pathogens, including Mycobacterium tuberculosis; TNF also plays a role in the immunopathology of tuberculosis (TB). Mycobacterial infection induces macrophages to secrete TNF. TNF enhances the ability of macrophages to phagocytose and kill mycobacteria. TNF also stimulates macrophage apoptosis, leading to increased killing and presentation of mycobacterial antigens by dendritic cells. TNF is also required for the formation and maintenance of granulomas; neutralization of TNF in mice chronically infected with Mycobacterium tuberculosis disrupts the integrity of the granulomas, worsens the infection, and increases mortality. TNF blockers, such as adalimumab and infliximab, increase susceptibility to infection by various pathogens, including Mycobacterium tuberculosis, and by inhibiting the maturation of mycobacteria-containing phagosomes in human macrophages. Increased risk of latent tuberculosis reactivation. Phagosome maturation (i.e., phagosome acidification and fusion with lysosomes) is critical for presentation of mycobacterial antigens to T cells and initiation of adaptive immune responses (see, e.g., Harris et al. (2008) J. Infect. Dis. 198 :1842-1850).

To identify and/or characterize TNFRl antagonists, the effects of the TNFRl antagonists provided herein on macrophage responses to Mycobacterium tuberculosis infection were assessed. Mycobacterial-containing phagosome maturation in human macrophages was analyzed using the method described in Harris et al. (2008) J. Infect. Dis. 198:1842-1850, and the results were analyzed with TNF blockers such as adalimumab. Anti-) to compare the phagosomes in phagosomes. Compared to known TNF blockers such as adalimumab, TNFR1 antagonists that do not increase susceptibility to infection are of interest. Preparation of THP-1 cells and monocyte-derived macrophages ( MDM )

Human THP-1 cells were cultured in RPMI 1640 (Invitrogen) with 10% fetal bovine serum (FBS; Gibco). Cells were differentiated into macrophage-like cells by treatment with 100 nmol/L phorbol myristate acetate (PMA) for 24 hours and subsequently cultured in normal medium for 3 days. To prepare human monocyte-derived macrophages (MDM), peripheral blood mononuclear cells (PBMC) were isolated from the blood of healthy donors using density gradient centrifugation on Histopaque®-1077 (Sigma). Mononuclear spheres were isolated by adhesion to gelatin-coated dishes and cultured overnight in RPMI 1640 with 5% human AB serum (Sigma). Adherent cells were removed with PBS containing 10 mmol/L EDTA and grown on coverslips in 12-well dishes for 10 days. THP-1 cells and MDM were grown on coverslips at a concentration of 2×10 ⁵ cells/well. Preparation of mycobacteria

Green fluorescent protein (GFP)-labeled Mycobacterium bovis Bacillus Calmette-Guérin (GFP-BCG) and attenuated Mycobacterium tuberculosis strain H37Ra and its virulent counterpart H37Rv in the presence of 0.5% Tween, 0.2% glycerol and 10% albumin- Growth in Middlebrook 7H9 medium with dextrose-catalase supplement (BD). Mycobacteria were grown to log phase before use and resuspended in RPMI 1640 with 10% FBS before infection. M. tuberculosis strain H37Ra was fluorescently labeled with PKH67 (Sigma), and strain H37Rv was fluorescently labeled with fluorescein isothiocyanate (FITC, 1 mg/mL; Sigma), following the manufacturer's protocol. Determination of phagosome maturation

Mycobacteria can inhibit the fusion of phagosomes and lysosomes and prevent the acidification and recruitment of lysosomal hydrolases. This block in phagosome maturation can be overcome by pretreating macrophages with IFN-γ. Treatment of mycobacterial-infected cells with TNF (5 ng/mL) also enhanced phagosome acidification. To determine the effects of TNFR1 antagonists and TNF blockers on the fusion of mycobacterial phagosomes and lysosomes in macrophages, in the presence of TNFR1 antagonists or TNF blockers, with or without IFN- In the case of gamma treatment, PMA-differentiated THP-1 cells or human peripheral blood MDM were infected with GFP-BCG or PKH67-tagged M. tuberculosis strain H37Ra or FITC-tagged M. tuberculosis strain H37Rv using LysoTracker® Red (LT) was used as a marker for acidified phagosomes and CD63 and cathepsin D were used as markers for phagolysosomes. Phagosome-lysosome fusions were analyzed by confocal microscopy. Inhibition of IFN-γ-induced phagosome maturation/acidification was determined by colocalization of labeled mycobacteria with LysoTracker® Red, CD63 or cathepsin D. For example, the percent colocalization of labeled mycobacteria with LT or CD63 or cathepsin D was reduced compared to controls, indicating inhibition of IFN-γ-induced phagosome acidification.

10 µg of a TNFR1 antagonist or TNF blocker (e.g., adalimumab, infliximab, etanercept, or others) with or without IFN-γ (200 U/mL) 24 hours before infection /mL) was added to THP-1 cells or MDM. As controls, cells were treated with culture medium alone or with 10 µg/mL human IgG1 (Calbiochem) from an IgG1-producing myeloma patient. Cells were then infected with M. bovis GFP-BCG, PKH67-labeled M. tuberculosis H37Ra, or FITC-labeled M. tuberculosis H37Rv for 15 minutes, washed three times with PBS to remove unbound mycobacteria, and incubated 2 hours. Fifteen minutes after macrophage infection, the magnification of infection (MOI) was recorded microscopically by staining with acid-fast bacilli. Cells were infected at an MOI of 1-5 bacilli in approximately 70% of the cells.

After 2 h of incubation, cells were fixed in 2% paraformaldehyde for 20 min at room temperature (RT); for strain H37Rv, cells were fixed in 4% paraformaldehyde overnight. Cells were then permeabilized with PBS containing 0.1% Triton X-100 and blocked with PBS containing 1% bovine serum albumin and 1% goat serum for 30 minutes at room temperature. Cells were incubated with primary antibodies (1 µg/mL mouse monoclonal antibody against CD63 (LAMP-3; Santa Cruz Biotechnology); or 10 µg/mL mouse monoclonal antibody against cathepsin D (Calbiochem)) at room temperature. Incubate for 1 hour at room temperature, followed by incubation with secondary antibody (4 µg/mL goat anti-mouse IgG labeled with Alexa Fluor 488 or 568; Invitrogen) for 1 hour at room temperature. Alternatively, cells were incubated with LysoTracker® Red DND-99 (100 nmol/L; Invitrogen) during the last 60 minutes of incubation with mycobacteria before fixation. LysoTracker® Red DND-99 is a red fluorescent dye used to label and track acidic organelles (such as acidified phagosomes) in living cells.

Coverslips were mounted on glass slides with fluorescent mounting medium (Dako), and images were recorded on a laser scanning confocal microscope, such as Olympus FluoView™ 1000 and Zeiss LSM 510 laser scanning confocal microscope. Use appropriate software and Adobe Photoshop to analyze and prepare images. Measurement of TNF

THP-1 cells were prepared as described above and infected with BCG or M. tuberculosis H37Ra with or without IFN-γ pretreatment. The amount of immunoreactive TNF (secreted in response to mycobacterial infection) in the supernatant was measured using a commercially available ELISA kit (R&D systems) according to the manufacturer's instructions. Differentiate between TNF blockade ( such as with adalimumab) , infliximab or etanercept treatment ) and specific TNFR1 inhibition regulatory T cell ( Treg cell ) analysis method and interleukin analysis method 1. Preserve FoxP3 expression

TNF blockade (using adalimumab, rituximab, or etanercept) was compared with specific TNFR1 inhibition, and methylation of the FoxP3 promoter was a surrogate marker of functional regulatory T cells. Transgenic mice constitutively expressing human TNFR1 (HuTNFR1) were used to evaluate the differential effects of TNF blockade and specific TNFR1 inhibition on FoxP3 promoter methylation. Transgenic mouse lines are prepared by standard methods and can be prepared by contractor services or any method, such as by Cyagen, Genoway or Polygene.

This effect was assessed in transgenic mice with collagen-induced arthritis (CIA), a widely used model of RA. Mice with C57/BL6N.Q;H-2q/HuTNFR1/Hunt background will be prepared by Genoway or Taconic Labs. Mice will be immunized with bovine type II collagen emulsified in complete Freund's adjuvant (CFA) as described by Tseng et al. ((2019) Proc. Natl. Acad. Sci. USA 116 :21666-21672) . Analysis of FoxP3 methylation was also performed as described by Tseng et al. ((2019) Proc. Natl. Acad. Sci. USA 116 :21666-21672). Regulatory T cells from TNF blockade-treated mice showed lower levels of FoxP3 than regulatory T cells with specific TNFR1 blockade, as measured by FoxP3 median fluorescence intensity (MFI) of CD4 ⁺ CD25 ⁺ cells and determined by the histogram. 2. Specific inhibition of TNFR1 and TNF blockade preserve regulatory T cells

Using the method described by McCann et al. ((2014) Arthritis & Rheumatology 66(10):2728-2738), the treatment of transgenic genes (C57/BL6N.Q;H- 2q/HuTNFR1/Hunt) The number of regulatory T cells in the posterior lymph nodes and spleen of CIA mice. 3. Inflammatory interleukins are upregulated in collagen-induced arthritis upon TNF blockade and specific TNFR1 inhibition

Transgenic mice (C57/BL6N.Q;H-2q/HuTNFR1/Hunt) with collagen-induced arthritis (CIA) (see e.g. McCann et al. (2014) Arthritis & Rheumatology 66(10):2728 -2738) were treated with TNF blockers and TNFR1-specific antagonists. Serum inflammatory cytokines (IFN-γ, IL-12p70, IL-10, RANTES (CCL5); see, e.g., McCann et al. (2014) Arthritis & Rheumatology 66(10):2728-2738) were assessed. Antagonists that specifically block TNFR1 induce significant reductions in one or more of IFN-γ, IL-12p70, IL-10, or RANTES (CCL5). This is due to the preservation of TNFR2 function and regulatory T cell function in the spleen and lymph nodes. in vivo analysis

Studies were conducted using humanized (HuTNFR1/HuTNF) transgenic mice. Evaluate the efficacy of TNFR1 antagonist molecules in various autoimmune disease models. Such models include those described above, which express human transgenes of TNFRl and TNF. Alternative models of autoimmune diseases are known. For example, models, including those of RA, are described in detail in Schinnerling et al. ((2019) Front. Immunol 10 :203). To determine efficacy, specific TNFRl antagonist constructs, as well as other constructs provided herein, were tested in more than one model. Included among such models are at least rheumatoid arthritis (RA), Crohn's disease, and multiple sclerosis (experimental autoimmune encephalitis) models (discussed in the embodiments).

Inflammatory bowel disease (IBD, including ulcerative colitis and Crohn's disease) was the first approved indication for TNF blockers. Many mouse models of these diseases are available and have been described by Mueller ((2002) Immunology 105(1):1-8). As discussed in the embodiments, autoimmune neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease, are important disease targets. Alzheimer's disease (AD) is the leading cause of dementia worldwide and represents one of the most serious health problems for the elderly. An estimated 5.4 million Americans have AD, and without medical breakthroughs to stop, prevent, or slow the disease, this number is expected to triple by 2050 (see, e.g., Chang et al. (2017 ) J. Cent. Nerv. Syst. Dis. 9 :1179573517709278). Evidence suggests that TNFR1 antagonist constructs and other constructs provided herein are therapeutic candidates because individuals who have undergone long-term treatment with TNF blockers are less likely to develop the disease (see, e.g., Chou et al. (2016) CNS Drugs 30 :1111). Data show that upregulated TNF expression is associated with different neurodegenerative diseases and conditions, such as Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis (see, e.g., McCoy et al. (2008) J. Neuroinflammation 5 (1):45). However, existing TNF blockers do not appear to be effective in treating, ameliorating, preventing or slowing disease progression (see, eg, Tortarolo et al. (2015) J. Neurochem. 135:109-124). As discussed here, various lines of evidence suggest that TNF blockers are not effective in this indication due to co-inhibition of TNFR1 and TNFR2; TNFR2 has neuroprotective properties that are lost with treatment with TNF blockers. Others have tried to solve this problem with various forms of "TNFR1 inhibitors" or "TNFR2 agonists." None of these studies included cross-reactivity to determine whether TNFR1 or TNFR2 was selectively targeted, rather than as one of many targetable epitopes in the body.

This issue is addressed in this article. First, a series of anti-TNFR1 antagonists were generated and tested in the above model, showing that their effects were consistent with predictions. This was subsequently demonstrated to be selective using immunochemistry. Several contract research laboratories provide this service (such as Sino Biological, Inc. and LSBio).

As discussed in the Examples, other autoimmune and chronic inflammatory disease states are associated with the presence of TNF. Such diseases include type II diabetes and endometriosis. Mouse models of these diseases are known, and HuTNFRl/HuTNF transgenic versions of these mice were used to demonstrate the efficacy of the specific anti-TNFRl antagonists provided herein. acute respiratory distress syndrome

Respiratory viral pathogens (e.g., influenza, SARS virus/coronavirus) infect respiratory epithelial cells, and tissue-resident alveolar macrophages are the first responders to viral infections in the lungs. It is cleared by phagocytosis of opsonized virus particles or infected apoptotic cells and the release of large amounts of inflammatory cytokines and chemokines to initiate an immune response (see, for example, Herold et al. (2015) Eur. Resp. J. 45 :1463-1478). TNF blockers have been shown to prolong survival of mice infected with influenza (see, eg, Shi et al. (2013) Crit. Care 17:R301). TNF blockers have been used to treat SARS-Cov 2 (see e.g. Feldmann et al. (2020) Lancet 395:1407-1409). As mentioned in the Examples, a known effect of TNF blockers is the reduction of regulatory T cells (Tregs), which is problematic because Tregs are natural suppressors of inflammation. Therefore, specific inhibitors of TNFRl as described and provided herein do not interact with or agonize TNFR2 and are superior for this purpose. To test the constructs provided herein, mice were engineered to lack endogenous TNFR1 and express HuTNFR1/HuTNF. These mice will exhibit HuTNF/HuTNFR1-induced acute respiratory distress syndrome after infection with influenza (as described in Shi et al. (2013) Crit. Care 17:R301). A TNFRl -specific antagonist construct that does not antagonize TNFR2 was administered. Efficacy is determined by any of several criteria: 1. Significant reduction in circulating inflammatory interleukins (such as IFN-γ, IL-1α, IL1-β, and IL-17) compared with TNF blockers; 2. Recovery as measured by weight gain is significantly accelerated compared to TNF blockers (see, e.g., Shi et al. (2013) Crit. Care 17:R301); and 3. Survival is significantly increased compared to TNF blockers. (See e.g. Shi et al. (2013) Crit. Care 17:R301).

Transgenic mouse lines expressing human TNFR1 and human TNFR2 for use in disease models were generated by standard genetic engineering methods known in the art, such as Atretkhany et al. (2018) Proc. Natl. Acad. Sci. USA 115(51):13051-13056. Specific in vivo assays for various diseases and conditions are as follows. For example, humanized RA mouse models, such as the collagen-induced arthritis (CIA) model of RA or any other RA animal model known in the art and/or described herein, are used to evaluate the methods provided herein. The therapeutic efficacy of TNFR1 antagonist molecules was compared with that of anti-TNF therapies such as etanercept or adalimumab. Following the development of clinical arthritis in one or more limbs, animals are administered a TNFRl antagonist molecule or an anti-TNF therapy (such as etanercept or adalimumab) provided herein daily for a total of 10 days. Monitor the initial swelling of the affected joint by measuring the thickness of the paw using calipers. Serum was drawn from mice to measure pro-inflammatory cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), IL-1β, IL-6, IL-8, RANTES (CCL5), and monocytogenes chemoattractant protein 1 (MCP-1; also known as CCL2). Regression of RA in the mouse model was then compared between mice administered TNFR1 antagonist molecules and mice administered etanercept or adalimumab.

The TNFR1 antagonist molecules provided herein were also tested in humanized mouse models of severe acute respiratory syndrome (SARS and virus-induced cytokine storm). Mouse models of SARS are developed, for example, by infecting humanized hTNFR1 (or hTNFR1/hTNFR2) gene knock-in with SARS-CoV at different doses, such as 10 ² , 10 ³ , 10 ⁴ and 10 ⁵ plaque forming units (PFU). Produced by mice. Infected mice are administered TNFR1 antagonist molecules, and survival is assessed and compared to survival of mice administered anti-TNF therapy, such as adalimumab.

Mouse models of virus-induced cytokine storm include, for example, the lymphocytic choriomeningitis virus (LCMV)-induced cytokine storm syndrome (CSS) model. The LCMV-induced CSS mouse model was generated by intraperitoneally administering 2 × 10 ⁵ PFU of LCMV-Armstrong to 8-12-week-old perforin-deficient ( Prf ^−/− ) or Prf-Tmem178 double-knockout mice. To deplete monocytes/macrophages, Prf ^−/− mice were injected intravenously with 100 μl clodronate-liposomes two days before and 48 and 96 h after LCMV infection. Alternatively, 1 mg of neutralizing anti-CSF1 antibody (Clone 5A1, BioXCell) was administered 2 days before infection, and 0.5 mg of antibody was administered 48 and 96 hours later. On days 3 and 8 post-infection, animals were bled via submandibular vein puncture to measure serum interleukins (see, e.g., Mahajan et al. (2019) J. Autoimmun. 100:62-74). Example 3 Identification and removal of immunogenic sequences

As described herein, immunogenic sequences within protein therapeutics, such as B-cell and/or T-cell epitopes, can negatively impact the activity, efficacy, and in vivo half-life of the therapeutic, for example, through the formation of anti-drug antibodies (ADAs). ) to neutralize the therapeutic agent and/or accelerate its removal from the body. Immunogenic sequences are also detrimental to the safety and tolerability of protein therapeutics because they can induce adverse immune responses that can lead to clinical complications such as delayed infusion-like anaphylaxis, severe anaphylaxis, and, in some cases, life-threatening autoimmune reactions. Body immunity. Therefore, candidate protein therapeutics are screened for immunogenicity and the identified immunogenic sequences are removed/replaced, e.g., through mutation induction, to improve the in vivo efficacy and safety profile of the therapeutic and ensure its success from preclinical Translation of research into clinic.

Immunogenic sequences are identified using methods such as those described in the Examples or known to those of ordinary skill in the art, including the use of in silico immunogenicity prediction tools and in vitro immunogenicity testing. For example, as described elsewhere herein, linear B cell epitopes use, for example, ABCPred, APCPred, BCPREDs, BepiPred, LBtope, BcePred, EPMLR, BEST, COBEpro and SVMTriP or those described herein and/or known in the art. Predictions are generally made by any other in silico linear B cell epitope prediction tool known to the person skilled in the art. Conformational B cell epitopes are determined using, for example, CEP, DiscoTope, BEpro, ElliPro, SEPPA, CBTOPE, EPITOPIA, EPCES, EPSVR, EPMeta, PEASE, EpiPred, 3DEX, PEPOP, PEPOP 2.0, and EpiSearch or those described and/or included herein. Any other in silico configurational B cell epitope prediction tool known to those of ordinary skill in the art may be used for prediction. T cell epitopes using, for example, EpiMatrix, JanusMatrix, IEDB, SYFPEITHI, MHC Thread, MHCPred, MHCPred 2.0, EpiJen, NetMHC, NetCTL, nHLAPred, SVMHC, ProPred, MMBPred, Protean 3D and Bimas or those described and/or included herein Prediction can be made by any other in silico T cell epitope prediction tool known in the art. The following is an exemplary analysis of the immunogenic linear B cell epitope of the human TNFR1 antagonist DMS5541 sequence (SEQ ID NO: 38). Analysis of immunogenic linear B cell epitopes of DMS5541

The potential immunogenicity of the human TNFR1 antagonist DMS5541 sequence (SEQ ID NO: 38) was analyzed using the SVMTriP algorithm to detect linear B cell epitopes within the molecule. This algorithm identified three possible epitopes in the DMS5541 sequence, as shown in Table 13 below. The results show that the epitope having the sequence AVKGRFTISRDNSKNTLYLQ corresponding to residues 63-82 of SEQ ID NO: 38 has a high probability of immunogenicity. The three identified epitopes were then tested for immunogenicity in an in vitro B cell assay. Any sequences that are positive for immunogenicity are scanned for alanine. The positive amino acids/sequences are modified by replacing each amino acid in the sequence one by one with alanine residues until the immunogenic epitope is destroyed. This results in a safer and more effective TNFR1 antagonist.

As a positive control, the SVMTriP algorithm was also used to predict the known high immunogenicity of adalimumab; adalimumab administered in the absence of methotrexate was immunogenic in approximately 50% of patients (see e.g. Ducourau et al. (2020) RMD Open 6:e001047). The SVMTriP algorithm identified at least ten possible epitopes in the heavy chain of adalimumab, four of which have a high probability, thus showing good correlation with clinical data and validating this program for predicting immunogenicity. purpose. Table 13 : B cell epitopes in the DMS5541 sequence as predicted by the SVMTriP algorithm sort epitope Location (SEQ ID NO:38 ) Rating 1 AVKGRFTISRDNSKNTLYLQ 63-82 1.000 2 LRAEDTAVYYCAIYTGRWVP 86-105 0.784 3 SPSSSLSASVGDRVTITCRAS 129-148 0.660

The results of the SVMTriP analysis of DMS5541 were supported by a second algorithm, ABCPred, which was used to predict the immunogenicity within the DMS5541 sequence. All three B cell epitopes predicted by SVMTriP were also included in the epitope prediction results of ABCPred. For example, as shown in Table 14 below, the epitopes AVKGRFTISRDNSKNT, TGRWVPFEYWGQGTLV and STDIQMTQSPSSLSAS (see table below for each residue position in SEQ ID 38) contain overlapping epitopes with the three epitopes identified by SVMTriP sequence. Table 14 : B cell epitopes in the DMS5541 sequence as predicted by the ABCPred prediction server sort epitope Starting position (SEQ ID NO:38 ) Rating 1 AQAGTHPTTFGQGTKV 211 0.92 2 SGSGTDFTLTISSLQP 187 0.90 3 AVKGRFTISRDNSKNT 63 0.89 3 RVTITCRASRPIGTTL 140 0.89 4 SASVGDRVTITCRASR 134 0.86 5 GWVRQAPGKGLEWVSQ 35 0.85 6 ASRPIGTTLSWYQQKP 147 0.84 7 LVTVSSASTDIQMTQS 114 0.83 8 SGFTFDKYSMGWVRQA 25 0.82 8 LQPEDFATYYCAQAGT 200 0.82 9 QISTADRTYYAHAVK 50 0.81 9 STDIQMTQSPSSLSAS 121 0.81 10 NSKNTLYLQMNSLRAE 74 0.80 10 TGRWVPFEYWGQGTLV 100 0.80 Example 4 Exemplary TNFR1 antagonist constructs containing human TNFR1 antagonist antibody fragments ( dAb , scFv , Fab )

Provided herein are TNFR1 antagonist constructs that selectively inhibit TNFR1 but not TNFR2. In order to avoid aggregation of TNFR1 receptors, TNFR1 agonists and TNFR1 antagonists are monomeric and monovalent. TNFR1 antagonists contain human single domain antibodies (dAb) specific for TNFR1. dAbs contain variable heavy ( _VH ) or variable light ( _VL ) domains. For example, the dAb contains any of the dAbs having an amino acid sequence set forth in any of SEQ ID NOs: 54-672, or a dAb having an amino acid sequence set forth in any of SEQ ID NOs: 54-672 A dAb that has at least or at least about 90% or 95% sequence identity and retains binding affinity for TNFR1. Alternatively, the TNFRl antagonist contains a scFv, Fab or other antigen-binding fragment, such as one derived from a human TNFRl antagonist antibody such as H398 or ATROSAB. For example, a TNFR1 antagonist contains a H398-derived scFv set forth in SEQ ID NO: 677 or 678; or an ATROSAB-derived scFv set forth in any of SEQ ID NO: 673-676; or an ATROSAB-derived scFv set forth in SEQ ID NO: 673-676, respectively. ID NO: 679 and 680 (FabATR) or the ATROSAB-derived Fab fragment light and heavy chains shown in either of SEQ ID NO: 681 or 682 (Fab 13.7), respectively; or with SEQ ID NO: 673 The scFv of any one of -678 or the Fab light chain and heavy chain of any one of SEQ ID NO: 679 and 680 (FabATR) respectively or SEQ ID NO: 681 or 682 (Fab 13.7) respectively has at least Or a scFv or Fab fragment that is at least about 90% or 95% sequence identical and retains affinity for TNFR1.

TNFR1 antagonists are fused to serum half-life extenders, such as IgG Fc, especially Fc modified to eliminate or reduce ADCC, ADCP and/or CDC, human serum albumin (HSA) and/or polyethylene glycol (PEG) molecules. For example, the C-terminus of a human anti-TNFR1 dAb, scFV, Fab or other antigen-binding fragment is fused to the N-terminus of the Fc region of a human IgG1 or IgG4 antibody via a linker. An IgG1 Fc region, such as the IgG1 Fc derived from trastuzumab (see SEQ ID NO: 27), or an IgG4 Fc region, such as the IgG4 Fc derived from nivolumab (see SEQ ID NO: 30), is used. When the Fc is derived from trastuzumab, the linker includes a portion of the hinge sequence of trastuzumab, containing the amino acid residue sequence SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), or When the Fc is derived from nivolumab, the linker may contain the hinge sequence of nivolumab, contain the amino acid residue sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29) or it may provide flexibility properties or other structural properties. To confer protease resistance and increase the flexibility of the fusion protein, the SCDKTH or ESKYGPPCPPCP hinge sequence is replaced with a short glycine-serine (GS) peptide linker, such as (GSGS) or (GGGGS) _n (see, e.g., SEQ. respectively ID NO: 707 residues 199-202 and 116-120), where n = 1-5 or 1-6, or other combinations of Gly and Ser residues, such as GGGGSGGGGSGGGGS (e.g., residue 116 of SEQ ID NO: 707 -130). In other embodiments, the C-terminus of the human anti-TNFR1 dAb, scFv, Fab or other antigen-binding fragment is linked to a GS linker, and the GS linker is linked to all or a portion of the trastuzumab or nivolumab hinge sequence , which is sufficient to provide flexibility, the hinge sequence is connected to the N-terminus of the corresponding Fc region. In some embodiments, a second Fc subunit is linked to the first Fc subunit to increase the serum half-life and stability of the molecule. Because there are two Fc regions, any resulting construct is not a fusion protein because it contains a discontinuous Fc region. In some embodiments, the N-terminus of a human TNFRl antagonist dAb, scFV, Fab or other antigen-binding fragment is fused to the C-terminus of a serum half-life extender via a linker, as described above.

Also provided herein are TNFR1 antagonist fusion proteins containing an anti-TNFR1 dAb, scFv, Fab or other antigen-binding fragment via a short peptide linker, such as (GSGS) _n or (GGGGS) _n , where n = 1-5 or 6, Such as GGGGSGGGGSGGGGS, fused to human serum albumin (HSA).

Also provided herein are TNFR1 antagonist molecules containing an anti-TNFR1 dAb, scFv, Fab or other antigen-binding fragment linked to a PEG molecule of at least 30 kDa in size.

As described herein, these constructs can be modified to reduce or eliminate immunogenicity. TNFR1 antagonist dAb, scFv, Fab or other antigen-binding fragments are analyzed by computer simulation, in vitro and/or in vivo methods to predict or identify immunogenic sequences. After identification of immunogenic sequences (such as B cell and/or T cell epitopes), the identified sequences are modified by induction of mutagenesis, for example by alanine scanning, as described elsewhere herein, such that the antigen De-immunization/removal or replacement of immunogenic sequences.

The following are exemplary constructs of TNFR1 antagonist fusion proteins described and provided herein. In all embodiments including the Fc of trastuzumab or the Fc of nivolumab, the Fc region is optionally modified to reduce or eliminate immune effector functions, including ADCC, ADCP, and CDC, and is also optionally modified to Enhance the binding to FcRn, increase the serum half-life of the fusion protein, and also replace or otherwise modify or remove the immunogenic sequence if necessary.

Fc modifications that reduce or eliminate immune effector function are summarized in Table 9 above, and Fc modifications that enhance FcRn binding are summarized in Table 7 above. Any one or combination of such modifications are included in the Fc region of the fusion proteins provided herein. All exemplary constructs provided herein were also prepared with a TNFR1 antagonist at the C-terminus of the fusion protein rather than the N-terminus. 1a) H398 scFv - SCDKTH - Trastuzumab Fc

Provided herein is a human TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of H398 scFv (SEQ ID NO: 678) is fused to a part of the hinge sequence of trastuzumab, which part contains at least the amino acid residue sequence SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26 ), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). The H398 scFv-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 706): QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLPVS LGDQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced by up to the complete sequence of the hinge region of trastuzumab, which contains or has the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues. 1b) H398 scFv - GGGGSGGGGSGGGGS - Trastuzumab Fc

Provided herein is a TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of the H398 scFv (SEQ ID NO: 678) is fused to the GGGGSGGGSGGGGS peptide linker to the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) N-terminal fusion. The H398 scFv-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 707): QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQ SPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1c) H398 scFv - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

Provided herein is a TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of H398 scFv (SEQ ID NO: 678) is fused to a GGGSGGGGSGGGGGS peptide linker, which is fused to a portion of the hinge sequence of trastuzumab, including at least the amino acid residue sequence SCDKTH (corresponding to SEQ ID NO: 26), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 6; see also SEQ ID NO: 27). The H398 scFv-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 708): QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGQGTTLTVSSGGGGSGGGGSGG GGSDIVMTQSPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by up to the complete sequence of the hinge region of trastuzumab, which contains at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues. 1d) H398 scFv - GGGGSGGGGSGGGGS - HSA

Provided herein is a TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of H398 scFv (SEQ ID NO: 678) is fused to the GGGGSGGGSGGGGS peptide linker to human serum albumin (HSA) without a signal peptide (corresponding to residues 19-609 of SEQ ID NO: 35) N-terminal fusion. The H398 scFv-GGGGSGGGGSGGGGS-HSA fusion protein has the following sequence (SEQ ID NO: 709): QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLPVSLG DQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRGGGGSGGGGSGGGGSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYG EMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESK DVCKNYAEAKDVFLGMFLYEYARRHHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSE KERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1e) H398 scFv - GGGGSGGGGSGGGGS - PEG _30kDa

Provided herein is a TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of H398 scFv (SEQ ID NO: 678) is fused to a GGGGSGGGSGGGGS peptide linker, which is covalently linked to a 30 kDa PEG molecule.

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the PEG molecule may have a molecular weight equal to about 30 kDa, or greater than 30 kDa, such as 35 kDa, 40 kDa, 45 kDa or 50 kDa. 1f) DOM1h-574-16 - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C-terminus of DOM1h-574-16 is fused to a portion of the hinge sequence of trastuzumab, which portion contains at least the amino acid residue sequence SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), which is N-terminal fusion of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOMlh-574-16-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 710): EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced by up to the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues. 1g) DOM1h-574-16 - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C terminus of DOM1h-574-16 is fused to the GGGGSGGGSGGGGGS peptide linker to the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) N-terminal fusion. The DOM1h-574-16-GGGGSGGGGSGGGGS-trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 711): EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSSGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1h) DOM1h-574-16 - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C-terminus of DOM1h-574-16 is fused to a GGGGSGGGSGGGGGS peptide linker, which is fused to a portion of the hinge sequence of trastuzumab, which portion contains at least the residue sequence SCDKTH (corresponding to the residue of SEQ ID NO: 26 residues 222-227), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOM1h-574-16-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 712): EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSSGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by up to the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or at least 5, 6, 7 thereof , 8, 9, 10 or 11 consecutive residues. 1i) DOM1h-574-16 - GGGGSGGGGSGGGGS - HSA

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C-terminus of DOM1h-574-16 is fused to the GGGGSGGGSGGGGS peptide linker, which is fused to the N-terminus of human serum albumin (HSA) without a signal peptide (corresponding to residues 19-609 of SEQ ID NO: 35) . The DOM1h-574-16-GGGGSGGGGSGGGGS-HSA fusion protein has the following sequence (SEQ ID NO: 713): EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSSGGGGSGGGGSGGGGSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHT LFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIA EVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVP KEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1j) DOM1h-574-16 - GGGGSGGGGSGGGGS - PEG _30kDa

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C-terminus of DOM1h-574-16 is fused to a GGGGSGGGSGGGGGS peptide linker, which is covalently linked to a 30 kDa PEG molecule.

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the PEG molecule may have a molecular weight greater than 30 kDa, such as 35 kDa, 40 kDa, 45 kDa or 50 kDa. 1k) DOM1h-549 - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOM1h-549 is fused to a portion of the hinge sequence of trastuzumab, which portion contains at least the residue sequence SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), which is consistent with trastuzumab N-terminal fusion of the Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOM1h-549-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 714): EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced by up to the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues. 1l) DOM1h-549 - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOMlh-549 is fused to the GGGGSGGGGSGGGGS peptide linker to N of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) end integration. DOM1h-549-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 715): EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1m) DOM1h-549 - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOM1h-549 is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to a portion of the hinge sequence of trastuzumab containing at least the residue sequence SCDKTH (corresponding to residue 222 of SEQ ID NO: 26 -227), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOM1h-549-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 716): EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by a portion containing at least 5, 6, 7, 8, 9, 10 or 11 contiguous residues of the hinge region of trastuzumab up to the hinge region of trastuzumab The complete sequence, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26). 1n) DOM1h-549 - GGGGSGGGGSGGGGS - HSA

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOM1h-549 is fused to the GGGGSGGGGSGGGGS peptide linker, which is fused to the N-terminus of human serum albumin (HSA) without a signal peptide (corresponding to residues 19-609 of SEQ ID NO: 35). The DOM1h-549-GGGGSGGGGSGGGGS-HSA fusion protein has the following sequence (SEQ ID NO: 717): EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLF GDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEV ENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETTFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1o) DOMlh-549 - GGGGSGGGGSGGGGS - PEG _30kDa

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOM1h-549 is fused to a GGGGSGGGGSGGGGS peptide linker, which is covalently linked to a 30 kDa PEG molecule.

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the PEG molecule may have a molecular weight greater than 30 kDa, such as 35 kDa, 40 kDa, 45 kDa or 50 kDa. 1p) DOM1h-574-208 - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C-terminus of DOM1h-574-208 is fused to a portion of the hinge sequence of trastuzumab, which portion contains at least the residue sequence SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), which is identical to trastuzumab. N-terminal fusion of the monoclonal antibody Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOM1h-574-208-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 718): EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSSCDKTHAPELLGGPSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced with a portion containing at least 5, 6, 7, 8, 9, 10 or 11 contiguous residues of the hinge region of trastuzumab, up to the complete hinge region of trastuzumab, It contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26). 1q) DOM1h-574-208 - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C terminus of DOM1h-574-208 is fused to the GGGGSGGGSGGGGGS peptide linker to the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) N-terminal fusion. The DOM1h-574-208-GGGGSGGGGSGGGGS-trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 719): EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1r) DOM1h-574-208 - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C-terminus of DOM1h-574-208 is fused to a GGGGSGGGSGGGGGS peptide linker, which is fused to a portion of the hinge sequence of trastuzumab, which portion contains at least the residue sequence SCDKTH (corresponding to the residue of SEQ ID NO: 26 residues 222-227), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOM1h-574-208-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 720): EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by a portion containing at least 5, 6, 7, 8, 9, 10 or 11 contiguous residues of the hinge region of trastuzumab up to the hinge of trastuzumab. The complete sequence of the region containing the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26). 1s) DOM1h-574-208 - GGGGSGGGGSGGGGS - HSA

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C-terminus of DOM1h-574-208 is fused to the GGGGSGGGSGGGGGS peptide linker, which is fused to the N-terminus of human serum albumin (HSA) without a signal peptide (corresponding to residues 19-609 of SEQ ID NO: 35) . The DOM1h-574-208-GGGGSGGGGSGGGGS-HSA fusion protein has the following sequence (SEQ ID NO: 721): EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSGGGGSGGGGSGGGGSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHT LFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIA EVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVP KEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1t) DOM1h-574-208 - GGGGSGGGGSGGGGS - PEG _30kDa

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C-terminus of DOM1h-574-208 is fused to a GGGGSGGGSGGGGGS peptide linker, which is covalently linked to a 30 kDa PEG molecule.

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the PEG molecule may have a molecular weight of at least or greater than 30 kDa, such as 35 kDa, 40 kDa, 45 kDa or 50 kDa. 1u) DOM1h-131-206 - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-131-206 (SEQ ID NO: 59). The C-terminus of DOM1h-131-206 is fused to a portion of the hinge sequence of trastuzumab, which portion contains at least the residue sequence SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), which is identical to trastuzumab. N-terminal fusion of the monoclonal antibody Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOM1h-131-206-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 722): EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced by a portion containing at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues of the hinge region of trastuzumab, up to the complete sequence of the hinge region of trastuzumab , which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26). 1v) DOM1h-131-206 - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-131-206 (SEQ ID NO: 59). The C terminus of DOM1h-131-206 is fused to the GGGGSGGGSGGGGGS peptide linker to the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) N-terminal fusion. The DOM1h-131-206-GGGGSGGGGSGGGGS-trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 723): EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1w) DOM1h-131-206 - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-131-206 (SEQ ID NO: 59). The C-terminus of DOM1h-131-206 is fused to a GGGGSGGGSGGGGGS peptide linker, which is fused to a portion of the hinge sequence of trastuzumab, which portion contains at least the residue sequence SCDKTH (corresponding to the residue of SEQ ID NO: 26 residues 222-227), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). DOM1h-131-206-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 724): EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with another Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or in the art Any other suitable short peptide linker known in . Alternatively or additionally, the SCDKTH hinge sequence is replaced by at least 5, 6, 7, 8, 9, 10 or 11 contiguous residues of the hinge region containing trastuzumab, up to all or part of the complete sequence, trastuzumab. The hinge region of the monoclonal antibody contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26). 1z) H398 scFv - ESKYGPPCPPCP - Nivolumab Fc

Provided herein is a human TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of H398 scFv (SEQ ID NO: 678) is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which is identical to nivolumab N-terminal fusion of the Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). The H398 scFv-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 726): QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLP VSLGDQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, use all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 1aa) H398 scFv - GGGGSGGGGSGGGGS - Nivolumab Fc

Provided herein is a TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of the H398 scFv (SEQ ID NO: 678) is fused to the GGGGSGGGSGGGGS peptide linker to the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO : 30) N-terminal fusion. The H398 scFv-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 727): QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSP LSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1ab) H398 scFv - GGGGSGGGGSGGGGS - ESKYGPPCPPCP - Nivolumab Fc

Provided herein is a TNFR1 antagonist fusion protein containing an scFv derived from the human TNFR1 antagonist antibody H398. The scFv contains the V _L and V _H domains of H398, linked together by a (GGGGS) ₃ peptide linker. The C-terminus of H398 scFv (SEQ ID NO: 678) is fused to a GGGSGGGGSGGGGS peptide linker, which is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to the residues of SEQ ID NO: 29 212-223), which is fused to the N-terminus of the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). The H398 scFv-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 728): QVQLQESGAELARPGASVKLSCKASGYTFTDFYINWVKQRTGQGLEWIGEIYPYSGHAYYNEKFKAKATLTADKSSSTAFMQLNSLTSEDSAVYFCVRWDFLDYWGQGTTLTVSSGGGGSGGGGS GGGGSDIVMTQSPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYVQKPGQSPKLLIYTVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, all or a portion of the nivolumab hinge sequence is used, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues. 1ac) DOM1h-574-16 - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C-terminus of DOM1h-574-16 is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which is fused to the Fc region of nivolumab (corresponding to Fusion at the N-terminus of residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). DOM1h-574-16-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 729): EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, use all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 1ad) DOM1h-574-16 - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C terminus of DOM1h-574-16 is fused to the GGGGSGGGSGGGGS peptide linker to the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30) N-terminal fusion. DOM1h-574-16-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 730): EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSSGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1ae) DOM1h-574-16 - GGGGSGGGGSGGGGS - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-16 (SEQ ID NO: 57). The C-terminus of DOM1h-574-16 is fused to the GGGGSGGGSGGGGGS peptide linker, which is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29) , which is fused to the N-terminus of the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). DOM1h-574-16-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 731): EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSSGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, at least a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues until the complete sequence. 1af) DOM1h-549 - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOM1h-549 is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which is fused to the Fc region of nivolumab (corresponding to SEQ ID NO: 29). N-terminal fusion of residues 224-440 of ID NO: 29; see also SEQ ID NO: 30). DOM1h-549-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 732): EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, include all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 1ag) DOM1h-549 - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOM1h-549 is fused to the GGGGSGGGGSGGGGS peptide linker to the N-terminus of the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30) Fusion. The DOM1h-549-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 733): EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1ah) DOM1h-549 - GGGGSGGGGSGGGGS - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO: 58). The C-terminus of DOM1h-549 is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which Fusion to the N-terminus of the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). DOM1h-549-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 734): EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

In some specific examples, the GGGGSGGGGSGGGGS linker is replaced with a GS linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4, or 5, or as described herein or in the art. Any other suitable short peptide linker known in . Alternatively or additionally, all or a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues. 1ai) DOM1h-574-208 - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C-terminus of DOM1h-574-208 is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which is fused to the Fc region of nivolumab (corresponding to Fusion at the N-terminus of residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). DOM1h-574-208-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 735): EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, all or a portion of the nivolumab hinge sequence may be included, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 1aj) DOM1h-574-208 - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C terminus of DOM1h-574-208 is fused to the GGGGSGGGSGGGGGS peptide linker to the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30) N-terminal fusion. DOM1h-574-208-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 736): EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 1ak) DOM1h-574-208 - GGGGSGGGGSGGGGS - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO: 54). The C-terminus of DOM1h-574-208 is fused to the GGGGSGGGSGGGGGS peptide linker, which is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29) , which is fused to the N-terminus of the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). DOM1h-574-208-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 737): EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a (GSGS ₎ or (GGGGS ₎ linker, where n = 1, 2, 3, 4 or 5, or any other suitable short linker as described herein or known in the art. Peptide linker. Alternatively or additionally, all or a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues. 1al) DOM1h-131-206 - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-131-206 (SEQ ID NO: 59). The C-terminus of DOM1h-131-206 is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which is fused to the Fc region of nivolumab (corresponding to Fusion at the N-terminus of residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). DOM1h-131-206-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 738): EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSESKYGPPCPPCPAPEFLGGPSSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, include all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 1am) DOM1h-131-206 - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-131-206 (SEQ ID NO: 59). The C terminus of DOM1h-131-206 is fused to the GGGGSGGGSGGGGGS peptide linker to the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30) N-terminal fusion. The DOM1h-131-206-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 739): EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a (GSGS ₎ or (GGGGS ₎ linker, where n = 1, 2, 3, 4 or 5, or any other suitable short linker as described herein or known in the art. Peptide linker. 1an) DOM1h-131-206 - GGGGSGGGGSGGGGS - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein containing the human TNFR1 antagonist dAb DOM1h-131-206 (SEQ ID NO: 59). The C terminus of DOM1h-131-206 is fused to a GGGGSGGGSGGGGGS peptide linker, which is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29) , which is fused to the N-terminus of the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). DOM1h-131-206-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 740): EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a (GSGS ₎ or (GGGGS ₎ linker, where n = 1, 2, 3, 4 or 5, or any other suitable short linker as described herein or known in the art. Peptide linker. Alternatively or additionally, all or a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues.

Vhh (nanobodies) linked to HSA have also been synthesized, particularly in their single chain form, which contain dAbs such as DOM1h-131-206. Exemplary Vhh constructs were assessed for binding and inhibition of TNFR1. These are described in the examples below. Example 5 Exemplary TNFR1 antagonist constructs containing human TNFR1 antagonist TNF mutein

Provided herein are TNFR1 antagonists that selectively inhibit TNFR1 without inhibiting TNFR2. In order to avoid TNFR1 receptor aggregation, its TNFR1 agonists and TNFR1 antagonists are monovalent. TNFR1 antagonists may include noncompetent dominant negative inhibitors of TNF signaling (DN-TNF), also known as TNF muteins, which are engineered variants of TNF with one or more abrogated signaling through TNFR1 Conducted mutations. For example, a TNF mutein may contain one or more mutations that confer selectivity for TNFR1 but not TNFR2. TNFR1 selective TNF mutations include L29S, L29G, L29Y, R31E, R31N, R32Y, R32W, S86T, L29S/R32W, L29S/S86T, R32W/S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/ R32T/S86T, E146R, V1M, R31C, C69V, Y87H, C101A, A145R, V1M/R31C/C69V/Y87H/C101A/A145R, I97T, I97T/A145R, A84S, V85T, Q88N, T89Q and A84S/V85 T/S86T/ For any one or more of Y87H/Q88N/T89Q and their combinations, refer to the sequence of soluble TNF (solTNF) shown in SEQ ID NO: 2.

For example, a TNFR1 antagonist can contain a peptide with mutations R32W/S86T (SEQ ID NO: 685), V1M/R31C/C69V/Y87H/C101A/A145R (SEQ ID NO: 701; as in XPro1595), A84S/V85T/ TNF mutant proteins of S86T/Y87H/Q88N/T89Q (SEQ ID NO: 703; as in R1antTNF) or I97T/A145R (SEQ ID NO: 702; as in XENP345).

TNFR1 antagonists are fused to serum half-life extenders, such as IgG Fc. For example, the C-terminus of a human TNFR1 antagonist TNF mutein is fused to the N-terminus of the Fc region of a human IgG1 or IgG4 antibody via a linker. An IgG1 Fc region, such as the IgG1 Fc derived from trastuzumab (see SEQ ID NO: 27), or an IgG4 Fc region, such as the IgG4 derived from nivolumab (see SEQ ID NO: 30), is used. When the Fc is derived from trastuzumab, the linker may contain all or part of the hinge sequence of trastuzumab, including at least residues SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), or When the Fc is derived from nivolumab, the linker may contain the hinge sequence ESKYGPPCPPCP of nivolumab (corresponding to residues 212-223 of SEQ ID NO: 29). To confer protease resistance and increase the flexibility of the fusion protein, the SCDKTH or ESKYGPPCPPCP hinge sequence or part thereof is replaced with a short glycine-serine (GS) peptide linker, such as (GSGS) _n or (GGGGS) _n , where n = 1-5, such as GGGGSGGGGSGGGGS. In an alternative embodiment, the C-terminus of the human anti-TNFR1 TNF mutein is linked to a GS linker, and the GS linker is linked to all or a portion of the trastuzumab or nivolumab hinge sequence sufficient to provide Flexible, the hinge sequence is connected to the N-terminus of the corresponding Fc region. In some embodiments, a second Fc subunit is linked to the first Fc region, which increases the serum half-life and stability of the molecule. The resulting construct is not a fusion protein.

The following are exemplary constructs of TNFR1 antagonist fusion proteins containing a TNFR1 selective antagonist TNF mutein as described and provided herein. In all embodiments containing the Fc of trastuzumab or the Fc of nivolumab, the Fc region is optionally modified to reduce or eliminate immune effector functions, including ADCC, ADCP, and CDC, and is also optionally modified to Enhance the binding to FcRn and increase the serum half-life of the fusion protein. Fc modifications that reduce or eliminate immune effector function are summarized in Table 9, and Fc modifications that enhance FcRn binding are summarized in Table 7. Any one or combination of such modifications are included in the Fc region of the fusion proteins provided herein. 2a) TNF(R32W/S86T) - SCDKTH - Trastuzumab Fc

This article provides a human TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation R32W/S86T, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (R32W/S86T) mutant protein (SEQ ID NO: 685) is fused to all or part of the hinge sequence of trastuzumab, which contains at least the residue SCDKTH (corresponding to the residue of SEQ ID NO: 26 222-227), fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). TNF(R32W/S86T)-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 741): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRWANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVTYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced by at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues of the hinge region of trastuzumab, up to the complete sequence, which contains the sequence EPKSCDKTHTCPPCP (corresponding to SEQ ID NO: 26 residues 219-233). 2b) TNF(R32W/S86T) - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation R32W/S86T, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF(R32W/S86T) mutant protein (SEQ ID NO: 685) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the Fc region of trastuzumab (corresponding to residue 234- of SEQ ID NO: 26). 450; see also SEQ ID NO: 27) N-terminal fusion. TNF(R32W/S86T)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 742): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRWANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVTYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2c) TNF(R32W/S86T) - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation R32W/S86T, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF(R32W/S86T) mutant protein (SEQ ID NO: 685) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to a part of the hinge sequence of trastuzumab, which part contains at least the residue SCDKTH ( Corresponding to residues 222-227 of SEQ ID NO: 26), which is N-terminal to the Fc region of trastuzumab (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) Fusion. TNF(R32W/S86T)-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 743): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRWANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVTYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or which contains at least 5, 6, 7 , a portion of 8, 9, 10 or 11 consecutive residues. 2d) TNF(V1M/R31C/C69V/Y87H/C101A/A145R) - SCDKTH - Trastuzumab Fc

This article provides a human TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations V1M, R31C, C69V, Y87H, C101A and A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (V1M/R31C/C69V/Y87H/C101A/A145R) mutant protein (SEQ ID NO: 701) is fused to a part of the hinge sequence of trastuzumab, which part contains at least the residue SCDKTH (corresponding to SEQ ID NO: 26), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 744): MRSSSRTPSDKPVAHVVANPQAEGQLQWLNCRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGVPSTHVLLTHTISRIAVSHQTKVNLLSAIKSPAQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced with the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or which contains at least 5, 6, 7, 8, A portion of 9, 10 or 11 consecutive residues. 2e) TNF(V1M/R31C/C69V/Y87H/C101A/A145R) - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations V1M, R31C, C69V, Y87H, C101A and A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (V1M/R31C/C69V/Y87H/C101A/A145R) mutant protein (SEQ ID NO: 701) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the trastuzumab Fc region (corresponding to SEQ ID N-terminal fusion of residues 234-450 of NO: 26; see also SEQ ID NO: 27). TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 745): MRSSSRTPSDKPVAHVVANPQAEGQLQWLNCRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGVPSTHVLLTHTISRIAVSHQTKVNLLSAIKSPAQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2f) TNF(V1M/R31C/C69V/Y87H/C101A/A145R) - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations V1M, R31C, C69V, Y87H, C101A and A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (V1M/R31C/C69V/Y87H/C101A/A145R) mutant protein (SEQ ID NO: 701) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to a part of the hinge sequence of trastuzumab, This portion contains at least the residues SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), which are identical to the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) N-terminal fusion. The TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGGS-SCDKTH-trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 746): MRSSSRTPSDKPVAHVVANPQAEGQLQWLNCRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGVPSTHVLLTHTISRIAVSHQTKVNLLSAIKSPAQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by a portion containing at least 5, 6, 7, 8, 9, 10 or 11 contiguous residues of the hinge region of trastuzumab up to the hinge region of trastuzumab The complete sequence, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26). 2g) TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q) - SCDKTH -Trastuzumab Fc

This article provides a human TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations A84S, V85T, S86T, Y87H, Q88N and T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (A84S/V85T/S86T/Y87H/Q88N/T89Q) mutant protein (SEQ ID NO: 703) is fused to a part of the hinge sequence of trastuzumab, which part contains at least the residue SCDKTH (corresponding to SEQ ID NO: 26), which is fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 747): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRISTTHNQKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced by a portion containing at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues of the hinge region of trastuzumab, up to the complete sequence of the hinge region of trastuzumab , which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26). 2h) TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q) - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations A84S, V85T, S86T, Y87H, Q88N and T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (A84S/V85T/S86T/Y87H/Q88N/T89Q) mutant protein (SEQ ID NO: 703) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the trastuzumab Fc region (corresponding to SEQ ID N-terminal fusion of residues 234-450 of NO: 26; see also SEQ ID NO: 27). TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 748): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRISTTHNQKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2i) TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q) - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations A84S, V85T, S86T, Y87H, Q88N and T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (A84S/V85T/S86T/Y87H/Q88N/T89Q) mutant protein (SEQ ID NO: 703) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to a part of the hinge sequence of trastuzumab, This portion contains at least the residues SCDKTH (corresponding to residues 222-227 of SEQ ID NO: 26), which are identical to the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) N-terminal fusion. TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 749): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRISTTHNQKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or which contains at least 5, 6, 7 , a portion of 8, 9, 10 or 11 consecutive residues. 2j) TNF(I97T/A145R) - SCDKTH - Trastuzumab Fc

This article provides a human TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation I97T/A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (I97T/A145R) mutant protein (SEQ ID NO: 702) is fused to all or part of the hinge sequence of trastuzumab, which contains at least the residue SCDKTH (corresponding to the residue of SEQ ID NO: 26 222-227), fused to the N-terminus of the trastuzumab Fc region (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27). TNF(I97T/A145R)-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 750): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSATKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the SCDKTH hinge sequence is replaced with the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or which contains at least 5, 6, 7, 8, A portion of 9, 10 or 11 consecutive residues. 2k) TNF(I97T/A145R) - GGGGSGGGGSGGGGS - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation I97T/A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (I97T/A145R) mutant protein (SEQ ID NO: 702) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the Fc region of trastuzumab (corresponding to residues 234-26 of SEQ ID NO: 26). 450; see also SEQ ID NO: 27) N-terminal fusion. TNF(I97T/A145R)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 751): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSATKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2l) TNF(I97T/A145R) - GGGGSGGGGSGGGGS - SCDKTH - Trastuzumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation I97T/A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF(I97T/A145R) mutant protein (SEQ ID NO: 702) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to a part of the hinge sequence of trastuzumab, which part contains at least the residue SCDKTH ( Corresponding to residues 222-227 of SEQ ID NO: 26), which is N-terminal to the Fc region of trastuzumab (corresponding to residues 234-450 of SEQ ID NO: 26; see also SEQ ID NO: 27) Fusion. TNF(I97T/A145R)-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein has the following sequence (SEQ ID NO: 752): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSATKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSSCDKTHAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, the SCDKTH hinge sequence is replaced by the complete sequence of the hinge region of trastuzumab, which contains the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26) or which contains at least 5, 6, 7 , a portion of 8, 9, 10 or 11 consecutive residues. 2m) TNF(R32W/S86T) - ESKYGPPCPPCP - Nivolumab Fc

This article provides a human TNFR1 antagonist fusion protein construct, which contains a TNFR1 selective antagonist TNF mutein with mutation R32W/S86T, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF(R32W/S86T) mutant protein (SEQ ID NO: 685) is fused to the hinge sequence of nivolumab, which contains the residues ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29) , which is fused to the N-terminus of the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). TNF(R32W/S86T)-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 753): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRWANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVTYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALESKYGPPCPPCPAPEFLGGPSSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, include all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 2n) TNF(R32W/S86T) - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation R32W/S86T, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF(R32W/S86T) mutant protein (SEQ ID NO: 685) is fused to the GGGGSGGGGSGGGGS peptide linker, which is fused to the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29 ; See also N-terminal fusion of SEQ ID NO: 30). TNF(R32W/S86T)-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 754): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRWANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVTYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2o) TNF(R32W/S86T) - GGGGSGGGGSGGGGS - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation R32W/S86T, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF(R32W/S86T) mutant protein (SEQ ID NO: 685) is fused to the GGGGSGGGGSGGGGS peptide linker, which is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to SEQ ID NO: 29), which is fused to the N-terminus of the nivolumab Fc region (corresponding to SEQ ID NO: 29 residues 224-440; see also SEQ ID NO: 30). TNF(R32W/S86T)-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 755): VrsssrtpsdkpvanpqaegQLNRWANALLANALDNQLDNQLDNQLIYSQVVCPSTHVLISRIAVTISRLLSAIKSPCQRETPEPEPYEPYEPYLGGVFQLGGVFQLGGVFQLGGVFQVFQVFQVFQVFQVFQ RLSAEINRPDYLDFGQVYFGIIALGGGGSGGGSGGGSESKPPCPAPEFLGGPSVFLFPPKDTLMISRTPEVSQFNWYVDGVDGVDGVHNAKPREEQFNSTYRV VSVLTVLHQDWLNKEYKCKCKVSNKGLPSSIEKTISKKQPREPQPPPPPSQEMTKNQVSLVKGFYPSDIAVESNGQPennyktttttttvdksrwqegnvFSCSV MHEALHNHYTQKSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 2p) TNF(V1M/R31C/C69V/Y87H/C101A/A145R) - ESKYGPPCPPCP -Nivolumab Fc

This article provides a human TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations V1M, R31C, C69V, Y87H, C101A and A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (V1M/R31C/C69V/Y87H/C101A/A145R) mutant protein (SEQ ID NO: 701) is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to SEQ ID NO: 29 (residues 212-223 of SEQ ID NO: 29), which is fused to the N-terminus of the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 756): MRSSSRTPSDKPVAHVVANPQAEGQLQWLNCRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGVPSTHVLLTHTISRIAVSHQTKVNLLSAIKSPAQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, include all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 2q) TNF(V1M/R31C/C69V/Y87H/C101A/A145R) - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations V1M, R31C, C69V, Y87H, C101A and A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (V1M/R31C/C69V/Y87H/C101A/A145R) mutant protein (SEQ ID NO: 701) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the nivolumab Fc region (corresponding to SEQ ID NO. : residues 224-440 of SEQ ID NO: 29; see also the N-terminal fusion of SEQ ID NO: 30). TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 757): MRSSSRTPSDKPVAHVVANPQAEGQLQWLNCRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGVPSTHVLLTHTISRIAVSHQTKVNLLSAIKSPAQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2r) TNF(V1M/R31C/C69V/Y87H/C101A/A145R) - GGGGSGGGGSGGGGS - ESKYGPPCPPCP -Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations V1M, R31C, C69V, Y87H, C101A and A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (V1M/R31C/C69V/Y87H/C101A/A145R) mutant protein (SEQ ID NO: 701) is fused to the GGGGSGGGGSGGGGS peptide linker. The peptide linker is fused to the hinge sequence of nivolumab. The hinge sequence Contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which is identical to the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30) N-terminal fusion. TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 758): MRSSSRTPSDKPVAHVVANPQAEGQLQWLNCRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGVPSTHVLLTHTISRIAVSHQTKVNLLSAIKSPAQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, all or a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues. 2s) TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q) - ESKYGPPCPPCP -Nivolumab Fc

This article provides a human TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations A84S, V85T, S86T, Y87H, Q88N and T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (A84S/V85T/S86T/Y87H/Q88N/T89Q) mutant protein (SEQ ID NO: 703) is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to SEQ ID NO: 29 (residues 212-223 of SEQ ID NO: 29), which is fused to the N-terminus of the Fc region of nivolumab (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 759): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRISTTHNQKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEV QFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, include all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 2t) TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q) - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations A84S, V85T, S86T, Y87H, Q88N and T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (A84S/V85T/S86T/Y87H/Q88N/T89Q) mutant protein (SEQ ID NO: 703) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the nivolumab Fc region (corresponding to SEQ ID NO. : residues 224-440 of SEQ ID NO: 29; see also the N-terminal fusion of SEQ ID NO: 30). TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 760): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRISTTHNQKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALGGGGSGGGGSGGGGSAPEFLGGPSSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2u) TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q) - GGGGSGGGGSGGGGS - ESKYGPPCPPCP -Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutations A84S, V85T, S86T, Y87H, Q88N and T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (A84S/V85T/S86T/Y87H/Q88N/T89Q) mutant protein (SEQ ID NO: 703) is fused to the GGGGSGGGGSGGGGS peptide linker. The peptide linker is fused to the hinge sequence of nivolumab. The hinge sequence Contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29), which is identical to the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30) N-terminal fusion. TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 761): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRISTTHNQKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIALGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, all or a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues. 2v) TNF(I97T/A145R) - ESKYGPPCPPCP -Nivolumab Fc

This article provides a human TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation I97T/A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (I97T/A145R) mutant protein (SEQ ID NO: 702) is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to residues 212-223 of SEQ ID NO: 29). It is fused to the N-terminus of the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29; see also SEQ ID NO: 30). TNF(I97T/A145R)-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 762): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSATKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, include all or a portion of the nivolumab hinge sequence, which contains at least 5, 6, 7, 8, 9, 10 or 11 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) consecutive residues. 2w) TNF(I97T/A145R) - GGGGSGGGGSGGGGS - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation I97T/A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (I97T/A145R) mutant protein (SEQ ID NO: 702) is fused to a GGGGSGGGGSGGGGS peptide linker, which is fused to the nivolumab Fc region (corresponding to residues 224-440 of SEQ ID NO: 29 ; See also N-terminal fusion of SEQ ID NO: 30). TNF(I97T/A145R)-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 763): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSATKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. 2x) TNF(I97T/A145R) - GGGGSGGGGSGGGGS - ESKYGPPCPPCP - Nivolumab Fc

This article provides a TNFR1 antagonist fusion protein, which contains a TNFR1 selective antagonist TNF mutant protein with mutation I97T/A145R, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2. The C-terminus of the TNF (I97T/A145R) mutant protein (SEQ ID NO: 702) is fused to the GGGGSGGGGSGGGGS peptide linker, which is fused to the hinge sequence of nivolumab, which contains the sequence ESKYGPPCPPCP (corresponding to SEQ ID NO: 29), which is fused to the N-terminus of the nivolumab Fc region (corresponding to SEQ ID NO: 29 residues 224-440; see also SEQ ID NO: 30). TNF(I97T/A145R)-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein has the following sequence (SEQ ID NO: 764): VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSATKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFRESGQVYFGIIALGGGGSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Alternatively, the GGGGSGGGSGGGGS linker is replaced with a Gly-Ser linker, such as a (GSGS) _n or (GGGGS) _n linker, where n = 1, 2, 3, 4 or 5, or as described herein or known in the art. Any other suitable short peptide linker known. Alternatively or additionally, all or a portion of the nivolumab hinge sequence is included, which contains at least 5, 6, 7, 8, 9, 10 of the ESKYGPPCPPCP hinge sequence (corresponding to residues 212-223 of SEQ ID NO: 29) or 11 consecutive residues. Example 6

There are difficulties in inhibiting target receptors presented in the context of antibodies. Bivalent antibodies induce dimerization of the target receptor, which may lead to its activation. In some cases, as discussed in the Examples, this is desirable, while for inhibitors of TNFR1 this is undesirable. As described in the Examples, even transient activation of TNFR1 can still cause a cytokine storm and significant toxicity. Therefore, monovalent inhibitors should be used. To this end, monovalent constructs are provided herein (see the entire specification and Example 5 above).

