CN117157321A - anti-TMEM 106B antibodies for the treatment and prevention of coronavirus infection - Google Patents

Abstract

The present disclosure relates generally to the use of antibodies that bind to TMEM106B protein for treating, preventing, or reducing the risk of coronavirus (e.g., SARS-CoV-2) infection.

Description

anti-TMEM 106B antibodies for the treatment and prevention of coronavirus infection

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application 63/164,873 filed on 3 month 23 of 2021, U.S. provisional application 63/239,498 filed on 1 month 9 of 2021, and U.S. provisional application 63/318,068 filed on 3 month 9 of 2022, each of which is incorporated herein by reference in its entirety.

Submission of sequence listing in the form of ASCII text files

The contents of the following ASCII text file submissions are incorporated herein by reference in their entirety: a Computer Readable Form (CRF) of the sequence listing (file name: 4503_015 pc03_seqlipping_st25.txt; date of creation: 2022, 3, 23 days; size: 258,941 bytes).

Technical Field

The present disclosure relates to the use of anti-TMEM 106B antibodies for the treatment and prevention of coronavirus (e.g., SARS-CoV-2) infection.

Background

Transmembrane protein 106B (TMEM 106B) is a single transmembrane glycoprotein of type 2, which is found predominantly in the membranes of late endosomes and lysosomes. (see, e.g., lang et al, 2012,J Biol Chem,287:19355-19365; chen-Plotkin et al, 2012,J Neurosci,32:11213-11227; brady et al, 2013,Human Molecular Genetics,22:685-695.) TMEM106B is highly conserved in mammals, human proteins share 99% sequence identity with cynomolgus variants, and 97% sequence identity with murine orthologs.

TMEM106B has cytoplasmic domains predicted to be in the range of amino acid residues 1-92 (of human TMEM106B; SEQ ID NO: 1), transmembrane domains predicted to be in the range of amino acid residues 96-117, and luminal domains predicted to be in the range of amino acid residues 118-274. Five sequence motifs of post-translational N-glycosylation sites (N-X-T/S) span its luminal domain. Simple glycans were added to three asparagine residues (N145, N151 and N164) and are not critical for TMEM106B localization. Adding complex glycans to most of the C-terminal motifs at N183 and N256; loss of complex glycans on N183 would impair TMEM106B forward transport to the endosome/lysosome and result in endoplasmic reticulum retention. In addition, N256 complex glycosylation is necessary for proper TMEM106B sorting. (see, e.g., nicholson and Rademakers,2016,Acta Neuropathol,132:639-651.)

The function of TMEM106B has not been fully characterized. Recent reports demonstrate a role for TMEM106B in lysosomal function and maintenance by inhibiting lysosomal transport along dendrites. See, for example, brady et al, 2013,Human Molecular Genetics,126:696-698; schwenk et al, 2014,EMBO J,33:450-467; clayton et al, 2018, brain 141 (12): 3428-3442. )

TMEM106B has been identified as a host factor for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Genetic deletion of TMEM106B reduced replication and infection of the SARS-CoV-2 coronavirus (Baggen et al, 2021,Nature Genetics,doi.org/10.1038/s41588-021-00805-2; baggen et al, 2020, bioRxiv, doi:10.1101/2020.09.28.316281; wang et al, 2020, bioRxiv, doi:10.1101/2020/09.24.312298; wang et al, 2021, cell,184: 1-14).

Therapies targeting TMEM106B are needed, including therapeutic antibodies that specifically bind TMEM106B, and/or therapies capable of inhibiting the activity of TMEM106B, such as by reducing TMEM106B protein levels or function, to treat various diseases, disorders, and conditions associated with TMEM106B activity, such as coronavirus infection.

All references, including patent applications and publications, cited herein are hereby incorporated by reference in their entirety.

Disclosure of Invention

The present disclosure relates generally to methods of treating, preventing, or reducing the risk of coronavirus (e.g., SARS-CoV-2) infection, comprising administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to TMEM 106B.

Thus, in certain aspects of the present disclosure, an anti-TMEM 106 antibody for use and methods as provided herein has properties selected from the group consisting of: reduced coronavirus replication, reduced coronavirus transmission, reduced coronavirus genome translation, reduced coronavirus cell entry, reduced coronavirus release from infected cells, and any combination thereof. In some embodiments, the antibody reduces the cytopathic effect in SARS-CoV-2 infected cells, optionally wherein the cells are VeroE6 cells or NCI-H1975 cells.

Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-TMEM 106B antibodies for treating, preventing, or reducing the risk of a coronavirus infection, wherein the anti-TMEM 106B antibodies comprise at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In some embodiments, the anti-TMEM 106B antibody comprises six HVRs of an antibody selected from the group consisting of (e.g., as shown in tables 1 to 4 below): TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94.

Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-TMEM 106B antibodies that bind substantially the same TMEM106B epitope as a reference anti-TMEM 106B antibody comprising an antibody selected from the group consisting ofV of antibodies of group (V) _H And V _L (e.g., as shown in tables 5 and 6 below): TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-TMEM 106B antibodies for treating, preventing, or reducing the risk of a coronavirus infection, wherein the anti-TMEM 106B antibodies competitively inhibit binding of TMEM106B to an antibody comprising a heavy chain variable region and a light chain variable region of any of the antibodies selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In some embodiments, the antibody binds to a truncated TMEM106B protein comprising amino acids 122-210 of SEQ ID NO. 1. In some embodiments, the antibody is in box 2. In some embodiments, the antibody is in box 3. In some embodiments, the antibody is in box 4 Is a kind of medium. In some embodiments, the antibody is not in box 5. In some embodiments, the antibody is not in frame 1.

In some embodiments that may be combined with any of the embodiments provided herein, the antibody is a monoclonal antibody. In some embodiments that may be combined with any of the embodiments provided herein, the antibody is of the IgG class, igM class, or IgA class. In some embodiments, the antibody belongs to the IgG class and has an IgG1, igG2, or IgG4 isotype. In certain embodiments that may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibody is an antibody fragment that binds to an epitope comprising amino acid residues on a human TMEM106B or mammalian TMEM106B protein. In certain embodiments that can be combined with any of the embodiments provided herein, the fragment is a Fab, fab '-SH, F (ab') 2, fv, or scFv fragment. In certain embodiments that may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibody is a full length antibody. In some embodiments that can be combined with any of the embodiments provided herein, the antibody is a humanized antibody or a chimeric antibody.

Other aspects of the disclosure relate to a pharmaceutical composition comprising an anti-TMEM 106B antibody of any of the preceding embodiments and a pharmaceutically acceptable carrier.

Other aspects of the disclosure relate to the use of an anti-TMEM 106B antibody of any of the embodiments herein for the manufacture of a medicament for treating, preventing, or reducing the risk of a coronavirus (e.g., SARS-CoV-2) infection.

