RU2776714C2 - Antigen-binding proteins against tigit and their application methods - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to the field of biotechnology, specifically to a method for the treatment or prevention of cancer in a subject. The proposed method includes the administration to a subject of effective amount of an antibody with binding specificity of a T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and an immunotherapeutic agent containing an antibody against human NRP, and it effectively inhibits the tumor growth.

EFFECT: obtaining a method for the treatment or prevention of cancer.

22 cl, 3 dwg, 7 tbl, 3 ex

Description

[0001] This application claims priority of U.S. Provisional Application No. 62/479042, filed March 30, 2017, the contents of which are hereby incorporated by reference in all senses.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] The invention provides antigen-binding proteins (ABPs) with binding specificity for T-cell immunoreceptor to Ig domains and ITIM (TIGIT) and compositions comprising such ABPs, including pharmaceutical compositions, diagnostic compositions, and kits. Also provided are methods for producing TIGIT ABPs and methods for using TIGIT ABPs, for example, for treatment, diagnosis, and research purposes.

BACKGROUND OF THE INVENTION

[0003] TIGIT has been identified as a co-inhibitory receptor that limits the T cell response to cancer and chronic infection. See Grogan et al., J Immunol., 2014, 192: (1 Supplement) 203,15, the contents of which are incorporated herein by reference. Blockade of TIGIT has been shown to increase the effector function of CD8+ T cells and improve virus clearance and tumor rejection. See the post mentioned above.

[0004] Therefore, there is a need for therapeutic agents that can antagonize TIGIT. The present invention proposes ABPs that solve this problem.

[0005] This application relates to U.S. Provisional Application No. 62/235990, filed Oct. 1, 2015, International Publication No. WO/2017/059095, and U.S. Patent No. 9,713,641, the contents of which are incorporated herein in all respects by way of links to them.

SUMMARY OF THE INVENTION

[0006] The invention provides ABPs that specifically bind TIGIT and methods for using such ABPs. In some embodiments, the TIGIT is selected from human TIGIT ("hTIGIT", SEQ ID NO: 1), cynomolgus TIGIT ("cTIGIT", SEQ ID NO: 2), and mouse TIGIT ("mTIGIT", SEQ ID NO: 3 or 138).

[0007] In one aspect, there is provided an isolated antigen binding protein (ABP) that specifically binds the human TIGIT epitope (hTIGIT; SEQ ID NO: 1) and that is capable of performing at least one of the following functions: a) blocking the binding of MAB7, MAB9, MAB10, MAB11 and MAB12 with human TIGIT; b) blocking the binding of human TIGIT to CD155; and c) specific binding to hTIGIT residues H76, I77, S78 and P79.

[0008] In another embodiment, ABP specifically binds one or more additional hTIGIT residues from the group consisting of T55, Q56, N58, L65, I68, N70, D72, L73, H111, T117, S129, and S130.

[0009] In another embodiment, ABP does not specifically bind hTIGIT residues Q61, Q62, D63, Q64, Y113, or P114.

[0010] In one embodiment, the ABP is MAB7, MAB9, MAB10, MAB11, or MAB12. In another embodiment, the ABP is capable of performing at least one of the following functions: a) blocking the binding of MAB1, MAB2, MAB3, MAB4 and MAB5 to human TIGIT, blocking the binding of human TIGIT to CD155; and specific binding to hTIGIT residues Q56 and I77. In another embodiment, ABP does not specifically bind hTIGIT residues I68, L73, H76, S78 and P79.

[0011] In one embodiment, the ABP is capable of performing at least one of the following functions: a) blocking the binding of MAB13, MAB14, MAB15, MAB16, MAB17 and MAB18 to human TIGIT; b) blocking the binding of human TIGIT to CD155; and c) specific binding to hTIGIT residues Q56, I68, L73, H76 and I77. In one embodiment, ABP does not specifically bind hTIGIT residue S78.

[0012] In one embodiment, the ABP is capable of performing at least one of the following functions: a) blocking the binding of MAB19, MAB20 and MAB21 to human TIGIT; b) blocking the binding of human TIGIT to CD155; and c) specific binding to hTIGIT residues Q56, I68, L73 and I77.

[0013] In one embodiment, the ABP is capable of performing at least one of the following functions: a) inhibiting hTIGIT binding to CD112; b) increasing the effector function of T cells; c) increased natural killer (NK) function; d) decrease in the number of regulatory T cells in tissues or in the bloodstream; e) suppression of regulatory T cells or activity of regulatory T cells; f) inhibition of the association of TIGIT and CD226; and g) non-specific binding to nectin-4 (also called poliovirus receptor-related protein 4, PVRL4).

[0014] In another embodiment, the ABP is MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB8, MAB13, MAB14, MAB15, MAB16, MAB17, MAB18, MAB19, MAB20, or MAB21.

[0015] In another aspect, a method is provided for treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of: (i) an ABP that specifically binds hTIGIT selected from the group consisting of MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB7, MAB8, MAB9, MAB10, MAB11, MAB12, MAB13, MAB14, MAB15, MAB16, MAB17, MAB18, MAB19, MAB20 and MAB21; and one or more of (ii) additional immunotherapeutic agents that block the activation of an inhibitory immune cell receptor signaling pathway or a ligand thereof; and (iii) an additional immunotherapeutic agent that modulates the activation of a co-stimulatory receptor signaling pathway, or a nucleic acid encoding such an agent.

[0016] In one embodiment, the inhibitory receptor or ligand thereof is selected from CTLA-4, PD-1, PD-L1, PD-L2, Tim-3, neuritin, BTLA, CECAM-1, CECAM-5, VISTA, LAIR1 , CD160, 2B4, KIR and their combinations.

[0017] In one embodiment, the costimulatory receptor is CD3, GITR OX40, ICOS, LAG-2, CD27, CD28, CD40, or 4-1BB.

[0018] In one embodiment, the additional therapeutic agent is MAB22. In another embodiment, the additional therapeutic agent is MAB23. In various embodiments, the ABP is MAB10, MAB2, MAB15, or MAB21.

[0019] In one embodiment, the additional immunotherapeutic agent is an antibody against Tim-3, 4-1BB, GITR, PD-1, or PD-L1, or is OX40. In some embodiments, the combination therapy achieves an additional or synergistic effect on the immune response in the subject undergoing such therapy.

[0020] In one embodiment, the disease or condition is cancer, and the cancer is selected from a solid tumor and a hematological tumor. In some embodiments, the cancer is a solid tumor.

[0021] In some embodiments, the additional therapeutic agent is formulated in the same pharmaceutical composition together with the ABP, and the ABP and the additional therapeutic agent are co-administered. In another embodiment, the additional therapeutic agent is formulated in a pharmaceutical composition separate from the ABP, and the ABP and the additional therapeutic agent are administered separately. Such separate administration may be carried out on the same day or on different days. In some embodiments, the ABP is administered prior to the administration of the additional therapeutic agent; in other embodiments, the additional therapeutic agent is administered prior to administration of the ABP.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figures 1A-1L graphically show the results of a lymphoid cell proliferation study to determine T-cell immune responses in cytomegalovirus (CMV+) positive T cells using peripheral blood mononuclear cells (PBMCs) from individual donors. Cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and pembrolizumab, either alone or in combination (Figures 1A-1C, respectively); cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and anti-TIM-3 antibody, either alone or in combination (Figures 1D-1F); cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and anti-41BB, either alone or in combination (Figures 1G-1I); and cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and rhOX40L, either alone or in combination (Figures 1J-1L). Statistically significant differences were calculated both between the two groups treated with individual drugs and compared with their similar controls, as well as between the two groups treated with individual drugs and groups treated with a combination of these drugs, using a two-sample t-test for independent samples (*=p<0.05, **=p<0.01, ***=p<0.005, ****=p<0.001).

[0023] Figures 2A-2B are graphical representations of the results of a dissociated tumor cell (DTC) study to determine T-cell immune responses in DTCs from undrug-treated cancer patients. Figure 2A shows activation of DTCs from a 50 year old man with stage IV melanoma as evidenced by IFNγ production. Cells were cultured and stimulated with the control OVA peptide (3 μg/ml) or with a peptide mixture with melanoma cells consisting of 1 μg/ml NY-ESO-1+1 μg/ml MelanA/MART-1+1 μg/ ml gp100. Anti-GITR antibody MAB22, pembrolizumab and anti-TIGIT antibody MAB10 were added to the peptide-stimulated samples, either alone or in combinations in pairs. As a control, equal amounts of isotype control antibodies were used. For stimulation with a single antibody, the total amount of antibody was kept constant by adding an isotype control antibody to the samples. MAB10 and pembrolizumab were used at a final concentration of 10 μg/ml, and MAB22 was used at a final concentration of 1 μg/ml. To assess activation, cells were cultured for 7 days, supernatants were collected and the level of IFNγ produced was quantified using ^AlphaLISA® (PerkinElmer). Statistical significance was calculated using one-way analysis of variance with multiple comparisons. Figure 2B shows the activation of DTCs taken from an 80 year old man with stage IIa non-small cell lung cancer (NSCLC). Cells were cultured and left unstimulated (control) or stimulated with soluble anti-CD3+CD28 antibodies for two days. As a control, an equal amount of isotype control antibody (IgG4) was used. For stimulation with a single antibody, the total amount of antibody was kept constant by adding an isotype control antibody to the samples. MAB10 and pembrolizumab were used at a final concentration of 10 μg/ml. To evaluate activation, brefeldin A was added to cells during the last 5 hours of culture and fluorescent cell sorting (FACS) and IFNγ producing CD4+ and CD8+ T cells were quantified using intracellular cytokine staining (ICS). Statistical significance was calculated using one-way analysis of variance with multiple comparisons.

[0024] Figures 3A-3D are graphical representations of tumor volume measurements using a combination of an anti-TIGIT antibody and an anti-NRP-1 antibody in an experimental mouse model of EMT6 breast cancer. Combinations of mMAB23 with 1B4 versus mMAB23 monotherapy and αPD-1 monotherapy are shown in Figures 3A (mean tumor volume) and 3C (individual tumor volume for each mouse), and combinations of mMAB23 with 1B4 versus 1B4 monotherapy and aPD-1 monotherapy are shown in Figures 3B (mean tumor volume) and 3D (individual tumor volume). In figures 3A-3B, 1×10 ⁵ murine EMT6 cells were implanted subcutaneously in female BALB/c mice. After reaching a mean tumor size of 80-120 mm ³ , mice were randomized into treatment groups and injected intraperitoneally with the indicated antibodies at a dose of 1000 μg/animal (control IgG2b and 1B4), 500 μg/animal (mMAB23 and 1B4), 250 μg/animal (mMAB23 and 1B4) or 200 µg/animal (αPD-1). The black arrows indicate the days of treatments. For each treatment group, the mean +/- standard error of the mean (SEM) of tumor volume for 8 mice per group is shown. On day 14, statistical significance (least squares mean differences adjusted for Tukey-Kramer multiple comparisons) was calculated for the treated mouse versus the control mouse. Curves for control, rat anti-mouse αPD-1 (clone RMPl-14), agent alone (250 μg) and combination (250 μg each) were evaluated over time using mixed model analysis. Figures 3C-3D show individual EMT6 tumor volumes for each of the 8 mice per group for all treated groups (indicated at the top of each graph). Mouse EMT6 tumor cells were injected into female BALB/c mice and mice were randomly assigned to treatment groups with an average tumor size of 80-120 mm ³ . Treatment was randomized and these antibodies were administered intraperitoneally at a dose of 1000 μg/animal (control IgG2b and 1B4), 500 μg/animal (mMAB23 and 1B4), 250 μg/animal (mMAB23 and 1B4) or 200 μg/animal (αPD- one). The black arrows indicate the days of treatments. The y-axes are the tumor volume, and the x-axes are the time since the start of treatment in days. The study was terminated on day 40 or when the tumor volume reached 2000 mm ³ depending on the treated group.

DETAILED DESCRIPTION OF THE INVENTION

1. Definitions

[0025] Unless otherwise indicated, all scientific and technical terms, symbols and other scientific terminology used in the present invention are assumed to have meanings that are generally accepted by specialists in the field to which this invention pertains. In some cases, terms with common meanings are defined in the present invention for a clearer understanding and/or to provide reference material, and the inclusion of such definitions in the present invention should not be construed as a desire to demonstrate their difference from the definitions generally accepted in science and technology. The techniques and procedures described or referred to in the invention are well known and commonly used by those skilled in the art using conventional methods such as, for example, the widely used methods for cloning nucleic acid molecules as described in Sam brook et al., Molecular Cloning. : A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Where appropriate, procedures involving the use of commercially available kits and reagents are generally performed according to the protocols and conditions specified by the manufacturer, unless otherwise indicated.

[0026] As used herein, the singular forms include the plural of the entities being defined, unless the context clearly dictates otherwise. The terms "includes", "such as" and other similar terms are intended to express inclusion without limitation, unless specifically stated otherwise.

[0027] As used herein, the term "comprising" also specifically includes the uses "consisting of" and "consisting essentially of" the named elements, unless specifically stated otherwise.

[0028] The term "approximately" defines and encompasses the specified value and the area above and below this value. In specific embodiments, the term "about" specifies the specified value of ± 10%, ± 5% or ± 1%. In specific embodiments, where appropriate, the term "approximately" specifies the specified value(s) ± one standard deviation of that value(s).

[0029] The terms "TIGIT," "TIGIT protein," and "TIGIT antigen" are used interchangeably herein to refer to human TIGIT or any variants (e.g., splice variants and allelic variants), isoforms, and cross-species homologues of human TIGIT that are naturally expressed by cells. or which are expressed by cells transfected with the TIGIT gene. In some aspects, the TIGIT protein is a TIGIT protein naturally expressed by a primate (eg, monkey or human), rodent (eg, mouse or rat), dog, camel, cat, cow, goat, horse, or sheep. In some aspects, the TIGIT protein is human TIGIT (hTIGIT; SEQ ID NO: 1). Without advocating any theory, however, it can be assumed that positions 1-21 of SEQ ID NO: 1 encode a signal peptide; positions 22-141 of SEQ ID NO: 1 encode the extracellular domain of the mature TIGIT protein; positions 142-162 of SEQ ID NO: 1 encode a transmembrane domain; and positions 163-244 of SEQ ID NO: 1 encode the cytoplasmic domain. See UniProt KB - Q495A1 (TIGIT_HUMAN), at www.uniprot.org/uniprot/Q495A1, accessed September 28, 2015. In some aspects, the TIGIT protein is cynomolgus monkey TIGIT (cTIGIT; SEQ ID NO: 2). In some aspects, the TIGIT protein is a rodent TIGIT (mTIGIT) having the sequence shown in SEQ ID NO: 3. In some aspects, the TIGIT protein is a rodent TIGIT (mTIGIT) having the sequence shown in SEQ ID NO: 138. In the present invention, if SEQ ID NO is not specified, then the terms "mTIGIT," "rodent TIGIT" and "mouse TIGIT" means the sequence of SEQ ID NO: 3 and/or SEQ ID NO: 138. In some aspects, the TIGIT protein is full length or unprocessed TIGIT protein. In some aspects, the TIGIT protein is a truncated or truncated TIGIT protein produced by post-translational modification. A number of synonyms are also known for the term TIGIT, including WUCAM, VSIG9, and Vstm3.

[0030] The term "immunoglobulin" refers to a class of structurally related proteins, usually containing two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In "intact immunoglobulin" all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins is well studied. See, for example, Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically includes a heavy chain variable region (V _H ) and a heavy chain constant region ( _CH ). The heavy chain constant region typically includes three domains, abbreviated as C _H1 , C _H2 and C _H3 . Each light chain typically includes a light chain variable region (V _L ) and a light chain constant region. The light chain constant region typically includes a single domain, abbreviated as C _L .

[0031] The term "antigen-binding protein" (ABP) refers to a protein that includes one or more antigen-binding domains that specifically bind to an antigen or epitope. In some embodiments, the antigen-binding domain binds an antigen or epitope with a specificity and affinity similar to that of natural antibodies. In some embodiments, the ABP includes an antibody. In some embodiments, the ABP is comprised of an antibody. In some embodiments, the ABP consists primarily of an antibody. In some embodiments, the ABP includes an alternate backbone. In some embodiments, the ABP consists of an alternate backbone. In some embodiments, the ABP consists primarily of an alternate backbone. In some embodiments, the ABP includes an antibody fragment. In some embodiments, the ABP consists of an antibody fragment. In some embodiments, the ABP consists primarily of an antibody fragment. "TIGIT ABP", "ABP against TIGIT", or "TIGIT-specific ABP" is an ABP according to the invention that specifically binds to the TIGIT antigen. In some embodiments, ABP binds the extracellular domain to TIGIT. In specific embodiments, the inventive TIGIT ABP binds to an epitope in TIGIT that is conserved between or among TIGIT proteins from different species of living organisms.

[0032] As used herein, the term "antibody" in its broad sense includes specific types of immunoglobulin molecules containing one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (eg, intact immunoglobulins), antibody fragments, and polyspecific antibodies. The antibody is one type of ABP.

[0033] The term "antigen-binding domain" means the portion of an ABP that is capable of specifically binding to an antigen or epitope. One example of an antigen-binding domain is an antigen-binding domain formed by the V _H -V _L dimer of an antibody. Another example of an antigen-binding domain is an antigen-binding domain formed by diversifying specific loop fragments from adnectin type III fibronectin domain 10.

[0034] The terms "full antibody", "intact antibody", and "complete antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to that of a natural antibody and having heavy chains that include an Fc region. For example, when used to refer to an IgG molecule, a "full-length antibody" is an antibody that includes two heavy chains and two light chains.

[0035] The term "Fc fragment" refers to the C-terminal region of the immunoglobulin heavy chain, which in natural antibodies interacts with Fc receptors and specific proteins of the complement system. The structures of Fc fragments of various immunoglobulins and the glycosylation sites contained in them are well studied. See Schroeder and Cavacini, J Allergy Clin. Immunol., 2010, 125:S41-52, the content of which is incorporated into the present invention by reference. The Fc fragment may be a natural Fc fragment or a modified Fc fragment as described in the prior art or elsewhere in this invention.

[0036] The V _H and V _L regions can be further subdivided into regions of hypervariability ("hypervariable regions (HVRs)", also referred to as "complementarity determining regions" (CDRs)) interspersed with regions that are more conserved. The more conservative regions are called framework regions (FRs). Each V _H and V _L typically includes three CDRs and four FRs in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. CDRs are involved in antigen binding and affect the antigen specificity and binding affinity of an antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, the contents of which are incorporated herein by reference.

[0037] A light chain in any vertebrate species can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the sequence of its constant domain.

[0038] The heavy chain in any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also denoted as α, δ, ε, γ and μ, respectively. The IgG and IgA classes are further subdivided based on differences in sequence and function. The following subclasses are expressed in humans: IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

[0039] CDR boundaries from amino acid sequences can be defined by one skilled in the art by using any number from known numbering schemes, including the numbering schemes described in Kabat et al., cited above ("Kabat" numbering scheme); in Al-Lazikani et al., 1997, J Mal. Biol., 273:927-948 (numbering scheme "Chothia"; in MacCallum et al., 1996, J Mal. Biol. 262:732-745 (numbering scheme "Contact"); in Lefranc et al., Dev Comp. Immunol., 2003, 27:55-77 (numbering scheme "IMGT"); and Honegge and Phickthun, J Mal. Biol., 2001, 309:657-70 (numbering scheme "AHo"); which are included in the present invention by reference to them.

[0040] Table 1 shows the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is given using both the Kabat numbering scheme and the Chothia numbering scheme.

[0041] CDRs can be determined, for example, using antibody numbering software such as Abnum, available from www.bioinf.org.uk/abs/abnum/ and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, the contents of which are incorporated into the present invention by reference.

Table 1. Residues in CDRs according to the Kabat and Chothia numbering schemes

CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H1 (Kabat numbering) H31-H35B H26-H32 or H34* H1 (Chothia numbering) H31-H35 H26-H32 H2 H50-H65 H52-H56 H3 H95-H102 H95-H102

* The C-terminus of CDR-H1, when numbered using the Kabat numbering scheme, varies between H32 and H34, depending on the length of the CDR.

[0042] "EU Numbering Scheme" is commonly used when referring to a residue of an antibody heavy chain constant region (eg, as described in Kabat et al., cited above). Unless otherwise indicated, the EU numbering scheme is used to denote residues of the antibody heavy chain constant regions described herein.

[0043] "Antibody fragment" includes a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab') ₂ fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0044] "Fv" fragments include a non-covalently linked dimer of a heavy chain variable domain and one light chain variable domain.

[0045] "Fab" fragments include, in addition to the heavy and light chain variable domains, a light chain constant domain and a heavy chain first constant domain (C _H1 ). Fab fragments can be generated, for example, by recombinant techniques or by cleavage of the full length antibody with the papain enzyme.

[0046] "F(ab') ₂ " fragments contain two Fab' fragments connected near the hinge region by disulfide bonds. F(ab') ₂ fragments can be generated, for example, by recombinant techniques or by digestion of an intact antibody with a pepsin enzyme. F(ab') fragments can be dissociated, for example, by treatment with β-mercaptoethanol.

[0047] "Single chain Fv" or "sFv" or "scFv" antibody fragments include a V _H domain and a V _L domain in the same polypeptide chain. V _H and V _L are usually connected by a peptide linker. See Phickthun A. (1994). Any suitable linker may be used. In some embodiments, the linker is (GGGGS) _n (SEQ ID NO: 127). In some embodiments, n=1, 2, 3, 4, 5, or 6. See Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, the contents of which are incorporated into the present invention by reference.

[0048] "scFv-Fc" fragments include scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal scFv. The Fc domain may follow V _H or V _L , depending on the orientation of the variable domains in the scFv (ie, V _H -V _L or V _L -V _H ). Any suitable known or inventive Fc domain can be used. In some cases, the Fc domain includes an IgG4 Fc domain.

[0049] A "monospecific ABP" is an ABP that includes one or more binding sites that specifically bind to one epitope. An example of a monospecific ABP is a natural IgG molecule which, being bivalent (ie having two antigen-binding domains), recognizes the same epitope in each of the two antigen-binding domains. Binding specificity may be present at any suitable valency.

[0050] The term "monoclonal antibody" refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies includes antibodies that are substantially similar and that bind the same epitope(s), with the exception of variations that would normally occur during the production of a monoclonal antibody. Such variants are usually only present in minor amounts. A monoclonal antibody is typically prepared by a process that involves selecting an individual antibody from a plurality of antibodies. For example, the selection process may be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further modified, for example, to increase affinity for the target ("affinity maturation"), to humanize the antibody, to increase its production in cell culture, and/or to reduce its immunogenicity in a subject.

[0051] The term "chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, with the remainder of the heavy and/or light chain derived from a different source or species.

[0052] "Humanized" forms of non-human antibodies are chimeric antibodies that contain a minimal sequence derived from a non-human antibody. A humanized antibody is typically a human antibody (recipient antibody) in which residues from one or more CDRs are replaced with residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody may be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken or non-human primate antibody, having the desired specificity, affinity, or biological activity. In some cases, selected framework region residues of the recipient antibody are replaced with the corresponding framework region residues from the donor antibody. Humanized antibodies may also include residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further improve antibody function. For more information, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, the content of each of which is included in the present invention by reference to it.

[0053] A "human antibody" is an antibody that has an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cells, or derived from a non-human source that uses the human antibody repertoire, or sequences encoding a human antibody (e.g., derived from human sources or designed from the start). Human antibodies specifically include humanized antibodies.

[0054] "Isolated ABP" or "isolated nucleic acid" is an ABP or nucleic acid that has been isolated and/or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or non-proteinaceous materials. In some embodiments, the isolated ABP is purified to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence, for example, by using a rotary beaker sequencer. In some embodiments, isolated ABP is purified to homogeneity by gel electrophoresis (eg, SDS-PAGE) under reducing or non-reducing conditions, with detection by Coomassie blue or silver staining. In some embodiments, the isolated ABP may include ABP generated within the recombinant cells due to the fact that at least one component of the natural environment of ABP is not present. In some aspects, the isolated ABP or isolated nucleic acid is prepared in at least one purification step. In some embodiments, the isolated ABP or isolated nucleic acid is purified to at least 80%, 85%, 90%, 95%, or 99% purity by weight. In some embodiments, the isolated ABP or isolated nucleic acid is purified to at least 80%, 85%, 90%, 95%, or 99% purity by volume. In some embodiments, the isolated ABP or isolated nucleic acid is obtained in the form of a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% ABP or nucleic acid by weight. In some embodiments, the isolated ABP or isolated nucleic acid is obtained in the form of a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% ABP or nucleic acid by volume.

[0055] "Affinity" refers to the strength of all cumulative interactions between one binding site of a molecule (eg, ABP) and its binding partner (eg, antigen or epitope). Unless otherwise indicated, the term "affinity" as used herein refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (eg, ABP and an antigen or epitope). The affinity of a molecule X for its partner Y can be characterized by the dissociation equilibrium constant (K _D ). The kinetic components that affect the dissociation equilibrium constant are described in more detail below. Affinity can be measured by well-known methods, including methods described in the present invention, such as the method of surface plasmon resonance (SPR) (eg, BIACORE®) or the method of biolayer interferometry (eg, FORTEBIO ^® ).

[0056] In relation to the binding of ABP to a target molecule, the terms "bind", "specific binding", "specifically binds to", "specific for", "selectively binds" and "selective for" a particular antigen (for example , target polypeptide) or to an epitope on a particular antigen, refers to a binding that is significantly quantitatively different from a non-specific or non-selective interaction (eg, with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics an epitope recognized on the target molecule. In this case, specific binding is said to be present if the binding of ABP to the target molecule is competitively inhibited by the control molecule. In some aspects, the affinity of TIGIT ABP for the non-target molecule is less than about 50% of the affinity for TIGIT. In some aspects, the affinity of TIGIT ABP for the non-target molecule is less than about 40% of the affinity for TIGIT. In some aspects, the affinity of TIGIT ABP for the non-target molecule is less than about 30% of the affinity for TIGIT. In some aspects, the affinity of TIGIT ABP for the non-target molecule is less than about 20% of the affinity for TIGIT. In some aspects, the affinity of TIGIT ABP for the non-target molecule is less than about 10% of the affinity for TIGIT. In some aspects, the affinity of TIGIT ABP for the non-target molecule is less than about 1% of the affinity for TIGIT. In some aspects, the affinity of TIGIT ABP for the non-target molecule is less than about 0.1% of the affinity for TIGIT.

[0057] As used herein, the term "k _d " (sec ^-1 ) refers to the dissociation rate constant of a particular ABP-antigen interaction. This value is also referred to as the k _off value.

[0058] As used herein, the term "k _a " (M ^-1 x sec ^-1 ) refers to the association rate constant of a particular ABP-antigen interaction. This value is also called the k _on value.

[0059] As used herein, the term "K _D "(M) refers to the dissociation equilibrium constant of a particular ABP-antigen interaction. K _D \u003d k _a / k _d . In some embodiments, the affinity of an ABP is described in terms of the K _D for the interaction between such an ABP and its antigen. By definition, a smaller K _D value is known to indicate a higher interaction affinity value, while a larger K _D value indicates a lower interaction affinity value.

[0060] As used herein, the term "K _A " (M ^-1 ) refers to the association equilibrium constant of a particular ABP-antigen interaction. K _A \u003d k _a / k _d .

[0061] An "affinity matured" ABP is an ABP with one or more alterations (e.g., in one or more CDRs or FRs) relative to the parent ABP (i.e., the ABP from which the altered ABP is derived or constructed), resulting in an increase the affinity of ABP for its antigen, compared to the original ABP, which has no alteration(s). In some embodiments, the affinity matured ABP has nanomolar or picomolar affinity for the target antigen. Affinity matured ABPs can be obtained using a number of known methods. For example, Marks et al., Bio/Technology, 1992, 10:779-783, the contents of which are hereby incorporated by reference, describe affinity maturation by shuffling the V _H and V _L domain. Random mutagenesis of CDRs and/or framework residues is described, for example, in Barbas et al., Proc. Nat. Acad. sci. USA, 1994, 91:3809-3813; Schier et al., Gene, 1995, 169:147-155; Yelton et al., J Immunol., 1995, 155:1994-2004; Jackson et al., J Immunol., 1995, 154:3310-33199; and Hawkins et al, J Mal. Biol., 1992, 226:889-896; the content of each of which is included in the present invention by reference to it.

[0062] An "immunoconjugate" is an ABP conjugated to one or more heterologous molecules, such as a therapeutic or diagnostic agent.

[0063] "Effector functions" refers to biological activities mediated by the Fc fragment of an antibody, the activities of which may vary depending on the isotype of the antibody. Examples of antibody effector functions include C1q binding of activated complement-dependent cytotoxicity (CDC), Fc receptor binding of activated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

[0064] When two or more ABPs are mentioned in the text of the invention, the term "competes with" or "cross-competes with" indicates that two or more ABPs compete for antigen binding (eg, TIGIT). In one test example, TIGIT is applied to a surface and contacted with a first TIGIT ABP, after which a second TIGIT ABP is added. In another test example, a first TIGIT ABP is applied to the surface and contacted with TIGIT, and then a second TIGIT ABP is added. If the presence of the first TIGIT ABP reduces the binding of the second TIGIT ABP, in both studies, then the ABPs compete with each other. The term "competes with" also includes combinations of ABPs in which one ABP reduces the binding of another ABP, but if no competition is found when the ABPs are added in reverse order. However, in some embodiments, the first and second ABPs inhibit each other's binding, regardless of the order in which they are added. In some embodiments, one ABP reduces the binding of another ABP to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%. One of skill in the art can select the concentrations of antibodies used in competition studies based on the TIGIT affinities of the ABPs and the valency of the ABPs. The test methods described in this invention are illustrative only, and any suitable test method can be used by a person skilled in the art to determine whether antibodies may compete with each other. Suitable assay methods are described, for example, in Cox et al., "Immunoassay Methods", in Assay Guidance Manual [Internet], Updated December 24, 2014 (www.ncbi.nlm.nih.gov/books/NBK92434/; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; and Finco et al., J Pharm. Biomed. Anal., 2011, 54:351-358; the content of each of which is included in the present invention by reference to it.

[0065] The term "epitope" refers to the portion of an antigen that specifically binds to ABP. Epitopes often consist of surface-accessible amino acid residues and/or side sugar chains, and they may have specific spatial structural characteristics as well as specific charge characteristics. Conformational and non-conformational epitopes differ in that binding for the first of the above, but not for the second, can be lost in the presence of denaturing solvents. An epitope may include amino acid residues that are directly involved in binding and other amino acid residues that are not directly involved in binding. The epitope to which ABP binds can be determined using known methods for determining the epitope, such as, for example, testing for ABP binding to TIGIT variants with various point mutations or to TIGIT chimeric variants.

[0066] Similarly, the term "paratope" refers to amino acid residues in an antibody that bind to an epitope of a target protein.

[0067] The percentage of "identity" between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residue in the reference sequence, after aligning the sequences and inserting gaps, if necessary, to achieve the maximum percent sequence identity. Alignment to determine percent amino acid sequence identity can be achieved in a variety of ways that are well known, for example by using publicly available computer software such as BLAST software, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA or MUSCLE. The person skilled in the art can determine the appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared.

[0068] "Conservative substitution" or "conservative amino acid substitution" refers to the replacement of an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables suggesting similar amino acids are well known. For example, the amino acid groups shown in Tables 2-4 are considered, in some embodiments, as conservative substitutions for each other.

Table 2. Selected groups of amino acids that are considered as conservative substitutions for each other in specific embodiments.

Acid Residue D and E Basic remains K, R and H Hydrophilic uncharged residues S, T, N and Q Aliphatic uncharged residues G,A,V, L and I Non-polar uncharged residues C, M and P aromatic residues F, Y and W

Table 3 Additional selected amino acid groups that are considered conservative substitutions for each other in specific embodiments

Group 1 A, S and T Group 2 D and E Group 3 N and Q Group 4 R and K Group 5 I, L and M Group 6 F, Y and W

Table 4. Additional selected groups of amino acids that are considered as conservative substitutions for each other in specific embodiments.