Interleukin networks are defined by cascades of interleukins. As described throughout this disclosure, tumor necrosis factor alpha (TNF) is a key interleukin within the network of pro-inflammatory and anti-inflammatory cytokines. Its role in promoting autoimmune diseases is fully demonstrated and discussed throughout this disclosure. TNF triggers its own production and the release of interleukin 1 (IL-1), IL-6, IL-8 and other interleukins, which can induce other inflammatory factors. Endotoxins (lipopolysaccharide; LPS) from Gram-negative bacteria are potent inducers of TNF-a and can induce sepsis. Viral infection can lead to an immune response that leads to a cytokine storm of inflammatory mediators triggered by TNF. Physical injury, including chemotherapy and surgery, can cause this result.

As described herein, these negative effects are primarily mediated through the TNF/TNFR1 interaction. The opposite of these effects is the effect of TNF binding to its other receptor, TNFR2. TNFR1 is considered a pro-inflammatory TNF receptor; while TNFR2 is considered an anti-inflammatory TNF receptor. As discussed herein, TNFR2 has other pathophysiological functions. For example, TNFR2 is critical for defense against opportunistic pathogens such as tuberculosis and for maintaining cardiomyocyte function.

Commonly used anti-interleukin drugs are TNF blockers, such as adalimumab (Humira ^® ), etanercept (Enbrel ^® ) and infliximab (Remicade ^® ). These antibodies bind TNF and prevent its binding to TNFR1 and TNFR2. The severe toxicities associated with TNF blockers are well documented, and as discussed herein, many of these toxicities are caused by inhibition of TNFR2 function. The constructs and products provided herein are designed to inhibit TNFR1 function, but not TNFR2 function.

Constructs provided herein include Vhh-4 exemplified below and others derived from the Camelidae Vhh domain. Vhh-4 is a Vhh anti-TNFR1 domain fused to the N-terminus of human serum albumin. The resulting construct provides a Vhh domain for blocking TNF but, unlike previous dAbs, has sufficient in vivo half-life to be useful as a therapeutic. The results below demonstrate that constructs such as Vhh-4 are active in inhibiting the effects of TNF on cells, at least as effectively as the TNF blockers adalimumab/ ^Humira® and etanercept/ ^Enbrel® .

This example illustrates the activity and properties of an exemplary construct, an N-terminal fusion protein of a single chain dAb and human serum albumin. A.Construction _

This example provides an exemplary Nanobody and its activity. As described in the embodiments, Nanobodies are Vhh domain-containing proteins that include only heavy chains and do not require the synergy of light chains, as is the case in humans and mice (Harmsen and De Haard, Appl Microbiol Biotechnol . 77:13 -22 (2007)). Because it is a single chain, it must be presented as a fusion protein, such as an antibody-style grafted CDR, due to its short half-life as a small protein (~13-15 KDa).

Exemplary constructs were prepared. Phage libraries were prepared using the method described in Sabir et al. (2014) Comptes Rendus Biologies 337 :244-249. Recover phages that bind with high affinity to tumor necrosis factor receptor-1 (TNFR1), and test their ability to bind to TNFR1 and compete with human tumor necrosis factor-alpha (TNF-a) for binding to TNFR1, as disclosed in the U.S. As described in Application No. US20140112929.

Nucleic acids encoding each of the Vhh antibodies containing a single chain were expressed in CHO cells (for a description of expression vectors, see Sokolowska-Wedzina et al. (2014) Protein Expression and Purification 99:50-57) and by HPLC Each antibody was chromatographically purified. Sample 1 is a control anti-TNFR1 antibody (H398 from ThermoFisher) and Vhh1-4 are Vhh antibodies containing dAb.序列（參見SEQ ID NO: 54、1478、58及59）如下： Vhh-1：EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS Vhh-2：EVQLLESGGGLVQPGGSLRLSCAASGFTFSQYRMHWVRQAPGKSLEWVSSIDTRGSSTYYADPVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAVTMFSPFFDYWGQGTLV Vhh-3：EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSS Vhh-4： EVQLLESGGGLVQPGGSLRLS C AASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYH C ALLPKRGPWFDYWGQGTLVTVSS Vhh-4中突出顯示且加下劃線The cysteine (C) forms a ring with the corresponding cysteine in other Vhh chains, so Vhh is a restricted polypeptide. Proline at amino acid residue 14 can be replaced by alanine.

Expression cassettes encoding Vhh domain antibody fragments were prepared and expressed and purified by HPLC chromatography. The table below shows the expression level of each Vhh antibody tested. Both molecules require His tags for purification. The results are shown in the table below: Table 15. Performance and Yield Results of Vhh 1-4 Project instruction label Harvest Yield Sample 1 Anti-human TNFRSF1A therapeutic antibody scFv fragment (H398)* His 146 µg About 1 mg/L Vhh-1 Recombinant human anti-TNFRSF1A single domain antibody without 500 µg 30mg/L Vhh-2 Recombinant human anti-TNFRSF1A single domain antibody His 1000 µg 49.4 mg/L Vhh-3 Tandem scFV bispecific antibodies without 500 µg 42 mg/L Vhh-4 Tandem scFV bispecific antibody (see SEQ ID NO: 1475) without 500 µg 51 mg/L *TNF receptor superfamily member 1A antibody H398 (ThermoFisher; H398 contains SEQ ID NO: 678).

Each of Vhh 1-4 was subsequently tested in binding studies using surface plasmon resonance (SPR) methods (Sciences GL. Biacore Assay Handbook. General Electric Company (2012); and Richter et al. (2019) MAbs 11:166-177). The competition assay of Vhh inhibiting the binding of TNF-a to the TNFR1 extracellular domain was also performed as described by Richter et al. (2019). Inhibition of TNF-induced expression of VCAM or IL8 using comparable assays as described by Lin et al ., (2015) J Biomed Sci 22:53 ; and Sonnier et al. (2010) Journal of Gastrointestinal Surgery 14 :1592-1599, respectively conduct.

A summary of the results is presented in the table below. The results show that Vhh-4 has extremely high affinity for the extracellular domain of TNFR-1 (6.6×10 ^-13 M); it is 100% competitive (IC50 ~1 nM) for the binding of TNF to TNFR1, and is one of the four candidates Among the substances, it is the most effective in inhibiting TNF-induced VCAM-1 synthesis (0.3 nM). Of the Vhh dAbs tested, Vhh-4 performed best, and constructs containing Vhh-4 and HSA were prepared.

The following sequence represents a construct containing Vhh-4 (SEQ ID NO: 1475): the dAb portion is residues 20-138 of SEQ ID NO: 1475 via a Gly-Ser linker (residue 139 of SEQ ID NO: 1475 -147) linked to human serum albumin (HSA; residues 148-732 of SEQ ID NO: 1475). EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSS…HSA… .Table 16. Comparative binding and competition assays (results for control antibodies not shown*) sample Kd(M, by SPR) TNF competition (maximum) TNF-dependent bioassay (IC50) Vhh-1 4.3 × 10 ^-10 Partially (33%) IL-8 (500 nM) Vhh-2 1.0× ^10-6 non-competitive VCAM (3 nM) Vhh-3 5.7× ^10-14 Partially (34%) IL-8 (1 nM) Vhh-4 6.6× ^10-13 Competitiveness (100%) VCAM (0.3 nM) *The amount of antibody recovered is a trace B. Results

Exemplary constructs containing Vhh-4 antibodies linked to HSA were shown to have activity as TNFR1 antagonists. It blocks TNFR1, as shown by a significant decrease in IL-6 and IL-8 gene expression in THP1 cells stimulated with LPS. 3 × 10 ⁵ THP1 cells were treated with 5 µg, 20 µg, and 0 µg (as control) construct for 30 min, followed by stimulation with LPS (10 ng/ml) for 4 h. RNA samples were collected and qPCR analysis was performed to analyze IL-6 and IL-8 gene expression using the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase (HPRT) as an internal control. The results showed that both doses significantly reduced IL-6 and IL-8 expression (n = 3, mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001).

In other experiments, the effect of Vhh-4 on inflammatory cytokine expression of TNFα-stimulated THP-1 cells was compared with the effect of each of etanercept/ ^Enbrel® and adalimumab/ ^Humira® . 3 × 10 ⁵ THP1 cells were treated with 20 µg Vhh-4, etanercept/ ^Enbrel® or adalimumab/ ^Humira® and subsequently stimulated with TNFα (50 ng/mL) for 7 hours. RNA sampling was performed, and qPCR analysis of IL-6, IL-8, and TNFα gene expression was performed, using the housekeeping gene product HPRT as an internal control. The results shown in Figure 6 indicate that the Vhh-4 construct is at least as effective as etanercept/ ^Enbrel® and adalimumab/ ^Humira® . Example 7

Various additional Vhh domains and fusion proteins were prepared to assess their properties. The results explain the clinical failure of prior art constructs, such as dAbs containing Vhh linked to anti-human serum albumin such that Vhh binds to human serum albumin (discussed and described in the Examples). Material

The synthetic Vhh domain protein has the following sequence. The signal peptide in each construct is residues 1-19 and is linked to the Vhh domain for expression as follows: The signal peptide for secretion, see SEQ ID NO: 1476, is the mouse immunoglobulin heavy chain leader sequence ( Uniprot: A0N1R4). Other signal sequences can be used instead. Construct 206 MEWSWVFLFFLSVTTGVHS EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSGGGGAGGGGHHHHHHHHHH Residues 20-138 are amino acid residues 1- of SEQ ID NO: 59 119 541 MEWSWVFLFFLSVTTGVHS EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSSGGGGAGGGGHHHHHHHHHH Residues 20-138 correspond to the amino acid residues of SEQ ID NO: 38 1-119 208a MEWSWVFLFFLSVTTGVHSEVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAGGGGAGGGGHHHHHHHHHH Residues 20-107 correspond to amino acid residues 1-88 of SEQ ID NO: 38 019 MEWSWVFLFFLSVTTGVHS QVQLQESGGG VVQPGGSLTLSCTRTGLTPSTGA V GWYRQAPGKKCELVSYITIPSGRTTYTDSVKGRFAISRDKAKNTVFLQMNSLKPEDTALYYCGDVPYSTIQAMCTDDGPWGQGTQVTVSS GGGGAGGGGHHHHHHHHHH The residues in italics are the same as SEQ ID NO: 40 in WO2021/256254, with one change is V, it is underlined. Method Protein Performance

His-tagged proteins were expressed using suspension CHO cells transfected with high-expression mammalian vectors and purified using immobilized metal affinity chromatography. Each completed construct is sequence confirmed prior to DNA scale-up. Suspension CHO cells (TunaCHO ^™ ) were seeded in shake flasks and expanded using serum-free and chemically defined media. On the day of transfection, the expanded cells were plated into new containers with fresh medium. After transfection, cells were maintained as fed-batch cultures until the end of the production run. No 208a fragment was detected in the culture medium of cultured cells transfected with the corresponding construct. The Vhh domain in the 206 construct is the same as that in the Vhh-4-human serum albumin construct of Example 6. Plastid DNA scales up

Each DNA expression construct was scaled up for transfection. Uncut plastid DNA was analyzed by agarose gel electrophoresis and quality assessed. Sequence confirmation of plastid DNA prior to transfection. CHO transient transfection ( TunaCHO™ method )

Suspension CHO cells are seeded in shake flasks and expanded using serum-free and chemically defined media. On the day of transfection, the expanded cells were plated into new containers with fresh medium. After transfection, cells were maintained as fed-batch cultures until the end of the production run. IMAC ( immobilized metal affinity chromatography ) purification of His- tagged proteins

Clarified and buffered conditioned media from the production run were loaded onto IMAC columns pre-equilibrated with binding buffer. Wash buffer containing 40 mM imidazole was passed through the column until the OD280 value returned to baseline. The target protein was eluted using a linear gradient increasing the imidazole concentration to 0.5 M. Collect the eluate in portions and record the OD280 value of each portion. Each aliquot was subjected to denaturing capillary electrophoresis (CE-SDS, LabChip GXII, Perkin Elmer) and analyzed. The fractions containing the target protein are pooled and dialyzed into customer-specified buffer. Proteins were filtered through a 0.2 µm membrane filter, and the protein concentration was calculated using the OD280 value and the calculated extinction coefficient. For an overview of protein yields and corresponding information, refer to the "Protein Produced and Aliquots" section. CE-SDS ( capillary electrophoresis using sodium dodecyl sulfate ) analysis

CE-SDS analysis of target proteins was performed using LabChip GXII (Perkin Elmer). Please refer to the Certificate of Analysis for results. SE-UPLC ( Size Exclusion - Ultra High Pressure Liquid Chromatography ) Analysis

Perform SE-UPLC analysis of target proteins. Chromatography was performed on SEC standard (MEDNA, Y3101) as a reference for protein size. Please refer to the sample analysis report for more details and results. protein purification

Clarified and buffered conditioned media from each production run were loaded onto IMAC columns pre-equilibrated with binding buffer. Wash buffer containing 40 mM imidazole was passed through the column until the OD280 value returned to baseline. The target protein was eluted using a linear gradient increasing the imidazole concentration to 0.5 M. Collect the eluate in portions and record the OD280 value of each portion. Each aliquot was subjected to denaturing capillary electrophoresis (CE-SDS, LabChip GXII, Perkin Elmer) and analyzed. Fractions containing target proteins were pooled and dialyzed into customer-specified buffer (PBS (137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2 mM KH2PO4, pH 7.4). Proteins were filtered through a 0.2 µm membrane filter, and Calculate the protein concentration using the OD280 value and the calculated extinction coefficient. Calculate the pI of each protein : 206: pI - 7.5 (similar to serum pH 7.4 (Merck Manual, 2021) * 541: pI - 8.3 208a: pI - 9.6 019: pI -8.3 *This is of concern because at the pI (isoelectric point), the negative and positive charges in the protein are balanced, thus reducing the repulsive electrostatic forces, and the attractive forces dominate, leading to aggregation and precipitation (see e.g. Proteomic Profiling and Analytical Chemistry (2nd ed.), 2016). Results Vhh protein

After IMAC purification, the protein was buffer exchanged to 20 mM histidine 150 mM NaCl pH 6.0, and yields obtained were approximately 19 mg of 206, approximately 4 mg of 541, and approximately 23 mg of 019; however, no capture and Enrich the target protein of 208a. Based on CE-SDS analysis, no detectable amounts of 208a were observed in CM.

Proteins were buffer exchanged to PBS pH 7.4. After buffer exchange, the final yields obtained were 10.76 mg of 206, 1.04 mg of 541, and 20.67 mg of 019. SE-UPLC analysis was performed and 019 was observed to contain >99% monomer. The SE-UPLC results of 206 and 541 were inconclusive, which may be caused by column interaction. SE-UPLC analysis was performed on all proteins. The results showed significant protein loss in 206 after buffer exchange due to aggregation. Vhh-4 human serum albumin construct

The Vhh-4 construct in Example 6 contains the same Vhh domain as 206 above, its pI is 7.4 and it aggregates. DNA encoding the construct described in Example 6 (Vhh-4 linked to human serum albumin) was selected into a high-performance mammalian vector, and the DNA sequence of the gene insert was confirmed. Each DNA construct was scaled up for transfection, and the DNA sequence was confirmed after DNA scale-up. Transient production of 0.1 liter in CHO cells (TunaCHO™ extended 14-day method). The protein was purified by anti-albumin purification, and 26.75 mg (1.07 mg/mL) of Vhh-4 fusion protein was obtained. Perform CE-SDS analysis. SE-UPLC analysis was performed and all proteins were observed to contain >97% monomer. No aggregates were observed, indicating that fused Vhh-4-HSA maintained the unaggregated form of Vhh-4.

These results provide insight into the clinical failure of prior art constructs containing Vhh domains linked to anti-human serum albumin. As occurs in buffers at pH 7.4, for 206 as described above, in vivo exposure to serum at a pH of approximately 7.4 induces aggregation, resulting in rapid clearance and targeting of Vhh-4 protein to free human serum albumin. Little or no correlation. The constructs provided herein that maintain the unaggregated form of Vhh-4 protein solve this problem.

Since modifications will be apparent to those of ordinary skill in the art, it is intended that the present invention be limited only by the scope of the appended claims.

without

[ Fig. 1] A plasmid map depicting the pCBL-1 expression plasmid containing the CMV promoter, in which TE19080L is the insert.

[ Figure 2] shows an exemplary bispecific construct that joins two ligands, such as a TNFR1 inhibitor (TNFR1 antagonist) and a TNFR2 agonist, using a linker (part of the hinge region) and an activity modulator.

[ Figures 3A-3D] Depict exemplary PEG-centered multispecific constructs for presenting/providing interaction with one or more targets or two or more with a target at a plurality of sites. parts. Figure 3A depicts exemplary bivalent constructs. A circle is, for example, a polypeptide agonist, antagonist or binding protein, such as an antibody or antigen-binding fragment thereof, or an aptamer (nucleic acid or peptide). Another circle represents the glycan or receptor ligand or other moiety that interacts with the relevant target. The bivalent nature provides target aggregation for receptor activation. In the specific examples provided herein, targets include TNFR1 and TNFR2; and as described throughout this disclosure, moieties include TNFR1 inhibitors, such as moieties that inhibit TNFR1 signaling, and TNFR2 agonists or others that act as Treg expanders. part. Figure 3B depicts a monovalent single ligand, such as CD3+, linked via a PEG moiety to an agonist, antagonist or binding protein (which is bivalent for receptor aggregation) to prevent interleukin release syndrome. Likewise, exemplary targets include TNFR1 and/or TNFR2. Figure 3C depicts a heterobifunctional PEG used to cross-link two different cell targeting agents or two agents that bind to different sites on the same receptor, such as trastuzumab and pertuzumab or portions thereof. . This construct can be used, for example, to aggregate checkpoint control receptors to stimulate or inhibit immune responses, or to cross-link two different receptors to achieve inhibition of receptor activity (i.e., CD3 and CD450), or to combine two different ligands (i.e., CD3 and CD450). such as stimulatory and costimulatory ligands) to two different receptors on the same cell. Figure 3D depicts the use of clustering the same receptor on the same or different cells based on chain length, or capturing circulating disease targets such as soluble receptors. or ligands, such as TNF). Additionally, in all such embodiments, additional PEG side chains may be included in these constructs, optionally connected to another reactive group or functionality. base, such as a serum half-life extending moiety, such as HSA, or an FcRn polypeptide. The PEG moiety may be modified or replaced with a moiety having similar properties to present a binding moiety.

[ Figure 4] Depicts other exemplary configurations and structures of PEG-centered constructs for presenting or providing binding or reactive moieties such as TNFRl inhibitors and/or TNFR2 agonists described herein.

[ Figure 5] Depicts other exemplary configurations and structures of PEG-centered constructs for presenting or providing binding moieties or reactive moieties such as TNFRl inhibitors and/or TNFR2 agonists. X and Y can be ligands and reactive moieties.

[ Fig. 6] Shows the effect of an exemplary construct named Vhh-4 (see Example 6) on gene expression in THP1 cells stimulated with TNFα. The ability to inhibit TNF-induced gene expression of interleukin-6 IL-8 and TNF (three inflammatory cytokines) compared these effects to those of etanercept/Enbrel and adalimumab/Humira® on genes Compare the impact on performance. Controls (four bars on the left side of each graph) show the amount of interleukin expression when cells were exposed to inhibitors without the addition of TNF. The four bars on the right side of each figure show the amount of cytokine expression in the presence of TNF. The first bar on the right side of each figure shows the relative gene expression of TNF induction by each interleukin (IL-6, IL-8, TNF) in the absence of inhibitors. The lower bar in each graph shows the relative expression of interleukins in the presence of Vhh-4, and the next bars show the results in the presence of etanercept/Enbrel® and adalimumab/Humira®. In each case, TNF-induced gene expression of IL-6, IL-8, and TNF was reduced approximately 10-fold, indicating that Vhh-4 is at least as effective as etanercept/Enbrel® or adalimumab/Humira® ( n=3; ± SEM; ^* p<0.05; ^** p<0.01; ^*** p<0.001).