It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the invention. These and other aspects of the invention will be apparent to those skilled in the art. These and other embodiments of the invention are further described by the following detailed description.

Drawings

Figure 1 lists data showing the effect of an anti-TMEM 106B antibody of the present disclosure on cell survival following infection of VeroE6 african green monkey kidney epithelial cells with SARS-CoV-2.

FIGS. 2A, 2B, 2C, 2D, 2E and 2F list data showing the effect of an anti-TMEM 106B antibody of the present disclosure on cell viability following SARS-CoV-2 infection of NCI-H1975 human lung epithelial cells.

Figures 3A, 3B, 3C and 3D list data showing the dose titration effect of anti-TMEM 106B antibodies of the present disclosure on cell viability following infection of NCI-H1975 human lung epithelial cells with SARS-CoV-2.

Detailed Description

The present disclosure relates to the use of anti-TMEM 106B antibodies (e.g., monoclonal antibodies) and pharmaceutical compositions thereof for treating, preventing, or reducing the risk of coronavirus infection. In some aspects, provided herein are methods for treating, preventing, or reducing the risk of a coronavirus infection by administering an anti-TMEM 106B antibody to an individual in need thereof.

The techniques and procedures described or referenced herein are well understood and generally employed by those skilled in the art using conventional methods, such as those widely employed, for example, sambrook et al Molecular Cloning: A Laboratory Manual, 3 rd edition (2001) Cold Spring Harbor Laboratory Press, cold Spring Harbor, n.y.; current Protocols in Molecular Biology (F.M. Ausubel et al, (2003); monoclonal Antibodies: A Practical Approach (P.shepherd and C.dean, oxford University Press, 2000).

Definition of the definition

Unless otherwise indicated, the term "TMEM106B" or "TMEM106B polypeptide" is used interchangeably herein to refer to any native TMEM106B from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos)) and rodents (e.g., mice and rats). In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences (e.g., splice variants or allelic variants). In some embodiments, the term encompasses "full length", unprocessed TMEM106B, and any form of TMEM106B resulting from processing in a cell. In some embodiments, TMEM106B is a human TMEM106B. In some embodiments, the amino acid sequence of exemplary TMEM106B is Uniprot accession number by month 6 and 27 of 2006: q9NUM4. In some embodiments, the amino acid sequence of an exemplary human TMEM106B is SEQ ID NO. 1.

The terms "anti-TMEM 106B antibody", "antibody that binds to TMEM106B" and "antibody that specifically binds TMEM106B" refer to an antibody that is capable of binding TMEM106B with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent that targets TMEM106B. In one embodiment, the degree of binding of an anti-TMEM 106B antibody to an unrelated non-TMEM 106B polypeptide is less than about 10% of the binding of the antibody to TMEM106B, as measured, for example, by Radioimmunoassay (RIA). In certain embodiments, the antibody that binds to TMEM106B has a dissociation constant (KD) <1μΜ、<100nM、<10nM、<1nM、<0.1nM、<0.01nM or<0.001nM (e.g., 10 ^-8 M or less, e.g. 10 ^-8 M to 10 ^-13 M, e.g. 10 ^-9 M to 10 ^-13 M). In certain embodiments, the anti-TMEM 106B antibody binds to an epitope of TMEM106B that is conserved between TMEMs 106B of different species.

With respect to binding of an antibody to a target molecule, the term "specifically binds" or "specifically binds" to an epitope on a particular polypeptide or a particular polypeptide target or "has specificity" for an epitope on a particular polypeptide or a particular polypeptide target means binding measurably distinct from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule. For example, specific binding can be determined by competition with a control molecule (e.g., excess unlabeled target) that is similar to the target. In this case, specific binding is indicated if binding of the labeled target to the probe is competitively inhibited by an excess of unlabeled target. As used herein, the term "specifically binds" to a particular polypeptide or an epitope on a particular polypeptide target or "specific junctionAn epitope that binds to or is "specific for" a particular polypeptide or particular polypeptide target may be, for example, produced by a KD of about 10 for the target ^-4 M or less, 10 ^-5 M or less, 10 ^-6 M or less, 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M or less, 10 ^-10 M or less, 10 ^-11 M or less, 10 ^-12 M or less or KD at 10 ^-4 M to 10 ^-6 M or 10 ^-6 M to 10 ^-10 M or 10 ^-7 M to 10 ^-9 Molecules within the range of M are displayed. As the skilled person will appreciate, the affinity and KD values are inversely proportional. High affinity to antigen was measured by low KD values. In one embodiment, the term "specific binding" refers to binding of a molecule to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody". The term "antibody" is used herein in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) (including those formed from at least two intact antibodies), and antibody fragments so long as they exhibit the desired biological activity.

"Natural antibodies" are typically hetero-tetrameric glycoproteins of about 150,000 daltons composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to the heavy chain by one covalent disulfide bond, with the number of disulfide bonds varying between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain at one end (V _H ) Then several constant domains. Each light chain has a variable domain at one end (V _L ) Having a constant domain at the other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain and the variable domain of the light chain is aligned with the variable domain of the heavy chain. It is believed that a particular amino acid residue will form an interface between the light and heavy chain variable domains。

For the structure and properties of different classes of antibodies, see e.g. Basic and Clinical Immunology, 8 th edition, daniel p.Stites, abba I.terr and Tristram G.Parslow (ed.), appleton & Lange, norwalk, CT,1994, page 71 and chapter 6.

Light chains can be categorized into one of two distinct types, called kappa ("kappa") and lambda ("lambda")), based on the amino acid sequence of the constant domain of the light chain from any vertebrate species. Immunoglobulins may be categorized into different classes or isotypes based on the amino acid sequence of the constant domain of the heavy Chain (CH) of the immunoglobulin. Immunoglobulins are of five classes: igA, igD, igE, igG and IgM, which have heavy chains called alpha ("α"), delta ("δ"), ilasticon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes can be further divided into subclasses (isoforms) based on relatively small differences in CH sequence and function, e.g., humans express the following subclasses: igG1, igG2, igG3, igG4, igA1, and IgA2. The subunit structure and three-dimensional configuration of different classes of immunoglobulins are well known and are generally described, for example, in Abbas et al, cellular and Molecular Immunology, 4 th edition (w.bsaunders co., 2000).

The "variable region" or "variable domain" of an antibody (such as an anti-TMEM 106B antibody of the present disclosure) refers to the amino terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains, respectively, may be referred to as "V _H "and" V _L ". These domains are typically the most variable parts of an antibody (relative to other antibodies of the same class) and contain antigen binding sites.