Group A A and G Group B D and E Group C N and Q Group D R, K and H Group E I, L, M, V

Group F F,Y and W Group G S and T Group H C and M

[0069] Additional conservative substitutions can be found, for example, in the monograph Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W.H. Freeman & Co., New York, NY. An ABP generated by one or more conservative amino acid residue substitutions in the original ABP is referred to as a "conservatively modified variant".

[0070] The term "amino acid" refers to the twenty basic natural amino acids. Natural amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), praline (Pro; P), serine (Ser; S), threonine (Tur; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0071] As used herein, the term "vector" refers to a nucleic acid molecule capable of reproducing another nucleic acid to which it is linked. The term includes a vector in the form of a self-replicating nucleic acid structure, as well as a vector inserted into the genome of the host cell into which it has been introduced. Specific vectors are capable of directing the expression of the nucleic acids to which they are operably linked. Such vectors are referred to in the invention as "expression vectors".

[0072] The terms "host cell", "host cell line" and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced and to the progeny of such cells. Host cells include "transformants" (or "transformed cells") and "transfectants" (or "transfected cells"), each of which includes the primary transformed or transfected cell and its progeny. Such progeny may not be completely identical to the nucleic acid contained in the original cell and may contain mutations.

[0073] The term "treatment" (and variations thereof, such as "treating" or "administering treatment") refers to a clinical intervention that seeks to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be carried out both for the purpose of prevention and in the process of developing clinical pathology. Desirable effects of treatment include preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or temporarily alleviating the disease state, and remission or improving prognosis.

[0074] As used herein, the term "therapeutically effective amount" or "effective amount" refers to the amount of the inventive ABP or pharmaceutical composition that, when administered to a subject, is effective in treating a disease or disorder.

[0075] As used herein, the term "subject" refers to a mammalian subject. Examples of subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In specific embodiments, the subject is a human. In some embodiments, the subject has a disease or condition that can be treated with the ABP of the invention. In some aspects, the disease or condition is cancer. In some aspects, the disease or condition is a viral infection.

[0076] The term "packaged instructions for the use of a medicinal product" is used to refer to instructions traditionally included in marketed packages of therapeutic or diagnostic products (for example, kits) that contain information on indications, use, dose, administration, combination therapy, contraindications and/or warnings regarding the use of such therapeutic or diagnostic products.

[0077] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or interferes with cell function and/or causes cell death or destruction.

[0078] "Chemotherapeutic agent" refers to a chemical compound used in the treatment of cancer. Chemotherapeutic agents include "antihormonal agents" or "endocrine therapeutic agents" that act to regulate, reduce, block, or inhibit the effects of hormones that can promote cancer.

[0079] The term "cytostatic agent" refers to a compound or composition that inhibits cell growth, either in vitro or in vivo. In some embodiments, the cytostatic agent is an agent that reduces the percentage of cells in S phase. In some embodiments, the cytostatic agent reduces the percentage of cells in S phase by at least about 20%, at least about 40%, at least about 60%, or at least about 80%.

[0080] The term "tumor" refers to the growth and proliferation of all neoplastic cells, both malignant and benign, and all precancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferation disorder", "proliferative disorder" and "tumor" are not mutually exclusive when used in the invention. The terms "cell proliferation disorder" and "proliferative disorder" refer to disorders that are associated to some extent with abnormal cell proliferation. In some embodiments, the cell proliferation disorder is cancer. In some aspects, the tumor is a solid tumor. In some aspects, the tumor is a hematological malignancy.

[0081] The term "pharmaceutical composition" refers to a preparation that is in a form that promotes the effective manifestation of the biological effect of the active ingredient contained therein in the treatment of a subject, and which does not contain additional components that are unacceptably toxic to the subject in quantities present in the pharmaceutical composition.

[0082] The terms "modulate" and "modulating" refer to the reduction or inhibition, or, conversely, the activation or increase of the specified variable factor.

[0083] The terms "increase" and "activate" refer to an increase in the specified variable factor by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% , 95%, 100%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more.

[0084] The terms "reduce" and "inhibit" refer to the reduction of the specified variable factor by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% , 95%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more.

[0085] The term "agonize" refers to the activation of a receptor signaling pathway to induce a biological response associated with receptor activation. An "agonist" is a compound that binds and agonizes a receptor.

[0086] The term "antagonize" refers to inhibition of the receptor signaling pathway to inhibit the biological response associated with receptor activation. An "antagonist" is a compound that binds and antagonizes a receptor.

[0087] The term "effector T cell" includes T helper (ie, CD4+) and cytotoxic (ie, CD8+) T cells. CD4+ effector T cells promote a number of immunological processes, including the maturation of B cells into plasma cells and memory B cells and the activation of cytotoxic T cells and macrophages. CD8+ effector T cells destroy virus-infected cells and tumor cells. For more information on effector T cells, see Seder and Ahmed, Nature Immunol., 2003, 4:835-842, the contents of which are incorporated herein by reference.

[0088] The term "regulatory T cell" includes cells that regulate immunological tolerance, for example, by suppressing effector T cells. In some aspects, the regulatory T cell has a CD4+CD25+Foxp3+ phenotype. In some aspects, the regulatory T cell has a CD8+CD25+ phenotype. For more information on regulatory T cells expressing TIGIT, see Nocentini et al., Br. J Pharmacol., 2012, 165:2089-2099, the contents of which are incorporated into the present invention by reference.

[0089] The term "dendritic cell" refers to "professional" antigen presenting cells capable of activating naive T cells and stimulating B cell growth and differentiation.

2. TIGIT antigen-binding proteins

2.1. TIGIT binding and target cells

[0090] The invention provides ABPs that specifically bind to TIGIT. In some aspects, TIGIT is hTIGIT (SEQ ID NO: 1). In some aspects, TIGIT is cTIGIT (SEQ ID NO: 2). In some aspects, TIGIT is an mTIGIT with the sequence shown in SEQ ID NO: 3. In some aspects, TIGIT is an mTIGIT with the sequence shown in SEQ ID NO: 138.

[0091] In some embodiments, the inventive ABPs specifically bind to hTIGIT (SEQ ID NO: 1), cTIGIT (SEQ ID NO: 2), and mTIGIT sequences of SEQ ID NO: 3. In some embodiments, the inventive ABPs specifically bind to hTIGIT (SEQ ID NO: 1), cTIGIT (SEQ ID NO: 2), and mTIGIT sequences of SEQ ID NO: 138. In some embodiments, the inventive ABPs specifically bind to hTIGIT (SEQ ID NO: 1), and cTIGIT (SEQ ID NO: 2). In some embodiments, the ABPs of the invention specifically bind to hTIGIT (SEQ ID NO: 1). In some embodiments, the inventive ABPs do not bind the mTIGIT of SEQ ID NO: 3. In some embodiments, the inventive ABPs do not bind the mTIGIT of SEQ ID NO: 138.

[0092] In some embodiments, the ABPs of the invention specifically bind to the extracellular domain of TIGIT.

[0093] In some embodiments, the ABP of the invention is an antibody. In some embodiments, the ABP of the invention is an antibody fragment. In some embodiments, the ABP according to the invention is an alternative backbone.

[0094] TIGIT can be expressed on the surface of any suitable target cell. In some embodiments, the target cell is a T cell. In some embodiments, the target cell is an effector T cell. In some embodiments, the target cell is a regulatory T cell. In some embodiments, the target cell is a natural killer (NK) cell. In some embodiments, the target cell is a natural killer T (NKT) cell.

[0095] In some embodiments, the ABPs of the invention include an immunoglobulin molecule. In some embodiments, the ABPs of the invention are composed of an immunoglobulin molecule. In some embodiments, the ABPs of the invention consist primarily of an immunoglobulin molecule. In some aspects, the immunoglobulin molecule includes an antibody. In some aspects, the immunoglobulin molecule consists of an antibody. In some aspects, the immunoglobulin molecule consists primarily of an antibody.

[0096] In some embodiments, the ABPs of the invention include a light chain. In some aspects, the light chain is a kappa light chain. In some aspects, the light chain is a lambda light chain.

[0097] In some embodiments, the ABPs of the invention comprise a kappa light chain comprising SEQ ID NO: 126.

[0098] In some embodiments, the ABPs of the invention include a heavy chain. In some aspects, the heavy chain is IgA. In some aspects, the heavy chain is IgD. In some aspects, the heavy chain is IgE. In some aspects, the heavy chain is an IgG. In some aspects, the heavy chain is an IgM. In some aspects, the heavy chain is IgG1. In some aspects, the heavy chain is IgG2. In some aspects, the heavy chain is IgG3. In some aspects, the heavy chain is IgG4. In some aspects, the heavy chain is IgA1. In some aspects, the heavy chain is IgA2.

[0099] In some embodiments, the inventive ABPs comprise an IgG4 heavy chain containing the sequence selected from SEQ ID NO: 55 and SEQ ID NO: 56. In some embodiments, the inventive ABPs comprise an IgG1 heavy chain containing the sequence selected from SEQ ID NO: 57 and SEQ ID NO: 125.

[0100] In some embodiments, the ABPs of the invention include an antibody fragment. In some embodiments, the ABPs of the invention are composed of an antibody fragment. In some embodiments, the ABPs of the invention consist primarily of an antibody fragment. In some aspects, the antibody fragment is an Fv fragment. In some aspects, the antibody fragment is a Fab fragment. In some aspects, the antibody fragment is a F(ab') ₂ fragment. In some aspects, the antibody fragment is a Fab' fragment. In some aspects, the antibody fragment is an scFv (sFv) fragment. In some aspects, the antibody fragment is a scFv-Fc fragment. In some aspects, the antibody fragment is a single domain antibody fragment.

[0101] In some embodiments, an antibody fragment of the invention is derived from an exemplary antibody of the invention. In some embodiments, inventive antibody fragments are not derived from an exemplary antibody of the invention, and may, for example, be isolated from the outset by the inventive methods for producing antibody fragments.

[0102] In some embodiments, the antibody fragment of the invention specifically binds hTIGIT. In some embodiments, the antibody fragment of the invention specifically binds cTIGIT. In some embodiments, the antibody fragment of the invention specifically binds mTIGIT. In some embodiments, the antibody fragment of the invention specifically binds hTIGIT and cTIGIT. In some embodiments, an antibody fragment of the invention specifically binds hTIGIT and mTIGIT. In some embodiments, the antibody fragment of the invention specifically binds cTIGIT and mTIGIT. In some embodiments, an antibody fragment of the invention specifically binds hTIGIT, cTIGIT, and mTIGIT.

[0103] In some embodiments, an antibody fragment derived from an antibody of the invention retains an affinity, measured by K _D , for hTIGIT that is about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such an antibody. In some embodiments, an antibody fragment derived from an antibody of the invention retains an affinity, measured by K _D , for cTIGIT that is about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such an antibody. In some embodiments, an antibody fragment derived from an antibody of the invention retains an affinity, measured by K _D , for mTIGIT that is about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such an antibody. In some embodiments, an antibody fragment derived from an antibody of the invention retains an affinity, as measured by K _D , for both hTIGIT and cTIGIT that is about 1.5-fold, about 2-fold, about 3-fold, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such an antibody. In some embodiments, an antibody fragment derived from an antibody of the invention retains an affinity, as measured by K _D , for both hTIGIT and mTIGIT that is about 1.5-fold, about 2-fold, about 3-fold, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such an antibody. In some embodiments, an antibody fragment derived from an antibody of the invention retains an affinity, as measured by K _D , for both cTIGIT and mTIGIT that is about 1.5-fold, about 2-fold, about 3-fold, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such an antibody. In some embodiments, an antibody fragment derived from an antibody of the invention retains an affinity, as measured by K _D , for all three hTIGIT, cTIGIT, and mTIGIT that is about 1.5 times, about 2 times, about 3 times , about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such an antibody.

[0104] In some embodiments, the inventive antibody fragment retains the ability to antagonize TIGIT, as measured by one or more assay methods, or the biological effects described in the invention. In some embodiments, the inventive antibody fragment retains the ability to prevent TIGIT from interacting with one or more of its inventive ligands.

[0105] In some embodiments, the inventive antibody fragment competes for TIGIT binding with an antibody selected from MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB7, MAB8, MAB9, MAB10, MAB11, MAB12, MAB13, MAB14, MAB15, MAB16, MAB17, MAB18, MAB19, MAB20 or MAB21, each of which is listed in Table 5 of this invention.

[0106] In some embodiments, the antibody fragment of the invention inhibits the binding of CD155 to TIGIT. In some embodiments, the antibody fragment of the invention inhibits the binding of CD112 to TIGIT. In some embodiments, the antibody fragment of the invention inhibits the association of CD226 with TIGIT.

[0107] In some embodiments, the antibody fragment of the invention activates an effector T cell or a natural killer (NK) cell. In some embodiments, the antibody fragment of the invention reduces the number of regulatory T cells in tissue or in the bloodstream. In some embodiments, an antibody fragment of the invention inhibits suppression of an effector T cell by a regulatory T cell.

[0108] In some embodiments, the inventive antibody fragment does not specifically bind to any of PVRL1, PVRL2, PVRL3, or PVRL4.

[0109] In some embodiments, the antibody fragment of the invention binds rodent TIGIT (mTIGIT; SEQ ID NO: 3) with an affinity lower (indicated by a higher K _D value) than the affinity of the antibody fragment for hTIGIT, or does not bind mTIGIT.

[0110] In some embodiments, an antibody fragment of the invention binds the same TIGIT epitope as the antibody.

[0111] In some embodiments, the ABPs of the invention are monoclonal antibodies. In some embodiments, the ABPs of the invention are polyclonal antibodies.

[0112] In some embodiments, the ABPs of the invention include a chimeric antibody. In some embodiments, the ABPs of the invention are composed of a chimeric antibody. In some embodiments, the ABPs of the invention consist primarily of a chimeric antibody. In some embodiments, the ABPs of the invention comprise a humanized antibody. In some embodiments, the ABPs of the invention are composed of a humanized antibody. In some embodiments, the ABPs of the invention consist primarily of a humanized antibody. In some embodiments, the ABPs of the invention comprise a human antibody. In some embodiments, the ABPs of the invention are composed of a human antibody. In some embodiments, the ABPs of the invention are composed primarily of a human antibody.

[0113] In some embodiments, the ABPs of the invention are affinity matured ABPs. In some aspects, the affinity matured ABPs are affinity matured ABPs derived from an exemplary ABP according to the invention.

[0114] In some embodiments, the ABPs of the invention include an alternative backbone. In some embodiments, the ABPs of the invention are composed of an alternate backbone. In some embodiments, the ABPs of the invention consist primarily of an alternative backbone. Any suitable alternative backbone may be used. In some aspects, the alternative backbone is selected from Adnectin ^™ , iMab, ^Antikalin® , EETI-II/AGRP, Kunitz domain, thioredoxin peptide aptamer, Affibody®, ^DARPin , affilin, tetranectin, finomer, and avimer.

[0115] In some embodiments, the inventive ABP inhibits TIGIT binding to one or more TIGIT ligands. In some aspects, the TIGIT ligand is selected from one or more of the poliovirus receptor (PVR; CD155) and nectin-2 (CD112, PVRL2). In some aspects, ABP inhibits TIGIT binding to one or more TIGIT ligands by at least about 50%. In some aspects, ABP inhibits TIGIT binding to one or more TIGIT ligands by at least about 75%. In some aspects, ABP inhibits TIGIT binding to one or more TIGIT ligands by at least about 90%. In some aspects, ABP inhibits TIGIT binding to one or more TIGIT ligands by at least about 95%.

[0116] In some embodiments, the ABP of the invention is an ABP that competes with the exemplary ABP of the invention. In some aspects, the ABP that competes with the inventive exemplary ABP binds the same epitope as the inventive exemplary ABP.

[0117] In some embodiments, the inventive ABP does not bind PVRL4.

[0118] It is known that when an antibody is expressed in cells, the antibody is modified after translation. Examples of post-translational modification include cleavage of lysine at the C-terminus of the heavy chain with carboxypeptidase, modification of glutamine or glutamic acid at the N-terminus of the heavy chain and light chain to pyroglutamic acid by pyroglutamylation, glycosylation, oxidation, deamidation and glycation, and such post-translational modifications are known to occur. in various antibodies (see Journal of Pharmaceutical Sciences, 2008, Vol. 97, p. 2426-2447, the contents of which are incorporated herein by reference). In some embodiments, the ABP of the invention is an antibody or antigen-binding fragment thereof that has been post-translationally modified. Examples of an antibody or antigen-binding fragment thereof that have been post-translationally modified include an antibody or antigen-binding fragments thereof that have been subjected to pyroglutamylation at the N-terminus of the heavy chain variable region and/or a lysine deletion at the C-terminus of the heavy chain. It is known that such post-translational modification, due to pyroglutamilation at the N-terminus and deletion of lysine at the C-terminus, does not affect the activity of the antibody or its fragment in any way (see Analytical Biochemistry, 2006, Vol. 348, p. 24-39, the contents of which included in the present invention by reference).

2.2. TIGIT sequences of antigen-binding proteins

2.2.1. V _H domains

[0119] In some embodiments, the inventive ABP comprises a V _H sequence selected from SEQ ID NOs: 4-24. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 4. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 5. In some embodiments, the inventive ABP comprises V _H SEQ ID NO: 6. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 7. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 8. In some embodiments, The inventive ABP comprises the V _H sequence of SEQ ID NO: 9. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 1O. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 1 l. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 12. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 13. In some embodiments, the inventive ABP comprises V _H SEQ ID NO: 14. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 15. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 16. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 17. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 18. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 19. In some embodiments, the inventive ABP comprises V _H SEQ ID NO: 20. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 21. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 22. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 23. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 24.

[0120] In some embodiments, the inventive ABP comprises a V _H sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity with the exemplary V _H sequence represented by in SEQ ID NOs: 4-24. In some embodiments, the inventive ABP comprises the V _H sequence shown in SEQ ID NOs: 4-24 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and may be isolated, for example, from the start using the methods of the invention to obtain ABPs.

2.2.2. V _L domains

[0121] In some embodiments, the inventive ABP comprises a V _L sequence selected from SEQ ID NOs: 25-28. In some embodiments, the inventive ABP comprises the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises V _L the sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _L sequence of SEQ ID NO: 28.

[0122] In some embodiments, the inventive ABP comprises a V _L sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity with the exemplary V _L sequence shown in SEQ ID NOs: 25-28. In some embodiments, the inventive ABP comprises the V _L sequence shown in SEQ ID NOs: 25-28 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described in the invention. In some embodiments, such variants are not derived from the inventive sequence and may be isolated, for example, from the start using the methods of the invention to obtain ABPs.

2.2.3. V _H - V _L combinations

[0123] In some embodiments, the inventive ABP comprises a V _H sequence selected from SEQ ID NOs: 4-24 and a V _L sequence selected from SEQ ID NOs: 25-28.

[0124] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 4 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 5 and The V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 6 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence SEQ ID NO: 7 and V _L the sequence of SEQ ID NO: 25. In some embodiments, the ABP of the invention includes the V _H sequence of SEQ ID NO: 8 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the implementation proposed in the inventive ABP comprises the V _H sequence of SEQ ID NO: 9 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises t V _H sequence of SEQ ID NO: 10 and V _L sequence of SEQ ID NO: 26. In some embodiments, the implementation proposed in the invention ABP includes V _H sequence of SEQ ID NO: 11 and V _L sequence of SEQ ID NO: 26. In some embodiments, The inventive ABP comprises the V _H sequence of SEQ ID NO: 12 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 13 and the V _L sequence of SEQ ID NO: 13 : 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 14 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 15 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 16 and the V _L sequence of SEQ ID NO: 2 7. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 17 and the V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 18 and V The _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 19 and the V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 20 and the V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 21 and the V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP The ABP includes the V _H sequence of SEQ ID NO: 22 and the V _L sequence of SEQ ID NO: 28. In some embodiments, the inventive ABP includes has a V _H sequence of SEQ ID NO: 23 and a V _L sequence of SEQ ID NO: 28. In some embodiments, an inventive ABP comprises a V _H sequence of SEQ ID NO: 24 and a V _L sequence of SEQ ID NO: 28.

[0125] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 4 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 4 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 4 and the V _L sequence of SEQ ID NO: 28.

[0126] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 5 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 5 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 5 and the V _L sequence of SEQ ID NO: 28.

[0127] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 6 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 6 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 6 and the V _L sequence of SEQ ID NO: 28.

[0128] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 7 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 7 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 7 and the V _L sequence of SEQ ID NO: 28.

[0129] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 8 and the V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 8 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 8 and the V _L sequence of SEQ ID NO: 28.

[0130] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 9 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 9 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 9 and the V _L sequence of SEQ ID NO: 28.

[0131] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 10 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 10 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 10 and the V _L sequence of SEQ ID NO: 28.

[0132] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 11 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 11 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 11 and the V _L sequence of SEQ ID NO: 28.

[0133] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 12 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 12 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 12 and the V _L sequence of SEQ ID NO: 28.

[0134] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 13 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 13 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 13 and the V _L sequence of SEQ ID NO: 28.

[0135] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 14 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 14 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 14 and the V _L sequence of SEQ ID NO: 28.

[0136] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 15 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 15 and The V _L sequence of SEQ ID NO: 27. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 15 and the V _L sequence of SEQ ID NO: 28.

[0137] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 16 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 16 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 16 and the V _L sequence of SEQ ID NO: 28.

[0138] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 17 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 17 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 17 and the V _L sequence of SEQ ID NO: 28.

[0139] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 18 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 18 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 18 and the V _L sequence of SEQ ID NO: 28.

[0140] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 19 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 19 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 19 and the V _L sequence of SEQ ID NO: 28.

[0141] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 20 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 20 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 20 and the V _L sequence of SEQ ID NO: 28.

[0142] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 21 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 21 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 21 and the V _L sequence of SEQ ID NO: 28.

[0143] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 22 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 22 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 22 and the V _L sequence of SEQ ID NO: 27.

[0144] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 23 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 23 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 23 and the V _L sequence of SEQ ID NO: 27.

[0145] In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 24 and the V _L sequence of SEQ ID NO: 25. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 24 and The V _L sequence of SEQ ID NO: 26. In some embodiments, the inventive ABP comprises the V _H sequence of SEQ ID NO: 24 and the V _L sequence of SEQ ID NO: 27.

[0146] In some embodiments, the inventive ABP comprises a V _H sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity with the exemplary V _H sequence represented by in SEQ ID NOs: 4-24, and a V _L sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity with the exemplary V _L sequence shown in SEQ ID NOs: 25-28. In some embodiments, the inventive ABP comprises the V _H sequence shown in SEQ ID NOs: 4-24 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, and the V _L sequence shown in SEQ ID NOs: 25-28, with the number of amino acid substitutions, reaching 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and may be isolated, for example, from the start using the methods of the invention to obtain ABPs.

2.2.4. CDRs

[0147] In some embodiments, the inventive ABP includes one to three CDRs of a V _H domain selected from SEQ ID NOs: 4-24. In some embodiments, the inventive ABP comprises two to three CDRs of a V _H domain selected from SEQ ID NOs: 4-24. In some embodiments, the inventive ABP includes three V _H domain CDRs selected from SEQ ID NOs: 4-24. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are IMGT CDRs.

[0148] In some embodiments, the CDRs are CDRs having at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-H1, CDR-H2, or CDR-H3 sequences of SEQ ID NOs: 4-24. In some embodiments, the CDR-H1 is a CDR-H1 of a V _H domain selected from SEQ ID NOs: 4-24, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR- H2 is a CDR-H2 of a V _H domain selected from SEQ ID NOs: 4-24, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, CDR-H3 is a CDR-H3 of a V _H domain selected from SEQ ID NOs: 4-24 with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0149] In some embodiments, the inventive ABP comprises one to three CDRs of a V _L domain selected from SEQ ID NOs: 25-28. In some embodiments, the inventive ABP comprises two to three CDRs of a V _L domain selected from SEQ ID NOs: 25-28. In some embodiments, the inventive ABP includes three CDRs of a V _L domain selected from SEQ ID NOs: 25-28. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are IMGT CDRs.

[0150] In some embodiments, the CDRs are CDRs having at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-L1, CDR-L2, or CDR-L3 sequences of SEQ ID NOs: 25-28. In some embodiments, the CDR-L1 is a CDR-L1 of a V _L domain selected from SEQ ID NOs: 25-28, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions. In some embodiments, CDR-L2 is a CDR-L2 V _L domain selected from SEQ ID NOs: 25-28 with up to 1, 2, 3, or 4 amino acid substitutions. In some embodiments, CDR-L3 is CDR-L3 V _L domain selected from SEQ ID NOs: 25-28, up to 1, 2, 3, 4, or 5 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0151] In some embodiments, the inventive ABP comprises one to three CDRs of a V _H domain selected from SEQ ID NOs: 4-24 and one to three CDRs of a V _L domain selected from SEQ ID NOs: 25- 28. In some embodiments, the inventive ABP comprises two to three V _H domain CDRs selected from SEQ ID NOs: 4-24 and two to three V _L domain CDRs selected from SEQ ID NOs: 25-28. In some embodiments, the inventive ABP includes three V _H domain CDRs selected from SEQ ID NOs: 4-24 and three V _L domain CDRs selected from SEQ ID NOs: 25-28. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are IMGT CDRs.

[0152] In some embodiments, the CDRs are CDRs having at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-H1, CDR-H2, or CDR-H3 sequences of SEQ ID NOs: 4-24, and at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with CDR-L1, CDR-L2, or CDR-L3 sequences of SEQ ID NOs: 25-28 .

In some embodiments, the CDR-H1 is a V _H domain CDR-H1 selected from SEQ ID NOs: 4-24 with up to 1, 2, 3, 4, or 5 amino acid substitutions; CDR-H2 is a CDR-H2 of a V _H domain selected from SEQ ID NOs: 4-24 with up to 1, 2, 3, 4, 5, 6, 7 or 8 amino acid substitutions; CDR-H3 is a CDR-H3 of a V _H domain selected from SEQ ID NOs: 4-24 with up to 1, 2, 3, 4, 5, 6, 7 or 8 amino acid substitutions; CDR-L1 is a CDR-L1 V _L domain selected from SEQ ID NOs: 25-28 with up to 1, 2, 3, 4, 5 or 6 amino acid substitutions; CDR-L2 is a CDR-L2 V _L domain selected from SEQ ID NOs: 25-28 with up to 1, 2, 3 or 4 amino acid substitutions; and CDR-L3 is the CDR-L3 of a V _L domain selected from SEQ ID NOs: 25-28 with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions . In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and may be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0153] In some embodiments, the inventive ABP comprises a CDR-H3 selected from SEQ ID NOs: 29-35. In some aspects, the CDR-H3 shares at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-H3 sequences of SEQ ID NOs: 29-35. In some aspects, CDR-H3 is a CDR-H3 according to the IMGT numbering system. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 29-35 with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0154] In some embodiments, the inventive ABP comprises a CDR-H2 selected from SEQ ID NOs: 36-47. In some aspects, the CDR-H2 shares at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-H2 sequences of SEQ ID NOs: 36-47. In some aspects, CDR-H2 is CDR-H2 according to the Kabat numbering system. In some embodiments, the CDR-H2 is a CDR-H2 selected from SEQ ID NOs: 36-47 with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0155] In some embodiments, the inventive ABP comprises a CDR-H1 selected from SEQ ID NOs: 48-54 or 58-62. In some aspects, the CDR-H1 shares at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-H1 sequences of SEQ ID NOs: 48-54 or 58-62. In some aspects, CDR-H1 is a CDR-H1 that overlaps with CDR-H1 defined by both the Chothia and Kabat numbering systems. In some embodiments, the CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 48-54 or 58-62 with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some aspects, amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0156] In some embodiments, the inventive ABP includes a CDR-H3 selected from SEQ ID NOs: 29-35 and a CDR-H2 selected from SEQ ID NOs: 36-47. In some embodiments, the inventive ABP includes CDR-H3 selected from SEQ ID NOs: 29-35, CDR-H2 selected from SEQ ID NOs: 36-47, and CDR-H1 selected from SEQ ID NOs: 48 -54 or 58-62. In some embodiments, CDR-H3 has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with CDR-H3 of SEQ ID NOs: 29-35, CDR-H2 has at least at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with CDR-H2 of SEQ ID NOs: 36-47, and CDR-H1 has at least about 50%, 75%, 80% , 85%, 90% or 95% identity with CDR-H1 sequences SEQ ID NOs: 48-54 or 58-62. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 29-35 with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-H2 is DR-H2 selected from SEQ ID NOs: 36-47 with up to 1, 2, 3, 4, 5, 6, 7 or 8 amino acid substitutions; and CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 48-54 or 58-62 with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid replacements. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0157] In some embodiments, the inventive ABP comprises a CDR-L3 selected from SEQ ID NOs: 63-66. In some aspects, the CDR-L3 shares at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-L3 sequences of SEQ ID NOs: 63-66. In some aspects, CDR-L3 is a CDR-L3 according to the Kabat, Chothia, and IMGT numbering systems. In some embodiments, the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 63-66 with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid replacements. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described in the invention. In some embodiments, such variants are not derived from the inventive sequence and may be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0158] In some embodiments, the inventive ABP comprises a CDR-L2 selected from SEQ ID NOs: 67-69. In some aspects, the CDR-L2 shares at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-L2 sequences of SEQ ID NOs: 67-69. In some aspects, CDR-L2 is a CDR-L2 according to the Kabat and Chothia numbering systems. In some embodiments, the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 67-69 with up to 1, 2, 3, or 4 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions . In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and may be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0159] In some embodiments, the inventive ABP comprises a CDR-L1 selected from SEQ ID NOs: 70-72. In some aspects, the CDR-L1 shares at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-L1 sequences of SEQ ID NOs: 70-72. In some aspects, CDR-L1 is a CDR-L1 according to the Kabat and Chothia numbering systems. In some embodiments, the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 70-72 with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0160] In some embodiments, the inventive ABP includes a CDR-L3 selected from SEQ ID NOs: 63-66 and a CDR-L2 selected from SEQ ID NOs: 67-69. In some embodiments, the inventive ABP includes CDR-L3 selected from SEQ ID NOs: 63-66, CDR-L2 selected from SEQ ID NOs: 67-69, and CDR-L1 selected from SEQ ID NOs: 70 -72. In some embodiments, CDR-L3 has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with CDR-L3 of SEQ ID NOs: 63-66, CDR-L2 has at least at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with CDR-L2 sequences of SEQ ID NOs: 67-69, and CDR-L1 has at least about 50%, 75%, 80% , 85%, 90% or 95% identity with CDR-L1 sequences SEQ ID NOs: 70-72. In some embodiments, the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 63-66 with up to 1, 2, 3, 4, or 5 amino acid substitutions; CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 67-69 with up to 1, 2, 3, or 4 amino acid substitutions; and CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 70-72 with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the inventive sequence, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described in the invention. In some embodiments, such variants are not derived from the inventive sequence and can be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0161] In some embodiments, the inventive ABP comprises CDR-H3 selected from SEQ ID NOs: 29-35, CDR-H2 selected from SEQ ID NOs: 36-47, CDR-H1 selected from SEQ ID NOs : 48-54 or 58-62, CDR-L3 selected from SEQ ID NOs: 63-66, CDR-L2 selected from SEQ ID NOs: 67-69, and CDR-L1 selected from SEQ ID NOs: 70- 72. In some embodiments, CDR-H3 has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with CDR-H3 of SEQ ID NOs: 29-35, CDR-H2 has at least at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-H2 sequence of SEQ ID NOs: 36-47, CDR-H1 has at least about 50%, 75%, 80%, 85%, 90% or 95% identity with CDR-H1 sequences SEQ ID NOs: 48-54 or 58-62, CDR-L3 has at least about 50%, 75%, 80%, 85%, 90% or 95 % identity with CDR-L3 of SEQ ID NOs: 63-66, CDR-L2 has at least approximately 50%, 75%, 80%, 85%, 90%, or 95% identity with CDR-L2 of SEQ ID NOs: 67-69, and the CDR-L1 shares at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the CDR-L1 sequences of SEQ ID NOs: 70-72. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 29-35 with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-H2 is DR-H2 selected from SEQ ID NOs: 36-47 with up to 1, 2, 3, 4, 5, 6, 7 or 8 amino acid substitutions; CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 48-54 or 58-62 with up to 1, 2, 3, 4 or 5 amino acid substitutions; CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 63-66 with up to 1, 2, 3, 4 or 5 amino acid substitutions; CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 67-69 with up to 1, 2, 3, or 4 amino acid substitutions; and CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 70-72 with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the ABPs described in this section are referred to in the invention as "variants". In some embodiments, such variants are derived from the sequence of the invention, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known or described herein. In some embodiments, such variants are not derived from the inventive sequence and may be isolated, for example, from the start using the methods of the invention to obtain ABPs.