         
           <![CDATA[ <110> American ENOSI LIFE SCIENCES CORP.]]>
           <![CDATA[ <120> Methods and compositions for treating autoimmune diseases and cancer]]>
           <![CDATA[ <130> 04555.05301.TW00/5301TW]]>
           <![CDATA[ <140>TW 111107730]]>
           <![CDATA[ <141> 2022-03-03 ]]>
           <![CDATA[ <160> 1479]]>
           <![CDATA[ <170> FastSEQ for Windows Version 4.0]]>
           <![CDATA[ <210> 1]]>
           <![CDATA[ <211> 233]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFα (TNF)]]>
           <![CDATA[ <400> 1]]>
          Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala
           1 5 10 15
          Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe
                      20 25 30
          Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe
                  35 40 45
          Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro
              50 55 60
          Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser
          65 70 75 80
          Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro
                          85 90 95
          Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu
                      100 105 110
          Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser
                  115 120 125
          Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly
              130 135 140
          Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala
          145 150 155 160
          Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro
                          165 170 175
          Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu
                      180 185 190
          Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu
                  195 200 205
          Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly
              210 215 220
          Gln Val Tyr Phe Gly Ile Ile Ala Leu
          225 230
           <![CDATA[ <210> 2]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Soluble form of TNFα (solTNF)]]>
           <![CDATA[ <400> 2]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 3]]>
           <![CDATA[ <211> 455]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223>TNFR1]]>
           <![CDATA[ <400> 3]]>
          Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu
           1 5 10 15
          Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro
                      20 25 30
          His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys
                  35 40 45
          Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys
              50 55 60
          Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp
          65 70 75 80
          Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu
                          85 90 95
          Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val
                      100 105 110
          Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg
                  115 120 125
          Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe
              130 135 140
          Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu
          145 150 155 160
          Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu
                          165 170 175
          Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr
                      180 185 190
          Lys Leu Cys Leu Pro Gln Ile Glu Asn Val Lys Gly Thr Glu Asp Ser
                  195 200 205
          Gly Thr Thr Val Leu Leu Pro Leu Val Ile Phe Phe Gly Leu Cys Leu
              210 215 220
          Leu Ser Leu Leu Phe Ile Gly Leu Met Tyr Arg Tyr Gln Arg Trp Lys
          225 230 235 240
          Ser Lys Leu Tyr Ser Ile Val Cys Gly Lys Ser Thr Pro Glu Lys Glu
                          245 250 255
          Gly Glu Leu Glu Gly Thr Thr Thr Lys Pro Leu Ala Pro Asn Pro Ser
                      260 265 270
          Phe Ser Pro Thr Pro Gly Phe Thr Pro Thr Leu Gly Phe Ser Pro Val
                  275 280 285
          Pro Ser Ser Thr Phe Thr Ser Ser Ser Thr Tyr Thr Pro Gly Asp Cys
              290 295 300
          Pro Asn Phe Ala Ala Pro Arg Arg Glu Val Ala Pro Pro Tyr Gln Gly
          305 310 315 320
          Ala Asp Pro Ile Leu Ala Thr Ala Leu Ala Ser Asp Pro Ile Pro Asn
                          325 330 335
          Pro Leu Gln Lys Trp Glu Asp Ser Ala His Lys Pro Gln Ser Leu Asp
                      340 345 350
          Thr Asp Asp Pro Ala Thr Leu Tyr Ala Val Val Glu Asn Val Pro Pro
                  355 360 365
          Leu Arg Trp Lys Glu Phe Val Arg Arg Leu Gly Leu Ser Asp His Glu
              370 375 380
          Ile Asp Arg Leu Glu Leu Gln Asn Gly Arg Cys Leu Arg Glu Ala Gln
          385 390 395 400
          Tyr Ser Met Leu Ala Thr Trp Arg Arg Arg Thr Pro Arg Arg Glu Ala
                          405 410 415
          Thr Leu Glu Leu Leu Gly Arg Val Leu Arg Asp Met Asp Leu Leu Gly
                      420 425 430
          Cys Leu Glu Asp Ile Glu Glu Ala Leu Cys Gly Pro Ala Ala Leu Pro
                  435 440 445
          Pro Ala Pro Ser Leu Leu Arg
              450 455
           <![CDATA[ <210> 4]]>
           <![CDATA[ <211> 461]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223>TNFR2]]>
           <![CDATA[ <400> 4]]>
          Met Ala Pro Val Ala Val Trp Ala Ala Leu Ala Val Gly Leu Glu Leu
           1 5 10 15
          Trp Ala Ala Ala His Ala Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr
                      20 25 30
          Ala Pro Glu Pro Gly Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln
                  35 40 45
          Thr Ala Gln Met Cys Cys Ser Lys Cys Ser Pro Gly Gln His Ala Lys
              50 55 60
          Val Phe Cys Thr Lys Thr Ser Asp Thr Val Cys Asp Ser Cys Glu Asp
          65 70 75 80
          Ser Thr Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu Cys Leu Ser Cys
                          85 90 95
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Cys Thr Arg
                      100 105 110
          Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu
                  115 120 125
          Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg
              130 135 140
          Pro Gly Phe Gly Val Ala Arg Pro Gly Thr Glu Thr Ser Asp Val Val
          145 150 155 160
          Cys Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr
                          165 170 175
          Asp Ile Cys Arg Pro His Gln Ile Cys Asn Val Val Ala Ile Pro Gly
                      180 185 190
          Asn Ala Ser Met Asp Ala Val Cys Thr Ser Thr Ser Pro Thr Arg Ser
                  195 200 205
          Met Ala Pro Gly Ala Val His Leu Pro Gln Pro Val Ser Thr Arg Ser
              210 215 220
          Gln His Thr Gln Pro Thr Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser
          225 230 235 240
          Phe Leu Leu Pro Met Gly Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly
                          245 250 255
          Asp Phe Ala Leu Pro Val Gly Leu Ile Val Gly Val Thr Ala Leu Gly
                      260 265 270
          Leu Leu Ile Ile Gly Val Val Asn Cys Val Ile Met Thr Gln Val Lys
                  275 280 285
          Lys Lys Pro Leu Cys Leu Gln Arg Glu Ala Lys Val Pro His Leu Pro
              290 295 300
          Ala Asp Lys Ala Arg Gly Thr Gln Gly Pro Glu Gln Gln His Leu Leu
          305 310 315 320
          Ile Thr Ala Pro Ser Ser Ser Ser Ser Ser Ser Leu Glu Ser Ser Ala Ser
                          325 330 335
          Ala Leu Asp Arg Arg Ala Pro Thr Arg Asn Gln Pro Gln Ala Pro Gly
                      340 345 350
          Val Glu Ala Ser Gly Ala Gly Glu Ala Arg Ala Ser Thr Gly Ser Ser
                  355 360 365
          Asp Ser Ser Pro Gly Gly His Gly Thr Gln Val Asn Val Thr Cys Ile
              370 375 380
          Val Asn Val Cys Ser Ser Ser Asp His Ser Ser Gln Cys Ser Ser Gln
          385 390 395 400
          Ala Ser Ser Thr Met Gly Asp Thr Asp Ser Ser Pro Ser Glu Ser Pro
                          405 410 415
          Lys Asp Glu Gln Val Pro Phe Ser Lys Glu Glu Cys Ala Phe Arg Ser
                      420 425 430
          Gln Leu Glu Thr Pro Glu Thr Leu Leu Gly Ser Thr Glu Glu Lys Pro
                  435 440 445
          Leu Pro Leu Gly Val Pro Asp Ala Gly Met Lys Pro Ser
              450 455 460
           <![CDATA[ <210> 5]]>
           <![CDATA[ <211> 235]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Mouse]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mouse TNFα (TNF)]]>
           <![CDATA[ <400> 5]]>
          Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala
           1 5 10 15
          Leu Pro Gln Lys Met Gly Gly Phe Gln Asn Ser Arg Arg Cys Leu Cys
                      20 25 30
          Leu Ser Leu Phe Ser Phe Leu Leu Val Ala Gly Ala Thr Thr Leu Phe
                  35 40 45
          Cys Leu Leu Asn Phe Gly Val Ile Gly Pro Gln Arg Asp Glu Lys Phe
              50 55 60
          Pro Asn Gly Leu Pro Leu Ile Ser Ser Met Ala Gln Thr Leu Thr Leu
          65 70 75 80
          Arg Ser Ser Ser Gln Asn Ser Ser Asp Lys Pro Val Ala His Val Val
                          85 90 95
          Ala Asn His Gln Val Glu Glu Gln Leu Glu Trp Leu Ser Gln Arg Ala
                      100 105 110
          Asn Ala Leu Leu Ala Asn Gly Met Asp Leu Lys Asp Asn Gln Leu Val
                  115 120 125
          Val Pro Ala Asp Gly Leu Tyr Leu Val Tyr Ser Gln Val Leu Phe Lys
              130 135 140
          Gly Gln Gly Cys Pro Asp Tyr Val Leu Leu Thr His Thr Val Ser Arg
          145 150 155 160
          Phe Ala Ile Ser Tyr Gln Glu Lys Val Asn Leu Leu Ser Ala Val Lys
                          165 170 175
          Ser Pro Cys Pro Lys Asp Thr Pro Glu Gly Ala Glu Leu Lys Pro Trp
                      180 185 190
          Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp
                  195 200 205
          Gln Leu Ser Ala Glu Val Asn Leu Pro Lys Tyr Leu Asp Phe Ala Glu
              210 215 220
          Ser Gly Gln Val Tyr Phe Gly Val Ile Ala Leu
          225 230 235
           <![CDATA[ <210> 6]]>
           <![CDATA[ <211> 156]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Mouse]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Soluble form of mouse TNFα (TNF)]]>
           <![CDATA[ <400> 6]]>
          Leu Arg Ser Ser Ser Gln Asn Ser Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn His Gln Val Glu Glu Gln Leu Glu Trp Leu Ser Gln Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Met Asp Leu Lys Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ala Asp Gly Leu Tyr Leu Val Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Asp Tyr Val Leu Leu Thr His Thr Val Ser
          65 70 75 80
          Arg Phe Ala Ile Ser Tyr Gln Glu Lys Val Asn Leu Leu Ser Ala Val
                          85 90 95
          Lys Ser Pro Cys Pro Lys Asp Thr Pro Glu Gly Ala Glu Leu Lys Pro
                      100 105 110
          Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly
                  115 120 125
          Asp Gln Leu Ser Ala Glu Val Asn Leu Pro Lys Tyr Leu Asp Phe Ala
              130 135 140
          Glu Ser Gly Gln Val Tyr Phe Gly Val Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 7]]>
           <![CDATA[ <211> 454]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Mouse]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mouse TNFR1]]>
           <![CDATA[ <400> 7]]>
          Met Gly Leu Pro Thr Val Pro Gly Leu Leu Leu Ser Leu Val Leu Leu
           1 5 10 15
          Ala Leu Leu Met Gly Ile His Pro Ser Gly Val Thr Gly Leu Val Pro
                      20 25 30
          Ser Leu Gly Asp Arg Glu Lys Arg Asp Ser Leu Cys Pro Gln Gly Lys
                  35 40 45
          Tyr Val His Ser Lys Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys
              50 55 60
          Gly Thr Tyr Leu Val Ser Asp Cys Pro Ser Pro Gly Arg Asp Thr Val
          65 70 75 80
          Cys Arg Glu Cys Glu Lys Gly Thr Phe Thr Ala Ser Gln Asn Tyr Leu
                          85 90 95
          Arg Gln Cys Leu Ser Cys Lys Thr Cys Arg Lys Glu Met Ser Gln Val
                      100 105 110
          Glu Ile Ser Pro Cys Gln Ala Asp Lys Asp Thr Val Cys Gly Cys Lys
                  115 120 125
          Glu Asn Gln Phe Gln Arg Tyr Leu Ser Glu Thr His Phe Gln Cys Val
              130 135 140
          Asp Cys Ser Pro Cys Phe Asn Gly Thr Val Thr Ile Pro Cys Lys Glu
          145 150 155 160
          Thr Gln Asn Thr Val Cys Asn Cys His Ala Gly Phe Phe Leu Arg Glu
                          165 170 175
          Ser Glu Cys Val Pro Cys Ser His Cys Lys Lys Asn Glu Glu Cys Met
                      180 185 190
          Lys Leu Cys Leu Pro Pro Pro Leu Ala Asn Val Thr Asn Pro Gln Asp
                  195 200 205
          Ser Gly Thr Ala Val Leu Leu Pro Leu Val Ile Leu Leu Gly Leu Cys
              210 215 220
          Leu Leu Ser Phe Ile Phe Ile Ser Leu Met Cys Arg Tyr Pro Arg Trp
          225 230 235 240
          Arg Pro Glu Val Tyr Ser Ile Ile Cys Arg Asp Pro Val Pro Val Lys
                          245 250 255
          Glu Glu Lys Ala Gly Lys Pro Leu Thr Pro Ala Pro Ser Pro Ala Phe
                      260 265 270
          Ser Pro Thr Ser Gly Phe Asn Pro Thr Leu Gly Phe Ser Thr Pro Gly
                  275 280 285
          Phe Ser Ser Pro Val Ser Ser Thr Pro Ile Ser Pro Ile Phe Gly Pro
              290 295 300
          Ser Asn Trp His Phe Met Pro Pro Val Ser Glu Val Val Pro Thr Gln
          305 310 315 320
          Gly Ala Asp Pro Leu Leu Tyr Glu Ser Leu Cys Ser Val Pro Ala Pro
                          325 330 335
          Thr Ser Val Gln Lys Trp Glu Asp Ser Ala His Pro Gln Arg Pro Asp
                      340 345 350
          Asn Ala Asp Leu Ala Ile Leu Tyr Ala Val Val Asp Gly Val Pro Pro
                  355 360 365
          Ala Arg Trp Lys Glu Phe Met Arg Phe Met Gly Leu Ser Glu His Glu
              370 375 380
          Ile Glu Arg Leu Glu Met Gln Asn Gly Arg Cys Leu Arg Glu Ala Gln
          385 390 395 400
          Tyr Ser Met Leu Glu Ala Trp Arg Arg Arg Thr Pro Arg His Glu Asp
                          405 410 415
          Thr Leu Glu Val Val Gly Leu Val Leu Ser Lys Met Asn Leu Ala Gly
                      420 425 430
          Cys Leu Glu Asn Ile Leu Glu Ala Leu Arg Asn Pro Ala Pro Ser Ser
                  435 440 445
          Thr Thr Arg Leu Pro Arg
              450
           <![CDATA[ <210> 8]]>
           <![CDATA[ <211> 474]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Mouse]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mouse TNFR2]]>
           <![CDATA[ <400> 8]]>
          Met Ala Pro Ala Ala Leu Trp Val Ala Leu Val Phe Glu Leu Gln Leu
           1 5 10 15
          Trp Ala Thr Gly His Thr Val Pro Ala Gln Val Val Leu Thr Pro Tyr
                      20 25 30
          Lys Pro Glu Pro Gly Tyr Glu Cys Gln Ile Ser Gln Glu Tyr Tyr Asp
                  35 40 45
          Arg Lys Ala Gln Met Cys Cys Ala Lys Cys Pro Pro Gly Gln Tyr Val
              50 55 60
          Lys His Phe Cys Asn Lys Thr Ser Asp Thr Val Cys Ala Asp Cys Glu
          65 70 75 80
          Ala Ser Met Tyr Thr Gln Val Trp Asn Gln Phe Arg Thr Cys Leu Ser
                          85 90 95
          Cys Ser Ser Ser Cys Thr Thr Asp Gln Val Glu Ile Arg Ala Cys Thr
                      100 105 110
          Lys Gln Gln Asn Arg Val Cys Ala Cys Glu Ala Gly Arg Tyr Cys Ala
                  115 120 125
          Leu Lys Thr His Ser Gly Ser Cys Arg Gln Cys Met Arg Leu Ser Lys
              130 135 140
          Cys Gly Pro Gly Phe Gly Val Ala Ser Ser Arg Ala Pro Asn Gly Asn
          145 150 155 160
          Val Leu Cys Lys Ala Cys Ala Pro Gly Thr Phe Ser Asp Thr Thr Ser
                          165 170 175
          Ser Thr Asp Val Cys Arg Pro His Arg Ile Cys Ser Ile Leu Ala Ile
                      180 185 190
          Pro Gly Asn Ala Ser Thr Asp Ala Val Cys Ala Pro Glu Ser Pro Thr
                  195 200 205
          Leu Ser Ala Ile Pro Arg Thr Leu Tyr Val Ser Gln Pro Glu Pro Thr
              210 215 220
          Arg Ser Gln Pro Leu Asp Gln Glu Pro Gly Pro Ser Gln Thr Pro Ser
          225 230 235 240
          Ile Leu Thr Ser Leu Gly Ser Thr Pro Ile Ile Glu Gln Ser Thr Lys
                          245 250 255
          Gly Gly Ile Ser Leu Pro Ile Gly Leu Ile Val Gly Val Thr Ser Leu
                      260 265 270
          Gly Leu Leu Met Leu Gly Leu Val Asn Cys Ile Ile Leu Val Gln Arg
                  275 280 285
          Lys Lys Lys Pro Ser Cys Leu Gln Arg Asp Ala Lys Val Pro His Val
              290 295 300
          Pro Asp Glu Lys Ser Gln Asp Ala Val Gly Leu Glu Gln Gln His Leu
          305 310 315 320
          Leu Thr Thr Ala Pro Ser Ser Ser Ser Ser Ser Leu Glu Ser Ser Ala
                          325 330 335
          Ser Ala Gly Asp Arg Arg Ala Pro Pro Gly Gly His Pro Gln Ala Arg
                      340 345 350
          Val Met Ala Glu Ala Gln Gly Phe Gln Glu Ala Arg Ala Ser Ser Arg
                  355 360 365
          Ile Ser Asp Ser Ser His Gly Ser His Gly Thr His Val Asn Val Thr
              370 375 380
          Cys Ile Val Asn Val Cys Ser Ser Ser Asp His Ser Ser Gln Cys Ser
          385 390 395 400
          Ser Gln Ala Ser Ala Thr Val Gly Asp Pro Asp Ala Lys Pro Ser Ala
                          405 410 415
          Ser Pro Lys Asp Glu Gln Val Pro Phe Ser Gln Glu Glu Cys Pro Ser
                      420 425 430
          Gln Ser Pro Cys Glu Thr Thr Glu Thr Leu Gln Ser His Glu Lys Pro
                  435 440 445
          Leu Pro Leu Gly Val Pro Asp Met Gly Met Lys Pro Ser Gln Ala Gly
              450 455 460
          Trp Phe Asp Gln Ile Ala Val Lys Val Ala
          465 470
           <![CDATA[ <210> 9]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> IgG1 heavy chain constant domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(98)]]>
           <![CDATA[ <223> CH1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (99)...(113)]]>
           <![CDATA[ <223> Hinge area]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (114)...(223)]]>
           <![CDATA[ <223> CH2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (224)...(230)]]>
           <![CDATA[ <223> CH3]]>
           <![CDATA[ <400> 9]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
           1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
          225 230 235 240
          Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 10]]>
           <![CDATA[ <211> 217]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> IgG1 Fc (CH2 and CH3 domains)]]>
           <![CDATA[ <400> 10]]>
          Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
           1 5 10 15
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
                      20 25 30
          Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
                  35 40 45
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
              50 55 60
          Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
          65 70 75 80
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
                          85 90 95
          Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
                      100 105 110
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
                  115 120 125
          Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
              130 135 140
          Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
          145 150 155 160
          Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
                          165 170 175
          Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
                      180 185 190
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
                  195 200 205
          Lys Ser Leu Ser Leu Ser Pro Gly Lys
              210 215
           <![CDATA[ <210> 11]]>
           <![CDATA[ <211> 326]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human IgG2 heavy chain constant domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(98)]]>
           <![CDATA[ <223> CH1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (99)...(110)]]>
           <![CDATA[ <223> Hinge area]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (111)...(219)]]>
           <![CDATA[ <223> CH2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (220)...(326)]]>
           <![CDATA[ <223> CH3]]>
           <![CDATA[ <400> 11]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
           1 5 10 15
          Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
                      100 105 110
          Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
                  115 120 125
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
              130 135 140
          Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
          145 150 155 160
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
                          165 170 175
          Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
                      180 185 190
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
                  195 200 205
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
              210 215 220
          Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
          225 230 235 240
          Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
                          245 250 255
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
                      260 265 270
          Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
                  275 280 285
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
              290 295 300
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
          305 310 315 320
          Ser Leu Ser Pro Gly Lys
                          325
           <![CDATA[ <210> 12]]>
           <![CDATA[ <211> 216]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> IgG2 Fc (CH2 and CH3 domains)]]>
           <![CDATA[ <400> 12]]>
          Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
           1 5 10 15
          Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
                      20 25 30
          Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
                  35 40 45
          Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
              50 55 60
          Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln
          65 70 75 80
          Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
                          85 90 95
          Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro
                      100 105 110
          Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
                  115 120 125
          Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
              130 135 140
          Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
          145 150 155 160
          Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
                          165 170 175
          Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
                      180 185 190
          Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
                  195 200 205
          Ser Leu Ser Leu Ser Pro Gly Lys
              210 215
           <![CDATA[ <210> 13]]>
           <![CDATA[ <211> 377]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> IgG3 heavy chain constant domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(98)]]>
           <![CDATA[ <223> CH1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (99)...(160)]]>
           <![CDATA[ <223> Hinge area]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (161)...(270)]]>
           <![CDATA[ <223> CH2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (271)...(377)]]>
           <![CDATA[ <223> CH3]]>
           <![CDATA[ <400> 13]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
           1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro
                      100 105 110
          Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg
                  115 120 125
          Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys
              130 135 140
          Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
          145 150 155 160
          Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
                          165 170 175
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
                      180 185 190
          Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
                  195 200 205
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
              210 215 220
          Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
          225 230 235 240
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
                          245 250 255
          Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
                      260 265 270
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
                  275 280 285
          Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
              290 295 300
          Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn
          305 310 315 320
          Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
                          325 330 335
          Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
                      340 345 350
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
                  355 360 365
          Lys Ser Leu Ser Leu Ser Pro Gly Lys
              370 375
           <![CDATA[ <210> 14]]>
           <![CDATA[ <211> 217]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> IgG3 Fc (CH2 and CH3 domains)]]>
           <![CDATA[ <400> 14]]>
          Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
           1 5 10 15
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
                      20 25 30
          Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
                  35 40 45
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
              50 55 60
          Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
          65 70 75 80
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
                          85 90 95
          Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
                      100 105 110
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
                  115 120 125
          Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
              130 135 140
          Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn
          145 150 155 160
          Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
                          165 170 175
          Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
                      180 185 190
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
                  195 200 205
          Lys Ser Leu Ser Leu Ser Pro Gly Lys
              210 215
           <![CDATA[ <210> 15]]>
           <![CDATA[ <211> 327]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> IgG4 heavy chain constant domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(98)]]>
           <![CDATA[ <223> CH1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (99)...(110)]]>
           <![CDATA[ <223> Hinge area]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (111)...(220)]]>
           <![CDATA[ <223> CH2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (221)...(327)]]>
           <![CDATA[ <223> CH3]]>
           <![CDATA[ <400> 15]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
           1 5 10 15
          Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
                      100 105 110
          Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
                  115 120 125
          Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
              130 135 140
          Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
          145 150 155 160
          Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
                          165 170 175
          Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
                      180 185 190
          Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
                  195 200 205
          Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
              210 215 220
          Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
          225 230 235 240
          Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
                          245 250 255
          Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
                      260 265 270
          Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
                  275 280 285
          Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
              290 295 300
          Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
          305 310 315 320
          Leu Ser Leu Ser Leu Gly Lys
                          325
           <![CDATA[ <210> 16]]>
           <![CDATA[ <211> 217]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> IgG4 Fc (CH2 and CH3 domains)]]>
           <![CDATA[ <400> 16]]>
          Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
           1 5 10 15
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
                      20 25 30
          Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
                  35 40 45
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
              50 55 60
          Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
          65 70 75 80
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
                          85 90 95
          Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
                      100 105 110
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
                  115 120 125
          Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
              130 135 140
          Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
          145 150 155 160
          Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
                          165 170 175
          Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
                      180 185 190
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
                  195 200 205
          Lys Ser Leu Ser Leu Ser Leu Gly Lys
              210 215
           <![CDATA[ <210> 17]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human Ig kappa light chain constant domain (CL)]]>
           <![CDATA[ <400> 17]]>
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
           1 5 10 15
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
                      20 25 30
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
                  35 40 45
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
              50 55 60
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
          65 70 75 80
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                          85 90 95
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
                      100 105
           <![CDATA[ <210> 18]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Immunoglobulin lambda constant 1 light chain domain (chain C)]]>
           <![CDATA[ <400> 18]]>
          Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser
           1 5 10 15
          Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
                      20 25 30
          Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
                  35 40 45
          Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
              50 55 60
          Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
          65 70 75 80
          Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
                          85 90 95
          Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
                      100 105
           <![CDATA[ <210> 19]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Immunoglobulin lambda constant 2 light chain domain (chain C)]]>
           <![CDATA[ <400> 19]]>
          Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
           1 5 10 15
          Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
                      20 25 30
          Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
                  35 40 45
          Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
              50 55 60
          Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
          65 70 75 80
          Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
                          85 90 95
          Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
                      100 105
           <![CDATA[ <210> 20]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Immunoglobulin lambda constant 3 light chain domain (chain C)]]>
           <![CDATA[ <400> 20]]>
          Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
           1 5 10 15
          Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
                      20 25 30
          Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
                  35 40 45
          Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
              50 55 60
          Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
          65 70 75 80
          Ser His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
                          85 90 95
          Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
                      100 105
           <![CDATA[ <210> 21]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Immunoglobulin lambda constant 6 light chain domain (chain C)]]>
           <![CDATA[ <400> 21]]>
          Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
           1 5 10 15
          Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
                      20 25 30
          Phe Tyr Pro Gly Ala Val Lys Val Ala Trp Lys Ala Asp Gly Ser Pro
                  35 40 45
          Val Asn Thr Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
              50 55 60
          Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
          65 70 75 80
          Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
                          85 90 95
          Glu Lys Thr Val Ala Pro Ala Glu Cys Ser
                      100 105
           <![CDATA[ <210> 22]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Immunoglobulin lambda constant 7 light chain domain (chain C)]]>
           <![CDATA[ <400> 22]]>
          Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
           1 5 10 15
          Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Val Ser Asp
                      20 25 30
          Phe Asn Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
                  35 40 45
          Val Lys Val Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
              50 55 60
          Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
          65 70 75 80
          Ser His Arg Ser Tyr Ser Cys Arg Val Thr His Glu Gly Ser Thr Val
                          85 90 95
          Glu Lys Thr Val Ala Pro Ala Glu Cys Ser
                      100 105
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Adalimumab light chain]]>
           <![CDATA[ <400> 23]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Adalimumab heavy chain]]>
           <![CDATA[ <400> 24]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
                      20 25 30
          Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
                  115 120 125
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
              130 135 140
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
          145 150 155 160
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
                          165 170 175
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
                      180 185 190
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Tyr Ile Cys Asn Val Asn His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215 220
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
          225 230 235 240
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                          245 250 255
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                      260 265 270
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
                  275 280 285
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
              290 295 300
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
          305 310 315 320
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                          325 330 335
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                      340 345 350
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
                  355 360 365
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
              370 375 380
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
          385 390 395 400
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                          405 410 415
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                      420 425 430
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
                  435 440 445
          Pro Gly Lys
              450
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Trastuzumab light chain]]>
           <![CDATA[ <400> 25]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Trastuzumab heavy chain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(120)]]>
           <![CDATA[ <223> VH]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (121)...(218)]]>
           <![CDATA[ <223> CH1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (219)...(233)]]>
           <![CDATA[ <223> Hinge area]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (234)...(343)]]>
           <![CDATA[ <223> CH2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (344)...(450)]]>
           <![CDATA[ <223> CH3]]>
           <![CDATA[ <400> 26]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
                      20 25 30
          Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
              130 135 140
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
          145 150 155 160
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
                          165 170 175
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
                      180 185 190
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
                  195 200 205
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
              210 215 220
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
          225 230 235 240
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                          245 250 255
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                      260 265 270
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
                  275 280 285
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
              290 295 300
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
          305 310 315 320
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                          325 330 335
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                      340 345 350
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
                  355 360 365
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
              370 375 380
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
          385 390 395 400
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                          405 410 415
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                      420 425 430
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
                  435 440 445
          Gly Lys
              450
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 217]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Trastuzumab Fc (CH2 and CH3 domains)]]>
           <![CDATA[ <400> 27]]>
          Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
           1 5 10 15
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
                      20 25 30
          Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
                  35 40 45
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
              50 55 60
          Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
          65 70 75 80
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
                          85 90 95
          Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
                      100 105 110
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
                  115 120 125
          Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
              130 135 140
          Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
          145 150 155 160
          Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
                          165 170 175
          Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
                      180 185 190
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
                  195 200 205
          Lys Ser Leu Ser Leu Ser Pro Gly Lys
              210 215
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Nivolumab light chain]]>
           <![CDATA[ <400> 28]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 440]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Nivolumab heavy chain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(113)]]>
           <![CDATA[ <223> VH]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (114)...(221)]]>
           <![CDATA[ <223> CH1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (212)...(223)]]>
           <![CDATA[ <223> Hinge area]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (224)...(333)]]>
           <![CDATA[ <223> CH2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (334)...(440)]]>
           <![CDATA[ <223> CH3]]>
           <![CDATA[ <400> 29]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
                      20 25 30
          Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
                      100 105 110
          Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
                  115 120 125
          Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
              130 135 140
          Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
          145 150 155 160
          Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
                          165 170 175
          Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
                      180 185 190
          Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
                  195 200 205
          Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
              210 215 220
          Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
          225 230 235 240
          Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
                          245 250 255
          Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
                      260 265 270
          Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
                  275 280 285
          Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
              290 295 300
          Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
          305 310 315 320
          Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
                          325 330 335
          Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
                      340 345 350
          Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
                  355 360 365
          Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
              370 375 380
          Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
          385 390 395 400
          Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
                          405 410 415
          Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
                      420 425 430
          Ser Leu Ser Leu Ser Leu Gly Lys
                  435 440
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 217]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Nivolumab Fc (CH2 and CH3 domains)]]>
           <![CDATA[ <400> 30]]>
          Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
           1 5 10 15
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
                      20 25 30
          Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
                  35 40 45
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
              50 55 60
          Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
          65 70 75 80
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
                          85 90 95
          Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
                      100 105 110
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
                  115 120 125
          Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
              130 135 140
          Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
          145 150 155 160
          Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
                          165 170 175
          Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
                      180 185 190
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
                  195 200 205
          Lys Ser Leu Ser Leu Ser Leu Gly Lys
              210 215
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> ATROSAB heavy chain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(115)]]>
           <![CDATA[ <223> VH]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (116)...(218)]]>
           <![CDATA[ <223> CH1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (219)...(234)]]>
           <![CDATA[ <223> Hinge area]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (235)...(337)]]>
           <![CDATA[ <223> CH2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (338)...(444)]]>
           <![CDATA[ <223> CH3]]>
           <![CDATA[ <400> 31]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
           1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
                  115 120 125
          Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
              130 135 140
          Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
          145 150 155 160
          Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
                          165 170 175
          Leu Tyr Ser Leu Ser Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
                      180 185 190
          Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
                  195 200 205
          Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
              210 215 220
          Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
          225 230 235 240
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                          245 250 255
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                      260 265 270
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                  275 280 285
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Tyr Arg Val Val Ser Val Leu Thr
              290 295 300
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
          305 310 315 320
          Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
                          325 330 335
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                      340 345 350
          Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                  355 360 365
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
              370 375 380
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
          385 390 395 400
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                          405 410 415
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                      420 425 430
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                  435 440
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> ATROSAB light chain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(113)]]>
           <![CDATA[ <223> VL]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (114)...(219)]]>
           <![CDATA[ <223> CL]]>
           <![CDATA[ <400> 32]]>
          Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
           1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
                          85 90 95
          Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 VH domain]]>
           <![CDATA[ <400> 33]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser
                  115
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 VL domain]]>
           <![CDATA[ <400> 34]]>
          Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly
           1 5 10 15
          Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
                          85 90 95
          Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
          Arg
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 609]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human serum albumin (HSA)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(18)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> PROPEP ]]>
           <![CDATA[ <222> (19)...(24)]]>
           <![CDATA[ <223> Propeptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> PEPTIDE ]]>
           <![CDATA[ <222> (25)...(609)]]>
           <![CDATA[ <223> Albumin]]>
           <![CDATA[ <400> 35]]>
          Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
           1 5 10 15
          Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
                      20 25 30
          His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
                  35 40 45
          Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
              50 55 60
          Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
          65 70 75 80
          Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
                          85 90 95
          Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
                      100 105 110
          Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
                  115 120 125
          His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
              130 135 140
          Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
          145 150 155 160
          Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
                          165 170 175
          Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
                      180 185 190
          Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
                  195 200 205
          Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
              210 215 220
          Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
          225 230 235 240
          Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
                          245 250 255
          Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
                      260 265 270
          Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
                  275 280 285
          Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
              290 295 300
          Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
          305 310 315 320
          Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
                          325 330 335
          Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
                      340 345 350
          Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
                  355 360 365
          Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
              370 375 380
          Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
          385 390 395 400
          Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
                          405 410 415
          Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
                      420 425 430
          Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
                  435 440 445
          Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
              450 455 460
          Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
          465 470 475 480
          Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
                          485 490 495
          Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
                      500 505 510
          Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
                  515 520 525
          Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
              530 535 540
          Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
          545 550 555 560
          Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
                          565 570 575
          Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
                      580 585 590
          Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
                  595 600 605
          Leu
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 365]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human FcRn (IgG receptor FcRn large subunit p51)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(23)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (24)...(297)]]>
           <![CDATA[ <223> Extracellular domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (298)...(321)]]>
           <![CDATA[ <223> Transmembrane domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (322)...(365)]]>
           <![CDATA[ <223> Cytoplasmic domain]]>
           <![CDATA[ <400> 36]]>
          Met Gly Val Pro Arg Pro Gln Pro Trp Ala Leu Gly Leu Leu Leu Phe
           1 5 10 15
          Leu Leu Pro Gly Ser Leu Gly Ala Glu Ser His Leu Ser Leu Leu Tyr
                      20 25 30
          His Leu Thr Ala Val Ser Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp
                  35 40 45
          Val Ser Gly Trp Leu Gly Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu
              50 55 60
          Arg Gly Glu Ala Glu Pro Cys Gly Ala Trp Val Trp Glu Asn Gln Val
          65 70 75 80
          Ser Trp Tyr Trp Glu Lys Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys
                          85 90 95
          Leu Phe Leu Glu Ala Phe Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr
                      100 105 110
          Leu Gln Gly Leu Leu Gly Cys Glu Leu Gly Pro Asp Asn Thr Ser Val
                  115 120 125
          Pro Thr Ala Lys Phe Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp
              130 135 140
          Leu Lys Gln Gly Thr Trp Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile
          145 150 155 160
          Ser Gln Arg Trp Gln Gln Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr
                          165 170 175
          Phe Leu Leu Phe Ser Cys Pro His Arg Leu Arg Glu His Leu Glu Arg
                      180 185 190
          Gly Arg Gly Asn Leu Glu Trp Lys Glu Pro Pro Ser Met Arg Leu Lys
                  195 200 205
          Ala Arg Pro Ser Ser Pro Gly Phe Ser Val Leu Thr Cys Ser Ala Phe
              210 215 220
          Ser Phe Tyr Pro Pro Glu Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu
          225 230 235 240
          Ala Ala Gly Thr Gly Gln Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser
                          245 250 255
          Phe His Ala Ser Ser Ser Leu Thr Val Lys Ser Gly Asp Glu His His
                      260 265 270
          Tyr Cys Cys Ile Val Gln His Ala Gly Leu Ala Gln Pro Leu Arg Val
                  275 280 285
          Glu Leu Glu Ser Pro Ala Lys Ser Ser Val Leu Val Val Gly Ile Val
              290 295 300
          Ile Gly Val Leu Leu Leu Thr Ala Ala Ala Val Gly Gly Ala Leu Leu
          305 310 315 320
          Trp Arg Arg Met Arg Ser Gly Leu Pro Ala Pro Trp Ile Ser Leu Arg
                          325 330 335
          Gly Asp Asp Thr Gly Val Leu Leu Pro Thr Pro Gly Glu Ala Gln Asp
                      340 345 350
          Ala Asp Leu Lys Asp Val Asn Val Ile Pro Ala Thr Ala
                  355 360 365
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 690]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DMS5541]]>
           <![CDATA[ <400> 37]]>
          gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
          tcctgtgcag cctccggatt cacctttgat aagtattcga tggggtgggt ccgccaggct 120
          ccagggaagg gtctagagtg ggtctcacag atttcggata ctgctgatcg tacatactac 180
          gcacacgcgg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgcg tgctgaggac accgcggtat attactgtgc gatatatact 300
          gggcgttggg tgccttttga gtactggggt cagggaaccc tggtcaccgt ctcgagcgct 360
          agcaccgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt aggagaccgt 420
          gtcaccatca cttgccgggc aagtcgtccg attgggacga cgttaagttg gtaccagcag 480
          aaaccaggga aagcccctaa gctcctgatc ctgtggaatt cccgtttgca aagtggggtc 540
          ccatcacgtt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagtctg 600
          caacctgaag attttgctac gtactactgt gcgcaggctg ggacgcatcc tacgacgttc 660
          ggccaaggga ccaaggtgga aatcaaacgg 690
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 230]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DMS5541]]>
           <![CDATA[ <400> 38]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ala Ser Thr Asp Ile Gln Met Thr Gln
                  115 120 125
          Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
              130 135 140
          Cys Arg Ala Ser Arg Pro Ile Gly Thr Thr Leu Ser Trp Tyr Gln Gln
          145 150 155 160
          Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Trp Asn Ser Arg Leu
                          165 170 175
          Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
                      180 185 190
          Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
                  195 200 205
          Tyr Cys Ala Gln Ala Gly Thr His Pro Thr Thr Phe Gly Gln Gly Thr
              210 215 220
          Lys Val Glu Ile Lys Arg
          225 230
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 231]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DMS5540 (mouse specific)]]>
           <![CDATA[ <400> 39]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr
                      20 25 30
          Ser Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Arg Ile Asp Ser Tyr Gly Arg Gly Thr Tyr Tyr Glu Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Gln Val Thr Val Ser Ser Ala Ser Thr Asp Ile Gln Met Thr
                  115 120 125
          Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
              130 135 140
          Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Met Leu Ser Trp Tyr Gln
          145 150 155 160
          Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Leu Phe Gly Ser Arg
                          165 170 175
          Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
                      180 185 190
          Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
                  195 200 205
          Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr Thr Phe Gly Gln Gly
              210 215 220
          Thr Lys Val Glu Ile Lys Arg
          225 230
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 1210]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human EGFR (HER1) precursor]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(24)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (25)...(645)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (646)...(668)]]>
           <![CDATA[ <223> Transmembrane region]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (669)...(1210)]]>
           <![CDATA[ <223> Cytoplasmic domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (712)...(979)]]>
           <![CDATA[ <223> Protein kinase]]>
           <![CDATA[ <400> 40]]>
          Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala
           1 5 10 15
          Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln
                      20 25 30
          Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe
                  35 40 45
          Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn
              50 55 60
          Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys
          65 70 75 80
          Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val
                          85 90 95
          Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr
                      100 105 110
          Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn
                  115 120 125
          Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu
              130 135 140
          His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu
          145 150 155 160
          Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met
                          165 170 175
          Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro
                      180 185 190
          Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln
                  195 200 205
          Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg
              210 215 220
          Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys
          225 230 235 240
          Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp
                          245 250 255
          Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro
                      260 265 270
          Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly
                  275 280 285
          Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His
              290 295 300
          Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu
          305 310 315 320
          Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val
                          325 330 335
          Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn
                      340 345 350
          Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp
                  355 360 365
          Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr
              370 375 380
          Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu
          385 390 395 400
          Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp
                          405 410 415
          Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln
                      420 425 430
          His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu
                  435 440 445
          Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser
              450 455 460
          Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu
          465 470 475 480
          Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu
                          485 490 495
          Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro
                      500 505 510
          Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn
                  515 520 525
          Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly
              530 535 540
          Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro
          545 550 555 560
          Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro
                          565 570 575
          Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val
                      580 585 590
          Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp
                  595 600 605
          Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys
              610 615 620
          Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly
          625 630 635 640
          Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu
                          645 650 655
          Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His
                      660 665 670
          Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu
                  675 680 685
          Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu
              690 695 700
          Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser
          705 710 715 720
          Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu
                          725 730 735
          Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser
                      740 745 750
          Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser
                  755 760 765
          Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser
              770 775 780
          Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp
          785 790 795 800
          Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn
                          805 810 815
          Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg
                      820 825 830
          Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro
                  835 840 845
          Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala
              850 855 860
          Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp
          865 870 875 880
          Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp
                          885 890 895
          Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser
                      900 905 910
          Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu
                  915 920 925
          Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr
              930 935 940
          Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys
          945 950 955 960
          Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln
                          965 970 975
          Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro
                      980 985 990
          Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp
                  995 1000 1005
          Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe Phe
              1010 1015 1020
          Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu Ser Ala
          1025 1030 1035 1040
          Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn Gly Leu Gln
                          1045 1050 1055
          Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg Tyr Ser Ser Asp
                      1060 1065 1070
          Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp Asp Thr Phe Leu Pro
                  1075 1080 1085
          Val Pro Glu Tyr Ile Asn Gln Ser Val Pro Lys Arg Pro Ala Gly Ser
              1090 1095 1100
          Val Gln Asn Pro Val Tyr His Asn Gln Pro Leu Asn Pro Ala Pro Ser
          1105 1110 1115 1120
          Arg Asp Pro His Tyr Gln Asp Pro His Ser Thr Ala Val Gly Asn Pro
                          1125 1130 1135
          Glu Tyr Leu Asn Thr Val Gln Pro Thr Cys Val Asn Ser Thr Phe Asp
                      1140 1145 1150
          Ser Pro Ala His Trp Ala Gln Lys Gly Ser His Gln Ile Ser Leu Asp
                  1155 1160 1165
          Asn Pro Asp Tyr Gln Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn
              1170 1175 1180
          Gly Ile Phe Lys Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val
          1185 1190 1195 1200
          Ala Pro Gln Ser Ser Glu Phe Ile Gly Ala
                          1205 1210
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 1186]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mature human EGFR/HER1 (minus signal peptide)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(621)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(165)]]>
           <![CDATA[ <223> ECD Domain I]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (166)...(313)]]>
           <![CDATA[ <223> ECD Domain II]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (314)...(481)]]>
           <![CDATA[ <223> ECD Domain III]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (482)...(621)]]>
           <![CDATA[ <223> ECD Domain IV]]>
           <![CDATA[ <400> 41]]>
          Leu Glu Glu Lys Lys Val Cys Gln Gly Thr Ser Asn Lys Leu Thr Gln
           1 5 10 15
          Leu Gly Thr Phe Glu Asp His Phe Leu Ser Leu Gln Arg Met Phe Asn
                      20 25 30
          Asn Cys Glu Val Val Leu Gly Asn Leu Glu Ile Thr Tyr Val Gln Arg
                  35 40 45
          Asn Tyr Asp Leu Ser Phe Leu Lys Thr Ile Gln Glu Val Ala Gly Tyr
              50 55 60
          Val Leu Ile Ala Leu Asn Thr Val Glu Arg Ile Pro Leu Glu Asn Leu
          65 70 75 80
          Gln Ile Ile Arg Gly Asn Met Tyr Tyr Glu Asn Ser Tyr Ala Leu Ala
                          85 90 95
          Val Leu Ser Asn Tyr Asp Ala Asn Lys Thr Gly Leu Lys Glu Leu Pro
                      100 105 110
          Met Arg Asn Leu Gln Glu Ile Leu His Gly Ala Val Arg Phe Ser Asn
                  115 120 125
          Asn Pro Ala Leu Cys Asn Val Glu Ser Ile Gln Trp Arg Asp Ile Val
              130 135 140
          Ser Ser Asp Phe Leu Ser Asn Met Ser Met Asp Phe Gln Asn His Leu
          145 150 155 160
          Gly Ser Cys Gln Lys Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp
                          165 170 175
          Gly Ala Gly Glu Glu Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala
                      180 185 190
          Gln Gln Cys Ser Gly Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys
                  195 200 205
          His Asn Gln Cys Ala Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys
              210 215 220
          Leu Val Cys Arg Lys Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys
          225 230 235 240
          Pro Pro Leu Met Leu Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn
                          245 250 255
          Pro Glu Gly Lys Tyr Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro
                      260 265 270
          Arg Asn Tyr Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly
                  275 280 285
          Ala Asp Ser Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys
              290 295 300
          Cys Glu Gly Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu
          305 310 315 320
          Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys
                          325 330 335
          Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe
                      340 345 350
          Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu
                  355 360 365
          Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln
              370 375 380
          Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu
          385 390 395 400
          Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val
                          405 410 415
          Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile
                      420 425 430
          Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala
                  435 440 445
          Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr
              450 455 460
          Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln
          465 470 475 480
          Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro
                          485 490 495
          Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val
                      500 505 510
          Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn
                  515 520 525
          Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn
              530 535 540
          Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His
          545 550 555 560
          Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met
                          565 570 575
          Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val
                      580 585 590
          Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly
                  595 600 605
          Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr
              610 615 620
          Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile
          625 630 635 640
          Gly Leu Phe Met Arg Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg
                          645 650 655
          Arg Leu Leu Gln Glu Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
                      660 665 670
          Glu Ala Pro Asn Gln Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe
                  675 680 685
          Lys Lys Ile Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
              690 695 700
          Gly Leu Trp Ile Pro Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile
          705 710 715 720
          Lys Glu Leu Arg Glu Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
                          725 730 735
          Asp Glu Ala Tyr Val Met Ala Ser Val Asp Asn Pro His Val Cys Arg
                      740 745 750
          Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu
                  755 760 765
          Met Pro Phe Gly Cys Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn
              770 775 780
          Ile Gly Ser Gln Tyr Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly
          785 790 795 800
          Met Asn Tyr Leu Glu Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala
                          805 810 815
          Arg Asn Val Leu Val Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe
                      820 825 830
          Gly Leu Ala Lys Leu Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu
                  835 840 845
          Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His
              850 855 860
          Arg Ile Tyr Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
          865 870 875 880
          Trp Glu Leu Met Thr Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala
                          885 890 895
          Ser Glu Ile Ser Ser Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
                      900 905 910
          Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
                  915 920 925
          Ile Asp Ala Asp Ser Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe
              930 935 940
          Ser Lys Met Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp
          945 950 955 960
          Glu Arg Met His Leu Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala
                          965 970 975
          Leu Met Asp Glu Glu Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr
                      980 985 990
          Leu Ile Pro Gln Gln Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr
                  995 1000 1005
          Pro Leu Leu Ser Ser Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala
              1010 1015 1020
          Cys Ile Asp Arg Asn Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser
          1025 1030 1035 1040
          Phe Leu Gln Arg Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp
                          1045 1050 1055
          Ser Ile Asp Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser
                      1060 1065 1070
          Val Pro Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn
                  1075 1080 1085
          Gln Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro
              1090 1095 1100
          His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln Pro
          1105 1110 1115 1120
          Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala Gln Lys
                          1125 1130 1135
          Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln Gln Asp Phe
                      1140 1145 1150
          Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys Gly Ser Thr Ala
                  1155 1160 1165
          Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln Ser Ser Glu Phe Ile
              1170 1175 1180
          Gly Ala
          1185
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 1255]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human HER2 (ErbB2) precursor]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(22)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (23)...(652)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (653)...(675)]]>
           <![CDATA[ <223> Transmembrane region]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (676)...(1255)]]>
           <![CDATA[ <223> Cytoplasmic domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (720)...(987)]]>
           <![CDATA[ <223> Protein kinase]]>
           <![CDATA[ <400> 42]]>
          Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
           1 5 10 15
          Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
                      20 25 30
          Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
                  35 40 45
          Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
              50 55 60
          Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
          65 70 75 80
          Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
                          85 90 95
          Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
                      100 105 110
          Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
                  115 120 125
          Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
              130 135 140
          Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
          145 150 155 160
          Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
                          165 170 175
          Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
                      180 185 190
          His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
                  195 200 205
          Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
              210 215 220
          Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
          225 230 235 240
          Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
                          245 250 255
          His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
                      260 265 270
          Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
                  275 280 285
          Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
              290 295 300
          Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
          305 310 315 320
          Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
                          325 330 335
          Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
                      340 345 350
          Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
                  355 360 365
          Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
              370 375 380
          Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
          385 390 395 400
          Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
                          405 410 415
          Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
                      420 425 430
          Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
                  435 440 445
          Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
              450 455 460
          Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
          465 470 475 480
          Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
                          485 490 495
          Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
                      500 505 510
          Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
                  515 520 525
          Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
              530 535 540
          Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
          545 550 555 560
          Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
                          565 570 575
          Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
                      580 585 590
          Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
                  595 600 605
          Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
              610 615 620
          Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
          625 630 635 640
          Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
                          645 650 655
          Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
                      660 665 670
          Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
                  675 680 685
          Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
              690 695 700
          Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
          705 710 715 720
          Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
                          725 730 735
          Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
                      740 745 750
          Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
                  755 760 765
          Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
              770 775 780
          Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
          785 790 795 800
          Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
                          805 810 815
          Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
                      820 825 830
          Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
                  835 840 845
          Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
              850 855 860
          Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
          865 870 875 880
          Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
                          885 890 895
          Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
                      900 905 910
          Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
                  915 920 925
          Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
              930 935 940
          Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
          945 950 955 960
          Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
                          965 970 975
          Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
                      980 985 990
          Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
                  995 1000 1005
          Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr Leu
              1010 1015 1020
          Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly Ala Gly
          1025 1030 1035 1040
          Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg Ser Gly Gly
                          1045 1050 1055
          Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu Glu Ala Pro Arg
                      1060 1065 1070
          Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser Asp Val Phe Asp Gly
                  1075 1080 1085
          Asp Leu Gly Met Gly Ala Ala Lys Gly Leu Gln Ser Leu Pro Thr His
              1090 1095 1100
          Asp Pro Ser Pro Leu Gln Arg Tyr Ser Glu Asp Pro Thr Val Pro Leu
          1105 1110 1115 1120
          Pro Ser Glu Thr Asp Gly Tyr Val Ala Pro Leu Thr Cys Ser Pro Gln
                          1125 1130 1135
          Pro Glu Tyr Val Asn Gln Pro Asp Val Arg Pro Gln Pro Pro Ser Pro
                      1140 1145 1150
          Arg Glu Gly Pro Leu Pro Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu
                  1155 1160 1165
          Arg Pro Lys Thr Leu Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val
              1170 1175 1180
          Phe Ala Phe Gly Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln
          1185 1190 1195 1200
          Gly Gly Ala Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala
                          1205 1210 1215
          Phe Asp Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala
                      1220 1225 1230
          Pro Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
                  1235 1240 1245
          Leu Gly Leu Asp Val Pro Val
              1250 1255
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 1233]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mature human HER2 (ErbB2) protein (minus signal peptide)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(628)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(172)]]>
           <![CDATA[ <223> ECD Domain I]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (173)...(319)]]>
           <![CDATA[ <223> ECD Domain II]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (320)...(488)]]>
           <![CDATA[ <223> ECD Domain III]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (489)...(628)]]>
           <![CDATA[ <223> ECD Domain IV]]>
           <![CDATA[ <400> 43]]>
          Thr Gln Val Cys Thr Gly Thr Asp Met Lys Leu Arg Leu Pro Ala Ser
           1 5 10 15
          Pro Glu Thr His Leu Asp Met Leu Arg His Leu Tyr Gln Gly Cys Gln
                      20 25 30
          Val Val Gln Gly Asn Leu Glu Leu Thr Tyr Leu Pro Thr Asn Ala Ser
                  35 40 45
          Leu Ser Phe Leu Gln Asp Ile Gln Glu Val Gln Gly Tyr Val Leu Ile
              50 55 60
          Ala His Asn Gln Val Arg Gln Val Pro Leu Gln Arg Leu Arg Ile Val
          65 70 75 80
          Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr Ala Leu Ala Val Leu Asp
                          85 90 95
          Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro Val Thr Gly Ala Ser Pro
                      100 105 110
          Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser Leu Thr Glu Ile Leu Lys
                  115 120 125
          Gly Gly Val Leu Ile Gln Arg Asn Pro Gln Leu Cys Tyr Gln Asp Thr
              130 135 140
          Ile Leu Trp Lys Asp Ile Phe His Lys Asn Asn Gln Leu Ala Leu Thr
          145 150 155 160
          Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys His Pro Cys Ser Pro Met
                          165 170 175
          Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser Ser Glu Asp Cys Gln Ser
                      180 185 190
          Leu Thr Arg Thr Val Cys Ala Gly Gly Cys Ala Arg Cys Lys Gly Pro
                  195 200 205
          Leu Pro Thr Asp Cys Cys His Glu Gln Cys Ala Ala Gly Cys Thr Gly
              210 215 220
          Pro Lys His Ser Asp Cys Leu Ala Cys Leu His Phe Asn His Ser Gly
          225 230 235 240
          Ile Cys Glu Leu His Cys Pro Ala Leu Val Thr Tyr Asn Thr Asp Thr
                          245 250 255
          Phe Glu Ser Met Pro Asn Pro Glu Gly Arg Tyr Thr Phe Gly Ala Ser
                      260 265 270
          Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu Ser Thr Asp Val Gly Ser
                  275 280 285
          Cys Thr Leu Val Cys Pro Leu His Asn Gln Glu Val Thr Ala Glu Asp
              290 295 300
          Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys Pro Cys Ala Arg Val Cys
          305 310 315 320
          Tyr Gly Leu Gly Met Glu His Leu Arg Glu Val Arg Ala Val Thr Ser
                          325 330 335
          Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys Lys Ile Phe Gly Ser Leu
                      340 345 350
          Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp Pro Ala Ser Asn Thr Ala
                  355 360 365
          Pro Leu Gln Pro Glu Gln Leu Gln Val Phe Glu Thr Leu Glu Glu Ile
              370 375 380
          Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro Asp Ser Leu Pro Asp Leu
          385 390 395 400
          Ser Val Phe Gln Asn Leu Gln Val Ile Arg Gly Arg Ile Leu His Asn
                          405 410 415
          Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu Gly Ile Ser Trp Leu Gly
                      420 425 430
          Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly Leu Ala Leu Ile His His
                  435 440 445
          Asn Thr His Leu Cys Phe Val His Thr Val Pro Trp Asp Gln Leu Phe
              450 455 460
          Arg Asn Pro His Gln Ala Leu Leu His Thr Ala Asn Arg Pro Glu Asp
          465 470 475 480
          Glu Cys Val Gly Glu Gly Leu Ala Cys His Gln Leu Cys Ala Arg Gly
                          485 490 495
          His Cys Trp Gly Pro Gly Pro Thr Gln Cys Val Asn Cys Ser Gln Phe
                      500 505 510
          Leu Arg Gly Gln Glu Cys Val Glu Glu Cys Arg Val Leu Gln Gly Leu
                  515 520 525
          Pro Arg Glu Tyr Val Asn Ala Arg His Cys Leu Pro Cys His Pro Glu
              530 535 540
          Cys Gln Pro Gln Asn Gly Ser Val Thr Cys Phe Gly Pro Glu Ala Asp
          545 550 555 560
          Gln Cys Val Ala Cys Ala His Tyr Lys Asp Pro Pro Phe Cys Val Ala
                          565 570 575
          Arg Cys Pro Ser Gly Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp
                      580 585 590
          Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro Ile Asn Cys
                  595 600 605
          Thr His Ser Cys Val Asp Leu Asp Asp Lys Gly Cys Pro Ala Glu Gln
              610 615 620
          Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser Ala Val Val Gly Ile Leu
          625 630 635 640
          Leu Val Val Val Leu Gly Val Val Phe Gly Ile Leu Ile Lys Arg Arg
                          645 650 655
          Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg Arg Leu Leu Gln Glu Thr
                      660 665 670
          Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Ala Met Pro Asn Gln Ala
                  675 680 685
          Gln Met Arg Ile Leu Lys Glu Thr Glu Leu Arg Lys Val Lys Val Leu
              690 695 700
          Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Ile Trp Ile Pro Asp
          705 710 715 720
          Gly Glu Asn Val Lys Ile Pro Val Ala Ile Lys Val Leu Arg Glu Asn
                          725 730 735
          Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met
                      740 745 750
          Ala Gly Val Gly Ser Pro Tyr Val Ser Arg Leu Leu Gly Ile Cys Leu
                  755 760 765
          Thr Ser Thr Val Gln Leu Val Thr Gln Leu Met Pro Tyr Gly Cys Leu
              770 775 780
          Leu Asp His Val Arg Glu Asn Arg Gly Arg Leu Gly Ser Gln Asp Leu
          785 790 795 800
          Leu Asn Trp Cys Met Gln Ile Ala Lys Gly Met Ser Tyr Leu Glu Asp
                          805 810 815
          Val Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys
                      820 825 830
          Ser Pro Asn His Val Lys Ile Thr Asp Phe Gly Leu Ala Arg Leu Leu
                  835 840 845
          Asp Ile Asp Glu Thr Glu Tyr His Ala Asp Gly Gly Lys Val Pro Ile
              850 855 860
          Lys Trp Met Ala Leu Glu Ser Ile Leu Arg Arg Arg Phe Thr His Gln
          865 870 875 880
          Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe
                          885 890 895
          Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala Arg Glu Ile Pro Asp Leu
                      900 905 910
          Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp
                  915 920 925
          Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ser Glu Cys Arg
              930 935 940
          Pro Arg Phe Arg Glu Leu Val Ser Glu Phe Ser Arg Met Ala Arg Asp
          945 950 955 960
          Pro Gln Arg Phe Val Val Ile Gln Asn Glu Asp Leu Gly Pro Ala Ser
                          965 970 975
          Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu Leu Glu Asp Asp Asp Met
                      980 985 990
          Gly Asp Leu Val Asp Ala Glu Glu Tyr Leu Val Pro Gln Gln Gly Phe
                  995 1000 1005
          Phe Cys Pro Asp Pro Ala Pro Gly Ala Gly Gly Met Val His His Arg
              1010 1015 1020
          His Arg Ser Ser Ser Thr Arg Ser Gly Gly Gly Asp Leu Thr Leu Gly
          1025 1030 1035 1040
          Leu Glu Pro Ser Glu Glu Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser
                          1045 1050 1055
          Glu Gly Ala Gly Ser Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala
                      1060 1065 1070
          Ala Lys Gly Leu Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln
                  1075 1080 1085
          Arg Tyr Ser Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly
              1090 1095 1100
          Tyr Val Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln
          1105 1110 1115 1120
          Pro Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
                          1125 1130 1135
          Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu Ser
                      1140 1145 1150
          Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly Gly Ala
                  1155 1160 1165
          Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala Ala Pro Gln
              1170 1175 1180
          Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp Asn Leu Tyr Tyr
          1185 1190 1195 1200
          Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro Pro Ser Thr Phe Lys
                          1205 1210 1215
          Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr Leu Gly Leu Asp Val Pro
                      1220 1225 1230
          Val
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 1342]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human HER3 (ErbB3) precursor]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(19)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (20)...(643)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (644)...(664)]]>
           <![CDATA[ <223> Transmembrane region]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (665)...(1342)]]>
           <![CDATA[ <223> Cytoplasmic domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (709)...(966)]]>
           <![CDATA[ <223> Protein kinase]]>
           <![CDATA[ <400> 44]]>
          Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
           1 5 10 15
          Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
                      20 25 30
          Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
                  35 40 45
          Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
              50 55 60
          Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
          65 70 75 80
          Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
                          85 90 95
          Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
                      100 105 110
          Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
                  115 120 125
          His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
              130 135 140
          Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
          145 150 155 160
          Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
                          165 170 175
          Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
                      180 185 190
          Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
                  195 200 205
          Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
              210 215 220
          Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
          225 230 235 240
          Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
                          245 250 255
          Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
                      260 265 270
          Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
                  275 280 285
          Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
              290 295 300
          Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
          305 310 315 320
          Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser
                          325 330 335
          Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val
                      340 345 350
          Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu
                  355 360 365
          Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu
              370 375 380
          Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln
          385 390 395 400
          Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr
                          405 410 415
          Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile
                      420 425 430
          Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu
                  435 440 445
          Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr
              450 455 460
          His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu
          465 470 475 480
          Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu
                          485 490 495
          Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro
                      500 505 510
          Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val
                  515 520 525
          Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala
              530 535 540
          His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu
          545 550 555 560
          Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys
                          565 570 575
          Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly
                      580 585 590
          Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn
                  595 600 605
          Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro
              610 615 620
          Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr
          625 630 635 640
          His Leu Thr Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe
                          645 650 655
          Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln
                      660 665 670
          Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu
                  675 680 685
          Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe
              690 695 700
          Lys Glu Thr Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe
          705 710 715 720
          Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys
                          725 730 735
          Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser
                      740 745 750
          Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His
                  755 760 765
          Ala His Ile Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln
              770 775 780
          Leu Val Thr Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg
          785 790 795 800
          Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val
                          805 810 815
          Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His
                      820 825 830
          Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val
                  835 840 845
          Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys
              850 855 860
          Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu
          865 870 875 880
          Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser
                          885 890 895
          Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr
                      900 905 910
          Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu
                  915 920 925
          Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met
              930 935 940
          Val Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu
          945 950 955 960
          Leu Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu
                          965 970 975
          Val Ile Lys Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro
                      980 985 990
          His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu
                  995 1000 1005
          Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala Thr
              1010 1015 1020
          Thr Thr Leu Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu Asn Arg
          1025 1030 1035 1040
          Pro Arg Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly Tyr Met Pro
                          1045 1050 1055
          Met Asn Gln Gly Asn Leu Gly Glu Ser Cys Gln Glu Ser Ala Val Ser
                      1060 1065 1070
          Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser Leu His Pro Met Pro
                  1075 1080 1085
          Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu Gly His Val Thr Gly Ser
              1090 1095 1100
          Glu Ala Glu Leu Gln Glu Lys Val Ser Met Cys Arg Ser Arg Ser Arg
          1105 1110 1115 1120
          Ser Arg Ser Pro Arg Pro Arg Gly Asp Ser Ala Tyr His Ser Gln Arg
                          1125 1130 1135
          His Ser Leu Leu Thr Pro Val Thr Pro Leu Ser Pro Pro Gly Leu Glu
                      1140 1145 1150
          Glu Glu Asp Val Asn Gly Tyr Val Met Pro Asp Thr His Leu Lys Gly
                  1155 1160 1165
          Thr Pro Ser Ser Arg Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser
              1170 1175 1180
          Val Leu Gly Thr Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met
          1185 1190 1195 1200
          Asn Arg Arg Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser
                          1205 1210 1215
          Leu Glu Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser
                      1220 1225 1230
          Ala Ser Leu Gly Ser Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile
                  1235 1240 1245
          Met Pro Thr Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met Asn
              1250 1255 1260
          Arg Gln Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly
          1265 1270 1275 1280
          Ala Cys Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg Ala Phe Gln
                          1285 1290 1295
          Gly Pro Gly His Gln Ala Pro His Val His Tyr Ala Arg Leu Lys Thr
                      1300 1305 1310
          Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe Asp Asn Pro Asp Tyr
                  1315 1320 1325
          Trp His Ser Arg Leu Phe Pro Lys Ala Asn Ala Gln Arg Thr
              1330 1335 1340
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 1323]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mature human HER3 (ErbB3) protein (minus signal peptide)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(621)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(166)]]>
           <![CDATA[ <223> ECD Domain I]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (167)...(311)]]>
           <![CDATA[ <223> ECD Domain II]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (312)...(480)]]>
           <![CDATA[ <223> ECD Domain III]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (481)...(621)]]>
           <![CDATA[ <223> ECD Domain IV]]>
           <![CDATA[ <400> 45]]>
          Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr Leu Asn Gly
           1 5 10 15
          Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr Leu Tyr Lys
                      20 25 30
          Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu Ile Val Leu
                  35 40 45
          Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile Arg Glu Val
              50 55 60
          Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr Leu Pro Leu
          65 70 75 80
          Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp Gly Lys Phe
                          85 90 95
          Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser His Ala Leu
                      100 105 110
          Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser Gly Gly Val
                  115 120 125
          Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr Ile Asp Trp
              130 135 140
          Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val Lys Asp Asn
          145 150 155 160
          Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly Arg Cys Trp
                          165 170 175
          Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr Ile Cys Ala
                      180 185 190
          Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn Gln Cys Cys
                  195 200 205
          His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp Thr Asp Cys
              210 215 220
          Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val Pro Arg Cys
          225 230 235 240
          Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu Glu Pro Asn
                          245 250 255
          Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala Ser Cys Pro
                      260 265 270
          His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala Cys Pro Pro
                  275 280 285
          Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys Glu Pro Cys
              290 295 300
          Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser Gly Ser Arg
          305 310 315 320
          Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val Asn Cys Thr
                          325 330 335
          Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu Asn Gly Asp
                      340 345 350
          Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu Asn Val Phe
                  355 360 365
          Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln Ser Trp Pro
              370 375 380
          Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr Thr Ile Gly
          385 390 395 400
          Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile Met Lys Asn
                          405 410 415
          Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu Ile Ser Ala
                      420 425 430
          Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr His His Ser
                  435 440 445
          Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu Arg Leu Asp
              450 455 460
          Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu Gly Lys Val
          465 470 475 480
          Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro Gly Pro Gly
                          485 490 495
          Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val Cys Val Thr
                      500 505 510
          His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala His Glu Ala
                  515 520 525
          Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu Gly Thr Ala
              530 535 540
          Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys Ala His Phe
          545 550 555 560
          Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly Val Leu Gly
                          565 570 575
          Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn Glu Cys Arg
                      580 585 590
          Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro Glu Leu Gln
                  595 600 605
          Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr His Leu Thr
              610 615 620
          Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe Met Met Leu
          625 630 635 640
          Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln Asn Lys Arg
                          645 650 655
          Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu Pro Leu Asp
                      660 665 670
          Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe Lys Glu Thr
                  675 680 685
          Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe Gly Thr Val
              690 695 700
          His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys Ile Pro Val
          705 710 715 720
          Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser Phe Gln Ala
                          725 730 735
          Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His Ala His Ile
                      740 745 750
          Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln Leu Val Thr
                  755 760 765
          Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg Gln His Arg
              770 775 780
          Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val Gln Ile Ala
          785 790 795 800
          Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His Arg Asn Leu
                          805 810 815
          Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val Gln Val Ala
                      820 825 830
          Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys Gln Leu Leu
                  835 840 845
          Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu Glu Ser Ile
              850 855 860
          His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val
          865 870 875 880
          Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr Ala Gly Leu
                          885 890 895
          Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Ala
                      900 905 910
          Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met Val Lys Cys
                  915 920 925
          Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu Leu Ala Asn
              930 935 940
          Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu Val Ile Lys
          945 950 955 960
          Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro His Gly Leu
                          965 970 975
          Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu Leu Asp Leu
                      980 985 990
          Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala Thr Thr Thr Leu
                  995 1000 1005
          Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu Asn Arg Pro Arg Gly
              1010 1015 1020
          Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly Tyr Met Pro Met Asn Gln
          1025 1030 1035 1040
          Gly Asn Leu Gly Glu Ser Cys Gln Glu Ser Ala Val Ser Gly Ser Ser
                          1045 1050 1055
          Glu Arg Cys Pro Arg Pro Val Ser Leu His Pro Met Pro Arg Gly Cys
                      1060 1065 1070
          Leu Ala Ser Glu Ser Ser Glu Gly His Val Thr Gly Ser Glu Ala Glu
                  1075 1080 1085
          Leu Gln Glu Lys Val Ser Met Cys Arg Ser Arg Ser Arg Ser Arg Ser
              1090 1095 1100
          Pro Arg Pro Arg Gly Asp Ser Ala Tyr His Ser Gln Arg His Ser Leu
          1105 1110 1115 1120
          Leu Thr Pro Val Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu Glu Asp
                          1125 1130 1135
          Val Asn Gly Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser
                      1140 1145 1150
          Ser Arg Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly
                  1155 1160 1165
          Thr Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg
              1170 1175 1180
          Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu Glu
          1185 1190 1195 1200
          Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala Ser Leu
                          1205 1210 1215
          Gly Ser Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile Met Pro Thr
                      1220 1225 1230
          Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met Asn Arg Gln Arg
                  1235 1240 1245
          Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala Cys Pro
              1250 1255 1260
          Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg Ala Phe Gln Gly Pro Gly
          1265 1270 1275 1280
          His Gln Ala Pro His Val His Tyr Ala Arg Leu Lys Thr Leu Arg Ser
                          1285 1290 1295
          Leu Glu Ala Thr Asp Ser Ala Phe Asp Asn Pro Asp Tyr Trp His Ser
                      1300 1305 1310
          Arg Leu Phe Pro Lys Ala Asn Ala Gln Arg Thr
                  1315 1320
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 1308]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human HER4 (ErbB4) precursor]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(25)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (26)...(651)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (652)...(675)]]>
           <![CDATA[ <223> Transmembrane region]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (676)...(1308)]]>
           <![CDATA[ <223> Cytoplasmic domain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (718)...(985)]]>
           <![CDATA[ <223> Protein kinase]]>
           <![CDATA[ <400> 46]]>
          Met Lys Pro Ala Thr Gly Leu Trp Val Trp Val Ser Leu Leu Val Ala
           1 5 10 15
          Ala Gly Thr Val Gln Pro Ser Asp Ser Gln Ser Val Cys Ala Gly Thr
                      20 25 30
          Glu Asn Lys Leu Ser Ser Leu Ser Asp Leu Glu Gln Gln Tyr Arg Ala
                  35 40 45
          Leu Arg Lys Tyr Tyr Glu Asn Cys Glu Val Val Met Gly Asn Leu Glu
              50 55 60
          Ile Thr Ser Ile Glu His Asn Arg Asp Leu Ser Phe Leu Arg Ser Val
          65 70 75 80
          Arg Glu Val Thr Gly Tyr Val Leu Val Ala Leu Asn Gln Phe Arg Tyr
                          85 90 95
          Leu Pro Leu Glu Asn Leu Arg Ile Ile Arg Gly Thr Lys Leu Tyr Glu
                      100 105 110
          Asp Arg Tyr Ala Leu Ala Ile Phe Leu Asn Tyr Arg Lys Asp Gly Asn
                  115 120 125
          Phe Gly Leu Gln Glu Leu Gly Leu Lys Asn Leu Thr Glu Ile Leu Asn
              130 135 140
          Gly Gly Val Tyr Val Asp Gln Asn Lys Phe Leu Cys Tyr Ala Asp Thr
          145 150 155 160
          Ile His Trp Gln Asp Ile Val Arg Asn Pro Trp Pro Ser Asn Leu Thr
                          165 170 175
          Leu Val Ser Thr Asn Gly Ser Ser Gly Cys Gly Arg Cys His Lys Ser
                      180 185 190
          Cys Thr Gly Arg Cys Trp Gly Pro Thr Glu Asn His Cys Gln Thr Leu
                  195 200 205
          Thr Arg Thr Val Cys Ala Glu Gln Cys Asp Gly Arg Cys Tyr Gly Pro
              210 215 220
          Tyr Val Ser Asp Cys Cys His Arg Glu Cys Ala Gly Gly Cys Ser Gly
          225 230 235 240
          Pro Lys Asp Thr Asp Cys Phe Ala Cys Met Asn Phe Asn Asp Ser Gly
                          245 250 255
          Ala Cys Val Thr Gln Cys Pro Gln Thr Phe Val Tyr Asn Pro Thr Thr
                      260 265 270
          Phe Gln Leu Glu His Asn Phe Asn Ala Lys Tyr Thr Tyr Gly Ala Phe
                  275 280 285
          Cys Val Lys Lys Cys Pro His Asn Phe Val Val Asp Ser Ser Ser Cys
              290 295 300
          Val Arg Ala Cys Pro Ser Ser Lys Met Glu Val Glu Glu Asn Gly Ile
          305 310 315 320
          Lys Met Cys Lys Pro Cys Thr Asp Ile Cys Pro Lys Ala Cys Asp Gly
                          325 330 335
          Ile Gly Thr Gly Ser Leu Met Ser Ala Gln Thr Val Asp Ser Ser Asn
                      340 345 350
          Ile Asp Lys Phe Ile Asn Cys Thr Lys Ile Asn Gly Asn Leu Ile Phe
                  355 360 365
          Leu Val Thr Gly Ile His Gly Asp Pro Tyr Asn Ala Ile Glu Ala Ile
              370 375 380
          Asp Pro Glu Lys Leu Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly
          385 390 395 400
          Phe Leu Asn Ile Gln Ser Trp Pro Pro Asn Met Thr Asp Phe Ser Val
                          405 410 415
          Phe Ser Asn Leu Val Thr Ile Gly Gly Arg Val Leu Tyr Ser Gly Leu
                      420 425 430
          Ser Leu Leu Ile Leu Lys Gln Gln Gly Ile Thr Ser Leu Gln Phe Gln
                  435 440 445
          Ser Leu Lys Glu Ile Ser Ala Gly Asn Ile Tyr Ile Thr Asp Asn Ser
              450 455 460
          Asn Leu Cys Tyr Tyr His Thr Ile Asn Trp Thr Thr Leu Phe Ser Thr
          465 470 475 480
          Ile Asn Gln Arg Ile Val Ile Arg Asp Asn Arg Lys Ala Glu Asn Cys
                          485 490 495
          Thr Ala Glu Gly Met Val Cys Asn His Leu Cys Ser Ser Asp Gly Cys
                      500 505 510
          Trp Gly Pro Gly Pro Asp Gln Cys Leu Ser Cys Arg Arg Phe Ser Arg
                  515 520 525
          Gly Arg Ile Cys Ile Glu Ser Cys Asn Leu Tyr Asp Gly Glu Phe Arg
              530 535 540
          Glu Phe Glu Asn Gly Ser Ile Cys Val Glu Cys Asp Pro Gln Cys Glu
          545 550 555 560
          Lys Met Glu Asp Gly Leu Leu Thr Cys His Gly Pro Gly Pro Asp Asn
                          565 570 575
          Cys Thr Lys Cys Ser His Phe Lys Asp Gly Pro Asn Cys Val Glu Lys
                      580 585 590
          Cys Pro Asp Gly Leu Gln Gly Ala Asn Ser Phe Ile Phe Lys Tyr Ala
                  595 600 605
          Asp Pro Asp Arg Glu Cys His Pro Cys His Pro Asn Cys Thr Gln Gly
              610 615 620