The term "variable" refers to the fact that: that is, certain segments of the variable domains vary widely in sequence between antibodies (such as the anti-TMEM 106B antibodies of the present disclosure). The variable domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains. In contrast, in the light and heavy chain variable domains, variability is concentrated in three segments called hypervariable regions (HVRs). The more highly conserved parts of the variable domains are called Framework Regions (FR). The variable domains of the natural heavy and light chains each comprise four FR regions, which are mostly in a β -sheet configuration, connected by three HVRs that form a loop connecting (and in some cases forming part of) the β -sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and together with the HVRs of the other chain contribute to the formation of the antigen-binding site of the antibody (see Kabat et al Sequences of Immunological Interest, fifth edition, national Institute of Health, bethesda, MD (1991)). The constant domains are not directly involved in binding of antibodies to antigens, but exhibit a variety of effector functions, such as participation of antibodies in antibody-dependent cytotoxicity.

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies (such as the monoclonal anti-TMEM 106B antibodies of the present disclosure), i.e., each individual antibody comprising the population of antibodies, which is otherwise identical except for possible naturally occurring mutations and/or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in minor amounts. Monoclonal antibodies are highly specific (against a single antigenic site). In contrast to polyclonal antibody preparations, which typically comprise different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to specificity, monoclonal antibodies have the advantage that they are synthesized by hybridoma culture and are not contaminated with other immunoglobulins. The modifier "monoclonal" refers to the characteristics of the antibody obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use according to the invention can be prepared by a variety of techniques including, for example, hybridoma methods, recombinant DNA methods, and techniques for producing human or human-like antibodies in animals having part or all of a human immunoglobulin locus or a gene encoding a human immunoglobulin sequence.

The terms "full length antibody," "whole antibody," or "complete antibody" are used interchangeably to refer to an antibody in substantially complete form (such as an anti-TMEM 106B antibody of the present disclosure) as compared to an antibody fragment. In particular, complete antibodies include those having heavy and light chains comprising an Fc region. The constant domain may be a natural sequence constant domain (e.g., a human natural sequence constant domain) or an amino acid sequence variant thereof. In some cases, an intact antibody may have one or more effector functions.

An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds to an antigen to which the intact antibody binds. Examples of antibody fragments include Fab, fab ', F (ab') 2, and Fv fragments; a double body; linear antibodies (see U.S. Pat. No. 5641870, example 2; zapata et al, protein Eng.8 (10): 1057-1062 (1995)); single chain antibody molecules formed from antibody fragments and multispecific antibodies.

Papain digestion of antibodies (such as the anti-TMEM 106B antibodies of the present disclosure) produces two identical antigen binding fragments, termed "Fab" fragments, and a residual "Fc" fragment (a name reflecting the ability to crystallize readily). Fab fragments consist of the entire light chain and the variable region domain of the heavy chain (V _H ) And a first constant domain of a heavy chain (C _H 1) Composition is prepared. Each Fab fragment is monovalent in terms of antigen binding, i.e. has a single antigen binding site. Pepsin treatment of antibodies produced single large F (ab') ₂ A fragment which corresponds approximately to two disulfide-linked Fab fragments having different antigen binding activities and which is still capable of cross-linking an antigen. Fab' fragments differ from Fab fragments in that at C _H The carboxy terminus of the 1 domain has several additional residues, including one or more cysteines from the antibody hinge region. Fab '-SH is the term herein for Fab' in which one or more cysteine residues of the constant domain carry a free thiol group. F (ab') ₂ The antibody fragments were initially produced in the form of pairs of Fab 'fragments with hinge cysteines between the Fab' fragments. Other chemical conjugates of antibody fragments are also known.

The Fc fragment comprises the carboxy-terminal portions of two heavy chains held together by disulfide bonds. The effector function of antibodies is determined by the sequence of the Fc region, which is also recognized by Fc receptors (fcrs) present on certain cell types.

A "functional fragment" of an antibody (such as an anti-TMEM 106B antibody of the present disclosure) comprises a portion of an intact antibody, typically comprising the antigen binding or variable region of the intact antibody, or the Fc region of an antibody that retains or has modified FcR binding capacity. Examples of antibody fragments include linear antibodies, single chain antibody molecules, and multispecific antibodies formed from antibody fragments.

The term "diabody" means by using V _H Domain and V _L Short linkers (about 5-10 residues) between the domains construct small antibody fragments prepared from sFv fragments (see paragraph above) such that inter-chain rather than intra-chain pairing of the variable domains is achieved, resulting in bivalent fragments, i.e., fragments with two antigen binding sites. Bispecific diabodies are heterodimers of two "cross-linked" sFv fragments, two of which are V _H Domain and V _L The domains are present on different polypeptide chains.

As used herein, "chimeric antibody" refers to an antibody (immunoglobulin) such as the chimeric anti-TMEM 106B antibody of the present disclosure: wherein a portion of the heavy and/or light chain is identical or homologous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, and the remainder of one or more chains is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, and fragments of such antibodies, so long as they exhibit the desired biological activity. Chimeric antibodies of interest herein includeAn antibody, wherein the antigen binding region of the antibody is derived from, for example, an antibody produced by immunization of cynomolgus monkeys with an antigen of interest. As used herein, "humanized antibodies" are used as a subset of "chimeric antibodies".

A "humanized" form of a non-human (e.g., murine) antibody (such as the humanized form of an anti-TMEM 106B antibody of the present disclosure) is a chimeric antibody comprising amino acid residues from a non-human HVR and amino acid residues from a human FR. In certain embodiments, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. The humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization.

A "human antibody" is an antibody that has an amino acid sequence corresponding to a human produced antibody (such as an anti-TMEM 106B antibody of the present disclosure) and/or that has been prepared using any of the techniques for preparing human antibodies as disclosed herein. This definition of human antibodies expressly excludes humanized antibodies that comprise non-human antigen binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries and yeast display libraries. Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to an antigen challenge, but the endogenous locus of the transgenic animal has been disabled (e.g., immunized xenomice), and produced via human B cell hybridoma technology.

As used herein, the term "hypervariable region," "HVR," or "HV" refers to a region of an antibody variable domain (such as the variable domain of an anti-TMEM 106B antibody of the disclosure) whose sequence is hypervariable and/or forms a structurally defined loop. Typically, an antibody comprises six HVRs; v (V) _H Three (H1, H2, H3), and V _L Three of these (L1, L2, L3). Of the natural antibodies, H3 and L3 show the most diversity of these six HVRs, and H3 is believed to play a unique role in particular in conferring fine specificity to antibodies. Naturally occurring camelid antibodies consisting of heavy chains only have functionality and stability in the absence of light chains.