[0162] In some embodiments, the inventive ABP comprises CDR-H3 of SEQ ID NO: 29, CDR-H2 of SEQ ID NO: 36, CDR-H1 of SEQ ID NO: 48, CDR-L3 of SEQ ID NO: : 63, CDR-L2 sequences SEQ ID NO: 67 and CDR-L1 sequences SEQ ID NO: 70.

[0163] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 29, a CDR-H2 of SEQ ID NO: 37, a CDR-H1 of SEQ ID NO: 49, a CDR-L3 of SEQ ID NO: : 63, CDR-L2 sequences SEQ ID NO: 67 and CDR-L1 sequences SEQ ID NO: 70.

[0164] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 29, a CDR-H2 of SEQ ID NO: 37, a CDR-H1 of SEQ ID NO: 50, a CDR-L3 of SEQ ID NO: : 63, CDR-L2 sequences SEQ ID NO: 67 and CDR-L1 sequences SEQ ID NO: 70.

[0165] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 30, a CDR-H2 of SEQ ID NO: 37, a CDR-H1 of SEQ ID NO: 50, a CDR-L3 of SEQ ID NO: : 63, CDR-L2 sequences SEQ ID NO: 67 and CDR-L1 sequences SEQ ID NO: 70.

[0166] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 29, a CDR-H2 of SEQ ID NO: 38, a CDR-H1 of SEQ ID NO: 50, a CDR-L3 of SEQ ID NO: : 63, CDR-L2 sequences SEQ ID NO: 67 and CDR-L1 sequences SEQ ID NO: 70.

[0167] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 31, a CDR-H2 of SEQ ID NO: 39, a CDR-H1 of SEQ ID NO: 51, a CDR-L3 of SEQ ID NO: : 64, CDR-L2 sequences SEQ ID NO: 68 and CDR-L1 sequences SEQ ID NO: 71.

[0168] In some embodiments, the inventive ABP comprises CDR-H3 of SEQ ID NO: 31, CDR-H2 of SEQ ID NO: 40, CDR-H1 of SEQ ID NO: 52, CDR-L3 of SEQ ID NO: : 64, CDR-L2 sequences SEQ ID NO: 68 and CDR-L1 sequences SEQ ID NO: 71.

[0169] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 31, a CDR-H2 of SEQ ID NO: 41, a CDR-H1 of SEQ ID NO: 53, a CDR-L3 of SEQ ID NO: : 64, CDR-L2 sequences SEQ ID NO: 68 and CDR-L1 sequences SEQ ID NO: 71.

[0170] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 31, a CDR-H2 of SEQ ID NO: 40, a CDR-H1 of SEQ ID NO: 54, a CDR-L3 of SEQ ID NO: : 64, CDR-L2 sequences SEQ ID NO: 68 and CDR-L1 sequences SEQ ID NO: 71.

[0171] In some embodiments, the inventive ABP comprises CDR-H3 of SEQ ID NO: 32, CDR-H2 of SEQ ID NO: 40, CDR-H1 of SEQ ID NO: 54, CDR-L3 of SEQ ID NO: : 64, CDR-L2 sequences SEQ ID NO: 68 and CDR-L1 sequences SEQ ID NO: 71.

[0172] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 32, a CDR-H2 of SEQ ID NO: 40, a CDR-H1 of SEQ ID NO: 54, a CDR-L3 of SEQ ID NO: : 64, CDR-L2 sequences SEQ ID NO: 68 and CDR-L1 sequences SEQ ID NO: 71.

[0173] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 32, a CDR-H2 of SEQ ID NO: 40, a CDR-H1 of SEQ ID NO: 54, a CDR-L3 of SEQ ID NO: : 64, CDR-L2 sequences SEQ ID NO: 68 and CDR-L1 sequences SEQ ID NO: 71.

[0174] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 33, a CDR-H2 of SEQ ID NO: 42, a CDR-H1 of SEQ ID NO: 58, a CDR-L3 of SEQ ID NO: : 65, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0175] In some embodiments, the inventive ABP comprises CDR-H3 of SEQ ID NO: 33, CDR-H2 of SEQ ID NO: 42, CDR-H1 of SEQ ID NO: 59, CDR-L3 of SEQ ID NO: : 65, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0176] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 33, a CDR-H2 of SEQ ID NO: 43, a CDR-H1 of SEQ ID NO: 60, a CDR-L3 of SEQ ID NO: : 65, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0177] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 34, a CDR-H2 of SEQ ID NO: 43, a CDR-H1 of SEQ ID NO: 60, a CDR-L3 of SEQ ID NO: : 65, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0178] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 34, a CDR-H2 of SEQ ID NO: 44, a CDR-H1 of SEQ ID NO: 61, a CDR-L3 of SEQ ID NO: : 65, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0179] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 33, a CDR-H2 of SEQ ID NO: 44, a CDR-H1 of SEQ ID NO: 59, a CDR-L3 of SEQ ID NO: : 65, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0180] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 35, a CDR-H2 of SEQ ID NO: 45, a CDR-H1 of SEQ ID NO: 62, a CDR-L3 of SEQ ID NO: : 66, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0181] In some embodiments, the inventive ABP comprises CDR-H3 of SEQ ID NO: 35, CDR-H2 of SEQ ID NO: 46, CDR-H1 of SEQ ID NO: 62, CDR-L3 of SEQ ID NO: : 66, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

[0182] In some embodiments, the inventive ABP comprises a CDR-H3 of SEQ ID NO: 35, a CDR-H2 of SEQ ID NO: 47, a CDR-H1 of SEQ ID NO: 62, a CDR-L3 of SEQ ID NO: : 66, CDR-L2 sequences SEQ ID NO: 69 and CDR-L1 sequences SEQ ID NO: 72.

2.2.5. Heavy chains and light chains

[0183] In some embodiments, the inventive ABP comprises a V _H selected from the V _H sequences of SEQ ID NOs: 4-24 (or the variant described in the invention) and a constant region selected from SEQ ID NOs: 55-57 or 125. In some embodiments, the inventive ABP comprises a V _L selected from the V _L sequences of SEQ ID NO: 25-28 (or the variant described in the invention) and a constant region of SEQ ID NO: 126.

[0184] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 79. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 80. In some embodiments, the inventive ABP includes a light chain of SEQ ID NO: 81. In some embodiments, an inventive ABP includes a heavy chain of SEQ ID NO: 79 and a light chain of SEQ ID NO: 81. In some embodiments, an inventive ABP includes a heavy chain sequences of SEQ ID NO: 80; and a light chain of sequence SEQ ID NO: 81.

[0185] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 82. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 83. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 82 and a light chain of SEQ ID NO: 81. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 83 and a light chain of SEQ ID NO: 81.

[0186] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 84. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 85. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 84 and a light chain of SEQ ID NO: 81. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 85 and a light chain of SEQ ID NO: 81.

[0187] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 86. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 87. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 86 and a light chain of SEQ ID NO: 81. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 87 and a light chain of SEQ ID NO: 81.

[0188] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 88. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 89. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 88 and a light chain of SEQ ID NO: 81. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 89 and a light chain of SEQ ID NO: 81.

[0189] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 90. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 91. In some embodiments, the inventive ABP includes a light chain of SEQ ID NO: 92. In some embodiments, the inventive ABP includes a heavy chain of SEQ ID NO: 90 and a light chain of SEQ ID NO: 92. In some embodiments, an inventive ABP includes a heavy chain sequences of SEQ ID NO: 91; and a light chain of sequence SEQ ID NO: 92.

[0190] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 93. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 94. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 93 and a light chain of SEQ ID NO: 92. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 94 and a light chain of SEQ ID NO: 92.

[0191] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 95. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 96. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 95 and a light chain of SEQ ID NO: 92. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 96 and a light chain of SEQ ID NO: 92.

[0192] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 97. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 98. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 97 and a light chain of SEQ ID NO: 92. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 98 and a light chain of SEQ ID NO: 92.

[0193] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 99. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 100. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 99 and a light chain of SEQ ID NO: 92. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 100 and a light chain of SEQ ID NO: 92.

[0194] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 101. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 102. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 101 and a light chain of SEQ ID NO: 92. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 102 and a light chain of SEQ ID NO: 92.

[0195] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 103. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 104. In some embodiments, the inventive ABP includes the heavy chain of SEQ ID NO: 103 and the light chain of SEQ ID NO: 92. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 104 and the light chain of SEQ ID NO: 92.

[0196] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 105. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 106. In some embodiments, the inventive ABP includes a light chain of SEQ ID NO: 107. In some embodiments, an inventive ABP includes a heavy chain of SEQ ID NO: 105 and a light chain of SEQ ID NO: 107. In some embodiments, an inventive ABP includes a heavy chain sequences of SEQ ID NO: 106; and a light chain of sequence SEQ ID NO: 107.

[0197] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 108. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 109. In some embodiments, the inventive ABP includes the heavy chain of SEQ ID NO: 108 and the light chain of SEQ ID NO: 107. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 109 and the light chain of SEQ ID NO: 107.

[0198] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 110. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 111. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 110 and a light chain of SEQ ID NO: 107. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 111 and a light chain of SEQ ID NO: 107.

[0199] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 112. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 113. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 112 and a light chain of SEQ ID NO: 107. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 113 and a light chain of SEQ ID NO: 107.

[0200] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 114. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 115. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 114 and a light chain of SEQ ID NO: 107. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 115 and a light chain of SEQ ID NO: 107.

[0201] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 116. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 117. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 116 and a light chain of SEQ ID NO: 107. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 117 and a light chain of SEQ ID NO: 107.

[0202] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 118. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 119. In some embodiments, the inventive ABP includes a light chain of SEQ ID NO: 120. In some embodiments, an inventive ABP includes a heavy chain of SEQ ID NO: 118 and a light chain of SEQ ID NO: 120. In some embodiments, an inventive ABP includes a heavy chain sequence of SEQ ID NO: 119; and a light chain of sequence SEQ ID NO: 120.

[0203] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 121. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 122. In some embodiments, the inventive ABP comprises a heavy chain of SEQ ID NO: 121 and a light chain of SEQ ID NO: 120. In some embodiments, an ABP of the invention comprises a heavy chain of SEQ ID NO: 122 and a light chain of SEQ ID NO: 120.

[0204] In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 123. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 124. In some embodiments, the inventive ABP includes the heavy chain of SEQ ID NO: 123 and the light chain of SEQ ID NO: 120. In some embodiments, the inventive ABP comprises the heavy chain of SEQ ID NO: 124 and the light chain of SEQ ID NO: 120.

2.2.6. Consensus Sequences

[0205] In some embodiments, the invention provides a first family of ABPs, where the ABP of that family includes the following six CDR sequences: (a) a CDR-H3 having the sequence ARDGVLX ₁ -LNKRSFDI, where X ₁ is A or T (SEQ ID NO: 128); (b) a CDR-H2 having the sequence SIYYSGX ₂ -TYYNPSLKS, where X ₂ is S, Q or G (SEQ ID NO: 129); (c) a CDR-H1 having the sequence GSIX ₃ -SGX ₄ -YYWG, where X ₃ is E or A and X ₄ is L, V or S (SEQ ID NO: 130); (d) a CDR-L3 having the sequence QQHTVRPPLT (SEQ ID NO: 64); (e) CDR-L2 having the sequence GASSRAT (SEQ ID NO: 68); and (f) a CDR-L1 having the sequence RASQSVSSSYLA (SEQ ID NO: 71). In some embodiments, the invention provides an ABP belonging to such a first family.

[0206] In some embodiments, the invention provides a second family of ABPs, where an ABP from such a family includes the following six CDR sequences: (a) a CDR-H3 having the sequence ARDANYYGX ₁ -AWAFDP, where X ₁ is S or G (SEQ ID NO: 131); (b) a CDR-H2 having the sequence SIYYSGX ₂ -TFYNPSLKX ₃ where X ₂ is S or A and X ₃ is S or G (SEQ ID NO: 132); (c) a CDR-H1 having the sequence GSIX ₄ -SX ₅ -X ₆ -X ₇ -YWG, where X ₄ is S or T, X ₅ is S or T, X ₆ is S or K, and X ₇ is H or Y (SEQ ID NO: 133); (d) a CDR-L3 having the sequence QQHFNLPT (SEQ ID NO: 63); (e) a CDR-L2 having the DASNRAT sequence (SEQ ID NO: 67); and (f) a CDR-L1 having the sequence RASQSVSSYLA (SEQ ID NO: 70). In some embodiments, the invention provides an ABP belonging to such a second family.

[0207] In some embodiments, the invention provides a third family of ABPs, where an ABP from such a family includes the following six CDR sequences: (a) a CDR-H3 having the sequence ARGGRTTWIGAX ₁ -DI, where X ₁ is F or L (SEQ ID NO: 134); (b) a CDR-H2 having the sequence IINPSX ₂ -GLTSYAX ₃ -KFQG, where X ₂ is L or I and X ₃ is Q or R (SEQ ID NO: 135); (c) a CDR-H1 having the sequence YTFX ₄ -X ₅ -YYX ₆ -H, where X ₄ is G, P or R, X ₅ is N, A or E, and X ₆ is M or I ( SEQ ID NO: 136); (d) a CDR-L3 having the sequence QQYVVWPPLT (SEQ ID NO: 65); (e) CDR-L2 having the sequence GASTRAT (SEQ ID NO: 69); and (f) a CDR-L1 having the sequence RASQSVSSNLA (SEQ ID NO: 72). In some embodiments, the invention provides an ABP belonging to such a third family.

[0208] In some embodiments, the invention provides a fourth family of ABPs, where an ABP from such a family includes the following six CDR sequences: (a) a CDR-H3 having the sequence ARLHVSGSYYPAYLDY (SEQ ID NO: 35); (b) a CDR-H2 having the sequence X ₁ -INPSMGATSYX ₂ -QKFX ₃ -G, where X ₁ is V or I, X ₂ is A or T, and X ₃ is Q or R (SEQ ID NO: 137); (c) CDR-H1 having the sequence YTFTSHYMG (SEQ ID NO: 62); (d) a CDR-L3 having the sequence QQYIVFPWT (SEQ ID NO: 66); (e) CDR-L2 having the sequence GASTRAT (SEQ ID NO: 69); and (f) a CDR-L1 having the sequence RASQSVSSNLA, (SEQ ID NO: 72). In some embodiments, the invention provides an ABP belonging to such a fourth family.

2.2.7. Functional properties of ABP variants

[0209] As described above and elsewhere in this invention, the invention provides ABP variants defined based on percent identity with an exemplary ABP inventive sequence or amino acid residue substitution when compared to an inventive exemplary ABP sequence.

[0210] In some embodiments, a variant of the inventive ABP has specificity for hTIGIT. In some embodiments, a variant of the inventive ABP has specificity for cTIGIT. In some embodiments, a variant of the inventive ABP has specificity for mTIGIT. In some embodiments, a variant of the inventive ABP has specificity for hTIGIT and cTIGIT. In some embodiments, a variant of the inventive ABP has specificity for hTIGIT and mTIGIT. In some embodiments, a variant of the inventive ABP has specificity for cTIGIT and mTIGIT. In some embodiments, a variant of the inventive ABP has specificity for hTIGIT, cTIGIT, and mTIGIT.

[0211] In some embodiments, an ABP variant that is derived from an exemplary ABP sequence according to the invention retains an affinity, measured by K _D , for hTIGIT that is about 1.5 times, about 2 times, about 3 times , about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such exemplary ABP. In some embodiments, an ABP variant that is derived from an exemplary ABP sequence according to the invention retains an affinity, measured by K _D , for cTIGIT that is about 1.5-fold, about 2-fold, about 3-fold, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such exemplary ABP. In some embodiments, an ABP variant that is derived from an exemplary ABP sequence according to the invention retains an affinity, measured by K _D , for mTIGIT that is about 1.5-fold, about 2-fold, about 3-fold, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such exemplary ABP. In some embodiments, an ABP variant that is derived from an exemplary ABP sequence according to the invention retains an affinity, as measured by K _D , for hTIGIT and cTIGIT that is about 1.5-fold, about 2-fold, about 3-fold, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such exemplary ABP. In some embodiments, an ABP variant that is derived from an exemplary ABP sequence according to the invention retains an affinity, as measured by K _D , for both hTIGIT and mTIGIT that is about 1.5 times, about 2 times, about 3 times , about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such exemplary ABP. In some embodiments, an ABP variant that is derived from an exemplary ABP sequence according to the invention retains an affinity, as measured by K _D , for both cTIGIT and mTIGIT that is about 1.5 times, about 2 times, about 3 times , about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such exemplary ABP. In some embodiments, an ABP variant that is derived from an exemplary ABP sequence according to the invention retains an affinity, as measured by K _D , for all three hTIGIT, cTIGIT, and mTIGIT that is about 1.5-fold, about 2-fold, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the affinity of such exemplary ABP.

[0212] In some embodiments, a variant of the inventive ABP retains the ability to antagonize TIGIT, as measured by one or more assay methods, or the biological effects described in the invention. In some embodiments, a variant of the inventive ABP retains the ability to prevent TIGIT from interacting with one or more of its inventive ligands.

[0213] In some embodiments, a variant of the inventive ABP competes for TIGIT binding to an antibody selected from MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB7, MAB8, MAB9, MAB10, MAB11, MAB12, MAB13, MAB14, MAB15, MAB16, MAB17, MAB18, MAB19, MAB20 or MAB21, each of which is listed in Table 5 of this invention.

[0214] In some embodiments, a variant of the inventive ABP inhibits CD155 binding to TIGIT. In some embodiments, a variant of the inventive ABP inhibits CD112 binding to TIGIT. In some embodiments, a variant of the inventive ABP inhibits association of CD226 with TIGIT.

[0215] In some embodiments, a variant of the inventive ABP activates an effector T cell or a natural killer (NK) cell. In some embodiments, a variant of the inventive ABP reduces the number of regulatory T cells in tissue or in the bloodstream. In some embodiments, a variant of the inventive ABP inhibits suppression of an effector T cell by a regulatory T cell.

[0216] In some embodiments, a variant of the inventive ABP does not specifically bind to any of PVRL1, PVRL2, PVRL3, or PVRL4.

[0217] In some embodiments, a variant of the inventive ABP binds rodent TIGIT (mTIGIT; SEQ ID NO: 3) with lower affinity (indicated by a higher K _D value) than ABP's affinity for hTIGIT, or does not bind mTIGIT . In some embodiments, a variant of the inventive ABP binds rodent TIGIT (SEQ ID NO: 138) with an affinity lower (indicated by a higher K _D value) than ABP's affinity for hTIGIT, or does not bind mTIGIT.

[0218] In some embodiments, a variant of the inventive ABP binds the same TIGIT epitope as such an ABP.

2.2.8. Other functional properties of ABPs

[0219] In some embodiments, the inventive ABP has one or more of the characteristics listed in the following paragraphs (a)-(j): (a) competes for TIGIT binding with an antibody selected from MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB7, MAB8, MAB9, MAB10, MAB11, MAB12, MAB13, MAB14, MAB15, MAB16, MAB17, MAB18, MAB19, MAB20 or MAB21, each of which is listed in Table 5 in this invention; (b) inhibits CD155 binding to TIGIT; (c) inhibits CD112 binding to TIGIT; (d) inhibits association of CD226 with TIGIT; (e) activates an effector T cell or natural killer (NK) cell; (f) reduces the number of regulatory T cells in tissue or in the bloodstream; (g) inhibits suppression of an effector T cell by a regulatory T cell; (h) does not specifically bind to any of PVRL1, PVRL2, PVRL3 or PVRL4; (i) specifically binds cynomolgus monkey TIGIT (cTIGIT; SEQ ID NO: 2); or (j) binds rodent TIGIT (mTIGIT; SEQ ID NO: 3) with an affinity lower (as indicated by a higher K _D value) than ABP's affinity for hTIGIT, or does not bind mTIGIT. In some embodiments, the inventive ABP has two or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has three or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has four or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has five or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has six or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has seven or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has eight or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has nine or more of the characteristics listed in paragraphs (a)-(j) above. In some embodiments, the inventive ABP has all ten of the characteristics listed in paragraphs (a)-(j) above.

[0220] In some embodiments, the inventive ABP exhibits a combination of the characteristics listed in the following paragraphs (a)-(j): (a) competes for TIGIT binding with an antibody selected from MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB7, MAB8, MAB9, MAB10, MAB1l, MAB12, MAB13, MAB14, MAB15, MAB16, MAB17, MAB18, MAB19, MAB20 or MAB21, each of which is listed in Table 5 in this invention; (b) inhibits CD155 binding to TIGIT; (c) inhibits CD112 binding to TIGIT; (d) inhibits association of CD226 with TIGIT; (e) activates an effector T cell or natural killer (NK) cell; (f) reduces the number of regulatory T cells in tissue or in the bloodstream; (g) inhibits suppression of an effector T cell by a regulatory T cell; (h) does not specifically bind to any of PVRL1, PVRL2, PVRL3 or PVRL4; (i) specifically binds TIGIT cynomolgus monkey TIGIT (cTIGIT; SEQ ID NO: 2); or (j) binds rodent TIGIT (mTIGIT; SEQ ID NO: 3) with an affinity lower (as indicated by a higher K _D value) than ABP's affinity for hTIGIT, or does not bind mTIGIT. In some embodiments, such an ABP exhibits a combination of characteristics selected from (a and b), (a and c), (a and d), (a and e), (a and f), (a and g), ( a and h), (a and i), (a and j), (b and a), (b and c), (b and d), (b and e), (b and f), (b and g), (b and h), (b and i), (b and j), (c and a), (c and b), (c and d), (c and e), (c and f) , (c and g), (c and h), (c and i), (c and j), (d and a), (d and b), (d and c), (d and e), ( d and f), (d and g), (d and h), (d and i), (d and j), (e and a), (e and b), (e and c), (e and d), (e and f), (e and g), (e and h), (e and i), (e and j), (f and a), (f and b), (f and c) , (f and d), (f and e), (f and g), (f and h), (f and i), (f and j), (g and a), (g and b), ( g and c), (g and d), (g and e), (g and f), (g and h), (g and i), (g and j), (h and a), (h and b), (h and c), (h and d), (h and e), (h and f), (h and g), (h and i), (h and j), (i and a) , (i and b), (i and c), (i and d), (i and e), (i and f), (i and g), (i and h), (i and j), ( j and a), (j and b), (j and c), (j and d), (j and e), (j and f), (j and g), (j and h) and (j and i). In some embodiments, such an ABP exhibits a combination of characteristics selected from (a and b and c), (a and b and d), (a and b and e), (a and b and f), (a and b and g), (a and b and h), (a and b and i), (a and b and j), (a and c and b), (a and c and d), (a and c and e) , (a and c and f), (a and c and g), (a and c and h), (a and c and i), (a and c and j), (a and d and b), ( a and d and c), (a and d and e), (a and d and f), (a and d and g), (a and d and h), (a and d and i), (a and d and j), (a and e and b), (a and e and c), (a and e and d), (a and e and f), (a and e and g), (a and e and h), (a and e and i), (a and e and j), (a and f and b), (a and f and c), (a and f and d), (a and f and e) , (a and f and g), (a and f and h), (a and f and i), (a and f and j), (a and g and b), (a and g and c), ( a and g and d), (a and g and e), (a and g and f), (a and g and h), (a and g and i), (a and g and j), (a and h and b), (a and h and c), (a and h and d), (a and h and e), (a and h and f), (a and h and g), (a and h and i), (a and h and j), (a and i and b), (a and i and c), (a and i and d), (a and i and e), (a and i and f) , (a and i and g), (a and i and h), (a and i and j), (a and j and b), (a and j and c), (a and j and d), ( a and j and e), (a and j and f), (a and j and g), (a and j and h), (a and j and i), (b and a and j), (b and a and c), (b and a and d), (b and a and e), (b and a and f), (b and a and g), (b and a and h), (b and a and i), (b and c and j), (b and c and a ), (b and c and d), (b and c and e), (b and c and f), (b and c and g), (b and c and h), (b and c and i), (b and d and j), (b and d and a), (b and d and c), (b and d and e), (b and d and f), (b and d and g), (b and d and h), (b and d and i), (b and e and j), (b and e and a), (b and e and c), (b and e and d), (b and e and f), (b and e and g), (b and e and h), (b and e and i), (b and f and j), (b and f and a), (b and f and c ), (b and f and d), (b and f and e), (b and f and g), (b and f and h), (b and f and i), (b and g and j), (b and g and a), (b and g and c), (b and g and d), (b and g and e), (b and g and f), (b and g and h), (b and g and i), (b and h and j), (b and h and a), (b and h and c), (b and h and d), (b and h and e), (b and h and f), (b and h and g), (b and h and i), (b and i and j), (b and i and a), (b and i and c), (b and i and d ), (b and i and e), (b and i and f), (b and i and g), (b and i and h), (b and j and i), (b and j and a), (b and j and c), (b and j and d), (b and j and e), (b and j and f), (b and j and g), (b and j and h), (c and a and i), (c and a and j), (c and a and b), (c and a and d), (c and a and e), (c and a and f), (c and a and g), (c and a and h), (c and b and i), (c and b and j), (c and b and a), (c and b and d), (c and b and e), (c and b and f), (c and b and g ), (c and b and h), (c and d and i), (c and d and j), (c and d and a), (c and d and b), (c and d and e), (c and d and f), (c and d and g), (c and d and h), (c and e and i), (c and e and j), (c and e and a), (c and e and b), (c and e and d), (c and e and f), (c and e and g), (c and e and h), (c and f and i), (c and f and j), (c and f and a), (c and f and b), (c and f and d), (c and f and e), (c and f and g), (c and f and h ), (c and g and i), (c and g and j), (c and g and a), (c and g and b), (c and g and d), (c and g and e), (c and g and f), (c and g and h), (c and h and i), (c and h and j), (c and h and a), (c and h and b), (c and h and d), (c and h and e), (c and h and f), (c and h and g), (c and i and h), (c and i and j), (c and i and a), (c and i and b), (c and i and d), (c and i and e), (c and i and f), (c and i and g), (c and j and h ), (c and j and i), (c and j and a), (c and j and b), (c and j and d), (c and j and e), (c and j and f), (c and j and g), (d and a and h), (d and a and i), (d and a and j), (d and a and b), (d and a and c), (d and a and e), (d and a and f), ( d and a and g), (d and b and h), (d and b and i), (d and b and j), (d and b and a), (d and b and c), (d and b and e), (d and b and f), (d and b and g), (d and c and h), (d and c and i), (d and c and j), (d and c and a), (d and c and b), (d and c and e), (d and c and f), (d and c and g), (d and e and h), (d and e and i) , (d and e and j), (d and e and a), (d and e and b), (d and e and c), (d and e and f), (d and e and g), ( d and f and h), (d and f and i), (d and f and j), (d and f and a), (d and f and b), (d and f and c), (d and f and e), (d and f and g), (d and g and h), (d and g and i), (d and g and j), (d and g and a), (d and g and b), (d and g and c), (d and g and e), (d and g and f), (d and h and g), (d and h and i), (d and h and j) , (d and h and a), (d and h and b), (d and h and c), (d and h and e), (d and h and f), (d and i and g), ( d and i and h), (d and i and j), (d and i and a), (d and i and b), (d and i and c), (d and i and e), (d and i and f), (d and j and g), (d and j and h), (d and j and i), (d and j and a), (d and j and b), (d and j and c), (d and j and e), (d and j and f), (e and a and g), (e and a and h), (e and a and i), (e and a and j) , (e and a and b), (e and a and c), (e and a and d), (e and a and f), (e and b and g), (e and b and h), ( e and b and i), (e and b and j), (e and b and a), (e and b and c), (e and b and d), (e and b and f), (e and c and g), (e and c and h), (e and c and i), (e and c and j), (e and c and a), (e and c and b), (e and c and d), (e and c and f), (e and d and g), (e and d and h), (e and d and i), (e and d and j), (e and d and a), (e and d and b), (e and d and c ), (e and d and f), (e and f and g), (e and f and h), (e and f and i), (e and f and j), (e and f and a), (e and f and b), (e and f and c), (e and f and d), (e and g and f), (e and g and h), (e and g and i), (e and g and j), (e and g and a), (e and g and b), (e and g and c), (e and g and d), (e and h and f), (e and h and g), (e and h and i), (e and h and j), (e and h and a), (e and h and b), (e and h and c), (e and h and d ), (e and i and f), (e and i and g), (e and i and h), (e and i and j), (e and i and a), (e and i and b), (e and i and c), (e and i and d), (e and j and f), (e and j and g), (e and j and h), (e and j and i), (e and j and a), (e and j and b), (e and j and c), (e and j and d), (f and a and e), (f and a and g), (f and a and h), (f and a and i), (f and a and j), (f and a and b), (f and a and c), (f and a and d), (f and b and e ), (f and b and g), (f and b and h), (f and b and i), (f and b and j), (f and b and a), (f and b and c), (f and b and d), (f and c and e), (f and c and g), (f and c and h), (f and c and i), (f and c and j), (f and c and a), (f and c and b), (f and c and d), (f and d and e), (f and d and g), (f and d and h), (f and d and i), (f and d and j), (f and d and a), (f and d and b), (f and d and c), (f and e and d), (f and e and g), (f and e and h), (f and e and i ), (f and e and j), (f and e and a), (f and e and b), (f and e and c), (f and g and d), (f and g and e), (f and g and h), (f and g and i), (f and g and j), (f and g and a), (f and g and b), (f and g and c), (f and h and d), (f and h and e), (f and h and g), (f and h and i), (f and h and j), (f and h and a), (f and h and b), (f and h and c), (f and i and d), (f and I and e), (f and i and g), (f and i and h), (f and i and j ), (f and i and a), (f and i and b), (f and i and c), (f and j and d), (f and j and e), (f and j and g), (f and j and h), (f and j and i), (f and j and a), (f and j and b), (f and j and c), (g and a and d), (g and a and e), (g and a and f), (g and a and h), (g and a and i), (g and a and j), (g and a and b), (g and a and c), (g and b and d), (g and b and e), (g and b and f), (g and b and h), (g and b and i), (g and b and j ), (g and b and a), (g and b and c), (g and c and d), (g and c and e), (g and c and f), (g and c and h), (g and c and i), (g and c and j) , (g and c and a), (g and c and b), (g and d and c), (g and d and e), (g and d and f), (g and d and h), ( g and d and i), (g and d and j), (g and d and a), (g and d and b), (g and e and c), (g and e and d), (g and e and f), (g and e and h), (g and e and i), (g and e and j), (g and e and a), (g and e and b), (g and f and c), (g and f and d), (g and f and e), (g and f and h), (g and f and i), (g and f and j), (g and f and a) , (g and f and b), (g and h and c), (g and h and d), (g and h and e), (g and h and f), (g and h and i), ( g and h and j), (g and h and a), (g and h and b), (g and i and c), (g and i and d), (g and i and e), (g and i and f), (g and i and h), (g and i and j), (g and i and a), (g and i and b), (g and j and c), (g and j and d), (g and j and e), (g and j and f), (g and j and h), (g and j and i), (g and j and a), (g and j and b) , (h and a and c), (h and a and d), (h and a and e), (h and a and f), (h and a and g), (h and a and i), ( h and a and j), (h and a and b), (h and b and c), (h and b and d), (h and b and e), (h and b and f), (h and b and g), (h and b and i), (h and b and j), (h and b and a), (h and c and b), (h and c and d), (h and c and e), (h and c and f), (h and c and g), (h and c and i), (h and c and j), (h and c and a), (h and d and b) , (h and d and c), (h and d and e ), (h and d and f), (h and d and g), (h and d and i), (h and d and j), (h and d and a), (h and e and b), (h and e and c), (h and e and d), (h and e and f), (h and e and g), (h and e and i), (h and e and j), (h and e and a), (h and f and b), (h and f and c), (h and f and d), (h and f and e), (h and f and g), (h and f and i), (h and f and j), (h and f and a), (h and g and b), (h and g and c), (h and g and d), (h and g and e ), (h and g and f), (h and g and i), (h and g and j), (h and g and a), (h and i and b), (h and i and c), (h and i and d), (h and i and e), (h and i and f), (h and i and g), (h and i and j), (h and i and a), (h and j and b), (h and j and c), (h and j and d), (h and j and e), (h and j and f), (h and j and g), (h and j and i), (h and j and a), (i and a and b), (i and a and c), (i and a and d), (i and a and e), (i and a and f ), (i and a and g), (i and a and h), (i and a and j), (i and b and a), (i and b and c), (i and b and d), (i and b and e), (i and b and f), (i and b and g), (i and b and h), (i and b and j), (i and c and a), (i and c and b), (i and c and d), (i and c and e), (i and c and f), (i and c and g), (i and c and h), (i and c and j), (i and d and a), (i and d and b), (i and d and c), (i and d and e), (i and d and f), (i and d and g ), (i and d and h), (i and d and j), (i and e and a), (i and e and b), (i and e and c), (i and e and d), (i and e and f), (i and e and g) , (i and e and h), (i and e and j), (i and f and a), (i and f and b), (i and f and c), (i and f and d), ( i and f and e), (i and f and g), (i and f and h), (i and f and j), (i and g and a), (i and g and b), (i and g and c), (i and g and d), (i and g and e), (i and g and f), (i and g and h), (i and g and j), (i and h and a), (i and h and b), (i and h and c), (i and h and d), (i and h and e), (i and h and f), (i and h and g) , (i and h and j), (i and j and a), (i and j and b), (i and j and c), (i and j and d), (i and j and e), ( i and j and f), (i and j and g), (i and j and h), (j and a and i), (j and a and b), (j and a and c), (j and a and d), (j and a and e), (j and a and f), (j and a and g), (j and a and h), (j and b and i), (j and b and a), (j and b and c), (j and b and d), (j and b and e), (j and b and f), (j and b and g), (j and b and h) , (j and c and i), (j and c and a), (j and c and b), (j and c and d), (j and c and e), (j and c and f), ( j and c and g), (j and c and h), (j and d and i), (j and d and a), (j and d and b), (j and d and c), (j and d and e), (j and d and f), (j and d and g), (j and d and h), (j and e and i), (j and e and a), (j and e and b), (j and e and c), (j and e and d), (j and e and f), (j and e and g), (j and e and h), (j and f and i), (j and f and a), (j and f and b) , (j and f and c), (j and f and d), (j and f and e), (j and f and g), (j and f and h), (j and g and i), ( j and g and a), (j and g and b), (j and g and c), (j and g and d), (j and g and e), (j and g and f), (j and g and h), (j and h and i), (j and h and a), (j and h and b), (j and h and c), (j and h and d), (j and h and e), (j and h and f), (j and h and g), (j and i and h), (j and i and a), (j and i and b), (j and i and c) , (j and i and d), (j and i and e), (j and i and f) and (j and i and g).