          Cys Asn Gly Pro Thr Ser His Asp Cys Ile Tyr Tyr Pro Trp Thr Gly
          625 630 635 640
          His Ser Thr Leu Pro Gln His Ala Arg Thr Pro Leu Ile Ala Ala Gly
                          645 650 655
          Val Ile Gly Gly Leu Phe Ile Leu Val Ile Val Gly Leu Thr Phe Ala
                      660 665 670
          Val Tyr Val Arg Arg Lys Ser Ile Lys Lys Lys Arg Ala Leu Arg Arg
                  675 680 685
          Phe Leu Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Thr Ala
              690 695 700
          Pro Asn Gln Ala Gln Leu Arg Ile Leu Lys Glu Thr Glu Leu Lys Arg
          705 710 715 720
          Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Ile
                          725 730 735
          Trp Val Pro Glu Gly Glu Thr Val Lys Ile Pro Val Ala Ile Lys Ile
                      740 745 750
          Leu Asn Glu Thr Thr Gly Pro Lys Ala Asn Val Glu Phe Met Asp Glu
                  755 760 765
          Ala Leu Ile Met Ala Ser Met Asp His Pro His Leu Val Arg Leu Leu
              770 775 780
          Gly Val Cys Leu Ser Pro Thr Ile Gln Leu Val Thr Gln Leu Met Pro
          785 790 795 800
          His Gly Cys Leu Leu Glu Tyr Val His Glu His Lys Asp Asn Ile Gly
                          805 810 815
          Ser Gln Leu Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Met
                      820 825 830
          Tyr Leu Glu Glu Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn
                  835 840 845
          Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe Gly Leu
              850 855 860
          Ala Arg Leu Leu Glu Gly Asp Glu Lys Glu Tyr Asn Ala Asp Gly Gly
          865 870 875 880
          Lys Met Pro Ile Lys Trp Met Ala Leu Glu Cys Ile His Tyr Arg Lys
                          885 890 895
          Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Ile Trp Glu
                      900 905 910
          Leu Met Thr Phe Gly Gly Lys Pro Tyr Asp Gly Ile Pro Thr Arg Glu
                  915 920 925
          Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile
              930 935 940
          Cys Thr Ile Asp Val Tyr Met Val Met Val Lys Cys Trp Met Ile Asp
          945 950 955 960
          Ala Asp Ser Arg Pro Lys Phe Lys Glu Leu Ala Ala Glu Phe Ser Arg
                          965 970 975
          Met Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Asp Arg
                      980 985 990
          Met Lys Leu Pro Ser Pro Asn Asp Ser Lys Phe Phe Gln Asn Leu Leu
                  995 1000 1005
          Asp Glu Glu Asp Leu Glu Asp Met Met Asp Ala Glu Glu Tyr Leu Val
              1010 1015 1020
          Pro Gln Ala Phe Asn Ile Pro Pro Pro Ile Tyr Thr Ser Arg Ala Arg
          1025 1030 1035 1040
          Ile Asp Ser Asn Arg Ser Glu Ile Gly His Ser Pro Pro Pro Ala Tyr
                          1045 1050 1055
          Thr Pro Met Ser Gly Asn Gln Phe Val Tyr Arg Asp Gly Gly Phe Ala
                      1060 1065 1070
          Ala Glu Gln Gly Val Ser Val Pro Tyr Arg Ala Pro Thr Ser Thr Ile
                  1075 1080 1085
          Pro Glu Ala Pro Val Ala Gln Gly Ala Thr Ala Glu Ile Phe Asp Asp
              1090 1095 1100
          Ser Cys Cys Asn Gly Thr Leu Arg Lys Pro Val Ala Pro His Val Gln
          1105 1110 1115 1120
          Glu Asp Ser Ser Thr Gln Arg Tyr Ser Ala Asp Pro Thr Val Phe Ala
                          1125 1130 1135
          Pro Glu Arg Ser Pro Arg Gly Glu Leu Asp Glu Glu Gly Tyr Met Thr
                      1140 1145 1150
          Pro Met Arg Asp Lys Pro Lys Gln Glu Tyr Leu Asn Pro Val Glu Glu
                  1155 1160 1165
          Asn Pro Phe Val Ser Arg Arg Lys Asn Gly Asp Leu Gln Ala Leu Asp
              1170 1175 1180
          Asn Pro Glu Tyr His Asn Ala Ser Asn Gly Pro Pro Lys Ala Glu Asp
          1185 1190 1195 1200
          Glu Tyr Val Asn Glu Pro Leu Tyr Leu Asn Thr Phe Ala Asn Thr Leu
                          1205 1210 1215
          Gly Lys Ala Glu Tyr Leu Lys Asn Asn Ile Leu Ser Met Pro Glu Lys
                      1220 1225 1230
          Ala Lys Lys Ala Phe Asp Asn Pro Asp Tyr Trp Asn His Ser Leu Pro
                  1235 1240 1245
          Pro Arg Ser Thr Leu Gln His Pro Asp Tyr Leu Gln Glu Tyr Ser Thr
              1250 1255 1260
          Lys Tyr Phe Tyr Lys Gln Asn Gly Arg Ile Arg Pro Ile Val Ala Glu
          1265 1270 1275 1280
          Asn Pro Glu Tyr Leu Ser Glu Phe Ser Leu Lys Pro Gly Thr Val Leu
                          1285 1290 1295
          Pro Pro Pro Pro Tyr Arg His Arg Asn Thr Val Val
                      1300 1305
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 1283]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mature human HER4 (ErbB4) protein (minus signal peptide)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(625)]]>
           <![CDATA[ <223> Extracellular domain (ECD)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (1)...(163)]]>
           <![CDATA[ <223> ECD Domain I]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (164)...(308)]]>
           <![CDATA[ <223> ECD Domain II]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (309)...(477)]]>
           <![CDATA[ <223> ECD Domain III]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (478)...(625)]]>
           <![CDATA[ <223> ECD Domain IV]]>
           <![CDATA[ <400> 47]]>
          Gln Ser Val Cys Ala Gly Thr Glu Asn Lys Leu Ser Ser Leu Ser Asp
           1 5 10 15
          Leu Glu Gln Gln Tyr Arg Ala Leu Arg Lys Tyr Tyr Glu Asn Cys Glu
                      20 25 30
          Val Val Met Gly Asn Leu Glu Ile Thr Ser Ile Glu His Asn Arg Asp
                  35 40 45
          Leu Ser Phe Leu Arg Ser Val Arg Glu Val Thr Gly Tyr Val Leu Val
              50 55 60
          Ala Leu Asn Gln Phe Arg Tyr Leu Pro Leu Glu Asn Leu Arg Ile Ile
          65 70 75 80
          Arg Gly Thr Lys Leu Tyr Glu Asp Arg Tyr Ala Leu Ala Ile Phe Leu
                          85 90 95
          Asn Tyr Arg Lys Asp Gly Asn Phe Gly Leu Gln Glu Leu Gly Leu Lys
                      100 105 110
          Asn Leu Thr Glu Ile Leu Asn Gly Gly Val Tyr Val Asp Gln Asn Lys
                  115 120 125
          Phe Leu Cys Tyr Ala Asp Thr Ile His Trp Gln Asp Ile Val Arg Asn
              130 135 140
          Pro Trp Pro Ser Asn Leu Thr Leu Val Ser Thr Asn Gly Ser Ser Gly
          145 150 155 160
          Cys Gly Arg Cys His Lys Ser Cys Thr Gly Arg Cys Trp Gly Pro Thr
                          165 170 175
          Glu Asn His Cys Gln Thr Leu Thr Arg Thr Val Cys Ala Glu Gln Cys
                      180 185 190
          Asp Gly Arg Cys Tyr Gly Pro Tyr Val Ser Asp Cys Cys His Arg Glu
                  195 200 205
          Cys Ala Gly Gly Cys Ser Gly Pro Lys Asp Thr Asp Cys Phe Ala Cys
              210 215 220
          Met Asn Phe Asn Asp Ser Gly Ala Cys Val Thr Gln Cys Pro Gln Thr
          225 230 235 240
          Phe Val Tyr Asn Pro Thr Thr Phe Gln Leu Glu His Asn Phe Asn Ala
                          245 250 255
          Lys Tyr Thr Tyr Gly Ala Phe Cys Val Lys Lys Cys Pro His Asn Phe
                      260 265 270
          Val Val Asp Ser Ser Ser Cys Val Arg Ala Cys Pro Ser Ser Lys Met
                  275 280 285
          Glu Val Glu Glu Asn Gly Ile Lys Met Cys Lys Pro Cys Thr Asp Ile
              290 295 300
          Cys Pro Lys Ala Cys Asp Gly Ile Gly Thr Gly Ser Leu Met Ser Ala
          305 310 315 320
          Gln Thr Val Asp Ser Ser Asn Ile Asp Lys Phe Ile Asn Cys Thr Lys
                          325 330 335
          Ile Asn Gly Asn Leu Ile Phe Leu Val Thr Gly Ile His Gly Asp Pro
                      340 345 350
          Tyr Asn Ala Ile Glu Ala Ile Asp Pro Glu Lys Leu Asn Val Phe Arg
                  355 360 365
          Thr Val Arg Glu Ile Thr Gly Phe Leu Asn Ile Gln Ser Trp Pro Pro
              370 375 380
          Asn Met Thr Asp Phe Ser Val Phe Ser Asn Leu Val Thr Ile Gly Gly
          385 390 395 400
          Arg Val Leu Tyr Ser Gly Leu Ser Leu Leu Ile Leu Lys Gln Gln Gly
                          405 410 415
          Ile Thr Ser Leu Gln Phe Gln Ser Leu Lys Glu Ile Ser Ala Gly Asn
                      420 425 430
          Ile Tyr Ile Thr Asp Asn Ser Asn Leu Cys Tyr Tyr His Thr Ile Asn
                  435 440 445
          Trp Thr Thr Leu Phe Ser Thr Ile Asn Gln Arg Ile Val Ile Arg Asp
              450 455 460
          Asn Arg Lys Ala Glu Asn Cys Thr Ala Glu Gly Met Val Cys Asn His
          465 470 475 480
          Leu Cys Ser Ser Asp Gly Cys Trp Gly Pro Gly Pro Asp Gln Cys Leu
                          485 490 495
          Ser Cys Arg Arg Phe Ser Arg Gly Arg Ile Cys Ile Glu Ser Cys Asn
                      500 505 510
          Leu Tyr Asp Gly Glu Phe Arg Glu Phe Glu Asn Gly Ser Ile Cys Val
                  515 520 525
          Glu Cys Asp Pro Gln Cys Glu Lys Met Glu Asp Gly Leu Leu Thr Cys
              530 535 540
          His Gly Pro Gly Pro Asp Asn Cys Thr Lys Cys Ser His Phe Lys Asp
          545 550 555 560
          Gly Pro Asn Cys Val Glu Lys Cys Pro Asp Gly Leu Gln Gly Ala Asn
                          565 570 575
          Ser Phe Ile Phe Lys Tyr Ala Asp Pro Asp Arg Glu Cys His Pro Cys
                      580 585 590
          His Pro Asn Cys Thr Gln Gly Cys Asn Gly Pro Thr Ser His Asp Cys
                  595 600 605
          Ile Tyr Tyr Pro Trp Thr Gly His Ser Thr Leu Pro Gln His Ala Arg
              610 615 620
          Thr Pro Leu Ile Ala Ala Gly Val Ile Gly Gly Leu Phe Ile Leu Val
          625 630 635 640
          Ile Val Gly Leu Thr Phe Ala Val Tyr Val Arg Arg Lys Ser Ile Lys
                          645 650 655
          Lys Lys Arg Ala Leu Arg Arg Phe Leu Glu Thr Glu Leu Val Glu Pro
                      660 665 670
          Leu Thr Pro Ser Gly Thr Ala Pro Asn Gln Ala Gln Leu Arg Ile Leu
                  675 680 685
          Lys Glu Thr Glu Leu Lys Arg Val Lys Val Leu Gly Ser Gly Ala Phe
              690 695 700
          Gly Thr Val Tyr Lys Gly Ile Trp Val Pro Glu Gly Glu Thr Val Lys
          705 710 715 720
          Ile Pro Val Ala Ile Lys Ile Leu Asn Glu Thr Thr Gly Pro Lys Ala
                          725 730 735
          Asn Val Glu Phe Met Asp Glu Ala Leu Ile Met Ala Ser Met Asp His
                      740 745 750
          Pro His Leu Val Arg Leu Leu Gly Val Cys Leu Ser Pro Thr Ile Gln
                  755 760 765
          Leu Val Thr Gln Leu Met Pro His Gly Cys Leu Leu Glu Tyr Val His
              770 775 780
          Glu His Lys Asp Asn Ile Gly Ser Gln Leu Leu Leu Asn Trp Cys Val
          785 790 795 800
          Gln Ile Ala Lys Gly Met Met Tyr Leu Glu Glu Arg Arg Leu Val His
                          805 810 815
          Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Ser Pro Asn His Val
                      820 825 830
          Lys Ile Thr Asp Phe Gly Leu Ala Arg Leu Leu Glu Gly Asp Glu Lys
                  835 840 845
          Glu Tyr Asn Ala Asp Gly Gly Lys Met Pro Ile Lys Trp Met Ala Leu
              850 855 860
          Glu Cys Ile His Tyr Arg Lys Phe Thr His Gln Ser Asp Val Trp Ser
          865 870 875 880
          Tyr Gly Val Thr Ile Trp Glu Leu Met Thr Phe Gly Gly Lys Pro Tyr
                          885 890 895
          Asp Gly Ile Pro Thr Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu
                      900 905 910
          Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr Met Val Met
                  915 920 925
          Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys Phe Lys Glu
              930 935 940
          Leu Ala Ala Glu Phe Ser Arg Met Ala Arg Asp Pro Gln Arg Tyr Leu
          945 950 955 960
          Val Ile Gln Gly Asp Asp Arg Met Lys Leu Pro Ser Pro Asn Asp Ser
                          965 970 975
          Lys Phe Phe Gln Asn Leu Leu Asp Glu Glu Asp Leu Glu Asp Met Met
                      980 985 990
          Asp Ala Glu Glu Tyr Leu Val Pro Gln Ala Phe Asn Ile Pro Pro Pro
                  995 1000 1005
          Ile Tyr Thr Ser Arg Ala Arg Ile Asp Ser Asn Arg Ser Glu Ile Gly
              1010 1015 1020
          His Ser Pro Pro Pro Ala Tyr Thr Pro Met Ser Gly Asn Gln Phe Val
          1025 1030 1035 1040
          Tyr Arg Asp Gly Gly Phe Ala Ala Glu Gln Gly Val Ser Val Pro Tyr
                          1045 1050 1055
          Arg Ala Pro Thr Ser Thr Ile Pro Glu Ala Pro Val Ala Gln Gly Ala
                      1060 1065 1070
          Thr Ala Glu Ile Phe Asp Asp Ser Cys Cys Asn Gly Thr Leu Arg Lys
                  1075 1080 1085
          Pro Val Ala Pro His Val Gln Glu Asp Ser Ser Thr Gln Arg Tyr Ser
              1090 1095 1100
          Ala Asp Pro Thr Val Phe Ala Pro Glu Arg Ser Pro Arg Gly Glu Leu
          1105 1110 1115 1120
          Asp Glu Glu Gly Tyr Met Thr Pro Met Arg Asp Lys Pro Lys Gln Glu
                          1125 1130 1135
          Tyr Leu Asn Pro Val Glu Glu Asn Pro Phe Val Ser Arg Arg Lys Asn
                      1140 1145 1150
          Gly Asp Leu Gln Ala Leu Asp Asn Pro Glu Tyr His Asn Ala Ser Asn
                  1155 1160 1165
          Gly Pro Pro Lys Ala Glu Asp Glu Tyr Val Asn Glu Pro Leu Tyr Leu
              1170 1175 1180
          Asn Thr Phe Ala Asn Thr Leu Gly Lys Ala Glu Tyr Leu Lys Asn Asn
          1185 1190 1195 1200
          Ile Leu Ser Met Pro Glu Lys Ala Lys Lys Ala Phe Asp Asn Pro Asp
                          1205 1210 1215
          Tyr Trp Asn His Ser Leu Pro Pro Arg Ser Thr Leu Gln His Pro Asp
                      1220 1225 1230
          Tyr Leu Gln Glu Tyr Ser Thr Lys Tyr Phe Tyr Lys Gln Asn Gly Arg
                  1235 1240 1245
          Ile Arg Pro Ile Val Ala Glu Asn Pro Glu Tyr Leu Ser Glu Phe Ser
              1250 1255 1260
          Leu Lys Pro Gly Thr Val Leu Pro Pro Pro Pro Tyr Arg His Arg Asn
          1265 1270 1275 1280
          Thr Val Val
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Cyclic FcRnBP]]>
           <![CDATA[ <400> 48]]>
          Gln Arg Phe Cys Thr Gly His Phe Gly Gly Leu Tyr Pro Cys Asn Gly
           1 5 10 15
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Cyclic FcRnBP]]>
           <![CDATA[ <400> 49]]>
          Gln Arg Phe Cys Thr Gly His Phe Gly Gly Leu His Pro Cys Asn Gly
           1 5 10 15
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Linear FcRnBP]]>
           <![CDATA[ <400> 50]]>
          Gln Arg Phe Val Thr Gly His Phe Gly Gly Leu Tyr Pro Ala Asn Gly
           1 5 10 15
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Linear FcRnBP]]>
           <![CDATA[ <400> 51]]>
          Gln Arg Phe Val Thr Gly His Phe Gly Gly Leu His Pro Ala Asn Gly
           1 5 10 15
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM7h-11-3 (albumin-binding dAb)]]>
           <![CDATA[ <400> 52]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Pro Ile Gly Thr Thr
                      20 25 30
          Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Leu Trp Asn Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Ala Gly Thr His Pro Thr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1m-21-23 (mouse anti-TNFR1 dAb from DMS5540)]]>
           <![CDATA[ <400> 53]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr
                      20 25 30
          Ser Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Arg Ile Asp Ser Tyr Gly Arg Gly Thr Tyr Tyr Glu Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Gln Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208 (human anti-TNFR1 dAb from DMS5541)]]>
           <![CDATA[ <400> 54]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GSK1995057 (anti-TNFR1 antagonist dAb)]]>
           <![CDATA[ <400> 55]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GSK2862277 (anti-TNFR1 antagonist dAb)]]>
           <![CDATA[ <400> 56]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ala
                  115 120
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 57]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 58]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 59]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 60]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-1]]>
           <![CDATA[ <400> 61]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-2]]>
           <![CDATA[ <400> 62]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-3]]>
           <![CDATA[ <400> 63]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-201 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 64]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-5]]>
           <![CDATA[ <400> 65]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-6]]>
           <![CDATA[ <400> 66]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Ala Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-7]]>
           <![CDATA[ <400> 67]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Ala Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-202 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 68]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-203 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 69]]>
          Glu Val Gln Leu Trp Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Ile Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-204 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 70]]>
          Glu Val Gln Leu Ser Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Asn Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-205 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 71]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Gln Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-12]]>
           <![CDATA[ <400> 72]]>
          Glu Val Arg Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Gln Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-13]]>
           <![CDATA[ <400> 73]]>
          Glu Val Arg Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Ser Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Gly Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-14]]>
           <![CDATA[ <400> 74]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-15]]>
           <![CDATA[ <400> 75]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-18]]>
           <![CDATA[ <400> 76]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-19]]>
           <![CDATA[ <400> 77]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-20]]>
           <![CDATA[ <400> 78]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Ser Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-21]]>
           <![CDATA[ <400> 79]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Lys Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-22]]>
           <![CDATA[ <400> 80]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Arg Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-23]]>
           <![CDATA[ <400> 81]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Gln Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-24]]>
           <![CDATA[ <400> 82]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Lys Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-511 anti-TNFR1 dAb variant 1-25]]>
           <![CDATA[ <400> 83]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Ala Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Codon optimized sequence of DOM1h-131-206 anti-TNFR1 dAb 1]]>
           <![CDATA[ <400> 84]]>
          gaggttcaat tgttggaatc cggtggtgga ttggttcaac ctggtggttc tttgagattg 60
          tcctgtgctg cttccggttt tactttcgct cacgagacta tggtttgggt tagacaggct 120
          ccaggtaaag gattggaatg ggtttcccac attccaccag atggtcaaga tccattctac 180
          gctgactccg ttaagggaag attcactatc tccagagaca actccaagaa cactttgtac 240
          ttgcagatga actccttgag agctgaggat actgctgttt accactgtgc tttgttgcca 300
          aagagaggac cttggtttga ttactgggga cagggaactt tggttatactgt ttcttcc 357
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 366]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Codon optimized sequence of DOM1h-131-206 anti-TNFR1 dAb 2]]>
           <![CDATA[ <400> 85]]>
          gagaaaagag aggttcaatt gcttgaatct ggaggaggtt tggtccagcc aggagggtcc 60
          cttcgactaa gttgtgctgc cagtgggttt acgtttgctc atgaaactat ggtatgggtc 120
          cgacaggcac ctggtaaagg tcttgaatgg gtttcacata tccctccaga cggtcaagac 180
          ccattttacg ctgattccgt gaaaggcaga tttacaattt cacgagataa ttctaaaaac 240
          accttgtact tacaaatgaa ctcattgaga gctgaggaca ctgcagttta tcactgcgct 300
          ttactaccaa aacgtggacc ttggtttgat tattggggcc aaggtacgtt agtgactgtt 360
          agttct 366
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Codon optimized sequence of DOM1h-131-206 anti-TNFR1 dAb 3]]>
           <![CDATA[ <400> 86]]>
          gaagtgcagc ttcttgaaag tggtggaggg ctagtgcagc cagggggatc tttaagatta 60
          tcatgcgctg ccagtggatt tacttttgct cacgagacga tggtctgggt gagacaagct 120
          cctggaaaag gtttagagtg ggtttctcac attccacctg atggtcaaga tcctttctac 180
          gcagattccg tcaaaggaag atttactatc tccagagata atagtaaaaa cactttgtac 240
          ctacagatga actcacttag agccgaagat accgctgtgt accactgcgc cttgttgcca 300
          aagagaggtc cttggttcga ttactggggt cagggtactc tggttacagt ctcatct 357
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Codon optimized sequence of DOM1h-131-206 anti-TNFR1 dAb 4]]>
           <![CDATA[ <400> 87]]>
          gaggttcaac tgctggaatc tggtggtggt ctggtacaac cgggtggttc cctgcgtctg 60
          agctgtgcag cctctggttt caccttcgct catgagacca tggtttgggt acgccaggct 120
          ccgggtaaag gcctggagtg ggtaagccat atccctcctg atggtcagga cccgttctat 180
          gctgattccg tcaaaggccg ttttaccatt tctcgtgaca acagcaaaaa cactctgtac 240
          ctgcaaatga actccctgcg tgcagaagac acggcggttt atcactgtgc actgctgcca 300
          aaacgcggcc cttggttcga ctactggggc cagggtactc tggtcactgt atcttct 357
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Codon optimized sequence of DOM1h-131-206 anti-TNFR1 dAb 5]]>
           <![CDATA[ <400> 88]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 89]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-12 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 90]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Ala Tyr
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Met Tyr Gly Ala Lys Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Cys Leu Met Asp Cys Ser Gly Asp Ile Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-13 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 91]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Ala Asp
                      20 25 30
          Glu Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Gly Trp Pro Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Gly Arg Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-14 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 92]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Gln Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Pro Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Val Phe Ser Asp Trp Pro Ala Val Glu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-16 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 93]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr
                      20 25 30
          Asp Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Gly Thr Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gln Glu Thr Asn Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-17 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 94]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Gly Tyr
                      20 25 30
          Gln Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Phe Thr Gly Ala His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Ser Asp Asp Leu Thr Leu Pro Glu Arg Phe Pro Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-18 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 95]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr
                      20 25 30
          Asn Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Trp Ile Asp Gln Glu Gly Val Phe Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Phe Ser Ala Ala Val Met Leu Arg Thr Ser Phe Asp Tyr
                      100 105 110
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-19 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 96]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe His Asp Tyr
                      20 25 30
          Gly Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Ile Asp Gly Arg Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Ile Phe Glu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-20 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 97]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr
                      20 25 30
          Asn Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Ser Gly Asn Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Ala Gly Glu Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-21 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 98]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Glu Tyr
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Gly His Ser Gly Gln His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Leu Asn Asn Leu Met Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-22 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 99]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Glu Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Gln Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Thr Gly Gly His Val Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ser Val Arg Phe Arg Ser Ser Ile Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-23 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 100]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
                      20 25 30
          Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Trp Ile Ala Val Asp Gly Ile His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Asp Trp Thr Ala Thr Asp Phe Ser Ile Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 101]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-24 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 101]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asn Tyr
                      20 25 30
          Thr Met Leu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Val Ile Ser Ala Glu Gly Arg Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Asn Met Lys Ala Thr Asn Phe Lys Asp Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-25 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 102]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Glu Tyr
                      20 25 30
          Ala Met Leu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Arg Thr Gly Val Ile Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Asp Tyr Gln Tyr His Leu Tyr Gln Asp Phe Asp Tyr Arg
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-26 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 103]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Thr Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Pro Glu Gly Tyr His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Thr Asn Arg Pro Leu Thr Tyr Lys Pro Trp Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 104]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-27 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 104]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Gln Glu Gly His His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ser Thr Ile Ala Thr Leu Ser Leu Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 105]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-29 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 105]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Thr Tyr
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ala Trp Leu Gly Ser Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys His Cys Lys Ala Glu Cys Thr Gly Asp Leu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 106]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-30 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 106]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ala Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ile Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Gly Val Gly Met Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys His Ser Tyr Pro Thr Arg Gly Arg His Leu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 107]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-32 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 107]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 108]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-33 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 108]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe His Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ser Thr Gln Ala Gln Gly Leu Glu Leu Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 109]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-1 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 109]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 110]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-2 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 110]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 111]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-3 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 111]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 112]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-4 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 112]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 113]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-5 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 113]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 114]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-6 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 114]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 115]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-7 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 115]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Lys Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 116]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-8 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 116]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 117]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-9 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 117]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 118]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-10 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 118]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Asp Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 119]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-11 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 119]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 120]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-12 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 120]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ala
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 121]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-13 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 121]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gly Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 122]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-14 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 122]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Xaa Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 123]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-15 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 123]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Arg
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 124]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-16 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 124]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Lys Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 125]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-17 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 125]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Gly Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 126]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-18 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 126]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ala
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 127]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-19 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 127]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gly Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Lys Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 128]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-20 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 128]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ala
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Lys Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 129]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-21 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 129]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Lys Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 130]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-22 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 130]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gly Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Asp Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 131]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-27 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 131]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 132]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-29 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 132]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 133]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-31 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 133]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 134]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-35 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 134]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu His Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 135]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-36 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 135]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 136]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-37 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 136]]>
          Glu Val Gln Leu Leu Gly Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 137]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-38 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 137]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Lys Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 138]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-45 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 138]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Pro Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 139]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-47 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 139]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Phe Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ser Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 140]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-48 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 140]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Pro Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 141]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-57 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 141]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 142]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-56 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 142]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Val Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 143]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-58 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 143]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 144]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-66 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 144]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Met Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Asn Arg Gly Leu
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 145]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-64 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 145]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ala
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asp Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 146]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-65 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 146]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Gly Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Glu Leu Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 147]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-68 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 147]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Asn Arg Gly Gln
                      100 105 110
          Gly Thr Pro Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 148]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-69 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 148]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Pro Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 149]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-67 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 149]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Asn Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 150]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-61 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 150]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 151]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-62 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 151]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 152]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-63 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 152]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Thr Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 153]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-60 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 153]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 154]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-55 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 154]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Gln Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 155]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-59 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 155]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 156]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-10-70 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 156]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Gly Pro Asn Tyr Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 157]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 157]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Leu Tyr
                      20 25 30
          Asn Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Gln Thr Gly Arg Leu Thr Trp Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Leu Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 158]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-34 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 158]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Glu Tyr
                      20 25 30
          Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Thr Ile Ser His Gly Gly Glu His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gln His Pro Val Ser His Pro Lys Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 159]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-35 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 159]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Ala Tyr
                      20 25 30
          Asn Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Ser Gly Arg Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Tyr Pro Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 160]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-36 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 160]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Arg Pro Gly Asn His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Trp Gly Leu Asn Val Glu Asp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 161]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-37 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 161]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ile Glu Tyr
                      20 25 30
          Asp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Ser Ser Asp Gly Arg Leu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Trp Asp Gly Leu Asn Arg Asn Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 162]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-38 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 162]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ile Gly Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Pro Ser Gly Arg Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Leu Ser Ala Asp Gly Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 163]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-39 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 163]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr
                      20 25 30
          Asp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Val Ser Gly Thr Leu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Val Glu Leu Asp Gly Leu Asp Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 164]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-40 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 164]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr
                      20 25 30
          Asp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Ser Ser Gly Ser Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Ala Glu Ile Val Asn Ser Arg Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 165]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-41 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 165]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Gln Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Ser Asn Gly His His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Leu Asp Asn Leu Ser Ile Thr Pro Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 166]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-42 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 166]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Lys Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Lys Gly Gln His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Gly Met Gly Ser Asp Ala Ile Thr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 167]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-43 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 167]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Thr Met Gly Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Ser Asp Gly Leu His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gln Asn Pro Gln Tyr Ala Tyr Glu Ser Ser Arg Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 168]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-44 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 168]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Gln Tyr
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Leu Ala Pro Gly Gly Pro Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys His Pro Thr His Thr Pro His Pro Asn Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 169]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-45 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 169]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Gly Tyr
                      20 25 30
          Arg Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Ser Glu Gly Val Leu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Cys Ser Ser Asn Cys Asn Met Arg Asn Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 170]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-47 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 170]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Val Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ala Gly Asn Gly Gln Gln Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ala Ser Lys Val Ser Pro Met Ser Leu Thr Asp Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 171]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-48 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 171]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe His Lys Tyr
                      20 25 30
          Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Leu Ala Gly Leu His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ala Thr Tyr Ser Ser Gly Asn Glu Glu Gln Pro Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 172]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-50 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 172]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ala Gln Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ser His Pro Asp Glu Glu Gly Thr Gln Met Phe Asp Tyr
                      100 105 110
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 173]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-51 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 173]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Thr Tyr
                      20 25 30
          Asn Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Asp Ala Gly Gly Met His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Thr Glu Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 174]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-66 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (33)...(33)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 174]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Glu Tyr
                      20 25 30
          Xaa Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Ser Pro Arg Gly Ser Lys Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Lys Pro Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 175]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-67 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 175]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Asp Tyr
                      20 25 30
          Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Gly Leu Lys Gly Ile His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Leu Asn Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 176]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-68 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 176]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Gly
                      20 25 30
          Asn Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Glu Tyr Gly Thr Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Arg Asn Asp Arg Pro Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 177]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-70 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 177]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Thr Glu
                      20 25 30
          His Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Asp Thr Gly Gly Ser His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Leu His Trp Ser Ser Asp Ser Gly Pro Val His Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 178]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-71 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 178]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Val
                      20 25 30
          Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Ser Ala Gly Gly Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Met Leu Ala Asn Ser Pro Leu Ala Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 179]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-72 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 179]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Tyr Glu
                      20 25 30
          Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Thr Ile Ser His Thr Gly Arg Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Trp Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 180]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-73 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 180]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Ser Glu
                      20 25 30
          Lys Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Glu Arg Gly Ile Met Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Trp Thr Phe Asn Thr Ala Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 181]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-74 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 181]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Glu
                      20 25 30
          Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Gly Pro Arg Gly Met Pro Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Met Asn Ser His Asp Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 182]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-75 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 182]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ala Tyr
                      20 25 30
          Thr Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Tyr Ile Asp Pro His Gly Thr Ile Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Arg Ala Ala Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 183]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-76 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 183]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Ala Ser
                      20 25 30
          Glu Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Ser Gly Ser Ala Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Trp Thr Pro Gly Arg Thr Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 184]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-77 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 184]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Thr Glu
                      20 25 30
          His Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Asp Thr Gly Gly Ser His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Leu His Trp Ser Ser Asp Ser Gly Pro Val His Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 185]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-78 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 185]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Leu Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ala Ala Ala Gly Pro Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Gly Asp Ile Ser Ser Ile Pro Gln His Pro Phe Asp Tyr
                      100 105 110
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 186]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-79 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 186]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Val
                      20 25 30
          Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Ser Ala Gly Gly Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ser Ala Asp Ile Thr Lys Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 187]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-15 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 187]]>
          Glu Val Arg Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
                      20 25 30
          Thr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Ser Asp Asp Gly Asn Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Pro Ile Leu Ala Pro Arg Asn Leu Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 188]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-131-8 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 188]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 189]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-131-24 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 189]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 190]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-15-8 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 190]]>
          Glu Val Arg Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Gly Lys Ser
                      20 25 30
          Thr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Ser Asp Asp Gly Asn Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Pro Ile Leu Ala Pro Arg Asn Leu Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 191]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-15-8-1 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 191]]>
          Glu Val Arg Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Asn Phe Gly Lys Ser
                      20 25 30
          Thr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Ser Asp Asp Gly Asn Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Pro Ile Leu Ala Pro Arg Asn Leu Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 192]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-15-8-2 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 192]]>
          Glu Val Arg Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Gly Lys Gly
                      20 25 30
          Thr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Ser Asp Asp Gly Asn Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Pro Ile Leu Ala Pro Arg Asn Leu Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 193]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-185-23 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (62)...(62)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 193]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Arg Tyr
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Pro Ser Gly Gly His Thr Tyr Tyr Ala Xaa Ser Val
              50 55 60
          Lys Gly Arg Ser Thr Ile Ser Arg Asn Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Gly Lys Pro Val Phe Ser Asp Trp Pro Ala Val Glu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 194]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-154-10-5 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 194]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Thr Phe Glu His Glu
                      20 25 30
          Gly Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Gly Glu Asp Gly Gln Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ser Ile Pro Lys Ala Gly Pro Ser Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 195]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-14-2 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 195]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Asp Gln Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Pro Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Thr Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Val Phe Ser Asp Trp Pro Ala Val Glu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 196]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-151-8 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 196]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Tyr Gly
                      20 25 30
          Asn Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Met Thr Thr Asp Ser Pro Pro Gly Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 197]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-152-7 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 197]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Lys Glu
                      20 25 30
          Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Trp Ile Ser Pro His Gly Ala His Thr Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Arg Phe Ser Tyr Tyr Pro Arg Val Ser Phe Asp Tyr Arg
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 198]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-35-4 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 198]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Ala Tyr
                      20 25 30
          Asn Met Phe Trp Phe Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Ala Ile Gly Pro Ser Gly Arg Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Tyr Pro Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 199]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-154-7 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 199]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu His Glu
                      20 25 30
          Gly Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Gly Glu Asp Gly Gln Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Asn Ile Pro Lys Ala Gly Pro Ser Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 200]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-80 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 200]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Leu Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ala Ala Ala Gly Pro Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Gly Asp Ile Ser Ser Ile Pro Gln His Pro Phe Asp Tyr
                      100 105 110
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 201]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-81 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 201]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Glu
                      20 25 30
          Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Gly Pro Arg Gly Met Pro Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Met Asn Ser His Asp Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 202]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-82 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 202]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Ala Ser
                      20 25 30
          Glu Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Ser Gly Ser Ala Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Met Leu Ala Asn Ser Pro Leu Ala Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 203]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-83 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 203]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ala Gln Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ser His Pro Asp Glu Glu Gly Thr Gln Met Phe Asp Tyr
                      100 105 110
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 204]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-84 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 204]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr
                      20 25 30
          Gln Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Arg Ile Asp Arg Gly Gly Phe His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Ser Trp His Ala Asp Gln Tyr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 205]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-85 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 205]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Asp Tyr
                      20 25 30
          Asn Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ala Thr Ser Gly Arg Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Thr Phe Gly Gly Asn Gln Asp Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 206]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-86 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 206]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Lys Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Lys Gly Gln His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Gly Met Gly Ser Asp Ala Ile Thr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 207]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-87 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 207]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ala Gln Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ser His Pro Asp Glu Glu Gly Thr Gln Met Phe Asp Tyr
                      100 105 110
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 208]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-88 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 208]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Arg Tyr
                      20 25 30
          Asp Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Ser Pro Arg Gly Arg Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Met Ile Asn Tyr His Gly Thr Pro Ser Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 209]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-89 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 209]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Asn Tyr
                      20 25 30
          Asn Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Trp Ile Ser Gly Ala Gly His Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Val Asp Met Ala Gly Lys Leu Asn Val Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 210]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-90 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 210]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Gln Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Pro Ser Gly Gly Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Val Asp Met Ala Gly Lys Leu Asn Val Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 211]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-91 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 211]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr
                      20 25 30
          Gln Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Arg Ile Asp Arg Gly Gly Phe His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Ser Trp His Ala Asp Gln Tyr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 212]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-92 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 212]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Val
                      20 25 30
          Asn Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Gly Pro Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys His Ser Lys Thr Gly Ser Ala Met Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 213]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-93 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 213]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Gly
                      20 25 30
          Asn Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Glu Tyr Gly Thr Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Arg Asn Asp Arg Pro Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 214]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-94 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 214]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Glu
                      20 25 30
          Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Gly Pro Arg Gly Met Pro Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Met Asn Ser His Asp Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 215]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-95 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 215]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Gly Ser
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Gly Arg Gly Gln His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Ser Val Arg Glu Phe Asp Tyr Arg Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 216]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-96 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 216]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Glu
                      20 25 30
          Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Gly Pro Arg Gly Met Pro Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Met Leu Ala Asn Ser Pro Leu Ala Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 217]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-97 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 217]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Glu Ser
                      20 25 30
          Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Val Ile Thr Ala Gln Gly Gly Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Asp Val Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 218]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-99 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 218]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Glu Tyr
                      20 25 30
          Asn Met Leu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Gly Pro Ser Gly Arg Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Ser Ile Thr Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 219]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-100 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 219]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Asp Ala Tyr Gly Thr His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Gly Leu Gln Thr Ser Asp His Gly Glu Arg Ile Ser Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 220]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-101 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 220]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Gln Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Pro Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Val Phe Ser Asp Trp Pro Ala Val Glu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 221]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-102 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 221]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Gln Tyr
                      20 25 30
          Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Pro Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Val Phe Ser Asp Trp Pro Ala Val Glu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 222]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-103 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 222]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Val Pro Gly Leu His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 223]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-104 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (62)...(62)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (104)...(104)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 223]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Trp Tyr
                      20 25 30
          Trp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Xaa Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Lys Leu Gly Gly Xaa Pro Asn Phe Gly Tyr Arg Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 224]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-105 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 224]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Pro Pro Ser Val His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 225]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-106 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (62)...(62)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 225]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Val Gly Gly Ser His Thr Tyr Tyr Ala Xaa Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 226]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-107 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (62)...(62)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 226]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Thr Gly Gly Val His Thr Tyr Tyr Ala Xaa Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 227]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-108 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 227]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Val Pro Gly Arg His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 228]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-109 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 228]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Ala His Ala Gly Pro Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 229]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-110 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 229]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Thr Arg Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 230]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-111 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 230]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Val Pro Gly Asn His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 231]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-112 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 231]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Asp Val Gly Gly Arg His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Pro Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 232]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-113 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 232]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Arg Ile Asp Ser Tyr Gly Arg Gly Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Val Arg Ser Pro Tyr Thr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 233]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-114 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 233]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Thr Ile Ser Thr Gln Gly Tyr His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ala Phe Thr Ser Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 234]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-115 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 234]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Ser Gly Pro Gly Leu Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gln Gly Met Ser Lys Thr Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 235]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-116 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 235]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Glu Tyr
                      20 25 30
          Tyr Met Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Pro Asp Gly Ser Leu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Pro Arg Glu Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 236]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-117 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 236]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Gln Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Ser Asn Gly His His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gln Leu Ser Val Gln Gly Ser Asn Leu Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 237]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-118 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 237]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val His Tyr
                      20 25 30
          Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Trp Ile His Ser Asp Gly Val His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Thr Trp Gly Glu Lys Lys Thr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 238]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-119 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 238]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Met Gly Tyr
                      20 25 30
          Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Ser Ala Lys Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Ser Ser Gly Ser Asp Gly Leu Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 239]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-120 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 239]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Val Tyr
                      20 25 30
          Asn Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ala Gly Asn Gly Gln Gln Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ala Ser Lys Val Ser Pro Met Ser Leu Thr Asp Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 240]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-121 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 240]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Gln Tyr
                      20 25 30
          Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Ser Ser Gly Gly Met Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Ile Arg Asp Ser Thr Leu Pro Arg Gly Thr Leu Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 241]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-122 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 241]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Thr Tyr
                      20 25 30
          Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Leu Pro Gly Ser Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys His Ser Lys Ser Ser His Arg Gln Ser Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 242]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-123 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 242]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Gln Tyr
                      20 25 30
          Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Ser Phe Ser Gly Tyr Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Arg Gly Pro Ala Pro Met Arg Ser Leu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 243]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-124 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 243]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Thr Ser Met Gly Glu Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Thr His Phe Pro Ile Arg Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 244]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-125 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 244]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Gln Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Pro Ser Gly Gly Glu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ser Ile Lys Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 245]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-126 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 245]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr
                      20 25 30
          Ser Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Phe Asp Gly Leu His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Phe Ser Thr Ser Thr Met Ala Leu Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 246]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-127 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 246]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Glu Tyr
                      20 25 30
          Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Gly Thr Ala Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Tyr Arg Pro Arg Thr Gly Ser Met Leu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 247]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-128 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 247]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Lys Tyr
                      20 25 30
          Asn Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Lys Gly Gln Gln Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Gly Met Gly Ser Asp Ala Ile Thr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 248]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-129 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 248]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr
                      20 25 30
          Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Arg Lys Gly His His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Thr Asp Ile Gln Arg Leu Asn Ser Ala Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 249]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-130 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 249]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Gly
                      20 25 30
          Val Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asn Glu Asn Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Ser Ile Glu Ser Pro Ile Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 250]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-131 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 250]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 251]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-132 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 251]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Glu Ser
                      20 25 30
          Val Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Pro Gly Gly Ser Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Thr Gly Pro Pro Gly Ser Thr Val Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 252]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-133 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 252]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asp Glu
                      20 25 30
          Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Gly Lys Glu Gly Gln Pro Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Gly Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 253]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-151 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 253]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Tyr Gly
                      20 25 30
          Asn Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Met Thr Thr Asp Ser Pro Pro Gly Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 254]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-152 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 254]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Lys Glu
                      20 25 30
          Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Trp Ile Ser Pro His Gly Ala Leu Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Arg Phe Ser Tyr Tyr Pro Arg Val Ser Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 255]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-153 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 255]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Gly
                      20 25 30
          Asn Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Glu Tyr Gly Thr Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Arg Asn Asp Arg Pro Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 256]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-154 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (53)...(53)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 256]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Gly
                      20 25 30
          Asn Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Xaa Tyr Gly Thr Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Arg Asn Asp Arg Pro Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 257]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-159 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 257]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Gly Gln
                      20 25 30
          Asp Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Pro Ser Ser Gly Phe Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Ala Lys Asp Arg Ser Val Ser Gln Met Pro Tyr Phe Asp
                      100 105 110
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 258]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-165 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 258]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Met Arg Pro
                      20 25 30
          Asp Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Thr Ile Lys Asp Trp Gly Asp Gln Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ala Asp Ser Arg Ala Gln Leu Asp Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 259]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-166 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 259]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Tyr Phe Leu Phe Arg Ala Thr Ser Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 260]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-168 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 260]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe His Asp Asp
                      20 25 30
          Asp Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Pro Gly Asn Gly Tyr Val Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Pro Asp Pro Thr Ser Val Phe Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 261]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-171 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 261]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asp Asp
                      20 25 30
          Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Ala Ala Tyr Gly Ile Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Ser Gly Lys Val Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser Ser
                  115
           <![CDATA[ <210> 262]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-172 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 262]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Glu Arg
                      20 25 30
          Pro Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Gly Ala Asp Gly Leu Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Phe Arg Pro Gly Leu Leu Trp Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 263]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-173 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 263]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Gly Gln
                      20 25 30
          Asp Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Asn Ala Asp Gly Met Ala Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Ser Pro Thr Met Arg Ser Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 264]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-174 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 264]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Glu Glu
                      20 25 30
          Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Pro His Thr Gly Asn Pro Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Ala Asn Ser Leu Leu Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 265]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-176 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 265]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe His Arg Cys
                      20 25 30
          Lys Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Glu Tyr Asp Gly Arg Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Glu Cys Thr Arg Pro Tyr Gly Met Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 266]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-178 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 266]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr
                      20 25 30
          Ser Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Lys Val Gly His His Thr Trp Tyr Glu Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Pro Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Gln Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 267]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-201 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (101)...(101)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 267]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Ala His Ala Gly Pro Glu Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Xaa Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 268]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-202 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 268]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Pro Pro Ser Val His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Asn Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 269]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-203 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (96)...(96)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 269]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Asp Pro Pro Ser Val His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Xaa
                          85 90 95
          Ala Glu Ile Ser Gln Phe Gly Ser Asn Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 270]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-204 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 270]]>
          Glu Val Gln Leu Phe Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Arg Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Met Ile Ala His Ala Gly Pro Glu Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Ser Gln Phe Gly Ser Asn Ala Leu Asp Tyr Trp Gly Arg
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 271]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-185-25 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 271]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Arg Tyr
                      20 25 30
          Asn Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Leu Ile Asp Pro Ser Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Gly Lys Pro Val Phe Ser Asp Trp Pro Ala Val Glu Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Val Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 272]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-154-10 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 272]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu His Glu
                      20 25 30
          Gly Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Gly Glu Asp Gly Gln Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Asn Ile Pro Lys Ala Gly Pro Ser Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 273]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-205 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 273]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 274]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d1 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 274]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Val Tyr
                      20 25 30
          Met Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Ala Leu Gly Gly Arg Thr Gly Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Met Ser Asn Lys Thr His Thr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 275]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d2 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 275]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Ala Tyr
                      20 25 30
          Asn Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asn Thr Phe Gly Asn Thr Arg Tyr Ala Asp Ser Val Lys
              50 55 60
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
          65 70 75 80
          Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys Gly Ser Arg Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
                      100 105 110
          Val Ser
           <![CDATA[ <210> 276]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d3 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 276]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Tyr Arg
                      20 25 30
          Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
                  35 40 45
          Trp Ile Thr Arg Thr Gly Gly Thr Thr Gln Tyr Ala Asp Ser Val Lys
              50 55 60
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
          65 70 75 80
          Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys Pro Ala Lys Leu Val Gly Val Gly Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 277]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d4 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 277]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Lys Tyr
                      20 25 30
          Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
                  35 40 45
          Gln Ile Gly Ala Lys Gly Gln Ser Thr Asp Tyr Ala Asp Ser Val Lys
              50 55 60
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
          65 70 75 80
          Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys Lys Lys Arg Gly Glu Asn Tyr Phe Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 278]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d5 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 278]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Arg Tyr
                      20 25 30
          Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Asp Ile Ser Arg Ser Gly Arg Tyr Thr His Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Ile Asp Ser Ser Gln Asn Gly Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 279]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d6 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 279]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Tyr Lys
                      20 25 30
          Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
                  35 40 45
          Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
              50 55 60
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
          65 70 75 80
          Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys Gln Lys Glu Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
                      100 105 110
          Val Ser
           <![CDATA[ <210> 280]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d7 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 280]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asp Tyr
                      20 25 30
          Ala Met Trp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Val Ile Ser Ser Asn Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Val Arg Lys Arg Thr Pro Glu Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 281]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d8 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 281]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Arg Tyr
                      20 25 30
          Lys Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Gly Arg Asn Gly Thr Lys Thr Asn Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Tyr Thr Gly Lys Pro Ala Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 282]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d9 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 282]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Lys Tyr
                      20 25 30
          Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
                  35 40 45
          Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
              50 55 60
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
          65 70 75 80
          Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys Met Leu Arg Thr Lys Asn Lys Val Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 283]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d10 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 283]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Arg Tyr
                      20 25 30
          Lys Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Gly Arg Asn Gly Thr Lys Thr Asn Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ile Tyr Thr Gly Lys Pro Ala Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 284]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d11 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 284]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Arg
                      20 25 30
          Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
                  35 40 45
          Ser Ile Ser Ser Arg Gly Arg His Thr Ser Tyr Ala Asp Ser Val Lys
              50 55 60
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
          65 70 75 80
          Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys Arg Val Pro Gly Arg Gly Arg Ser Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 285]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d12 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 285]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Arg Arg Tyr
                      20 25 30
          Arg Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Ile Ser Pro Gly Gly Lys His Thr Thr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Glu Gly Gly Ala Ser Ser Ala Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 286]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d13 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 286]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Tyr Gly
                      20 25 30
          Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
                  35 40 45
          Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
              50 55 60
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
          65 70 75 80
          Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys Arg His Ser Ser Glu Ala Arg Gln Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 287]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d1 variant anti-TNFR1 dAb]]>
           <![CDATA[ <400> 287]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Val Tyr
                      20 25 30
          Met Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Ala Leu Gly Gly Arg Thr Gly Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Thr Met Ser Asn Lys Thr His Thr Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Ser
                  115
           <![CDATA[ <210> 288]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d2 variant anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (57)...(57)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 288]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Ala Tyr
                      20 25 30
          Asn Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asn Thr Phe Gly Asn Xaa Thr Arg Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gly Ser Arg Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser
                  115
           <![CDATA[ <210> 289]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d3 variant anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 289]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Gly Tyr
                      20 25 30
          Arg Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Trp Ile Thr Arg Thr Gly Gly Thr Thr Gln Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Pro Ala Lys Leu Val Gly Val Gly Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 290]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d4 variant anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (33)...(33)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 290]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Lys Tyr
                      20 25 30
          Xaa Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Gly Ala Lys Gly Gln Ser Thr Asp Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Lys Lys Arg Gly Glu Asn Tyr Phe Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 291]]>
           <![CDATA[ <211> 115]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d6 variant anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 291]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Gly Tyr
                      20 25 30
          Lys Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Gln Lys Glu Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
                      100 105 110
          Thr Val Ser
                  115
           <![CDATA[ <210> 292]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d9 variant anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (33)...(33)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 292]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Lys Tyr
                      20 25 30
          Xaa Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Met Leu Arg Thr Lys Asn Lys Val Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 293]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d11 variant anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 293]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Ser Tyr
                      20 25 30
          Arg Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Ser Arg Gly Arg His Thr Ser Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Val Pro Gly Arg Gly Arg Ser Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 294]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TAR2h-5d13 variant anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 294]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Arg Tyr
                      20 25 30
          Gly Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg His Ser Ser Glu Ala Arg Gln Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser
                  115
           <![CDATA[ <210> 295]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-1 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 295]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Tyr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 296]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-2 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 296]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly His Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 297]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-3 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 297]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 298]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-4 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 298]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 299]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-5 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 299]]>
          Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Tyr Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 300]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-6 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 300]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 301]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-7 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 301]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Ala Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 302]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-9 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 302]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 303]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-10 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 303]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 304]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-11 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 304]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 305]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-12 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 305]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 306]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-13 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 306]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 307]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-14 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 307]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Ala Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 308]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-15 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 308]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Ser Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 309]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-16 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 309]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Pro Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 310]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-17 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 310]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Lys Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 311]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-18 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 311]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Ala Asp Ser Ala
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 312]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-19 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 312]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Pro Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 313]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-20 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 313]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 314]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-21 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 314]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Tyr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Met Leu Pro Lys Arg Gly Pro Arg Phe Gly Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 315]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-22 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 315]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Cys Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Leu Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 316]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-23 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 316]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gly Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 317]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-25 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 317]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gln Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 318]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-26 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 318]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ser Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 319]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-27 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 319]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Tyr Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 320]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-28 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 320]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Gly Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 321]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-29 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 321]]>
          Glu Gly Gln Leu Leu Glu Ser Gly Gly Gly Leu Xaa Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Leu Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 322]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-30 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 322]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 323]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-31 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 323]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 324]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-32 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 324]]>
          Glu Gly Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 325]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-33 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 325]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Asn Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 326]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-34 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 326]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Gly Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 327]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-35 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 327]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Val Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 328]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-36 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 328]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Tyr Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 329]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-37 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 329]]>
          Glu Gly Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Leu Leu Ser Cys Ala Pro Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Lys Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 330]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-38 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 330]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Val Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 331]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-39 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 331]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Leu Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 332]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-40 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 332]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ser Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 333]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-41 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 333]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Gly Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 334]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-42 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 334]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 335]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-43 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 335]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gly Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Pro Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 336]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-44 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 336]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 337]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-45 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 337]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Met Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 338]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-46 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 338]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Pro Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 339]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-47 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (32)...(32)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 339]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Xaa
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 340]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-48 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (32)...(32)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 340]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Xaa
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Ile Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 341]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-49 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 341]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Asn Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 342]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-50 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 342]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Val Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 343]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-51 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 343]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Leu Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 344]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-52 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 344]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Asn Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 345]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-53 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 345]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 346]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-54 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 346]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 347]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-55 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 347]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Ala Thr Val Ser Ser
                  115
           <![CDATA[ <210> 348]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-56 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 348]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 349]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-57 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 349]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 350]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-58 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 350]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Asp
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Gln Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 351]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-59 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 351]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Asp
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 352]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-60 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 352]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Arg Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 353]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-61 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 353]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 354]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-62 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 354]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 355]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-63 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 355]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Gln Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 356]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-64 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 356]]>
          Glu Val Gln Leu Ser Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 357]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-65 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 357]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 358]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-66 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 358]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Met Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 359]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-67 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 359]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Ser Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 360]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-68 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 360]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ser Met Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 361]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-69 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 361]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 362]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-70 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 362]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 363]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-71 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 363]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Met Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 364]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-72 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 364]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Asp
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 365]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-73 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 365]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Glu Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 366]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-74 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 366]]>
          Asp Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ala Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 367]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-75 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 367]]>
          Glu Val Gln Leu Met Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Glu Leu Pro Lys Arg Gly Pro Trp Phe Asp His Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 368]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-76 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 368]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Met Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 369]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-77 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 369]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Met Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 370]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-78 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 370]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Met Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Leu Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 371]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-79 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 371]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Met Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Gln Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 372]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-80 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 372]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 373]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-81 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 373]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Ser Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 374]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-82 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 374]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ala Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 375]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-83 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 375]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 376]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-86 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 376]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Glu Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 377]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-87 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 377]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 378]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-88 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 378]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 379]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-89 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 379]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Asp Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 380]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-90 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 380]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Ser Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 381]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-91 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 381]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu His Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 382]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-92 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 382]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Asp
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 383]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-93 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 383]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 384]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-94 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 384]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 385]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-95 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 385]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Asp
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 386]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-96 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 386]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 387]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-97 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 387]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Glu Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 388]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-99 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 388]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile His Pro Gly Gly