Many HVR descriptions are in use and are encompassed herein. In some embodiments, the HVR may be a Kabat Complementarity Determining Region (CDR) based on sequence variability, and is most commonly used (Kabat et al, supra). In some embodiments, the HVR may be a Chothia CDR. Chothia refers to the position of the structural ring (Chothia and Lesk J. Mol. Biol.196:901-917 (1987)). In some embodiments, the HVR may be an AbM HVR. AbM HVR represents a compromise between Kabat CDR and Chothia structural loops and is used by Oxford Molecular AbM antibody modeling software. In some embodiments, the HVR may be a "contact" HVR. The "contact" HVR is based on analysis of available complex crystal structures. Residues from each of these HVRs are annotated as follows.

The HVR may comprise an "extended HVR" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in VL, 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2) and 93-102, 94-102 or 95-102 (H3) in VH. For each of these extended HVR definitions, the variable domain residues were numbered according to Kabat et al (supra).

"framework" or "FR" residues are those variable domain residues other than HVR residues as defined herein.

As used herein, a "recipient human framework" is a V comprising a framework derived from a human immunoglobulin or a human consensus framework _L Or V _H Framework of the amino acid sequence of the framework. The recipient human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise their identical amino acid sequence, or it may comprise pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or2 or less. If pre-existing amino acid changes are present in the VH, preferably those changes occur only at three, two or one of the 71H, 73H and 78H positions; for example, the amino acid residues at those positions may be 71A, 73T and/or 78A. In one embodiment, the VL acceptor human framework is sequence-wise to V _L The human immunoglobulin framework sequences or the human consensus framework sequences are identical.

The "human consensus framework" is in human immunoglobulin V _L Or V _H The framework sequence is selected to represent the most common framework of amino acid residues. In general, human immunoglobulin V _L Or V _H The selection of sequences is from a subset of variable domain sequences. In general, a subset of sequences is that described by Kabat et al, sequences of Proteins of Immunological Interest, 5 th edition, public Health Service, national Institutes of Health, bethesda, MD (1991). Examples include: for V _L The subgroup may be subgroup κI, κII, κIII or κIV as described by Kabat et al (supra). In addition, for V _H The subgroup may be subgroup I, subgroup II or subgroup III as described by Kabat et al (supra).

"amino acid modification" at a specified position of, for example, an anti-TMEM 106B antibody of the present disclosure refers to substitution or deletion of a specific residue, or insertion of at least one amino acid residue adjacent to the specified residue. By "adjacent" to a specified residue is meant an insertion within one to two residues of the specified residue. The insertion may be at the N-terminus or C-terminus of the indicated residue. Preferred amino acid modifications herein are substitutions.

An "affinity matured" antibody (such as an affinity matured anti-TMEM 106B antibody of the present disclosure) is an antibody that has one or more alterations in one or more HVRs of the antibody, thereby resulting in improved affinity of the antibody for the antigen as compared to a parent antibody that does not have one or more of those alterations. In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are generated by procedures known in the art. For example, marks et al, bio/Technology 10:779-783 (1992) describe the passage ofV _H Domain and V _L Affinity maturation by domain shuffling. Random mutagenesis of HVR and/or framework residues such as, for example: barbas et al Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); schier et al Gene 169:147-155 (1995); yelton et al J.Immunol.155:1994-2004 (1995); jackson et al J.Immunol.154 (7): 3310-9 (1995); and Hawkins et al, J.mol. Biol.226:889-896 (1992).

"Fv" is the smallest antibody fragment that contains the complete antigen recognition and binding site. The fragment consists of a dimer of one heavy and one light chain variable region domain in close, non-covalent association. Six hypervariable loops (3 loops from the H and L chains, respectively) are generated from the folding of these two domains, which contribute amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, albeit with less than the entire binding site.

"Single chain Fv" also abbreviated "sFv" or "scFv" is an antibody fragment comprising VH and VL antibody domains linked to a single polypeptide chain. Preferably, the sFv polypeptide further comprises V _H And V _L Polypeptide linkers between domains that allow sFv to form the desired structure for antigen binding.

Antibody "effector functions" refer to those biological activities attributable to the Fc region of an antibody (native sequence Fc region or amino acid sequence variant Fc region) and which vary with the antibody isotype.

The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, a human IgG heavy chain Fc region is generally defined as the sequence stretch from amino acid residue at Cys226 or from Pro230 to their carboxy-terminus. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region can be removed, for example, during production or purification of the antibody or by recombinant engineering of the nucleic acid encoding the heavy chain of the antibody. Thus, a composition of intact antibodies may include a population of antibodies with all K447 residues removed, a population of antibodies with no K447 residues removed, and a population of antibodies with and without a mixture of antibodies with K447 residues. Native sequence Fc regions suitable for antibodies of the present disclosure include human IgG1, igG2, igG3, and IgG4.

"native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Natural sequence human Fc regions include natural sequence human IgG1 Fc regions (non-a and a allotypes); a native sequence human IgG2 Fc region; a native sequence human IgG3 Fc region; and the native sequence human IgG4 Fc region and naturally occurring variants thereof.

A "variant Fc region" comprises an amino acid sequence that differs from the native sequence Fc region by at least one amino acid modification (preferably one or more amino acid substitutions). Preferably, the variant Fc-region has at least one amino acid substitution, e.g., about one to about ten amino acid substitutions, and preferably about one to about five amino acid substitutions, in the Fc-region of the native sequence or in the Fc-region of the parent polypeptide as compared to the Fc-region of the native sequence or the Fc-region of the parent polypeptide. The variant Fc-regions herein preferably have at least about 80% homology with the native sequence Fc-region and/or with the Fc-region of the parent polypeptide, most preferably at least about 90% homology with them, more preferably at least about 95% homology.

"Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Furthermore, preferred fcrs are those that bind IgG antibodies (gamma receptors) and include receptors of the fcγri, fcγrii and fcγriii subclasses, including allelic variants and alternatively spliced forms of these receptors, fcγrii receptors including fcγriia ("activating receptor") and fcγriib ("inhibitory receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. The activating receptor fcγriia contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. The inhibitory receptor fcyriib contains an immunoreceptor tyrosine-based inhibitory motif ("ITIM") in its cytoplasmic domain. Other fcrs (including those identified in the future) are also encompassed by the term "FcR" herein. Fcrs can also increase the serum half-life of antibodies.

As used herein, with respect to peptide, polypeptide, or antibody sequences, "percent (%) amino acid sequence identity" and "homology" refer to the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a particular peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without regard to any conservative substitutions as part of the sequence identity. Alignment for determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN ^TM (DNASTAR) software. One of skill in the art can determine appropriate parameters for measuring the alignment, including any algorithms known in the art required to achieve maximum alignment over the full length of the compared sequences.