2.3. Embryonic configurations

[0221] Proposed in the invention ABPs may include any suitable germline configuration V _H and V _L sequences.

[0222] In some embodiments, the V _H region of the inventive ABP is derived from the VH4 germline configuration. In some embodiments, the V _H region of the inventive ABP is derived from the VH1 germline configuration.

[0223] In some embodiments, the V _H region of the inventive ABP is derived from the VH4-39 germline configuration. In some embodiments, the V _H region of the inventive ABP is derived from the VH4-3 germline configuration. In some embodiments, the V _H region of the inventive ABP is derived from the VH1-46 germline configuration.

[0224] In some embodiments, the V _L region of the inventive ABP is derived from the VK3 germline configuration.

[0225] In some embodiments, the V _L region of the inventive ABP is derived from the VK3-11 germline configuration. In some embodiments, the V _L region of the inventive ABP is derived from the VK3-20 germline configuration. In some embodiments, the V _L region of the inventive ABP is derived from the VK3-15 germline configuration.

[0226] Table 5. Sequences and germline configurations (GL) of TIGIT ABPs.

¹ Includes CDR-H1 defined by both Chothia and Kabat numbering systems, including the boundaries of both numbering systems.

² According to the Kabat numbering system.

³ According to the IMGT numbering system.

⁴ According to the Kabat and Chothia numbering systems.

⁵ According to the Kabat and Chothia numbering systems.

⁶ According to the Kabat, Chothia and IMGT numbering systems.

2.4. Antagonistic action against TIGIT

[0227] In some embodiments, the ABPs of the invention antagonize TIGIT by binding.

[0228] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT causes dimerization and/or activation of CD226 (also referred to as DNAM-1), a costimulatory receptor whose dimerization and function is impaired by direct interaction with TIGIT. See Grogan et al., J Immunol., 2014, 192 (1 Supplement) 2013.15, the contents of which are incorporated herein by reference.

[0229] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT increases the number of interacting CD226 and CD155, compared to the amount that interacts in the absence of ABP.

[0230] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT causes the activation of an effector T cell. In some aspects, the effector T cell is a CD8+ T cell. In some aspects, the effector T cell is a CD4+ T cell.

[0231] In some embodiments, In some embodiments, the antagonistic effect of the inventive ABP against TIGIT causes NK cell activation. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT causes activation of the NKT cell.

[0232] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT causes a decrease in the inhibitory activity of the regulatory T cell against the effector T cell.

[0233] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT causes an increase in the secretion of IL-2, IL-6, GM-CSF, TNF, LT-α and/or IFN-γ by the target cell.

[0234] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT increases the proliferation, survival and/or function of the effector T cell. In some aspects, the effector T cell is a CD4+ effector T cell. In some aspects, the effector T cell is a CD8+ effector T cell.

[0235] In some embodiments, the antagonistic action of the inventive ABP against TIGIT abolishes the suppression of the effector T cell by the regulatory T cell. In some aspects, the regulatory T cell is a CD4+CD25+Foxp3+ regulatory T cell. In some aspects, the regulatory T cell is a CD8+CD25+ regulatory T cell.

[0236] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT causes an increase in the immune response.

[0237] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in the prevention of tumor initiation. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in a delay in the onset of a tumor. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in a reduction in tumor size. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in elimination of the tumor. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in a reduction in the number of metastases.

[0238] In some embodiments, the antagonistic effect of the inventive ABP against TIGIT prevents a viral disease. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in a delay in the onset of the viral disease. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in a reduction in the subject's viral load. In some embodiments, the antagonistic effect of the inventive ABP against TIGIT results in elimination of the viral infection.

2.5. Affinity and kinetics of antigen-binding proteins for TIGIT; activity

[0239] In some embodiments, the affinity of the inventive ABP for TIGIT is measured using the methods disclosed in the Examples section of International Publication No. WO/2017/059095 and US Patent No. 9713641, the contents of which are incorporated into the present invention by reference. In some embodiments, the affinity of the inventive ABP for TIGIT, as measured by K _D , is less than about 10 ^-5 M, less than about 10 ^-6 M, less than about 10 ^-7 M, less than about 10 ^{- 8} M, less than about 10 ^-9 M, less than about 10 ^-10 M, less than about 10 ^-11 M, or less than about 10 ^{-12 M.} up to 10 ^-12 M. In some embodiments, the ABP affinity is defined as from about 10 ^-7 M to 10 ^-11 M. In some embodiments, the ABP affinity is defined as from about 10 ^-7 M to 10 ^-10 M. In some embodiments, ABP affinity is defined as about 10 ^-7 M to about 10 ^-9 M. In some embodiments, ABP affinity is defined as about 10 ^-7 M to about 10 ^-8 M. In some embodiments, ABP affinity is defined as between about 10 ^-8 M and 10 ^-12 M. In some embodiments, ABP affinity is defined as between about 10 ^-8 M and 10 ^-11 M. In some embodiments, ABP affinity is defined as about 10 ^-9 M to 10 ^-11 M. In some embodiments, the ABP affinity is defined as about 10 ^-10 M to 10 ^-11 M.

[0240] In some embodiments, the affinity of the inventive ABP for hTIGIT, as measured by the K _D value measured using the ForteBio system, is selected from about 5.24 x 10 ^-10 M, about 4.57 x 10 ^-10 M , approximately 3.32×10 ^-10 M, approximately 2.46×10 ^-10 M, approximately 1.96×10 ^-10 M, approximately 3.11×10 ^-9 M, approximately 2.54×10 ^-9 M , approximately 3.13×10 ^-9 M, approximately 2.83×10 ^-9 M, approximately 1.71×10 ^-9 M, approximately 2.47×10 ^-9 M, approximately 2.35×10 ^-9 M , approximately 1.44×10 ^-9 M, approximately 1.23×10 ^-9 M, approximately 5.26×10 ^-10 M, approximately 3.78×10 ^-10 M, approximately 4.29×10 ^-10 M or about 4.48×10 ^-10 M. In some embodiments, this affinity is a value in the range from about 3.13×10 ^-9 M to about 1.96×10 ^-10 M. In some embodiments, such a value K _D is approximately 3.13×10 ^-9 M or less.

[0241] In some embodiments, the affinity of the inventive ABP for cTIGIT, as measured by the K _D value measured using the ForteBio system, is selected from about 2.64 x 10 ^-9 M, about 6.55 x 10 ^-9 M , approximately 8.14×10 ^-9 M, approximately 6.57 × 10 ^-9 M, approximately 7.94 × 10 ^-8 M, approximately 7.04 × 10 ^-8 M, approximately 1.10 × 10 ^-7 M , approximately 7.20×10 ^-8 M, approximately 1.57×10 ^-9 M, approximately 8.02×10 ^-10 M, approximately 3.67×10 ^-10 M, approximately 8.98×10 ^-10 M , approximately 1.75×10 ^-8 M or approximately 2.58×10 ^-8 M, approximately 9.35×10 ^-9 M. In some embodiments, this affinity is in the range of approximately 1.10×10 ^{- 7} M to about 3.69 x 10 ^-10 M. In some embodiments, this K _D value is about 1.10 x 10 ^-7 M or less.

[0242] In some embodiments, the affinity of the inventive ABP for hTIGIT, as measured by the K _D value measured by solution equilibrium methods (MSD-SET), is selected from about 5.40 x 10 ^-11 M, about 1, 10 x 10 ^-10 M, approx. 1.50 x 10 ^-10 M, approx. 5.60 x 10 ^-11 M, approx. 4.00 x ^{10 -10} M, approx. 10×10 ^-10 M, approximately 7.00×10 ^-11 M, approximately 4.10×10 ^-11 M, approximately 2.50×10 ^-11 M, approximately 3.00×10 ^-11 M, approximately 8, 00 x 10 ^-11 M, about 8.10 x 10 ^-12 M, about 5.00 x 10 ^-12 M, or about 4.90 x 10 ^-12 M. In some embodiments, such affinity is in the range of about 4.00 x 10 ^-10 M to about 4.90 x 10 ^-12 M. In some embodiments, this K _D value is about 4.00 x 10 ^-10 M or less.

[0243] In some embodiments, the affinity of the inventive ABP for cTIGIT, as measured by the K _D value measured by the MSD-SET method, is selected from about 3.20 x 10 ^-10 M, about 2.30 x 10 ^-10 M , about 3.50 x 10 ^-11 M, about 1.50 x 10 ^-11 M, or about 4.60 x 10 ^-11 M. In some embodiments, this affinity is in the range of about 3.20 x 10 ^{- 10} M to about 1.50×10 ^-11 M. In some embodiments, this K _D value is about 3.20×10 ^-10 M or less.

[0244] In some embodiments, the affinity of the inventive ABP for hTIGIT, as measured by the K _D value measured using the ForteBio system, is selected from about 7.1 x 10 ^-10 M, about 8.1 x 10 ^-10 M , approximately 1.9× ^10–10 M, approximately 5.6× ^10–10 M, approximately 2.4× ^10–10 M, approximately 2.8× ^10–10 M, approximately 1.6× ^10–10 M , approximately 5.8× ^10–10 M, approximately 1.1× ^10–9 M, approximately 8.1× ^10–10 M, approximately 4.6× ^10–10 M, or approximately 3.6× ^10–10 M In some embodiments, this affinity is in the range of about 1.1 x 10 ^-9 M to about 8.1 x 10 ^-11 M. In some embodiments, this K _D is about 1.1 x 10 ^{- 9M} or less.

[0245] In some embodiments, the affinity of the inventive ABP for hTIGIT, as measured by the K _D value measured using the ForteBio system, is approximately 2.4×10 ^-10 M. In some embodiments, the affinity of the inventive ABP in relation to cTIGIT, which is estimated by the K _D value measured using the ForteBio system, is approximately 6.2×10 ^-9 M. In some embodiments, the implementation, such a K _D value is approximately 6.2×10 ^-9 M or less.

[0246] In some embodiments, the affinity of the inventive ABP for hTIGIT expressed on the surface of Jurkat cells, as estimated by a K _D value, is approximately 5.1 x 10 ^-10 M. In some embodiments, this K _D value is approximately 5.1×10 ^-10 M or less.

[0247] In some embodiments, the affinity of the inventive ABP for cTIGIT expressed on the surface of Jurkat cells, as estimated by the K _D value, is approximately 4.0×10 ^-10 M. In some embodiments, the K _D value is approximately 4.0×10 ^-10 M or less.

[0248] In some embodiments, the affinity of the inventive ABP for mTIGIT (SEQ ID NO: 3) expressed on the surface of Jurkat cells, as measured by the K _D value, is approximately 9.8 x 10 ^-9 M. In some embodiments, implementation, such a value of K _D is approximately 9.8×10 ^-9 M or less. In some embodiments, such a K _D value is approximately 9.8×10 ^-9 M or more.

[0249] In some embodiments, the affinity of the inventive ABP for hTIGIT expressed on the surface of human CD8+ T cells, which is estimated by a K _D value, is approximately 1.3×10 ^-9 M. In some embodiments, such a value K _D is approximately 1.3×10 ^-9 M or less.

[0250] In some embodiments, the affinity of the inventive ABP for cTIGIT expressed on the surface of cynomolgus CD8+ T cells, as measured by a K _D value, is approximately 2.8 x 10 ^-9 M. In some embodiments, such the value of K _D is approximately 2.8×10 ^-9 M or less.

[0251] In some embodiments, the affinity of the inventive ABP for mTIGIT expressed on the surface of rodent regulatory T cells (i.e., for mTIGIT naturally present on such cells, whether or not such mTIGIT has the sequence SEQ ID NO: 3 or 138, or not, but including such sequences SEQ ID Nos), which is estimated by the value of K _D is approximately 2.5×10 ^-3 M. In some embodiments, such a K _D value is approximately 2, 5×10 ^-3 M or less.

[0252] In some embodiments, the inventive ABPs specifically bind to hTIGIT (SEQ ID NO: 1) with a K _D value of X and cTIGIT (SEQ ID NO: 2) or mTIGIT (SEQ ID NO: 3 or 138) with a K _D value of ≤10X. In some embodiments, the inventive ABPs specifically bind to hTIGIT (SEQ ID NO: 1) with a K _D value of X and cTIGIT (SEQ ID NO: 2) or mTIGIT (SEQ ID NO: 3 or 138) with the value of K _D component ≤5X. In some embodiments, the inventive ABPs specifically bind to hTIGIT (SEQ ID NO: 1) with a K _D value of X and to cTIGIT (SEQ ID NO: 2) or mTIGIT (SEQ ID NO: 3 or 138) with the value of K _D component ≤2X. In some aspects, X is any value of K _D described in this invention. In some aspects, X is 0.01 nM, 0.1 nM, 1 nM, 10 nM, 20 nM, 50 nM, or 100 nM.

[0253] In some embodiments, the K _D(hTIGIT) : K _{D(cTIGIT) ratio} for the inventive ABP, as measured by the ForteBio system, is selected from about 1.98 x 10 ^-1 , about 2.61 x 10 ^{- 1} , approximately 3.03×10 ^-1 , approximately 3.58×10 ^-1 , approximately 6.62×10 ^-3 , approximately 1.98 × 10 ^-1 , approximately 5.37 × 10 ^-3 , approximately 3, 90× ^10–3 , approximately 6.22× ^10–3 , approximately 2.91× ^10–1 , approximately 4.14× ^10–1 , approximately 6.67× ^10–1 , approximately 2.18× ^10–1 , about 1.78 x 10 ^-1 , about 1.21 x 10 ^-1 or about 3.03 x 10 ^-1 . In some embodiments, this ratio is in the range of about 3.90×10 ^-3 to about 6.67×10 ^-1 .

[0254] In some embodiments, the K _D(hTIGIT) : K _{D(cTIGIT) ratio} for the inventive ABP, as measured by the ForteBio system, is approximately 3.87 x 10 ^-2 .

0255] In some embodiments, the K _D(hTIGIT) : K _{D(cTIGIT) ratio} for the inventive ABP measured by MSD-SET is selected from about 3.33x10 ^-1 , about 2.31x10 ^-1 , approximately 1.09×10 ^-1 , approximately 1.07×10 ^-1 , or approximately 1.69×10 ^-1 . In some embodiments, this ratio is in the range of about 1.07×10 ^-1 M to about 3.33×10 ^-1 M.

[0256] In some embodiments, the inventive ABP has an order of magnitude k _a of at least about 10 ⁴ M ^-1 x sec ^-1 . In some embodiments, the ABP is of the order of magnitude k _a of at least [

approximately 10 ⁵ M ^–1 x sec ^–1 . In some embodiments, the ABP has an order of magnitude k _a of at least about 10 ⁶ M ^-1 x sec ^-1 . In some embodiments, ABP has an order of magnitude k _a ranging from about 10 ⁴ M ^-1 x sec ^-1 to about 10 ⁵ M ^-1 x sec ^-1 . In some embodiments, the ABP has an order of magnitude k _a ranging from about 10 ⁵ M ^-1 x sec ^-1 to about 10 ⁶ M ^-1 x sec ^-1 . In some embodiments, this order of magnitude of k _a is at least about 10 ⁵ M ^-1 x sec ^-1 .

[0257] In some embodiments, the inventive ABP has a k _a value for hTIGIT, as measured by the ForteBio system, selected from approximately 3.2×10 ⁵ M ⁻¹ × sec ⁻¹ , approximately 7.0×10 ⁵ M ^–1 × sec ^{–1 ,} approx. 7.7× ^{10 5 M –1} × sec ^{–1 , approx . 1} , approximately 1.3×10 ⁶ M ^-1 × s ^-1 , approximately 1.5 × 10 ⁶ M ^-1 × s ^-1 , approximately 1.1 × 10 ⁶ M ^-1 × s ^-1 , approximately 4, ⁵ ×10 ^{5 M -1 x sec -1 , approx . –1} × sec ^–1 . In some embodiments, such a value of k _a ranges from about 3.2x10 ⁵ M ^-1 x sec ^-1 to about 2.0 x 10 ⁶ M ^-1 x sec ^-1 . In some embodiments, the implementation, such a value of k _a is approximately 2.0×10 ⁶ M or less.

[0258] In some embodiments, the inventive ABP has a k _a value for hTIGIT, as measured by the ForteBio system, of approximately 2.0×10 ⁶ M– ¹ ×sec– ¹ . In some embodiments, such a value of k _a is at least about 2.0×10 ⁶ M ^-1 * sec ^-1 .

[0259] In some embodiments, the inventive ABP has a cTIGIT k _a value, as measured by the ForteBio system, of approximately 7.9×10 ⁵ M– ¹ ×sec– ¹ . In some embodiments, such a value of k _a is at least about 7.9×10 ⁵ M ^-1 * sec ^-1 .

[0260] In some embodiments, the inventive ABP has a k _d value of approximately 10 ^-5 sec ^-1 or less. In some embodiments, the ABP has a k _d value of approximately 10 ^-4 sec ^-1 or less. In some embodiments, the ABP has a k _d value of approximately 10 ^-3 sec ^-1 or less. In some embodiments, the ABP has a k _d value ranging from about 10 ^-2 sec ^-1 to about 10 ^-5 sec ^-1 . In some embodiments, the ABP has a k _d value ranging from about 10 ^-2 sec ^-1 to about 10 ^-4 sec ^-1 . In some embodiments, the ABP has a k _d value ranging from about 10 ^-3 sec ^-1 to about 10 ^-5 sec ^-1 .

[0261] In some embodiments, the inventive ABP has a k _d value for hTIGIT, as measured by the ForteBio system, selected from about 2.3x10 ^-4 sec ^-1 , about 6.3x10 ^-5 sec ^-1 , approximately 1.4×10 ^-4 s ^-1 , approximately 8.5 × 10 ^-4 s ^-1 , approximately 3.8 × 10 ^{-4 s -1 ,} approximately 2.4 x 10 ^-4 sec ^-1 , about 6.6 x 10 ^-4 sec ^-1 , about 5.9 x 10 ^-4 sec ^-1 or about 5.0 x 10 ^-4 sec ^-1 . In some embodiments, such k _d value is in the range from about 6.3×10 ^-5 sec ^-1 to about 8.5 x 10 ^-4 sec ^-1 . In some embodiments, this k _d value is less than approximately 8.5×10 ^-4 sec ^-1 .

[0262] In some embodiments, the inventive ABP has a k _d value for hTIGIT, as measured by the ForteBio system, of approximately 3.8 x 10 ^-4 sec ^-1 . In some embodiments, this k _d value is less than approximately 3.8×10 ^-4 sec ^-1 .

[0263] In some embodiments, the inventive ABP has a cTIGIT k _d value, as measured by the ForteBio system, of approximately 4.6 x 10 ^-3 sec ^-1 . In some embodiments, this k _d value is less than approximately 4.6×10 ^-3 sec ^-1 .

[0264] In some embodiments, the inventive ABP has a k _a value for hTIGIT of approximately 3.2×10 ⁵ M ⁻¹ x sec ⁻¹ , a k _d for hTIGIT value of approximately 2.3×10 ⁻⁴ sec ⁻¹ , and a K _D value for hTIGIT of approximately 7.1×10 ^-10 M. In some embodiments, the inventive ABP has a k _a value for hTIGIT of approximately 7.0×10 ⁵ M ^-1 x sec ^-1 , a k _d value for hTIGIT approximately 6.3×10 ^-5 sec ^-1 and a K _D value for hTIGIT approximately 8.1×10 ^-11 M. In some embodiments, ABP has a k _a value for hTIGIT approximately 7.7×10 ⁵ M ^-1 × sec ^-1 , a k _d value for hTIGIT of approximately 1.4×10 ^-4 sec ^-1 , and a K _D value for hTIGIT of approximately 1.9×10 ^-10 M. In some embodiments, the inventive ABP has a value of k _a ^{for hTIGIT approx} _. ^{_ _} _{_} ^_ some options embodiment, the inventive ABP has a k _a value for hTIGIT of approximately 2.0×10 ⁶ M– ¹ ×s– ¹ , a k _d value for hTIGIT of approximately 3.8× ^10–4 s– ¹ , and a K _D value for hTIGIT of approximately 2.4×10 ^-10 M. In some embodiments, the inventive ABP has a k _a value for hTIGIT of approximately 1.3×10 ⁶ M ^-1 × sec ^-1 , a k _d value for hTIGIT of approximately 3.5×10 ^-4 sec ^-1 and a K _D value for hTIGIT of approximately 2.8×10 ^-10 M. In some embodiments, the inventive ABP has a k _a value for hTIGIT of approximately 1.5×10 ⁶ M ^-1 x sec ^-1 , a k _d value for hTIGIT of approximately 2.4×10 ^-4 sec ^-1 and a K _D value for hTIGIT of approximately 1.6×10 ^-10 M. In some embodiments, an inventive ABP has a k _a value for hTIGIT of approximately 1 ,1×10 ⁶ M ^–1 x sec ^–1 , the k _d value for hTIGIT is approximately 6.6 × 10 ^–4 sec ^–1 and the K _D value for hTIGIT is approximately 5.8 × 10 ^–10 M. In some implementations, The inventive ABP has a k _a value for hTIGIT of approximately 4.5×10 ⁵ M– ¹ ×s– ¹ , a k _d value for hTIGIT of approximately 3.5× ^10–4 s– ¹ , and a K _D value for hTIGIT of approximately 1.1×10 ^-9 M. In some embodiments, the inventive ABP has a k _a value for hTIGIT of approximately 7.5×10 ⁵ M ^-1 × sec ^-1 , a k _d value for hTIGIT of approximately 5.9×10 ^-4 sec ^-1 and a K _D value for hTIGIT of approximately 8.1×10 ^-10 M. In some embodiments, the inventive ABP has a k _a value for hTIGIT of approximately 8.9×10 ⁵ M ^-1 × sec ^-1 , a k _d value for hTIGIT of approximately 3.8×10 ^-4 sec ^-1 and a K _D value for hTIGIT of approximately 4.6×10 ^-10 M. In some embodiments, an inventive ABP has a k _a value for hTIGIT of approximately 1 .4x10 ⁶ M ^-1 x sec ^-1 , the k _d value for hTIGIT is about 5.0 x 10 ^-4 sec ^-1 , and the K _D value for hTIGIT is about 3.6 x 10 ^-10 M. In some embodiments, However, such values of k _a , k _d and K _D are determined by the methods described, for example, in example 6 of US Patent No. 9713641.

[0265] In some embodiments, the inventive ABP has a k _a value for hTIGIT of approximately 2.0×10 ⁶ M ⁻¹ × sec ⁻¹ , a k _d value for hTIGIT of approximately 3.8 × 10 ⁻⁴ sec ⁻¹ , K _D value for hTIGIT approximately 2.4×10 ^–10 M, ka value for _cTIGIT approximately 7.9 × 10 ⁵ M ^–1 × s ^–1 , k _d value for cTIGIT approximately 4.6 × 10 ^–3 s ^{– 1} , a K _D value for cTIGIT of about 6.2×10 ^-9 M, and a K _D value for mTIGIT (SEQ ID NO: 3) greater than about 7.0×10 ^-7 M. In some embodiments, such values of k _a , k _d and K _D are determined by the methods described, for example, in Example 6 of US Patent No. 9713641.

[0266] In some embodiments, the implementation, the values of K _D , ka and k _d determined by the method of surface plasmon resonance ₍ SPR). In some aspects, the SPR analysis is performed on a ^BIACORE® instrument. In some aspects, the antigen is immobilized on a biosensor chip coated with a layer of carboxylated dextran (CM4 or CM5) and contacted with the inventive ABP. Association and dissociation rate constants can be calculated using BIAevaluation® software and a Langmuir model for 1:1 binding. In some aspects, the study is carried out at 25°C. In some aspects, the study is carried out at 37°C.

[0267] In some embodiments, the implementation, the values of K _D , ka and k _d determined by the method of biolayer interferometry ₍ BLI). Any suitable BLI method may be used. In some aspects, the BLI analysis is performed on a ^FORTEBIO® instrument. In some aspects, a biosensor with immobilized anti-IgG Fc (AHC) antibodies is used to capture ABPs on the sensor surface. The association of ABP and antigen is then monitored by contacting the immobilized ABP with various concentrations of TIGIT. Then measure the dissociation of the antigen and ABP in buffer without TIGIT. Association and dissociation rate constants are calculated using Analysis Software ^FORTEBIO® kinetic modules. In some aspects, the study is carried out at 30°C.

[0268] In other embodiments, the K _D value can be determined by the radiolabeled antigen binding assay described in Chen et al. J Mal. Biol., 1999, 293:865-881, the contents of which are incorporated herein by reference.

[0269] In other embodiments, the K _D value may be determined by the MSD-SET method described, for example, in Example 4 of US Patent No. 9713641.

[0270] In some embodiments, the inventive ABP has an EC ₅₀ value as measured by the human TIGIT co-cultivation study of IL-2 production and the Jurkat T cell line, as described, for example, in Example 7 of US Patent No. 9713641, approximately 0.22 nM, approximately 0.31 nM, approximately 0.33 nM, approximately 0.34 nM, approximately 0.25 nM, approximately 0.24 nM, approximately 0.11 nM, approximately 0.06 nM, approximately 0.14 nM, approximately 0.16 nM, approximately 1.40 nM, approximately 0.71 nM, approximately 0.21 nM, approximately 1.11 nM, approximately 0.13 nM, approximately 0.20 nM, approximately 0 .68 nM or approximately 0.61 nM. In some embodiments, this EC ₅₀ value is in the range of about 0.06 nM to about 1.40 nM. In some embodiments, this EC ₅₀ value is about 1.40 nM or less.

[0271] In some embodiments, the inventive ABP has an EC ₅₀ value, as measured by the co-cultured IL-2 production assay of cynomolgus monkey TIGIT and the Jurkat T cell line, of approximately 2.87 nM. In some embodiments, this EC ₅₀ value is about 2.87 nM or less. In some embodiments, the value of the ratio EC _{50 (cTIGIT)} : EC _{50 (hTIGIT)} in such a study is in the range from about 2.05 to about 47.8.

[0272] In some embodiments, the inventive ABP has an EC ₁₀ value as measured by TNF production in peripheral blood mononuclear cells (PBMCs) isolated from a human donor and treated as described, for example, in Example 9 of the US Patent document. no. 9713641, ranging from about 5.02 nM to about 18.86 nM. In some embodiments, this EC ₁₀ value is about 18.86 nM or less.

[0273] In some embodiments, the inventive ABP has an EC ₅₀ value, as measured by TNF production in PBMCs isolated from a human donor, ranging from about 12.60 nM to about 20.60 nM. In some embodiments, this EC ₅₀ value is about 20.60 nM or less.

[0274] In some embodiments, the inventive ABP has an EC ₉₀ value, as measured by TNF production in PBMCs isolated from a human donor, ranging from about 22.49 nM to about 31.59 nM. In some embodiments, this EC ₅₀ value is approximately 31.59 nM or less.

[0275] In some embodiments, the inventive ABP has an EC ₁₀ value in the range of about 5.02 nM to about 18.86 nM, an EC ₅₀ value in the range of about 12.60 nM to about 20.60 nM, and an EC ₉₀ value ranging from about 22.49 nM to about 31.59 nM, in each case measured by TNF production in PBMCs isolated from a human donor.

[0276] In some embodiments, the inventive ABP has an EC ₁₀ value of about 11.94 nM or less, an EC ₅₀ value of about 16.60 nM or less, and an EC ₉₀ value of about 27.04 nM or less, in each case measured by TNF production in PBMCs isolated from a human donor.

[0277] In some embodiments, the inventive ABP has an EC ₁₀ value of about 18.86 nM or less, an EC ₅₀ value of about 20.06 nM or less, and an EC ₉₀ value of about 31.59 nM or less, in each case measured by TNF production in PBMCs isolated from a human donor.

[0278] In some embodiments, the inventive ABP has an EC ₁₀ value of about 5.02 nM or less, an EC ₅₀ value of about 12.60 nM or less, and an EC ₉₀ value of about 22.49 nM or less, in each case measured by TNF production in PBMCs isolated from a human donor.

[0279] In some embodiments, the inventive ABP has an EC ₁₀ value, as measured by IFN-γ production in CD4+ T cells isolated from a human donor, in the range of about 0.37 nM to about 1.05 nM. In some embodiments, this EC ₁₀ value is about 1.05 nM or less.

[0280] In some embodiments, the inventive ABP has an EC ₅₀ value, as measured by IFN-γ production in CD4+ T cells isolated from a human donor, in the range of about 0.94 nM to about 1.12 nM. In some embodiments, this EC ₅₀ value is about 1.12 nM or less.

[0281] In some embodiments, the inventive ABP has an EC ₉₀ value, as measured by IFN-γ production in CD4+ T cells isolated from a human donor and treated as described in Example 9, ranging from about 1.04 nM to about 2.72 nM. In some embodiments, this EC ₉₀ value is about 2.72 nM or less.

[0282] In some embodiments, the inventive ABP has an EC ₁₀ value ranging from about 0.37 nM to about 1.05 nM, an EC ₅₀ value ranging from about 0.94 nM to about 1.12 nM, and the value of EC ₉₀ in the range from about 1.04 nm to about 2.72 nm, in each case, measured by the production of IFN-γ in PBMCs isolated from a human donor.