           1 5 10 15
          Thr Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 389]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-100 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 389]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Gln Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 390]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-101 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 390]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 391]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-102 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 391]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 392]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-103 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 392]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 393]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-104 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 393]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Asp Gly Gln Asp Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 394]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-105 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 394]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 395]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-106 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 395]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Asp Gly Gln Asp Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Met Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Ile Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 396]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-107 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 396]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 397]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-108 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 397]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Thr Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 398]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-109 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 398]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Thr Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Leu Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 399]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-110 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 399]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Ile Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 400]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-111 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 400]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Gln Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 401]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-112 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 401]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Ile Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 402]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-113 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 402]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Asp
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 403]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-114 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 403]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Asp
                      20 25 30
          Val Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 404]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-115 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 404]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Thr Asp Ser Val
              50 55 60
          Glu Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 405]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-116 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 405]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 406]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-117 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 406]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 407]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-120 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 407]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 408]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-121 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 408]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Glu
                      20 25 30
          Thr Met Val Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 409]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-122 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 409]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 410]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-123 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 410]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 411]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-124 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 411]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Arg Asp Thr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 412]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-125 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 412]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 413]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-126 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 413]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Gln
                      20 25 30
          Val Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 414]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-127 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 414]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Leu Asp Thr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 415]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-128 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 415]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Ala Val Gly Ser Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 416]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-129 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 416]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 417]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-130 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 417]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Glu
                      20 25 30
          Val Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Gly
                  115
           <![CDATA[ <210> 418]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-131 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 418]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Gln
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 419]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-132 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 419]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asn Thr
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 420]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-136 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 420]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 421]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-151 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 421]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 422]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-180 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 422]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 423]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-181 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 423]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 424]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-182 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 424]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 425]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-183 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 425]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 426]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-184 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 426]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 427]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-185 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 427]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 428]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-188 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 428]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 429]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-189 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 429]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 430]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-190 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 430]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 431]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-191 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 431]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 432]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-192 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 432]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 433]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-193 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 433]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 434]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-194 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 434]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 435]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-195 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 435]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 436]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-196 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 436]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 437]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-197 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 437]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Val Asp Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 438]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-198 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 438]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 439]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-500 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 439]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe His Asp Gln
                      20 25 30
          His Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 440]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-501 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 440]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asn Asn
                      20 25 30
          Ile Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 441]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-502 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 441]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Lys Asn Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Gln Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 442]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-503 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 442]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys His
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 443]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-504 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 443]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 444]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-505 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 444]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Arg Gly Gly Gly Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 445]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-506 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 445]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gln Gln Gly Glu Gly Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 446]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-507 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 446]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 447]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-508 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 447]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Leu Gly Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 448]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-509 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 448]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 449]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-510 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 449]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Arg Gly Glu Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 450]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-511 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 450]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 451]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-512 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 451]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 452]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-513 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 452]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Arg Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 453]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-514 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 453]]>
          Glu Val Gln Xaa Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 454]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-515 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 454]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Ser Asp Asp Gly Asn Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 455]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-516 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 455]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Ala Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Pro Pro Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 456]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-517 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 456]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe His Asn Lys
                      20 25 30
          Asp Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Leu Leu Leu Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 457]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-518 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 457]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Met Arg
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 458]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-519 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 458]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 459]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-520 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 459]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Leu Val Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 460]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-521 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 460]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Thr
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Val Gly Gly Asp Thr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 461]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-522 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 461]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asn Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Leu Gly Leu Val Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 462]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-523 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 462]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Thr
                      20 25 30
          Asn Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Glu Ile Arg Val Gly Gly Gly Asp Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 463]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-524 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 463]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Asn Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gln Glu Gly Glu Gly Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 464]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-525 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 464]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Thr
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Glu Gly Ser Val Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 465]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-526 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 465]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Asn Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Ala Thr Gly Thr Ile Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 466]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-527 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 466]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Ala Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 467]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-528 anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 467]]>
          Glu Val Gln Xaa Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Arg Val Gly Gln Asp Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 468]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-529 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 468]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 469]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-530 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 469]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 470]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-531 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 470]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Asn Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Ala Thr Gly Thr Ile Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Arg Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 471]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-532 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 471]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Ala Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 472]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-533 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 472]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Asp Pro Phe Tyr Thr Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 473]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-534 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 473]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Leu Val Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 474]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-535 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 474]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Leu Val Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 475]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-536 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 475]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Leu Val Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 476]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-537 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 476]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 477]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-538 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 477]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 478]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-539 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 478]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Thr Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 479]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-540 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 479]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 480]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-541 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 480]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 481]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-542 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 481]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 482]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-543 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 482]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 483]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-544 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 483]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Ala Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 484]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-545 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 484]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Ala Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 485]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-546 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 485]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Ala Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 486]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-547 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 486]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Thr Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 487]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-548 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 487]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 488]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-549 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 488]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Asp Pro Phe Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 489]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-550 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 489]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Asp Pro Phe Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 490]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-551 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 490]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Asp Pro Phe Tyr Thr Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 491]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-552 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 491]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Asp Pro Phe Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 492]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-553 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 492]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Lys
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Lys Gly Gln Asp Pro Phe Tyr Thr Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 493]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-554 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 493]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Thr Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 494]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-555 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 494]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Pro Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 495]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-556 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 495]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 496]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-557 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 496]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 497]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-558 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 497]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Thr Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 498]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-559 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 498]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Val Gly Gln Asp Pro Phe Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 499]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-560 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 499]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 500]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-561 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 500]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 501]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-562 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 501]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Thr Asp Ser Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 502]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Tar2h-131-563 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 502]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Asp Gly Gly Gly Glu Ser Thr Tyr Tyr Thr Asp Pro Val
              50 55 60
          Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 503]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574'anti-TNFR1 dAb]]>
           <![CDATA[ <400> 503]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly His Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 504]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-1 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 504]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly Arg Trp Glu Pro Tyr Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 505]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-2 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 505]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 506]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-4 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 506]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 507]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-72 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 507]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 508]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-109 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 508]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 509]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-132 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 509]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 510]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-135 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 510]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 511]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-138 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 511]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 512]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-156 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 512]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 513]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-162 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 513]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ser His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 514]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-180 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 514]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 515]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-14 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 515]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 516]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-93 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 516]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 517]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-123 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 517]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 518]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-125 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 518]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Ala Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 519]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-126 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 519]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 520]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-129 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 520]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Val Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 521]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-133 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 521]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 522]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-137 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 522]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 523]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-160 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 523]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 524]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-139 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 524]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 525]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-155 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 525]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 526]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-509 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 526]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gln Tyr
                      20 25 30
          Arg Met His Trp Val Arg Gln Ala Pro Gly Lys Ser Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Thr Arg Gly Ser Ser Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ala Val Thr Met Phe Ser Pro Phe Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 527]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-510 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 527]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr
                      20 25 30
          Gly Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Thr Arg Thr Gly Arg Val Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Trp Arg Asn Arg His Gly Glu Tyr Leu Ala Asp Phe Asp Tyr
                      100 105 110
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 528]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-543 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 528]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Met Arg Tyr
                      20 25 30
          Arg Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Ser Asn Gly Ser Ser Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Asp Arg Thr Glu Arg Ser Pro Val Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 529]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-549 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 529]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 530]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-7 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 530]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 531]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-8 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 531]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 532]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-9 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 532]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Met Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 533]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-10 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 533]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 534]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-11 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 534]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Gly His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe Asp His Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 535]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-12 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 535]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 536]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-13 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 536]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 537]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-15 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 537]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 538]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-16 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 538]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 539]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-17 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 539]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 540]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-18 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 540]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 541]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-19 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 541]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp His Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 542]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-25 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 542]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 543]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-26 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 543]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 544]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-27 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 544]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 545]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-28 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 545]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 546]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-29 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 546]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 547]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-30 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 547]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ala Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 548]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-31 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 548]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asn Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 549]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-32 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 549]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 550]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-33 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 550]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Asp Asn Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 551]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-35 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 551]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ile Thr Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Gln Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 552]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-36 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 552]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 553]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-37 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 553]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 554]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-38 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 554]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 555]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-39 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 555]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 556]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-40 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 556]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Lys Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 557]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-53 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 557]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Glu Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 558]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-54 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 558]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asn Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Tyr Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Thr Ser
                  115
           <![CDATA[ <210> 559]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-65 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 559]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 560]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-66 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 560]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 561]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-67 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 561]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 562]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-68 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 562]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 563]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-69 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 563]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 564]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-70 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 564]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 565]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-71 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 565]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 566]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-73 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 566]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 567]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-74 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 567]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 568]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-75 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 568]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 569]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-76 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 569]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 570]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-77 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 570]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 571]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-78 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 571]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 572]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-79 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 572]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 573]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-84 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 573]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 574]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-85 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 574]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Lys Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 575]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-86 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 575]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 576]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-87 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 576]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 577]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-88 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 577]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 578]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-90 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 578]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Phe
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 579]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-91 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 579]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 580]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-92 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 580]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 581]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-94 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 581]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ala Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 582]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-95 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 582]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ala Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 583]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-96 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 583]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 584]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-97 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 584]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 585]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-98 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 585]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 586]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-99 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 586]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Pro Asp Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 587]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-100 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 587]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Ala Trp Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 588]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-101 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 588]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Gly Gly Gln Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 589]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-102 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 589]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Ser Gly Tyr Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 590]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-103 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 590]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Gly Gly Thr Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 591]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-104 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 591]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Lys Gly Thr Arg Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 592]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-105 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 592]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Glu Thr Gly Arg Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 593]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-106 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 593]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Asn Asn Thr Gly Ser Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 594]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-107 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 594]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 595]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-108 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 595]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 596]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-110 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 596]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 597]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-111 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 597]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 598]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-112 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 598]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 599]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-113 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 599]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Arg Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 600]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-114 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 600]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Leu Asn Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 601]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-115 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 601]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 602]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-116 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 602]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Arg Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 603]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-117 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 603]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Arg Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 604]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-118 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 604]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Tyr Thr Gly Arg Trp Val Ser Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 605]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-119 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 605]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Tyr Thr Gly Arg Trp Val Ser Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 606]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-120 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 606]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 607]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-121 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 607]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Leu Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 608]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-122 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 608]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Ala Asp Arg Arg Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 609]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-124 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 609]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Arg Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 610]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-127 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 610]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Ala Asp Arg Arg Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 611]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-128 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 611]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Ala Asp Arg Arg Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 612]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-130 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 612]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asn Thr Gly Asp Arg Arg Tyr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 613]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-131 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 613]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 614]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-134 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 614]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ser His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 615]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-140 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 615]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 616]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-141 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 616]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 617]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-142 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 617]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 618]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-143 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 618]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 619]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-144 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 619]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Asp Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 620]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-145 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 620]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 621]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-146 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 621]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Gly Asp Arg Arg Tyr Tyr Asp Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 622]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-147 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 622]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Gly Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 623]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-148 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 623]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Ala Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 624]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-149 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 624]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Gly Pro Phe Gln Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 625]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-150 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 625]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Gln Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 626]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-151 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 626]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 627]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-152 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 627]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Gln Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 628]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-153 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 628]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Gln Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 629]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-154 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 629]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 630]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-157 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 630]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 631]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-158 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 631]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Arg Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 632]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-159 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 632]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 633]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-161 anti-TNFR1 dAb ]]>
           <![CDATA[ <400> 633]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ser His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 634]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-163 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 634]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 635]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-164 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 635]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Thr His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 636]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-165 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 636]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 637]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-166 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 637]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 638]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-167 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 638]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Leu Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 639]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-168 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 639]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Gly Asp Arg Arg Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 640]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-169 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 640]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 641]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-170 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 641]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 642]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-171 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 642]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 643]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-172 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 643]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Thr Tyr Tyr Asp His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 644]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-173 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 644]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 645]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-174 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 645]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Arg Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 646]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-175 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 646]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 647]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-176 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 647]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Arg Tyr Tyr Asp His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 648]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-177 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 648]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Asp His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 649]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-178 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 649]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ala Asp Thr Ala Asp Arg Arg Tyr Tyr Asp His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 650]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-179 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 650]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Arg Tyr Tyr Asp Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Val Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 651]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-188 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 651]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 652]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-189 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 652]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 653]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-190 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 653]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 654]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-191 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 654]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 655]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-192 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 655]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Asn Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 656]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-193 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 656]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Asn Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 657]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-194 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 657]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 658]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-195 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 658]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 659]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-196 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 659]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 660]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-201 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 660]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Asn
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Leu
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 661]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-202 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 661]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 662]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-203 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 662]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 663]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-204 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 663]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Gln Trp Ala Pro Tyr Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Arg Ala
                  115
           <![CDATA[ <210> 664]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-205 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 664]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Asn Trp Gly His Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 665]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-206 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 665]]>
          Glu Val Gln Leu Leu Asp Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ser Pro Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gly Asn Thr Leu Asn
          65 70 75 80
          Leu Gln Met Thr Pro Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 666]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-207 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 666]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ser Ser Ser Gly Phe Thr Phe Ser Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Leu Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Glu Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Ala Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 667]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 667]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 668]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-209 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 668]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Phe Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Gln Trp Ala Pro Tyr Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 669]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-211 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 669]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 670]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-212 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 670]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 671]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-213 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 671]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 672]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-214 anti-TNFR1 dAb]]>
           <![CDATA[ <400> 672]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 673]]>
           <![CDATA[ <211> 251]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> ATROSAB scFv (scFv IZI06.1)]]>
           <![CDATA[ <400> 673]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
           1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ser
                  115 120 125
          Ala Gln Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr
              130 135 140
          Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu
          225 230 235 240
          Ile Lys Arg Gly Gly Ser Gly Gly Ala Ala Ala
                          245 250
           <![CDATA[ <210> 674]]>
           <![CDATA[ <211> 243]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> scFV IG11]]>
           <![CDATA[ <400> 674]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
           1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Val Pro Thr Gln Gly Glu Ala Lys Tyr Asn Asp Lys Phe
              50 55 60
          Lys Ala Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ser
                  115 120 125
          Ala Gln Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr
              130 135 140
          Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu
          225 230 235 240
          Ile Lys Arg
           <![CDATA[ <210> 675]]>
           <![CDATA[ <211> 243]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> scFV T12B]]>
           <![CDATA[ <400> 675]]>
          His Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
           1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Val Pro Ser Gln Gly Glu Ala Lys Tyr Asn Asp Lys Phe
              50 55 60
          Lys Ala Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ser
                  115 120 125
          Ala Gln Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr
              130 135 140
          Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser
              210 215 220
          Gln Gly Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu
          225 230 235 240
          Ile Lys Arg
           <![CDATA[ <210> 676]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> scFV 13.7]]>
           <![CDATA[ <400> 676]]>
          His Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
           1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Val Pro Ser Gln Gly Glu Ala Lys Tyr Asn Asp Lys Phe
              50 55 60
          Lys Ala Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
              130 135 140
          Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly
                          165 170 175
          Lys Ala Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu
          225 230 235 240
          Ile Lys
           <![CDATA[ <210> 677]]>
           <![CDATA[ <211> 231]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFV with AST linker]]>
           <![CDATA[ <400> 677]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Ala Ser Thr Asp Ile Val Met Thr Gln Ser Pro Leu Ser
                  115 120 125
          Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser
              130 135 140
          Gln Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val
          145 150 155 160
          Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn
                          165 170 175
          Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
                      180 185 190
          Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val
                  195 200 205
          Tyr Phe Cys Ser Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly
              210 215 220
          Thr Lys Leu Glu Ile Lys Arg
          225 230
           <![CDATA[ <210> 678]]>
           <![CDATA[ <211> 243]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv with (GGGGS)3 linker]]>
           <![CDATA[ <400> 678]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg
           <![CDATA[ <210> 679]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> FabATR (ATROSAB Fab) light chain]]>
           <![CDATA[ <400> 679]]>
          Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
           1 5 10 15
          Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
                  35 40 45
          Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
          65 70 75 80
          Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
                          85 90 95
          Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 680]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> FabATR (ATROSAB Fab) heavy chain]]>
           <![CDATA[ <400> 680]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
           1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
                  115 120 125
          Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
              130 135 140
          Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
          145 150 155 160
          Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
                          165 170 175
          Leu Tyr Ser Leu Ser Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
                      180 185 190
          Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
                  195 200 205
          Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215
           <![CDATA[ <210> 681]]>
           <![CDATA[ <211> 219]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Fab 13.7 light chain]]>
           <![CDATA[ <400> 681]]>
          Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Leu Leu His Ser
                      20 25 30
          Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
                  35 40 45
          Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro
              50 55 60
          Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
          65 70 75 80
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Ser
                          85 90 95
          Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105 110
          Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
                  115 120 125
          Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
              130 135 140
          Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
          145 150 155 160
          Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
                          165 170 175
          Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
                      180 185 190
          Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
                  195 200 205
          Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
              210 215
           <![CDATA[ <210> 682]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Fab 13.7 heavy chain]]>
           <![CDATA[ <400> 682]]>
          His Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
           1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Val Pro Ser Gln Gly Glu Ala Lys Tyr Asn Asp Lys Phe
              50 55 60
          Lys Ala Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
                      100 105 110
          Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
                  115 120 125
          Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
              130 135 140
          Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
          145 150 155 160
          Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
                          165 170 175
          Leu Tyr Ser Leu Ser Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
                      180 185 190
          Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
                  195 200 205
          Val Asp Lys Lys Val Glu Pro Lys Ser Cys
              210 215
           <![CDATA[ <210> 683]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Nb 70 nanometer antibody]]>
           <![CDATA[ <400> 683]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
           1 5 10 15
          Pro Leu Arg Leu Ser Cys Ala Ala Ser Val Arg Thr Phe Ser Ser Tyr
                      20 25 30
          Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
                  35 40 45
          Ala Ala Ile Ser Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Val Leu His Glu Asp Leu Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Gln Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 684]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Nb 96 Nanobody]]>
           <![CDATA[ <400> 684]]>
          Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Thr Leu Ser Cys Thr Arg Thr Gly Phe Thr Ala Ser Thr Asn
                      20 25 30
          Ala Tyr Gly Trp Tyr Arg Gln Gly Pro Gly Lys Lys Cys Glu Trp Val
                  35 40 45
          Ser Tyr Met Thr Ile Pro Ser Gly Arg Thr Thr Tyr Ala Asp Ala Val
              50 55 60
          Lys Gly Arg Phe Ala Met Ser Arg Asp Lys Ala Lys Ser Thr Val Phe
          65 70 75 80
          Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Gly Asp Val Pro Phe Ser Thr Leu Pro Ala Met Cys Thr Asn Asp Gly
                      100 105 110
          Pro Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 685]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R32W/S86T]]>
           <![CDATA[ <400> 685]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 686]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein L29S]]>
           <![CDATA[ <400> 686]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Ser Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 687]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein L29G]]>
           <![CDATA[ <400> 687]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Gly Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 688]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein L29Y]]>
           <![CDATA[ <400> 688]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Tyr Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 689]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R31E]]>
           <![CDATA[ <400> 689]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Glu Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 690]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R31N]]>
           <![CDATA[ <400> 690]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Asn Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 691]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R32W]]>
           <![CDATA[ <400> 691]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 692]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R32Y]]>
           <![CDATA[ <400> 692]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Tyr
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 693]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein S86T]]>
           <![CDATA[ <400> 693]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 694]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R31N/R32T]]>
           <![CDATA[ <400> 694]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Asn Thr
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 695]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein L29S/R32W]]>
           <![CDATA[ <400> 695]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Ser Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 696]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein L29S/S86T]]>
           <![CDATA[ <400> 696]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Ser Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 697]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein L29S/R32W/S86T]]>
           <![CDATA[ <400> 697]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Ser Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 698]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R31E/S86T]]>
           <![CDATA[ <400> 698]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Glu Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 699]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein R31N/R32T/S86T]]>
           <![CDATA[ <400> 699]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Asn Thr
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 700]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR1 selective antagonist TNF mutant protein E146R]]>
           <![CDATA[ <400> 700]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Arg Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 701]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> XPro1595]]>
           <![CDATA[ <400> 701]]>
          Met Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Cys Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Val Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser His Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Ala Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 702]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> XENP345]]>
           <![CDATA[ <400> 702]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Thr Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 703]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> R1antTNF]]>
           <![CDATA[ <400> 703]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ser Thr Thr His Asn Gln Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 704]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208 - albudAb fusion protein]]>
           <![CDATA[ <400> 704]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
              130 135 140
          Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
          145 150 155 160
          Arg Pro Ile Gly Thr Thr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys
                          165 170 175
          Ala Pro Lys Leu Leu Ile Leu Trp Asn Ser Arg Leu Gln Ser Gly Val
                      180 185 190
          Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
                  195 200 205
          Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln
              210 215 220
          Ala Gly Thr His Pro Thr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
          225 230 235 240
          Lys Arg
           <![CDATA[ <210> 705]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206 dAb - albudAb fusion protein]]>
           <![CDATA[ <400> 705]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
              130 135 140
          Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
          145 150 155 160
          Arg Pro Ile Gly Thr Thr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys
                          165 170 175
          Ala Pro Lys Leu Leu Ile Leu Trp Asn Ser Arg Leu Gln Ser Gly Val
                      180 185 190
          Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
                  195 200 205
          Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln
              210 215 220
          Ala Gly Thr His Pro Thr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
          225 230 235 240
          Lys Arg
           <![CDATA[ <210> 706]]>
           <![CDATA[ <211> 466]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 706]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg Ser Cys Asp Lys Thr His Ala Pro Glu Leu Leu Gly Gly
                          245 250 255
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                      260 265 270
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
                  275 280 285
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
              290 295 300
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
          305 310 315 320
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
                          325 330 335
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
                      340 345 350
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                  355 360 365
          Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
              370 375 380
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
          385 390 395 400
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
                          405 410 415
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
                      420 425 430
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
                  435 440 445
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
              450 455 460
          Gly Lys
          465
           <![CDATA[ <210> 707]]>
           <![CDATA[ <211> 475]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 707]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                          245 250 255
          Gly Ser Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
                      260 265 270
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                  275 280 285
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
              290 295 300
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
          305 310 315 320
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
                          325 330 335
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
                      340 345 350
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                  355 360 365
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
              370 375 380
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
          385 390 395 400
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
                          405 410 415
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
                      420 425 430
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                  435 440 445
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
              450 455 460
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
          465 470 475
           <![CDATA[ <210> 708]]>
           <![CDATA[ <211> 481]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 708]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                          245 250 255
          Gly Ser Ser Cys Asp Lys Thr His Ala Pro Glu Leu Leu Gly Gly Pro
                      260 265 270
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                  275 280 285
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
              290 295 300
          Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
          305 310 315 320
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
                          325 330 335
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
                      340 345 350
          Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
                  355 360 365
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
              370 375 380
          Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
          385 390 395 400
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
                          405 410 415
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
                      420 425 430
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
                  435 440 445
          Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
              450 455 460
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
          465 470 475 480
          Lys
           <![CDATA[ <210> 709]]>
           <![CDATA[ <211> 849]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv-GGGGSGGGGSGGGGS-HSA fusion protein]]>
           <![CDATA[ <400> 709]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                          245 250 255
          Gly Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
                      260 265 270
          His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
                  275 280 285
          Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
              290 295 300
          Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
          305 310 315 320
          Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
                          325 330 335
          Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
                      340 345 350
          Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
                  355 360 365
          His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
              370 375 380
          Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
          385 390 395 400
          Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
                          405 410 415
          Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
                      420 425 430
          Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
                  435 440 445
          Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
              450 455 460
          Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
          465 470 475 480
          Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
                          485 490 495
          Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
                      500 505 510
          Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
                  515 520 525
          Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
              530 535 540
          Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
          545 550 555 560
          Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
                          565 570 575
          Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
                      580 585 590
          Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
                  595 600 605
          Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
              610 615 620
          Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
          625 630 635 640
          Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
                          645 650 655
          Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
                      660 665 670
          Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
                  675 680 685
          Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
              690 695 700
          Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
          705 710 715 720
          Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
                          725 730 735
          Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
                      740 745 750
          Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
                  755 760 765
          Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
              770 775 780
          Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
          785 790 795 800
          Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
                          805 810 815
          Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
                      820 825 830
          Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
                  835 840 845
          Leu
           <![CDATA[ <210> 710]]>
           <![CDATA[ <211> 342]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 710]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Cys Asp Lys Thr His Ala Pro Glu
                  115 120 125
          Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
              130 135 140
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
          145 150 155 160
          Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
                          165 170 175
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
                      180 185 190
          Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
                  195 200 205
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
              210 215 220
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
          225 230 235 240
          Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
                          245 250 255
          Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
                      260 265 270
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
                  275 280 285
          Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
              290 295 300
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
          305 310 315 320
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
                          325 330 335
          Ser Leu Ser Pro Gly Lys
                      340
           <![CDATA[ <210> 711]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 711]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                          165 170 175
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                      340 345 350
           <![CDATA[ <210> 712]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 712]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys Thr His Ala Pro Glu Leu
              130 135 140
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
          145 150 155 160
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                          165 170 175
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
                      180 185 190
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
                  195 200 205
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
              210 215 220
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
          225 230 235 240
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                          245 250 255
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
                      260 265 270
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
                  275 280 285
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
              290 295 300
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
          305 310 315 320
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                          325 330 335
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
                      340 345 350
          Leu Ser Pro Gly Lys
                  355
           <![CDATA[ <210> 713]]>
           <![CDATA[ <211> 725]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16-GGGGSGGGGSGGGGS-HSA fusion protein]]>
           <![CDATA[ <400> 713]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys
              130 135 140
          Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys
          145 150 155 160
          Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
                          165 170 175
          Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr
                      180 185 190
          Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr
                  195 200 205
          Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr
              210 215 220
          Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu
          225 230 235 240
          Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val
                          245 250 255
          Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu
                      260 265 270
          Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr
                  275 280 285
          Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala
              290 295 300
          Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
          305 310 315 320
          Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln
                          325 330 335
          Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys
                      340 345 350
          Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe
                  355 360 365
          Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu
              370 375 380
          Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu
          385 390 395 400
          Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
                          405 410 415
          Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu
                      420 425 430
          Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp
                  435 440 445
          Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
              450 455 460
          Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
          465 470 475 480
          Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr
                          485 490 495
          Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys
                      500 505 510
          Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile
                  515 520 525
          Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln
              530 535 540
          Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
          545 550 555 560
          Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys
                          565 570 575
          Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr
                      580 585 590
          Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro
                  595 600 605
          Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg
              610 615 620
          Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys
          625 630 635 640
          Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu
                          645 650 655
          Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu
                      660 665 670
          Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met
                  675 680 685
          Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys
              690 695 700
          Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln
          705 710 715 720
          Ala Ala Leu Gly Leu
                          725
           <![CDATA[ <210> 714]]>
           <![CDATA[ <211> 342]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 714]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Cys Asp Lys Thr His Ala Pro Glu
                  115 120 125
          Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
              130 135 140
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
          145 150 155 160
          Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
                          165 170 175
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
                      180 185 190
          Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
                  195 200 205
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
              210 215 220
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
          225 230 235 240
          Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
                          245 250 255
          Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
                      260 265 270
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
                  275 280 285
          Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
              290 295 300
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
          305 310 315 320
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
                          325 330 335
          Ser Leu Ser Pro Gly Lys
                      340
           <![CDATA[ <210> 715]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 715]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                          165 170 175
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                      340 345 350
           <![CDATA[ <210> 716]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 716]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys Thr His Ala Pro Glu Leu
              130 135 140
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
          145 150 155 160
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                          165 170 175
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
                      180 185 190
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
                  195 200 205
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
              210 215 220
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
          225 230 235 240
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                          245 250 255
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
                      260 265 270
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
                  275 280 285
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
              290 295 300
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
          305 310 315 320
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                          325 330 335
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
                      340 345 350
          Leu Ser Pro Gly Lys
                  355
           <![CDATA[ <210> 717]]>
           <![CDATA[ <211> 725]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549-GGGGSGGGGSGGGGS-HSA fusion protein]]>
           <![CDATA[ <400> 717]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys
              130 135 140
          Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys
          145 150 155 160
          Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
                          165 170 175
          Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr
                      180 185 190
          Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr
                  195 200 205
          Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr
              210 215 220
          Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu
          225 230 235 240
          Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val
                          245 250 255
          Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu
                      260 265 270
          Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr
                  275 280 285
          Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala
              290 295 300
          Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
          305 310 315 320
          Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln
                          325 330 335
          Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys
                      340 345 350
          Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe
                  355 360 365
          Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu
              370 375 380
          Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu
          385 390 395 400
          Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
                          405 410 415
          Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu
                      420 425 430
          Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp
                  435 440 445
          Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
              450 455 460
          Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
          465 470 475 480
          Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr
                          485 490 495
          Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys
                      500 505 510
          Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile
                  515 520 525
          Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln
              530 535 540
          Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
          545 550 555 560
          Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys
                          565 570 575
          Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr
                      580 585 590
          Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro
                  595 600 605
          Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg
              610 615 620
          Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys
          625 630 635 640
          Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu
                          645 650 655
          Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu
                      660 665 670
          Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met
                  675 680 685
          Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys
              690 695 700
          Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln
          705 710 715 720
          Ala Ala Leu Gly Leu
                          725
           <![CDATA[ <210> 718]]>
           <![CDATA[ <211> 342]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 718]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Cys Asp Lys Thr His Ala Pro Glu
                  115 120 125
          Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
              130 135 140
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
          145 150 155 160
          Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
                          165 170 175
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
                      180 185 190
          Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
                  195 200 205
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
              210 215 220
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
          225 230 235 240
          Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
                          245 250 255
          Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
                      260 265 270
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
                  275 280 285
          Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
              290 295 300
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
          305 310 315 320
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
                          325 330 335
          Ser Leu Ser Pro Gly Lys
                      340
           <![CDATA[ <210> 719]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 719]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                          165 170 175
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                      340 345 350
           <![CDATA[ <210> 720]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 720]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys Thr His Ala Pro Glu Leu
              130 135 140
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
          145 150 155 160
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                          165 170 175
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
                      180 185 190
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
                  195 200 205
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
              210 215 220
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
          225 230 235 240
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                          245 250 255
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
                      260 265 270
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
                  275 280 285
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
              290 295 300
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
          305 310 315 320
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                          325 330 335
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
                      340 345 350
          Leu Ser Pro Gly Lys
                  355
           <![CDATA[ <210> 721]]>
           <![CDATA[ <211> 725]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208-GGGGSGGGGSGGGGS-HSA fusion protein]]>
           <![CDATA[ <400> 721]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys
              130 135 140
          Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys
          145 150 155 160
          Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
                          165 170 175
          Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr
                      180 185 190
          Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr
                  195 200 205
          Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr
              210 215 220
          Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu
          225 230 235 240
          Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val
                          245 250 255
          Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu
                      260 265 270
          Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr
                  275 280 285
          Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala
              290 295 300
          Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
          305 310 315 320
          Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln
                          325 330 335
          Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys
                      340 345 350
          Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe
                  355 360 365
          Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu
              370 375 380
          Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu
          385 390 395 400
          Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
                          405 410 415
          Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu
                      420 425 430
          Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp
                  435 440 445
          Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
              450 455 460
          Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
          465 470 475 480
          Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr
                          485 490 495
          Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys
                      500 505 510
          Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile
                  515 520 525
          Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln
              530 535 540
          Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
          545 550 555 560
          Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys
                          565 570 575
          Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr
                      580 585 590
          Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro
                  595 600 605
          Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg
              610 615 620
          Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys
          625 630 635 640
          Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu
                          645 650 655
          Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu
                      660 665 670
          Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met
                  675 680 685
          Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys
              690 695 700
          Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln
          705 710 715 720
          Ala Ala Leu Gly Leu
                          725
           <![CDATA[ <210> 722]]>
           <![CDATA[ <211> 342]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 722]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Cys Asp Lys Thr His Ala Pro Glu
                  115 120 125
          Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
              130 135 140
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
          145 150 155 160
          Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
                          165 170 175
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
                      180 185 190
          Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
                  195 200 205
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
              210 215 220
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
          225 230 235 240
          Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
                          245 250 255
          Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
                      260 265 270
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
                  275 280 285
          Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
              290 295 300
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
          305 310 315 320
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
                          325 330 335
          Ser Leu Ser Pro Gly Lys
                      340
           <![CDATA[ <210> 723]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 723]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
                          165 170 175
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                      340 345 350
           <![CDATA[ <210> 724]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 724]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys Thr His Ala Pro Glu Leu
              130 135 140
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
          145 150 155 160
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                          165 170 175
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
                      180 185 190
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
                  195 200 205
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
              210 215 220
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
          225 230 235 240
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                          245 250 255
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
                      260 265 270
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
                  275 280 285
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
              290 295 300
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
          305 310 315 320
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                          325 330 335
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
                      340 345 350
          Leu Ser Pro Gly Lys
                  355
           <![CDATA[ <210> 725]]>
           <![CDATA[ <211> 725]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206-GGGGSGGGGSGGGGS-HSA fusion protein]]>
           <![CDATA[ <400> 725]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys
              130 135 140
          Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys
          145 150 155 160
          Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
                          165 170 175
          Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr
                      180 185 190
          Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr
                  195 200 205
          Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr
              210 215 220
          Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu
          225 230 235 240
          Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val
                          245 250 255
          Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu
                      260 265 270
          Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr
                  275 280 285
          Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala
              290 295 300
          Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
          305 310 315 320
          Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln
                          325 330 335
          Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys
                      340 345 350
          Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe
                  355 360 365
          Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu
              370 375 380
          Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu
          385 390 395 400
          Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
                          405 410 415
          Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu
                      420 425 430
          Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp
                  435 440 445
          Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
              450 455 460
          Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
          465 470 475 480
          Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr
                          485 490 495
          Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys
                      500 505 510
          Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile
                  515 520 525
          Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln
              530 535 540
          Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
          545 550 555 560
          Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys
                          565 570 575
          Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr
                      580 585 590
          Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro
                  595 600 605
          Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg
              610 615 620
          Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys
          625 630 635 640
          Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu
                          645 650 655
          Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu
                      660 665 670
          Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met
                  675 680 685
          Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys
              690 695 700
          Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln
          705 710 715 720
          Ala Ala Leu Gly Leu
                          725
           <![CDATA[ <210> 726]]>
           <![CDATA[ <211> 472]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 726]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
                          245 250 255
          Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
                      260 265 270
          Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
                  275 280 285
          Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
              290 295 300
          Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
          305 310 315 320
          Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
                          325 330 335
          Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
                      340 345 350
          Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
                  355 360 365
          Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
              370 375 380
          Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
          385 390 395 400
          Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
                          405 410 415
          Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
                      420 425 430
          Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
                  435 440 445
          Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
              450 455 460
          Ser Leu Ser Leu Ser Leu Gly Lys
          465 470
           <![CDATA[ <210> 727]]>
           <![CDATA[ <211> 475]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 727]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                          245 250 255
          Gly Ser Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
                      260 265 270
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                  275 280 285
          Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
              290 295 300
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
          305 310 315 320
          Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
                          325 330 335
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
                      340 345 350
          Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
                  355 360 365
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
              370 375 380
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
          385 390 395 400
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
                          405 410 415
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
                      420 425 430
          Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
                  435 440 445
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
              450 455 460
          Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
          465 470 475
           <![CDATA[ <210> 728]]>
           <![CDATA[ <211> 487]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> H398 scFv-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 728]]>
          Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
           1 5 10 15
          Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
                      20 25 30
          Tyr Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Glu Ile Tyr Pro Tyr Ser Gly His Ala Tyr Tyr Asn Glu Lys Phe
              50 55 60
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Phe
          65 70 75 80
          Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
                          85 90 95
          Val Arg Trp Asp Phe Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
                      100 105 110
          Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser
              130 135 140
          Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu
          145 150 155 160
          His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly
                          165 170 175
          Gln Ser Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly
                      180 185 190
          Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
                  195 200 205
          Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser
              210 215 220
          Gln Ser Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
                          245 250 255
          Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
                      260 265 270
          Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
                  275 280 285
          Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
              290 295 300
          Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
          305 310 315 320
          Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
                          325 330 335
          Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
                      340 345 350
          Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
                  355 360 365
          Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
              370 375 380
          Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
          385 390 395 400
          Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
                          405 410 415
          Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
                      420 425 430
          Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
                  435 440 445
          Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
              450 455 460
          Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
          465 470 475 480
          Leu Ser Leu Ser Leu Gly Lys
                          485
           <![CDATA[ <210> 729]]>
           <![CDATA[ <211> 348]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 729]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