The term "compete" when used in the context of antibodies that compete for the same epitope (e.g., neutralizing antibodies) means competition between the antibodies as determined by an assay in which the tested antibodies prevent or inhibit (e.g., reduce) specific binding of a reference molecule (e.g., ligand or reference antibody) to a common antigen (e.g., TMEM106B or a fragment thereof). Various types of competitive binding assays may be used to determine whether an antibody competes with another antibody, for example: solid phase direct or indirect Radioimmunoassay (RIA), solid phase direct or indirect Enzyme Immunoassay (EIA), sandwich competition assay (see, e.g., stahli et al, 1983,Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., kirkland et al, 1986, J. Immunol. 137:3614-3619), solid phase direct labeling assay, solid phase direct labeling sandwich assay (see, e.g., harlow and Lane,1988,Antibodies,A Laboratory Manual,Cold Spring Harbor Press); RIA is directly labeled using a 1-125 labeled solid phase (see, e.g., morel et al, 1988, molecular. Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see, e.g., cheung et al, 1990,Virology 176:546-552); and direct labelling of RIA (Moldenhauer et al, 1990, scand. J. Immunol. 32:77-82). Typically, such assays involve the use of purified antigens bound to a solid surface or carrying cells of either of these unlabeled test antibodies and labeled reference antibodies. Competitive inhibition is measured by determining the amount of label bound to a solid surface or cell in the presence of a test antibody. Typically, the test antibody is present in excess. Antibodies identified by competition assays (competing antibodies) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to an adjacent epitope sufficiently close to the epitope to which the reference antibody binds to sterically hindered. Additional details regarding the method of determining competitive binding are provided below and in the examples herein. Typically, when the competing antibody is present in excess, it will inhibit (e.g., reduce) the specific binding of the reference antibody to the common antigen by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5% and/or nearly 100%.

Antibodies competing for binding to the same region of TMEM106B are considered to belong to the same antibody "box". Exemplary blocks of antibodies that bind TMEM06B are discussed herein, for example, in examples 4 and 6.

As used herein, an antibody in "box 1" refers to an antibody that competes for binding to the same or overlapping TMEM106B region of the TM1, TM17, TM22, TM26, TM79, and/or TM82 antibodies provided herein.

As used herein, an antibody in "box 2" refers to an antibody that competes for binding to the same or overlapping TMEM106B region of the TM3, TM9, TM10, TM11, TM12, TM13, TM18, TM19, TM21, TM24, TM25, TM32, TM35, TM37, TM42, TM45, TM48, TM54, TM59, TM60, TM61, and/or TM76 antibodies provided herein.

As used herein, an antibody in "box 3" refers to an antibody that competes for binding to the same or overlapping TMEM106B region of the TM7, TM15, TM83, and/or TM84 antibodies provided herein.

As used herein, an antibody in "box 4" refers to an antibody that competes for binding to the same or overlapping TMEM106B region of the TM5, TM28, TM29, TM30, TM63, TM64, TM72, TM78, TM80, TM86, and/or TM88 antibodies provided herein.

As used herein, an antibody in "box 5" refers to an antibody that does not bind to truncated TMEM106B comprising amino acids 122-210 of SEQ ID No. 1.

As used herein, "interaction" between a TMEM106B polypeptide and a second polypeptide encompasses, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, binding, covalent binding, and ionic binding. As used herein, an antibody "inhibits" an "interaction between two polypeptides when the antibody disrupts, reduces, or completely eliminates the interaction between the two polypeptides. An antibody of a polypeptide of the present disclosure "inhibits" the "interaction" between two polypeptides when the antibody of the polypeptide binds to one of the two polypeptides. In some embodiments, the interaction may be inhibited by at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, and/or nearly 100%.

The term "epitope" includes any determinant capable of being bound by an antibody. An epitope is a region of an antigen that is bound by an antibody that targets the antigen, and when the antigen is a polypeptide, includes specific amino acids that directly contact the antibody. Most often, the epitope is located on a polypeptide, but in some cases may be located on other types of molecules (such as nucleic acids). Epitope determinants may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three dimensional structural characteristics and/or specific charge characteristics. In general, antibodies specific for a particular target antigen will preferentially recognize epitopes on the target antigen in a complex mixture of polypeptides and/or macromolecules.

An "agonistic" antibody or "activating" antibody is an antibody that induces (e.g., increases) one or more activities or functions of an antigen after the antibody binds to the antigen.

An "antagonist" antibody or "blocking" antibody or "inhibitory" antibody is an antibody that reduces, inhibits, and/or eliminates (e.g., reduces) the binding of an antigen to one or more ligands after the antibody binds to the antigen, and/or reduces, inhibits, and/or eliminates (e.g., reduces) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, the antagonistic or blocking or inhibitory antibody substantially or completely inhibits binding of the antigen to one or more ligands and/or one or more activities or functions of the antigen.

An "isolated" antibody (such as an isolated anti-TMEM 106B antibody of the present disclosure) is an antibody that has been identified, isolated, and/or recovered from a component (e.g., natural or recombinant) of the antibody's production environment. Preferably, the isolated antibody is independent of all other contaminating components of the antibody production environment. The contaminating components of the antibody-producing environment, such as those produced from recombinant transfected cells, are substances that generally interfere with the research, diagnostic or therapeutic uses of the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In a preferred embodiment, the antibody will be purified as: (1) Greater than 95 wt%, in some embodiments, greater than 99 wt% of the antibody, as determined by, for example, the Lowry method; (2) As determined by using a spin cup sequencer to a degree sufficient to obtain at least 15N-terminal residues or internal amino acid sequences, or (3) homogeneity as determined by SDS-PAGE under non-reducing or reducing conditions using coomassie blue or preferably silver staining. Because at least one component of the antibody's natural environment will not be present, the isolated antibody includes in situ antibodies within the recombinant T cell. However, typically, the isolated polypeptide or antibody will be prepared by at least one purification step.

An "isolated" nucleic acid molecule encoding an antibody (such as an anti-TMEM 106B antibody of the present disclosure) is a nucleic acid molecule identified and isolated from at least one contaminating nucleic acid molecule that is typically associated with the environment in which the isolated nucleic acid molecule is produced. Preferably, the isolated nucleic acid is independent of all components associated with the production environment. The form of the isolated nucleic acid molecules encoding the polypeptides and antibodies herein is different from the form or background in which the nucleic acid molecules exist in nature. Thus, an isolated nucleic acid molecule differs from nucleic acids encoding polypeptides and antibodies naturally occurring in cells herein.

As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. One type of vector is a "plasmid," which refers to circular double stranded DNA to which additional DNA segments may be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, thereby replicating along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operably linked. These vectors are referred to herein as "recombinant expression vectors," or simply "expression vectors. In general, expression vectors useful in recombinant DNA technology are typically in the form of plasmids. In this specification, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector.

"Polynucleotide" or "nucleic acid" as used interchangeably herein refers to a polymer of nucleotides of any length, and includes DNA and RNA. The nucleotide may be a deoxyribonucleotide, a ribonucleotide, a modified nucleotide or base and/or analogue thereof or any substrate that can be incorporated into a polymer by a DNA or RNA polymerase or by a synthetic reaction.