[0283] In some embodiments, the inventive ABP has an EC ₁₀ value of about 0.37 nM or less, an EC ₅₀ value of about 1.00 nM or less, and an EC ₉₀ value of about 2.72 nM or less, in each case measured by IFN-γ production in PBMCs isolated from a human donor.

[0284] In some embodiments, the inventive ABP has an EC _{10 of} about 0.85 nM or less, an EC _{50 of} about 0.94 nM or less, and an EC _{90 of} about 1.04 nM or less, in each case measured by IFN-γ production in PBMCs isolated from a human donor.

[0285] In some embodiments, the inventive ABP has an EC _{10 of} about 1.05 nM or less, an EC _{50 of} about 1.12 nM or less, and an EC _{90 of} about 1.19 nM or less, in each case measured by IFN-γ production in PBMCs isolated from a human donor.

[0286] In some embodiments, the inventive ABP has an EC _{10 of} about 0.75 nM or less, an EC _{50 of} about 1.02 nM or less, and an EC _{90 of} about 1.65 nM or less, in each case measured by IFN-γ production in PBMCs isolated from a human donor.

[0287] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 5.24×10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 2.64 × 10 ^-9 M (determined by the ForteBio method). ForteBio), hTIGIT with a K _D value of approximately 5.40×10 ^-11 M (determined by the MSD-SET method) and cTIGIT with a K _D value of approximately 3.20 × 10 ^-10 M (determined by the MSD-SET method).

[0288] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 4.57×10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 1.57 × 10 ^-9 M (determined by the ForteBio method). ForteBio), hTIGIT with a K _D value of approximately 2.50×10 ^-11 M (determined by the MSD-SET method) and cTIGIT with a K _D value of approximately 2.30×10 ^-10 M (determined by the MSD-SET method).

[0289] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 3.32×10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 8.02 × 10 ^-10 M (determined by the ForteBio), hTIGIT with a K _D value of approximately 8.10×10 ^-12 M (determined by the MSD-SET method) and cTIGIT with a K _D value of approximately 3.50 × 10 ^-1 M (determined by the MSD-SET method).

[0290] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 2.46 x 10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 3.69 x 10 ^-10 M (determined by the ForteBio method). ForteBio), hTIGIT with a K _D value of approximately 5.00×10 ^-12 M (determined by the MSD-SET method) and cTIGIT with a K _D value of approximately 1.50 × 10 ^-11 M (determined by the MSD-SET method).

[0291] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 1.96 x 10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 8.98 x 10 ^-10 M (determined by the ForteBio method). ForteBio), hTIGIT with a K _D value of approximately 4.90×10 ^-12 M (determined by the MSD-SET method) and cTIGIT with a K _D value of approximately 4.60 × 10 ^-11 M (determined by the MSD-SET method).

[0292] In some embodiments, the inventive ABP binds hTIGIT with a K _D value of approximately 3.11 x 10 ^-9 M (determined by the ForteBio method) and cTIGIT with a K _D value of approximately 1.75 x 10 ^-5 M (determined by the ForteBio).

[0293] In some embodiments, the inventive ABP binds hTIGIT to a K _D value of approximately 2.54×10 ^-9 M as determined by the ForteBio method.

[0294] In some embodiments, the inventive ABP binds hTIGIT with a K _D value of approximately 3.13×10 ^-9 M (determined by the ForteBio method) and cTIGIT with a K _D value of approximately 2.58 × 10 ^-8 M (determined by the ForteBio).

[0295] In some embodiments, the inventive ABP binds hTIGIT with a K _D value of approximately 2.83×10 ^-9 M (determined by the ForteBio method) and cTIGIT with a K _D value of approximately 9.35×10 ^-9 M (determined by the ForteBio).

[0296] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 1.71 x 10 ^-9 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 6.55 x 10 ^-9 M (determined by the ForteBio method). ForteBio) and hTIGIT with a K _D value of approximately 1.10×10 ^-10 M (determined by the MSD-SET method).

[0297] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 2.47×10 ^-9 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 8.14 × 10 ^-9 M (determined by the ForteBio) and hTIGIT with a K _D value of approximately 1.50×10 ^-10 M (determined by the MSD-SET method).

[0298] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 2.35×10 ^-9 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 6.57 × 10 ^-9 M (determined by the ForteBio method). ForteBio) and hTIGIT with a K _D value of approximately 5.60×10 ^-11 M (determined by the MSD-SET method).

[0299] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 1.44 x 10 ^-9 M (determined by the ForteBio method) and hTIGIT with a K _D value of approximately 4.00 x 10 ^-10 M (determined by the MSD-SET).

[0300] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 1.23×10 ^-9 M (determined by the ForteBio method) and hTIGIT with a K _D value of approximately 3.80 × 10 ^-10 M (determined by the MSD-SET).

[0301] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 5.26×10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 7.94 × 10 ^-8 M (determined by the ForteBio) and hTIGIT with a K _D value of approximately 2.10×10 ^-10 M (determined by the MSD-SET method).

[0302] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 3.78 x 10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 7.04 x 10 ^-8 M (determined by the ForteBio method). ForteBio) and hTIGIT with a K _D value of approximately 7.00×10 ^-11 M (determined by the MSD-SET method).

[0303] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 4.29 x 10 ^-10 M (determined by the ForteBio method), cTIGIT with a K _D value of approximately 1.10 x 10 ^-7 M (determined by the ForteBio method). ForteBio) and hTIGIT with a K _D value of approximately 4.10×10 ^-11 M (determined by the MSD-SET method).

[0304] In some embodiments, the inventive ABP associates hTIGIT with a K _D value of approximately 4.48 x 10 ^-10 M (determined by the ForteBio method) and cTIGIT with a K _D value of approximately 7.20 x 10 ^-8 M (determined by the ForteBio method) ForteBio).

[0305] In some embodiments, the inventive ABP binds hTIGIT with a K _D value of approximately 3.00 x 10 ^-11 M.

[0306] In some embodiments, the inventive ABP binds hTIGIT with a K _D value of approximately 8.00 x 10 ^-11 M.

[0307] In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of about 2.2 nM, about 2.3 nM, about 1.6 nM, about 1.9 nM, about 1.7 nM , approximately 3.2 nM, approximately 2.6 nM, approximately 2.9 nM, approximately 3.3 nM, approximately 2 nM, approximately 2.2 nM, approximately 2.1 nM, approximately 1.8 nM, approximately 6, 4 nM or approximately 1 nM. In some embodiments, this IC ₅₀ value is in the range of about 1 nM to about 6.4 nM. In some embodiments, this IC ₅₀ value is about 6.4 nM or less. In some embodiments, this IC ₅₀ value is determined as described in Example 5 of US Patent No. 9713641.

[0308] In some embodiments, the inventive ABP inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of about 1.4 nM, about 1.3 nM, about 1.2 nM, about 1.6 nM, about 2 nM, about 1.2 nM, about 1.1 nM, about 1 nM, about 1.8 nM, about 1.9 nM, about 2 nM, or about 0.8 nM. In some embodiments, this IC ₅₀ value is in the range of about 0.8 nM to about 2 nM. In some embodiments, this IC ₅₀ value is about 2 nM or less.

[0309] In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.2 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.4 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.3 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.3 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 1.6 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.2 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 1.9 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.6 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 1.7 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.4 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 3.2 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.4 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.6 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 2 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.9 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.2 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 1.9 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.1 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 3.3 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.2 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 1.7 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.2 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.1 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.8 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.6 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.6 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.2 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.1 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.1 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.3 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.6 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.9 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 1.8 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.9 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 6.4 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 2 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 2.3 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 1.9 nM. In some embodiments, the inventive ABP inhibits PVR binding to TIGIT with an IC ₅₀ value of approximately 1 nM and inhibits PVRL2 binding to TIGIT with an IC ₅₀ value of approximately 0.8 nM. In some embodiments, this IC ₅₀ value is about 2 nM or less.

2.5.1. Glycosylated variants

[0310] In specific embodiments, the implementation proposed in the invention ABP can be modified to increase, decrease or eliminate the degree of glycosylation. Glycosylation of polypeptides is either "N-linked" or "O-linked".

[0311] "N-linked" glycosylation refers to the attachment of a carbohydrate moiety to the side chain of an aspartic residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except praline, are recognition sequences for enzymatic attachment of a carbohydrate moiety to an aspartic side chain. Therefore, the presence of one of these tripeptide sequences in a polypeptide creates a potential site for glycosylation.

[0312] "O-linked" glycosylation refers to the attachment of one of the N-acetylgalactosamine, galactose, or xylose sugars to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used.

[0313] The addition or removal of N-linked glycosylation sites to or removal from the inventive ABP can be accomplished by amino acid sequence alteration that creates or removes one or more of the tripeptide sequences described above. The addition or removal of O-linked glycosylation sites can be accomplished by adding, deleting, or substituting one or more serine or threonine residues in the ABP sequence or to the ABP sequence (as the case may be).

[0314] In some embodiments, the ABP of the invention includes a glycosylation motif that is different from natural ABP. Any suitable natural glycosylation motif can be modified in the ABPs of the invention. For example, the structural properties and properties of glycosylated immunoglobulins are well known and more detailed information can be found, for example, in Schroeder and Cavacini, J Allergy Clin. Immunol., 2010, 125:S41-52, the content of which is incorporated into the present invention by reference.

[0315] In some embodiments, the ABP of the invention includes an IgG1 Fc fragment with a modified oligosaccharide attached to asparagine 297 (Asn 297). Natural IgG1 antibodies produced by mammalian cells typically include a branched, 2-antennary oligosaccharide that is typically N-linked to Asn 297 in the CH2 domain of the Fc fragment. See Wright et al., TIBTECH, 1997, 15:26-32, the contents of which are incorporated herein by reference. The oligosaccharide attached to Asn 297 may include various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, as well as fucose attached to GlcNAc in the stem of the 2-anthenary oligosaccharide structure.

[0316] In some embodiments, the oligosaccharide attached to Asn 297 is modified to create ABPs having an altered oligosaccharide (ADCC). In some embodiments, the oligosaccharide is changed to improve ADCC. In some embodiments, the oligosaccharide is altered to restore ADCC.

[0317] In some aspects, the ABP of the invention includes an IgG1 domain with reduced fucose at position Asn 297 compared to the natural IgG1 domain. Such Fc domains are known to have improved ADCC. See Shields et al., J Biol. Chem., 2002, 277:26733-26740, the contents of which are incorporated herein by reference. In some aspects, such ABPs do not contain any fucose at position Asn 297. The amount of fucose can be determined by any suitable method, for example, described in patent document WO 2008/077546, the content of which is incorporated into the present invention by reference to it.

[0318] In some embodiments, the ABP of the invention includes a bisected oligosaccharide, such as a 2-antennary oligosaccharide, attached to an Fc fragment of the ABP that is equidistant with GlcNAc. Such ABP variants may have reduced fucosylation and/or improved ADCC function. Examples of such ABP variants are described, for example, in patent documents WO 2003/011878; U.S. Pat. no. 6602684 and U.S. Pat. Pub. no. 2005/0123546; the content of each of which is included in the present invention by reference to it.

[0319] Other exemplary glycosylation variants that can be incorporated into the inventive ABPs are described, for example, in U.S. Pat. Pub. nos. 2003/0157108 2004/0093621 2003/0157108 2003/0115614 2002/0164328 2004/0093621 2004/0132140 2004/0110704 2004/0110282 International Pat. Pub. nos. 2000/61739, 2001/29246, 2003/085119, 2003/084570, 2005/035586, 2005/035778; 2005/053742, 2002/031140; Okazaki et al., J Mal. Biol., 2004, 336: 1239-1249; and Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; the content of each of which is included in the present invention by reference to it.

[0320] In some embodiments, the ABP of the invention includes an Fc fragment with at least one galactose residue in the oligosaccharide attached to the Fc fragment. Such ABP variants may have an improved CDC function. Examples of such ABP variants are described, for example, in patent documents WO 1997/30087; WO 1998/58964; and WO 1999/22764; the content of each of which is included in the present invention by reference to it.

[0321] Examples of a cell line capable of producing defucosylated ABPs include Lec13 CHO cells that are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub No. 2003/0157108; WO 2004/056312; the contents of each of which are incorporated herein by reference) and knockout cell lines such as CHO cells knockout for the alpha-1,6-fucosyltransferase or FUT8 gene ( see Yamane-Ohnuki et al., Biotech. included in the present invention by reference).

[0322] In some embodiments, the ABP of the invention is an aglycosylated ABP. Aglycosylated ABP can be obtained by any method known or described in the invention. In some aspects, aglycosylated ABP is obtained by modifying the ABP to remove all glycosylation sites. In some aspects, glycosylation sites are removed only from the Fc fragment of ABP. In some aspects, aglycosylated ABP is obtained by expressing ABP in an organism that is not capable of glycosylation, such as E. coli, or by expressing ABP in a cell-free reaction mixture.

[0323] In some embodiments, the inventive ABP has a constant region with reduced effector function compared to native IgG1 antibody. In some embodiments, the constant region affinity of the Fc fragment of the inventive ABP for the Fc receptor is less than the affinity of the native IgG1 constant region for that Fc receptor.

2.6. Amino acid sequence variants of the Fc fragment

[0324] In specific embodiments, the inventive ABP comprises an Fc fragment with one or more amino acid substitutions, insertions, or deletions compared to the natural Fc fragment. In some aspects, such substitutions, insertions, or deletions produce ABPs with altered stability, glycosylation, or other characteristics. In some aspects, such substitutions, insertions or deletions allow aglycosylated ABPs to be obtained.

[0325] In some aspects, the Fc fragment of the inventive ABP is modified to produce an ABP with an altered affinity for the Fc receptor, or an ABP that is more immunologically inert. In some embodiments, the inventive ABP variants have some, but not all, effector functions. Such ABPs can be used, for example, in cases where the in vivo half-life of the ABP is important, but where certain effector functions (eg, complement activation and ADCC) are unnecessary or detrimental.

[0326] In some embodiments, the Fc fragment of the inventive ABP is a human IgG4 Fc fragment comprising one or more of the hinge stabilizing mutations S228P and L235E. See Aalberse et al., Immunology, 2002, 105:9-19, the contents of which are incorporated herein by reference. In some embodiments, the IgG4 Fc fragment includes one or more of the following mutations: E233P, F234V, and L235A. See Armour et al., Mol. Immunol., 2003, 40:585-593, the contents of which are incorporated into the present invention by reference. In some embodiments, the IgG4 Fc fragment includes a deletion at position G236.

[0327] In some embodiments, the Fc fragment of the inventive ABP is a human IgG1 Fc fragment comprising one or more mutations to reduce Fc receptor binding. In some aspects, one or more mutations are at residues selected from S228 (eg S228A), L234 (eg L234A), L235 (eg L235A), D265 (eg D265A) and N297 (eg N297A). In some aspects, ABP includes a PVA236 mutation. PVA236 means that the amino acid sequence of ELLG, from amino acid position 233-236 in IgG1 or EFLG in IgG4, is changed to PVA. See the U.S. patent document. Pat. no. 9150641, the contents of which are incorporated into the present invention by reference.

[0328] In some embodiments, the Fc fragment of the inventive ABP is modified as described in Armor et al., Eur. J Immunol., 1999, 29:2613-2624; patent documents WO 1999/058572; and/or U.K. Pat. app. no. 98099518; the content of each of which is included in the present invention by reference to it.

[0329] In some embodiments, the Fc fragment of the inventive ABP is a human IgG2 Fc fragment comprising one or more A330S and P331S mutations.

[0330] In some embodiments, the Fc fragment of the inventive ABP has an amino acid substitution at one or more positions selected from 238, 265, 269, 270, 297, 327, and 329. See U.S. Pat. no. 6737056, the contents of which are incorporated into the present invention by reference. Such Fc mutants include Fc mutants with substitutions at two or more amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant with residues 265 and 297 replaced by alanine. See the U.S. patent document. Pat. no. 7332581, the contents of which are incorporated into the present invention by reference. In some embodiments, ABP includes alanine at amino acid position 265. In some embodiments, ABP includes alanine at amino acid position 297.

[0331] In specific embodiments, the inventive ABP comprises an Fc fragment with one or more amino acid substitutions that improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc fragment. In some embodiments, the inventive ABP comprises an Fc fragment with one or more amino acid substitutions at positions 239, 332, and 330 as described in Lazar et al., Proc. Natl. Acad. sci. USA, 2006, 103:4005-4010, the contents of which are incorporated into the present invention by reference.

[0332] In some embodiments, the inventive ABP includes one or more alterations that improve or decrease Clq binding and/or CDC. See U.S. Patent Documents. Pat. no. 6194551; W099/51642; and Idusogie et al., J Immunol., 2000, 164:4178-4184; the contents of which are incorporated into the present invention by reference.

[0333] In some embodiments, the inventive ABP includes one or more alterations to increase the half-life. ABPs with increased half-lives and improved binding to the neonatal Fc receptor (FcRn) are described, for example, in Hinton et al., J Immunol., 2006, 176:346-356; and in the U.S. patent document. Pat. Pub. no. 2005/0014934; the contents of which are incorporated into the present invention by reference. Such Fc variants include Fc variants with substitutions at one or more of the Fc residues: 238, 250, 256, 265, 272, 286, 303, 305, 307, 311, 312, 314, 317, 362, 376, 378, 380, 382, 413, 424, 428 and 434 IgG.

[0334] In some embodiments, the inventive ABP includes one or more Fc fragment variants described in U.S. Pat. nos. 7371826, 5648260 and 5624821; in Duncan and Winter, Nature, 1988, 322:738-740; and in patent document WO 94/29351; the contents of which are incorporated into the present invention by reference.

2.7. pyroglutamate

[0335] As is known, both glutamate (E) and glutamine (Q) at the N-terminus of recombinant proteins can spontaneously cyclize to form pyroglutamate (pE) in vitro and in vivo. See Liu et al., J Biol. Chem., 2011, 286:11211-11217, the contents of which are incorporated into the present invention by reference.

[0336] In some embodiments, the invention provides ABPs comprising a polypeptide sequence having a pE residue at the N-terminal position. In some embodiments, the invention provides ABPs comprising a polypeptide sequence in which the N-terminal residue has been converted from Q to pE. In some embodiments, the invention provides ABPs comprising a polypeptide sequence in which the N-terminal residue has been converted from E to pE.

[0337] In some embodiments, the invention provides ABPs comprising V _H sequences having a pE residue at the N-terminal position. In some embodiments, the invention provides ABPs comprising a V _H sequence in which the N-terminal residue has been converted from Q to pE. In some embodiments, the invention provides ABPs comprising a V _H sequence selected from SEQ ID NOs: 4-24, wherein the N-terminal Q residue has been converted to pE. In some embodiments, the invention provides a composition comprising ABP, wherein the ABP comprises a V _H selected from SEQ ID NOs: 4-24 wherein at least about 20%, at least about 40%, at least about 60 %, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the N-terminal residues of such V _H in such a composition were converted from Q to pE.

[0338] In some embodiments, the invention provides ABPs comprising V _L sequences having a pE residue at the N-terminal position. In some embodiments, the invention provides ABPs comprising a V _L sequence in which the N-terminal residue has been converted from E to pE. In some embodiments, the invention provides an ABP comprising a V _L sequence selected from SEQ ID NOs: 25-28, wherein the N-terminal E residue has been converted to pE. In some embodiments, the invention provides a composition comprising ABP, wherein the ABP comprises V _L selected from SEQ ID NOs: 25-28, wherein at least about 20%, at least about 40%, at least about 60 %, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the N-terminal residues of such a V _L in such a composition were converted from E to pE.

[0339] In some embodiments, the invention provides ABPs comprising heavy chain sequences having a pE residue at the N-terminal position. In some embodiments, the invention provides ABPs comprising a heavy chain sequence in which the N-terminal residue has been converted from Q to pE. In some embodiments, the invention provides an ABP comprising a heavy chain sequence selected from SEQ ID NOs: 79, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 93, 94, 95 , 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 121, 122 , 123 or 124, where the N-terminal Q residue was converted to pE. In some embodiments, the invention provides a composition comprising an ABP, wherein the ABP comprises a heavy chain selected from SEQ ID NOs: 79, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 93 , 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 , 121, 122, 123, or 124, wherein at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 90%, at least about 95% or at least about 99% of the N-terminal residues of such a heavy chain in such a composition were converted from Q to pE.

[0340] In some embodiments, the invention provides ABPs comprising light chain sequences having a pE residue at the N-terminal position. In some embodiments, the invention provides ABPs comprising a light chain sequence in which the N-terminal residue has been converted from E to pE. In some embodiments, the invention provides an ABP comprising a light chain sequence selected from SEQ ID NOs: 81, 92, 107, or 120, wherein the N-terminal E residue has been converted to pE. In some embodiments, the invention provides a composition comprising an ABP, wherein the ABP comprises a light chain selected from SEQ ID NOs: 81, 92, 107, or 120, wherein at least about 20%, at least about 40%, of at least about 60%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the N-terminal residues of such a light chain in such a composition were converted from E to pE.

2.8. Engineered cysteine variants of the antigen-binding protein

[0341] In specific embodiments, the invention provides engineered cysteine ABPs, also known as "thioMAbs," in which one or more ABP residues are replaced with cysteine residues. In specific embodiments, the substituted residues occur at ABP sites that are solvent accessible. By replacing such residues with cysteine, reactive thiol groups are introduced into the solvent-accessible sites of ABP, and these can be used to conjugate ABP to other moieties, such as drug moieties or linker-drug moieties, for example, to create immunoconjugate.

[0342] In specific embodiments, any one or more of the following residues may be replaced with a cysteine: V205 light chain; A118 Fc fragment of the heavy chain; and S400 Fc fragment of the heavy chain. Engineered cysteine ABPs can be formed as described, for example, in U.S. Pat. no. 7521541, the contents of which are incorporated into the present invention by reference.

2.8.1. Immunoconjugates

2.8.1.1. Antigen-binding protein-polymer conjugates

[0343] In some embodiments, the ABP of the invention is derivatized by polymer conjugation. Any suitable polymer may be conjugated to ABP.

[0344] In some embodiments, the polymer is a water-soluble polymer. Illustrative examples of water-soluble polymers include polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acids ( either homopolymers or random copolymers), poly(p-vinylpyrrolidone)-co-polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (eg, glycerol), polyvinyl alcohol, and mixtures thereof. In some aspects, polyethylene glycol-propionaldehyde can be used in the creation of conjugates due to its stability in water.

[0345] The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to each ABP may vary, and if more than one polymer is attached, the polymers may be the same or different. Typically, the number and/or type of polymers used for derivatization may be determined based on considerations including the specific properties or functions of the ABP to be improved and the intended use of the ABP.

2.8.1.2. Antigen-binding protein-drug conjugates

[0346] In some embodiments, the ABPs of the invention are conjugated to one or more therapeutic agents. Any suitable therapeutic agent may be conjugated to ABP. Examples of therapeutic agents include cytokines, chemokines, and other agents that induce the desired activity of T cells, such as OX40L, 4-1BBL, TNF-alpha (referred to in the invention as "TNF"), IL-2, fused IL-15, CXCL9 , CXCL10, IL-10 associated with TNF activation, IL-27 associated with TNF activation, and IL-35 associated with TNF activation. Cytokines associated with TNF activation and their use are well known and described, for example, in Economides et al., Nature Medicine, 2003, 9:47-52, the content of which is incorporated herein by reference.

3. Methods for producing TIGIT antigen-binding proteins

3.1. Obtaining the TIGIT antigen

[0347] The TIGIT antigen used to isolate the ABPs of the invention may be an intact TIGIT or a TIGIT fragment. The TIGIT antigen may, for example, be in the form of an isolated protein or a protein expressed on a cell surface.

[0348] In some embodiments, the TIGIT antigen is a non-naturally occurring TIGIT variant, such as a TIGIT protein having an amino acid sequence or post-translational modification that does not occur naturally.

[0349] In some embodiments, the TIGIT antigen is processed by removing, for example, intracellular or transmembrane sequences or signal sequences. In some embodiments, the TIGIT antigen is recombined at its C-terminus with a human IgG1 Fc domain or polyhistidine tail.

3.2. Methods for obtaining monoclonal antibodies

[0350] Monoclonal antibodies can be obtained, for example, by using the hybridoma method first described in Kohler et al., Nature, 1975, 256:495-497 (the content of which is incorporated into the present invention by reference) and/or recombinant DNA (see, for example, U.S. Patent No. 4,816,567, the contents of which are incorporated herein by reference). Monoclonal antibodies can also be generated, for example, by using phage display or yeast display libraries. See, for example, U.S. patent documents. Patent Nos. 8258082 and 8691730, the contents of each of which are incorporated into the present invention by reference to them.

[0351] In the hybridoma method, a mouse or other appropriate host animal is immunized to recover lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes can be immunized in vitro. The lymphocytes are then fused with myeloma cells using an appropriate fusion reagent such as polyethylene glycol to obtain hybridoma cells. See Goding JW, Monoclonal Antibodies: Principles and Practice 3rd ^ed . (1986) Academic Press, San Diego, CA, the contents of which are incorporated into the present invention by reference.

[0352] Hybridoma cells are seeded and grown in an appropriate culture medium that contains one or more substances that inhibit the growth or survival of unfused parental myeloma cells. For example, if the parent myeloma cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), then the culture medium for hybridomas will typically include hypoxanthine, aminopterine, and thymidine (HAT medium), substances that prevent the growth of HGPRT-deficient cells.

[0353] Suitable myeloma cells are those that effectively participate in fusion, maintain a consistently high level of antibody production by the selected antibody-producing cells, and are sensitive to environmental conditions such as the presence or absence of HAT media. Among these, preferred myeloma cell lines are rodent myeloma cell lines such as myeloma cells derived from mouse tumors MOP-21 and MC-11 (which can be purchased from the Salk Institute Cell Distribution Center, San Diego, CA) and SP- 2 or X63-Ag8-653 cells (available from the American Type Culture Collection, Rockville, MD). Human myeloma cell lines and mouse-human heteromyeloma cell lines have also been described for the production of human monoclonal antibodies. See , for example, the publication of Kozbor, J Immunol., 1984, 133:3001, the contents of which are incorporated into the present invention by reference to it.

[0354] Once hybridoma cells have been identified that produce antibodies of the desired specificity, affinity, and/or biological activity, selected clones can be subcloned using limiting dilution techniques and grown by standard methods. See the Goding post mentioned above. Suitable culture media for this purpose include, for example, D-MEM and RPMI-1640. In addition, hybridoma cells can be grown in vivo to form ascitic tumors in an animal.

[0355] DNA encoding monoclonal antibodies can be easily isolated and sequenced using conventional techniques (eg, by using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of monoclonal antibodies). Therefore, hybridoma cells can serve as a suitable source of DNA encoding antibodies with the desired properties. Once isolated, the DNA can be placed into expression vectors which are then transfected into host cells such as bacteria (eg E. coli), yeast (eg Saccharomyces or Pichia sp.), COS cells, Chinese hamster ovary (CHO) cells or myeloma cells that do not otherwise produce the antibody to produce monoclonal antibodies.

3.3. Methods for obtaining chimeric antibodies

[0356] Exemplary methods for producing chimeric antibodies are described, for example, in U.S. Pat. no. 4816567; and the publications of Morrison et al., Proc. Natl. Acad. sci. USA, 1984, 81:6851-6855; the contents of which are incorporated into the present invention by reference. In some embodiments, a chimeric antibody is produced by using recombinant techniques to combine an animal variable region (eg, a variable region derived from a mouse, rat, hamster, rabbit, or a lower primate such as a monkey) with a human constant region.

3.4. Methods for obtaining humanized antibodies

[0357] Humanized antibodies can be formed by replacing most or all of the structural parts of a non-human monoclonal antibody with the corresponding human antibody sequences. As a result, a hybrid molecule is obtained in which only the antigen-specific variable or complementary defined region (CDR) consists of a non-human sequence. Methods for making humanized antibodies include those described, for example, in Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. sci. U.S.A., 1998, 95:8910-8915; Steinberger et al., J Biol. Chem., 2000, 275:36073-36078; Queen et al., Proc. Natl. Acad. sci. U S.A., 1989, 86: 10029-10033; and U.S. patent documents. Patent Nos. 5585089, 5693761, 5693762 and 6180370; the contents of which are incorporated into the present invention by reference.

3.5. Methods for obtaining human antibodies

[0358] Human antibodies can be formed using a number of known methods, for example, by using transgenic animals (eg, humanized mice). See, for example, Jakobovits et al., Proc. Natl. Acad. sci. U.S.A., 1993, 90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggermann et al., Year in Immuno., 1993, 7:33; and patent documents U.S. Patent Nos. 5591669, 5589369 and 5545807; the contents of which are incorporated into the present invention by reference. Human antibodies can also be generated from phage display libraries (see, for example, Hoogenboom et al., J Mal. Biol., 1991, 227:381-388; Marks et al., J Mal. Biol., 1991, 222: 581-597; and U.S. Pat. Nos. 5,565,332 and 5,573,905, the contents of which are incorporated herein by reference). Human antibodies can also be generated in vitro by activated B cells (see, for example, U.S. Patent Nos. 5,567,610 and 5,229,275, the contents of each of which are hereby incorporated by reference). Human antibodies can also be generated from yeast display libraries (see, for example, U.S. Patent No. 8691730, the contents of which are hereby incorporated by reference).

3.6. Methods for obtaining antibody fragments

, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); патентных документах WO 93/16185 и U.S. Pat. Nos. 5571894 и 5587458; содержание которых включено в настоящее изобретение путем ссылки на них.[0359] Proposed in the invention fragments of antibodies can be obtained by any suitable method, including illustrative methods described in the invention, and well-known methods. Suitable methods include recombinant methods and proteolytic digestion of whole antibodies. Illustrative methods for obtaining antibody fragments are described, for example, in Hudson et al., Nat. Med., 2003, 9: 129-134, the contents of which are incorporated into the present invention by reference. Methods for obtaining scFv antibodies are described, for example, in the publication

, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); patent documents WO 93/16185 and US Pat. nos. 5571894 and 5587458; the contents of which are incorporated into the present invention by reference.

3.7. Methods for Obtaining Alternative Cores

[0360] Alternative backbones of the invention may be prepared by any suitable method, including the illustrative methods described in the invention or known methods. For example, methods for producing Adnectin™ are described in Emanuel et al., mAbs, 2011, 3:38-48, the contents of which are incorporated herein by reference. Methods for obtaining iMabs are described in the U.S. Pat. Pub. no. 2003/0215914, the contents of which are incorporated into the present invention by reference. Methods for preparing anticalins® are described in Vogt and Skerra, Chem. Biochem., 2004, 5:191-199, the content of which is incorporated into the present invention by reference. Methods for obtaining Kunitz domains are described in Wagner et al., Biochem. & Biophys. Res. Somm., 1992, 186:118-1145, the contents of which are incorporated into the present invention by reference. Methods for preparing peptide aptamers of thioredoxin are given in Geyer and Brent, Meth. Enzymol., 2000, 328:171-208, the contents of which are incorporated into the present invention by reference. Affibody AB antibody mimetic protein preparation methods are provided in Fernandez, Curr. Opinion in Biotech., 2004, 15:364-373, the contents of which are incorporated into the present invention by reference. Methods for obtaining DARPins are given in Zahnd et al., J Mal. Biol., 2007, 369: 1015-1028, the content of which is incorporated into the present invention by reference. Methods for obtaining affilins are given in Ebersbach et al., J Mal. Biol., 2007, 372:172-185, the content of which is incorporated into the present invention by reference. Methods for preparing tetranectins are given in Graversen et al., J Biol. Chem., 2000, 275:37390-37396, the contents of which are incorporated herein by reference. Methods for preparing avimers are given in Silverman et al., Nature Biotech., 2005, 23:1556-1561, the contents of which are incorporated herein by reference. Methods for preparing finomers are given in Silacci et al., J Biol. Chem., 2014, 289: 14392-14398, the contents of which are incorporated herein by reference.

[0361] For more information on alternative backbones, see Binz et al., Nat. Biotechnol., 2005 23: 1257-1268; and Skerra, Current Opin. in Biotech., 2007 18:295-304, the content of each of which is included in the present invention by reference to it.