                  115 120 125
          Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
              130 135 140
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
          145 150 155 160
          Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
                          165 170 175
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                      180 185 190
          Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
                  195 200 205
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
              210 215 220
          Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
          225 230 235 240
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
                          245 250 255
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                      260 265 270
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
                  275 280 285
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
              290 295 300
          Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
          305 310 315 320
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                          325 330 335
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345
           <![CDATA[ <210> 730]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 730]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
                          165 170 175
          Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345 350
           <![CDATA[ <210> 731]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-574-16-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 731]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asn Thr Gly Asp Arg Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Glu Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
              130 135 140
          Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          145 150 155 160
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          165 170 175
          Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
                      180 185 190
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  195 200 205
          Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              210 215 220
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          225 230 235 240
          Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          245 250 255
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
                      260 265 270
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  275 280 285
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              290 295 300
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          305 310 315 320
          Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
                          325 330 335
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      340 345 350
          Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                  355 360
           <![CDATA[ <210> 732]]>
           <![CDATA[ <211> 348]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 732]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
                  115 120 125
          Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
              130 135 140
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
          145 150 155 160
          Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
                          165 170 175
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                      180 185 190
          Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
                  195 200 205
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
              210 215 220
          Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
          225 230 235 240
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
                          245 250 255
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                      260 265 270
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
                  275 280 285
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
              290 295 300
          Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
          305 310 315 320
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                          325 330 335
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345
           <![CDATA[ <210> 733]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 733]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
                          165 170 175
          Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345 350
           <![CDATA[ <210> 734]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOMlh-549-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 734]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp Tyr
                      20 25 30
          Glu Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Ser Glu Ser Gly Thr Thr Thr Tyr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Arg Arg Phe Ser Ala Ser Thr Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
              130 135 140
          Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          145 150 155 160
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          165 170 175
          Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
                      180 185 190
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  195 200 205
          Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              210 215 220
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          225 230 235 240
          Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          245 250 255
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
                      260 265 270
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  275 280 285
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              290 295 300
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          305 310 315 320
          Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
                          325 330 335
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      340 345 350
          Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                  355 360
           <![CDATA[ <210> 735]]>
           <![CDATA[ <211> 348]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 735]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
                  115 120 125
          Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
              130 135 140
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
          145 150 155 160
          Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
                          165 170 175
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                      180 185 190
          Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
                  195 200 205
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
              210 215 220
          Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
          225 230 235 240
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
                          245 250 255
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                      260 265 270
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
                  275 280 285
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
              290 295 300
          Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
          305 310 315 320
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                          325 330 335
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345
           <![CDATA[ <210> 736]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 736]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
                          165 170 175
          Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345 350
           <![CDATA[ <210> 737]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-574-208-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 737]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Lys Tyr
                      20 25 30
          Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gln Ile Ser Asp Thr Ala Asp Arg Thr Tyr Tyr Ala His Ala Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ile Tyr Thr Gly Arg Trp Val Pro Phe Glu Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
              130 135 140
          Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          145 150 155 160
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          165 170 175
          Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
                      180 185 190
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  195 200 205
          Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              210 215 220
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          225 230 235 240
          Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          245 250 255
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
                      260 265 270
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  275 280 285
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              290 295 300
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          305 310 315 320
          Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
                          325 330 335
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      340 345 350
          Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                  355 360
           <![CDATA[ <210> 738]]>
           <![CDATA[ <211> 348]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 738]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
                  115 120 125
          Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
              130 135 140
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
          145 150 155 160
          Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
                          165 170 175
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
                      180 185 190
          Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
                  195 200 205
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
              210 215 220
          Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
          225 230 235 240
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
                          245 250 255
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
                      260 265 270
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
                  275 280 285
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
              290 295 300
          Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
          305 310 315 320
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                          325 330 335
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345
           <![CDATA[ <210> 739]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 739]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
              130 135 140
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
          145 150 155 160
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
                          165 170 175
          Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
                      180 185 190
          Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
                  195 200 205
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
              210 215 220
          Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
          225 230 235 240
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
                          245 250 255
          Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
                      260 265 270
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
                  275 280 285
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
              290 295 300
          Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
          305 310 315 320
          Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
                          325 330 335
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                      340 345 350
           <![CDATA[ <210> 740]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> DOM1h-131-206-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 740]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His Glu
                      20 25 30
          Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys
                          85 90 95
          Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
                  115 120 125
          Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
              130 135 140
          Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
          145 150 155 160
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                          165 170 175
          Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
                      180 185 190
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
                  195 200 205
          Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
              210 215 220
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
          225 230 235 240
          Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
                          245 250 255
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
                      260 265 270
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
                  275 280 285
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
              290 295 300
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
          305 310 315 320
          Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
                          325 330 335
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
                      340 345 350
          Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
                  355 360
           <![CDATA[ <210> 741]]>
           <![CDATA[ <211> 380]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(R32W/S86T)-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 741]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Ser Cys Asp
          145 150 155 160
          Lys Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
                          165 170 175
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                      180 185 190
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                  195 200 205
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
              210 215 220
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Tyr Arg Val Val Ser Val Leu Thr
          225 230 235 240
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
                          245 250 255
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                      260 265 270
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                  275 280 285
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
              290 295 300
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
          305 310 315 320
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
                          325 330 335
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                      340 345 350
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                  355 360 365
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
              370 375 380
           <![CDATA[ <210> 742]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(R32W/S86T)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 742]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
                      260 265 270
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Pro Gly Lys
          385
           <![CDATA[ <210> 743]]>
           <![CDATA[ <211> 395]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(R32W/S86T)-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 743]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys
                          165 170 175
          Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
                      180 185 190
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                  195 200 205
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
              210 215 220
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
          225 230 235 240
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
                          245 250 255
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
                      260 265 270
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                  275 280 285
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
              290 295 300
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
          305 310 315 320
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
                          325 330 335
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
                      340 345 350
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                  355 360 365
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
              370 375 380
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
          385 390 395
           <![CDATA[ <210> 744]]>
           <![CDATA[ <211> 380]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 744]]>
          Met Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Cys Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Val Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser His Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Ala Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Ser Cys Asp
          145 150 155 160
          Lys Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
                          165 170 175
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                      180 185 190
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                  195 200 205
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
              210 215 220
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Tyr Arg Val Val Ser Val Leu Thr
          225 230 235 240
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
                          245 250 255
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                      260 265 270
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                  275 280 285
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
              290 295 300
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
          305 310 315 320
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
                          325 330 335
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                      340 345 350
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                  355 360 365
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
              370 375 380
           <![CDATA[ <210> 745]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 745]]>
          Met Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Cys Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Val Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser His Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Ala Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
                      260 265 270
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Pro Gly Lys
          385
           <![CDATA[ <210> 746]]>
           <![CDATA[ <211> 395]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 746]]>
          Met Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Cys Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Val Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser His Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Ala Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys
                          165 170 175
          Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
                      180 185 190
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                  195 200 205
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
              210 215 220
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
          225 230 235 240
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
                          245 250 255
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
                      260 265 270
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                  275 280 285
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
              290 295 300
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
          305 310 315 320
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
                          325 330 335
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
                      340 345 350
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                  355 360 365
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
              370 375 380
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
          385 390 395
           <![CDATA[ <210> 747]]>
           <![CDATA[ <211> 380]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 747]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ser Thr Thr His Asn Gln Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Ser Cys Asp
          145 150 155 160
          Lys Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
                          165 170 175
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                      180 185 190
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                  195 200 205
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
              210 215 220
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Tyr Arg Val Val Ser Val Leu Thr
          225 230 235 240
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
                          245 250 255
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                      260 265 270
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                  275 280 285
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
              290 295 300
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
          305 310 315 320
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
                          325 330 335
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                      340 345 350
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                  355 360 365
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
              370 375 380
           <![CDATA[ <210> 748]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 748]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ser Thr Thr His Asn Gln Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
                      260 265 270
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Pro Gly Lys
          385
           <![CDATA[ <210> 749]]>
           <![CDATA[ <211> 395]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 749]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ser Thr Thr His Asn Gln Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys
                          165 170 175
          Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
                      180 185 190
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                  195 200 205
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
              210 215 220
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
          225 230 235 240
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
                          245 250 255
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
                      260 265 270
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                  275 280 285
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
              290 295 300
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
          305 310 315 320
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
                          325 330 335
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
                      340 345 350
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                  355 360 365
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
              370 375 380
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
          385 390 395
           <![CDATA[ <210> 750]]>
           <![CDATA[ <211> 380]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(I97T/A145R)-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 750]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Thr Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Ser Cys Asp
          145 150 155 160
          Lys Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
                          165 170 175
          Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
                      180 185 190
          Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
                  195 200 205
          Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
              210 215 220
          Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Tyr Arg Val Val Ser Val Leu Thr
          225 230 235 240
          Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
                          245 250 255
          Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
                      260 265 270
          Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
                  275 280 285
          Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
              290 295 300
          Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
          305 310 315 320
          Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
                          325 330 335
          Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
                      340 345 350
          Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
                  355 360 365
          Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
              370 375 380
           <![CDATA[ <210> 751]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(I97T/A145R)-GGGGSGGGGSGGGGS-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 751]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Thr Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Leu
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
                      260 265 270
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Pro Gly Lys
          385
           <![CDATA[ <210> 752]]>
           <![CDATA[ <211> 395]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(I97T/A145R)-GGGGSGGGGSGGGGS-SCDKTH-Trastuzumab Fc fusion protein]]>
           <![CDATA[ <400> 752]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Thr Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Cys Asp Lys
                          165 170 175
          Thr His Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
                      180 185 190
          Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
                  195 200 205
          Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
              210 215 220
          Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
          225 230 235 240
          Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
                          245 250 255
          Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
                      260 265 270
          Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
                  275 280 285
          Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
              290 295 300
          Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
          305 310 315 320
          Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
                          325 330 335
          Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
                      340 345 350
          Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
                  355 360 365
          Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
              370 375 380
          Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
          385 390 395
           <![CDATA[ <210> 753]]>
           <![CDATA[ <211> 386]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(R32W/S86T)-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 753]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Glu Ser Lys
          145 150 155 160
          Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
                          165 170 175
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                      180 185 190
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
                  195 200 205
          Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
              210 215 220
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
          225 230 235 240
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
                          245 250 255
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
                      260 265 270
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                  275 280 285
          Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
              290 295 300
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
          305 310 315 320
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
                          325 330 335
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
                      340 345 350
          Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
                  355 360 365
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
              370 375 380
          Gly Lys
          385
           <![CDATA[ <210> 754]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(R32W/S86T)-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 754]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
                      260 265 270
          Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Leu Gly Lys
          385
           <![CDATA[ <210> 755]]>
           <![CDATA[ <211> 401]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(R32W/S86T)-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 755]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Trp
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Thr Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
                          165 170 175
          Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
                      180 185 190
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                  195 200 205
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
              210 215 220
          Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
          225 230 235 240
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
                          245 250 255
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
                      260 265 270
          Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
                  275 280 285
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
              290 295 300
          Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
          305 310 315 320
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
                          325 330 335
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
                      340 345 350
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
                  355 360 365
          Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
              370 375 380
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
          385 390 395 400
          Lys
           <![CDATA[ <210> 756]]>
           <![CDATA[ <211> 386]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 756]]>
          Met Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Cys Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Val Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser His Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Ala Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Glu Ser Lys
          145 150 155 160
          Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
                          165 170 175
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                      180 185 190
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
                  195 200 205
          Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
              210 215 220
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
          225 230 235 240
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
                          245 250 255
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
                      260 265 270
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                  275 280 285
          Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
              290 295 300
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
          305 310 315 320
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
                          325 330 335
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
                      340 345 350
          Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
                  355 360 365
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
              370 375 380
          Gly Lys
          385
           <![CDATA[ <210> 757]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGG S-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 757]]>
          Met Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Cys Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Val Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser His Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Ala Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
                      260 265 270
          Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Leu Gly Lys
          385
           <![CDATA[ <210> 758]]>
           <![CDATA[ <211> 401]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(V1M/R31C/C69V/Y87H/C101A/A145R)-GGGGSGGGGSGGGG S-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 758]]>
          Met Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Cys Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Val Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser His Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Ala Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
                          165 170 175
          Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
                      180 185 190
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                  195 200 205
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
              210 215 220
          Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
          225 230 235 240
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
                          245 250 255
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
                      260 265 270
          Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
                  275 280 285
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
              290 295 300
          Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
          305 310 315 320
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
                          325 330 335
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
                      340 345 350
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
                  355 360 365
          Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
              370 375 380
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
          385 390 395 400
          Lys
           <![CDATA[ <210> 759]]>
           <![CDATA[ <211> 386]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 759]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ser Thr Thr His Asn Gln Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Glu Ser Lys
          145 150 155 160
          Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
                          165 170 175
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                      180 185 190
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
                  195 200 205
          Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
              210 215 220
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
          225 230 235 240
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
                          245 250 255
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
                      260 265 270
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                  275 280 285
          Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
              290 295 300
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
          305 310 315 320
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
                          325 330 335
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
                      340 345 350
          Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
                  355 360 365
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
              370 375 380
          Gly Lys
          385
           <![CDATA[ <210> 760]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 760]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ser Thr Thr His Asn Gln Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
                      260 265 270
          Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Leu Gly Lys
          385
           <![CDATA[ <210> 761]]>
           <![CDATA[ <211> 401]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(A84S/V85T/S86T/Y87H/Q88N/T89Q)-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 761]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ser Thr Thr His Asn Gln Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
                          165 170 175
          Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
                      180 185 190
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                  195 200 205
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
              210 215 220
          Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
          225 230 235 240
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
                          245 250 255
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
                      260 265 270
          Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
                  275 280 285
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
              290 295 300
          Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
          305 310 315 320
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
                          325 330 335
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
                      340 345 350
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
                  355 360 365
          Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
              370 375 380
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
          385 390 395 400
          Lys
           <![CDATA[ <210> 762]]>
           <![CDATA[ <211> 386]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(I97T/A145R)-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 762]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Thr Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Glu Ser Lys
          145 150 155 160
          Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
                          165 170 175
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
                      180 185 190
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
                  195 200 205
          Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
              210 215 220
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
          225 230 235 240
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
                          245 250 255
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
                      260 265 270
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
                  275 280 285
          Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
              290 295 300
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
          305 310 315 320
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
                          325 330 335
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
                      340 345 350
          Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
                  355 360 365
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
              370 375 380
          Gly Lys
          385
           <![CDATA[ <210> 763]]>
           <![CDATA[ <211> 389]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(I97T/A145R)-GGGGSGGGGSGGGGS-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 763]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Thr Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Phe
                          165 170 175
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      180 185 190
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  195 200 205
          Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
              210 215 220
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
          225 230 235 240
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          245 250 255
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
                      260 265 270
          Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  275 280 285
          Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
              290 295 300
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          305 310 315 320
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          325 330 335
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
                      340 345 350
          Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
                  355 360 365
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              370 375 380
          Leu Ser Leu Gly Lys
          385
           <![CDATA[ <210> 764]]>
           <![CDATA[ <211> 401]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF(I97T/A145R)-GGGGSGGGGSGGGGS-ESKYGPPCPPCP-nivolumab Fc fusion protein]]>
           <![CDATA[ <400> 764]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Thr Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly
          145 150 155 160
          Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
                          165 170 175
          Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
                      180 185 190
          Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
                  195 200 205
          Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
              210 215 220
          Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
          225 230 235 240
          Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
                          245 250 255
          Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
                      260 265 270
          Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
                  275 280 285
          Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
              290 295 300
          Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
          305 310 315 320
          Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
                          325 330 335
          Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
                      340 345 350
          Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
                  355 360 365
          Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
              370 375 380
          Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
          385 390 395 400
          Lys
           <![CDATA[ <210> 765]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein K65W]]>
           <![CDATA[ <400> 765]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Trp Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 766]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143Y]]>
           <![CDATA[ <400> 766]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Tyr Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 767]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143F]]>
           <![CDATA[ <400> 767]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Phe Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 768]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143N]]>
           <![CDATA[ <400> 768]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asn Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 769]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143E]]>
           <![CDATA[ <400> 769]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Glu Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 770]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143W]]>
           <![CDATA[ <400> 770]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Trp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 771]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143V]]>
           <![CDATA[ <400> 771]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Val Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 772]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145R]]>
           <![CDATA[ <400> 772]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 773]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145H]]>
           <![CDATA[ <400> 773]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          His Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 774]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145K]]>
           <![CDATA[ <400> 774]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Lys Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 775]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145F]]>
           <![CDATA[ <400> 775]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Phe Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 776]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145W]]>
           <![CDATA[ <400> 776]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Trp Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 777]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein E146Q]]>
           <![CDATA[ <400> 777]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Gln Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 778]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein E146H]]>
           <![CDATA[ <400> 778]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala His Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 779]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein E146K]]>
           <![CDATA[ <400> 779]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Lys Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 780]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein E146N]]>
           <![CDATA[ <400> 780]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Asn Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 781]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143N/A145R]]>
           <![CDATA[ <400> 781]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asn Phe
              130 135 140
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 782]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145R/S147T]]>
           <![CDATA[ <400> 782]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Thr Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 783]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein Q88N/T89S/A145S/E146A/S147D]]>
           <![CDATA[ <400> 783]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Asn Ser Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ser Ala Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 784]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein Q88N/A145I/E146G/S147D]]>
           <![CDATA[ <400> 784]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Asn Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ile Gly Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 785]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145H/E146S/S147D]]>
           <![CDATA[ <400> 785]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          His Ser Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 786]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145H/S147D]]>
           <![CDATA[ <400> 786]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          His Glu Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 787]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein L29V/A145D/E146D/S147D]]>
           <![CDATA[ <400> 787]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Val Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Asp Asp Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 788]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145N/E146D/S147D]]>
           <![CDATA[ <400> 788]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Asn Asp Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 789]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145T/E146S/S147D]]>
           <![CDATA[ <400> 789]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Thr Ser Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 790]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145Q/E146D/S147D]]>
           <![CDATA[ <400> 790]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Gln Asp Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 791]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145T/E146D/S147D]]>
           <![CDATA[ <400> 791]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Thr Asp Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 792]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145D/E146G/S147D]]>
           <![CDATA[ <400> 792]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Asp Gly Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 793]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145D/S147D]]>
           <![CDATA[ <400> 793]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Asp Glu Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 794]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145K/E146D/S147T]]>
           <![CDATA[ <400> 794]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Lys Asp Thr Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 795]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145R/E146T/S147D]]>
           <![CDATA[ <400> 795]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Thr Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 796]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein A145R/S147T]]>
           <![CDATA[ <400> 796]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Arg Glu Thr Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 797]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein E146D/S147D]]>
           <![CDATA[ <400> 797]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Asp Asp Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 798]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143V/F144L/A145S]]>
           <![CDATA[ <400> 798]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Val Leu
              130 135 140
          Ser Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 799]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2 selective agonist TNF mutant protein D143V/A145S]]>
           <![CDATA[ <400> 799]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Val Phe
              130 135 140
          Ser Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 800]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNF07 (TNFR2 selective agonist TNF mutant protein S95C/G148C)]]>
           <![CDATA[ <400> 800]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Cys Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Cys Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 801]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2-selective TNF mutant protein A145T]]>
           <![CDATA[ <400> 801]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Thr Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 802]]>
           <![CDATA[ <211> 157]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223>DN-TNF L57Y]]>
           <![CDATA[ <400> 802]]>
          Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
           1 5 10 15
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
                      20 25 30
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                  35 40 45
          Val Val Pro Ser Glu Gly Leu Tyr Tyr Ile Tyr Ser Gln Val Leu Phe
              50 55 60
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
          65 70 75 80
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
                          85 90 95
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
                      100 105 110
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                  115 120 125
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
              130 135 140
          Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
          145 150 155
           <![CDATA[ <210> 803]]>
           <![CDATA[ <211> 472]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> scTNFR2 (human TNFR2 selective single-chain agonist TNF mutein trimer D143N/A145R)]]>
           <![CDATA[ <400> 803]]>
          Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn
           1 5 10 15
          Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala
                      20 25 30
          Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro
                  35 40 45
          Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln
              50 55 60
          Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile
          65 70 75 80
          Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser
                          85 90 95
          Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr
                      100 105 110
          Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg
                  115 120 125
          Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asn Phe Arg Glu Ser
              130 135 140
          Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly Gly Ser Ser
          145 150 155 160
          Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro
                          165 170 175
          Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu
                      180 185 190
          Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser
                  195 200 205
          Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly
              210 215 220
          Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala
          225 230 235 240
          Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro
                          245 250 255
          Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu
                      260 265 270
          Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu
                  275 280 285
          Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asn Phe Arg Glu Ser Gly
              290 295 300
          Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly Gly Gly Ser Ser Ser
          305 310 315 320
          Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro Gln
                          325 330 335
          Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu Leu
                      340 345 350
          Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser Glu
                  355 360 365
          Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly Cys
              370 375 380
          Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala Val
          385 390 395 400
          Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro Cys
                          405 410 415
          Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu Pro
                      420 425 430
          Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu Ser
                  435 440 445
          Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asn Phe Arg Glu Ser Gly Gln
              450 455 460
          Val Tyr Phe Gly Ile Ile Ala Leu
          465 470
           <![CDATA[ <210> 804]]>
           <![CDATA[ <211> 1808]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Chicken]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Chicken tenascin C (TNC)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (110)...(139)]]>
           <![CDATA[ <223> Trimerization domain]]>
           <![CDATA[ <400> 804]]> Met Gly Leu Pro Ser Gln Val Leu Ala Cys Ala Ile Leu Gly Leu Leu 1 5 10 15 Tyr Gln His Ala Ser Gly Gly Leu Ile Lys Arg Ile Ile Arg Gln Lys 20 25 30 Arg Glu Thr Gly Leu Asn Val Thr Leu Pro Glu Asp Asn Gln Pro Val 35 40 45 Val Phe Asn His Val Tyr Asn Ile Lys Leu Pro Val Gly Ser Leu Cys 50 55 60 Ser Val Asp Leu Asp Thr Ala Ser Gly Asp Ala Asp Leu Lys Ala Glu 65 70 75 80 Ile Glu Pro Val Lys Asn Tyr Glu Glu His Thr Val Asn Glu Gly Asn 85 90 95 Gln Ile Val Phe Thr His Arg Ile Asn Ile Pro Arg Arg Ala Cys Gly 100 105 110 Cys Ala Ala Ala Pro Asp Ile Lys Asp Leu Leu Ser Arg Leu Glu Glu 115 120 125 Leu Glu Gly Leu Val Ser Ser Leu Arg Glu Gln Cys Ala Ser Gly Ala 130 135 140 Gly Cys Cys Pro Asn Ser Gln Thr Ala Glu Gly Arg Leu Asp Thr Ala 145 150 155 160 Pro Tyr Cys Ser Gly His Gly Asn Tyr Ser Thr Glu Ile Cys Gly Cys 165 170 175 Val Cys Glu Pro Gly Trp Lys Gly Pro Asn Cys Ser Glu Pro Ala Cys 180 185 190 Pro Arg Asn Cys Leu Asn Arg Gly Leu Cys Val Arg Gly Lys Cys Ile 195 200 205 Cys Glu Glu Gly Phe Thr Gly Glu Asp Cys Ser Gln Ala Ala Cys Pro 210 215 220 Ser Asp Cys Asn Asp Gln Gly Lys Cys Val Asp Gly Val Cys Val Cys 225 230 235 240 Phe Glu Gly Tyr Thr Gly Pro Asp Cys Gly Glu Glu Leu Cys Pro His 245 250 255 Gly Cys Gly Ile His Gly Arg Cys Val Gly Gly Arg Cys Val Cys His 260 265 270 Glu Gly Phe Thr Gly Glu Asp Cys Asn Glu Pro Leu Cys Pro Asn Asn 275 280 285 Cys His Asn Arg Gly Arg Cys Val Asp Asn Glu Cys Val Cys Asp Glu 290 295 300 Gly Tyr Thr Gly Glu Asp Cys Gly Glu Leu Ile Cys Pro Asn Asp Cys 305 310 315 320 Phe Asp Arg Gly Arg Cys Ile Asn Gly Thr Cys Phe Cys Glu Glu Gly 325 330 335 Tyr Thr Gly Glu Asp Cys Gly Glu Leu Thr Cys Pro Asn Asn Cys Asn 340 345 350 Gly Asn Gly Arg Cys Glu Asn Gly Leu Cys Val Cys His Glu Gly Phe 355 360 365 Val Gly Asp Asp Cys Ser Gln Lys Arg Cys Pro Lys Asp Cys Asn Asn 370 375 380 Arg Gly His Cys Val Asp Gly Arg Cys Val Cys His Glu Gly Tyr Leu 385 390 395 400 Gly Glu Asp Cys Gly Glu Leu Arg Cys Pro Asn Asp Cys His Asn Arg 405 410 415 Gly Arg Cys Ile Asn Gly Gln Cys Val Cys Asp Glu Gly Phe Ile Gly 420 425 430 Glu Asp Cys Gly Glu Leu Arg Cys Pro Asn Asp Cys His Asn Arg Gly 435 440 445 Arg Cys Val Asn Gly Gln Cys Glu Cys His Glu Gly Phe Ile Gly Glu 450 455 460 Asp Cys Gly Glu Leu Arg Cys Pro Asn Asp Cys Asn Ser His Gly Arg 465 470 475 480 Cys Val Asn Gly Gln Cys Val Cys Asp Glu Gly Tyr Thr Gly Glu Asp 485 490 495 Cys Gly Glu Leu Arg Cys Pro Asn Asp Cys His Asn Arg Gly Arg Cys 500 505 510 Val Glu Gly Arg Cys Val Cys Asp Asn Gly Phe Met Gly Glu Asp Cys 515 520 525 Gly Glu Leu Ser Cys Pro Asn Asp Cys His Gln His Gly Arg Cys Val 530 535 540 Asp Gly Arg Cys Val Cys His Glu Gly Phe Thr Gly Glu Asp Cys Arg 545 550 555 560 Glu Arg Ser Cys Pro Asn Asp Cys Asn Asn Val Gly Arg Cys Val Glu 565 570 575 Gly Arg Cys Val Cys Glu Glu Gly Tyr Met Gly Ile Asp Cys Ser Asp 580 585 590 Val Ser Pro Pro Thr Glu Leu Thr Val Thr Asn Val Thr Asp Lys Thr 595 600 605 Val Asn Leu Glu Trp Lys His Glu Asn Leu Val Asn Glu Tyr Leu Val 610 615 620 Thr Tyr Val Pro Thr Ser Ser Gly Gly Leu Asp Leu Gln Phe Thr Val 625 630 635 640 Pro Gly Asn Gln Thr Ser Ala Thr Ile His Glu Leu Glu Pro Gly Val 645 650 655 Glu Tyr Phe Ile Arg Val Phe Ala Ile Leu Lys Asn Lys Lys Ser Ile 660 665 670 Pro Val Ser Ala Arg Val Ala Thr Tyr Leu Pro Ala Pro Glu Gly Leu 675 680 685 Lys Phe Lys Ser Val Arg Glu Thr Ser Val Gln Val Glu Trp Asp Pro 690 695 700 Leu Ser Ile Ser Phe Asp Gly Trp Glu Leu Val Phe Arg Asn Met Gln 705 710 715 720 Lys Lys Asp Asp Asn Gly Asp Ile Thr Ser Ser Leu Lys Arg Pro Glu 725 730 735 Thr Ser Tyr Met Gln Pro Gly Leu Ala Pro Gly Gln Gln Tyr Asn Val 740 745 750 Ser Leu His Ile Val Lys Asn Asn Thr Arg Gly Pro Gly Leu Ser Arg 755 760 765 Val Ile Thr Thr Lys Leu Asp Ala Pro Ser Gln Ile Glu Ala Lys Asp 770 775 780 Val Thr Asp Thr Thr Ala Leu Ile Thr Trp Ser Lys Pro Leu Ala Glu 785 790 795 800 Ile Glu Gly Ile Glu Leu Thr Tyr Gly Pro Lys Asp Val Pro Gly Asp 805 810 815 Arg Thr Thr Ile Asp Leu Ser Glu Asp Glu Asn Gln Tyr Ser Ile Gly 820 825 830 Asn Leu Arg Pro His Thr Glu Tyr Glu Val Thr Leu Ile Ser Arg Arg 835 840 845 Gly Asp Met Glu Ser Asp Pro Ala Lys Glu Val Phe Val Thr Asp Leu 850 855 860 Asp Ala Pro Arg Asn Leu Lys Arg Val Ser Gln Thr Asp Asn Ser Ile 865 870 875 880 Thr Leu Glu Trp Lys Asn Ser His Ala Asn Ile Asp Asn Tyr Arg Ile 885 890 895 Lys Phe Ala Pro Ile Ser Gly Gly Asp His Thr Glu Leu Thr Val Pro 900 905 910 Lys Gly Asn Gln Ala Thr Thr Arg Ala Thr Leu Thr Gly Leu Arg Pro 915 920 925 Gly Thr Glu Tyr Gly Ile Gly Val Thr Ala Val Arg Gln Asp Arg Glu 930 935 940 Ser Ala Pro Ala Thr Ile Asn Ala Gly Thr Asp Leu Asp Asn Pro Lys 945 950 955 960 Asp Leu Glu Val Ser Asp Pro Thr Glu Thr Thr Leu Ser Leu Arg Trp 965 970 975 Arg Arg Pro Val Ala Lys Phe Asp Arg Tyr Arg Leu Thr Tyr Val Ser 980 985 990 Pro Ser Gly Lys Lys Asn Glu Met Glu Ile Pro Val Asp Ser Thr Ser 995 1000 1005 Phe Ile Leu Arg Gly Leu Asp Ala Gly Thr Glu Tyr Thr Ile Ser Leu 1010 1015 1020 Val Ala Glu Lys Gly Arg His Lys Ser Lys Pro Thr Thr Ile Lys Gly 1025 1030 1035 1040 Ser Thr Glu Glu Glu Pro Glu Leu Gly Asn Leu Ser Val Ser Glu Thr 1045 1050 1055 Gly Trp Asp Gly Phe Gln Leu Thr Trp Thr Ala Ala Asp Gly Ala Tyr 1060 1065 1070 Glu Asn Phe Val Ile Gln Val Gln Gln Ser Asp Asn Pro Glu Glu Thr 1075 1080 1085 Trp Asn Ile Thr Val Pro Gly Gly Gln His Ser Val Asn Val Thr Gly 1090 1095 1100 Leu Lys Ala Asn Thr Pro Tyr Asn Val Thr Leu Tyr Gly Val Ile Arg 1105 1110 1115 1120 Gly Tyr Arg Thr Lys Pro Leu Tyr Val Glu Thr Thr Thr Gly Ala His 1125 1130 1135 Pro Glu Val Gly Glu Leu Thr Val Ser Asp Ile Thr Pro Glu Ser Phe 1140 1145 1150 Asn Leu Ser Trp Thr Thr Thr Asn Gly Asp Phe Asp Ala Phe Thr Ile 1155 1160 1165 Glu Ile Ile Asp Ser Asn Arg Leu Leu Glu Pro Met Glu Phe Asn Ile 1170 1175 1180 Ser Gly Asn Ser Arg Thr Ala His Ile Ser Gly Leu Ser Pro Ser Thr 1185 1190 1195 1200 Asp Phe Ile Val Tyr Leu Tyr Gly Ile Ser His Gly Phe Arg Thr Gln 1205 1210 1215 Ala Ile Ser Ala Ala Ala Thr Thr Glu Ala Glu Pro Glu Val Asp Asn 1220 1225 1230 Leu Leu Val Ser Asp Ala Thr Pro Asp Gly Phe Arg Leu Ser Trp Thr 1235 1240 1245 Ala Asp Asp Gly Val Phe Asp Ser Phe Val Leu Lys Ile Arg Asp Thr 1250 1255 1260 Lys Arg Lys Ser Asp Pro Leu Glu Leu Ile Val Pro Gly His Glu Arg 1265 1270 1275 1280 Thr His Asp Ile Thr Gly Leu Lys Glu Gly Thr Glu Tyr Glu Ile Glu 1285 1290 1295 Leu Tyr Gly Val Ser Ser Gly Arg Arg Ser Gln Pro Ile Asn Ser Val 1300 1305 1310 Ala Thr Thr Val Val Gly Ser Pro Lys Gly Ile Ser Phe Ser Asp Ile 1315 1320 1325 Thr Glu Asn Ser Ala Thr Val Ser Trp Thr Pro Pro Arg Ser Arg Val 1330 1335 1340 Asp Ser Tyr Arg Val Ser Tyr Val Pro Ile Thr Gly Gly Thr Pro Asn 1345 1350 1355 1360 Val Val Thr Val Asp Gly Ser Lys Thr Arg Thr Lys Leu Val Lys Leu 1365 1370 1375 Val Pro Gly Val Asp Tyr Asn Val Asn Ile Ile Ser Val Lys Gly Phe 1380 1385 1390 Glu Glu Ser Glu Pro Ile Ser Gly Ile Leu Lys Thr Ala Leu Asp Ser 1395 1400 1405 Pro Ser Gly Leu Val Val Met Asn Ile Thr Asp Ser Glu Ala Leu Ala 1410 1415 1420 Thr Trp Gln Pro Ala Ile Ala Ala Ala Val Asp Asn Tyr Ile Val Ser Tyr 1425 1430 1435 1440 Ser Ser Glu Asp Glu Pro Glu Val Thr Gln Met Val Ser Gly Asn Thr 1445 1450 1455 Val Glu Tyr Asp Leu Asn Gly Leu Arg Pro Ala Thr Glu Tyr Thr Leu 1460 1465 1470 Arg Val His Ala Val Lys Asp Ala Gln Lys Ser Glu Thr Leu Ser Thr 1475 1480 1485 Gln Phe Thr Thr Gly Leu Asp Ala Pro Lys Asp Leu Ser Ala Thr Glu 1490 1495 1500 Val Gln Ser Glu Thr Ala Val Ile Thr Trp Arg Pro Pro Arg Ala Pro 1505 1510 1515 1520 Val Thr Asp Tyr Leu Leu Thr Tyr Glu Ser Ile Asp Gly Arg Val Lys 1525 1530 1535 Glu Val Ile Leu Asp Pro Glu Thr Thr Ser Tyr Thr Leu Thr Glu Leu 1540 1545 1550 Ser Pro Ser Thr Gln Tyr Thr Val Lys Leu Gln Ala Leu Ser Arg Ser 1555 1560 1565 Met Arg Ser Lys Met Ile Gln Thr Val Phe Thr Thr Thr Gly Leu Leu 1570 1575 1580 Tyr Pro Tyr Pro Lys Asp Cys Ser Gln Ala Leu Leu Asn Gly Glu Val 1585 1590 1595 1600 Thr Ser Gly Leu Tyr Thr Ile Tyr Leu Asn Gly Asp Arg Thr Gln Pro 1605 1610 1615 Val Leu Gln Phe Cys Asp Met Ala Glu Asp Gly Gly Gly Trp Ile Val 1620 1625 1630 Phe Leu Arg Arg Gln Asn Gly Lys Glu Asp Phe Tyr Arg Asn Trp Lys 1635 1640 1645 Asn Tyr Val Ala Gly Phe Gly Asp Pro Lys Asp Glu Phe Trp Ile Gly 1650 1655 1660 Leu Glu Asn Leu His Lys Ile Ser Ser Gln Gly Gln Tyr Glu Leu Arg 1665 1670 1675 1680 Val Asp Leu Arg Asp Arg Gly Glu Thr Ala Tyr Ala Val Tyr Asp Lys 1685 1690 1695 Phe Ser Val Gly Asp Ala Lys Thr Arg Tyr Arg Leu Arg Val Asp Gly 1700 1705 1710 Tyr Ser Gly Thr Ala Gly Asp Ser Met Thr Tyr His Asn Gly Arg Ser 1715 1720 1725 Phe Ser Thr Phe Asp Lys Asp Asn Asp Ser Ala Ile Thr Asn Cys Ala 1730 1735 1740 Leu Ser Tyr Lys Gly Ala Phe Trp Tyr Lys Asn Cys His Arg Val Asn 1745 1750 1755 1760 Leu Met Gly Arg Tyr Gly Asp Asn Asn His Ser Gln Gly Val Asn Trp 1765 1770 1775 Phe His Trp Lys Gly His Glu Tyr Ser Ile Gln Phe Ala Glu Met Lys 1780 1785 1790 Leu Arg Pro Ser Ser Phe Arg Asn Leu Glu Gly Arg Arg Lys Arg Ala 1795 1800 1805 <![CDATA[ <210> 805]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Chicken]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Trimerization domain of chicken tenascin C (TNC)]]>
           <![CDATA[ <400> 805]]>
          Ala Cys Gly Cys Ala Ala Ala Pro Asp Ile Lys Asp Leu Leu Ser Arg
           1 5 10 15
          Leu Glu Glu Leu Glu Gly Leu Val Ser Ser Leu Arg Glu Gln
                      20 25 30
           <![CDATA[ <210> 806]]>
           <![CDATA[ <211> 2201]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human tenascin C (TNC)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (110)...(139)]]>
           <![CDATA[ <223> Trimerization domain]]>
           <![CDATA[ <400> 806]]> Met Gly Ala Met Thr Gln Leu Leu Ala Gly Val Phe Leu Ala Phe Leu 1 5 10 15 Ala Leu Ala Thr Glu Gly Gly Val Leu Lys Lys Val Ile Arg His Lys 20 25 30 Arg Gln Ser Gly Val Asn Ala Thr Leu Pro Glu Glu Asn Gln Pro Val 35 40 45 Val Phe Asn His Val Tyr Asn Ile Lys Leu Pro Val Gly Ser Gln Cys 50 55 60 Ser Val Asp Leu Glu Ser Ala Ser Gly Glu Lys Asp Leu Ala Pro Pro 65 70 75 80 Ser Glu Pro Ser Glu Ser Phe Gln Glu His Thr Val Asp Gly Glu Asn 85 90 95 Gln Ile Val Phe Thr His Arg Ile Asn Ile Pro Arg Arg Ala Cys Gly 100 105 110 Cys Ala Ala Ala Pro Asp Val Lys Glu Leu Leu Ser Arg Leu Glu Glu 115 120 125 Leu Glu Asn Leu Val Ser Ser Leu Arg Glu Gln Cys Thr Ala Gly Ala 130 135 140 Gly Cys Cys Leu Gln Pro Ala Thr Gly Arg Leu Asp Thr Arg Pro Phe 145 150 155 160 Cys Ser Gly Arg Gly Asn Phe Ser Thr Glu Gly Cys Gly Cys Val Cys 165 170 175 Glu Pro Gly Trp Lys Gly Pro Asn Cys Ser Glu Pro Glu Cys Pro Gly 180 185 190 Asn Cys His Leu Arg Gly Arg Cys Ile Asp Gly Gln Cys Ile Cys Asp 195 200 205 Asp Gly Phe Thr Gly Glu Asp Cys Ser Gln Leu Ala Cys Pro Ser Asp 210 215 220 Cys Asn Asp Gln Gly Lys Cys Val Asn Gly Val Cys Ile Cys Phe Glu 225 230 235 240 Gly Tyr Ala Gly Ala Asp Cys Ser Arg Glu Ile Cys Pro Val Pro Cys 245 250 255 Ser Glu Glu His Gly Thr Cys Val Asp Gly Leu Cys Val Cys His Asp 260 265 270 Gly Phe Ala Gly Asp Asp Asp Cys Asn Lys Pro Leu Cys Leu Asn Asn Cys 275 280 285 Tyr Asn Arg Gly Arg Cys Val Glu Asn Glu Cys Val Cys Asp Glu Gly 290 295 300 Phe Thr Gly Glu Asp Cys Ser Glu Leu Ile Cys Pro Asn Asp Cys Phe 305 310 315 320 Asp Arg Gly Arg Cys Ile Asn Gly Thr Cys Tyr Cys Glu Glu Gly Phe 325 330 335 Thr Gly Glu Asp Cys Gly Lys Pro Thr Cys Pro His Ala Cys His Thr 340 345 350 Gln Gly Arg Cys Glu Glu Gly Gln Cys Val Cys Asp Glu Gly Phe Ala 355 360 365 Gly Val Asp Cys Ser Glu Lys Arg Cys Pro Ala Asp Cys His Asn Arg 370 375 380 Gly Arg Cys Val Asp Gly Arg Cys Glu Cys Asp Asp Gly Phe Thr Gly 385 390 395 400 Ala Asp Cys Gly Glu Leu Lys Cys Pro Asn Gly Cys Ser Gly His Gly 405 410 415 Arg Cys Val Asn Gly Gln Cys Val Cys Asp Glu Gly Tyr Thr Gly Glu 420 425 430 Asp Cys Ser Gln Leu Arg Cys Pro Asn Asp Cys His Ser Arg Gly Arg 435 440 445 Cys Val Glu Gly Lys Cys Val Cys Glu Gln Gly Phe Lys Gly Tyr Asp 450 455 460 Cys Ser Asp Met Ser Cys Pro Asn Asp Cys His Gln His Gly Arg Cys 465 470 475 480 Val Asn Gly Met Cys Val Cys Asp Asp Gly Tyr Thr Gly Glu Asp Cys 485 490 495 Arg Asp Arg Gln Cys Pro Arg Asp Cys Ser Asn Arg Gly Leu Cys Val 500 505 510 Asp Gly Gln Cys Val Cys Glu Asp Gly Phe Thr Gly Pro Asp Cys Ala 515 520 525 Glu Leu Ser Cys Pro Asn Asp Cys His Gly Gln Gly Arg Cys Val Asn 530 535 540 Gly Gln Cys Val Cys His Glu Gly Phe Met Gly Lys Asp Cys Lys Glu 545 550 555 560 Gln Arg Cys Pro Ser Asp Cys His Gly Gln Gly Arg Cys Val Asp Gly 565 570 575 Gln Cys Ile Cys His Glu Gly Phe Thr Gly Leu Asp Cys Gly Gln His 580 585 590 Ser Cys Pro Ser Asp Cys Asn Asn Leu Gly Gln Cys Val Ser Gly Arg 595 600 605 Cys Ile Cys Asn Glu Gly Tyr Ser Gly Glu Asp Cys Ser Glu Val Ser 610 615 620 Pro Pro Lys Asp Leu Val Val Thr Glu Val Thr Glu Glu Thr Val Asn 625 630 635 640 Leu Ala Trp Asp Asn Glu Met Arg Val Thr Glu Tyr Leu Val Val Tyr 645 650 655 Thr Pro Thr His Glu Gly Gly Leu Glu Met Gln Phe Arg Val Pro Gly 660 665 670 Asp Gln Thr Ser Thr Ile Ile Gln Glu Leu Glu Pro Gly Val Glu Tyr 675 680 685 Phe Ile Arg Val Phe Ala Ile Leu Glu Asn Lys Lys Ser Ile Pro Val 690 695 700 Ser Ala Arg Val Ala Thr Tyr Leu Pro Ala Pro Glu Gly Leu Lys Phe 705 710 715 720 Lys Ser Ile Lys Glu Thr Ser Val Glu Val Glu Trp Asp Pro Leu Asp 725 730 735 Ile Ala Phe Glu Thr Trp Glu Ile Ile Phe Arg Asn Met Asn Lys Glu 740 745 750 Asp Glu Gly Glu Ile Thr Lys Ser Leu Arg Arg Pro Glu Thr Ser Tyr 755 760 765 Arg Gln Thr Gly Leu Ala Pro Gly Gln Glu Tyr Glu Ile Ser Leu His 770 775 780 Ile Val Lys Asn Asn Thr Arg Gly Pro Gly Leu Lys Arg Val Thr Thr 785 790 795 800 Thr Arg Leu Asp Ala Pro Ser Gln Ile Glu Val Lys Asp Val Thr Asp 805 810 815 Thr Thr Ala Leu Ile Thr Trp Phe Lys Pro Leu Ala Glu Ile Asp Gly 820 825 830 Ile Glu Leu Thr Tyr Gly Ile Lys Asp Val Pro Gly Asp Arg Thr Thr 835 840 845 Ile Asp Leu Thr Glu Asp Glu Asn Gln Tyr Ser Ile Gly Asn Leu Lys 850 855 860 Pro Asp Thr Glu Tyr Glu Val Ser Leu Ile Ser Arg Arg Gly Asp Met 865 870 875 880 Ser Ser Asn Pro Ala Lys Glu Thr Phe Thr Thr Gly Leu Asp Ala Pro 885 890 895 Arg Asn Leu Arg Arg Val Ser Gln Thr Asp Asn Ser Ile Thr Leu Glu 900 905 910 Trp Arg Asn Gly Lys Ala Ala Ile Asp Ser Tyr Arg Ile Lys Tyr Ala 915 920 925 Pro Ile Ser Gly Gly Asp His Ala Glu Val Asp Val Pro Lys Ser Gln 930 935 940 Gln Ala Thr Thr Lys Thr Thr Leu Thr Gly Leu Arg Pro Gly Thr Glu 945 950 955 960 Tyr Gly Ile Gly Val Ser Ala Val Lys Glu Asp Lys Glu Ser Asn Pro 965 970 975 Ala Thr Ile Asn Ala Ala Thr Glu Leu Asp Thr Pro Lys Asp Leu Gln 980 985 990 Val Ser Glu Thr Ala Glu Thr Ser Leu Thr Leu Leu Trp Lys Thr Pro 995 1000 1005 Leu Ala Lys Phe Asp Arg Tyr Arg Leu Asn Tyr Ser Leu Pro Thr Gly 1010 1015 1020 Gln Trp Val Gly Val Gln Leu Pro Arg Asn Thr Thr Ser Tyr Val Leu 1025 1030 1035 1040 Arg Gly Leu Glu Pro Gly Gln Glu Tyr Asn Val Leu Leu Thr Ala Glu 1045 1050 1055 Lys Gly Arg His Lys Ser Lys Pro Ala Arg Val Lys Ala Ser Thr Glu 1060 1065 1070 Gln Ala Pro Glu Leu Glu Asn Leu Thr Val Thr Glu Val Gly Trp Asp 1075 1080 1085 Gly Leu Arg Leu Asn Trp Thr Ala Ala Asp Gln Ala Tyr Glu His Phe 1090 1095 1100 Ile Ile Gln Val Gln Glu Ala Asn Lys Val Glu Ala Ala Arg Asn Leu 1105 1110 1115 1120 Thr Val Pro Gly Ser Leu Arg Ala Val Asp Ile Pro Gly Leu Lys Ala 1125 1130 1135 Ala Thr Pro Tyr Thr Val Ser Ile Tyr Gly Val Ile Gln Gly Tyr Arg 1140 1145 1150 Thr Pro Val Leu Ser Ala Glu Ala Ser Thr Gly Glu Thr Pro Asn Leu 1155 1160 1165 Gly Glu Val Val Val Val Ala Glu Val Gly Trp Asp Ala Leu Lys Leu Asn 1170 1175 1180 Trp Thr Ala Pro Glu Gly Ala Tyr Glu Tyr Phe Phe Ile Gln Val Gln 1185 1190 1195 1200 Glu Ala Asp Thr Val Glu Ala Ala Gln Asn Leu Thr Val Pro Gly Gly 1205 1210 1215 Leu Arg Ser Thr Asp Leu Pro Gly Leu Lys Ala Ala Thr His Tyr Thr 1220 1225 1230 Ile Thr Ile Arg Gly Val Thr Gln Asp Phe Ser Thr Thr Pro Leu Ser 1235 1240 1245 Val Glu Val Leu Thr Glu Glu Val Pro Asp Met Gly Asn Leu Thr Val 1250 1255 1260 Thr Glu Val Ser Trp Asp Ala Leu Arg Leu Asn Trp Thr Thr Pro Asp 1265 1270 1275 1280 Gly Thr Tyr Asp Gln Phe Thr Ile Gln Val Gln Glu Ala Asp Gln Val 1285 1290 1295 Glu Glu Ala His Asn Leu Thr Val Pro Gly Ser Leu Arg Ser Met Glu 1300 1305 1310 Ile Pro Gly Leu Arg Ala Gly Thr Pro Tyr Thr Val Thr Leu His Gly 1315 1320 1325 Glu Val Arg Gly His Ser Thr Arg Pro Leu Ala Val Glu Val Val Thr 1330 1335 1340 Glu Asp Leu Pro Gln Leu Gly Asp Leu Ala Val Ser Glu Val Gly Trp 1345 1350 1355 1360 Asp Gly Leu Arg Leu Asn Trp Thr Ala Ala Asp Asn Ala Tyr Glu His 1365 1370 1375 Phe Val Ile Gln Val Gln Glu Val Asn Lys Val Glu Ala Ala Gln Asn 1380 1385 1390 Leu Thr Leu Pro Gly Ser Leu Arg Ala Val Asp Ile Pro Gly Leu Glu 1395 1400 1405 Ala Ala Thr Pro Tyr Arg Val Ser Ile Tyr Gly Val Ile Arg Gly Tyr 1410 1415 1420 Arg Thr Pro Val Leu Ser Ala Glu Ala Ser Thr Ala Lys Glu Pro Glu 1425 1430 1435 1440 Ile Gly Asn Leu Asn Val Ser Asp Ile Thr Pro Glu Ser Phe Asn Leu 1445 1450 1455 Ser Trp Met Ala Thr Asp Gly Ile Phe Glu Thr Phe Thr Ile Glu Ile 1460 1465 1470 Ile Asp Ser Asn Arg Leu Leu Glu Thr Val Glu Tyr Asn Ile Ser Gly 1475 1480 1485 Ala Glu Arg Thr Ala His Ile Ser Gly Leu Pro Pro Ser Thr Asp Phe 1490 1495 1500 Ile Val Tyr Leu Ser Gly Leu Ala Pro Ser Ile Arg Thr Lys Thr Ile 1505 1510 1515 1520 Ser Ala Thr Ala Thr Thr Glu Ala Leu Pro Leu Leu Glu Asn Leu Thr 1525 1530 1535 Ile Ser Asp Ile Asn Pro Tyr Gly Phe Thr Val Ser Trp Met Ala Ser 1540 1545 1550 Glu Asn Ala Phe Asp Ser Phe Leu Val Thr Val Val Asp Ser Gly Lys 1555 1560 1565 Leu Leu Asp Pro Gln Glu Phe Thr Leu Ser Gly Thr Gln Arg Lys Leu 1570 1575 1580 Glu Leu Arg Gly Leu Ile Thr Gly Ile Gly Tyr Glu Val Met Val Ser 1585 1590 1595 1600 Gly Phe Thr Gln Gly His Gln Thr Lys Pro Leu Arg Ala Glu Ile Val 1605 1610 1615 Thr Glu Ala Glu Pro Glu Val Asp Asn Leu Leu Val Ser Asp Ala Thr 1620 1625 1630 Pro Asp Gly Phe Arg Leu Ser Trp Thr Ala Asp Glu Gly Val Phe Asp 1635 1640 1645 Asn Phe Val Leu Lys Ile Arg Asp Thr Lys Lys Gln Ser Glu Pro Leu 1650 1655 1660 Glu Ile Thr Leu Leu Ala Pro Glu Arg Thr Arg Asp Ile Thr Gly Leu 1665 1670 1675 1680 Arg Glu Ala Thr Glu Tyr Glu Ile Glu Leu Tyr Gly Ile Ser Lys Gly 1685 1690 1695 Arg Arg Ser Gln Thr Val Ser Ala Ile Ala Thr Thr Ala Met Gly Ser 1700 1705 1710 Pro Lys Glu Val Ile Phe Ser Asp Ile Thr Glu Asn Ser Ala Thr Val 1715 1720 1725 Ser Trp Arg Ala Pro Thr Ala Gln Val Glu Ser Phe Arg Ile Thr Tyr 1730 1735 1740 Val Pro Ile Thr Gly Gly Thr Pro Ser Met Val Thr Val Asp Gly Thr 1745 1750 1755 1760 Lys Thr Gln Thr Arg Leu Val Lys Leu Ile Pro Gly Val Glu Tyr Leu 1765 1770 1775 Val Ser Ile Ile Ala Met Lys Gly Phe Glu Glu Ser Glu Pro Val Ser 1780 1785 1790 Gly Ser Phe Thr Thr Ala Leu Asp Gly Pro Ser Gly Leu Val Thr Ala 1795 1800 1805 Asn Ile Thr Asp Ser Glu Ala Leu Ala Arg Trp Gln Pro Ala Ile Ala 1810 1815 1820 Thr Val Asp Ser Tyr Val Ile Ser Tyr Thr Gly Glu Lys Val Pro Glu 1825 1830 1835 1840 Ile Thr Arg Thr Val Ser Gly Asn Thr Val Glu Tyr Ala Leu Thr Asp 1845 1850 1855 Leu Glu Pro Ala Thr Glu Tyr Thr Leu Arg Ile Phe Ala Glu Lys Gly 1860 1865 1870 Pro Gln Lys Ser Ser Thr Ile Thr Ala Lys Phe Thr Thr Asp Leu Asp 1875 1880 1885 Ser Pro Arg Asp Leu Thr Ala Thr Glu Val Gln Ser Glu Thr Ala Leu 1890 1895 1900 Leu Thr Trp Arg Pro Pro Arg Ala Ser Val Thr Gly Tyr Leu Leu Val 1905 1910 1915 1920 Tyr Glu Ser Val Asp Gly Thr Val Lys Glu Val Ile Val Gly Pro Asp 1925 1930 1935 Thr Thr Ser Tyr Ser Leu Ala Asp Leu Ser Pro Ser Thr His Tyr Thr 1940 1945 1950 Ala Lys Ile Gln Ala Leu Asn Gly Pro Leu Arg Ser Asn Met Ile Gln 1955 1960 1965 Thr Ile Phe Thr Thr Ile Gly Leu Leu Tyr Pro Phe Pro Lys Asp Cys 1970 1975 1980 Ser Gln Ala Met Leu Asn Gly Asp Thr Thr Ser Gly Leu Tyr Thr Ile 1985 1990 1995 2000 Tyr Leu Asn Gly Asp Lys Ala Glu Ala Leu Glu Val Phe Cys Asp Met 2005 2010 2015 Thr Ser Asp Gly Gly Gly Trp Ile Val Phe Leu Arg Arg Lys Asn Gly 2020 2025 2030 Arg Glu Asn Phe Tyr Gln Asn Trp Lys Ala Tyr Ala Ala Ala Gly Phe Gly 2035 2040 2045 Asp Arg Arg Glu Glu Phe Trp Leu Gly Leu Asp Asn Leu Asn Lys Ile 2050 2055 2060 Thr Ala Gln Gly Gln Tyr Glu Leu Arg Val Asp Leu Arg Asp His Gly 2065 2070 2075 2080 Glu Thr Ala Phe Ala Val Tyr Asp Lys Phe Ser Val Gly Asp Ala Lys 2085 2090 2095 Thr Arg Tyr Lys Leu Lys Val Glu Gly Tyr Ser Gly Thr Ala Gly Asp 2100 2105 2110 Ser Met Ala Tyr His Asn Gly Arg Ser Phe Ser Thr Phe Asp Lys Asp 2115 2120 2125 Thr Asp Ser Ala Ile Thr Asn Cys Ala Leu Ser Tyr Lys Gly Ala Phe 2130 2135 2140 Trp Tyr Arg Asn Cys His Arg Val Asn Leu Met Gly Arg Tyr Gly Asp 2145 2150 2155 2160 Asn Asn His Ser Gln Gly Val Asn Trp Phe His Trp Lys Gly His Glu 2165 2170 2175 His Ser Ile Gln Phe Ala Glu Met Lys Leu Arg Pro Ser Asn Phe Arg 2180 2185 2190 Asn Leu Glu Gly Arg Arg Lys Arg Ala 2195 2200 <![CDATA[ <210> 807]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Trimerization domain of human tenascin C (TNC)]]>
           <![CDATA[ <400> 807]]>
          Ala Cys Gly Cys Ala Ala Ala Pro Asp Val Lys Glu Leu Leu Ser Arg
           1 5 10 15
          Leu Glu Glu Leu Glu Asn Leu Val Ser Ser Leu Arg Glu Gln
                      20 25 30
           <![CDATA[ <210> 808]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> EHD2 dimerization domain]]>
           <![CDATA[ <400> 808]]>
          Asp Phe Thr Pro Pro Thr Val Lys Ile Leu Gln Ser Ser Cys Asp Gly
           1 5 10 15
          Gly Gly His Phe Pro Pro Thr Ile Gln Leu Leu Cys Leu Val Ser Gly
                      20 25 30
          Tyr Thr Pro Gly Thr Ile Asn Ile Thr Trp Leu Glu Asp Gly Gln Val
                  35 40 45
          Met Asp Val Asp Leu Ser Thr Ala Ser Thr Thr Gln Glu Gly Glu Leu
              50 55 60
          Ala Ser Thr Gln Ser Glu Leu Thr Leu Ser Gln Lys His Trp Leu Ser
          65 70 75 80
          Asp Arg Thr Tyr Thr Cys Gln Val Thr Tyr Gln Gly His Thr Phe Glu
                          85 90 95
          Asp Ser Thr Lys Lys Cys Ala Asp Ser Asn
                      100 105
           <![CDATA[ <210> 809]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide linker between EHD2 and scTNFR2 in EHD2-scTNFR2]]>
           <![CDATA[ <400> 809]]>
          Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
           1 5 10 15
          Gly Gly Gly Ser Gly Gly Ser Glu Phe Leu Ala
                      20 25
           <![CDATA[ <210> 810]]>
           <![CDATA[ <211> 605]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> EHD2-scTNFR2]]>
           <![CDATA[ <400> 810]]>
          Asp Phe Thr Pro Pro Thr Val Lys Ile Leu Gln Ser Ser Cys Asp Gly
           1 5 10 15
          Gly Gly His Phe Pro Pro Thr Ile Gln Leu Leu Cys Leu Val Ser Gly
                      20 25 30
          Tyr Thr Pro Gly Thr Ile Asn Ile Thr Trp Leu Glu Asp Gly Gln Val
                  35 40 45
          Met Asp Val Asp Leu Ser Thr Ala Ser Thr Thr Gln Glu Gly Glu Leu
              50 55 60
          Ala Ser Thr Gln Ser Glu Leu Thr Leu Ser Gln Lys His Trp Leu Ser
          65 70 75 80
          Asp Arg Thr Tyr Thr Cys Gln Val Thr Tyr Gln Gly His Thr Phe Glu
                          85 90 95
          Asp Ser Thr Lys Lys Cys Ala Asp Ser Asn Gly Gly Gly Ser Gly Gly
                      100 105 110
          Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
                  115 120 125
          Ser Glu Phe Leu Ala Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala
              130 135 140
          His Val Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn
          145 150 155 160
          Arg Arg Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn
                          165 170 175
          Gln Leu Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val
                      180 185 190
          Leu Phe Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His
                  195 200 205
          Thr Ile Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu
              210 215 220
          Ser Ala Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu
          225 230 235 240
          Ala Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu
                          245 250 255
          Glu Lys Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu
                      260 265 270
          Asn Phe Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly
                  275 280 285
          Gly Gly Gly Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His
              290 295 300
          Val Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg
          305 310 315 320
          Arg Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln
                          325 330 335
          Leu Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu
                      340 345 350
          Phe Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr
                  355 360 365
          Ile Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser
              370 375 380
          Ala Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala
          385 390 395 400
          Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu
                          405 410 415
          Lys Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asn
                      420 425 430
          Phe Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu Gly Gly
                  435 440 445
          Gly Gly Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
              450 455 460
          Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
          465 470 475 480
          Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
                          485 490 495
          Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
                      500 505 510
          Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
                  515 520 525
          Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
              530 535 540
          Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
          545 550 555 560
          Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
                          565 570 575
          Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asn Phe
                      580 585 590
          Arg Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
                  595 600 605
           <![CDATA[ <210> 811]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> MHD2 (IgM dimerization domain)]]>
           <![CDATA[ <400> 811]]>
          Ala Glu Leu Pro Pro Lys Val Ser Val Phe Val Pro Pro Arg Asp Gly
           1 5 10 15
          Phe Phe Gly Asn Pro Arg Lys Ser Lys Leu Ile Cys Gln Ala Thr Gly
                      20 25 30
          Phe Ser Pro Arg Gln Ile Gln Val Ser Trp Leu Arg Glu Gly Lys Gln
                  35 40 45
          Val Gly Ser Gly Val Thr Thr Asp Gln Val Gln Ala Glu Ala Lys Glu
              50 55 60
          Ser Gly Pro Thr Thr Tyr Lys Val Thr Ser Thr Leu Thr Ile Lys Glu
          65 70 75 80
          Ser Asp Trp Leu Gly Gln Ser Met Phe Thr Cys Arg Val Asp His Arg
                          85 90 95
          Gly Leu Thr Phe Gln Gln Asn Ala Ser Ser Met Cys Val Pro Asp
                      100 105 110
           <![CDATA[ <210> 812]]>
           <![CDATA[ <211> 31]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> The stem region of TNF that can be used as a linker in scTNFR2-Fc]]>
           <![CDATA[ <400> 812]]>
          Gly Pro Gln Arg Glu Glu Phe Pro Arg Asp Leu Ser Leu Ile Ser Pro
           1 5 10 15
          Leu Ala Gln Ala Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys
                      20 25 30
           <![CDATA[ <210> 813]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Part of the trastuzumab hinge sequence]]>
           <![CDATA[ <400> 813]]>
          Ser Cys Asp Lys Thr His
           1 5
           <![CDATA[ <210> 814]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Trastuzumab hinge sequence]]>
           <![CDATA[ <400> 814]]>
          Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
           1 5 10 15
           <![CDATA[ <210> 815]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Nivolumab hinge sequence]]>
           <![CDATA[ <400> 815]]>
          Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
           1 5 10
           <![CDATA[ <210> 816]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 816]]>
          Gly Ser Gly Ser
           1              
           <![CDATA[ <210> 817]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 817]]>
          Gly Gly Gly Gly Ser
           1 5
           <![CDATA[ <210> 818]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 818]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
           1 5 10 15
           <![CDATA[ <210> 819]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 819]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
           1 5 10 15
          Gly Gly Gly Ser
                      20
           <![CDATA[ <210> 820]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 820]]>
          Gly Ser Gly Gly Ser Ser Gly Gly
           1 5
           <![CDATA[ <210> 821]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 821]]>
          Gly Ser Ser Ser Gly Ser Gly Ser Gly Ser Ser Gly
           1 5 10
           <![CDATA[ <210> 822]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 822]]>
          Gly Ser Ser Ser Gly Ser Gly Ser Gly Ser Ser Gly Gly
           1 5 10
           <![CDATA[ <210> 823]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 823]]>
          Gly Gly Ser Ser Gly Gly
           1 5
           <![CDATA[ <210> 824]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 824]]>
          Gly Gly Ser Ser Gly Gly Ser Gly Gly Ser Ser Ser Gly
           1 5 10
           <![CDATA[ <210> 825]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 825]]>
          Gly Ser Ser Ser Gly Ser Gly Ser Gly Gly Ser Ser Ser Gly Ser Gly
           1 5 10 15
          Ser Gly
           <![CDATA[ <210> 826]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 826]]>
          Gly Gly Ser Ser Gly Gly Ser Ser Gly Gly Gly Ser Ser Gly Gly Ser
           1 5 10 15
          Ser Gly
           <![CDATA[ <210> 827]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <400> 827]]>
          Gly Ser Ser Ser Gly Ser
           1 5
           <![CDATA[ <210> 828]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Connector sequence]]>
           <![CDATA[ <400> 828]]>
          Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe
           1 5 10
           <![CDATA[ <210> 829]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Connector sequence]]>
           <![CDATA[ <400> 829]]>
          Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser
           1 5 10 15
          Leu Asp
           <![CDATA[ <210> 830]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Connector sequence]]>
           <![CDATA[ <400> 830]]>
          Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr
           1 5 10
           <![CDATA[ <210> 831]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Connector formed by α-helix, (EAAAK)n]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> REPEAT ]]>
           <![CDATA[ <222> (1)...(5)]]>
           <![CDATA[ <223> appears n times, where n= 1 to 10]]>
           <![CDATA[ <400> 831]]>
          Glu Ala Ala Ala Lys
           1 5
           <![CDATA[ <210> 832]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Rigid linker, A(EAAAK)Na, where n = 2 to 5]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> REPEAT ]]>
           <![CDATA[ <222> (2)...(6)]]>
           <![CDATA[ <223> appears 2, 3, 4 or 5 times]]>
           <![CDATA[ <400> 832]]>
          Ala Glu Ala Ala Ala Lys Ala
           1 5
           <![CDATA[ <210> 833]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> C-terminal extension of human IgG linker]]>
           <![CDATA[ <400> 833]]>
          Glu Leu Gln Leu Glu Glu Ser Ser Ala Glu Ala Gln Asp Gly Glu Leu
           1 5 10 15
          AspGly
           <![CDATA[ <210> 834]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> C-terminal extension of human IgG variant linker]]>
           <![CDATA[ <400> 834]]>
          Glu Leu Gln Leu Glu Glu Ser Ser Ala Glu Ala Gln Gly Gly
           1 5 10
           <![CDATA[ <210> 835]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human immunoglobulin light chain kappa leader signal peptide sequence; human Ig kappa chain V-III region signal peptide (IgGkSP)]]>
           <![CDATA[ <400> 835]]>
          Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
           1 5 10 15
          Gly Ser Thr Gly
                      20
           <![CDATA[ <210> 836]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> 6×His tag]]>
           <![CDATA[ <400> 836]]>
          His His His His His
           1 5
           <![CDATA[ <210> 837]]>
           <![CDATA[ <211> 100]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> SUMO sequence]]>
           <![CDATA[ <400> 837]]>
          Gly Ser Leu Gln Asp Ser Glu Val Asn Gln Glu Ala Lys Pro Glu Val
           1 5 10 15
          Lys Pro Glu Val Lys Pro Glu Thr His Ile Asn Leu Lys Val Ser Asp
                      20 25 30
          Gly Ser Ser Glu Ile Phe Phe Lys Ile Lys Lys Thr Thr Pro Leu Arg
                  35 40 45
          Arg Leu Met Glu Ala Phe Ala Lys Arg Gln Gly Lys Glu Met Asp Ser
              50 55 60
          Leu Arg Phe Leu Tyr Asp Gly Ile Arg Ile Gln Ala Asp Gln Ala Pro
          65 70 75 80
          Glu Asp Leu Asp Met Glu Asp Asn Asp Ile Ile Glu Ala His Arg Glu
                          85 90 95
          Gln Ile Gly Gly
                      100
           <![CDATA[ <210> 838]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> His tag-SUMO sequence]]>
           <![CDATA[ <400> 838]]>
          Met Gly His His His His His Gly Ser Leu Gln Asp Ser Glu Val
           1 5 10 15
          Asn Gln Glu Ala Lys Pro Glu Val Lys Pro Glu Val Lys Pro Glu Thr
                      20 25 30
          His Ile Asn Leu Lys Val Ser Asp Gly Ser Ser Glu Ile Phe Phe Lys
                  35 40 45
          Ile Lys Lys Thr Thr Pro Leu Arg Arg Leu Met Glu Ala Phe Ala Lys
              50 55 60
          Arg Gln Gly Lys Glu Met Asp Ser Leu Arg Phe Leu Tyr Asp Gly Ile
          65 70 75 80
          Arg Ile Gln Ala Asp Gln Ala Pro Glu Asp Leu Asp Met Glu Asp Asn
                          85 90 95
          Asp Ile Ile Glu Ala His Arg Glu Gln Ile Gly Gly
                      100 105
           <![CDATA[ <210> 839]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 839]]>
          Lys Cys Ser Pro Gly
           1 5
           <![CDATA[ <210> 840]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 840]]>
          Lys Cys Arg Pro Gly
           1 5
           <![CDATA[ <210> 841]]>
           <![CDATA[ <211> 59]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 841]]>
          Cys Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Cys Thr
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys Ala
                      20 25 30
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys
                  35 40 45
          Arg Pro Gly Phe Gly Val Ala Arg Pro Gly Thr
              50 55
           <![CDATA[ <210> 842]]>
           <![CDATA[ <211> 40]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 842]]>
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys
           1 5 10 15
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys
                      20 25 30
          Cys Arg Pro Gly Phe Gly Val Ala
                  35 40
           <![CDATA[ <210> 843]]>
           <![CDATA[ <211> 28]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 843]]>
          Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys
           1 5 10 15
          Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys
                      20 25
           <![CDATA[ <210> 844]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 844]]>
          Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu
           1 5 10 15
           <![CDATA[ <210> 845]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 845]]>
          Cys Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Cys Thr
           1 5 10 15
          Arg
           <![CDATA[ <210> 846]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 846]]>
          Ser Ser Asp Gln Val Glu Thr
           1 5
           <![CDATA[ <210> 847]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 847]]>
          Gln Thr Ala Gln Met Cys Cys Ser Lys Cys Ser Pro Gly Gln His Ala
           1 5 10 15
          Lys Val Phe Cys
                      20
           <![CDATA[ <210> 848]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 848]]>
          Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro
           1 5 10 15
          Gly Phe Gly Val
                      20
           <![CDATA[ <210> 849]]>
           <![CDATA[ <211> 38]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 849]]>
          Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg
                      20 25 30
          Lys Cys Arg Pro Gly Phe
                  35
           <![CDATA[ <210> 850]]>
           <![CDATA[ <211> 50]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 850]]>
          Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg
           1 5 10 15
          Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys
                      20 25 30
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                  35 40 45
          Thr Glu
              50
           <![CDATA[ <210> 851]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 851]]>
          Cys Ala Pro Leu Arg Lys Cys Arg
           1 5
           <![CDATA[ <210> 852]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope]]>
           <![CDATA[ <400> 852]]>
          Arg Lys Cys Arg Pro Gly Phe Gly Val
           1 5
           <![CDATA[ <210> 853]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 853]]>
          Cys Arg Pro His Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn
           1 5 10 15
           <![CDATA[ <210> 854]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 854]]>
          Cys Arg Pro His Gln Ile Cys Asn Val Val Gly Ala Pro Gly Asn
           1 5 10 15
           <![CDATA[ <210> 855]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 855]]>
          Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Ala Ala Cys Arg Pro
           1 5 10 15
           <![CDATA[ <210> 856]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 856]]>
          Thr Phe Ser Asn Thr Thr Ser Ser Ser Thr Asp Ala Ala Arg Pro His
           1 5 10 15
           <![CDATA[ <210> 857]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 857]]>
          Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro Ser Pro Pro Ala
           1 5 10 15
           <![CDATA[ <210> 858]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 858]]>
          Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys
           1 5 10 15
           <![CDATA[ <210> 859]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 859]]>
          Leu Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys
           1 5 10 15
           <![CDATA[ <210> 860]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 860]]>
          Gln Leu Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg
           1 5 10 15
           <![CDATA[ <210> 861]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 861]]>
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro
           1 5 10 15
           <![CDATA[ <210> 862]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 862]]>
          Thr Phe Ser Asn Thr Thr Ser Ser Ser Thr Asp Ile Cys Arg Pro His
           1 5 10 15
           <![CDATA[ <210> 863]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 863]]>
          Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu
           1 5 10 15
           <![CDATA[ <210> 864]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 864]]>
          Cys Gln Leu Trp Asn Trp Val Pro Glu Ala Leu Ala Gly Gly Ser Arg
           1 5 10 15
           <![CDATA[ <210> 865]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 865]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 866]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 866]]>
          Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Ala Ala Arg Cys Ser
           1 5 10 15
           <![CDATA[ <210> 867]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 867]]>
          Leu Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 868]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 868]]>
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
           1 5 10 15
           <![CDATA[ <210> 869]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 869]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 870]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 870]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 871]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 871]]>
          Leu Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 872]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 872]]>
          Gln Leu Trp Asn Trp Val Pro Glu Cys Leu Ala Ala Gly Ser Arg
           1 5 10 15
           <![CDATA[ <210> 873]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 873]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 874]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 874]]>
          Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Ala Ala Tyr Cys Ala
           1 5 10 15
           <![CDATA[ <210> 875]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 875]]>
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln Ile Cys Asn
           1 5 10 15
           <![CDATA[ <210> 876]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 876]]>
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly
           1 5 10 15
           <![CDATA[ <210> 877]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 877]]>
          Cys Gln Leu Trp Asn Trp Val Pro Glu Ala Leu Ser Ala Gly Ser Arg
           1 5 10 15
           <![CDATA[ <210> 878]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 878]]>
          Arg Pro His Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala
           1 5 10 15
           <![CDATA[ <210> 879]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 879]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 880]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 880]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 881]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 881]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 882]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 882]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 883]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 883]]>
          Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
           1 5 10 15
           <![CDATA[ <210> 884]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 884]]>
          Leu Trp Asn Trp Val Pro Glu Cys Leu Ser Ala Ala Ser Arg Cys
           1 5 10 15
           <![CDATA[ <210> 885]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 885]]>
          Gln Thr Ala Gln Met Cys Cys Ser Lys Cys Ser Pro Gly Gln His
           1 5 10 15
           <![CDATA[ <210> 886]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 886]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 887]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (15)...(15)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 887]]>
          Cys Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 888]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 888]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 889]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 889]]>
          Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 890]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 890]]>
          Leu Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 891]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 891]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 892]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 892]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 893]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 893]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 894]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 894]]>
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Ala Ala Arg Pro Gly
           1 5 10 15
           <![CDATA[ <210> 895]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 895]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 896]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 896]]>
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Ala Gly Arg Pro Gly
           1 5 10 15
           <![CDATA[ <210> 897]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 897]]>
          Ile Cys Arg Pro His Gln Ile Cys Asn Val Ala Gly Ile Pro Gly
           1 5 10 15
           <![CDATA[ <210> 898]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 898]]>
          Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys
           1 5 10 15
           <![CDATA[ <210> 899]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 899]]>
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Ala Ala Cys Arg Pro
           1 5 10 15
           <![CDATA[ <210> 900]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 900]]>
          Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser
           1 5 10 15
           <![CDATA[ <210> 901]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 901]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 902]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 902]]>
          Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 903]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 903]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 904]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 904]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 905]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 905]]>
          Ala Pro Glu Pro Gly Ser Thr Cys Arg Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 906]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 906]]>
          Leu Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa
                      20 25
           <![CDATA[ <210> 907]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 907]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 908]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 908]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 909]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 909]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 910]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 910]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 911]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 911]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 912]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 912]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 913]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 913]]>
          Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg
           1 5 10 15
           <![CDATA[ <210> 914]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 914]]>
          Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Cys Arg Leu
           1 5 10 15
           <![CDATA[ <210> 915]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 915]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 916]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 916]]>
          Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 917]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 917]]>
          Thr Ser Asp Val Val Xaa Lys Pro Cys Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 918]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 918]]>
          Ile Cys Arg Pro His Gln Ile Cys Asn Val Val Ala Ile Pro Gly
           1 5 10 15
           <![CDATA[ <210> 919]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 919]]>
          Arg Leu Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 920]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 920]]>
          Pro Thr Arg Ser Met Ala Pro Gly Ala Val His Leu Pro Gln Pro
           1 5 10 15
           <![CDATA[ <210> 921]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 921]]>
          Tyr Ala Pro Glu Pro Gly Ser Thr Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 922]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 922]]>
          Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 923]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 923]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr
                      20 25
           <![CDATA[ <210> 924]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 924]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 925]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 925]]>
          Pro Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 926]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 926]]>
          Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 927]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 927]]>
          Pro Gly Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 928]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 928]]>
          Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro
           1 5 10 15
           <![CDATA[ <210> 929]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 929]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 930]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 930]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 931]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 931]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 932]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 932]]>
          Pro Tyr Ala Pro Glu Pro Gly Ser Thr Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 933]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 933]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr
                      20 25
           <![CDATA[ <210> 934]]>
           <![CDATA[ <211> 22]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 934]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg Glu Gln Asn
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg
                      20
           <![CDATA[ <210> 935]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 935]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 936]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 936]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 937]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 937]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 938]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 938]]>
          Pro Glu Pro Gly Ser Thr Cys Arg Leu Arg Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 939]]>
           <![CDATA[ <211> 22]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 939]]>
          Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys
           1 5 10 15
          Gln Glu Gly Xaa Arg Leu
                      20
           <![CDATA[ <210> 940]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 940]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 941]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 941]]>
          Glu Pro Gly Ser Thr Cys Arg Leu Arg Glu Tyr Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 942]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 942]]>
          Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 943]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 943]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 944]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 944]]>
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 945]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 945]]>
          Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 946]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 946]]>
          Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 947]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 947]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 948]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 948]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 949]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 949]]>
          Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly Thr
           1 5 10 15
           <![CDATA[ <210> 950]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 950]]>
          Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa
                      20 25
           <![CDATA[ <210> 951]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 951]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 952]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 952]]>
          Cys Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 953]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 953]]>
          Cys Gln Ile Xaa Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 954]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 954]]>
          Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr
           1 5 10 15
           <![CDATA[ <210> 955]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 955]]>
          Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 956]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 956]]>
          Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 957]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 957]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 958]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 958]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 959]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 959]]>
          Pro Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 960]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 960]]>
          Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 961]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 961]]>
          Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 962]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 962]]>
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 963]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 963]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 964]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 964]]>
          Cys Gln Ala Ala Thr Arg Glu Gln Asn Arg Ile Gly Ala Ala Arg Pro
           1 5 10 15
          Cys
           <![CDATA[ <210> 965]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 965]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 966]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 966]]>
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 967]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 967]]>
          Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 968]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 968]]>
          Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro Gly
           1 5 10 15
           <![CDATA[ <210> 969]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 969]]>
          Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ala Ala Cys Arg Leu
           1 5 10 15
           <![CDATA[ <210> 970]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 970]]>
          Cys Xaa Glu Asp Ser Thr Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu
           1 5 10 15
          Cys Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25 30
          Cys
           <![CDATA[ <210> 971]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 971]]>
          Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 972]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 972]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa
                      20 25
           <![CDATA[ <210> 973]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 973]]>
          Leu Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 974]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 974]]>
          Leu Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg
                      20 25
           <![CDATA[ <210> 975]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 975]]>
          Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 976]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 976]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 977]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 977]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                      20 25
           <![CDATA[ <210> 978]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 978]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 979]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 979]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25
           <![CDATA[ <210> 980]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 980]]>
          Cys Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe
           1 5 10 15
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
                      20 25 30
          Cys
           <![CDATA[ <210> 981]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 981]]>
          Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 982]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 982]]>
          Cys Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 983]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 983]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 984]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 984]]>
          Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa
                      20 25
           <![CDATA[ <210> 985]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 985]]>
          Leu Ser Lys Gln Glu Gly Xaa Arg Leu Cys Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 986]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 986]]>
          Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Ala Ala Pro Gly Trp
           1 5 10 15
           <![CDATA[ <210> 987]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 987]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 988]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 988]]>
          Xaa Arg Leu Cys Ala Pro Leu Arg Lys Xaa Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 989]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 989]]>
          Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Ala Ala Cys Ala Leu
           1 5 10 15
           <![CDATA[ <210> 990]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 990]]>
          Cys Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 991]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 991]]>
          Asp Val Val Xaa Lys Pro Cys Ala Pro Gly Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 992]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 992]]>
          Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Gly Gly Ser Gly Gly
           1 5 10 15
          Tyr Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg
                      20 25
           <![CDATA[ <210> 993]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 993]]>
          Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Ala Ala Pro Pro Ala
           1 5 10 15
           <![CDATA[ <210> 994]]>
           <![CDATA[ <211> 22]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 994]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
           1 5 10 15
          Gly Val Ala Arg Pro Gly
                      20
           <![CDATA[ <210> 995]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 995]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr
                      20 25
           <![CDATA[ <210> 996]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 996]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 997]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 997]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 998]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 998]]>
          Gly Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 999]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 999]]>
          Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro Ser Pro Pro
           1 5 10 15
           <![CDATA[ <210> 1000]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1000]]>
          Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1001]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1001]]>
          Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Tyr Gly Gly Ser Gly Gly
           1 5 10 15
          Tyr Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg
                      20 25
           <![CDATA[ <210> 1002]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1002]]>
          Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1003]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1003]]>
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
           1 5 10 15
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
                      20 25 30
          Cys
           <![CDATA[ <210> 1004]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1004]]>
          Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 1005]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1005]]>
          Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa
                      20 25
           <![CDATA[ <210> 1006]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1006]]>
          Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro Ser Pro
           1 5 10 15
           <![CDATA[ <210> 1007]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1007]]>
          Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 1008]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1008]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1009]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1009]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 1010]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1010]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1011]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1011]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1012]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1012]]>
          Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 1013]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1013]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1014]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1014]]>
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1015]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1015]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1016]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1016]]>
          Val Xaa Lys Pro Cys Ala Pro Gly Thr Phe Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 1017]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1017]]>
          Trp Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg
                      20 25
           <![CDATA[ <210> 1018]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1018]]>
          Asp Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
           1 5 10 15
           <![CDATA[ <210> 1019]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1019]]>
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1020]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1020]]>
          Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser
           1 5 10 15
           <![CDATA[ <210> 1021]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1021]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1022]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1022]]>
          Cys Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1023]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1023]]>
          Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln Ile
           1 5 10 15
           <![CDATA[ <210> 1024]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1024]]>
          Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Ala Ala Arg Pro Gly
           1 5 10 15
           <![CDATA[ <210> 1025]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1025]]>
          Cys Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu Arg Glu Tyr Tyr Asp
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1026]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1026]]>
          Arg Glu Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Tyr Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg
                      20 25
           <![CDATA[ <210> 1027]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1027]]>
          Cys Ser Arg Xaa Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1028]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1028]]>
          Val Val Xaa Lys Pro Cys Ala Pro Gly Thr Phe Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1029]]>
           <![CDATA[ <211> 22]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1029]]>
          Xaa Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr
           1 5 10 15
          Asp Ile Cys Arg Pro His
                      20
           <![CDATA[ <210> 1030]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1030]]>
          Thr Glu Thr Ser Asp Val Val Xaa Lys Pro Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 1031]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1031]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 1032]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1032]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 1033]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1033]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa
                      20 25
           <![CDATA[ <210> 1034]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1034]]>
          Thr Arg Glu Gln Asn Arg Ile Xaa Thr Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu
                      20 25
           <![CDATA[ <210> 1035]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1035]]>
          Thr Arg Glu Gln Asn Arg Ile Xaa Thr Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Tyr Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg
                      20 25
           <![CDATA[ <210> 1036]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1036]]>
          Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Ala Gly Pro Gly Ala
           1 5 10 15
           <![CDATA[ <210> 1037]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1037]]>
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1038]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1038]]>
          Ser Asp Val Val Xaa Lys Pro Cys Ala Pro Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 1039]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1039]]>
          Cys Ala Ala Thr Arg Glu Gln Asn Arg Ile Ala Ala Gly Arg Pro Gly
           1 5 10 15
          Cys
           <![CDATA[ <210> 1040]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa can be any naturally occurring amino acid]]>
           <![CDATA[ <400> 1040]]>
          Cys Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1041]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1041]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1042]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1042]]>
          Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro Ser
           1 5 10 15
           <![CDATA[ <210> 1043]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1043]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr
                      20 25
           <![CDATA[ <210> 1044]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1044]]>
          Cys Leu Ser Lys Gln Glu Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys
           1 5 10 15
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
                      20 25 30
          Cys
           <![CDATA[ <210> 1045]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1045]]>
          Cys Asn Trp Val Pro Glu Ala Leu Ser Ala Gly Pro Gly Ala Ser Ser
           1 5 10 15
          Asp Gln Val Glu Thr Gln Ala Cys
                      20
           <![CDATA[ <210> 1046]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1046]]>
          Glu Thr Ser Asp Val Val Xaa Lys Pro Cys Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 1047]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1047]]>
          Val Xaa Lys Pro Cys Ala Pro Gly Thr Phe Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1048]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1048]]>
          Cys Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala Val Xaa Thr Ser
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1049]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1049]]>
          Ser Asp Val Val Xaa Lys Pro Cys Ala Pro Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1050]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1050]]>
          Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala
                      20 25
           <![CDATA[ <210> 1051]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1051]]>
          Asp Ile Cys Arg Pro His Gln Ile Cys Asn Val Val Ala Ile Pro
           1 5 10 15
           <![CDATA[ <210> 1052]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1052]]>
          Cys Leu Trp Asn Trp Val Pro Glu Ala Leu Ser Ala Gly Ser Arg Ala
           1 5 10 15
          Cys
           <![CDATA[ <210> 1053]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1053]]>
          Cys Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu Arg Glu Tyr Tyr Asp
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1054]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1054]]>
          Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln His
                      20 25
           <![CDATA[ <210> 1055]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1055]]>
          Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1056]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1056]]>
          Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 1057]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1057]]>
          Cys Xaa Glu Asp Ser Thr Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu
           1 5 10 15
          Cys Gln Ile Xaa Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp
                      20 25 30
          Cys
           <![CDATA[ <210> 1058]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1058]]>
          Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 1059]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1059]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 1060]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1060]]>
          Cys Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val His Leu Pro
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1061]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1061]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 1062]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1062]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1063]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1063]]>
          Cys Ala Ala Thr Arg Glu Gln Asn Arg Ile Ala Thr Ala Arg Pro Gly
           1 5 10 15
          Cys
           <![CDATA[ <210> 1064]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1064]]>
          Cys Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His Ala Lys Val Phe Xaa
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1065]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1065]]>
          Cys Asp Val Val Xaa Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn Thr
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1066]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1066]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr
                      20 25
           <![CDATA[ <210> 1067]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1067]]>
          Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1068]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (15)...(15)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1068]]>
          Cys Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu Xaa Leu Ser Xaa Gly
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1069]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1069]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa
                      20 25
           <![CDATA[ <210> 1070]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1070]]>
          Cys Xaa Leu Ser Xaa Gly Ser Arg Xaa Ser Ser Asp Gln Val Glu Thr
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1071]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1071]]>
          Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1072]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1072]]>
          Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu
                      20 25
           <![CDATA[ <210> 1073]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1073]]>
          Ser Asp Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg
           1 5 10 15
           <![CDATA[ <210> 1074]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1074]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 1075]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1075]]>
          Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Tyr Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu
                      20 25
           <![CDATA[ <210> 1076]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (29)...(29)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (32)...(32)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1076]]>
          Cys Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe
           1 5 10 15
          Cys Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa
                      20 25 30
          Cys
           <![CDATA[ <210> 1077]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1077]]>
          Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr Ala Ala Cys Arg Pro
           1 5 10 15
           <![CDATA[ <210> 1078]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1078]]>
          Cys Thr Val Xaa Asp Ser Xaa Glu Asp Ser Thr Tyr Thr Gln Leu Trp
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1079]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1079]]>
          Pro Gly Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln
                      20 25
           <![CDATA[ <210> 1080]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1080]]>
          Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg
                      20 25
           <![CDATA[ <210> 1081]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1081]]>
          Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1082]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1082]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa
                      20 25
           <![CDATA[ <210> 1083]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1083]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1084]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1084]]>
          Pro Tyr Ala Pro Glu Pro Gly Ser Thr Cys Arg Leu Arg Glu Tyr
           1 5 10 15
           <![CDATA[ <210> 1085]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1085]]>
          Cys Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His Ala Lys Val Phe Xaa
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1086]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1086]]>
          Cys Thr Ser Ser Thr Asp Ile Xaa Arg Pro His Gln Ile Xaa Asn Val
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1087]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1087]]>
          Cys Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His Ala Lys Val Phe Xaa
           1 5 10 15
          Cys Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly
                      20 25 30
          Cys
           <![CDATA[ <210> 1088]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1088]]>
          Pro Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1089]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1089]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1090]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1090]]>
          Lys Gln Glu Gly Xaa Arg Leu Cys Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 1091]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1091]]>
          Pro His Gln Ile Cys Asn Val Val Ala Ile Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala
                      20 25
           <![CDATA[ <210> 1092]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1092]]>
          Cys Leu Pro Met Gly Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly Asp
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1093]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1093]]>
          Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa
                      20 25
           <![CDATA[ <210> 1094]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1094]]>
          Xaa Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
                      20 25
           <![CDATA[ <210> 1095]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1095]]>
          Cys Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His
           1 5 10 15
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
                      20 25 30
          Cys
           <![CDATA[ <210> 1096]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1096]]>
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln Ile Cys Asn Val
           1 5 10 15
           <![CDATA[ <210> 1097]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1097]]>
          Cys Glu Gly Ala Arg Leu Ala Ala Pro Leu Arg Ala Gly Arg Pro Gly
           1 5 10 15
          Cys
           <![CDATA[ <210> 1098]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1098]]>
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
           1 5 10 15
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
                      20 25 30
          Cys
           <![CDATA[ <210> 1099]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1099]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1100]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa can be any naturally occurring amino acid]]>
           <![CDATA[ <400> 1100]]>
          Cys Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile
           1 5 10 15
          Cys Ala Pro Leu Arg Xaa Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1101]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1101]]>
          Val Xaa Lys Pro Cys Ala Pro Gly Thr Phe Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Asp Ile Cys Arg Pro His Gln Ile Xaa Asn Val
                      20 25
           <![CDATA[ <210> 1102]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1102]]>
          Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr
                      20 25
           <![CDATA[ <210> 1103]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1103]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys
                      20 25
           <![CDATA[ <210> 1104]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1104]]>
          Cys Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1105]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1105]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25
           <![CDATA[ <210> 1106]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1106]]>
          Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Asp Ile Cys Arg Pro His Gln Ile Xaa Asn
                      20 25
           <![CDATA[ <210> 1107]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1107]]>
          Asp Ile Xaa Arg Pro His Gln Ile Cys Asn Val Gly Gly Ser Gly Gly
           1 5 10 15
          Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met
                      20 25
           <![CDATA[ <210> 1108]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1108]]>
          Cys Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu Gly Ala Ser Ala Gly
           1 5 10 15
          Cys
           <![CDATA[ <210> 1109]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1109]]>
          Gly Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln
                      20 25
           <![CDATA[ <210> 1110]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1110]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25
           <![CDATA[ <210> 1111]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1111]]>
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1112]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1112]]>
          Cys Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1113]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1113]]>
          Cys Gly Ser Arg Xaa Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Xaa
                      20 25
           <![CDATA[ <210> 1114]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1114]]>
          Cys Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1115]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1115]]>
          Cys Leu Trp Asn Trp Val Pro Glu Ala Leu Ser Pro Gly Ser Arg Ala
           1 5 10 15
          Ser Ser Asp Gln Val Glu Thr Cys
                      20
           <![CDATA[ <210> 1116]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1116]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr
                      20 25
           <![CDATA[ <210> 1117]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1117]]>
          Cys Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro Ser
           1 5 10 15
          Cys
           <![CDATA[ <210> 1118]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1118]]>
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
           1 5 10 15
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
                      20 25 30
          Cys
           <![CDATA[ <210> 1119]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1119]]>
          Cys Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1120]]>
           <![CDATA[ <211> 22]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1120]]>
          Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser
           1 5 10 15
          Lys Gln Glu Gly Xaa Arg
                      20
           <![CDATA[ <210> 1121]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1121]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1122]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1122]]>
          Xaa Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1123]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1123]]>
          Asn Trp Val Pro Glu Xaa Leu Ser Cys Gly Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa
                      20 25
           <![CDATA[ <210> 1124]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1124]]>
          Cys Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1125]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1125]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa
                      20 25
           <![CDATA[ <210> 1126]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1126]]>
          Gln Glu Gly Xaa Arg Leu Cys Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 1127]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1127]]>
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1128]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1128]]>
          Asp Ile Xaa Arg Pro His Gln Ile Cys Asn Val Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala
                      20 25
           <![CDATA[ <210> 1129]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1129]]>
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1130]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1130]]>
          Cys Thr Ser Ser Thr Asp Ile Xaa Arg Pro His Gln Ile Xaa Asn Val
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1131]]>
           <![CDATA[ <211> 32]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1131]]>
          Cys Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
           <![CDATA[ <210> 1132]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1132]]>
          Val Pro Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg
                      20 25
           <![CDATA[ <210> 1133]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1133]]>
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1134]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1134]]>
          Cys Ile Xaa Arg Pro His Gln Ile Xaa Asn Val Val Ala Ile Pro Gly
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1135]]>
           <![CDATA[ <211> 32]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1135]]>
          Cys Ser Thr Ser Phe Leu Leu Pro Met Gly Pro Ser Pro Pro Ala Glu
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
           <![CDATA[ <210> 1136]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1136]]>
          Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Tyr Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg
                      20 25
           <![CDATA[ <210> 1137]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1137]]>
          Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1138]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1138]]>
          Cys Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1139]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1139]]>
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1140]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (15)...(15)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1140]]>
          Cys Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu Xaa Leu Ser Xaa Gly
           1 5 10 15
          Cys Leu Ser Lys Gln Glu Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys
                      20 25 30
          Cys
           <![CDATA[ <210> 1141]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1141]]>
          Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln
                      20 25
           <![CDATA[ <210> 1142]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1142]]>
          Met Asp Ala Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala
           1 5 10 15
           <![CDATA[ <210> 1143]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1143]]>
          Cys Ala Val His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1144]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1144]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1145]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1145]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1146]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1146]]>
          Arg Glu Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu
                      20 25
           <![CDATA[ <210> 1147]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1147]]>
          Cys Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1148]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1148]]>
          Cys Xaa Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu Ser Lys Gln Glu
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1149]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1149]]>
          Cys Asn Trp Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Xaa Ser Ser
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1150]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1150]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1151]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1151]]>
          Tyr Asp Gln Thr Ala Gln Met Cys Cys Ser Lys Cys Ser Pro Gly
           1 5 10 15
           <![CDATA[ <210> 1152]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1152]]>
          Cys Ser Pro Gly Gln His Ala Lys Val Phe Xaa Thr Lys Thr Ser Asp
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1153]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1153]]>
          Cys Leu Ser Lys Gln Glu Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys
           1 5 10 15
          Cys Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile
                      20 25 30
          Cys
           <![CDATA[ <210> 1154]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1154]]>
          Cys Ser Asp Gln Val Glu Thr Gln Pro Gly Thr Arg Glu Gln Asn Arg
           1 5 10 15
          Ile Cys
           <![CDATA[ <210> 1155]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1155]]>
          Glu Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu
                      20 25
           <![CDATA[ <210> 1156]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1156]]>
          Asp Val Val Xaa Lys Pro Cys Ala Pro Gly Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1157]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1157]]>
          Ser Thr Asp Ile Xaa Arg Pro His Gln Ile Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala
                      20 25
           <![CDATA[ <210> 1158]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1158]]>
          Cys Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1159]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1159]]>
          Gly Ala Val His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His
           1 5 10 15
           <![CDATA[ <210> 1160]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1160]]>
          Cys Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1161]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1161]]>
          Cys Xaa Xaa Ser Lys Xaa Ser Pro Gly Gln His Ala Lys Val Phe Xaa
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1162]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1162]]>
          Cys Gly Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu Xaa
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1163]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1163]]>
          Cys Leu Ser Lys Gln Glu Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1164]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1164]]>
          Cys Thr Ser Ser Thr Asp Ile Xaa Arg Pro His Gln Ile Xaa Asn Val
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1165]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1165]]>
          Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1166]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1166]]>
          Cys Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile
           1 5 10 15
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
                      20 25 30
          Cys
           <![CDATA[ <210> 1167]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1167]]>
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1168]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1168]]>
          Pro Glu Pro Gly Ser Thr Cys Arg Leu Arg Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln
                      20 25
           <![CDATA[ <210> 1169]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1169]]>
          Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln
                      20 25
           <![CDATA[ <210> 1170]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1170]]>
          Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Gly Ala Pro Gly Thr
           1 5 10 15
           <![CDATA[ <210> 1171]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (29)...(29)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (32)...(32)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1171]]>
          Cys Leu Ser Lys Gln Glu Gly Xaa Arg Leu Xaa Ala Pro Leu Arg Lys
           1 5 10 15
          Cys Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Xaa Xaa Ser Lys Xaa
                      20 25 30
          Cys
           <![CDATA[ <210> 1172]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (16)...(16)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1172]]>
          Cys Gly Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu Xaa
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1173]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1173]]>
          Cys Thr Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Xaa Arg Pro His
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1174]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1174]]>
          Ser Cys Gly Ser Arg Xaa Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile
                      20 25
           <![CDATA[ <210> 1175]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (18)...(18)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1175]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1176]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1176]]>
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Ala Ala Cys Asn Val
           1 5 10 15
           <![CDATA[ <210> 1177]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1177]]>
          Cys Arg Ser Gln His Thr Gln Pro Thr Pro Glu Pro Ser Thr Ala Pro
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1178]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1178]]>
          Cys Asp Gln Val Glu Thr Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1179]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1179]]>
          Cys Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val His Leu Pro
           1 5 10 15
          Cys Asn Ala Ser Met Asp Ala Val Xaa Thr Ser Thr Ser Pro Thr Arg
                      20 25 30
          Cys
           <![CDATA[ <210> 1180]]>
           <![CDATA[ <211> 22]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1180]]>
          Cys Gly Ser Arg Xaa Ser Ser Asp Gln Val Glu Thr Gln Ala Cys Thr
           1 5 10 15
          Arg Glu Gln Asn Arg Ile
                      20
           <![CDATA[ <210> 1181]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1181]]>
          Ala Pro Glu Pro Gly Ser Thr Cys Arg Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Met Cys Xaa Ser Lys Xaa Ser Pro Gly Gln
                      20 25
           <![CDATA[ <210> 1182]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1182]]>
          Glu Xaa Leu Ser Cys Gly Ser Arg Xaa Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa
                      20 25
           <![CDATA[ <210> 1183]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1183]]>
          Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Asp Ala Val Cys Thr Ser Thr Ser Pro Thr Arg
                      20 25
           <![CDATA[ <210> 1184]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1184]]>
          Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Ala Ala Ser Pro Pro
           1 5 10 15
           <![CDATA[ <210> 1185]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1185]]>
          Cys Glu Gln Asn Arg Ile Ala Thr Ala Arg Pro Ala Ala Tyr Ala Ala
           1 5 10 15
          Cys
           <![CDATA[ <210> 1186]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1186]]>
          Cys Gln Val Ala Phe Thr Pro Tyr Pro Gly Glu Pro Gly Ser Thr Ala
           1 5 10 15
          Arg Cys
           <![CDATA[ <210> 1187]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1187]]>
          Arg Pro His Gln Ile Cys Asn Val Val Ala Ile Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala
                      20 25
           <![CDATA[ <210> 1188]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1188]]>
          Thr Arg Ser Met Ala Pro Gly Ala Val His Leu Pro Gln Pro Val
           1 5 10 15
           <![CDATA[ <210> 1189]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1189]]>
          Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu
                      20 25
           <![CDATA[ <210> 1190]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> The peptide sequence within TNFR2 represents the epitope that the TNFR2 agonist antibody can bind to]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1190]]>
          Ala Leu Ser Lys Gln Glu Gly Xaa Arg Leu Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Lys Pro Xaa Ala Pro Gly Thr Phe Ser Asn
                      20 25
           <![CDATA[ <210> 1191]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (15)...(15)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1191]]>
          Cys Gly Val Ala Arg Pro Gly Thr Glu Thr Ser Asp Val Val Xaa Lys
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1192]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <400> 1192]]>
          Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln
                      20 25
           <![CDATA[ <210> 1193]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (28)...(28)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (30)...(30)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1193]]>
          Cys Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Xaa Arg Leu
           1 5 10 15
          Cys Gln Ala Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Xaa Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1194]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide sequence within human TNFR2, representing the epitope to which TNFR2 agonist antibodies or fragments thereof can bind]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1194]]>
          Cys Gly Thr Glu Thr Ser Asp Val Val Xaa Lys Pro Xaa Ala Pro Gly
           1 5 10 15
          Cys Ala Pro Leu Arg Lys Xaa Arg Pro Gly Phe Gly Val Ala Arg Pro
                      20 25 30
          Cys
           <![CDATA[ <210> 1195]]>
           <![CDATA[ <211> 185]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide derived from human TNFR2 with affinity for binding agonist antibody MR2-1]]>
           <![CDATA[ <400> 1195]]>
          Tyr Tyr Asp Gln Thr Ala Gln Met Cys Cys Ser Lys Cys Ser Pro Gly
           1 5 10 15
          Gln His Ala Lys Val Phe Cys Thr Lys Thr Ser Asp Thr Val Cys Asp
                      20 25 30
          Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu
                  35 40 45
          Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln
              50 55 60
          Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp
          65 70 75 80
          Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu
                          85 90 95
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly Thr Glu Thr
                      100 105 110
          Ser Asp Val Val Cys Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr
                  115 120 125
          Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln Ile Cys Asn Val Val
              130 135 140
          Ala Ile Pro Gly Asn Ala Ser Met Asp Ala Val Cys Thr Ser Thr Ser
          145 150 155 160
          Pro Thr Arg Ser Met Ala Pro Gly Ala Val His Leu Pro Gln Pro Val
                          165 170 175
          Ser Thr Arg Ser Gln His Thr Gln Pro
                      180 185
           <![CDATA[ <210> 1196]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> The peptide sequence within human TNFR2 represents the epitope to which TNFR2 agonist antibodies and fragments thereof can bind]]>
           <![CDATA[ <400> 1196]]>
          Gln Thr Ala Gln Met Cys Cys Ser Lys Cys Ser Pro Gly Gln His Ala
           1 5 10 15
          Lys Val Phe Cys
                      20
           <![CDATA[ <210> 1197]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide derived from human TNFR2 with affinity for binding agonist antibody MR2-1]]>
           <![CDATA[ <400> 1197]]>
          Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys Ala
           1 5 10 15
          Leu Ser Lys Gln
                      20
           <![CDATA[ <210> 1198]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide derived from human TNFR2 with affinity for binding agonist antibody MR2-1]]>
           <![CDATA[ <400> 1198]]>
          Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg
           1 5 10 15
          Leu Cys Ala Pro
                      20
           <![CDATA[ <210> 1199]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide derived from human TNFR2 with affinity for binding agonist antibody MR2-1]]>
           <![CDATA[ <400> 1199]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys
           1 5 10 15
          Arg Pro Gly Phe
                      20
           <![CDATA[ <210> 1200]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Peptide derived from human TNFR2 with affinity for binding agonist antibody MR2-1]]>
           <![CDATA[ <400> 1200]]>
          Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro
           1 5 10 15
          Gly Phe Gly Val
                      20
           <![CDATA[ <210> 1201]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> The peptide sequence within human TNFR2 represents the epitope to which TNFR2 agonist antibodies and fragments thereof can bind]]>
           <![CDATA[ <400> 1201]]>
          Lys Cys Ser Pro Gly
           1 5
           <![CDATA[ <210> 1202]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope bound by agonist antibody MR2-1]]>
           <![CDATA[ <400> 1202]]>
          Ser Ser Asp Gln Val Glu Thr
           1 5
           <![CDATA[ <210> 1203]]>
           <![CDATA[ <211> 28]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> The peptide sequence within human TNFR2 represents the epitope to which TNFR2 agonist antibodies and fragments thereof can bind]]>
           <![CDATA[ <400> 1203]]>
          Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys
           1 5 10 15
          Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys
                      20 25
           <![CDATA[ <210> 1204]]>
           <![CDATA[ <211> 40]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human TNFR2 epitope bound by agonist antibody MR2-1]]>
           <![CDATA[ <400> 1204]]>
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys
           1 5 10 15
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys
                      20 25 30
          Cys Arg Pro Gly Phe Gly Val Ala
                  35 40
           <![CDATA[ <210> 1205]]>
           <![CDATA[ <211> 59]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> The peptide sequence within human TNFR2 represents the epitope to which TNFR2 agonist antibodies and fragments thereof can bind]]>
           <![CDATA[ <400> 1205]]>
          Cys Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Cys Thr
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys Ala
                      20 25 30
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys
                  35 40 45
          Arg Pro Gly Phe Gly Val Ala Arg Pro Gly Thr
              50 55
           <![CDATA[ <210> 1206]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes within human TNFR2 that can bind agonist TNFR2 antibodies and fragments thereof ]]>
           <![CDATA[ <400> 1206]]>
          Cys Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Cys Thr
           1 5 10 15
          Arg
           <![CDATA[ <210> 1207]]>
           <![CDATA[ <211> 39]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes within human TNFR2 that can bind agonist TNFR2 antibodies and fragments thereof ]]>
           <![CDATA[ <400> 1207]]>
          Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr
           1 5 10 15
          Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg
                      20 25 30
          Lys Cys Arg Pro Ser Gly Phe
                  35
           <![CDATA[ <210> 1208]]>
           <![CDATA[ <211> 50]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes within human TNFR2 that can bind agonist TNFR2 antibodies and fragments thereof ]]>
           <![CDATA[ <400> 1208]]>
          Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg
           1 5 10 15
          Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Cys
                      20 25 30
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro Gly
                  35 40 45
          Thr Glu
              50
           <![CDATA[ <210> 1209]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes within human TNFR2 that can bind agonist TNFR2 antibodies and fragments thereof ]]>
           <![CDATA[ <400> 1209]]>
          Lys Cys Arg Pro Gly
           1 5
           <![CDATA[ <210> 1210]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes within human TNFR2 that can bind agonist TNFR2 antibodies and fragments thereof ]]>
           <![CDATA[ <400> 1210]]>
          Cys Ala Pro Leu Arg Lys Cys Arg
           1 5
           <![CDATA[ <210> 1211]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes within human TNFR2 that can bind agonist TNFR2 antibodies and fragments thereof ]]>
           <![CDATA[ <400> 1211]]>
          Lys Cys Arg Pro Gly Phe Gly Val
           1 5
           <![CDATA[ <210> 1212]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB1 (human TNFR2 antagonist antibody) heavy chain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(32)]]>
           <![CDATA[ <223> CDR-H1 = GFTFSSY]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (52)...(57)]]>
           <![CDATA[ <223> CDR-H2 = SSGGSY]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (99)...(112)]]>
           <![CDATA[ <223> CDR-H3 = QRVDGYSSYWYFDV]]>
           <![CDATA[ <400> 1212]]>
          Glu Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
           1 5 10 15
          Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
                      20 25 30
          Val Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
                  35 40 45
          Ala Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
                          85 90 95
          Ala Arg Gln Arg Val Asp Gly Tyr Ser Ser Tyr Trp Tyr Phe Asp Val
                      100 105 110
          Trp Gly Ala Gly Thr Ala Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 1213]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB1 (human TNFR2 antagonist antibody) light chain]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(33)]]>
           <![CDATA[ <223> CDR-L1 = SASSSVYYMY]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (49)...(55)]]>
           <![CDATA[ <223> CDR-L2 = STSNLAS]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (88)...(96)]]>
           <![CDATA[ <223> CDR-L3 = QQRRNYPYT]]>
           <![CDATA[ <400> 1213]]>
          Asp Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
           1 5 10 15
          Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Tyr Tyr Met
                      20 25 30
          Tyr Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr
                  35 40 45
          Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
              50 55 60
          Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
          65 70 75 80
          Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Asn Tyr Pro Tyr Thr
                          85 90 95
          Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
                      100 105
           <![CDATA[ <210> 1214]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) heavy chain CDR-H1 variant 1]]>
           <![CDATA[ <400> 1214]]>
          Gly Tyr Thr Phe Thr Asp Tyr Leu
           1 5
           <![CDATA[ <210> 1215]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) heavy chain CDR-H1 variant 2]]>
           <![CDATA[ <400> 1215]]>
          Gly Tyr Thr Phe Thr Asp Tyr Ile
           1 5
           <![CDATA[ <210> 1216]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) heavy chain CDR-H2]]>
           <![CDATA[ <400> 1216]]>
          Val Asp Pro Glu Tyr Gly Ser Thr
           1 5
           <![CDATA[ <210> 1217]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) heavy chain CDR-H3]]>
           <![CDATA[ <400> 1217]]>
          Ala Arg Asp Asp Gly Ser Tyr Ser Pro Phe Asp Tyr Trp Gly
           1 5 10
           <![CDATA[ <210> 1218]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) light chain CDR-L1]]>
           <![CDATA[ <400> 1218]]>
          Gln Asn Ile Asn Lys Tyr
           1 5
           <![CDATA[ <210> 1219]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) light chain CDR-L2 variant 1]]>
           <![CDATA[ <400> 1219]]>
          Thr Tyr Ser
           1          
           <![CDATA[ <210> 1220]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) light chain CDR-L2 variant 2]]>
           <![CDATA[ <400> 1220]]>
          Tyr Thr Ser
           1          
           <![CDATA[ <210> 1221]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) light chain CDR-L3 variant 1]]>
           <![CDATA[ <400> 1221]]>
          Cys Leu Gln Tyr Val Asn Leu Leu Thr
           1 5
           <![CDATA[ <210> 1222]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFRAB2 (human TNFR2 antagonist antibody) light chain CDR-L3 variant 2]]>
           <![CDATA[ <400> 1222]]>
          Cys Leu Gln Tyr Val Asn Leu Ile Thr
           1 5
           <![CDATA[ <210> 1223]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> TNFR2A3 (human TNFR2 antagonist antibody) heavy chain CDR-H3]]>
           <![CDATA[ <400> 1223]]>
          Ala Arg Asp Asp Gly Ser Tyr Ser Pro Phe Asp Tyr Phe Gly
           1 5 10
           <![CDATA[ <210> 1224]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H2 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is Gly or Ala]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is Asn, Gln, Ser or Thr]]>
           <![CDATA[ <400> 1224]]>
          Val Asp Pro Glu Tyr Xaa Xaa Thr
           1 5
           <![CDATA[ <210> 1225]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is Arg, Lys or His]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is Asp or Glu]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is Gly or Ala]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is Asn, Gln, Ser or Thr]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is Asp or Glu]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <400> 1225]]>
          Gln Xaa Val Xaa Xaa Tyr Xaa Ser Xaa Trp Tyr Xaa Xaa Xaa
           1 5 10
           <![CDATA[ <210> 1226]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is Lys, Arg or His]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is Asp or Glu]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is Gly or Ala]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is Asn, Gln, Ser or Thr]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is Asp or Glu]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <400> 1226]]>
          Ala Xaa Asp Xaa Xaa Xaa Xaa Ser Pro Xaa Xaa Xaa Trp Gly
           1 5 10
           <![CDATA[ <210> 1227]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <400> 1227]]>
          Xaa Arg Xaa Asp Gly Xaa Ser Xaa Tyr Xaa Xaa Phe Asp Xaa
           1 5 10
           <![CDATA[ <210> 1228]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (12)...(12)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (13)...(13)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (14)...(14)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <400> 1228]]>
          Xaa Arg Xaa Asp Gly Ser Tyr Xaa Xaa Phe Asp Xaa Xaa Xaa
           1 5 10
           <![CDATA[ <210> 1229]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1229]]>
          Gln Arg Val Asp Gly Tyr Ser Ser Tyr Trp Tyr Phe Asp Val
           1 5 10
           <![CDATA[ <210> 1230]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H2 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1230]]>
          Ser Ser Gly Gly Ser Tyr
           1 5
           <![CDATA[ <210> 1231]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H1 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1231]]>
          Gly Phe Thr Phe Ser Ser Tyr
           1 5
           <![CDATA[ <210> 1232]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H1 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is any amino acid]]>
           <![CDATA[ <400> 1232]]>
          Gly Xaa Thr Phe Xaa Xaa Tyr Xaa
           1 5
           <![CDATA[ <210> 1233]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-H1 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is Leu or Ile]]>
           <![CDATA[ <400> 1233]]>
          Gly Tyr Thr Phe Thr Asp Tyr Xaa
           1 5
           <![CDATA[ <210> 1234]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L1 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <400> 1234]]>
          Gln Asn Ile Asn Lys Xaa
           1 5
           <![CDATA[ <210> 1235]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L1 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1235]]>
          Ser Ala Ser Ser Ser Val Tyr Tyr Met Tyr
           1 5 10
           <![CDATA[ <210> 1236]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L1 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1236]]>
          Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Tyr Ser Tyr Met His
           1 5 10 15
           <![CDATA[ <210> 1237]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L2 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1237]]>
          Ser Thr Ser Asn Leu Ala Ser
           1 5
           <![CDATA[ <210> 1238]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L2 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1238]]>
          Leu Ala Ser Asn Leu Glu Ser
           1 5
           <![CDATA[ <210> 1239]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Framework region that binds to the N-terminus of CDR-L2 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1239]]>
          Leu Leu Ile Arg
           1              
           <![CDATA[ <210> 1240]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Framework region that binds to the C-terminus of CDR-L2 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1240]]>
          Thr Leu Glu
           1          
           <![CDATA[ <210> 1241]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is Ala, Val, Leu, Ile, Pro, Met, Trp, Phe or Tyr]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is Leu or Ile]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is Asn, Gln, Ser or Thr]]>
           <![CDATA[ <400> 1241]]>
          Cys Leu Gln Xaa Val Asn Leu Xaa Xaa
           1 5
           <![CDATA[ <210> 1242]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1242]]>
          Gln Gln Arg Arg Asn Tyr Pro Tyr Thr
           1 5
           <![CDATA[ <210> 1243]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is Leu or Ile]]>
           <![CDATA[ <400> 1243]]>
          Cys Leu Gln Tyr Val Asn Leu Xaa Thr
           1 5
           <![CDATA[ <210> 1244]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> CDR-L3 of human TNFR2 antagonist antibody (or antigen-binding fragment thereof)]]>
           <![CDATA[ <400> 1244]]>
          Gln His Ser Arg Glu Leu Pro Arg Thr
           1 5
           <![CDATA[ <210> 1245]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Exemplary common sequences of human antibody heavy chain variable domains]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(35)]]>
           <![CDATA[ <223> Replaceable CDR-H1 = GFTFSDYAMS]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (50)...(66)]]>
           <![CDATA[ <223> Replaceable CDR-H2 = VISENGSDTYYADSVKG]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (99)...(110)]]>
           <![CDATA[ <223> Replaceable CDR-H3 = DRGGAVSYFDVW]]>
           <![CDATA[ <400> 1245]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 1246]]>
           <![CDATA[ <211> 109]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Exemplary common sequences of human antibody light chain variable domains]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(35)]]>
           <![CDATA[ <223> Replaceable CDR-L1 = RASQDVSSYLAW]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (50)...(56)]]>
           <![CDATA[ <223> Replaceable CDR-L2 = AASSLES]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (89)...(97)]]>
           <![CDATA[ <223> Replaceable CDR-L3 = QQYNSLPYT]]>
           <![CDATA[ <400> 1246]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
                      100 105
           <![CDATA[ <210> 1247]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes to which antagonistic antibodies or fragments thereof bind within human TNFR2]]>
           <![CDATA[ <400> 1247]]>
          Asp Ser Thr Tyr Thr Gln Leu
           1 5
           <![CDATA[ <210> 1248]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes to which antagonistic antibodies or fragments thereof bind within human TNFR2]]>
           <![CDATA[ <400> 1248]]>
          Pro Glu Cys Leu Ser Cys Gly Ser
           1 5
           <![CDATA[ <210> 1249]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes to which antagonistic antibodies or fragments thereof bind within human TNFR2]]>
           <![CDATA[ <400> 1249]]>
          Arg Ile Cys Thr Cys Arg Pro Gly
           1 5
           <![CDATA[ <210> 1250]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes to which antagonistic antibodies or fragments thereof bind within human TNFR2]]>
           <![CDATA[ <400> 1250]]>
          Cys Ala Pro Leu Arg Lys Cys Arg
           1 5
           <![CDATA[ <210> 1251]]>
           <![CDATA[ <211> 54]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Antigenic determinants within human TNFR2 that antagonistic TNFR2 antibodies or fragments thereof can bind (at least 5 consecutive or discontinuous residues)]]>
           <![CDATA[ <400> 1251]]>
          Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu Trp Asn Trp Val
           1 5 10 15
          Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser Asp Gln Val Glu
                      20 25 30
          Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro
                  35 40 45
          Gly Trp Tyr Cys Ala Leu
              50
           <![CDATA[ <210> 1252]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Antigenic determinants within human TNFR2 that antagonistic TNFR2 antibodies or fragments thereof can bind (at least 5 consecutive or discontinuous residues)]]>
           <![CDATA[ <400> 1252]]>
          Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu Trp Asn Trp Val
           1 5 10 15
           <![CDATA[ <210> 1253]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Antigenic determinants within human TNFR2 that antagonistic TNFR2 antibodies or fragments thereof can bind (at least 5 consecutive or discontinuous residues)]]>
           <![CDATA[ <400> 1253]]>
          Leu Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser
           1 5 10 15
           <![CDATA[ <210> 1254]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Antigenic determinants within human TNFR2 that antagonistic TNFR2 antibodies or fragments thereof can bind (at least 5 consecutive or discontinuous residues)]]>
           <![CDATA[ <400> 1254]]>
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys
           1 5 10 15
           <![CDATA[ <210> 1255]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> The epitope (at least 5 consecutive or discontinuous residues) within human TNFR2 that the antagonistic TNFR2 antibody or fragment thereof can bind to]]>
           <![CDATA[ <400> 1255]]>
          Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro
           1 5 10 15
           <![CDATA[ <210> 1256]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic TNFR2 antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <400> 1256]]>
          Lys Cys Arg Pro Gly
           1 5
           <![CDATA[ <210> 1257]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <400> 1257]]>
          Lys Cys Arg Pro Gly Phe Gly Val
           1 5
           <![CDATA[ <210> 1258]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies (such as TNFRAB1) or fragments thereof within human TNFR2]]>
           <![CDATA[ <400> 1258]]>
          Cys Lys Pro Cys Ala Pro Gly Thr Phe
           1 5
           <![CDATA[ <210> 1259]]>
           <![CDATA[ <211> 41]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Antigenic determinants within human TNFR2 that antagonistic TNFR2 antibodies or fragments thereof can bind (at least 5 consecutive or discontinuous residues)]]>
           <![CDATA[ <400> 1259]]>
          Ala Arg Pro Gly Thr Glu Thr Ser Asp Val Val Cys Lys Pro Cys Ala
           1 5 10 15
          Pro Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro
                      20 25 30
          His Gln Ile Cys Asn Val Val Ala Ile
                  35 40
           <![CDATA[ <210> 1260]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1260]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1261]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1261]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1262]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1262]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1263]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1263]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1264]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1264]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1265]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1265]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1266]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1266]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1267]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1267]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1268]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1268]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1269]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1269]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1270]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1270]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1271]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1271]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1272]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1272]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1273]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1273]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1274]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1274]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1275]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1275]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1276]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1276]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1277]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1277]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1278]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1278]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1279]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1279]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1280]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1280]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1281]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1281]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1282]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1282]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1283]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1283]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1284]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1284]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1285]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1285]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1286]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1286]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1287]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1287]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1288]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1288]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1289]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1289]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1290]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1290]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1291]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1291]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1292]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1292]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1293]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1293]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1294]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1294]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1295]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1295]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1296]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1296]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1297]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1297]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1298]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1298]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1299]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1299]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1300]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1300]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1301]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1301]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1302]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1302]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1303]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1303]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1304]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1304]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1305]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1305]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1306]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1306]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1307]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1307]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1308]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1308]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1309]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1309]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1310]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1310]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1311]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1311]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1312]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1312]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1313]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1313]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1314]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1314]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1315]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1315]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1316]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1316]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1317]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1317]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1318]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1318]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1319]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1319]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1320]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1320]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1321]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1321]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1322]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1322]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1323]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1323]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1324]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1324]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1325]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1325]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1326]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1326]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1327]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1327]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1328]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1328]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1329]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1329]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1330]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1330]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1331]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1331]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1332]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1332]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1333]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1333]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1334]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1334]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1335]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1335]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1336]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1336]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1337]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1337]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1338]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1338]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1339]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1339]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1340]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1340]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1341]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1341]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1342]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1342]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1343]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1343]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1344]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1344]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1345]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1345]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1346]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1346]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Thr Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg
                      20 25
           <![CDATA[ <210> 1347]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1347]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1348]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1348]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1349]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1349]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1350]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1350]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1351]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1351]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1352]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1352]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1353]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1353]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1354]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1354]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1355]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1355]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1356]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1356]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1357]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1357]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro
                      20 25
           <![CDATA[ <210> 1358]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1358]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1359]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1359]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1360]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1360]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1361]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1361]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1362]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1362]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1363]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1363]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1364]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1364]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1365]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1365]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1366]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1366]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1367]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1367]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1368]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (24)...(24)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1368]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Glu Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly
                      20 25
           <![CDATA[ <210> 1369]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1369]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1370]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1370]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1371]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1371]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1372]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1372]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1373]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1373]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1374]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1374]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1375]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1375]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1376]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1376]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1377]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1377]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1378]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1378]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1379]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (23)...(23)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1379]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Gln Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp
                      20 25
           <![CDATA[ <210> 1380]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1380]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1381]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1381]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1382]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1382]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1383]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1383]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1384]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1384]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1385]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1385]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1386]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1386]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1387]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1387]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1388]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1388]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1389]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1389]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1390]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (22)...(22)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1390]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Asn Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr
                      20 25
           <![CDATA[ <210> 1391]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1391]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1392]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1392]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1393]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1393]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1394]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1394]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1395]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1395]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1396]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1396]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1397]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1397]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1398]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1398]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1399]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1399]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1400]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1400]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1401]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (21)...(21)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (27)...(27)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1401]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa
                      20 25
           <![CDATA[ <210> 1402]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1402]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1403]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1403]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1404]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1404]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1405]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1405]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1406]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1406]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1407]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1407]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1408]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1408]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1409]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (20)...(20)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (26)...(26)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1409]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Ile Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala
                      20 25
           <![CDATA[ <210> 1410]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1410]]>
          Val Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1411]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1411]]>
          Pro Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1412]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1412]]>
          Glu Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1413]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1413]]>
          Xaa Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1414]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1414]]>
          Leu Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1415]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1415]]>
          Ser Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1416]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1416]]>
          Xaa Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1417]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1417]]>
          Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1418]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1418]]>
          Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1419]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1419]]>
          Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1420]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (19)...(19)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (25)...(25)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1420]]>
          Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Cys Thr Xaa Arg Pro Gly Trp Tyr Xaa Ala Leu
                      20 25
           <![CDATA[ <210> 1421]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1421]]>
          Xaa Thr Arg Glu Gln Asn Arg Ile Xaa Thr Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln
                      20 25
           <![CDATA[ <210> 1422]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1422]]>
          Thr Arg Glu Gln Asn Arg Ile Xaa Thr Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln
                      20 25
           <![CDATA[ <210> 1423]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1423]]>
          Arg Glu Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln
                      20 25
           <![CDATA[ <210> 1424]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1424]]>
          Glu Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln
                      20 25
           <![CDATA[ <210> 1425]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (5)...(5)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1425]]>
          Gln Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln
                      20 25
           <![CDATA[ <210> 1426]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (4)...(4)]]>
           <![CDATA[ <223> Xaa can be any naturally occurring amino acid]]>
           <![CDATA[ <400> 1426]]>
          Asn Arg Ile Xaa Thr Cys Arg Pro Gly Trp Tyr Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln
                      20 25
           <![CDATA[ <210> 1427]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1427]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1428]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1428]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1429]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1429]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1430]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1430]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1431]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1431]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1432]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1432]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1433]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1433]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1434]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1434]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1435]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (17)...(17)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1435]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Xaa Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe
                      20 25
           <![CDATA[ <210> 1436]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1436]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1437]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1437]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1438]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1438]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1439]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1439]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1440]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1440]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1441]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1441]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1442]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1442]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1443]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1443]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1444]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1444]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly
                      20 25
           <![CDATA[ <210> 1445]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1445]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1446]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1446]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1447]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1447]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1448]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1448]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1449]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1449]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1450]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1450]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1451]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1451]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1452]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1452]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1453]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1453]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val
                      20 25
           <![CDATA[ <210> 1454]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (3)...(3)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1454]]>
          Trp Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Gly Gly Ser Gly Gly
           1 5 10 15
          Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala
                      20 25
           <![CDATA[ <210> 1455]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (2)...(2)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1455]]>
          Tyr Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1456]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (1)...(1)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1456]]>
          Xaa Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1457]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (11)...(11)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1457]]>
          Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1458]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (10)...(10)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1458]]>
          Leu Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1459]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (9)...(9)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1459]]>
          Ser Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1460]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (8)...(8)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1460]]>
          Lys Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1461]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (7)...(7)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1461]]>
          Gln Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1462]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> VARIANT ]]>
           <![CDATA[ <222> (6)...(6)]]>
           <![CDATA[ <223> Xaa is the Cys residue protected with ACM protecting group]]>
           <![CDATA[ <400> 1462]]>
          Glu Gly Cys Arg Leu Xaa Ala Pro Leu Arg Lys Gly Gly Ser Gly Gly
           1 5 10 15
          Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg
                      20 25
           <![CDATA[ <210> 1463]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <400> 1463]]>
          Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala
           1 5 10
           <![CDATA[ <210> 1464]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Epitopes bound by antagonistic antibodies or fragments thereof within human TNFR2]]>
           <![CDATA[ <400> 1464]]>
          Val Val Cys Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn
           1 5 10
           <![CDATA[ <210> 1465]]>
           <![CDATA[ <211> 645]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> RB242 human EGFR ECD with modified T15S and G564S (residue numbers do not include signal peptide)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(24)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (25)...(645)]]>
           <![CDATA[ <223> EGFR/HER1 extracellular domain (ECD)]]>
           <![CDATA[ <400> 1465]]>
          Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala
           1 5 10 15
          Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln
                      20 25 30
          Gly Thr Ser Asn Lys Leu Ser Gln Leu Gly Thr Phe Glu Asp His Phe
                  35 40 45
          Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn
              50 55 60
          Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys
          65 70 75 80
          Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val
                          85 90 95
          Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr
                      100 105 110
          Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn
                  115 120 125
          Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu
              130 135 140
          His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu
          145 150 155 160
          Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met
                          165 170 175
          Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro
                      180 185 190
          Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln
                  195 200 205
          Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg
              210 215 220
          Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys
          225 230 235 240
          Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp
                          245 250 255
          Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro
                      260 265 270
          Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly
                  275 280 285
          Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His
              290 295 300
          Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu
          305 310 315 320
          Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val
                          325 330 335
          Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn
                      340 345 350
          Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp
                  355 360 365
          Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr
              370 375 380
          Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu
          385 390 395 400
          Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp
                          405 410 415
          Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln
                      420 425 430
          His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu
                  435 440 445
          Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser
              450 455 460
          Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu
          465 470 475 480
          Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu
                          485 490 495
          Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro
                      500 505 510
          Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn
                  515 520 525
          Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Lys Leu Leu Glu Gly
              530 535 540
          Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro
          545 550 555 560
          Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro
                          565 570 575
          Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Ser Pro His Cys Val
                      580 585 590
          Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp
                  595 600 605
          Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys
              610 615 620
          Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly
          625 630 635 640
          Pro Lys Ile Pro Ser
                          645
           <![CDATA[ <210> 1466]]>
           <![CDATA[ <211> 621]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> RB242 human EGFR ECD (without signal peptide), with modifications T15S and G564S]]>
           <![CDATA[ <400> 1466]]>
          Leu Glu Glu Lys Lys Val Cys Gln Gly Thr Ser Asn Lys Leu Ser Gln
           1 5 10 15
          Leu Gly Thr Phe Glu Asp His Phe Leu Ser Leu Gln Arg Met Phe Asn
                      20 25 30
          Asn Cys Glu Val Val Leu Gly Asn Leu Glu Ile Thr Tyr Val Gln Arg
                  35 40 45
          Asn Tyr Asp Leu Ser Phe Leu Lys Thr Ile Gln Glu Val Ala Gly Tyr
              50 55 60
          Val Leu Ile Ala Leu Asn Thr Val Glu Arg Ile Pro Leu Glu Asn Leu
          65 70 75 80
          Gln Ile Ile Arg Gly Asn Met Tyr Tyr Glu Asn Ser Tyr Ala Leu Ala
                          85 90 95
          Val Leu Ser Asn Tyr Asp Ala Asn Lys Thr Gly Leu Lys Glu Leu Pro
                      100 105 110
          Met Arg Asn Leu Gln Glu Ile Leu His Gly Ala Val Arg Phe Ser Asn
                  115 120 125
          Asn Pro Ala Leu Cys Asn Val Glu Ser Ile Gln Trp Arg Asp Ile Val
              130 135 140
          Ser Ser Asp Phe Leu Ser Asn Met Ser Met Asp Phe Gln Asn His Leu
          145 150 155 160
          Gly Ser Cys Gln Lys Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp
                          165 170 175
          Gly Ala Gly Glu Glu Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala
                      180 185 190
          Gln Gln Cys Ser Gly Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys
                  195 200 205
          His Asn Gln Cys Ala Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys
              210 215 220
          Leu Val Cys Arg Lys Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys
          225 230 235 240
          Pro Pro Leu Met Leu Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn
                          245 250 255
          Pro Glu Gly Lys Tyr Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro
                      260 265 270
          Arg Asn Tyr Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly
                  275 280 285
          Ala Asp Ser Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys
              290 295 300
          Cys Glu Gly Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu
          305 310 315 320
          Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys
                          325 330 335
          Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe
                      340 345 350
          Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu
                  355 360 365
          Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln
              370 375 380
          Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu
          385 390 395 400
          Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val
                          405 410 415
          Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile
                      420 425 430
          Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala
                  435 440 445
          Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr
              450 455 460
          Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln
          465 470 475 480
          Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro
                          485 490 495
          Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val
                      500 505 510
          Asp Lys Cys Lys Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn
                  515 520 525
          Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn
              530 535 540
          Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His
          545 550 555 560
          Tyr Ile Asp Ser Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met
                          565 570 575
          Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val
                      580 585 590
          Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly
                  595 600 605
          Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser
              610 615 620
           <![CDATA[ <210> 1467]]>
           <![CDATA[ <211> 643]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> RB242 human HER3 ECD with modification Y246A (residue numbering does not include signal peptide)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(19)]]>
           <![CDATA[ <223> Signal peptide]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (20)...(643)]]>
           <![CDATA[ <223> HER3 extracellular domain (ECD)]]>
           <![CDATA[ <400> 1467]]>
          Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
           1 5 10 15
          Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
                      20 25 30
          Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
                  35 40 45
          Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
              50 55 60
          Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
          65 70 75 80
          Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
                          85 90 95
          Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
                      100 105 110
          Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
                  115 120 125
          His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
              130 135 140
          Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
          145 150 155 160
          Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
                          165 170 175
          Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
                      180 185 190
          Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
                  195 200 205
          Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
              210 215 220
          Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
          225 230 235 240
          Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
                          245 250 255
          Pro Arg Cys Pro Gln Pro Leu Val Ala Asn Lys Leu Thr Phe Gln Leu
                      260 265 270
          Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
                  275 280 285
          Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
              290 295 300
          Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
          305 310 315 320
          Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser
                          325 330 335
          Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val
                      340 345 350
          Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu
                  355 360 365
          Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu
              370 375 380
          Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln
          385 390 395 400
          Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr
                          405 410 415
          Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile
                      420 425 430
          Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu
                  435 440 445
          Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr
              450 455 460
          His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu
          465 470 475 480
          Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu
                          485 490 495
          Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro
                      500 505 510
          Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val
                  515 520 525
          Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala
              530 535 540
          His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu
          545 550 555 560
          Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys
                          565 570 575
          Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly
                      580 585 590
          Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn
                  595 600 605
          Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro
              610 615 620
          Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr
          625 630 635 640
          His Leu Thr
           <![CDATA[ <210> 1468]]>
           <![CDATA[ <211> 624]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> RB242 human HER3 ECD (without signal peptide) with modification Y246A]]>
           <![CDATA[ <400> 1468]]>
          Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr Leu Asn Gly
           1 5 10 15
          Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr Leu Tyr Lys
                      20 25 30
          Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu Ile Val Leu
                  35 40 45
          Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile Arg Glu Val
              50 55 60
          Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr Leu Pro Leu
          65 70 75 80
          Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp Gly Lys Phe
                          85 90 95
          Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser His Ala Leu
                      100 105 110
          Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser Gly Gly Val
                  115 120 125
          Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr Ile Asp Trp
              130 135 140
          Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val Lys Asp Asn
          145 150 155 160
          Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly Arg Cys Trp
                          165 170 175
          Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr Ile Cys Ala
                      180 185 190
          Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn Gln Cys Cys
                  195 200 205
          His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp Thr Asp Cys
              210 215 220
          Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val Pro Arg Cys
          225 230 235 240
          Pro Gln Pro Leu Val Ala Asn Lys Leu Thr Phe Gln Leu Glu Pro Asn
                          245 250 255
          Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala Ser Cys Pro
                      260 265 270
          His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala Cys Pro Pro
                  275 280 285
          Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys Glu Pro Cys
              290 295 300
          Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser Gly Ser Arg
          305 310 315 320
          Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val Asn Cys Thr
                          325 330 335
          Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu Asn Gly Asp
                      340 345 350
          Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu Asn Val Phe
                  355 360 365
          Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln Ser Trp Pro
              370 375 380
          Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr Thr Ile Gly
          385 390 395 400
          Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile Met Lys Asn
                          405 410 415
          Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu Ile Ser Ala
                      420 425 430
          Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr His His Ser
                  435 440 445
          Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu Arg Leu Asp
              450 455 460
          Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu Gly Lys Val
          465 470 475 480
          Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro Gly Pro Gly
                          485 490 495
          Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val Cys Val Thr
                      500 505 510
          His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala His Glu Ala
                  515 520 525
          Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu Gly Thr Ala
              530 535 540
          Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys Ala His Phe
          545 550 555 560
          Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly Val Leu Gly
                          565 570 575
          Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn Glu Cys Arg
                      580 585 590
          Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro Glu Leu Gln
                  595 600 605
          Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr His Leu Thr
              610 615 620
           <![CDATA[ <210> 1469]]>
           <![CDATA[ <211> 227]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human IgG1 Fc with mutations S354C and T366W (according to EU numbering)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SITE ]]>
           <![CDATA[ <222> (1)...(10)]]>
           <![CDATA[ <223> DKTHTCPPCP = part of the hinge region of human IgG1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (11)...(227)]]>
           <![CDATA[ <223> CH2 and CH3 domains of human IgG1]]>
           <![CDATA[ <400> 1469]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
           1 5 10 15
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                      20 25 30
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                  35 40 45
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
              50 55 60
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
          65 70 75 80
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
                          85 90 95
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                      100 105 110
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                  115 120 125
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
              130 135 140
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
          145 150 155 160
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
                          165 170 175
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
                      180 185 190
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                  195 200 205
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
              210 215 220
          Pro Gly Lys
          225
           <![CDATA[ <210> 1470]]>
           <![CDATA[ <211> 227]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Human IgG1 Fc with mutations Y349C, T366S, L368A and Y407V (according to EU numbering)]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SITE ]]>
           <![CDATA[ <222> (1)...(10)]]>
           <![CDATA[ <223> DKTHTCPPCP = part of the hinge region of human IgG1]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (11)...(227)]]>
           <![CDATA[ <223> CH2 and CH3 domains of human IgG1]]>
           <![CDATA[ <400> 1470]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
           1 5 10 15
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
                      20 25 30
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
                  35 40 45
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
              50 55 60
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
          65 70 75 80
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
                          85 90 95
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
                      100 105 110
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
                  115 120 125
          Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
              130 135 140
          Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
          145 150 155 160
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
                          165 170 175
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
                      180 185 190
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
                  195 200 205
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
              210 215 220
          Pro Gly Lys
          225
           <![CDATA[ <210> 1471]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> REPEAT ]]>
           <![CDATA[ <222> (1)...(5)]]>
           <![CDATA[ <223> appears 1, 2, 3, 4 or 5 times]]>
           <![CDATA[ <400> 1471]]>
          Gly Gly Gly Gly Ser
           1 5
           <![CDATA[ <210> 1472]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> GS linker]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> REPEAT ]]>
           <![CDATA[ <222> (1)...(5)]]>
           <![CDATA[ <223> appears 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times]]>
           <![CDATA[ <400> 1472]]>
          Gly Gly Gly Gly Ser
           1 5
           <![CDATA[ <210> 1473]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Gly linker]]>
           <![CDATA[ <400> 1473]]>
          Gly Gly Gly Gly Gly Gly
           1 5
           <![CDATA[ <210> 1474]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Gly linker]]>
           <![CDATA[ <400> 1474]]>
          Gly Gly Gly Gly Gly Gly Gly Gly
           1 5
           <![CDATA[ <210> 1475]]>
           <![CDATA[ <211> 732]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Constructs containing Vhh-4]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> SIGNAL ]]>
           <![CDATA[ <222> (1)...(19)]]>
           <![CDATA[ <223> Mouse immunoglobulin heavy chain leader sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (20)...(138)]]>
           <![CDATA[ <223> Anti-TNFR1 dAb]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> PEPTIDE]]>
           <![CDATA[ <222> (139)...(147)]]>
           <![CDATA[ <223> Connector]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> DOMAIN ]]>
           <![CDATA[ <222> (148)...(732)]]>
           <![CDATA[ <223> Human serum albumin (HSA)]]>
           <![CDATA[ <400> 1475]]>
          Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
           1 5 10 15
          Val His Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
                      20 25 30
          Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
                  35 40 45
          Ala His Glu Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
              50 55 60
          Glu Trp Val Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala
          65 70 75 80
          Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
                          85 90 95
          Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
                      100 105 110
          Tyr His Cys Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp
                  115 120 125
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
              130 135 140
          Gly Gly Gly Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp
          145 150 155 160
          Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln
                          165 170 175
          Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu
                      180 185 190
          Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn
                  195 200 205
          Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val
              210 215 220
          Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys
          225 230 235 240
          Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn
                          245 250 255
          Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr
                      260 265 270
          Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu
                  275 280 285
          Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe
              290 295 300
          Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp
          305 310 315 320
          Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly
                          325 330 335
          Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys
                      340 345 350
          Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln
                  355 360 365
          Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp
              370 375 380
          Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys
          385 390 395 400
          Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp
                          405 410 415
          Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu
                      420 425 430
          Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp
                  435 440 445
          Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys
              450 455 460
          Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu
          465 470 475 480
          Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu
                          485 490 495
          Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp
                      500 505 510
          Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val
                  515 520 525
          Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln
              530 535 540
          Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys
          545 550 555 560
          Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn
                          565 570 575
          Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg
                      580 585 590
          Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys
                  595 600 605
          Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys
              610 615 620
          Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val
          625 630 635 640
          Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe
                          645 650 655
          His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys
                      660 665 670
          Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys
                  675 680 685
          Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys
              690 695 700
          Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys
          705 710 715 720
          Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
                          725 730
           <![CDATA[ <210> 1476]]>
           <![CDATA[ <211> 19]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Mouse]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Mouse immunoglobulin heavy chain leader sequence Uniprot: A0N1R4]]>
           <![CDATA[ <400> 1476]]>
          Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
                          5 10 15
          Val His Ser
           <![CDATA[ <210> 1477]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Connector]]>
           <![CDATA[ <400> 1477]]>
          Gly Gly Ser Gly Gly Gly Gly
           1 5
           <![CDATA[ <210> 1478]]>
           <![CDATA[ <211> 116]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Vhh-2]]>
           <![CDATA[ <400> 1478]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gln Tyr
                      20 25 30
          Arg Met His Trp Val Arg Gln Ala Pro Gly Lys Ser Leu Glu Trp Val
                  35 40 45
          Ser Ser Ile Asp Thr Arg Gly Ser Ser Thr Tyr Tyr Tyr Ala Asp Pro Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ala Val Thr Met Phe Ser Pro Phe Phe Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val
                  115
           <![CDATA[ <210> 1479]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Vhh]]>
           <![CDATA[ <400> 1479]]>
          Glu Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Ala Gly
           1 5 10 15
          Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala His
                      20 25 30
          Glu Thr Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Val Ser His Ile Pro Pro Asp Gly Gln Asp Pro Phe Tyr Ala Asp Ser
              50 55 60
          Val Lys Gly Arg Phe Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
          65 70 75 80
          Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
                          85 90 95
          His Cys Ala Leu Leu Pro Lys Arg Gly Pro Trp Phe Asp Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Tyr Thr Val Ser Ser Ala
                  115 120
          