"host cells" include single cells or cell cultures, which may or may not be the recipient of the vector for incorporation of the polynucleotide insert. Host cells include progeny of a single host cell, and due to natural, accidental, or deliberate mutation, the progeny are not necessarily identical (in morphology or genomic DNA complement) to the original parent cell. Host cells include cells transfected in vivo with one or more polynucleotides of the invention.

As used herein, a "carrier" includes a pharmaceutically acceptable carrier, excipient, or stabilizer that is non-toxic to the exposed cells or mammals at the dosages and concentrations employed.

As used herein, the term "preventing" includes providing prophylaxis against the occurrence or recurrence of a particular disease, disorder or condition in an individual. An individual may be predisposed to, susceptible to, or at risk of suffering from a particular disease, disorder, or condition, but not yet diagnosed as suffering from the disease, disorder, or condition.

As used herein, an individual at "risk" for a particular disease, disorder, or condition may or may not have a detectable disease or symptom of a disease, and may or may not exhibit a detectable disease or symptom of a disease prior to the methods of treatment described herein. As known in the art, "at risk" means that an individual has one or more risk factors, which are measurable parameters associated with the development of a particular disease, disorder, or condition. Individuals with one or more of these risk factors have a higher probability of suffering from a particular disease, disorder, or condition than individuals without one or more of these risk factors.

As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a treated individual during a clinical pathology. Desirable therapeutic effects include reducing the rate of progression, improving or alleviating a pathological condition, and alleviating or improving the prognosis of a particular disease, disorder or condition. For example, an individual is successfully "treated" if one or more symptoms associated with a particular disease, disorder, or condition are reduced or eliminated.

An "effective amount" refers to an amount effective to achieve a desired therapeutic or prophylactic result, at least at the dosages and for periods of time necessary. An effective amount may be provided in one or more administrations. The effective amounts herein may vary depending on various factors, such as the disease state, age, sex, and weight of the individual, and the ability of the treatment to elicit a desired response in the individual. An effective amount is also an amount of any toxic or detrimental effect of the treatment that is beyond the therapeutic benefit. For prophylactic use, beneficial or desired results include results such as eliminating or reducing risk, lessening severity, or delaying the onset of a disease, including biochemical, histological, and/or behavioral symptoms of a disease, complications of a disease, and intermediate pathological phenotypes that occur during the development of a disease. For therapeutic use, beneficial or desired results include clinical results such as reducing one or more symptoms caused by a disease, improving quality of life for a patient with a disease, reducing the dosage of other drugs required to treat a disease, enhancing the effect of another drug, such as via targeting, slowing the progression of a disease, and/or extending survival. An effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to achieve, directly or indirectly, a prophylactic or therapeutic treatment. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if the single agent in combination with one or more other agents may achieve or have achieved the desired result.

For the purposes of treatment, prevention or risk reduction, "individual" refers to any animal classified as a mammal, including humans, domestic and farm animals, zoo animals, sports animals or pets, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, mink, rats, cats, and the like. In some embodiments, the subject is a human.

As used herein, "co-administration" with another compound or composition includes simultaneous administration and/or administration at different times. Co-administration also encompasses administration as co-formulations or as separate compositions, including administration at different dosing frequencies or intervals, and using the same route of administration or different routes of administration. In some embodiments, the combination administration is administered as part of the same therapeutic regimen.

As used herein, the term "about" refers to a common range of error for the corresponding value as readily known to those skilled in the art. References herein to "about" a value or parameter include (and describe) embodiments that relate to the value or parameter itself.

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "an antibody" refers to a reference to one of a plurality of antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

As used herein, "TMEM106B" proteins of the present disclosure include, but are not limited to, mammalian TMEM106B proteins, human TMEM106B proteins, primate TMEM106B proteins, cynomolgus monkey (cyno) TMEM106B proteins, mouse TMEM106B proteins, and rat TMEM106B proteins. In addition, the anti-TMEM 106B antibodies of the present disclosure may bind to an epitope within one or more of a mammalian TMEM106B protein, a human TMEM106B protein, a primate TMEM106B, a cynomolgus TMEM106B protein, a mouse TMEM106B protein, and a rat TMEM106B protein.

It should be understood that the aspects and embodiments of the present disclosure described herein include, consist of, and consist essentially of the recited aspects and embodiments.

TMEM106B protein

Provided herein are methods of treating, preventing, or reducing the risk of a coronavirus infection by administering an anti-TMEM 106B antibody to an individual in need thereof.

In one aspect, the present disclosure provides an isolated (e.g., monoclonal) antibody for treating, preventing, or reducing the risk of a coronavirus infection, wherein the antibody binds to an epitope within TMEM106B protein of the present disclosure. The TMEM106B proteins of the present disclosure include, but are not limited to, mammalian TMEM106B proteins, human TMEM106B proteins, mouse TMEM106B proteins, and cynomolgus TMEM106B proteins.

Human TMEM106B is a 274 amino acid protein encoding a type 2 membrane glycoprotein. The amino acid sequence of human TMEM106B is shown below (SEQ ID NO: 1):

MGKSLSHLPLHSSKEDAYDGVTSENMRNGLVNSEVHNEDGRNGDVSQFPYVEFTGRDSVTCPTCQGTGRIPRGQENQLVALIPYSDQRLRPRRTKLYVMASVFVCLLLSGLAVFFLFPRSIDVKYIGVKSAYVSYDVQKRTIYLNITNTLNITNNNYYSVEVENITAQVQFSKTVIGKARLNNITIIGPLDMKQIDYTVPTVIAEEMSYMYDFCTLISIKVHNIVLMMQVTVTTTYFGHSEQISQERYQYVDCGRNTTYQLGQSEYLNVLQPQQ

in some embodiments, TMEM106B protein is expressed in a cell. In some embodiments, TMEM106B protein is expressed in an endosome and/or lysosome. In some embodiments, TMEM106B protein is expressed in late endosomes and/or late lysosomes. In some embodiments, TMEM106B protein is expressed on the cell surface.

The TMEM106B protein of the present disclosure includes several domains, including but not limited to the N-terminal lumen domain (expected to be in the range of amino acid residues 11-274 of human TMEM 106B; see SEQ ID NO: 1), the transmembrane domain (expected to be in the range of amino acid residues 96-117 of human TMEM 106B) and the C-terminal domain (expected to be in the range of amino acid residues 1-92 of human TMEM 106B).