3.8. Methods for obtaining variants

[0362] In some embodiments, the inventive ABP is an affinity matured variant of the parent ABP, which can be generated, for example, by using phage display-based affinity maturation techniques. Briefly, one or more CDR residues can be mutated and ABPs variants, or portions thereof, are displayed on phage display and screened for affinity. Such alterations can be made at CDR hotspots or codon-encoded residues that mutate at high frequency during the somatic maturation process (see Chowdhury, Methods Mal. Biol., 2008, 207: 179-196, the contents of which are included in the present invention by reference to it), and/or residues that come into contact with the antigen. Alternatively, affinity matured variants of the original ABP can be generated or selected to use a yeast-based presentation platform (see, for example, patent documents WO2009/036379, WO 2010/105256, WO 2012/009568 and Xu et al., Protein Eng Des Sel., Vol.26(10), pp.663-670 (2013)).

[0363] Any suitable method can be used to introduce variability into the polynucleotide sequence(s) encoding the ABP, including the error-correcting polymerase chain reaction (PCR) method, the strand recombination method, and the oligonucleotide site-directed mutagenesis method, such as site-directed mutagenesis using trinucleotides (TRIM). In some aspects, multiple CDR residues (eg, 4-6 residues at a time) are randomized. CDR residues involved in antigen binding can be specifically identified, for example, using alanine scanning or mutagenesis modeling. CDR-H3 and CDR-L3 in particular are often targets for mutation.

[0364] Introduction of diversity into variable regions and/or CDRs can be used to produce a secondary library. The secondary library is then screened to identify ABP variants with improved affinity. Affinity maturation by construction and reselection from secondary libraries has been described, for example, in Hoogenboom et al., Methods in Molecular Biology, 2001, 178:1-37, the contents of which are hereby incorporated by reference.

3.9. Vectors, host cells and recombinant methods

[0365] In addition, isolated nucleic acids encoding TIGIT ABPs, vectors including nucleic acids and host cells, including vectors and nucleic acids, as well as recombinant methods for producing ABPs are provided.

[0366] For recombinant production of ABP, the nucleic acid(s) encoding it can be isolated and inserted into a replicable vector for further cloning (i.e., DNA amplification) or expression. In some aspects, the nucleic acid can be obtained by homologous recombination, such as described in U.S. Patent No. 5204244, the contents of which are incorporated into the present invention by reference.

[0367] Many different vectors are known. Vector components typically include one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription terminator sequence, such as those described in U.S. Patent No. 5534615, the contents of which are incorporated into the present invention by reference.

[0368] Illustrative examples of suitable host cells are provided below. But it is understood that these host cells are not limitations to the invention, and any host cell can be used to produce proposed in the invention ABPs.

[0369] Suitable host cells include any prokaryotic (eg, bacterial), lower eukaryotic (eg, yeast), or higher eukaryotic (eg, mammalian) cells. Suitable prokaryotes include eubacteria such as gram-negative or gram-positive organisms, for example, enterobacteria such as Escherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (S. typhimurium), Serration (Serration marcescens), Shigella , bacilli (hay bacillus and B. licheniformis), pseudomonas (pseudomonas aeruginosa) and streptomycetes. One suitable E. coli cloning host is E. coli 294, although other strains such as E. coli B, E. coli X1776 and E. coli W3110 may also be used.

[0370] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are also suitable cloning or expression hosts for TIGIT ABP-encoding vectors. Saccharomyces cerevisiae or common baker's yeast is a traditionally used lower eukaryotic host microorganism. However, a number of other genera, species and strains are available and can be used, such as Schizosaccharomyces pombe, Kluyveromyces (K. lactis, K. fragilis, K. bulgaricus, K. wickeramii, K. waltii, K. drosophilarum, K. thermotolerans and K. marxianus), Yarrowia, Pichia pastoris, Candida (C. albicans), Trichoderma reesia, Neurospora crassa, Schwanniomyces (S. occidentalis) and filamentous fungi such as, for example, Penicillium, Tolypocladium and Aspergillus (A. nidulans and A. niger ).

[0371] Suitable mammalian host cells include COS-7 cells, HEK293 cells, newborn hamster kidney (BHK) cells, Chinese hamster ovary (CHO) cells, mouse testis support cells, African green monkey kidney (VERO-76) cells, and the like. cells.

[0372] The host cells used to produce TIGIT ABP of this invention can be cultured in a variety of media. Commercial media such as, for example, Ham's F10, Minimal Maintenance Medium (MEM), RPMI-1640, and Dulbecco's Modified Eagle's Medium (DMEM) can be used to culture host cells. In addition, any of the media described in Ham et al., Meth. Enz., 1979, 58:44; Barnes et al., Anal. Biochem., 1980, 102:255; and U.S. patent documents. Patent Nos. 4,767,704; 4,657,866; 4,927,762;

[0373] Any of these media can be supplemented, if necessary, with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium, calcium, magnesium chlorides and phosphates), buffers (such as such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements (defined as inorganic compounds typically present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary additives, which are well known to those skilled in the art, may also be included at appropriate concentrations.

[0374] Culture conditions such as temperature, pH, and the like are conditions previously used for host cells selected for expression, and are well known to any person skilled in the art.

[0375] When using recombinant methods, ABP can be produced intracellularly, in the periplasmic space, or directly secreted into the environment. If ABP is produced intracellularly, debris particles, either host cells or lysed fragments, are first removed, for example, by centrifugation or ultrafiltration. For example, Carter et al., Bio/Technology, 1992, 10:163-167, the contents of which are incorporated herein by reference, describe a technique for isolating ABPs that are secreted in the periplasmic space of E. coli. Briefly, the cell mass is thawed in the presence of sodium acetate (pH 3.5), EDTA and phenylmethylsulfonyl fluoride (PMSF) for approximately 30 minutes. Cellular debris can be removed by centrifugation.

[0376] In some embodiments, ABP is produced in a cell-free system. In some aspects, the cell-free system is the in vitro transcription and translation system described in Yin et al., mAbs, 2012, 4:217-225, the content of which is incorporated herein by reference. In some aspects, the cell-free system uses a cell-free extract from eukaryotic cells or from prokaryotic cells. In some aspects, the prokaryotic cell is E. coli. Cell-free expression of ABP can be used, for example, in cases where ABP accumulates in the cell in the form of an insoluble aggregate or when yields from periplasmic expression are low.

[0377] When ABP is secreted into the medium, supernatants from such expression systems are typically first concentrated using a commercially available protein concentration filter, such as an ^Amicon® or Millipore® ^{Pellcon® ultrafiltration} device. A protease inhibitor such as PMSF may be added at any of the preceding steps to inhibit proteolysis, and antibiotics may be added to prevent the growth of foreign matter.

[0378] The ABP composition prepared from cells can be purified, for example, by hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a particularly suitable purification method. The possibility of using protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the ABP. Protein A can be used to purify ABPs that include human γ1, γ2, or γ4 heavy chains (Lindmark et al., J Immunol. Meth., 1983, 62:1-13, the contents of which are incorporated herein by reference ). Protein G is used for all mouse isotypes and for human γ3 (Guss et al., EMBO J, 1986, 5: 1567-1575, the contents of which are hereby incorporated by reference).

[0379] The matrix to which the affinity ligand is attached is most often aragose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or polystyrenedivinylbenzene allow higher flow rates and shorter processing times than with aragose. In the case where the ABP includes a C _H3 domain, BakerBond ^ABX® resin is used for purification.

[0380] In addition, other methods for protein purification are available, such as fractionation on an ion exchange resin column, ethanol precipitation, reverse phase high performance liquid chromatography, silica gel chromatography, heparin- ^sepharose® chromatography, chromatofocusing, polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and precipitation with ammonium sulfate, and they can be used by any person skilled in the art.

[0381] After any pre-purification step(s), the mixture including the appropriate ABP and impurities can be subjected to low pH hydrophobic interaction chromatography using an elution buffer at a pH of about 2.5 to about 4.5, which is typically carried out at low salt concentrations (eg, from about 0 to about 0.25 M salt).

4. Research

[0382] A number of well known assays can be used to identify and analyze the inventive ABPs for TIGIT.

4.1. Binding, competition and epitope mapping studies

[0383] The specific antigen-binding activity of the inventive ABPs can be assessed by any suitable method, including using the SPR BLI, RIA, and MSD-SET methods described elsewhere in this invention. In addition, antigen-binding activity can be assessed by conducting studies using enzyme-linked immunosorbent assay (ELISA) and Western blotting.

[0384] Studies to measure competition between two ABPs or an ABP and another molecule (e.g., one or more TIGIT ligands) are described at various places in this invention and, for example, in Harlow and Lane, Antibodies: A Laboratory Manual ch.14, 1988, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., the contents of which are incorporated herein by reference.

[0385] Epitope mapping studies to which the inventive ABPs are associated are described, for example, in Morris publication "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66, 1996, Humana Press, Totowa, N.J., the contents of which are incorporated herein by reference. In some embodiments, the epitope is determined by peptide competition. In some embodiments, the epitope is determined by mass spectroscopy. In some embodiments, the epitope is determined by a crystallographic method.

[0386] In some embodiments, "alanine scanning" or "alanine mapping" is used to map target protein epitopes and/or antibody paratopes. An alanine scan is used to determine the contribution of a specified residue to the stability or function of a given protein. See, for example, Weiss et al., Proc Natl Acad Sci 2000 Augl; 97(16): 8950-8954.

4.2. Antagonism studies for TIGIT

[0387] In some embodiments, the ABPs of the invention are screened for identification or analysis of ABPs with TIGIT antagonistic activity. Any suitable assay may be used to identify or analyze such ABPs. In some aspects, the assay measures the amount of a cytokine secreted by an effector T cell after the effector T cell is contacted with the inventive ABP. In some aspects, the cytokine is selected from IL-2, IL-6, LT-α, TNF, GM-CSF, IFNγ, and combinations thereof. In some aspects, the cytokine is selected from sCD40L, VEGF, TGF-α, RANTES, PDGF-AB/BB, PDGF-AA, MIP-1β, MIP-1α, MDC (CCL22), MCP-3, MCP-1, IP- 10, IL-17A, IL-2Rα, IL-15, IL-13, IL-12 (p70), IL-12 (p40), IL-10, IL-9, IL-8, IL-7, IL- 5, IL-4, IL-3, IL-2, IL-2Rα, IL-IRA, IL-1β, IL-1α, IFNγ, IFNα2, GRO, GM-CSF, G-CSF, fractalkine, Flt-3 ligand , FGF-2, eotaxin, EGF and combinations thereof.

[0388] In some embodiments, effector cells co-stimulate with a CD3 agonist to promote cytokine secretion by the effector cell. In some aspects, a CD3 agonist is provided at a submaximal level.

[0389] In some aspects, such assays measure the proliferation of an effector T cell following contact of an effector T cell with an ABP of the invention. In some aspects, effector T cell proliferation is measured by dye dilution (e.g., carboxyfluorescein diacetate succinimidyl ester; CFSE), tritiated thymidine uptake, by performing fluorescent cell survival assays, or by other known assays.

[0390] In some aspects, such assays measure the differentiation, cytokine production, viability (eg, survival), proliferation, or suppressive activity of a regulatory T cell after the regulatory T cell is contacted with the inventive ABP.

[0391] In some aspects, such assays measure the cytotoxic activity of an NK cell after contacting the NK cell with the inventive ABP. In some aspects, the cytotoxic activity of a NK cell is measured using a cytotoxicity assay that quantifies NK-mediated killing of target cells (eg, K562 cell line). See Jang et al., Ann. Clin. Lab. Sci., 2012, 42:42-49, the contents of which are incorporated into the present invention by reference.

[0392] In some aspects, such assays measure the amount of granzyme B. In some aspects, such assays measure the amount of perforin.

4.3. Effector Function Studies

[0393] Effector function after treatment with the inventive ABPs can be assessed by conducting a number of well-known in vitro and in vivo studies, including studies described in publications and patent documents Ravetch and Kinet, Annu. Rev. Immunol., 1991, 9:457-492; U.S. Pat. nos. 5500362, 5821337; Hellstrom et al., Proc. Nat'l Acad. sci. USA, 1986, 83:7059-7063; Hellstrom et al., Proc. Nat'l Acad. sci. USA, 1985, 82: 1499-1502; Bruggemann et al., J Exp. Med., 1987, 166:1351-1361; Clynes et al., Proc. Nat'l Acad. sci. USA, 1998, 95:652-656; W02006/029879; WO2005/100402; Gazzano-Santoro et al., J Immunol. Methods, 1996, 202:163-171; Cragg et al., Blood, 2003, 101:1045-1052; Cragg et al. Blood, 2004, 103:2738-2743; and Petkova et al., Int'l. Immunol., 2006, 18:1759-1769; the contents of which are included in the present invention by reference to them.

5. Pharmaceutical compositions

[0394] The ABPs of the invention may be formulated into any suitable pharmaceutical composition and administered by any suitable route of administration. Suitable routes of administration include, but are not limited to, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes of administration.

[0395] The pharmaceutical composition may include one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and any person skilled in the art will be able to select suitable pharmaceutical excipients. Accordingly, the following pharmaceutical excipients are intended to be illustrative examples only and do not limit the present invention. Additional pharmaceutical excipients include, for example, the pharmaceutical excipients described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), the contents of which are incorporated into the present invention by reference.

[0396] In some embodiments, the pharmaceutical composition includes an antifoam. Any suitable antifoam may be used. In some aspects, the antifoam is selected from alcohol, ether, oil, wax, silicone, surfactant, and combinations thereof. In some aspects, the antifoam is selected from mineral oil, vegetable oil, ethylene bis-stearamide, paraffin wax, wax ester, fatty alcohol in wax form, long chain fatty alcohol, fatty acid soap, fatty acid ester, silicone glycol, fluorosilicone, polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silica, ether, octyl alcohol, caprylic alcohol, sorbitan trioleate, ethyl alcohol, 2-ethylhexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0397] In some embodiments, the pharmaceutical composition includes a co-solvent. Illustrative examples of co-solvents include ethanol, polyethylene glycol, butylene glycol, dimethylacetamide, glycerin, propylene glycol, and combinations thereof.

[0398] In some embodiments, the pharmaceutical composition includes a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, monosodium glutamate, and combinations thereof.

[0399] In some embodiments, the pharmaceutical composition includes a carrier or excipient. Illustrative examples of carriers or excipients include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, guar gum, and combinations thereof.

[0400] In some embodiments, the pharmaceutical composition includes a surfactant. Illustrative examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl esters, polyoxyethylene sorbitan ethers. and fatty acids, polyoxyethylene stearates, polyoxyglycerides, sodium lauryl sulfate, sorbitan esters, vitamin E polyethylene glycol succinate, and combinations thereof.

[0401] In some embodiments, the pharmaceutical composition includes an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethylcellulose, hydroxypropylcellulose, magnesium oxide, and combinations thereof.

[0402] Other excipients that can be used in pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, release control agents, diluents, dispersing agents, dissolution enhancers, emulsifiers, gelling agents , ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizers, sugars, and combinations thereof. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, the contents of which are incorporated into the present invention by reference.

[0403] In some embodiments, the pharmaceutical composition includes a solvent. In some aspects, the solvent is a saline solution, such as sterile isotonic saline or dextrose solution. In some aspects, the solvent is water for injection.

[0404] In some embodiments, the pharmaceutical compositions are in the form of particles, such as a microparticle or a nanoparticle. Microparticles and nanoparticles can be formed from any suitable material such as a polymer or lipid. In some aspects, the microparticles or nanoparticles are micelles, liposomes, or polymersomes.

[0405] In addition, the invention provides anhydrous pharmaceutical compositions and dosage forms, including ABP, since water can promote the degradation of some ABPs.

[0406] The anhydrous pharmaceutical compositions and dosage forms of the invention can be formulated using anhydrous or low moisture ingredients and under low host or low humidity conditions. Pharmaceutical compositions and dosage forms that include lactose and at least one active ingredient that includes a primary or secondary amine may be anhydrous if significant contact with moisture and/or moisture is expected during preparation, packaging and/or storage.

[0407] Anhydrous pharmaceutical composition should be prepared and stored in such a way that its anhydrous nature is preserved. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water, whereby they may be included in appropriate pharmacological kits. Examples of suitable packaging include, but are not limited to, sealable foil materials, plastics, single dose containers (eg, ampoules), blister packs, and strip packs.

5.1. Parenteral dosage forms

[0408] In specific embodiments, the ABPs of the invention are formulated into parenteral dosage forms. Parenteral dosage forms can be administered to subjects by a variety of routes, including, but not limited to, subcutaneous, intravenous (including infusions and bolus injections), intramuscular, and intra-arterial routes of administration. Since their administration is usually bypassing the subject's natural defenses against contaminants, parenteral dosage forms are usually sterile or may be sterilized prior to administration to the subject. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry (eg, lyophilized) products, readily soluble or suspended in a pharmaceutically acceptable injection medium, injectable suspensions, and emulsions.

[0409] Suitable media that can be used to prepare parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to, water for injection USP; aqueous media such as, but not limited to, sodium chloride injection, Ringer's solution for injection, dextrose solution for injection, dextrose and sodium chloride solution for injection, and lactated Ringer's solution for injection; water-miscible media such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous media such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0410] Parenteral dosage forms can also be introduced adjuvants that increase the solubility of one or more of the ABPs disclosed in the invention.

[0411] In some embodiments, the parenteral dosage form is lyophilized. Examples of lyophilized preparations are described, for example, in U.S. Pat. nos. 6267958 and 6171586; and WO 2006/044908, the contents of each of which are incorporated into the present invention by reference.

6. Dose and dosage forms with a single dose

[0412] In the medical treatment of a person, the physician must determine the dose that he considers most suitable for prophylaxis or treatment, taking into account age, body weight, condition and other factors specific to the subject being treated.

[0413] In specific embodiments, the composition of the invention is a pharmaceutical composition or a single dose dosage form. The inventive pharmaceutical compositions and single dose dosage forms comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic ABPs.

[0414] The amount of ABP or composition that will be effective in preventing or treating a disorder or one or more of its symptoms will vary depending on the nature and severity of the disease or condition and route of administration of the ABP. Dosing frequency and dose will also vary according to factors specific to each subject, depending on the specific therapeutic agents administered (for example, therapeutic or prophylactic agents), the severity of the disorder, disease or condition, the route of administration, as well as age, body weight, response reactions and medical history of the subject. Effective doses can be extrapolated from dose-response curve data obtained in in vitro test systems or experimental animal models.

[0415] In specific embodiments, exemplary dosages of the composition include milligram or microgram amounts of ABP per kilogram of subject or sample weight (e.g., from about 10 micrograms per kilogram to about 50 milligrams per kilogram, from about 100 micrograms per kilogram to about 25 milligrams per kilogram, or from about 100 micrograms per kilogram to about 10 milligrams per kilogram). In specific embodiments, the dose of the inventive ABP, based on the weight of the ABP, administered to prevent, treat, control, or alleviate a disorder or one or more of its symptoms in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of the subject's body weight. In some cases, it may be necessary to use doses of ABP outside the ranges disclosed in the invention, which is obvious to those skilled in the art. In addition, it should be noted that the clinician or attending physician is well aware of how and when to interrupt, adjust or terminate treatment, taking into account the subject's response to treatment.

[0416] Various therapeutically effective amounts can be used in the case of various diseases and conditions, which is obvious to those of ordinary skill in the art. Likewise, amounts sufficient to prevent, control, treat, or alleviate such disorders, but not sufficient to cause unwanted side effects or sufficient to reduce unwanted side effects associated with the inventive ABPs, are also included in the inventive dosage values and dosing frequency. In addition, when multiple doses of a composition of the invention are administered to a subject, it is not necessary that all doses be the same. For example, the dose administered to a subject may be increased to improve the prophylactic or therapeutic effect of the composition, or it may be lowered to reduce one or more side effects experienced by a particular subject.

[0417] In specific embodiments, treatment or prophylaxis can be initiated using one or more loading doses of the inventive ABP or composition, and then using one or more maintenance doses.

[0418] In specific embodiments, a dose of the inventive ABP or composition may be administered to achieve a steady state ABP concentration in the subject's blood or serum. Steady-state concentration may be determined by measurement using methods available to those skilled in the art, or may be based on physical characteristics of the subject such as height, weight and age.

[0419] In specific embodiments, administration of the same composition may be repeated and administrations may be spaced apart in time by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months.

[0420] As discussed in more detail elsewhere in this invention, the ABP of the invention may optionally be administered with one or more additional agents used to prevent or treat a disease or disorder. The effective amount of such additional agents may depend on the amount of ABP present in the composition, the type of disorder or treatment, and other factors known in the art or described in the invention.

7. Therapeutic use

[0421] For therapeutic use, the ABPs of the invention are administered to a mammal, typically a human, in a pharmaceutically acceptable dosage form known to those skilled in the art or described above. For example, the ABPs of the invention may be administered to a human intravenously as a bolus or by continuous infusion over a period of time, intramuscularly, intraperitoneally, intracerebrospinally, subcutaneously, intraarticularly, intrasynovially, intrathecally, or intratumorally. ABPs are also conveniently administered peritumorally, intralesionally, or in close proximity to the lesion site to provide local as well as systemic therapeutic effects. Intraperitoneal administration may be particularly useful, for example, in the treatment of an ovarian tumor.

[0422] The ABPs of the invention can be used to treat any disease or condition in which TIGIT is involved. In some embodiments, the disease or condition is a disease or condition that may benefit from treatment with ABP against TIGIT. In some embodiments, the disease or condition is a tumor. In some embodiments, the disease or condition is a cell proliferative disorder. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a viral infection.

[0423] In some embodiments, the ABPs of the invention are used as a drug. In some embodiments, the ABPs of the invention are used in the manufacture or formulation of a drug. In some embodiments, the drug is for the treatment of a disease or condition that may benefit from treatment with an anti-TIGIT ABP. In some embodiments, the disease or condition is a tumor. In some embodiments, the disease or condition is a cell proliferative disorder. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a viral infection.

[0424] In some embodiments, the invention provides a method of treating a disease or condition in a subject in need thereof by administering an effective amount of the inventive ABP to the subject. In some aspects, the disease or condition is cancer. In some aspects, the disease or condition is a viral infection.

[0425] Any suitable cancer can be treated with the ABPs of the invention. Illustrative examples of cancers suitable for treatment include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer , breast cancer, bronchial tumor, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, embryonic tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing's sarcoma, eye cancer, embryonic cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic tumor, glioma, head and neck cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma , insulinoma , Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and mouth cancer, liver cancer, lobular carcinoma in situ, lung cancer, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous carcinoma neck of unknown primary origin, NUT median carcinoma, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasia, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oropharyngeal cancer , osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, cancer renal pelvis and ureter, retinoblastoma, rod-shaped tumor, salivary gland cancer, Cesari syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, gastric cancer, T-cell lymphoma, teratoid tumor, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, female genital cancer and Wilms tumor.

[0426] Any suitable virus can be treated with the ABPs of the invention. Illustrative examples of viruses suitable for treatment include, for example, adeno-associated virus, Aichi virus, Australian bat lyssavirus, BK polyomavirus, Banna virus, Barma forest virus, Bunyamwera virus, La Crosse bunyavirus, European hare bunyavirus, marmoset herpesvirus, Chandipura virus , chikungunya virus, cosavirus A, vaccinia virus, coxsackie virus, Crimean-Congo hemorrhagic fever virus, dengue virus, dhori virus, Dugbe virus, Duvenhage virus, eastern equine encephalitis virus, ebolavirus, echovirus, encephalomyocarditis virus, Epstein-Barr virus, European bat lyssavirus, GB virus C/hepatitis G virus, Hantaan virus, Hendra virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, hepatitis delta virus, horse pox virus, human adenovirus, human astrovirus, coronavirus human, human cytomegalovirus, human enterovirus, human herpesvirus 1, human herpesvirus 2, human herpesvirus 6, herpes human papillomavirus 7, human herpesvirus 8, human immunodeficiency virus, human papillomavirus 1, human papillomavirus 2, human papillomavirus, human parainfluenza, human parvovirus B19, human respiratory syncytial virus, human rhinovirus, human severe acute respiratory syndrome coronavirus, human foamy retrovirus, T -human lymphotropic virus, human torovirus, influenza A virus, influenza B virus, influenza C virus, Isfahan virus, John Cunningham (JC) polyomavirus, Japanese encephalitis virus, Junin arenavirus, KI polyomavirus, Kunjin virus, Lagos bat virus, lake virus Victoria causing "Marburg disease", Langat virus, Lassa virus, Lordsdale virus, ovine encephalomyelitis virus, lymphocytic choriomeningitis virus, Machupo virus, Mayaro virus, Middle East respiratory syndrome coronavirus, measles virus, Mengo encephalomyocarditis virus, Merkel cell polyomavirus, Mokola virus, molluscum contagiosum virus, monkeypox virus, e mumps virus, Murray Valley encephalitis virus, New York virus, Nipah virus, norovirus, o'nong nyong virus, pustular dermatitis contagious virus, Oropuch virus, Pichinde virus, poliovirus, Punta Toro phlebovirus, Puumala virus, rabies virus, virus Rift Valley Fever, Rosavirus A, Ross River Virus, Rotavirus A, Rotavirus B, Rotavirus C, Rubella Measles Virus, Sagiyama Virus, Salivirus A, Sicilian Phlebotomy Virus, Sapporo Virus, Semliki Forest Virus, Seoul Virus, Monkey Foam Virus, Virus monkeys 5, Sindbis virus, Southampton virus, St. Louis encephalitis virus, tick-borne Powassan virus, TTV hepatitis virus, Tuscan fever virus, Uukuniemi virus, vaccinia virus, varicella zoster virus, variola virus, Venezuelan equine encephalitis virus, vesicular stomatitis virus , Western equine encephalitis virus, WU polyomavirus, West Nile virus, Yaba monkey tumor virus, Yaba-like disease virus, yellow li virus ferrets and the Zika virus.

[0427] In some embodiments, the invention provides a method of agonizing TIGIT in a target cell of a subject in need thereof by administering to the subject an effective amount of an ABP of the invention. In some aspects, the antagonistic effect of the inventive ABP against TIGIT results in increased secretion of IL-2, LT-α, IL-6, TNF, GM-CSF, IFNγ, or combinations thereof by the target cell.

[0428] In some embodiments, the invention provides a method of increasing the proliferation, survival, and/or function of an effector T cell in a subject in need thereof by administering to the subject an effective amount of the inventive ABP. In some aspects, the effector T cell is a CD4+ effector T cell. In some aspects, the effector T cell is a CD8+ effector T cell.

[0429] In some embodiments, the invention provides a method of terminating the suppression of an effector T cell by a regulatory T cell in a subject in need thereof by administering to the subject an effective amount of the inventive ABP. In some aspects, the regulatory T cell is a CD4+CD25+Foxp3+ regulatory T cell. In some aspects, the regulatory T cell is a CD8+CD25+ regulatory T cell.

[0430] In some embodiments, the invention provides a method of increasing natural killer (NK) or natural killer T (NKT) cell activity in a subject in need thereof by administering to the subject an effective amount of the inventive ABP.

[0431] In some embodiments, the invention provides a method for enhancing an immune response in a subject in need thereof by administering to the subject an effective amount of an ABP of the invention.

[0432] In some embodiments, the invention provides a method of delaying the onset of tumor development in a subject in need thereof by administering to the subject an effective amount of an ABP of the invention.

[0433] In some embodiments, the invention provides a method of preventing the onset of tumor development in a subject in need thereof by administering to the subject an effective amount of the inventive ABP.

[0434] In some embodiments, the invention provides a method of delaying the onset of cancer in a subject in need thereof by administering to the subject an effective amount of an ABP of the invention.

[0435] In some embodiments, the invention provides a method of preventing the onset of cancer in a subject in need thereof by administering to the subject an effective amount of an ABP of the invention.

[0436] In some embodiments, the invention provides a method of reducing the size of a tumor in a subject in need thereof by administering to the subject an effective amount of the inventive ABP.

[0437] In some embodiments, the invention provides a method for reducing the number of metastases in a subject in need thereof by administering to the subject an effective amount of the inventive ABP.

[0438] In some embodiments, the invention provides a method of delaying the onset of a viral infection in a subject in need thereof by administering to the subject an effective amount of an ABP of the invention.

[0439] In some embodiments, the invention provides a method of preventing a subject from developing a viral infection in a subject in need thereof by administering to the subject an effective amount of an ABP of the invention.

[0440] In some embodiments, the invention provides a method of reducing the virus titer of a subject in need thereof by administering to the subject an effective amount of the inventive ABP.

[0441] In some embodiments, the invention provides a method of eliminating a virus from a subject in need thereof by administering to the subject an effective amount of an ABP of the invention.

[0442] In some embodiments, the invention provides a method of increasing overall survival, median survival, or progression-free survival in a subject in need thereof by administering to the subject an effective amount of the inventive ABP.

[0443] In some embodiments, the invention provides a method of treating a subject who has become resistant to standard medical treatment by administering to the subject an effective amount of the inventive ABP. In some embodiments, the standard medical treatment to which the subject has become resistant is treatment with a PD-1 inhibitor. In other embodiments, the standard medical treatment to which the subject has become resistant is treatment with a PD-L1 inhibitor. In other embodiments, the standard medical treatment to which the subject has become resistant is treatment with a CTLA-4 inhibitor.

8. Combination therapies

[0444] In some embodiments, the ABP of the invention is administered with at least one additional therapeutic agent. Any suitable additional therapeutic agent may be administered with the ABP of the invention. In some aspects, the additional therapeutic agent is selected from radiation therapy, a cytotoxic agent, a chemotherapeutic agent, a cytostatic agent, an antihormonal agent, an EGFR inhibitor, an immunostimulatory agent, an antiangiogenic agent, and a combination thereof.

[0445] In some embodiments, the ABP of the invention is administered after surgical removal of the tumor.

[0446] In some embodiments, the additional therapeutic agent includes an epigenetic modifier. Examples of epigenetic modifiers include DNA methyltransferase (DNMT) inhibitors such as 5-aza-2'-deoxycytidine or 5-azacytidine, which have been approved for use in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and histone deacetylase inhibitors. (HDis), including vorinostat, romidepsin, panobinostat, belinostat and entinostat, which have been shown to be active in cutaneous T-cell lymphoma and peripheral T-cell lymphoma. In some embodiments, at least one additional therapeutic agent is an epigenetic modifier combined with a PD-1 inhibitor PD-L1.

[0447] In some embodiments, the additional therapeutic agent includes an immunostimulatory agent.

[0448] In some embodiments, the immunostimulatory agent is an agent that blocks the activation of an inhibitory immune cell receptor signaling pathway or a ligand thereof. In some aspects, the inhibitory receptor or its ligand is selected from cytotoxic T-lymphocyte-associated protein (CTLA-4, also referred to as CD152), programmed cell death protein 1 (also PD-1 or CD279), programmed cell death ligand 1 (also PD- L1 or CD274), transforming growth factor beta (TGFβ), lymphocyte activation gene-3 (LAG-3, also CD223), Tim-3 (hepatitis A virus cell receptor-2 or HAVCR2 or CD366), neuritin, B- and T-lymphocytes (also BTLA or CD272), immunoglobulin-like killer cell receptors (KIRs), and combinations thereof. In some aspects, the agent is selected from an anti-PD-1 antibody (eg, pembrolizumab or nivolumab) and an anti-PD-L1 antibody (eg, atezolizumab), an anti-CTLA-4 antibody (eg, ipilimumab), an anti-TIM3 antibody, cell adhesion molecules carcinoembryonic antigen 1 (CECAM-1, also CD66a) and 5 (CEACAM-5, also CD66e), immunoregulatory receptor v-set (also VISR or VISTA), leukocyte-coupled immunoglobulin-like receptor 1 (also LAIR1 or CD305), CD160 , the natural killer cell 2B4 receptor (also CD244 or SLAMF4), and combinations thereof. In some aspects, the agent is pembrolizumab. In some aspects, the agent is nivolumab. In some aspects, the agent is atezolizumab.