      

Claims (351)

A construct that is a tumor necrosis factor receptor 1 (TNFR1) antagonist construct of formula 1: (TNFR1 inhibitor) _n - linker _p - (activity modulator) _q , wherein: each of n and q are integers, and are each independently 1, 2, or 3; p is 0, 1, 2, or 3; a TNFR1 inhibitor is a molecule that binds to TNFR1 to inhibit (antagonize) the activity of TNFR1; an activity modulator is and does not exist Compared with the construct of the active modulator, the part that modulates or changes the activity or pharmacological properties of the construct; and the linker increases the flexibility of the construct, and/or alleviates or reduces the steric effect of the construct, or Its interaction with the receptor and/or increases the solubility of the construct in aqueous media. The construct of claim 1, wherein the linker is selected from the group consisting of chemical linkers, polypeptide linkers and combinations thereof. Such as the construct of claim 1 or claim 2, which is a fusion protein. The construct of any one of claims 1 to 3, wherein the linker contains a plurality of linker components. The construct of any one of claims 1 to 4, wherein the TNFR1 inhibitor comprises a domain antibody (dAb). The construct of any one of claims 1 to 5, wherein if the TNFR1 inhibitor is a domain antibody (dAb), the activity modulator is not an unmodified single Fc region or human serum albumin antibody. The construct of any one of claims 1 to 6, wherein the TNFR1 inhibitor inhibits TNFR1 signaling. The construct of any one of claims 1 to 7, wherein the activity modulator increases the serum half-life of the construct. The construct of any one of claims 1 to 8, wherein the activity modulator is albumin or Fc modified to have reduced or no ADCC activity and/or to have reduced or no CDC activity. The construct of any one of claims 1 to 9, wherein the TNFR1 inhibitor inhibits TNFR1 activity but does not antagonize tumor necrosis factor receptor 2 (TNFR2) activity. The construct of claim 10, wherein the TNFR1 inhibitor inhibits TNFR1 signaling. A construct is a multispecific construct comprising a TNFR1 inhibitor and a Treg expander, wherein the bispecific construct interacts with two different target receptors or antigens or epitopes on the receptors. Such as the construct of claim 12, which has bispecificity for TNFR1 and Treg amplifying agent. The construct of claim 12 or claim 13, wherein the Treg amplifying agent is a TNFR2 agonist. The construct of any one of claims 12 to 14, comprising a linker to provide flexibility, increase solubility or alleviate or reduce steric hindrance or Van der Waals interactions. The construct of any one of claims 12 to 15, further comprising an activity modulator to change the activity of the construct. Such as the construct of any one of claims 12 to 16, which has formula 2: (TNFR1 inhibitor) _n - (activity modulator) _r1 - (linker (L)) _p - (activity modulator) _r2 - ( TNFR2 agonist) _q , or (TNFR1 inhibitor) _n ―(activity modulator) _r1 ―(linker (L)) _p ―(activity modulator) _r2 ―(Treg amplifier) _q , where: n= 1, 2, or 3, p = 1, 2, or 3, q = 0, 1, or 2, and each of r1 and r2 is independently 0, 1, or 2; and as long as the construct is mutually exclusive with TNFR1 and TNFR2 It acts to antagonize TNFR1 and agonize TNFR2, or has Treg expander activity, and the components can be arranged in a specified order or any other order. The construct of any one of claims 1 to 17, wherein the TNFR1 inhibitor partially inhibits the binding of TNFα to TNFR1 and/or inhibits signal transduction. A construct of Formula 3a or 3b, (TNFR2 agonist or Treg amplifier) _n ― linker _p ― (activity modulator) _q , Formula 3a, or (activity modulator) _q ― linker _p ― (TNFR2 Agonist or Treg expander) _n , Formula 3b, where: each of n and q is an integer, and each is independently 1, 2 or 3; p is 0, 1, 2 or 3; activity modulation The agent is a portion that changes the pharmacological properties of the construct; the TNFR2 agonist interacts with TNFR2 to produce TNFR2 activity; the Treg expander includes a TNFR2 agonist and is a molecule that causes an increase in Treg cells; and the increase in the linker can Flexibility and/or alleviating or reducing the steric effect of the construct or its interaction with the receptor; and/or changing the solubility of the construct. The construct of any one of claims 1 to 19, wherein the activity modulator is an Fc region or a modified Fc region or a short FcRnBP; and The linker includes a hinge region, or is a linker including G and S residues. The construct of any one of claims 1 to 20, wherein the linker has the sequence shown in any one of SEQ ID NOs: 812-834, or is a PEG partial linker. The construct of any one of claims 1 to 21, which includes an activity modulator that is a modified Fc region or a peptide that increases the serum half-life of the construct. The construct of any one of claims 1 to 22, comprising an Fc region or an Fc dimer. The construct of any one of claims 1 to 23, comprising an Fc region modified to have reduced ADCC and/or CDC activity. The construct of claim 24, wherein the Fc is modified to have reduced or no ADCC activity. Such as requesting a structure in any one of items 1 to 25, wherein: The TNFR1 inhibitor is any one as defined in the sequence listing, listed below, or known in the technical field; The Treg amplifying agent is any one known in the art, a TNFR2 agonist, or any Treg amplifying agent shown in the sequence listing, listed below, or known in the art; The linker is any one listed in the Sequence Listing or below or known in the art; and The activity modulator is any one shown in the sequence listing, known in the art and/or shown below. A construct that is a TNFR1 antagonist construct, comprising a TNFR1 inhibitor that specifically targets and inhibits TNFR1 but does not antagonize a single chain antibody or antigen-binding portion thereof of TNFR2, thereby preventing the aggregation of TNFR1 via the receptor (clustering) and instantaneous activation. The construct of claim 27, wherein the antibody or antigen-binding portion thereof contains modifications that improve the pharmacological properties and/or structure of the construct. The construct of any one of claims 1 to 28 promotes TNFR2 signaling, thereby increasing the expression of regulatory T cells (Treg). The construct of any one of claims 27 to 29, wherein the single chain antibody inhibits TNFR1 by inhibiting TNFR1 signaling. The TNFR1 antagonist construct of any one of claims 27 to 30, wherein the antibody portion or antigen-binding portion of the construct inhibits the binding of TNFα to TNFR1. The construct of any one of claims 27 to 30, wherein the antibody or antigen-binding portion of the construct does not inhibit the binding of TNFα to TNFR1, but does inhibit TNFR1 signaling. The construct of any one of claims 28 to 32, wherein the pharmacological property is increased serum half-life. The construct of any one of claims 27 to 33, wherein the TNFR1 construct comprises an Fc modified to eliminate ADCC and/or CDC activity. The construct of any one of claims 27 to 34, wherein the TNFR1 construct comprises an Fc dimer. Such as the construct of claim 35, wherein one Fc monomer contains a hole and the other contains a knob to form a heterodimer. Such as the structure of claim 35, wherein: According to EU numbering, the pestle mutant line is selected from S354C, T366Y, T366W and T394W; and According to EU numbering, the acetabulum mutant lines are selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V. The Fc monomers thereby form the heterodimer. The construct of any one of claims 1 to 37, comprising Fc, wherein the Fc is from trastuzumab. The construct of claim 38, comprising a linker that is a hinge region from the Fc region. The construct of claim 39, wherein the hinge region is from trastuzumab and is connected to the Fc region. The construct of any one of claims 27 to 40, comprising a linker connected to the anti-TNFR1 antagonist antibody or antigen-binding portion thereof. The construct of claims 27 to 41, comprising a linker connected to the anti-TNFR1 antagonist antibody or antigen-binding portion thereof, directly or via a hinge region to the Fc region. The construct of any one of claims 1 to 42, which includes an amino acid sequence containing an amino acid sequence shown in any one of SEQ ID NO: 10, 12, 14, 16, 27, 30, 1469 and 1470 Fc region or modified Fc region. The construct of any one of claims 1 to 43, wherein the construct includes a hinge region connected to the Fc portion. The construct of any one of claims 1 to 44, wherein the construct binds to a nascent Fc receptor (FcRn). Such as the structure of claim 45, wherein: The TNFR1 construct includes a short FcRn-binding peptide (FcRnBP); and Short FcRn-binding peptides (FcRnBP) provide the interaction of this construct with FcRn and contain 6-25 or 10-20 amino acid residues. The TNFR1 antagonist construct of claim 46, wherein the FcRnBP contains 12-20 residues or 15 residues or 16 residues. The TNFR1 antagonist construct of claim 46 or claim 47, wherein the FcRn-binding peptide (FcRnBP) includes any of the peptides of SEQ ID NOs: 48-51. The TNFR1 antagonist construct of any one of claims 46 to 48, wherein the FcRn binding peptide (FcRnBP) consists of any peptide of SEQ ID NOs: 48-51. The construct of any one of claims 1 to 49, wherein the TNFR1 construct comprises an Fc heterodimer, one of the Fc monomers comprising an ester and the other comprising a pestle, and the resulting Fc dimer is a heterodimer. Dimer. The construct of any one of claims 1 to 50, which is a TNFR1 antagonist construct, includes: TNFR1 inhibitor; Fc dimer; and Treg amplifying agent, which: The Fc dimer contains two complementary Fc monomers; The TNFRl inhibitor is linked to one of the Fc monomers, and the Treg expander is linked to the other Fc monomer. The construct of claim 51, wherein the Treg expander is a TNFR2 agonist. The construct of claim 51 or claim 52, further comprising a second Treg amplifying agent linked to the same Fc monomer as the TNFR1 inhibitor, wherein the first and second Treg amplifying agents are the same or different . The construct of claim 53, wherein the second Treg expander is a TNFR2 agonist. The construct of claim 53, wherein the Treg amplifying agents are the same. The construct of any one of claims 51 to 55, wherein the TNFR1 inhibitor inhibits or blocks TNFR1 signaling. The construct of any one of claims 51 to 56, wherein the TNFR1 inhibitor binds to TNFR1 and blocks or inhibits TNFα binding and TNFR1 signaling. The construct of any one of claims 51 to 56, wherein the TNFR1 inhibitor binds to TNFR1, does not interfere with TNFα binding, and blocks or inhibits TNFR1 signaling. The construct of any one of claims 51 to 58, wherein the Treg expander is a TNFR2 agonist. The construct of claim 59, wherein the TNFR2 agonist stimulates or induces TNFR2 signaling. The construct of any one of claims 51 to 60, wherein the Treg amplifying agent is a TNFR2 agonist, which is a scFv, VHH single domain antibody or Fab of a TNFR2 agonist monoclonal antibody. The construct of any one of claims 1 to 61, which contains all or part of trastuzumab and is dimerized by fusion with the N-terminus of the C-terminus of trastuzumab. The construct of any one of claims 7 to 16, wherein the Treg amplifying agent is a TNFR2 agonist, which is a small molecule or a nucleic acid aptamer or a peptide aptamer. Such as the construct of any one of claims 1 to 63, which is a TNFR2 agonist construct of formula 3: (Treg amplifier) _n - linker _p - (activity modulator) _q , formula 3a, or ( Activity modulator) _q - linker _p - (Treg amplifying agent) _n , Formula 3b, where: each of n and q is an integer, and each is independently 1, 2 or 3; p is 0, 1 , 2 or 3; the activity modulator is a part that modulates or changes the activity or pharmacological properties of the construct compared to the construct without the activity modulator; and the linker increases the flexibility of the construct, and/or alleviate or reduce the steric hindrance effect of the construct or its interaction with the receptor, and/or increase the solubility of the construct in aqueous media. The construct of any one of claims 51 to 64, wherein the Treg expander is a TNFR2 agonist. The construct of claim 65, wherein the TNFR2 agonist stimulates or induces TNFR2 signaling. The construct of any one of claims 51 to 66, wherein the Treg amplifying agent is a TNFR2 agonist, which is a scFv, VHH single domain antibody or Fab of a TNFR2 agonist monoclonal antibody. The construct of claim 67 dimerizes by N-terminal fusion with the C-terminus of trastuzumab. The TNFR1 antagonist construct of any one of claims 51 to 68, wherein the Treg amplifying agent is a TNFR2 agonist, which is a small molecule or nucleic acid or peptide aptamer. A construct comprising a TNFR1 inhibitor moiety linked to one or more Treg expanders via a central PEG linker, or at least two identical or different TNFR1 inhibitors, or two identical or different Treg expanders. Additive. The construct of claim 70, comprising a branched PEG moiety connecting the TNFR1 inhibitor and one or more Treg expanders. For example, the structure of Claim 70 or Claim 71 has a structure selected from Formulas 4A to 4D: Formula 4A: ,or n is 1 to 5; R ¹ is H or CH ₃ or CH ₂ CH ₃ or other C1-C5 alkyl It is a TNFR1 inhibitor (TNFR1 antagonist); It is a Treg amplifying agent; or formula 4B: For TNFR1 inhibitors (TNFR1 antagonists) is a Treg amplifying agent; n is 1 to 5; or formula 4C: Is a TNFR1 inhibitor (TNFR1 antagonist), or is a Treg expander; and n is 1 to 5; or Formula 4D: or , each of which are the same or different and are each independently selected from the group consisting of TNFR1 inhibitors (TNFR1 antagonists) and TNFR2 agonists; the activity modulator is optional and can be linked to any suitable locus in the molecule; and n is 1 to 5. The construct of any one of claims 70 to 72, wherein the Treg expander is a TNFR2 agonist. The construct of any one of claims 1 to 73, comprising an active modulator, wherein: The activity modulator is an Fc region, or an Fc region that includes a hinge region or other linker; and The Fc region or an Fc region with a hinge region is an Fc modified to reduce or eliminate ADCC and/or CDC activity. The construct of claim 74, wherein the Fc or modified Fc is an IgG Fc or is an IgG1 or IgG4 Fc. The construct of any one of claims 1 to 75, which binds to a nascent Fc receptor (FcRn). Such as the structure of claim 76, wherein: The construct includes a short FcRn-binding peptide (FcRnBP); and The short FcRn binding peptide (FcRnBP) provides the interaction of the construct with FcRn and contains 6-25, such as 10-20, amino acid residues. The construct of claim 77, wherein the FcRnBP contains 12-20 residues or 15 residues or 16 residues. The TNFR1 antagonist construct of claim 78, wherein the FcRn-binding peptide (FcRnBP) includes any of the peptides of SEQ ID NOs: 48-51. The TNFR1 antagonist construct of claim 78, wherein the FcRn-binding peptide (FcRnBP) consists of any of the peptides of SEQ ID NOs: 48-51. The construct of any one of claims 1 to 80, which is a TNFR1 antagonist construct, includes: a) TNFR1 inhibitor moiety, which is TNFR1 selective; b) Select one or more connectors as needed; and c) The half-life extension part selected as needed, among which The antagonist construct includes at least one of b) and c). The construct of claim 81, wherein the TNFR1-selective antagonist selectively binds to and inhibits TNFR1 signaling, but not TNFR2 signaling. The construct of claim 81 or claim 82, wherein the TNFR1 inhibitor as a selective antagonist comprises an antigen-binding fragment that selectively binds and inhibits TNFR1 signaling but not TNFR2 signaling. The construct of claim 83, wherein the antigen-binding fragment that selectively binds and inhibits TNFR1 signaling but not TNFR2 signaling comprises a domain antibody (dAb), scFv, or Fab fragment. The construct of any one of claims 1 to 84, wherein the TNFR1 inhibitor comprises an antigen-binding fragment of a human anti-TNFR1 antagonist monoclonal antibody. Such as the construct of claim 85, wherein the human anti-TNFR1 antagonist monoclonal antibody is H398 comprising SEQ ID NO: 678, or is ATROSAB, or an antigen-binding portion thereof, or has SEQ ID NO: 31 or 32 or 673 or 678 A sequence with at least 95% sequence identity, or an antigen-binding portion thereof that binds TNFR1. The construct of any one of claims 1 to 86, wherein the TNFR1 inhibitor comprises a domain antibody (dAb) antigen-binding portion thereof, or an amine group shown in any one of SEQ ID NOs: 52-672 acid sequence or a sequence with at least 95% sequence identity thereto that retains TNFR1 inhibitor activity. The construct of any one of claims 1 to 87, wherein the TNFR1 inhibitor comprises the scFv shown in any one of SEQ ID NOs: 673-678 or has at least 90% or 95% sequence identity thereto Variants of such polypeptides retain TNFR1 inhibitor activity. The construct of any one of claims 1 to 88, wherein the TNFR1 inhibitor comprises the Fab shown in any one of SEQ ID NOs: 679-682 or has at least 90% or 95% sequence identity therewith Sequences that retain TNFR1 inhibitory or binding activity. The construct of any one of claims 1 to 89, wherein the TNFR1 inhibitor comprises a sequence shown in SEQ ID NO: 683 or 684 or is a retained TNFR1 inhibitor with at least 90% or 95% sequence identity thereto Or nanobodies that bind active sequences. The construct of any one of claims 1 to 90, wherein the TNFR1 inhibitor comprises dominant negative tumor necrosis factor (DN-TNF) or a TNF mutant protein. The construct of claim 91, wherein the DN-TNF or TNF mutein is a soluble TNF molecule that contains one or more amino acid substitutions that confer selective inhibition of TNFR1 and are selected from the group consisting of: V1M, L29S, L29G, L29Y, R31C, R31E, R31N, R32Y, R32W, C69V, A84S, V85T, S86T, Y87H, Q88N, T89Q, I97T, C101A, A145R, E146R, L29S/R32W, L29S/S86T, R32W/ S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T, I97T/A145R, V1M/R31C/C69V/Y87H/C101A/A145R and A84S/V85T/S86T/Y87H/Q88N/ T89Q, Reference is made to the sequence of soluble TNF shown in SEQ ID NO: 2. The construct of claim 91 or claim 92, wherein the TNFR1 inhibitor TNF mutein comprises the residue sequence shown in any one of SEQ ID NOs: 701-703, or is the same as SEQ ID NOs: 701-703 The sequence of residues shown in any one of them, or a fragment thereof, has at least or at least about 90% or 95% sequence identity to a sequence that retains TNFR1 inhibitor activity. The construct of any one of claims 1 to 93, comprising a linker, wherein the linker comprises all or part of the hinge sequence of trastuzumab, corresponding to residues 222-227 of SEQ ID NO: 26 SCDKTH or up to the entire sequence of the hinge region of trastuzumab containing or having the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26), or at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues, or residues ESKYGPPCPPCP from residues 212 to 223 of SEQ ID NO: 29, or a sequence having at least 98% or 99% sequence identity thereto as a linker. The construct of any one of claims 1 to 94, comprising a linker, wherein the linker comprises the sequence SCDKTH corresponding to residues 222-227 of SEQ ID NO: 26. The construct of any one of claims 1 to 95, comprising a linker, wherein the linker comprises a glycine-serine (GS) linker. The construct of claim 96, wherein the GS linker is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS. The construct of any one of claims 1 to 97, comprising a linker, wherein the linker comprises a GS linker and trastuzumab corresponding to residues EPKSCDKTHTCPPCP (SEQ ID NO: 26 of 219-233) all or part of the hinge sequence. The construct of any one of claims 1 to 98, wherein the linker comprises a GS linker and comprises the sequence SCDKTH corresponding to residues 217-222 of SEQ ID NO: 31. The construct of any one of claims 1 to 99, wherein the linker includes the GS linker and all or all of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29 part. The construct of any one of claims 1 to 100, comprising an activity modulator, wherein the activity modulator is a half-life extending moiety, which is an IgG Fc, a polyethylene glycol (PEG) molecule or a human serum albumin (HSA) ). The construct of claim 101, wherein the IgG Fc is IgG1 or IgG4 Fc. The construct of claim 101 or claim 102, wherein the IgG1 Fc is the Fc of trastuzumab shown in SEQ ID NO: 27 or an amino acid sequence with at least 95% sequence identity thereto. The construct of claim 101 or claim 102, wherein the IgG4 Fc is the Fc of nivolumab shown in SEQ ID NO: 30 or an amino acid sequence with at least 95% sequence identity thereto. The construct of any one of claims 101 to 104, wherein the IgG1 Fc is the Fc of human IgG1 shown in SEQ ID NO: 10. The construct of any one of claims 101 to 104, wherein the IgG4 Fc is the Fc of human IgG4 shown in SEQ ID NO: 16. The construct of any one of claims 1 to 106, comprising a TNFR1 inhibitor, wherein the TNFR1 inhibitor is monovalent. The construct of any one of claims 81 to 107, comprising a linker, wherein the linker comprises (Gly ₄ Ser) ₃ . The construct of any one of claims 81 to 107, which includes a linker, wherein the linker includes (Gly ₄ Ser) ₃ and SCDKTH (residues 217-222 of SEQ ID NO: 31). The construct of any one of claims 1 to 109, which includes a linker, wherein the linker includes (Gly ₄ Ser) ₃ and trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26 The hinge sequence. The construct of any one of claims 1 to 109, which includes a linker, wherein the linker includes (Gly ₄ Ser) ₃ and nivolumab corresponding to residues 212-223 of SEQ ID NO: 29 Hinge sequence. The construct of any one of claims 1 to 111, comprising the residue sequence shown in any one of SEQ ID NOs: 704-764, or inhibiting TNFR1 and having the same residue sequence as in any one of SEQ ID NOs: 704-764 The residue sequences shown in any one of the constructs have a sequence identity of at least, or at least about 95%, sequence identity. The construct of any one of claims 1 to 112, which is a TNFR1 antagonist construct, wherein: The TNFR1 construct includes a short FcRn-binding peptide (FcRnBP); and Short FcRn binding peptides (FcRnBP) provide interaction of this construct with FcRn and contain 6-25, such as 10-20, amino acid residues. The construct of claim 113, wherein the FcRnBP contains 12-20 residues or 15 residues or 16 residues. The construct of claim 113, wherein the FcRn binding peptide (FcRnBP) comprises any of the peptides of SEQ ID NOs: 48-51. The TNFR1 antagonist construct of claim 113, wherein the FcRn binding peptide (FcRnBP) consists of any of the peptides of SEQ ID NOs: 48-51. For example, the structure of any one of claim items 1 to 116 includes: a) Domain antibodies that inhibit TNFR1; b) Linkers that increase flexibility, reduce steric hindrance, or increase solubility; and c) Half-life extension part. The construct of claim 117, wherein the half-life extending moiety is not a human serum albumin antibody or unmodified Fc. The construct of any one of claim 117 or claim 118, which is a TNFR1 antagonist, comprising: a) a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or SEQ ID NO: The scFv of any one of 673-678, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or one of SEQ ID NO: 685-703 Any TNF mutein; b) GS linker, selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; ; and GSSSGS; and c) half-life extending moiety, which is IgG Fc. The TNFR1 antagonist construct of any one of claims 117 to 119, wherein: the GS linker is (GGGGS) ₃ ; and the IgG Fc is the Fc of trastuzumab or the Fc of nivolumab. The construct of any one of claims 1 to 120, which is a TNFR1 antagonist construct, includes: a) A domain antibody (dAb) of any one of SEQ ID NO: 52-672, or a scFv of any one of SEQ ID NO: 673-678, or any one of SEQ ID NO: 679-682 Fab, or Nanobody of SEQ ID NO: 683 or 684, or TNF mutant protein of any one of SEQ ID NO: 685-703; b) a linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab; and c) Half-life extending moiety, which is IgG Fc. Such as the structure of claim 121, wherein: The linker includes all or part of the hinge sequence of trastuzumab; and The IgG Fc is the Fc of trastuzumab. Such as the structure of claim 121, wherein: The linker includes all or part of the hinge sequence of nivolumab; and The IgG Fc is the Fc of nivolumab. The construct of any one of claims 1 to 123, which is a TNFR1 antagonist construct, comprising: a) a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or SEQ ID NO: The scFv of any one of 673-678, or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or one of SEQ ID NO: 685-703 Any TNF mutein; b) GS linker, selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; ; and GSSSGS; c) a second linker selected from all or a portion of the hinge sequence of trastuzumab and all or a portion of the hinge sequence of nivolumab; and d) a half-life extending portion, which is an IgG Fc . The construct of claim 124, wherein: the GS linker is (GGGGS) ₃ ; the second linker includes the sequence SCDKTH (residues 217-222 of SEQ ID NO: 31); and the IgG Fc is trastuzumab Fc of monoclonal antibody. For example, the construct of claim 124, wherein: the GS linker is (GGGGS) ₃ ; the second linker includes all or part of the hinge sequence of nivolumab; and the IgG Fc is the Fc of nivolumab. A construct that is a TNFR1 agonist, comprising: a) a domain antibody (dAb) of any of SEQ ID NOs: 52-672, or a scFv of any of SEQ ID NOs: 673-678, Or the Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or the TNF mutant protein of any one of SEQ ID NO: 685-703; b) GS A linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5 ; (SerGly ₄ ) _n , where n = 1-5; (GlySerSerGly) _n , where n = 1-5; GSGGSSGG; GSSSSGSGSGSSG; GSSSGGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and c) half-life extension portion, It is a PEG molecule. Such as the construct of claim 127, wherein the GS linker is (GGGGS) ₃ . Such as the construct of claim 127 or claim 128, wherein the molecular weight of the PEG molecule is 30 kDa or greater. The construct of any one of claims 1 to 129, which is a TNFR1 agonist construct, comprising: a) a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or SEQ ID NO : scFv of any one of 673-678, or Fab of any one of SEQ ID NO: 679-682, or Nanobody of SEQ ID NO: 683 or 684, or SEQ ID NO: 685-703 The TNF mutant protein of any one; b) GS linker, which is selected from (GlySer) _n , wherein n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , wherein n= 1-10; ( Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GGSSGGSSGGGSSGGSSG; and GSSSGS; and c) half-life extending moiety, which is human serum albumin. Such as the construct of claim 130, wherein the GS linker is (GGGGS) ₃ . The construct of any one of claims 1 to 131 which is a TNFR1 antagonist, wherein the construct is optimized to eliminate immunogenic sequences or immunogenic epitopes. The construct of any one of claims 1 to 132, wherein the IgG Fc contains one or more of the following modifications: a) Modification by introducing knobs-into-holes; b) Modifications that increase or enhance recycling of nascent Fc receptors (FcRn); and c) Modification that reduces or eliminates immune effector function. The TNFR1 antagonist construct of claim 133, wherein: According to EU numbering, the pestle mutant line is selected from S354C, T366Y, T366W and T394W; and According to EU numbering, the acetabulum mutant lines were selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V. Such as the TNFR1 antagonist construct of claim 133 or claim 134, wherein the modification(s) that increases or enhances FcRn recycling is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y. The TNFR1 antagonist construct of any one of claims 133 to 135, wherein the immune effector function(s) is selected from the group consisting of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and One or more of antibody-dependent cell-mediated phagocytosis (ADCP). Such as the TNFR1 antagonist construct of claim 136, wherein the modification(s) that reduce or eliminate the immune effector function are selected from one or more of the following: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A. The construct of any one of claims 1 to 137, which is a TNFR1 antagonist or multispecific or contains a central PEG linker moiety, and the construct contains a modified Fc region. The construct of claim 138, wherein the Fc region is a modified IgG Fc and the modified IgG Fc includes one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to EU numbering, the pestle mutant line is selected from S354C, T366Y, T366W and T394W; and According to EU numbering, the acetabulum mutant lines were selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance one or more immune effector functions, wherein: The immune effector function(s) are selected from one or more of CDC, ADCC and ADCP; and The modification(s) that increase or enhance the immune effector function are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan introduced at residue N297; afucosylated glycan introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/ E333S; K326M/E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S3 24T; S267E/H268F/S324T; G236A/ I332E/S267E/H268F/S324T; E345R; and E345R/E430G/S440Y. The construct of any one of claims 1 to 139, comprising an Fc region comprising an IgG1 Fc containing one or more modifications that increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb. Such as the TNFR1 antagonist construct of claim 140, wherein the modifications that increase binding to FcγRIIb are selected from the group consisting of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/ according to EU numbering One or more of L368H/P395K. A construct, which is a Treg amplifying agent construct, includes: a) Treg amplification agent; b) Linkers, wherein the linkers increase the flexibility of the construct, and/or alleviate or reduce the steric effect of the construct or its interaction with the receptor, and/or increase the stability of the construct in aqueous media solubility; and c) Activity modulator, wherein the activity modulator is a moiety that modulates or changes the activity or pharmacological properties of the construct compared to the construct in the absence of the activity modulator. The construct of claim 142 or any one of claims 1 to 141, comprising a Treg amplifying agent, wherein the Treg amplifying agent is a TNFR2 agonist. The construct of claim 142 or claim 143, further comprising a TNFR1 inhibitor. The construct of claim 143 or claim 144, wherein the TNFR2 agonist is a TNFR2 selective agonist. The construct of any one of claims 1 to 145, which is a TNFR2 agonist construct, includes: a) TNFR2 agonist; b) Linkers, wherein the linkers increase the flexibility of the construct, and/or alleviate or reduce the steric effect of the construct or its interaction with the receptor, and/or increase the stability of the construct in aqueous media solubility; and c) Activity modulator, wherein the activity modulator is a moiety that modulates or changes the activity or pharmacological properties of the construct compared to the construct in the absence of the activity modulator. The construct of claim 146, wherein the TNFR2 agonist is a TNFR2 selective agonist. The construct of any one of claims 142 to 147, comprising an activity modulator, wherein the activity modulator is a half-life extending moiety. The construct of any one of claims 142 to 148, wherein the TNFR2 agonist selectively activates or antagonizes TNFR2 but does not activate or antagonize TNFR1. The construct of any one of claims 1 to 149, comprising a TNFR2 agonist, wherein the TNFR2 agonist binds to one or more epitopes within TNFR2. The construct of claim 150, wherein the TNFR2 is human TNFR2. The construct of claim 151, wherein the epitopes are selected from one or more of the epitopes comprising or consisting of the amino acid sequences shown in SEQ ID NOs: 839-865, 1202 and 1204 . The construct of any one of claims 149 to 152, wherein the TNFR2 agonist comprises an agonist human anti-TNFR2 antibody or an antigen-binding fragment of a humanized anti-TNFR2 antibody, or an antigen-binding portion thereof, or a single chain form thereof . Such as the construct of claim 153, wherein the agonist anti-TNFR2 antibody system is selected from MR2-1 (also named ab8161; US Patent No. 9,821,010) or MAB2261 (US Patent No. 9,821,010). The construct of any one of claims 149 to 154, wherein the TNFR2 agonist is an antigen-binding fragment selected from the group consisting of dAb, scFv or Fab fragment. The construct of any one of claims 149 to 155, wherein the TNFR2 agonist is a TNFR2 selective agonist. The construct of any one of claims 1 to 156, comprising a TNFR2 agonist, wherein the TNFR2 agonist comprises a TNFR2 agonist TNF mutein. Such as the construct of claim 157, wherein the TNFR2 mutant protein is a soluble TNF variant comprising one or more TNFR2 selective mutations selected from the following: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D ,A145H/E146S/S147D,A145H/ S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A14 5D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S and combinations of any of the foregoing, refer to SEQ ID NO: 2. The construct of claim 157, wherein the TNFR2 agonist is a TNF mutein comprising the mutation D143N/A145R. The construct of any one of claims 142 to 159, wherein the linker includes all or part of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26, or includes All or part of the hinge sequence of nivolumab from residues 212 to 223 of SEQ ID NO: 29. The construct of any one of claims 1 to 160, comprising a linker, wherein the linker comprises the sequence SCDKTH corresponding to residues 217-222 of SEQ ID NO: 31. The construct of claim 161, comprising a linker, wherein the linker comprises a glycine-serine (GS) linker. The construct of claim 162, wherein the GS linker is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS. The construct of any one of claims 146 to 163, wherein the linker comprises a GS linker and all or part of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26. The construct of any one of claims 146 to 163, wherein the linker comprises a GS linker and the sequence SCDKTH corresponding to residues 217-222 of SEQ ID NO: 31. The construct of any one of claims 146 to 163, wherein the linker comprises a GS linker and all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29. The construct of any one of claims 1 to 166, comprising a half-life extending moiety, wherein the half-life extending moiety is IgG Fc, a polyethylene glycol (PEG) molecule or human serum albumin (HSA). The construct of claim 167, wherein the IgG Fc is IgG1 or IgG4 Fc. The construct of claim 168, wherein the IgG1 Fc is the Fc of trastuzumab shown in SEQ ID NO: 27. The construct of claim 168, wherein the IgG4 Fc is the Fc of nivolumab shown in SEQ ID NO: 30. The construct of claim 168, wherein the IgG1 Fc is the Fc of human IgG1 shown in SEQ ID NO: 10. The construct of claim 168, wherein the IgG4 Fc is the Fc of human IgG4 shown in SEQ ID NO: 16. The construct of any one of claims 146 to 172, wherein the TNFR2 agonist is monovalent. The construct of any one of claims 1 to 173, which is a TNFR2 agonist construct, wherein the TNFR2 agonist is bivalent. The construct of any one of claims 1 to 173, which is a TNFR2 agonist construct, wherein the TNFR2 is trivalent. The construct of any one of claims 1 to 175, which is a TNFR2 agonist construct, wherein the linker includes (Gly ₄ Ser) ₃ . The construct of any one of claims 1 to 176, which is a TNFR2 agonist construct TNFR2, wherein the linker includes (Gly ₄ Ser) ₃ and SCDKTH (residues 217-222 of SEQ ID NO: 31) . The construct of any one of claims 1 to 177, which is a TNFR2 agonist construct, wherein the linker includes (Gly ₄ Ser) ₃ and a sequence corresponding to residues 219-233 of SEQ ID NO: 26 Hinge sequence of tocilizumab. The construct of any one of claims 1 to 177, which is a TNFR2 agonist construct, wherein the linker includes (Gly ₄ Ser) ₃ and Na corresponding to residues 212-223 of SEQ ID NO: 29 The hinge sequence of Vulumab. The construct of any one of claims 1 to 179, comprising an activity modulator as a half-life extending moiety. The construct of claim 180, wherein the half-life extending moiety is PEG. The construct of claim 180, wherein the PEG has a molecular weight of at least or at least about 30 kDa. The construct of claim 180, wherein the half-life extending moiety is human serum albumin (HSA). The construct of any one of claims 1 to 183, which is a TNFR2 agonist construct, includes: a) a TNFR2 agonist that binds to one or more epitopes in human TNFR2, which antigens The determinant is selected from the epitopes shown in SEQ ID NO: 839-865, 1202 and 1204; b) GS linker, which is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); ( Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1- 5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and c) an activity modulator that is a half-life extending portion, the half-life extending portion is IgG Fc. For example, the construct of claim 184, wherein: the GS linker is (GGGGS) ₃ ; and the IgG Fc is the Fc of trastuzumab or the Fc of nivolumab. The construct of any one of claims 1 to 185, which is a TNFR2 agonist construct, includes: a) TNFR2 agonist, which binds to one or more epitopes in human TNFR2, and these epitopes are selected from the epitopes shown in SEQ ID NO: 839-865, 1202 and 1204; b) a linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab; and c) Activity modulator, which is a half-life extending moiety, the half-life extending moiety is IgG Fc. Such as the structure of claim 186, wherein: The linker includes all or part of the hinge sequence of trastuzumab; and The IgG Fc is the Fc of trastuzumab. Such as the structure of claim 187, wherein: The linker includes all or part of the hinge sequence of nivolumab; and The IgG Fc is the Fc of nivolumab. The construct of any one of claims 1 to 183, which is a TNFR2 construct, comprising: a) a TNFR2 agonist that binds to one or more epitopes in human TNFR2, the epitopes being selected From the epitopes shown in SEQ ID NO: 839-865, 1202 and 1204; b) GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser ) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG ; GSSSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGG; GGSSGGSSGGGSSGGSSG; and GSSSGS; c) a second linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab ; and d) an activity modulator which is a half-life extending moiety, the half-life extending moiety is IgG Fc. The construct of claim 189, wherein: the GS linker is (GGGGS) ₃ ; the second linker includes the sequence SCDKTH (residues 217-222 of SEQ ID NO: 31); and the IgG Fc is trastuzumab Fc of monoclonal antibody. For example, the construct of claim 189, wherein: the GS linker is (GGGGS) ₃ ; the second linker includes all or part of the hinge sequence of nivolumab; and the IgG Fc is the Fc of nivolumab. The construct of any one of claims 1 to 191, which is a TNFR2 agonist construct, comprising: a) the TNFR2 agonist, which comprises an agonist human anti-TNFR2 antibody selected from MR2-1 or MAB2261 An antigen-binding fragment; b) a linker, comprising: i) a GS linker, selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1 -10; (Gly ₃ Ser) _n , where n = 1-5; (SerGly ₄ ) _n , where n = 1-5; (GlySerSerGly) _n , where n = 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and/or ii) all or part of the hinge sequence of trastuzumab or all or part of the hinge sequence of nivolumab; and c) an activity modulator, which is selected from IgG1 or IgG4 Fc, PEG molecules and the half-life extending portion of human serum albumin (HSA), wherein: the IgG1 Fc is the Fc of human IgG1 shown in SEQ ID NO: 10, or is shown in SEQ ID NO: 27 the Fc of trastuzumab; and the molecular weight of the PEG molecule is at least or at least about 30 kDa. The construct of any one of claims 1 to 192, which is or comprises a TNFR2 agonist construct, comprising: a) a TNFR2 selective TNF mutein, which is a TNFR2 selection comprising one or more selected from the following Sexually mutated soluble TNF variants: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A14 5R/S147T, Q88N/ T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T /E146S/S147D、A145Q/E146D/ S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F1 44L/A145S, S95C/G148C and D143V/ A145S, refer to SEQ ID NO: 2; b) linker, which includes: i) GS linker, which is selected from (GlySer) _n , where n=1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSSGSGSGSSG; GSSSGSGSGSSGG; GGSSGG; GGSSGGSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and/or ii) all or part of the hinge sequence of trastuzumab or all or part of the hinge sequence of nivolumab; and c) an activity modulator, It is a half-life extending portion selected from the group consisting of IgG1 or IgG4 Fc, PEG molecules and human serum albumin (HSA), wherein: the IgG1 Fc is the Fc of human IgG1 shown in SEQ ID NO: 10, or is SEQ ID NO: The Fc of trastuzumab shown in 27; and the molecular weight of the PEG molecule is at least or at least about 30 kDa. The construct of any one of claims 1 to 193, which is or includes a TNFR2 agonist construct, including: a) a TNFR2 TNF mutein including the mutation D143N/A145R; b) (GGGGS) ₃ linker; and c) Activity modulator, which is a half-life extending portion, and the half-life extending portion is the Fc of trastuzumab or the Fc of nivolumab. The construct of any one of claims 1 to 194, which is a TNFR2 agonist construct, comprising: a) a TNFR2-selective TNF mutein comprising mutation D143N/A145R; b) (GGGGS) ₃ linker and comprising The second linker of the sequence SCDKTH (residues 217-222 of SEQ ID NO: 31); and c) an activity modulator that is a half-life extending portion, the half-life extending portion being the Fc of trastuzumab. A construct that is a TNFR2 agonist construct, comprising: a) a TNFR2-selective TNF mutein comprising mutation D143N/A145R; b) all or all of the (GGGGS) ₃ linker and hinge sequence comprising nivolumab a portion of the second linker; and c) an activity modulator that is a half-life extending portion, the half-life extending portion being the Fc of nivolumab. The construct of any one of claims 1 to 196, which is a TNFR2 agonist construct, includes: a) TNFR2-selective TNF mutant protein containing mutation D143N/A145R; b) a linker comprising all or part of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26; and c) The half-life extending part, which is the Fc of trastuzumab. The construct of any one of claims 1 to 197, which is or contains a TNFR2 agonist construct, including: a) TNFR2-selective TNF mutant protein containing mutation D143N/A145R; b) a linker comprising all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29; and c) Activity modulator, which is a half-life extending portion, and the half-life extending portion is the Fc of nivolumab. The construct of any one of claims 1 to 198, which is a TNFR1 antagonist construct or a TNFR2 agonist construct or both, wherein the IgG Fc is a monomer or dimer. The construct of any one of claims 1 to 199, comprising a dAb. For example, the construct of claim 200 includes a Vhh single chain or double chain (nanobody) containing a dAb. The construct of claim 201, comprising HSA linked to the dAb either directly or via a linker. For example, the construct of claim 202, wherein the linker is a Gly-Ser (GS) linker and/or the HSA is connected to the C-terminus of the dAb via the linker or directly. The construct of any one of claims 1 to 203, comprising residues 20-732 linked to HSA via a linker as shown in SEQ ID NO: 1475, i.e. dAb Dom1h-131 of SEQ ID NO: 59 -206, or a construct having at least 95%, 96%, 97%, 98%, 99% sequence identity to the construct of SEQ ID NO: 1475 and having TNFR1 antagonist activity. Such as the construct of claim 200 or 203, which includes the dAb shown in any one of SEQ ID NO: 52-83, 503-672, 1478 and 1479 and has at least 95%, 96%, 97%, Its variants have 98% and 99% sequence identity, thus the construct has TNFR1 antagonist activity. The construct of claim 205, wherein the dAb has a sequence shown in any one of SEQ ID NOs: 57-59 and a variant thereof has at least 95% sequence identity thereto, whereby the construct has TNFR1 antagonism agent activity. The construct of claim 206, wherein the dAb is designated DOM1h-131-206 of SEQ ID NO: 59 and variants thereof having TNFR1 antagonist activity. The construct of any one of claims 200 to 207, wherein the dAb or the sequence of a necessary portion of the construct for administration to humans is humanized. The construct of any one of claims 1 to 208, which contains a TNFR2 agonist or is a TNFR2 agonist construct. The construct of any one of claims 1 to 208, which is, is, or includes a TNFR2 agonist construct, wherein the TNFR2 agonist is modified to eliminate an amine that is immunogenic in the individual to be treated amino acid sequence or epitope. Such as the structure of claim 200, wherein the individual is a human being. The construct of any one of claims 189 to 211, wherein the TNFR2 agonist is a TNFR2 selective agonist. The construct of any one of claims 1 to 212, which is a TNFR2 agonist construct and includes a modified IgG Fc, wherein the IgG Fc includes one or more of the following modifications: a) Modification by introducing pestle and mortar; b) Modifications that increase or enhance recycling of nascent Fc receptors (FcRn); and c) Modifications that reduce or eliminate immune effector functions selected from complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis ( ADCP) one or more. Such as the structure of request item 213, wherein: a) The modification introduced into the pestle and mortar is selected from: One or more mutations selected from S354C, T366Y, T366W and T394W according to the EU number; and According to EU numbering, one or more mutations are selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V, whereby the Fc forms a dimer; b) According to the EU number, the modification(s) that increases or enhances FcRn recycling is selected from T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F , N434A, N434W, N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/ M428L, M428L/N434S, V259I/V308F , one or more of V259I/V308F/M428L, E294del/T307P/N434Y and T256N/A378V/S383N/N434Y; and c) The modification(s) that reduce or eliminate the immune effector function are selected from one or more of the following: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A. The construct of any one of claims 1 to 213, which is a TNFR2 agonist construct containing a modified IgG Fc, wherein the IgG Fc contains one or more of the following modifications: a) One or more modifications introducing a pestle and mortar, wherein: According to EU numbering, the pestle mutant line is selected from S354C, T366Y, T366W and T394W; and According to EU numbering, the acetabulum mutant lines were selected from Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector functions are selected from one or more of CDC, ADCC and ADCP; and The modification(s) that increase or enhance the immune effector function are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan is introduced at residue N297; afucosylated glycan is introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y. The construct of any one of claims 1 to 215, which is or includes a TNFR2 agonist construct containing a modified IgG1 Fc, wherein the Fc is modified to increase interaction with the inhibitory Fcγ receptor (FcγR) FcγRIIb combine. Such as the construct of claim 216, wherein the modifications that increase binding to FcγRIIb are selected from the group consisting of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K according to EU numbering one or more of them. The construct of any one of claims 1 to 217, which is or includes a TNFR2 agonist construct and selectively activates or agonizes TNFR2 without activating or antagonizing TNFR1, including: a) TNFR2 agonist; b) one or more linkers; and c) Activity modulators which are half-life extending moieties, wherein: The TNFR2 agonist construct is a fusion protein containing a single-chain TNFR2-selective TNF mutein trimer fused to a multimerization domain, and contains the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula III), MD is the same or different multimerization domain; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 are the same or different linkers. Such as the construct of claim 218, wherein the TNF muteins comprise one or more TNFR2 selective mutations selected from the following: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F , A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S14 7D, A145H/S147D, L29V/A145D /E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E 146D/S147T, A145R/E146T/S147D , A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2. The construct of claim 218, wherein the TNF muteins comprise the TNFR2 selective mutation D143N/A145R. The construct of any one of claims 218 to 220, wherein the multimerization domain is selected from the group consisting of EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO: 811), and chicken tenascin C (TNC). The polymerization domain (residues 110-139 of SEQ ID NO: 804; SEQ ID NO: 805) or the trimerization domain of human TNC (residues 110-139 of SEQ ID NO: 806, SEQ ID NO: 807). The TNFR2 agonist construct of any one of claims 218 to 221, wherein the multimerization domain is IgG1 Fc or IgG4 Fc and wherein the IgG1 Fc or IgG4 Fc is also the half-life extending portion. The TNFR2 agonist construct of any one of claims 218 to 222, wherein the L1, L2 and/or L3 linkers are independently selected from (GGGGS) _n , where n = 1-5, or the stem of TNF All or part of the area (SEQ ID NO: 812). The TNFR2 agonist construct of any one of claims 218 to 223, wherein the linker between the TNFR2 agonist and the half-life extending portion is: GS linker, which is selected from (GlySer) _n , where n = 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5 ; (GlySerSerGly) _n , where n=1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; or a linker selected from all or part of the hinge sequence of trastuzumab and All or part of the hinge sequence of nivolumab; or a combination thereof. The TNFR2 agonist construct of any one of claims 218 to 224, wherein the half-life extending moiety is selected from: IgG1 Fc, which is the Fc of human IgG1 shown in SEQ ID NO: 10 or the Fc of trastuzumab shown in SEQ ID NO: 27; IgG4 Fc, which is the Fc of human IgG4 shown in SEQ ID NO: 16 or the Fc of nivolumab shown in SEQ ID NO: 30; PEG molecules with a size of at least or at least about 30 kDa; and Human serum albumin (HSA). The construct of any one of claims 1 to 217, which is or includes a TNFR2 agonist construct, including: a) the construct has the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut ( Formula II); or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula III), where MD is the multimerization domain; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 can be the same or Different linkers, wherein: i) the MD system is selected from the group consisting of EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO: 811), and the trimerization domain of chicken tenascin C (TNC) (SEQ ID NO: 804 Residues 110-139 of SEQ ID NO: 805) or the trimerization domain of human TNC (residues 110-139 of SEQ ID NO: 806, SEQ ID NO: 807); ii) L1, L2 and L3 are each (GGGGS) _n , where n = 1-5, or all or part of the stem region of TNF (SEQ ID NO: 812), or a mixture thereof; and iii) the TNF mutant proteins comprise the TNFR2 selective mutation D143N/A145R; b) A half-life extending moiety selected from: IgG1 Fc, which is the Fc of human IgG1 shown in SEQ ID NO: 10 or the Fc of trastuzumab shown in SEQ ID NO: 27; IgG4 Fc, It is the Fc of human IgG4 shown in SEQ ID NO: 16 or the Fc of nivolumab shown in SEQ ID NO: 30; a PEG molecule having a size of at least or at least about 30 kDa; and human serum albumin ( ₍ GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , Where n= 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; or a linker selected from all or part of the hinge sequence of trastuzumab and the hinge of nivolumab All or part of a sequence; or a combination thereof. The construct of any one of claims 1 to 217, which is a TNFR2 agonist construct, including the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut-L1- TNFmut-L2-TNFmut-L3-MD (Formula III), where MD is the multimerization domain; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 are the same or different linkers, and where: i ) the MD is selected from IgG1 Fc or IgG4 Fc; ii) L2 and L3 in Formula II, and L1 and L2 in Formula III are each independently (GGGGS) _n , where n = 1-5, or the stem of TNF All or part of the region (SEQ ID NO: 812), or a combination thereof; iii) Each of L1 in Formula II and L3 in Formula III is independently selected from: a GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n = 1-5; (GlySerSerGly) _n , where n = 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; or a linker selected from the hinge sequence of trastuzumab all or part of the hinge sequence of nivolumab; or a combination thereof; and iv) the TNF muteins comprise the TNFR2 selective mutation D143N/A145R. For example, the structure of claim 227, wherein the MD is selected from: IgG1 Fc, which is the Fc of human IgG1 shown in SEQ ID NO: 10 or the Fc of trastuzumab shown in SEQ ID NO: 27; or IgG4 Fc, which is the Fc of human IgG4 shown in SEQ ID NO: 16 or the Fc of nivolumab shown in SEQ ID NO: 30. The construct of claim 227 or claim 228, wherein the MD is the IgG1 Fc of trastuzumab, and the linker between the MD and the adjacent TNF mutein is the residue corresponding to SEQ ID NO: 26 All or part of the hinge sequence of trastuzumab 219-233. Such as the construct of claim 227 or claim 228, wherein the MD is the IgG1 Fc of trastuzumab, and the linker between the MD and the adjacent TNF mutein includes the sequence SCDKTH (residues of SEQ ID NO: 31 Base 217-222). Such as the construct of any one of claims 227 to 230, wherein the MD is the IgG1 Fc of trastuzumab, and the linker between the MD and the adjacent TNF mutant protein includes (Gly ₄ Ser) ₃ and the corresponding The hinge sequence of trastuzumab at residues 219-233 of SEQ ID NO: 26. Such as the construct of claim 227 or claim 228, wherein the MD is the IgG1 Fc of trastuzumab, and the linker between the MD and the adjacent TNF mutant protein includes (Gly ₄ Ser) ₃ and SCDKTH (SEQ Residues 222-227 of ID NO: 31). The construct of claim 227 or claim 228, wherein the MD is the IgG4 Fc of nivolumab, and the linker between the MD and the adjacent TNF mutein includes residue 212 corresponding to SEQ ID NO: 29 All or part of the hinge sequence of nivolumab -223. Such as the construct of claim 227 or claim 228, wherein the MD is the IgG4 Fc of nivolumab, and the linker between the MD and the adjacent TNF mutant protein includes (Gly ₄ Ser) ₃ and corresponds to SEQ ID All or part of the hinge sequence of nivolumab at residues 212-223 of NO: 29. The construct of any one of claims 1 to 234, which is an agonist construct, wherein the TNFR2 agonist is modified to eliminate an immunogenic sequence or epitope that is immunogenic in the individual. Such as the construct of claim 235, wherein the individual is a human being. The construct of any one of claims 1 to 236, which is a TNFR2 agonist construct and includes a modified IgG Fc, wherein the IgG Fc includes one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that reduce or eliminate immune effector functions, wherein: The immune effector functions are selected from one or more of CDC, ADCC and ADCP; and The modification(s) that reduce or eliminate the immune effector function are selected from one or more of the following: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A. The construct of any one of claims 1 to 237, which is a TNFR2 agonist construct comprising a modified IgG Fc, wherein the IgG Fc comprises one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector functions are selected from one or more of CDC, ADCC and ADCP; and The modification(s) that increase or enhance the immune effector function are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan is introduced at residue N297; afucosylated glycan is introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y. The TNFR2 agonist construct of any one of claims 1 to 238, which is a TNFR2 agonist construct comprising an IgG1 Fc modified to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb . Such as the TNFR2 agonist construct of claim 239, wherein the modifications that increase binding to FcγRIIb are selected from the group consisting of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R according to EU numbering One or more of /L368H/P395K. Such as the construct of any one of claims 1 to 240, which is a multispecific TNFR1 inhibitor/TNFR2 agonist construct and has the following formula: (TNFR1 inhibitor) _n - linker (L) _p - ( TNFR2 antagonist) _q (Formula I), or (TNFR1 inhibitor) _n - linker (L) _p - (TNFR2 antagonist) _q , or (TNFR1 inhibitor) _n - (TNFR2 antagonist) _q - linker ( L) _p , or (TNFR2 antagonist) _q - (TNFR1 inhibitor) _n - linker (L) _p , or any of the above, which contains an optional activity modulator, where: n= 1 or 2, p = 1, 2 or 3, and q = 1 or 2; The TNFR1 inhibitor interacts with TNFR1 to inhibit its activity; The activity modulator is a modulator that modulates or changes compared to a construct in which the activity modulator is not present Part of the active or pharmacological properties of the construct; and the linker increases the solubility of the construct, or increases flexibility, or changes the steric effect of the construct. The construct of any one of claims 1 to 241, which is a multispecific TNFR1 inhibitor/TNFR2 agonist construct, wherein: The TNFR1 inhibitor selectively inhibits or antagonizes TNFR1 signaling but does not inhibit or antagonize TNFR2 signaling; The TNFR1 inhibitor does not interfere with the activation or agonism of TNFR2; The TNFR2 agonist selectively activates or potentiates TNFR2 signaling but does not activate or potentiate TNFR1 signaling; and The TNFR2 agonist does not interfere with the inhibitory or antagonistic effects of TNFR1. Such as the construct of claim 241 or claim 242, wherein: a) the TNFR1 inhibitor is selected from: i) the antigen-binding fragment of a human anti-TNFR1 antagonist monoclonal antibody selected from H398 or ATROSAB or has at least 95% affinity therewith A polypeptide with sequence identity; or ii) a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or a scFv of any one of SEQ ID NO: 673-678, or SEQ ID NO : Fab of any one of 679-682, or Nanobody of SEQ ID NO: 683 or 684, or TNF mutant protein of any one of SEQ ID NO: 701-703, or with any of the aforementioned polypeptides A polypeptide with a sequence of at least 95% sequence identity that is a TNFR1 inhibitor; or iii) a dominant negative tumor necrosis factor (DN-TNF) or a TNF mutant protein containing a soluble TNF molecule, which has one or more Amino acid substitutions that confer selective inhibition of TNFR1 and are selected from the following: V1M, L29S, L29G, L29Y, R31C, R31E, R31N, R32Y, R32W, C69V, A84S, V85T, S86T, Y87H, Q88N, T89Q, I97T, C101A, A145R, E146R, L29S/R32W, L29S/S86T, R32W/S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T, I97T/A145R, V1M/R31C /C69V/ Y87H/C101A/A145R and A84S/V85T/S86T/Y87H/Q88N/T89Q, refer to the sequence of soluble TNF shown in SEQ ID NO: 2; b) The linker is selected from: i) GS linker, which is selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and/or ii) corresponding to SEQ ID NO: 26 All or part of the hinge sequence of trastuzumab at residues 219-233 of SEQ ID NO: 29, or all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29; and iii) IgG1 or IgG4 Fc, wherein: the IgG1 Fc is selected from the IgG1 Fc of human IgG1 shown in SEQ ID NO: 10, or the IgG1 Fc of trastuzumab shown in SEQ ID NO: 27; the IgG4 Fc Is selected from the IgG4 Fc of human IgG4 shown in SEQ ID NO: 16, or the IgG4 Fc of nivolumab shown in SEQ ID NO: 30; and if necessary, the Fc includes one or more introduction adapters and /or modifications that increase or enhance nascent Fc receptor (FcRn) recycling and/or reduce or eliminate immune effector functions; and c) the TNFR2 agonist is selected from: i) one or more antigens within human TNFR2 An epitope-binding antigen-binding fragment selected from the epitopes shown in SEQ ID NOs: 839-865, 1202 and 1204; or ii) a agonist human selected from MR2-1 or MAB2261 An antigen-binding fragment of an anti-TNFR2 antibody; or iii) a TNFR2-selective TNF mutein, which is a soluble TNF variant comprising one or more TNFR2-selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N /A145I/E146G/S147D、A145H/ E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A14 5D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2; or iv) contains mutation D143N/A 145R of Single-chain TNFR2-selective TNF mutein trimers, wherein the TNF muteins are linked by (GGGGS) _n , where n = 1-5, or all or part of the stem region of TNF (SEQ ID NO: 812); or v) TNFR2 selective agonists comprising the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula III) ; Wherein MD is the multimerization domain; TNFmut is the TNFR2 selective TNF mutant protein; and L1, L2 and L3 are the same or different linkers, and wherein: the MD is selected from EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO: 811), the trimerization domain of chicken tenascin C (TNC) (residues 110-139 of SEQ ID NO: 804; SEQ ID NO: 805) or the trimerization domain of human TNC (SEQ ID NO: 806 (residues 110-139, SEQ ID NO: 807); L1, L2 and L3 are each (GGGGS) _n , where n = 1-5, or the stem region of TNF (SEQ ID NO: 812) All or part thereof, or mixtures thereof; and the TNF muteins comprise the TNFR2 selective mutation D143N/A145R. The construct of claim 241 or claim 242, which is a multispecific TNFR1 antagonist/TNFR2 agonist construct, wherein: a) the TNFR1 inhibitor comprises any one of SEQ ID NOs: 52-672 Domain antibody (dAb), or scFv of any one of SEQ ID NO: 673-678, or Fab of any one of SEQ ID NO: 679-682, or Nanobody of SEQ ID NO: 683 or 684 , or the TNF mutant protein of any one of SEQ ID NO: 701-703, or a sequence having at least or at least about 95% sequence identity therewith; b) the linker includes (GGGGS) ₃ , including the sequence SCDKTH (SEQ ID NO: 26 (residues 222-227) of the polypeptide and the Fc of trastuzumab; and c) the TNFR2 agonist comprises a TNFR2-selective TNF mutein, which is one or more selected from the following Soluble TNF variants with selective mutations in TNFR2: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/ D1 43V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2. Such as the construct of claim 241 or claim 242, wherein: a) the TNFR1 inhibitor comprises a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or a domain antibody (dAb) of any one of SEQ ID NO: 673-678 Any scFv, or Fab of any one of SEQ ID NO: 679-682, or Nanobody of SEQ ID NO: 683 or 684, or TNF of any one of SEQ ID NO: 701-703 The mutant protein, or a sequence with at least or at least about 95% sequence identity thereto; b) the linker includes (GGGGS) ₃ , all or part of the hinge sequence of nivolumab and the Fc of nivolumab; and c ) The TNFR2 agonist comprises a TNFR2-selective TNF mutein, which is a soluble TNF variant comprising one or more TNFR2-selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G /S147D、A145H/E146S/S147D、 A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S14 7D、A145D/S147D、A145K/E146D/ S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2. Such as the construct of claim 241 or claim 242, wherein: a) the TNFR1 inhibitor comprises a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or a domain antibody (dAb) of any one of SEQ ID NO: 673-678 Any scFv, or Fab of any one of SEQ ID NO: 679-682, or Nanobody of SEQ ID NO: 683 or 684, or TNF of any one of SEQ ID NO: 701-703 A mutein, or a sequence having at least or at least about 95% sequence identity thereto; b) the linker comprises (GGGGS) ₃ and the Fc of trastuzumab; and c) the TNFR2 agonist comprises a TNFR2-selective TNF A mutein that is a soluble TNF variant comprising one or more TNFR2 selective mutations selected from: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q , E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S14 7D、L29V/A145D/E146D/S147D , A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T , E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, refer to SEQ ID NO: 2. Such as the construct of claim 241 or claim 242, wherein: a) the TNFR1 inhibitor comprises a domain antibody (dAb) of any one of SEQ ID NO: 52-672, or a domain antibody (dAb) of any one of SEQ ID NO: 673-678 Any scFv, or Fab of any one of SEQ ID NO: 679-682, or Nanobody of SEQ ID NO: 683 or 684, or TNF of any one of SEQ ID NO: 701-703 A mutein, or a sequence having at least or at least about 95% sequence identity thereto; b) the linker includes (GGGGS) ₃ and the Fc of nivolumab; and c) the TNFR2 agonist includes a TNFR2-selective TNF mutation A protein that is a soluble TNF variant comprising one or more TNFR2 selective mutations selected from the group consisting of: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A145R/S147T, Q88N/T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D ,L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T/E146S/S147D, A145Q/E146D/S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A1 45R/E146T/S147D, A145R/S147T, For E146D/S147D, D143V/F144L/A145S, S95C/G148C and D143V/A145S, and any combination of the aforementioned mutations, refer to SEQ ID NO: 2. The construct of any one of claims 241 to 247, which includes a modified Fc, wherein the IgG Fc includes one or more of the following modifications: a) Modification by introducing pestle and mortar; b) Modifications that increase or enhance recycling of nascent Fc receptors (FcRn); and c) Modifications that reduce or eliminate immune effector functions. For example, the structure of request item 248, in which the Fc contains the pestle and mortar modification: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V. The construct of claim 248, wherein the Fc includes a modification that increases or enhances FcRn recycling, which is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y. The construct of claim 248, wherein the Fc includes a modification of an immune effector function selected from the group consisting of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody dependent cell-mediated phagocytosis (ADCP). The construct of claim 248, which includes a modification that reduces or eliminates immune effector functions selected from one or more of the following: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A. The construct of any one of claims 241 to 247, wherein the IgG Fc contains one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector functions are selected from one or more of CDC, ADCC and ADCP; and The modification(s) that increase or enhance the immune effector function are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan is introduced at residue N297; afucosylated glycan is introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y. The construct of any one of claims 241 to 253, wherein the construct comprises an IgG1 Fc modified to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb. Such as the construct of claim 254, wherein the modifications that increase binding to FcγRIIb are selected from the group consisting of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K according to EU numbering one or more of them. The construct of any one of claims 1 to 255, which is a multispecific TNFR1 antagonist/TNFR2 agonist, wherein: The TNFR1 antagonist is monovalent; and The TNFR2 agonist is monovalent. The construct of any one of claims 1 to 255, which is a multispecific TNFR1 antagonist/TNFR2 agonist, wherein: The TNFR1 antagonist is monovalent; and The TNFR2 agonist is bivalent. The construct of any one of claims 241 to 257, which is a multispecific TNFR1 antagonist/TNFR2 agonist, wherein: a) the TNFR1 antagonist is selected from: i) a human antibody selected from H398 or ATROSAB An antigen-binding fragment of a TNFR1 antagonist monoclonal antibody; or ii) a domain antibody (dAb) of any of SEQ ID NO: 52-672, or a scFv of any of SEQ ID NO: 673-678, or The Fab of any one of SEQ ID NO: 679-682, or the Nanobody of SEQ ID NO: 683 or 684, or the TNF mutant protein of any one of SEQ ID NO: 701-703, or having at least or a sequence with at least about 95% sequence identity; or iii) a dominant negative tumor necrosis factor (DN-TNF) or a TNF mutein comprising a soluble TNF molecule that has one or more genes conferring selective inhibition of TNFR1 and selected Amino acid substitutions from: V1M, L29S, L29G, L29Y, R31C, R31E, R31N, R32Y, R32W, C69V, A84S, V85T, S86T, Y87H, Q88N, T89Q, I97T, C101A, A145R, E146R, L29S /R32W, L29S/S86T, R32W/S86T, L29S/R32W/S86T, R31N/R32T, R31E/S86T, R31N/R32T/S86T, I97T/A145R, V1M/R31C/C69V/Y87H/C101A/A145R and A84S /V85T /S86T/Y87H/Q88N/T89Q, with reference to the sequence of soluble TNF shown in SEQ ID NO: 2; b) the linker is a branched chain PEG molecule with a size of at least or at least about 30 kDa; and c) the TNFR2 promotes The effector is selected from: i) An antigen-binding fragment that binds to one or more epitopes within human TNFR2 selected from the antigens shown in SEQ ID NOs: 839-865, 1202 and 1204 determinant; or ii) an antigen-binding fragment of a agonist human anti-TNFR2 antibody selected from MR2-1 or MAB2261; or iii) a TNFR2-selective TNF mutein, which is a TNFR2 selection comprising one or more selected from Sexually mutated soluble TNF variants: K65W, D143Y, D143F, D143N, D143E, D143W, D143V, A145R, A145H, A145K, A145F, A145W, E146Q, E146H, E146K, E146N, D143N/A145R, A14 5R/S147T, Q88N/ T89S/A145S/E146A/S147D, Q88N/A145I/E146G/S147D, A145H/E146S/S147D, A145H/S147D, L29V/A145D/E146D/S147D, A145N/E146D/S147D, A145T /E146S/S147D、A145Q/E146D/ S147D, A145T/E146D/S147D, A145D/E146G/S147D, A145D/S147D, A145K/E146D/S147T, A145R/E146T/S147D, A145R/S147T, E146D/S147D, D143V/F1 44L/A145S, S95C/G148C and D143V/ A145S, with reference to SEQ ID NO: 2; or iv) a single-chain TNFR2-selective TNF mutein trimer comprising mutations D143N/A145R, wherein the TNF muteins are expressed by (GGGGS) _n , where n = 1-5 or All or part of the stem region of TNF (SEQ ID NO: 812) is connected; or v) a TNFR2 selective agonist comprising the following formula: MD-L1-TNFmut-L2-TNFmut-L3-TNFmut (Formula II); Or TNFmut-L1-TNFmut-L2-TNFmut-L3-MD (Formula III); where MD is the multimerization domain; TNFmut is the TNFR2-selective TNF mutein; and L1, L2 and L3 are the same or different linkers. , and wherein: the MD is selected from the group consisting of EHD2 (SEQ ID NO: 808), MHD2 (SEQ ID NO: 811), and the trimerization domain of chicken tenascin C (TNC) (residues 110- of SEQ ID NO: 804). 139; SEQ ID NO: 805) or the trimerization domain of human TNC (residues 110-139 of SEQ ID NO: 806, SEQ ID NO: 807); L1, L2 and L3 are each (GGGGS) _n , where n = 1-5, or all or part of the stem region of TNF (SEQ ID NO: 812), or a mixture thereof; and the TNF mutant proteins comprise the TNFR2 selective mutation D143N/A145R. The construct of claim 258, wherein each of the TNFR1 antagonist and the TNFR2 agonist is monovalent. The construct of claim 258, wherein the TNFR1 antagonist is monovalent and the TNFR2 agonist is bivalent. The construct of any one of claims 1 to 260, which is a multispecific TNFR1 antagonist/TNFR2 agonist for the treatment of chronic inflammatory, autoimmune, neurodegenerative, demyelinating or respiratory diseases or disorder, or a disease, condition or disorder characterized in its etiology by overexpression of TNF or dysregulation of TNFR1 signaling. The use of a construct according to any one of claims 1 to 260, which construct is a multispecific TNFR1 antagonist/TNFR2 agonist, for the treatment of chronic inflammation, autoimmunity, neurodegeneration, degeneration, Myelin or respiratory disease or disorder, or a disease, condition or disorder characterized in its etiology by overexpression of TNF or dysregulation of TNFRl signaling. A composition comprising the construct of any one of claims 1 to 260 in a pharmaceutically acceptable carrier or vehicle. Compositions such as claim 263 for the treatment of chronic inflammatory, autoimmune, neurodegenerative, demyelinating or respiratory diseases or conditions, or in which the etiology is characterized by overexpression of TNF or dysregulation of TNFR1 signaling. disease, condition or disorder. The construct of any one of claims 1 to 261, or the use of claim 262, or the composition of claim 263 or claim 264, wherein the chronic inflammatory, autoimmune, neurodegenerative, A demyelinating or respiratory disease or disorder, or a disease, condition or disorder characterized in its etiology by an overexpression of TNF or dysregulation of TNFR1 signaling is selected from: Rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), spondyloarthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), uveitis, fibrotic diseases, endometriosis, lupus, multiple sclerosis (MS), congestive heart failure, cardiovascular disease, myocardial infarction (MI), atherosclerosis, metabolism Diseases, interleukin release syndrome, septic shock, sepsis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), SARS-CoV-2, influenza, acute and chronic neurodegenerative diseases, demyelinating diseases and disorders, stroke, Alzheimer's disease, Parkinson's disease, Behçet's disease, Dupuytren's disease, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Pancreatitis, Type I Diabetes, Chronic Obstructive Pulmonary Disease (COPD), Chronic Bronchitis, Emphysema, Graft Rejection, Graft-versus-Host Disease (GvHD), Pulmonary Inflammation, Lung Diseases and Conditions, Asthma, Cyst fibrosis, idiopathic pulmonary fibrosis, acute fulminant viral or bacterial infection, pneumonia, genetic diseases with TNF/TNFR1 as a pathogenic pathological mediator, periodic fever syndrome or cancer. The construct according to any one of claims 1 to 261, or the use according to claim 262, or the composition according to claim 263 or claim 264, for the treatment of rheumatoid arthritis. A construct according to any one of claims 1 to 261 or use according to claim 262 or use of a composition according to claim 263 or claim 264 for the treatment of rheumatoid arthritis. A construct, which is a TNFR2 antagonist construct, includes a TNFR2 antagonist and an optional linker and an optional activity modulator. Such as the construct of claim 268, which includes formula 5: (TNFR2 antagonist) _n - linker _p - (activity modulator) _q , or linker _p - (activity modulator) _q - (TNFR2 antagonist) _n , where: each of n and q is an integer and is each independently 1, 2 or 3; p is 0, 1, 2 or 3; a TNFR2 antagonist interacts with TNFR2 to inhibit (antagonize) TNFR2 activity, Molecules that thereby inhibit the proliferation of Treg and/or induce their death, and can also inhibit the proliferation of tumor cells expressing TNFR2 and induce their death; The activity modulator is a molecule that regulates or changes compared with a construct without the activity modulator. part of the active or pharmacological properties of the construct; and the linker increases the flexibility of the construct, and/or mitigates or reduces the steric effect of the construct or its interaction with the receptor, and/or increases Solubility of the construct in aqueous media. The construct of claim 268 or claim 269, wherein each of the activity modulator and the linker is as defined and described in the construct of any one of claims 1 to 250. The construct of any one of claims 268 to 270, wherein the TNFR2 antagonist: reduces and/or inhibits the proliferation of myeloid-derived suppressor cells (MDSCs); and/or by binding to the surface of MDSCs present in the tumor microenvironment Expressed TNFR2 induces apoptosis in MDSCs; and/or induces the expansion of effector T cells, including cytotoxic CD8 ⁺ T cells, by inhibiting Treg expansion and activity. The construct of any one of claims 268 to 271, wherein the TNFR2 antagonist is an antibody, an antigen-binding fragment thereof or a single chain antibody that is identical to, for example, human TNFR2 containing residue KCRPG (corresponding to SEQ ID NO: 4 An epitope of one or more of residues 142-146), or a larger epitope containing residues 130-149, 137-144, or 142-149, or at least 5 of these epitopes Binds to contiguous or discontinuous residues and does not bind to the epitope containing residues KCSPG (corresponding to residues 56-60 of SEQ ID NO: 4); or to the TNFR2 epitope PECLSCGS (corresponding to SEQ ID NO: 4) 4), RICTCRPG (corresponding to residues 116-123 of SEQ ID NO: 4), CAPLRKCR (corresponding to residues 137-144 of SEQ ID NO: 4), LRKCRPGFGVA (corresponding to SEQ ID NO: 4 residues 137-144) : residues 140-150 of SEQ ID NO: 4) and/or VVCKPCAPGTFSN (corresponding to residues 159-171 of SEQ ID NO: 4), and/or contains residues 75-128, 86-103, 111 of SEQ ID NO: 4 -An epitope binding of at least 5 consecutive or non-consecutive residues within 128 or 150-190. The construct of any one of claims 268 to 272, wherein the antibody, fragment thereof or single chain form thereof binds to an epitope containing one or more residues of the KCRPG sequence (SEQ ID NO: 840), which The affinity is at least 10 times greater than the affinity of the same antibody or antigen-binding fragment for a peptide containing the KCSPG sequence of human TNFR2 (SEQ ID NO: 839). The construct of any one of claims 268 to 273, wherein the TNFR2 antagonist is an antibody or a fragment or single chain form of an antibody selected from: TNFRAB1 (for the sequences of the heavy and light chains of TNFRAB1, see SEQ ID NO: 1212 and 1213, respectively), TNFRAB2 and TNFR2A3 (for a description of these antibodies, see, for example, U.S. Patent Publication No. 2019/0144556); Contains or has at least a CDR-H3 sequence of TNFRAB1 (QRVDGYSSYWYFDV; corresponding to residues 99-112 of SEQ ID NO: 1212), TNFRAB2 (ARDDGSYSPFDYWG; SEQ ID NO: 1217) or TNFR2A3 (ARDDGSYSPFDYFG; SEQ ID NO: 1223) Antibodies and antibody fragments and single-chain forms of the CDR-H3 sequence with approximately 85% sequence identity. For example, TNFRAB1 specifically binds to residues 130-149 of KCRPG containing TNFR2 residues with a 40-fold higher affinity than residues 48-67 of KCSPG containing TNFR2 residues. The construct of any one of claims 268 to 274, wherein the TNFR2 antagonist binds to one or more epitopes in TNFR2 selected from the following: Epitope containing residues 137-144 (CAPLRKCR; SEQ ID NO: 851) Including one or more of positions 80-86 (DSTYTQL; SEQ ID NO: 1247), 91-98 (PECLSCGS; SEQ ID NO: 1248) and/or 116-123 (RICTCRPG; SEQ ID NO: 1249) of human TNFR2 an epitope of residues; and The epitope targeted by TNFR2A3 is selected from the group consisting of the first epitope including residues 140-150 of human TNFR2 (LRKCRPGFGVA; SEQ ID NO: 1463) and containing the KCRPG motif, and/or the residues containing human TNFR2 The second epitope of 159-171 (VVCKPCAPGTFSN; SEQ ID NO: 1464). The construct of any one of claims 268 to 275, wherein the TNFR2 antagonist is an antibody, a fragment thereof or a single chain form thereof containing any one of SEQ ID NOs: 1214, 1215 and 1231-1233 CDR-H1 amino acid of the sequence shown, any one of SEQ ID NOs: 1216, 1224 and 1230 CDR-H2 sequence shown, any one of SEQ ID NOs: 1217, 1223 and 1225-1229 The CDR-H3 sequence shown in, and/or the CDR-H3 of TNFRAB1 corresponding to residues 99-112 of SEQ ID NO: 1212; shown in any of SEQ ID NO: 1218 and 1234-1236 The CDR-L1 sequence of TNFRAB1, and/or the CDR-L1 sequence of TNFRAB1 corresponding to residues 24-33 of SEQ ID NO: 1213; as shown in any of SEQ ID NO: 1219, 1220, 1237 and 1238 The CDR-L2 sequence, or the CDR-L2 sequence of TNFRAB1 corresponding to residues 49-55 of SEQ ID NO: 1213; and/or as set forth in any of SEQ ID NOs: 1221, 1222, and 1241-1244 The CDR-L3 sequence, or one or more of the CDR-L3 sequences of TNFRABl corresponding to residues 88-96 of SEQ ID NO: 1213; and/or the human antibody heavy chain variable domain of SEQ ID NO: 1245 The CDR-H1 and CDR-H2 sequences of the consensus sequence are replaced by the corresponding CDR sequences of the phenotypically neutral TNFR2-specific antibody, and/or the CDR-L1 and CDR of the human antibody light chain variable domain sequence of SEQ ID NO: 1246 -The L2 and CDR-L3 sequences are replaced with the corresponding CDR sequences of a phenotypically neutral TNFR2-specific antibody to generate a humanized antagonist TNFR2 antibody. The construct of any one of claims 268 to 275, wherein the TNFR2 antagonist specifically binds to an epitope within TNFR2 set forth in any one of SEQ ID NOs: 1247-1464. The construct of any one of claims 268 to 277, wherein the TNFR2 antagonist specifically binds to an epitope selected from: (a) Human TNFR2 contains one or more epitopes corresponding to one or more of the KCRPG residues 142-146 of SEQ ID NO: 4, or contains residues 130-149, 137-144 or larger epitopes 142-149, or at least 5 contiguous or discontinuous residues within such epitopes, and are not identical to KCSPG containing residues 56-60 corresponding to residues 56-60 of SEQ ID NO: 4 Epitope binding; and/or (b) One or more TNFR2 epitopes, which comprise the following amino acid sequences: PECLSCGS corresponding to residues 91-98 of SEQ ID NO: 4, and/or RICTCRPG corresponding to residues 116-123 of SEQ ID NO: 4, and/or CAPLRKCR, corresponding to residues 137-144 of SEQ ID NO: 4), and/or LRKCRPGFGVA, corresponding to residues 140-150 of SEQ ID NO: 4), and/or VVCKPCAPGTFSN (corresponding to residues 140-150 of SEQ ID NO: 4) residues 159-171), and/or An epitope containing at least 5 consecutive or discontinuous residues within residues 75-128, 86-103, 111-128 or 150-190 of SEQ ID NO: 4. The construct of any one of claims 268 to 278, comprising a TNFR2 antagonist as a small molecule. The construct of claim 279, wherein the TNFR2 antagonist is thalidomide or an analog thereof. Such as the construct of claim 280, wherein the thalidomide analogs are lenalidomide and pomalidomide. The construct of any one of claims 268 to 281, comprising a TNFR2 antagonist that reduces FoxP3 expression and inhibits the suppressive activity of Tregs. The construct of claim 282, wherein the TNFR2 antagonist is a histone deacetylase inhibitor that reduces FoxP3 expression and inhibits the suppressive activity of Tregs. For example, the construct of claim 282 or claim 283, wherein the inhibitor is panobinostat, cyclophosphamide, or triptolide. The construct of any one of claims 268 to 282 is used to treat infectious diseases and cancer expressing TNFR2. The construct of claim 285, wherein the cancer is a cancer selected from: T-cell lymphoma, such as Hodgkin's lymphoma and cutaneous non-Hodgkin's lymphoma, ovarian cancer, colon cancer, multiple myeloid tumors, renal cell carcinoma, breast cancer, cervical cancer, endometrial cancer, glioma, head and neck cancer, liver cancer and lung cancer. A construct that is a growth factor trap (GFT), wherein: The GFT contains two different extracellular domains (ECD) of the ligand and an activity modulator that serves as the multimerization domain; One or both of the ECD and/or the multimerization domain are modified to alter the binding of the ECD or the multimerization domain(s); and The multimerization domain is linked to the ECD directly or via a linker. The construct of claim 287, wherein the multimerization domain is modified Fc. The construct of claim 287 or claim 288, wherein the multimerization domain includes a modified Fc, wherein the Fc or IgG Fc includes one or more of the following modifications: a) Modification by introducing pestle and mortar; b) Modifications that increase or enhance recycling of nascent Fc receptors (FcRn); and c) Modifications that reduce or eliminate immune effector functions. Such as the structure of request item 289, wherein the Fc includes a pestle and mortar modification, where: According to the EU number, the pestle modification is selected from one or more of S354C, T366Y, T366W and T394W; and According to the EU number, the acetal modification is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V. The construct of claim 289 or claim 290, wherein the Fc contains one or more modifications that increase or enhance FcRn recycling, which are selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y. The construct of any one of claims 289 to 291, wherein the Fc includes modifications to immune effector functions, and the immune effector functions are selected from the group consisting of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cell One or more of toxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). Such as the construct of any one of claims 287 to 292, which includes a modification selected from one or more of the following to reduce or eliminate immune effector function: In IgG1: according to EU numbering, L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P33 1S、G236R/L328R、 and Among IgG4: according to EU numbering, L235E, F234A/L235A, S228P/L235E and S228P/F234A/L235A. The construct of any one of claims 287 to 293, wherein the IgG Fc contains one or more of the following modifications: a) Introduce the modification of pestle and mortar, where: According to the EU number, the mutant line is selected from one or more of S354C, T366Y, T366W and T394W; and According to EU numbering, the acetal mutation line is selected from one or more of Y349C, T366S, L368A, F405A, Y407T, Y407A and Y407V; b) Modification that increases or enhances recycling of nascent Fc receptor (FcRn), wherein the modification is selected from one or more of the following: According to EU number, T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436 H, M252Y/T256Q, M252F/ T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L, M428L/N434S, V259I/V308F, V259I/V308F/M428L, E2 94del/T307P/N434Y and T256N/A378V/ S383N/N434Y; and c) Modifications that increase or enhance immune effector functions, wherein: The immune effector functions are selected from one or more of CDC, ADCC and ADCP; and The modification(s) that increase or enhance the immune effector function are selected from one or more of the following: In IgG1: According to EU numbering, S239D, I332E, S239D/I332E, S239D/A330L/I332E, S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y30 0L/P396L;F243L/ R292P/Y300L; L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain; L234Y/L235Q/G236W/S239M/H268D/D270E/S298A and the second heavy chain in the first heavy chain D270E/K326D/A330M/K334E in the heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I33 2E;G236A/S239D/I332E; G236A/S239D/A330L/I332E; biantennary glycan is introduced at residue N297; afucosylated glycan is introduced at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/ E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C; C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F; S324T; S267E/H2 68F/S324T;G236A/I332E/S267E/ H268F/S324T; E345R; and E345R/E430G/S440Y. The construct of any one of claims 287 to 294, wherein the construct comprises an IgG1 Fc modified to increase binding to the inhibitory Fcγ receptor (FcγR) FcγRIIb. Such as the construct of claim 295, wherein the modifications that increase binding to FcγRIIb are selected from the group consisting of S267E, N297A, L328F, L351S, T366R, L368H, P395K, S267E/L328F and L351S/T366R/L368H/P395K according to EU numbering one or more of them. The construct of any one of claims 287 to 296, wherein the ECD includes a modification. The construct of any one of claims 287 to 297, wherein one or more of the ECDs comprise all or part of the extracellular domain (ECD) of a HER family member. The construct of claim 298, wherein the construct includes an ECD that is EGFR/HER1, HER2, HER3, or HER4. The construct of any one of claims 297 to 299, comprising a linker connecting one or two ECDs to the multimerization domain. The construct of claim 300, wherein the linker provides flexibility, increases solubility, and/or alleviates or reduces steric hindrance or van der Waals interactions. The construct of claim 300 or claim 301, wherein the linker includes a hinge region, or is a linker including G and S residues. The construct of any one of claims 300 to 302, wherein the linker has the sequence shown in any one of SEQ ID NOs: 812-834, or is a PEG partial linker. The construct of any one of claims 300 to 302, wherein the linker includes a hinge region, or is a linker including G and S residues, or is IgG1 or IgG4 Fc. The construct of any one of claims 300 to 302, wherein the linker is selected from: i) a GS linker selected from (GlySer) _n , where n= 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n= 1-10; (Gly ₃ Ser) _n , where n= 1-5; (SerGly ₄ ) _n , where n= 1-5; (GlySerSerGly) _n , where n= 1-5 ; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSGSGSGGSSSGSGSGG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and/or ii) all or part of the hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26, Or all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29; and iii) IgG1 or IgG4 Fc, wherein: the IgG1 Fc is selected from the group consisting of SEQ ID NO: 10 The IgG1 Fc of human IgG1 shown in SEQ ID NO: 27, or the IgG1 Fc of trastuzumab shown in SEQ ID NO: 27; the IgG4 Fc is selected from the IgG4 Fc of human IgG4 shown in SEQ ID NO: 16, or SEQ The IgG4 Fc of nivolumab as shown in ID NO: 30; and, if appropriate, the Fc includes one or more introducers and/or increase or enhancement of nascent Fc receptor (FcRn) recycling and/or decrease or elimination Modification of immune effector functions. The construct of any one of claims 300 to 305, wherein the linker comprises all or part of the hinge sequence of nivolumab corresponding to residues 212-223 of SEQ ID NO: 29. Such as the structure of request item 306, wherein: The linker contains IgG1 or IgG4 Fc; The IgG1 Fc is selected from the IgG1 Fc of human IgG1 shown in SEQ ID NO: 10, or the IgG1 Fc of trastuzumab shown in SEQ ID NO: 27; The IgG4 Fc is selected from the IgG4 Fc of human IgG4 shown in SEQ ID NO: 16, or the IgG4 Fc of nivolumab shown in SEQ ID NO: 30; and Optionally, the Fc includes one or more modifications that introduce binding and/or increase or enhance recycling of nascent Fc receptors (FcRn) and/or reduce or eliminate immune effector functions. The construct of any one of claims 287 to 307, comprising a linker, wherein the linker comprises all or part of the hinge sequence of trastuzumab, corresponding to residues 222-227 of SEQ ID NO: 26 SCDKTH or up to the entire sequence of the hinge region of trastuzumab containing or having the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO: 26), or at least 5, 6, 7, 8, 9, 10 or 11 consecutive residues, or residues ESKYGPPCPPCP from residues 212 to 223 of SEQ ID NO: 29, or a sequence having at least 98% or 99% sequence identity thereto as a linker. The construct of any one of claims 287 to 308, comprising a linker, wherein the linker comprises the sequence SCDKTH corresponding to residues 222-227 of SEQ ID NO: 26. The construct of any one of claims 287 to 309, comprising a linker, wherein the linker comprises a GS linker and trastuzumab corresponding to residues EPKSCDKTHTCPPCP (SEQ ID NO: 26 of 219-233) all or part of the hinge sequence. The construct of any one of claims 287 to 310, wherein the linker comprises a GS linker and comprises the sequence SCDKTH corresponding to residues 217-222 of SEQ ID NO: 31. The construct of any one of claims 287 to 311, comprising a linker, wherein the linker is selected from one or more of the following linkers: comprising a GS linker and a residue corresponding to SEQ ID NO: 29 All or part of the hinge sequence of nivolumab based on bases 212-223; a linker including (Gly ₄ Ser) ₃ ; including (Gly ₄ Ser) ₃ and SCDKTH (residues 217-222 of SEQ ID NO: 31) A linker comprising (Gly ₄ Ser) ₃ and a hinge sequence of trastuzumab corresponding to residues 219-233 of SEQ ID NO: 26; comprising (Gly ₄ Ser) ₃ and a linker corresponding to SEQ ID NO: 26 NO: Linker of the hinge sequence of nivolumab at residues 212-223 of NO: 29. The construct of any one of claims 287 to 312, which includes a GS linker (GGGGS) ₃ ; and the multimerization domain IgG Fc is the Fc of trastuzumab or the Fc of nivolumab. The construct of any one of claims 287 to 312, comprising: a GS linker selected from (GlySer) _n , where n = 1-10; (GlySer ₂ ); (Gly ₄ Ser) _n , where n = 1-10; (Gly ₃ Ser) _n , where n = 1-5; (SerGly ₄ ) _n , where n = 1-5; (GlySerSerGly) _n , where n = 1-5; GSGGSSGG; GSSGSGSGSSG; GSSGSGSGSSSGG; GGSSGG; GGSSGGSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS; and a second linker selected from all or part of the hinge sequence of trastuzumab and all or part of the hinge sequence of nivolumab. The construct of claim 314, further comprising a half-life extending moiety, the half-life extending moiety is IgG Fc. The construct of any one of claims 287 to 314, comprising a half-life extending moiety, wherein the half-life extending moiety is IgG Fc, a polyethylene glycol (PEG) molecule, or human serum albumin (HSA). The construct of claim 316, wherein the IgG Fc is IgG1 or IgG4 Fc. Such as the structure of request item 317, wherein: The IgG1 Fc is the Fc of trastuzumab shown in SEQ ID NO: 27; or The IgG4 Fc is the Fc of nivolumab shown in SEQ ID NO:30. The construct of any one of claims 300 to 318, which includes Fc, which is the Fc of human IgG1 shown in SEQ ID NO: 10, and/or is the Fc of IgG4, that is, in SEQ ID NO: 16 The Fc of human IgG4 is shown. The construct of any one of claims 287 to 319, which is a bispecific heterodimeric construct comprising a first ECD polypeptide and a second ECD each linked directly to the multimerization domain or indirectly via the linker. peptides, including: The first ECD polypeptide and the second ECD polypeptide are different; and The first ECD polypeptide and the second ECD polypeptide are selected from ECD, which includes an ECD selected from: The ECD of HER1/EGFR corresponding to residues 1-621 of SEQ ID NO: 41 or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity with SEQ ID NO: 41; The ECD polypeptide comprises an ECD of HER2 corresponding to residues 1-628 of SEQ ID NO: 43, or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity with SEQ ID NO: 43; The ECD polypeptide comprises an ECD of HER3 corresponding to residues 1-621 of SEQ ID NO: 45, or a portion thereof, or a variant thereof that has at least 95% or 98% sequence identity with SEQ ID NO: 45; and The ECD polypeptide comprises an ECD of HER4 corresponding to residues 1-625 of SEQ ID NO: 47, or a portion thereof, or a variant thereof that has at least 95% or 98% sequence identity with SEQ ID NO: 47; and Parts or variants of each ECD may affect ligand binding and/or may dimerize with cell surface receptors. The construct of any one of claims 287 to 320, which is a bispecific heterodimeric construct comprising a first ECD polypeptide and a second ECD each linked directly to the multimerization domain or indirectly via the linker. peptides, including: The first ECD polypeptide comprises an ECD of HER1/EGFR corresponding to residues 1-621 of SEQ ID NO: 41, or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity to SEQ ID NO: 41 ; And the second ECD polypeptide comprises an ECD of HER2 corresponding to residues 1-628 of SEQ ID NO: 43, or a portion thereof, or a variant thereof having at least 95% or 98% sequence identity with SEQ ID NO: 43; or The second ECD polypeptide comprises an ECD of HER3 corresponding to residues 1-621 of SEQ ID NO: 45, or a portion thereof, or a variant thereof that has at least 95% or 98% sequence identity to SEQ ID NO: 45; or The second ECD polypeptide comprises an ECD of HER4 corresponding to residues 1-625 of SEQ ID NO: 47, or a portion thereof, or a variant thereof that has at least 95% or 98% sequence identity to SEQ ID NO: 47; and Portions or variants of each ECD retain sufficient affinity for ligand binding and/or dimerization with cell surface receptors. The construct of claim 320 or 321, wherein the portion or variant of each ECD retains sufficient affinity for binding to the respective cell surface target or ligand, wherein the affinity is at least 10% of that of the full-length ECD. The construct of any one of claims 287 to 322, which is a polymer containing at least two different ECDs. Such as the construct of claim 323, which is a heterodimer. The construct of any one of claims 300 to 324, which is a heterodimer of ECD comprising EGFR and HER3. Such as the construct of claim 325, which includes the mutations T15S and G564S in the EGFR ECD subdomains I and IV respectively according to the sequence of the mature EGFR protein shown in SEQ ID NO: 41 or its allele variant, and the reference SEQ The sequence of the mature HER3 protein shown in ID NO: 45 or its allele variant is Y246A in HER3 ECD subdomain II. The construct of any one of claims 287 to 326, which contains less than the full-length ECD of the HER protein, contains at least a sufficient portion of subdomains I, II and III for ligand binding and receptor dimerization. The construct of claim 327, wherein the ECD may contain a sufficient portion of subdomains I and III for ligand binding, and/or a sufficient portion of the ECD to dimerize with a cell surface receptor, including a sufficient portion Subdomain II. For example, the structure of any one of claims 287 to 328, wherein the ECD in the structure contains at least module 1 of subdomains I, II and III and domain IV. The construct of any one of claims 287 to 328, comprising a first ECD containing all or part of an ECD of HER1/EGFR, HER2, HER3 or HER4, and a second ECD from a different cell surface receptor (CSR) . The construct of claim 330, wherein the second ECD is different from the first ECD and is from a CSR selected from: HER2, HER3, HER4, insulin growth factor 1 receptor (IGF1-R), vascular endothelial growth factor Receptor (VEGFR, such as VEGFR1), fibroblast growth factor receptor (FGFR, such as FGFR2 or FGFR4), TNFR, platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR), with immunoglobulin Protein-like and EGF-like domain 1 tyrosine kinases (TIEs, such as TIE-1 or TEK (TIE-2)), receptors for advanced glycation end products (RAGE), Eph receptors, or T cell receptors. The construct of claim 330 or claim 331, wherein the first ECD polypeptide comprises the full-length ECD of HER1/EGFR (corresponding to residues 1-621 of SEQ ID NO: 41), or a portion thereof or a combination thereof with SEQ ID NO : 41 Allele gene variants that have at least 95% or 98% sequence identity and retain binding activity and/or dimerization activity. Such as the construct of claim 332, wherein the part is residues 1-501 of SEQ ID NO: 41, which corresponds to module 1 of subdomains I-III and domain IV, or is the same as residues of SEQ ID NO: 41 Base 1-501 is a variant that has at least 95% or 98% sequence identity and retains binding and/or dimerization activity. The construct of any one of claims 287 to 333, comprising a first and a second ECD, wherein the second ECD polypeptide comprises the full-length ECD of HER3 corresponding to residues 1-621 of SEQ ID NO: 45, or A portion thereof, or a variant thereof that has at least 95% or 98% sequence identity with residues 1-501 of SEQ ID NO: 45 and retains binding and/or dimerization activity. The construct of claim 334, wherein the portion has residues 1-500 of SEQ ID NO: 45, which correspond to module 1 of subdomains I-III and domain IV, or are identical to residues 1-500 of SEQ ID NO: 45 Bases 1-500 are variants that have at least 95% or 98% sequence identity and retain binding and/or dimerization activity. The construct of claim 335, wherein the ECD portion contains at least a sufficient portion of subdomains I and III to bind a ligand of the HER receptor, and A sufficient portion of this ECD to dimerize with cell surface receptors includes a sufficient portion of subdomain II. The construct of any one of claims 287 to 336, wherein the first ECD polypeptide and the second ECD polypeptide form a multimer that is compared to the first or second chimeric polypeptide alone or its The homodimer binds additional ligands and/or dimerizes with more cell surface receptors than the first or second chimeric polypeptide or homodimer thereof alone. The construct of claim 337, wherein the first ECD polypeptide and the second ECD polypeptide form a heterodimer that binds a HER1 ligand and a HER3 ligand. The construct of any one of claims 287 to 338, wherein at least one of the ECD domains, or a portion or variant thereof, includes altered ligand binding, specificity or other activity compared to an unmodified ECD polypeptide. or modification of characteristics. The construct of any one of claims 287 to 339, wherein at least one ECD comprises an ECD that changes the ligand binding, specificity, or specificity of the ECD or full-length receptor containing the ECD compared to an unmodified ECD or full-length receptor. or modification of other activities or properties whereby the heteromultimer exhibits altered activity or properties. The construct of claim 340, wherein the property or activity is altered ligand binding and/or specificity and/or dimerization activity. The construct of any one of claims 287 to 341, wherein the ECD includes modifications that eliminate, add, or enhance the activity of the ECD or the resulting construct. The construct of claim 342, wherein the construct comprises a HER1 ECD containing a mutation in subdomain III that increases its affinity for ligands other than EGF. Such affinity increases at least 2 times, 10 times, 100 times, 1000 times, 10 ⁴ times, 10 ⁵ times, 10 ⁶ times, The construct of any one of claims 287 to 343, which is a heterodimer containing a HER1 (EGFR) chimeric fusion polypeptide and a HER3 chimeric fusion polypeptide, wherein each chimeric fusion polypeptide contains a peptide linker, as appropriate. ECD of the receptor linked to the Fc of human IgG1. The construct of any one of claims 287 to 344, wherein the C-terminus of the ECD polypeptide is linked to the N-terminus of the multimerization domain The construct of any one of claims 287 to 345, wherein the multimerization domain is IgG1 Fc or a modified form thereof. The construct of any one of claims 287 to 346, comprising a HER1 ECD and/or a HER ECD modified to have increased or altered ligand binding and/or biological activity. Such as the structure of request item 347, wherein: HER1 includes S418F with reference to the sequence of the mature protein shown in SEQ ID NO: 41, whereby the HER3 ligand NRG2-β stimulates HER1, and the resulting ECD is combined with at least two ligands, namely EGF for HER1 and NRG2-β for HER3. Beta binding or interaction. Such as the construct of any one of claims 287 to 348, wherein the construct includes ECD HER1 (EGFR), and the sequence of the reference mature EGFR protein (SEQ ID NO: 41) in EGFR/HER1 ECD subdomains I and IV respectively. Mutations T15S and G564S in , and Y246A in HER3 ECD subdomain II with reference to the sequence of the mature HER3 protein (SEQ ID NO: 45); and The HER1 ECD contains additional mutations selected from the group consisting of E330D/G588S, S193N/E330D/G588S and T43K/S193N/E330D/G588S with reference to the sequence of the precursor HER1 (including signal peptide) shown in SEQ ID NO: 40 One or a combination, and with reference to the sequence of the mature HER1 polypeptide shown in SEQ ID NO: 41, corresponds to E306D/G564S, S169N/E306D/G564S and T19K/S169N/E306D/G564S. The construct of any one of claims 287 to 349, comprising an EGFR (HER1):HER3 heterodimer, with reference to the sequence of the mature EGFR protein (SEQ ID NO: 41 or the pair of SEQ ID NO: 41 with N516K Gene variants) mutations T15S and G564S in EGFR ECD subdomains I and IV respectively, and Y246A in HER3 ECD subdomain II based on the sequence of the mature HER3 protein (SEQ ID NO: 45). The ligand capture agent construct of claim 350, wherein the Fc domain in the construct is modified to enhance nascent Fc receptor (FcRn) recycling and/or effector function.

Images