Epitope frame

Epitope-frame is also a competitive immunoassay for the characterization and sorting of monoclonal antibody libraries against target proteins (Abroche et al, 2009,Analytical Biochemistry,386:172-180). Epitope frames and are also known as epitope mapping and epitope characterization (Brooks, 2014,Current Drug Discovery Technology,11:109-112). Antibodies directed against a particular target (e.g., TMEM 106B) were tested in pairs against all other antibodies in the library to determine if any antibodies blocked binding to each other to an epitope of the target. After each antibody has a profile generated against all other antibodies in the library, a competitive antibody blocking profile is generated against each antibody relative to the other antibodies in the library. The closely related box-and-box spectra indicate that the antibodies have identical or closely related (e.g., overlapping) epitopes and are "box-and-box" together.

As shown in the examples below, the anti-TMEM 106B antibodies of the present disclosure exhibit a variety of box profiles characterized by box 1, box 5, and box 2 (box 2 includes related sub-boxes 3 and 4).

The results provided herein demonstrate that the anti-TMEM 106B antibodies of the present disclosure that exhibit overlapping or similar epitope binding characteristics (as demonstrated by their frame-and-profile) exhibit varying degrees of effectiveness in reducing the coronavirus cytopathic effect (CPE). In particular, anti-TMEM 106B antibodies belonging to box 2 (and associated subframes 3 and 4) may be effective in reducing cell death (as measured by CPE assay) after coronavirus infection in vitro, as compared to results obtained from observations using anti-TMEM 106B antibodies belonging to box 1 or 5.

Coronavirus

Coronaviruses are a group of related enveloped sense RNA viruses that can cause disease in mammals and birds. To date, seven human coronaviruses (hcovs) have been discovered. These human coronaviruses include four seasonal spreading human "common cold HCoV", including alpha coronaviruses 229E and NL63, and beta coronaviruses OC43 and HKU1, each of which cause mild upper respiratory illness in humans. Three highly pathogenic coronaviruses have emerged in the past two decades; these highly pathogenic coronaviruses are the beta coronaviruses SARS-CoV, MERS-CoV and the recently occurring SARS-CoV-2, each of which causes severe, potentially fatal respiratory infections in humans. SARS-CoV-2 coronavirus is a virus that causes 2019 coronavirus disease (COVID-19).

After binding of the receptor to the infected cell and membrane fusion, the coronavirus RNA is released into the cytoplasm where it is translated to produce viral proteins. Viral replication/transcription complexes form on double membrane vesicles within the infected cells and create a genomic copy, which is then packaged into new viral particles via a budding process by which the viral envelope is obtained and the resulting viral particles are released from the infected cells.

Coronaviruses primarily target epithelial cells (e.g., respiratory epithelial cells) and require certain host factors to infect the cells. These host factors may play a role in one or more steps of the coronavirus replication cycle (e.g., receptor binding, endocytosis, fusion, translation of viral replication proteins and structural proteins, genome replication, viral particle assembly, and viral particle release). Infected individuals are able to shed viruses into the environment, which may lead to the transmission of the virus to other individuals. In humans, the SARS-CoV-2 coronavirus infects airway epithelial cells via the aerosol route by binding to the angiotensin converting enzyme 2 (ACE 2) receptor.

TMEM106B has been identified as a host factor for SARS-CoV-2 coronavirus infection (Baggen et al 2020, bioRxiv, doi:10.1101/2020.09.28.316281; wang et al 2020, bioRxiv, doi:10.1101/2020/09.24.312298; wang et al 2021, cell, 184:1-14). Genetic deletion and whole genome loss-of-function screening of TMEM106B in human cells determined host factors important for infection and replication of SARS-CoV-2 coronavirus. In particular, deletion of TMEM106B reduced viral replication and reduced cytopathic effect (CPE) of SARS-CoV-2 coronavirus in cultured human cell lines derived from liver and lung. CPE refers to the structural changes of host cells caused by viral infection. CPE occurs when infectious viruses cause lysis (lysis) of host cells or when host cells undergo non-lytic death due to inability to reproduce. Viruses are said to have cytopathogenic properties if they cause these morphological changes in the host cell. Common examples of CPE include rounding of infected cells, fusion with neighboring cells to form syncytia, and the appearance of nuclei or cytoplasmic inclusion bodies.

Thus, in some embodiments, provided herein are methods and compositions for treating, preventing, or reducing the risk of coronavirus infection. In some embodiments, the methods and compositions provided herein are effective in treating, preventing, or reducing the risk of SARS-CoV-2 infection. In some embodiments, which may be combined with any of the embodiments provided herein, the methods and compositions provided herein are effective in treating, preventing, or reducing the risk of infection of SARS-CoV-2 (including variants of SARS-CoV-2 coronavirus, such as alpha variants, beta variants, gamma variants, delta variants, lambda variants, etc.), or SARS-CoV-2 (including variants of SARS-CoV-2 coronavirus, such as alpha variants, beta variants, gamma variants, delta variants, lambda variants, etc.).

In some embodiments, which may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure reduce coronavirus replication. In some embodiments, which may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure reduce coronavirus replication in vitro. In some embodiments, which may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure reduce coronavirus replication in vivo. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In other embodiments, which may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure reduce coronavirus infection. In some embodiments, which may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure reduce coronavirus in vitro infection. In some embodiments, which may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure reduce coronavirus in vivo infection. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In still other embodiments that may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure reduce cytopathic effects (CPE) of coronaviruses. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In some embodiments, which may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure are effective in reducing coronavirus infection by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM 106B antibody of the present disclosure may be effective to reduce coronavirus replication by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM 106B antibody of the present disclosure may be effective to reduce coronavirus transmission by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM 106B antibody of the present disclosure may be effective to reduce coronavirus assembly by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In some embodiments that may be combined with any of the embodiments provided herein, the anti-TMEM 106B antibodies of the present disclosure are effective to reduce coronavirus release from an infected cell by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM 106B antibody of the present disclosure may be effective to reduce coronavirus cell entry by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM 106B antibody of the present disclosure may be effective to reduce coronavirus genomic translation by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is a SARS-CoV-2 coronavirus.

Exemplary anti-TMEM 106B antibodies and certain other antibody embodiments

The present disclosure provides anti-TMEM 106B antibodies for treating, preventing, or reducing the risk of a coronavirus infection, including anti-TMEM 106B antibodies TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-52, TM-60, TM-64, TM-75, TM-70, TM-60, TM-70, TM-35, TM-70, TM-60, and/or-75, and/or-60. TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. The amino acid sequences of exemplary anti-TMEM 106B antibodies are provided in tables 1-6 below.