[0449] In some embodiments, the additional therapeutic agent is an agent that inhibits the interaction between PD-1 and PD-L1. In some aspects, the additional therapeutic agent that inhibits the interaction between PD-1 and PD-L1 is selected from an antibody, a peptidomimetic, and a small molecule. In some aspects, the additional therapeutic agent that inhibits the interaction between PD-1 and PD-L1 is selected from pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), atezolizumab, avelumab, pidilizumab, durvalumab, BMS-936559, sulfamonomethoxin 1, and sulfamethizole 2. In some embodiments, the additional therapeutic agent that inhibits the interaction between PD-1 and PD-L1 is any therapeutic agent known to have such activity, such as that described in Weinmann et al., Chem Med Chem, 2016, 14:1576 (DOI: 10.1002/cmdc.201500566), the contents of which are incorporated into the present invention by reference. In some embodiments, an agent that inhibits the interaction between PD-1 and PD-L1 is formulated in the same pharmaceutical composition as the inventive ABP. In some embodiments, an agent that inhibits the interaction between PD-1 and PD-L1 is formulated in a pharmaceutical composition other than the inventive ABP. In some embodiments, an agent that inhibits the interaction between PD-1 and PD-L1 is administered prior to administration of the inventive ABP. In some embodiments, an agent that inhibits the interaction between PD-1 and PD-L1 is administered after administration of the inventive ABP. In some embodiments, an agent that inhibits the interaction between PD-1 and PD-L1 is administered concurrently with the ABP of the invention, but the agent and ABP are administered in separate pharmaceutical compositions.

[0450] In some embodiments, the immunostimulatory agent is an immune cell costimulatory receptor agonist. In some aspects, the costimulatory receptor is selected from GITR, OX40, ICOS, LAG-2, CD27, CD28, 4-1BB, CD40, STING, toll-like receptor, RIG-1, and NOD-like receptor. In some embodiments, the agonist is an antibody.

[0451] In some embodiments, the immunostimulatory agent modulates the activity of the arginase, indolamine-2,3-dioxygenase, or adenosine A2A receptor.

[0452] In some embodiments, the immunostimulatory agent is a cytokine. In some aspects, the cytokine is selected from IL-2, IL-5, IL-7, IL-12, IL-15, IL-21, and combinations thereof.

[0453] In some embodiments, the immunostimulatory agent is an oncolytic virus. In some aspects, the oncolytic virus is selected from herpes simplex virus, vesicular stomatitis virus, adenovirus, pseudodistemper virus, vaccinia virus, and Marab virus.

[0454] In some embodiments, the immunostimulatory agent is a chimeric antigen receptor T cell (CAR-T cell). In some embodiments, the immunostimulatory agent is a bi- or polyspecific antibody directed to a T cell. In some embodiments, the immunostimulatory agent is an anti-TGF-β antibody. In some embodiments, the immunostimulatory agent is a TGF-β decoy.

[0455] In some embodiments, the additional therapeutic agent is a tumor antigen vaccine. Any suitable antigen can be targeted by the vaccine, provided it is present in the tumor being treated with the treatments of the invention. In some aspects, the tumor antigen is a tumor antigen that is overexpressed compared to its expression levels in normal tissue. In some aspects, the tumor antigen is selected from testicular cancer antigen, differentiation antigen, NY-ESO-1, MAGE-A1, MART, and combinations thereof.

[0456] In addition, examples of additional therapeutic agents include a taxane (eg, paclitaxel or docetaxel); a platinum compound agent (eg carboplatin, oxaliplatin and/or cisplatin); a topoisomerase inhibitor (eg, irinotecan, topotecan, etoposide and/or mitoxantrone); folinic acid (eg leucovorin) or a nucleoside metabolic inhibitor (eg fluorouracil, capecitabine and/or gemcitabine). In some embodiments, the additional therapeutic agent is folinic acid, 5-fluorouracil and/or oxaliplatin. In some embodiments, the additional therapeutic agent is 5-fluorouracil and irinotecan. In some embodiments, the additional therapeutic agent is a taxane and a platinum compound agent. In some embodiments, the additional therapeutic agent is paclitaxel and carboplatin. In some embodiments, the additional therapeutic agent is pemetrexate. In some embodiments, the additional therapeutic agent is a targeted therapeutic agent, such as an EGFR, RAF, or MEK targeting agent.

[0457] The additional therapeutic agent may be administered by any suitable route. In some embodiments, the ABP of the invention and the additional therapeutic agent are included in the same pharmaceutical composition. In some embodiments, the ABP of the invention and the additional therapeutic agent are included in different pharmaceutical compositions.

[0458] In embodiments in which the inventive ABP and the additional therapeutic agent are included in different pharmaceutical compositions, the administration of the ABP may be before, simultaneously with, and/or after the administration of the additional therapeutic agent. In some aspects, the administration of the inventive ABP and the additional therapeutic agent is approximately one month apart from each other. In some aspects, the administration of the inventive ABP and the additional therapeutic agent is approximately one week apart from each other. In some aspects, the administration of the inventive ABP and the additional therapeutic agent is approximately one day apart from each other. In some aspects, the administration of the inventive ABP and the additional therapeutic agent is approximately twelve hours apart. In some aspects, the administration of the inventive ABP and the additional therapeutic agent is approximately one hour apart from each other.

[0459] In one aspect, the present invention provides a pharmaceutical composition comprising an effective amount of an anti-hTIGIT antibody for treating or preventing cancer in a subject, wherein the composition is administered in combination with an antibody against Tim-3, 4-1BB, GITR, PD-1, or PD-L1, or OX40L, wherein the hTIGIT antibody comprises CDR-H3 of SEQ ID NO: 32, CDR-H2 of SEQ ID NO: 40, CDR-H1 of SEQ ID NO: 54, CDR-L3 of SEQ ID NO: 64, CDR-L2 of SEQ ID NO: 68 and CDR-L1 of SEQ ID NO: 71. In one aspect, the present invention provides a pharmaceutical composition comprising an effective amount of an anti-hTIGIT antibody for treating or preventing cancer in a subject, wherein the composition is administered in combination with an antibody against Tim-3, 41BB, GITR, PD-1 or PD-L1, or OX40L, wherein the anti-hTIGIT antibody comprises V _H of SEQ ID NO: 13 and V _L of SEQ ID NO: 26. In one asp ect, the present invention provides a pharmaceutical composition comprising an effective amount of an anti-hTIGIT antibody for treating or preventing cancer in a subject, wherein the composition is administered in combination with an antibody against Tim-3, 41BB, GITR, PD-1 or PD-L1, or OX40L where the anti-hTIGIT antibody comprises the heavy chain of SEQ ID NO: 99 and the light chain of SEQ ID NO: 92.

[0460] In one aspect, the present invention provides an anti-hTIGIT antibody for use in treating or preventing cancer in a subject, wherein the anti-hTIGIT antibody is administered in combination with an anti-Tim-3, 41BB, GITR, PD-1, or PD-L1 antibody, or OX40L, wherein the hTIGIT antibody comprises CDR-H3 of SEQ ID NO: 32, CDR-H2 of SEQ ID NO: 40, CDR-H1 of SEQ ID NO: 54, CDR-L3 of SEQ ID NO: 64, CDR- L2 of SEQ ID NO: 68 and CDR-L1 of SEQ ID NO: 71. In one aspect, the present invention provides an anti-hTIGIT antibody for use in the treatment or prevention of cancer in a subject, wherein the anti-hTIGIT antibody is administered in combination with an anti-Tim antibody. -3, 41BB, GITR, PD-1 or PD-L1, or OX40L, wherein the hTIGIT antibody comprises the V _H sequence of SEQ ID NO: 13 and the V _L sequence of SEQ ID NO: 26. In one aspect, the present invention provides an antibody against hTIGIT for application n in the treatment or prevention of cancer in a subject, wherein the hTIGIT antibody is administered in combination with an antibody against Tim-3, 41BB, GITR, PD-1 or PD-L1, or OX40L, wherein the hTIGIT antibody comprises the heavy chain of SEQ ID NO: 99 and a light chain of the sequence SEQ ID NO: 92.

9. Diagnostic methods

[0461] In addition, methods are provided for detecting the presence of TIGIT on cells taken from a subject. Such methods can be used, for example, to predict and evaluate responsiveness to treatment with the ABP of the invention.

[0462] In some embodiments, a blood sample is taken from the subject and the fraction of cells expressing TIGIT is determined. In some aspects, the relative amount of TIGIT expressed by such cells is determined. The fraction of cells expressing TIGIT and the relative amount of TIGIT expressed by such cells can be determined by any suitable method. In some embodiments, flow cytometry is used to make such measurements. In some embodiments, fluorescence-assisted cell sorting (FACS) is used to make such a measurement. For methods for assessing TIGIT expression in peripheral blood, see Li et al., J Autoimmunity, 2003, 21:83-92.

10. Sets

[0463] In addition, kits are provided that include the ABPs of the invention. The kits can be used to treat, prevent and/or diagnose the disease or disorder described in the invention.

[0464] In some embodiments, the kit includes a container and a label or package leaflet attached to the container or associated with the container. Suitable containers include, for example, bottles, ampoules, syringes and bags for intravenous solutions. Containers can be made from various materials such as glass or plastic. The container contains a composition that, by itself, or in combination with another composition, is effective in treating, preventing and/or diagnosing a disease or disorder. The container may have a sterile inlet. For example, if the container is an intravenous solution bag or vial, it may have an entry hole that can be pierced with a needle. At least one active agent in the composition is an ABP according to the invention. The label or instructions for use of the medicinal product enclosed in the package indicates that the composition is intended for the treatment of the specified condition.

[0465] In some embodiments, the kit includes (a) a first container containing a first composition, wherein the first composition comprises an inventive ABP; and (b) a second container containing a second composition, wherein the second composition includes an additional therapeutic agent. The kit in this embodiment of the invention may further include enclosed package leaflet indicating that the compositions may be used to treat a particular condition.

[0466] Alternatively or additionally, the kit may also include a second (or third) container containing a pharmaceutically acceptable excipient. In some aspects, the excipient is a buffer. In addition, the kit may include other materials required from a commercial and consumer point of view, including filters, needles, and syringes.

EXAMPLES

[0467] The following are examples of the methods and compositions of the invention. It should be borne in mind that various other embodiments may be practiced in accordance with the general description given in the invention.

Example 1 Mutation Analysis for Epitope Determination

Alanine scan

[0468] To identify an epitope for binding MAB10 to human TIGIT, single point mutations were performed at position 18 of alanine. The proteins were expressed in HEK-293 cells, secreted as a soluble protein, purified on Ni-NTA resin and analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Binding was assessed by biomolecular layer interferometry (BLI) using the Octet platform. MAB10 was captured on anti-human Fc sensors, washed and exposed to either monomeric wild-type human TIGIT or one of the selected point mutants. The reviewed portion of the binding epitope residues showed reduced binding (eg, K _D more than 5-fold lower than binding to wild-type human TIGIT). Alanine substitution at residues Q56, N58, L65, I68, N70, L73, H76, I77 and P79 resulted in decreased binding. Alanine substitution at residues M23, T24, T55, Q62, S78, S80, K82, Y113, and P114 did not reduce binding.

[0469] To identify an epitope for MAB2, MAB15 and MAB21 binding to human TIGIT, binding to alanine with point mutations at position 7 was assessed using the biomolecule layer interferometry (BLI) method described in the previous paragraph.

[0470] For MAB2, alanine substitution at residues Q56 and I77 resulted in reduced binding, and alanine substitution at residues I68, L73, H76, S78 and P79 did not result in reduced binding.

[0471] For MAB15, alanine substitution at residues Q56, I68, L73, H76, and I77 resulted in decreased binding, and alanine substitution at residues S78 and P79 did not result in reduced binding.

[0472] For MAB21, alanine substitution at residues Q56, I68, L73, and I77 resulted in decreased binding, and alanine substitution at residues H76, S78, and P79 did not result in reduced binding.

Mass spectrometry

[0473] To identify the epitope for MAB10 binding to human TIGIT, purified MAB10 and human TIGIT HIS samples were submitted to CovalX (Saugus, MA USA) for mass spectrometry analysis using a cross-linking methodology that allows detection of non-covalent interactions. Human MAB10 and HIS TIGIT were incubated with deuterated crosslinkers and subjected to multienzymatic digestion. After enrichment of the cross-linked peptides, the samples were analyzed by high resolution mass spectrometry. Proteolysis with both trypsin and elastase did not produce any crosslinked peptides, while proteolysis with chymotrypsin, ASP-N and thermolysin did detect at least one crosslinked peptide in a volume of 11 crosslinked peptides. The results indicate that the binding epitope includes residues that have been crosslinked. They include residues in two regions, one region including residues S78 and R84 and another region including residues T117, S129 and S130.

Crystallographic approach to determine the epitope

от тяжелой и легкой цепи представляли собой рассматриваемую часть эпитопа связывания и включали T55, Q56, L65, D72, L73, H76, I77, S78, P79 и H111.[0474] The MAB10 binding epitope was also identified by crystallographic studies. The MAB10 Fab was complexed with human TIGIT, purified by gel chromatography and concentrated to 10 mg/mL. Crystals were grown from a solution of 14% PEG4000, 0.1 MES pH 6, 10 mM β-nicotinamide adenine dinucleotide hydrate, 0.5% n-dodecyl-β-D-maltoside. X-ray analysis was performed at Argonne National Laboratories (GM/CA CAT 231D-D) and the resulting data was processed using CCP4 (Collaborative Computational Project No. 4, Software for Macromolecular X-Ray Crystallography) and Phenix (Python-based Hierarchical ENVIRONMENT for Integrated Xtallography). TIGIT residues at a contact distance of no more than

from the heavy and light chain were considered part of the binding epitope and included T55, Q56, L65, D72, L73, H76, I77, S78, P79 and H111.

Example 2 Combination Therapies Including Anti-TIGIT ABPs and Immunotherapies

[0475] To evaluate T cell immune responses in cytomegalovirus-specific (CMV+) T cells, a lymphoid cell proliferation assay was performed. Peripheral blood mononuclear cells (PBMCs) from individual donors that were screened for CMV antigenic reactivity were obtained from Astarte Biologics (Bothell, WA). Cell lysates from CMV-infected cells were also obtained from Astarte Biologics. Peripheral blood mononuclear cells (PBMCs) were plated at a density of 5×10 ⁵ cells/well, and antigen-specific stimulation was performed by adding a cell lysate that stimulates CMV+ T cells in the sample at 1 mg/ml, 0.1 mg/ml or 0.01 mg/ml. Unstimulated cells, stimulated cells without immunotherapy treatment, and stimulated cells with both control antibodies for the combined treatment group were used as controls. Experimental groups were treated with MAB10 (20 μg/ml) in combination with a control antibody for additional immunotherapy, with additional immunotherapy with IgG4 control antibody (as a control for MAB10) (see Table 6), or with a combination of MAB10 and additional therapeutic agent. Each treatment was performed on cells stimulated with all three lysate concentrations. Dosing of the immunotherapeutic agent was determined based on a combination of functional doses published in the literature, ED ₅₀ values and empirical data. Cells were cultured for four days and supernatants were collected and analyzed for the production of the effector cytokine TNF as a measure of activation.

Table 6

Immunotherapeutic agent Dose Manufacturing firm Catalog number Clone Function αTIM-3 25 µg/ml ^{eBioscience®} 16-3109-85 F38-2E2 Antagonist αTGF 10 µg/ml R&D ^Systems® MAB1835 1D11 Antagonist OX40L 500 ng/ml R&D ^Systems® 1054-OX-010 No information Agonist α41BB 30 µg/ml R&D ^Systems® AF838 Polyclonal Agonist αLAG-3 20 µg/ml ^Novus Biologicals® NBP1-97657 17B4 Antagonist PD-1 10 µg/ml Potenza Therapeutics™ No information pembro-lizumab Antagonist

αCTLA-4 20 µg/ml ^BioLegend® 349902 L3D10 Antagonist

results

[0476] The results are presented in Figure 1 as follows: Cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and pembrolizumab, either alone or in combination (Figure 1A -1C, respectively); cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and anti-TIM-3 antibody, either alone or in combination (Figures 1D-1F); cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and anti-41BB each alone or in combination (Figures 1G-1I); and cells were stimulated with 1 μg/ml, 0.1 μg/ml, or 0.01 μg/ml CMV lysate and treated with MAB10 and rhOX40L, either alone or in combination (Figures 1J-1L). Each combination treatment, including pembrolizumab, anti-TIM-3 antibody, anti-41BB antibody, or OX40 ligand, demonstrated an additive effect on immune activation (as measured by TNFα production) compared to single agent alone treatments.

[0477] In the case of treatment with anti-LAG-3 and anti-TGF, treatments with only one individual agent led to better results, and it was not possible to determine whether additive or synergistic effects were achieved in this study. Treatment with anti-CTLA-4 alone did not increase the immune response and therefore another assay should be used to determine any potential combination effects.

[0478] Further determination of the ability of MAB10 combinations to activate cells was performed using dissociated tumor cells (DTCs, Conversant Bio) from unmedicated cancer patients. DTCs are a single cell suspension containing all cells from a tumor sample, including immune cells, tumor cells, and supporting cells.

[0479] DTCs from a 50-year-old man with stage IV melanoma were cultured and stimulated with a control OVA peptide (3 μg/mL, Miltenyi Biotec, Cat# 130-099-771) or with a melanoma cell peptide mixture consisting of 1 µg/ml NY-ES0-1+1 µg/ml MelanA/MART-1+1 µg/ml gp100 (Miltenyi Biotec, Cat #s 130-095-381, 130-094-477 and 130-094-450, respectively). Anti-GITR antibody, MAB22 (see, for example, co-pending International Patent Application No. PCT/US 2017/062443), pembrolizumab, and MAB10 were added to the peptide-stimulated samples, either singly or in paired combinations. As a control, equal amounts of isotype control antibodies were used. In the case of stimulation with only one antibody, the total amount of antibody was kept constant by adding an isotype control antibody. MAB10 and pembrolizumab were used at a final concentration of 10 μg/ml, and MAB22 was used at a final concentration of 1 μg/ml. To assess activation, cells were cultured for 7 days, supernatants were collected and IFNγ produced was quantified using AlphaLISA® reagents (PerkinElmer). Statistical significance was calculated using one-way analysis of variance with multiple comparisons.

results

[0480] As can be seen in Figure 2A, each combination therapy treatment resulted in greater stimulation of IFNγ production than treatment with each agent alone, suggesting an additive effect.

[0481] Further, DTCs from an 80-year-old woman with stage IIa non-small cell lung cancer (NSCLC) were cultured and left unstimulated or stimulated with soluble anti-CD3+ and anti-CD28 antibodies (Becton Dickenson Cat#s 555336 and 555726, respectively) for two days. As a control, an equal amount of isotype control antibody (IgG4) was used. In the case of stimulation with only one antibody, the total amount of antibody was kept constant by adding an isotype control antibody. MAB10 and pembrolizumab were used at a final concentration of 10 mg/ml. To evaluate activation, brefeldin A (EBioscience, Cat# 00-4506-51) was added to cells during the last 5 hours of culture, and fluorescence-activated cell sorter (FACS) analysis and quantification of IFNγ CD4+ and CD8+ T- production were performed. cells using intracellular cytokine staining. Statistical significance was calculated using one-way analysis of variance with multiple comparisons.

results

[0482] As seen in Figure 2B, treatment of cells with the combination of MAB10 and pembrolizumab produced an additive effect compared to treatment with the agent alone, as measured by IFNγ production in both CD4+ and CD8+ T cells.

Example 3 Combination Therapies Including Anti-TIGIT ABPs and an Immunotherapeutic Agent in Vivo

[0483] To determine if the combination of an anti-TIGIT antibody and an anti-neuropilin-1 antibody provides an increase in antitumor activity compared to single agents in vivo, the combination was tested in the EMT6 experimental mouse model of breast cancer (Charles River Labs).

[0484] Antibodies against NRP-1 are described, for example, in the co-pending International Patent Application No. PCT/US2017/067782, filed December 21, 2017, which also discloses a panel of mouse versions of anti-NRP-1 antibodies tested as chimeric mouse IgG2a antibodies containing an N297A mutation that abolishes the effector function of antibody-mediated cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).

[0485] To test the combination of anti-NRP and anti-TIGIT antibodies in mice, a mouse version of the anti-human NRP-1 antibody, MAB23 (mouse version of "mMAB23", SEQ ID NOS: l43-144, Appendix A), was used in combination with an anti-human NRP-1 antibody, Rodent TIGIT, 1B4 (mouse IgG1, Cell Essentials). The control antibody used was mouse IgG2b MPC-11 (BioXCell, Cat#BE0086).

EMT6 tumor model

[0486] Balb/c female mice were inoculated with 1×10 ⁵ EMT6 cells. Mice were randomized by tumor volume into 12 groups after tumors reached an average size of 80-120 mm ³ . Treatment (treatment) was started on the same day that randomization was performed. Antibodies were administered by intraperitoneal (ip) injection. Tumors and body weights were measured three times a week. The study was terminated on day 40, or when the mean tumor volume reached 2000 mm ³ regardless of the treatment group.

results

[0487] In an EMT6 tumor study in mice, combined treatment with mMAB23 and 1B4 inhibited tumor growth to a greater extent than their control alone (Figure 3A-3B). Combination treatment including 250 μg mouse mMAB23+250 μg 1B4 achieved 57.4% TGI (tumor growth inhibition), and combination treatment including 500 μg mMAB23+500 μg 1B4 achieved 69.4% TGI compared to treatment control antibody. Combined treatment with mMAB23+1B4 at both concentrations was statistically significant after 14 days of treatment (p<0.05). Treatment with anti-PD-1 achieved a 60.2% TGI on day 14. Evaluation of curves versus time for control, rat anti-mouse αPD-1 (clone RMP1-14), agent alone (250 μg) and combination ( 250 µg each) using mixed model analysis (similar to repeated measures analysis of variance (RM ANOVA)) showed that both αPD-1 and mMAB239+1B4 combination treatments were significantly different from the control group and from both treatments alone (p<0 .03).

[0488] Analysis of the gossamer growth curves of individual tumors from all treated mice showed a marked slowdown in tumor growth in mice treated with a combination of mMAB23 and 1B4 (Figure 3C-3D). The individual EMT6 tumor volumes for each of the 8 mice per group are for all treated groups (indicated at the top of each graph). EMT6 mouse tumor cells were injected into female BALB/c mice and the mice were randomized for a mean tumor size of 80-120 mm3. Treatment was started at random and indicated antibodies were administered ip at 1000 μg/animal (control IgG2b and 1B4), 500 μg/animal (mMAB23 and 1B4), 250 μg/animal (mMAB23 and 1B4) or 200 μg/animal (αPD- one). Black arrows indicate treatment days. The study ended on day 40, or when the mean tumor volume reached 2000 mm ³ regardless of the treatment group.

[0489] These data show that the combination of mMAB23 and 1B4 allows for increased inhibition of tumor growth compared to using the agents alone. Mice treated with this combination showed marked tumor growth inhibition (57.4% TGI and 69.4% TGI for 250 µg and 500 µg of each antibody, respectively) that was similar to treatment with anti-PD-1 (60.2% TGI).

INCLUDING IN THE DESCRIPTION OF THE INVENTION THE CONTENTS OF CITED PUBLICATIONS BY REFERENCE TO THEM

[0490] The contents of all cited patent and non-patent publications are incorporated in all respects in the present invention by reference to them.

OTHER IMPLEMENTATION OPTIONS

[0491] the above invention may cover many separate inventions with independent utility. While each of these inventions has been disclosed in its preferred form(s), nonetheless, the specific embodiments thereof disclosed and illustrated in this invention should not be construed as limitations as many variations may exist. The subject matter of the inventions includes all novel and non-obvious combinations and subcombinations of various elements, features, functions and/or properties disclosed in the present invention. The following claims specifically indicate certain combinations and subcombinations that are recognized as novel and non-obvious. Inventions embodied in other combinations and subcombinations of features, functions, elements and/or properties may be claimed in this application, in applications claiming the priority of this application, or in related applications. Such claims, whether they relate to another invention or to the same invention, and whether they are broader, narrower, the same or different in scope than the original claims, are also considered to be included in the scope of the present invention. .

APPENDIX A: REFERENCE SEQUENCE TABLE

--->

SEQUENCE LIST

<110> POTENZA THERAPEUTICS, INC.

<120> ANTIGEN-BINDING PROTEINS AGAINST TIGIT AND METHODS OF THEIR APPLICATION

<130> 32248-40232/WO

<140> PCT/US2018/025460

<141> 2018-03-30

<150> 62/479.042

<151> 2017-03-30

<160> 144

<170>PatentIn version 3.5

<210> 1

<211> 244

<212> PROTEIN

<213> Homo sapiens

<220>

<221> OTHER_INDICATOR

<222> (1)..(244)

<223> /note="hTIGIT"

<400> 1

Met Arg Trp Cys Leu Leu Leu Ile Trp Ala Gln Gly Leu Arg Gln Ala

1 5 10 15

Pro Leu Ala Ser Gly Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn

20 25 30

Ile Ser Ala Glu Lys Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser

35 40 45

Ser Thr Thr Ala Gln Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln

50 55 60

Leu Leu Ala Ile Cys Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser

65 70 75 80

Phe Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln

85 90 95

Ser Leu Thr Val Asn Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr

100 105 110

Tyr Pro Asp Gly Thr Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu

115 120 125

Ser Ser Val Ala Glu His Gly Ala Arg Phe Gln Ile Pro Leu Leu Gly

130 135 140

Ala Met Ala Ala Thr Leu Val Val Ile Cys Thr Ala Val Ile Val Val

145 150 155 160

Val Ala Leu Thr Arg Lys Lys Lys Ala Leu Arg Ile His Ser Val Glu

165 170 175

Gly Asp Leu Arg Arg Lys Ser Ala Gly Gln Glu Glu Glu Trp Ser Pro Ser

180 185 190

Ala Pro Ser Pro Pro Gly Ser Cys Val Gln Ala Glu Ala Ala Pro Ala

195 200 205

Gly Leu Cys Gly Glu Gln Arg Gly Glu Asp Cys Ala Glu Leu His Asp

210 215 220

Tyr Phe Asn Val Leu Ser Tyr Arg Ser Leu Gly Asn Cys Ser Phe Phe

225 230 235 240

Thr Glu Thr Gly

<210> 2

<211> 245

<212> PROTEIN

<213> Crab Eating Macaque

<220>

<221> OTHER_ SIGN

<222> (1)..(245)

<223> /note="cTIGIT"

<400> 2

Met Arg Trp Cys Leu Phe Leu Ile Trp Ala Gln Gly Leu Arg Gln Ala

1 5 10 15

Pro Leu Ala Ser Gly Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn

20 25 30

Ile Ser Ala Lys Lys Gly Gly Ser Val Ile Leu Gln Cys His Leu Ser

35 40 45

Ser Thr Met Ala Gln Val Thr Gln Val Asn Trp Glu Gln His Asp His

50 55 60

Ser Leu Leu Ala Ile Arg Asn Ala Glu Leu Gly Trp His Ile Tyr Pro

65 70 75 80

Ala Phe Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu

85 90 95

Gln Ser Leu Thr Met Asn Asp Thr Gly Glu Tyr Phe Cys Thr Tyr His

100 105 110

Thr Tyr Pro Asp Gly Thr Tyr Arg Gly Arg Ile Phe Leu Glu Val Leu

115 120 125

Glu Ser Ser Val Ala Glu His Ser Ala Arg Phe Gln Ile Pro Leu Leu

130 135 140

Gly Ala Met Ala Met Met Leu Val Val Ile Cys Ile Ala Val Ile Val

145 150 155 160

Val Val Val Leu Ala Arg Lys Lys Lys Ser Leu Arg Ile His Ser Val

165 170 175

Glu Ser Gly Leu Gln Arg Lys Ser Thr Gly Gln Glu Glu Gln Ile Pro

180 185 190

Ser Ala Pro Ser Pro Pro Gly Ser Cys Val Gln Ala Glu Ala Ala Pro

195 200 205

Ala Gly Leu Cys Gly Glu Gln Gln Gly Asp Asp Cys Ala Glu Leu His

210 215 220

Asp Tyr Phe Asn Val Leu Ser Tyr Arg Ser Leu Gly Ser Cys Ser Phe

225 230 235 240

Phe Thr Glu Thr Gly

245

<210> 3

<211> 241

<212> PROTEIN

<213> House mouse

<220>

<221> OTHER_ SIGN

<222> (1)..(241)

<223> /note="mTIGIT"

<400> 3

Met His Gly Trp Leu Leu Leu Val Trp Val Gln Gly Leu Ile Gln Ala

1 5 10 15

Ala Phe Leu Ala Thr Gly Ala Thr Ala Gly Thr Ile Asp Thr Lys Arg

20 25 30

Asn Ile Ser Ala Glu Glu Gly Gly Ser Val Ile Leu Gln Cys His Phe

35 40 45

Ser Ser Asp Thr Ala Glu Val Thr Gln Val Asp Trp Lys Gln Gln Asp

50 55 60

Gln Leu Leu Ala Ile Tyr Ser Val Asp Leu Gly Trp His Val Ala Ser

65 70 75 80

Val Phe Ser Asp Arg Val Val Pro Gly Pro Ser Leu Gly Leu Thr Phe

85 90 95

Gln Ser Leu Thr Met Asn Asp Thr Gly Glu Tyr Phe Cys Thr Tyr His

100 105 110

Thr Tyr Pro Gly Gly Ile Tyr Lys Gly Arg Ile Phe Leu Lys Val Gln

115 120 125

Glu Ser Ser Val Ala Gln Phe Gln Thr Ala Pro Leu Gly Gly Thr Met

130 135 140

Ala Ala Val Leu Gly Leu Ile Cys Leu Met Val Thr Gly Val Thr Val

145 150 155 160

Leu Ala Arg Lys Lys Ser Ile Arg Met His Ser Ile Glu Ser Gly Leu

165 170 175

Gly Arg Thr Glu Ala Glu Pro Gln Glu Trp Asn Leu Arg Ser Leu Ser

180 185 190

Ser Pro Gly Ser Pro Val Gln Thr Gln Thr Ala Pro Ala Gly Pro Cys

195 200 205

Gly Glu Gln Ala Glu Asp Asp Tyr Ala Asp Pro Gln Glu Tyr Phe Asn

210 215 220

Val Leu Ser Tyr Arg Ser Leu Glu Ser Phe Ile Ala Val Ser Lys Thr

225 230 235 240

gly

<210> 4

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4; VH"

<400> 4

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Ser

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ala Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 5

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB2-IgG4; VH"

<400> 5

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Lys Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 6

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB3-IgG4; VH"

<400> 6

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 7

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB4-IgG4; VH"

<400> 7

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Gly Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 8

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB5-IgG4; VH"

<400> 8

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 9

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4; VH"

<400> 9

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 10

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB7-IgG4; VH"

<400> 10

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Val Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 11

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB8-IgG4; VH"

<400> 11

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ala Ser Gly

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Gln Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 12

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB9-IgG4; VH"

<400> 12

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 13

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB10-IgG4; VH"

<400> 13

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 14

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB11-IgG4; VH"

<400> 14

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 15

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB12-IgG4; VH"

<400> 15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 16

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4; VH"

<400> 16

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Gly Asn Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 17

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB14-IgG4; VH"

<400> 17

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 18

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB15-IgG4; VH"

<400> 18

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Glu Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Ile Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 19

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB16-IgG4; VH"

<400> 19

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Glu Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Ile Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Leu Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 20

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic - MAB17-IgG4; vh"

<400> 20

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Leu Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 21

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB18-IgG4; VH"

<400> 21

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 22

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB19-IgG4; VH"

<400> 22

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Val Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 23

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB20-IgG4; VH"

<400> 23

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Val

35 40 45

Gly Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 24

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB21-IgG4; VH"

<400> 24

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Thr Gln Lys Phe

50 55 60

Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 25

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4, MAB2-IgG4, MAB3-IgG4,

MAB4-IgG4, MAB5-IgG4; VL"

<400> 25

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 His Phe Asn Leu Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 26

<211> 109

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4, MAB7-IgG4, MAB8-IgG4,

MAB9-IgG4, MAB10-IgG4, MAB11-IgG4, MAB12-IgG4; VL"

<400> 26

Glu Ile Val Leu Thr Gln Ser Pro Gly 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 Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Thr Val Arg Pro

85 90 95

Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 27

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4, MAB14-IgG4, MAB15-IgG4,

MAB16-IgG4, MAB17-IgG4, MAB18-IgG4; VL"

<400> 27

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Val Val Trp Pro Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 28

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB19-IgG4, MAB20-IgG4, MAB21-IgG4; VL"

<400> 28

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg His Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ile Val Phe Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 29

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4, MAB2-IgG4, MAB3-IgG4,

MAB5-IgG4; H3-IMGT"

<400> 29

Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

1 5 10 15

<210> 30

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB4-IgG4; H3-IMGT"

<400> 30

Ala Arg Asp Ala Asn Tyr Tyr Gly Gly Ala Trp Ala Phe Asp Pro

1 5 10 15

<210> 31

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4, MAB7-IgG4, MAB8-IgG4,

MAB9-IgG4; H3-IMGT"

<400> 31

Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

1 5 10 15

<210> 32

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB10-IgG4, MAB11-IgG4, MAB12-IgG4;

H3-IMGT"

<400> 32

Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

1 5 10 15

<210> 33

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4, MAB14-IgG4, MAB15-IgG4,

MAB18-IgG4; H3-IMGT"

<400> 33

Ala Arg Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile

1 5 10

<210> 34

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB16-IgG4, MAB17-IgG4; H3-IMGT"

<400> 34

Ala Arg Gly Gly Arg Thr Thr Trp Ile Gly Ala Leu Asp Ile

1 5 10

<210> 35

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB19-IgG4, MAB20-IgG4, MAB21-IgG4;

H3-IMGT"

<400> 35

Ala Arg Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

1 5 10 15

<210> 36

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4; H2-Kabat"

<400> 36

Ser Ile Tyr Tyr Ser Gly Ala Thr Phe Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 37

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB2-IgG4, MAB3-IgG4, MAB4-IgG4;

H2-Kabat"

<400> 37

Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 38

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB5-IgG4; H2-Kabat"

<400> 38

Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser Leu Lys Gly

1 5 10 15

<210> 39

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4; H2-Kabat"

<400> 39

Ser Ile Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 40

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB7-IgG4, MAB9-IgG4, MAB10-IgG4,

MAB11-IgG4, MAB12-IgG4; H2-Kabat"

<400> 40

Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 41

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB8-IgG4; H2-Kabat"

<400> 41

Ser Ile Tyr Tyr Ser Gly Gln Thr Tyr Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 42

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4, MAB14-IgG4; H2-Kabat"

<400> 42

Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe Gln

1 5 10 15

gly

<210> 43

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB15-IgG4, MAB16-IgG4; H2-Kabat"

<400> 43

Ile Ile Asn Pro Ser Ile Gly Leu Thr Ser Tyr Ala Arg Lys Phe Gln

1 5 10 15

gly

<210> 44

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB17-IgG4, MAB18-IgG4; H2-Kabat"

<400> 44

Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Arg Lys Phe Gln

1 5 10 15

gly

<210> 45

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB19-IgG4; H2-Kabat"

<400> 45

Val Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe Gln

1 5 10 15

gly

<210> 46

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB20-IgG4; H2-Kabat"

<400> 46

Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe Gln

1 5 10 15

gly

<210> 47

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB21-IgG4; H2-Kabat"

<400> 47

Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Thr Gln Lys Phe Arg

1 5 10 15

gly

<210> 48

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4; H1-Chothia + Kabat"

<400> 48

Gly Ser Ile Thr Ser Ser Ser Tyr Tyr Trp Gly

1 5 10

<210> 49

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<220>

<221> source

<223> /note="Synthetic - MAB2-IgG4; H1-Chothia + Kabat"

<400> 49

Gly Ser Ile Ser Ser Ser Lys Tyr Tyr Trp Gly

1 5 10

<210> 50

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<220>

<221> source

<223> /note="Synthetic - MAB3-IgG4, MAB4-IgG4, MAB5-IgG4;

H1-Chothia + Kabat"

<400> 50

Gly Ser Ile Ser Ser Thr Ser His Tyr Trp Gly

1 5 10

<210> 51

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4; H1-Chothia + Kabat"

<400> 51

Gly Ser Ile Glu Ser Gly Ser Tyr Tyr Trp Gly

1 5 10

<210> 52

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB7-IgG4; H1-Chothia + Kabat"

<400> 52

Gly Ser Ile Glu Ser Gly Val Tyr Tyr Trp Gly

1 5 10

<210> 53

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB8-IgG4; H1-Chothia + Kabat"

<400> 53

Gly Ser Ile Ala Ser Gly Ser Tyr Tyr Trp Gly

1 5 10

<210> 54

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<220>

<221> source

<223> /note="Synthetic - MAB9-IgG4, MAB10-IgG4, MAB11-IgG4,

MAB12-IgG4; H1-Chothia + Kabat"

<400> 54

Gly Ser Ile Glu Ser Gly Leu Tyr Tyr Trp Gly

1 5 10

<210> 55

<211> 327

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - IgG4; constant, S228P stabilizing

the loop"

<400> 55

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 Pro 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 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

<210> 56

<211> 326

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - IgG4; constant S228P, N297A,

C terminal remote Lys"

<400> 56

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 Pro 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

Ala 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 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

325

<210> 57

<211> 330

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - IgG1; constant (G1m(3) allotype)"

<400> 57

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

Arg 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 Glu Glu

225 230 235 240

Met 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

<210> 58

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4; H1-Chothia + Kabat"

<400> 58

Tyr Thr Phe Gly Asn Tyr Tyr Met His

fifteen

<210> 59

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB14-IgG4, MAB18-IgG4; H1-Chothia

+ Kabat"

<400> 59

Tyr Thr Phe Pro Ala Tyr Tyr Met His

fifteen

<210> 60

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB15-IgG4, MAB16-IgG4; H1-Chothia

+ Kabat"

<400> 60

Tyr Thr Phe Arg Glu Tyr Tyr Met His

fifteen

<210> 61

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB17-IgG4; H1-Chothia + Kabat"

<400> 61

Tyr Thr Phe Pro Ala Tyr Tyr Ile His

fifteen

<210> 62

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB19-IgG4, MAB20-IgG4, MAB21-IgG4;

H1-Chothia + Kabat"

<400> 62

Tyr Thr Phe Thr Ser His Tyr Met Gly

fifteen

<210> 63

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4, MAB2-IgG4, MAB3-IgG4,

MAB4-IgG4, MAB5-IgG4; L3 - Chothia/Kabat/IMGT"

<400> 63

Gln Gln His Phe Asn Leu Pro Thr

fifteen

<210> 64

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4, MAB7-IgG4, MAB8-IgG4,

MAB9-IgG4, MAB10-IgG4, MAB11-IgG4, MAB12-IgG4; L-Chothia/Kabat/IMGT"

<400> 64

Gln Gln His Thr Val Arg Pro Pro Leu Thr

1 5 10

<210> 65

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4, MAB14-IgG4, MAB15-IgG4,

MAB16-IgG4, MAB17-IgG4, MAB18-IgG4; L3-Chothia/

Kabat/IMGT"

<400> 65

Gln Gln Tyr Val Val Trp Pro Pro Leu Thr

1 5 10

<210> 66

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB19-IgG4, MAB20-IgG4, MAB21-IgG4;

L3 - Chothia/Kabat/IMGT"

<400> 66

Gln Gln Tyr Ile Val Phe Pro Trp Thr

fifteen

<210> 67

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4, MAB2-IgG4, MAB3-IgG4,

MAB4-IgG4, MAB5-IgG4; L2-Chothia/Kabat"

<400> 67

Asp Ala Ser Asn Arg Ala Thr

fifteen

<210> 68

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4, MAB7-IgG4, MAB8-IgG4,

MAB9-IgG4, MAB10-IgG4, MAB11-IgG4, MAB12-IgG4; L2- Chothia/Kabat"

<400> 68

Gly Ala Ser Ser Arg Ala Thr

fifteen

<210> 69

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4, MAB14-IgG4, MAB15-IgG4,

MAB16-IgG4, MAB17-IgG4, MAB18-IgG4, MAB19-IgG4, MAB20-IgG4, MAB21-IgG4;

L2-Chothia/Kabat"

<400> 69

Gly Ala Ser Thr Arg Ala Thr

fifteen

<210> 70

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB1-IgG4, MAB2-IgG4, MAB3-IgG4,

MAB4-IgG4; L1-Chothia/Kabat"

<400> 70

Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala

1 5 10

<210> 71

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB6-IgG4, MAB7-IgG4, MAB8-IgG4,

MAB9-IgG4, MAB10-IgG4, MAB11-IgG4, MAB12-IgG4; L1-Chothia/Kabat"

<400> 71

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 72

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - MAB13-IgG4, MAB14-IgG4, MAB15-IgG4,

MAB16-IgG4, MAB17-IgG4, MAB18-IgG4, MAB19-IgG4, MAB20

-IgG4, MAB21-IgG4; L1-Chothia/Kabat"

<400> 72

Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala

1 5 10

<210> 73

<211> 446

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - SEC1; IgG4 S228P human heavy chain"

<400> 73

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Thr Gln Pro Gly Lys

1 5 10 15

Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Thr Met His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Ser Gly Ser Gly Ile Val Phe Tyr Ala Asp Ala Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe

65 70 75 80

Leu Gln Met Asn Asp Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Arg Pro Leu Gly His Asn Thr Phe Asp Ser Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val

260 265 270

Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 74

<211> 119

<212> PROTEIN

<213> Homo sapiens

<220>

<221> OTHER_ SIGN

<222> (1)..(119)

<223> /note="SEC1; heavy chain variable region"

<400> 74

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Thr Gln Pro Gly Lys

1 5 10 15

Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Thr Met His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Ser Gly Ser Gly Ile Val Phe Tyr Ala Asp Ala Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe

65 70 75 80

Leu Gln Met Asn Asp Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Arg Pro Leu Gly His Asn Thr Phe Asp Ser Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 75

<211> 220

<212> PROTEIN

<213> Homo sapiens

<220>

<221> OTHER_ SIGN

<222> (1)..(220)

<223> /note="SEC1 human kappa chain"

<400> 75

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Tyr Tyr Ser

20 25 30

Gly Val Lys Glu Asn Leu Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Ile Arg Phe Thr Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

65 70 75 80

Ile Thr Ser Val Gln Ala Glu Asp Met Gly Gln Tyr Phe Cys Gln Gln

85 90 95

Gly Ile Asn Asn Pro Leu Thr Phe Gly Asp Gly Thr Lys Leu Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 76

<211> 113

<212> PROTEIN

<213> Homo sapiens

<220>

<221> OTHER_ SIGN

<222> (1)..(113)

<223> /note="SEC1; light chain variable region"

<400> 76

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Tyr Tyr Ser

20 25 30

Gly Val Lys Glu Asn Leu Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Ile Arg Phe Thr Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

65 70 75 80

Ile Thr Ser Val Gln Ala Glu Asp Met Gly Gln Tyr Phe Cys Gln Gln

85 90 95

Gly Ile Asn Asn Pro Leu Thr Phe Gly Asp Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 77

<211> 449

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - SEC1; mouse IgG2a N297A heavy chain"

<400> 77

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Thr Gln Pro Gly Lys

1 5 10 15

Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Phe

20 25 30

Thr Met His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Ser Gly Ser Gly Ile Val Phe Tyr Ala Asp Ala Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe

65 70 75 80

Leu Gln Met Asn Asp Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Arg Pro Leu Gly His Asn Thr Phe Asp Ser Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val Tyr

115 120 125

Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu

130 135 140

Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp

145 150 155 160

Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser

180 185 190

Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser

195 200 205

Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys

210 215 220

Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro

225 230 235 240

Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser

245 250 255

Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp

260 265 270

Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr

275 280 285

Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Ala Ser Thr Leu Arg Val

290 295 300

Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu

305 310 315 320

Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg

325 330 335

Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val

340 345 350

Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr

355 360 365

Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr

370 375 380

Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys

405 410 415

Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu

420 425 430

Gly Leu His Asn His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly

435 440 445

Lys

<210> 78

<211> 220

<212> PROTEIN

<213> House mouse

<220>

<221> OTHER_ SIGN

<222> (1)..(220)

<223> /note="SEC1; mouse kappa chain"

<400> 78

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Tyr Tyr Ser

20 25 30

Gly Val Lys Glu Asn Leu Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Ile Arg Phe Thr Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

65 70 75 80

Ile Thr Ser Val Gln Ala Glu Asp Met Gly Gln Tyr Phe Cys Gln Gln

85 90 95

Gly Ile Asn Asn Pro Leu Thr Phe Gly Asp Gly Thr Lys Leu Glu Ile

100 105 110

Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser

115 120 125

Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn

130 135 140

Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu

145 150 155 160

Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr

180 185 190

Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr

195 200 205

Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys

210 215 220

<210> 79

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB1; full length IgG4 S228P"

<400> 79

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Ser

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ala Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 80

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB1; full length IgG1"

<400> 80

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Ser

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ala Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 81

<211> 213

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB1, MAB2, MAB3, MAB4, MAB5;

full size mouth guard

<400> 81

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 His Phe Asn Leu Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210> 82

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB2; full length IgG4 S228P"

<400> 82

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Lys Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 83

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB2; full length IgG1"

<400> 83

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Lys Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 84

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB3; full length IgG4 S228P"

<400> 84

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 85

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB3; full length IgG1"

<400> 85

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 86

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB4; full length IgG4 S228P"

<400> 86

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Gly Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 87

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB4; full length IgG1"

<400> 87

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Gly Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 88

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB5; full length IgG4 S228P"

<400> 88

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 89

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB5; full length IgG1"

<400> 89

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser

50 55 60

Leu Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 90

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB6; full length IgG4 S228P"

<400> 90

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 91

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB6; full length IgG1"

<400> 91

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 92

<211> 216

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB6, MAB7, MAB8, MAB9, MAB10,

MAB11, MAB12; full size mouth guard

<400> 92

Glu Ile Val Leu Thr Gln Ser Pro Gly 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 Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Thr Val Arg Pro

85 90 95

Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val

100 105 110

Ala Ala Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys

115 120 125

Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg

130 135 140

Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn

145 150 155 160

Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser

165 170 175

Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys

180 185 190

Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr

195 200 205

Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 93

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB7; full length IgG4 S228P"

<400> 93

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Val Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 94

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB7; full length IgG1"

<400> 94

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Val Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 95

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB8; full length IgG4 S228P"

<400> 95

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ala Ser Gly

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Gln Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 96

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB8; full length IgG1"

<400> 96

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ala Ser Gly

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Gln Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 97

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB9; full length IgG4 S228P"

<400> 97

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 98

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB9; full length IgG1"

<400> 98

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Thr Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 99

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB10; full length IgG4 S228P"

<400> 99

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 100

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB10; full length IgG1"

<400> 100

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 101

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB11; full length IgG4 S228P"

<400> 101

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 102

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB11; full length IgG1"

<400> 102

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 103

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB12; full length IgG4 S228P"

<400> 103

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 104

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB12; full length IgG1"

<400> 104

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Gly Ser Ile Glu Ser Gly

20 25 30

Leu Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 105

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB13; full length IgG4 S228P"

<400> 105

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Gly Asn Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

210 215 220

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

260 265 270

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 106

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB13; full length IgG1"

<400> 106

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Gly Asn Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met 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 Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 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 Glu Glu Met 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

<210> 107

<211> 215

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB13, MAB14, MAB15, MAB16, MAB17,

MAB18; full size mouth guard

<400> 107

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Val Val Trp Pro Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 108

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB14; full length IgG4 S228P"

<400> 108

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

210 215 220

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

260 265 270

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 109

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB14; full length IgG1"

<400> 109

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met 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 Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 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 Glu Glu Met 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

<210> 110

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB15; full length IgG4 S228P"

<400> 110

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Glu Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Ile Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

210 215 220

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

260 265 270

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 111

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB15; full length IgG1"

<400> 111

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Glu Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Ile Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met 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 Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 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 Glu Glu Met 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

<210> 112

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB16; full length IgG4 S228P"

<400> 112

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Glu Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Ile Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Leu Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

210 215 220

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

260 265 270

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 113

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB16; full length IgG1"

<400> 113

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Glu Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Ile Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Leu Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met 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 Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 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 Glu Glu Met 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

<210> 114

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB17; full length IgG4 S228P"

<400> 114

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Leu Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

210 215 220

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

260 265 270

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 115

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB17; full length IgG1"

<400> 115

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Leu Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met 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 Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 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 Glu Glu Met 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

<210> 116

<211> 448

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB18; full length IgG4 S228P"

<400> 116

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly

210 215 220

Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro

260 265 270

Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 117

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB18; full length IgG1"

<400> 117

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Ala Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Arg Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met 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 Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 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 Glu Glu Met 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

<210> 118

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB19; full length IgG4 S228P"

<400> 118

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Val Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 119

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB19; full length IgG1"

<400> 119

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Val Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 120

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB19, MAB20, MAB21;

full size mouth guard

<400> 120

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg His Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ile Val Phe Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe 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

<210> 121

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB20; full length IgG4 S228P"

<400> 121

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Val

35 40 45

Gly Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 122

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB20; full length IgG1"

<400> 122

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Val

35 40 45

Gly Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 123

<211> 450

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB21; full length IgG4 S228P"

<400> 123

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Thr Gln Lys Phe

50 55 60

Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu

260 265 270

Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Glu 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 Leu

435 440 445

Gly Lys

450

<210> 124

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - MAB21; full length IgG1"

<400> 124

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Met Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Thr Gln Lys Phe

50 55 60

Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Leu His Val Ser Gly Ser Tyr Tyr Pro Ala Tyr Leu Asp Tyr

100 105 110

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 125

<211> 330

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - IgG1; constant (G1m(17,1)

allotype, N297A"

<400> 125

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 Ala 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

<210> 126

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<220>

<221> source

<223> /note="Synthetic - kappa; constant"

<400> 126

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

<210> 127

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - linker"

<400> 127

Gly Gly Gly Gly Ser

fifteen

<210> 128

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H3"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Thr"

<220>

<221> OTHER_ SIGN

<222> (1)..(15)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 128

Ala Arg Asp Gly Val Leu Ala Leu Asn Lys Arg Ser Phe Asp Ile

1 5 10 15

<210> 129

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H2"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Gln" or "Gly"

<220>

<221> OTHER_ SIGN

<222> (1)..(16)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 129

Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 130

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<220>

<221> source

<223> /note="Synthetic - CDR-H1"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Ala"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Val" or "Ser"

<220>

<221> OTHER_ SIGN

<222> (1)..(11)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 130

Gly Ser Ile Glu Ser Gly Leu Tyr Tyr Trp Gly

1 5 10

<210> 131

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H3"

<220>

<221> OPTION

<222>(9)..(9)

<223> /replace="Gly"

<220>

<221> OTHER_ SIGN

<222> (1)..(15)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 131

Ala Arg Asp Ala Asn Tyr Tyr Gly Ser Ala Trp Ala Phe Asp Pro

1 5 10 15

<210> 132

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H2"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Ala"

<220>

<221> OPTION

<222> (16)..(16)

<223> /replace="Gly"

<220>

<221> OTHER_ SIGN

<222> (1)..(16)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 132

Ser Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 133

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H1"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Thr"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Thr"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Lys"

<220>

<221> OPTION

<222>(8)..(8)

<223> /replace="Tyr"

<220>

<221> OTHER_ SIGN

<222> (1)..(11)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 133

Gly Ser Ile Ser Ser Ser Ser His Tyr Trp Gly

1 5 10

<210> 134

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H3"

<220>

<221> OPTION

<222> (12)..(12)

<223> /replace="Leu"

<220>

<221> OTHER_ SIGN

<222> (1)..(14)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 134

Ala Arg Gly Gly Arg Thr Thr Trp Ile Gly Ala Phe Asp Ile

1 5 10

<210> 135

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide"

<220>

<221> source

<223> /note="Synthetic - CDR-H2"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Ile"

<220>

<221> OPTION

<222> (13)..(13)

<223> /replace="Arg"

<220>

<221> OTHER_ SIGN

<222> (1)..(17)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 135

Ile Ile Asn Pro Ser Leu Gly Leu Thr Ser Tyr Ala Gln Lys Phe Gln

1 5 10 15

gly

<210> 136

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H1"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Pro" or "Arg"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Ala" or "Glu"

<220>

<221> OPTION

<222>(8)..(8)

<223> /replace="Ile"

<220>

<221> OTHER_ SIGN

<222> (1)..(9)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 136

Tyr Thr Phe Gly Asn Tyr Tyr Met His

fifteen

<210> 137

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic peptide

<220>

<221> source

<223> /note="Synthetic - CDR-H2"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Ile"

<220>

<221> OPTION

<222> (12)..(12)

<223> /replace="Thr"

<220>

<221> OPTION

<222> (16)..(16)

<223> /replace="Arg"

<220>

<221> OTHER_ SIGN

<222> (1)..(17)

<223> /note="Variant residues given in sequence,

do not take precedence over variant residues in annotations

for variant positions"

<400> 137

Val Ile Asn Pro Ser Met Gly Ala Thr Ser Tyr Ala Gln Lys Phe Gln

1 5 10 15

gly

<210> 138

<211> 249

<212> PROTEIN

<213> House mouse

<220>

<221> source

<223> /note="mTIGIT2"

<400> 138

Met His Gly Trp Leu Leu Leu Val Trp Val Gln Gly Leu Ile Gln Ala

1 5 10 15

Ala Phe Leu Ala Thr Ala Ile Gly Ala Thr Ala Gly Thr Ile Asp Thr

20 25 30

Lys Arg Asn Ile Ser Ala Glu Glu Gly Gly Ser Val Ile Leu Gln Cys

35 40 45

His Phe Ser Ser Asp Thr Ala Glu Val Thr Gln Val Asp Trp Lys Gln

50 55 60

Gln Asp Gln Leu Leu Ala Ile Tyr Ser Val Asp Leu Gly Trp His Val

65 70 75 80

Ala Ser Val Phe Ser Asp Arg Val Val Pro Gly Pro Ser Leu Gly Leu

85 90 95

Thr Phe Gln Ser Leu Thr Met Asn Asp Thr Gly Glu Tyr Phe Cys Thr

100 105 110

Tyr His Thr Tyr Pro Gly Gly Ile Tyr Lys Gly Arg Ile Phe Leu Lys

115 120 125

Val Gln Glu Ser Ser Asp Asp Arg Asn Gly Leu Ala Gln Phe Gln Thr

130 135 140

Ala Pro Leu Gly Gly Thr Met Ala Ala Val Leu Gly Leu Ile Cys Leu

145 150 155 160

Met Val Thr Gly Val Thr Val Leu Ala Arg Lys Asp Lys Ser Ile Arg

165 170 175

Met His Ser Ile Glu Ser Gly Leu Gly Arg Thr Glu Ala Glu Pro Gln

180 185 190

Glu Trp Asn Leu Arg Ser Leu Ser Ser Pro Gly Ser Pro Val Gln Thr

195 200 205

Gln Thr Ala Pro Ala Gly Pro Cys Gly Glu Gln Ala Glu Asp Asp Tyr

210 215 220

Ala Asp Pro Gln Glu Tyr Phe Asn Val Leu Ser Tyr Arg Ser Leu Glu

225 230 235 240

Ser Phe Ile Ala Val Ser Lys Thr Gly

245

<210> 139

<211> 687

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<400> 139

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly

20 25 30

Leu Gly Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Gly Ile Tyr Glu Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala His Glu Arg Val Arg Gly Tyr Gly Asp Tyr Gly Gly His His Ala

100 105 110

Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser

115 120 125

Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr

130 135 140

Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

145 150 155 160

Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val

165 170 175

His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser

180 185 190

Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile

195 200 205

Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val

210 215 220

Glu Pro Lys Ser Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu

225 230 235 240

Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys

245 250 255

Ala Val Ser Gly Tyr Ser Ile Ser Ser Gly Leu Gly Trp Gly Trp Ile

260 265 270

Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Gly Ile Tyr Glu

275 280 285

Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile

290 295 300

Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val

305 310 315 320

Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala His Glu Arg Val Arg

325 330 335

Gly Tyr Gly Asp Tyr Gly Gly His His Ala Phe Asp Ile Trp Gly Gln

340 345 350

Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

355 360 365

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

370 375 380

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

385 390 395 400

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

405 410 415

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

420 425 430

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

435 440 445

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

450 455 460

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

465 470 475 480

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

485 490 495

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

500 505 510

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

515 520 525

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

530 535 540

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

545 550 555 560

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

565 570 575

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

580 585 590

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

595 600 605

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

610 615 620

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

625 630 635 640

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

645 650 655

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

660 665 670

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

675 680 685

<210> 140

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<400> 140

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 Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser 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 Gln Gln Glu Tyr Ala Thr Pro Pro

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe 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

<210> 141

<211> 454

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<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 Phe Thr Phe Ser Ser Val

20 25 30

Ala Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly 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 Lys Asp Pro Gly Tyr Asp Ser Ser Arg Tyr Tyr Tyr Ser Asn Tyr

100 105 110

Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala

115 120 125

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

130 135 140

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

145 150 155 160

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

165 170 175

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

180 185 190

Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr

195 200 205

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg

210 215 220

Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu

225 230 235 240

Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

245 250 255

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

260 265 270

Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

290 295 300

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

305 310 315 320

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

325 330 335

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

340 345 350

Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn

355 360 365

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

370 375 380

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

385 390 395 400

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg

405 410 415

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

420 425 430

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

435 440 445

Ser Leu Ser Leu Gly Lys

450

<210> 142

<211> 213

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<400> 142

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 Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser 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 Gln Gln Thr Tyr Ser Leu Tyr Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210> 143

<211> 457

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<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 Phe Thr Phe Ser Ser Val

20 25 30

Ala Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly 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 Lys Asp Pro Gly Tyr Asp Ser Ser Arg Tyr Tyr Tyr Ser Asn Tyr

100 105 110

Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala

115 120 125

Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp

130 135 140

Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe

145 150 155 160

Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly

165 170 175

Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser

180 185 190

Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr

195 200 205

Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile

210 215 220

Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro

225 230 235 240

Ala Pro Asn Leu Leu Gly Pro Ser Val Phe Ile Phe Pro Pro Lys

245 250 255

Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val

260 265 270

Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe

275 280 285

Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu

290 295 300

Asp Tyr Ala Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His

305 310 315 320

Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys

325 330 335

Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser

340 345 350

Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met

355 360 365

Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro

370 375 380

Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn

385 390 395 400

Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met

405 410 415

Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser

420 425 430

Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr

435 440 445

Lys Ser Phe Ser Arg Thr Pro Gly Lys

450 455

<210> 144

<211> 213

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

synthetic polypeptide

<400> 144

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 Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser 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 Gln Gln Thr Tyr Ser Leu Tyr Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Asp Ala Ala Pro

100 105 110

Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly

115 120 125

Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn

130 135 140

Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn

145 150 155 160

Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser

165 170 175

Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr

180 185 190

Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe

195 200 205

Asn Arg Asn Glu Cys

210

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Claims (47)

1. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of: (i) an antibody or antigen-binding fragment thereof, comprising: a) VH sequence of SEQ ID NO: 4 and VL sequence of SEQ ID NO: 25; b) VH sequence of SEQ ID NO: 5 and VL sequence of SEQ ID NO: 25; c) VH sequence of SEQ ID NO: 6 and VL sequence of SEQ ID NO: 25; d) VH sequence of SEQ ID NO: 7 and VL sequence of SEQ ID NO: 25; e) VH sequence of SEQ ID NO: 8 and VL sequence of SEQ ID NO: 25; f) VH sequence of SEQ ID NO: 9 and VL sequence of SEQ ID NO: 26; g) VH sequence of SEQ ID NO: 10 and VL sequence of SEQ ID NO: 26; h) VH sequence of SEQ ID NO: 11 and VL sequence of SEQ ID NO: 26; i) VH sequence of SEQ ID NO: 12 and VL sequence of SEQ ID NO: 26; j) VH sequence of SEQ ID NO: 13 and VL sequence of SEQ ID NO: 26; k) VH sequence of SEQ ID NO: 14 and VL sequence of SEQ ID NO: 26; l) VH sequence of SEQ ID NO: 15 and VL sequence of SEQ ID NO: 26; m) VH sequence of SEQ ID NO: 16 and VL sequence of SEQ ID NO: 27; n) VH sequence of SEQ ID NO: 17 and VL sequence of SEQ ID NO: 27; o) VH sequence of SEQ ID NO: 18 and VL sequence of SEQ ID NO: 27; p) VH sequence of SEQ ID NO: 19 and VL sequence of SEQ ID NO: 27; q) VH sequence SEQ ID NO: 20 and VL sequence SEQ ID NO: 27; r) VH sequence of SEQ ID NO: 21 and VL sequence of SEQ ID NO: 27; s) VH sequence of SEQ ID NO: 22 and VL sequence of SEQ ID NO: 28; t) VH sequence of SEQ ID NO: 23 and VL sequence of SEQ ID NO: 28; or u) VH sequence of SEQ ID NO: 24 and VL sequence of SEQ ID NO: 28; and (ii) one or more additional immunotherapeutic agents containing an anti-human NRP antibody. 2. The method of claim 1, wherein the one or more additional immunotherapeutic agents further comprise one or more of the immunotherapeutic agents selected from the group consisting of: a) an immunotherapeutic agent that blocks the activation of an inhibitory immune cell receptor signaling pathway, or a ligand thereof, or a nucleic acid encoding an immunotherapeutic agent; and b) an immunotherapeutic agent that modulates the activation of a co-stimulatory receptor signaling pathway, or a nucleic acid encoding an immunotherapeutic agent. 3. The method of claim 2 wherein the inhibitory receptor or ligand thereof is selected from CTLA-4, PD-1, PD-L1, PD-L2, Tim-3, neuritin, BTLA, CECAM-1, CECAM-5, VISTA , LAIR1, CD160, 2B4, KIR and their combinations. 4. The method of claim 2, wherein the costimulatory receptor is CD3, GITR OX40, ICOS, LAG-2, CD27, CD28, CD40, or 4-1BB. 5. The method according to any one of paragraphs. 1-4, wherein the cancer is selected from a solid tumor and a hematological tumor. 6. The method of claim 5 wherein the cancer is a solid tumor. 7. The method of claim 1, wherein one or more of the additional immunotherapeutic agents further comprises an antibody against Tim-3, 41BB, GITR, PD-1 or PD-L1 or further comprises OX40. 8. The method of claim 1, wherein the one or more additional immunotherapeutic agents further comprise an anti-GITR antibody comprising the VH sequence of SEQ ID NO: 139 and the VL sequence of SEQ ID NO: 140. 9. The method of claim 1, wherein the anti-human NRP antibody comprises the VH sequence of SEQ ID NO: 141 and the VL sequence of SEQ ID NO: 142. 10. The method of claim 8 or 9, wherein the antibody or antigen-binding fragment thereof comprises the VH sequence of SEQ ID NO: 13 and the VL sequence of SEQ ID NO: 26. 11. The method of claim 8 or 9, wherein the antibody or antigen-binding fragment thereof comprises the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 25. 12. The method of claim 8 or 9, wherein the antibody or antigen-binding fragment thereof comprises the VH sequence of SEQ ID NO: 18 and the VL sequence of SEQ ID NO: 27. 13. The method of claim 8 or 9, wherein the antibody or antigen-binding fragment thereof comprises the VH sequence of SEQ ID NO: 24 and the VL sequence of SEQ ID NO: 27. 14. The method according to any one of paragraphs. 1-4, in which the combination therapy has an additive effect on immune activation. 15. The method according to any one of paragraphs. 1-4, in which the combination therapy has a synergistic effect on immune activation. 16. The method of claim. 14, wherein the determination of additive or synergistic effect on immune activation is carried out by studying the secondary immune response to cytomegalovirus (CMV). 17. The method of claim. 14, in which the determination of the additive or synergistic effect on immune activation is carried out by examining dissociated tumor cells. 18. The method according to any one of paragraphs. 1-4, wherein the additional therapeutic agent is formulated in the same pharmaceutical composition as the antibody or antigen-binding fragment thereof. 19. The method according to any one of paragraphs. 1-4, in which the additional therapeutic agent is prepared in a separate antibody or antigen-binding fragment from the pharmaceutical composition. 20. The method according to any one of paragraphs. 1-4, wherein the additional therapeutic agent is administered prior to the administration of the antibody or antigen-binding fragment thereof. 21. The method according to any one of paragraphs. 1-4, wherein the additional therapeutic agent is administered following administration of the antibody or antigen-binding fragment thereof. 22. The method according to any one of paragraphs. 1-4, in which the additional therapeutic agent is administered simultaneously with the antibody or antigen-binding fragment.

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