In some aspects, anti-TMEM 106B antibodies useful in the methods of the present disclosure comprise such heavy chain variable domains (V _H ) Amino acid sequence of a heavy chain variable domain amino acid sequence of an anti-TMEM 106B antibody selected from the group consisting of (V _H ) Has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In certain embodiments, the heavy chain variable domain (V _H ) V having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of (c) _H Amino acid sequence: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93 and TM-94 contain substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but anti-TMEM 106B antibodies comprising this sequence retain the ability to bind to TMEM 106B. In certain embodiments, the heavy chain variable domain (V _H ) In total 1 to 10 amino acids are substituted, inserted and/or deleted in the amino acid sequence: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In certain embodiments, the heavy chain variable domain (V _H ) In total 1 to 5 amino acids are substituted, inserted and/or deleted in the amino acid sequence: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, and the like, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVR (i.e., in the FR). Optionally, the anti-TMEM 106B antibody of the present disclosure comprises a heavy chain variable domain (V _H ) V of (2) _H Amino acid sequence: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93 and TM-94, including post-translational modifications of the sequence. In certain embodiments, V _H Comprising the amino acid sequences provided in tables 5 and 6 below. In certain embodiments, V _H Comprising one, two or three HVRs selected from the group consisting of the HVR-H1, HVR-H2 and HVR-H3 amino acid sequences provided in tables 1 and 3 below.

In another aspect, an anti-TMEM 106B antibody useful in the methods of the present disclosure comprises such a light chain variable domain (V _L ) Amino acid sequence of an anti-TMEM 106B antibody selected from the group consisting of (V _L ) Has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of (a): anti-TMEM 106B antibodies TM-1, TM-2, TM-3, TM-4, TM-5, TM-6TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-75, and 77, and 80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In certain embodiments, the light chain variable domain (V _L ) V having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of (c) _L Amino acid sequence: anti-TMEM 106B antibodies TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-66, TM-70, TM-75, TM-70, TM-67, and/or 77, and/or the like. TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93 and TM-94 contain substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but anti-TMEM 106B antibodies comprising this sequence retain the ability to bind to TMEM 106B. In some embodiments, the light chain variable domain (V _L ) In total 1 to 10 amino acids are substituted, inserted and/or deleted in the amino acid sequence: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM- -10. TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-77, and TM-78. TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In certain embodiments, the light chain variable domain (V _L ) In total 1 to 5 amino acids are substituted, inserted and/or deleted in the amino acid sequence: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM-90, TM-91, TM-92, TM-93 and TM-94. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVR (i.e., in the FR). Optionally, the anti-TMEM 106B antibody of the present disclosure comprises a light chain variable domain (V _L ) V of (2) _L Sequence: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37. TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93 and TM-94, including post-translational modifications of the sequence. In certain embodiments, V _L Comprising the amino acid sequences provided in tables 5 and 6 below. In certain embodiments, V _L Comprising one, two or three HVRs selected from the HVR-L1, HVR-L2 and HVR-L3 amino acid sequences provided in tables 2 and 4 below.

In some embodiments, an anti-TMEM 106B antibody for use in the methods described herein is provided, wherein the antibody comprises V in any of the embodiments as provided above _H And V in any of the embodiments as provided above _L . In some embodiments, provided herein are anti-TMEM 106B antibodies wherein the antibodies comprise V in any embodiment as provided above _H And V in any of the embodiments as provided above _L . In one embodiment, the antibody comprises V of an anti-TMEM 106B antibody selected from the group consisting of _H And V _L Sequence: anti-TMEM 106B antibodies TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-66, TM-70, TM-75, TM-70, TM-67, and/or 77, and/or the like. TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93 and TM-94, including post-translational modifications of the sequence.

In some embodiments, the antibody competitively inhibits binding of TMEM106B to an antibody comprising a heavy chain variable region and a light chain variable region of any of the anti-TMEM 106B antibodies selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93 and TM-94, including post-translational modifications of the sequence. In some embodiments, the antibody binds to a truncated TMEM106B protein comprising amino acids 122-210 of SEQ ID NO. 1. In some embodiments, the antibody is in box 2. In some embodiments, the antibody is in box 3. In some embodiments, the antibody is in box 4. In some embodiments, the antibody is not in frame 1. In some embodiments, the antibody is not in box 5.

anti-TMEM 106B antibodies for use in the methods of the present disclosure may bind to various regions of TMEM106B, including various regions of human TMEM 106B. Such regions of TMEM106B include cytoplasmic domains of TMEM106B or luminal domains of TMEM 106B.

In some embodiments, the anti-TMEM 106B antibodies used in the methods of the present disclosure bind to one or more regions or domains of TMEM 106B. In some embodiments, the anti-TMEM 106B antibodies used in the methods of the present disclosure bind to one or more regions or domains of human TMEM 106B.

In some embodiments, an anti-TMEM 106B antibody according to any of the above embodiments is a monoclonal antibody, including a humanized antibody and/or a human antibody. In some embodiments, the anti-TMEM 106B antibody is an antibody fragment, e.g., fv, fab, fab ', scFv, diabody, or F (ab') 2 fragment. In some embodiments, the anti-TMEM 106B antibody is a substantially full length antibody, e.g., an IgG1 antibody, an IgG2a antibody, or other antibody class or isotype as defined herein.

In some embodiments, an anti-TMEM 106B antibody useful in any of the methods according to any of the above embodiments may comprise any of the features described in paragraphs 1-7 below, alone or in combination:

(1) anti-TMEM 106B antibody binding affinity

In some embodiments of any one of the antibodies provided herein, the antibody has a dissociation constant (Kd)<1μM、<100nM、<10nM、<1nM、<0.1nM、<0.01nM or<0.001nM (e.g., 10 ^-8 M or less, e.g. 10 ^-8 M to 10 ^{- 13} M, e.g. 10 ^-9 M to 10 ^-13 M). The dissociation constant may be determined by any analytical technique including any biochemical or biophysical technique such as ELISA, surface Plasmon Resonance (SPR), biological layer interferometry (see, e.g., the Octet system by ForteBio), isothermal Titration Calorimetry (ITC), differential Scanning Calorimetry (DSC), circular Dichroism (CD), stop-stream analysis, and colorimetric or fluorescent protein melting analysis. In one embodiment, kd is measured by radiolabeled antigen binding assay (RIA). In a certain embodiment, RIA is performed with the Fab version of the antibody of interest and its antigen, e.g., as described in Chen et al J.mol.biol.293:865-881 (1999)). In some embodiments, kd is measured using BIACORE surface plasmon resonance assay, e.g., an assay performed with immobilized antigen CM5 at about 10 Response Units (RU) at 25 ℃ by BIACORE-2000 or BIACORE-3000 (BIACORE, inc., piscataway, NJ). In some embodiments, a monovalent antibody (e.g., fab) or full length antibody is used to determine K _D . In some embodiments, a monovalent form of the full length antibody is used to determine K _D 。

In some embodiments, an anti-TMEM 106B antibody of the present disclosure may have nanomolar or even picomolar affinity for TMEM 106B. In some embodiments, the dissociation constant (Kd) of the antibody is about 0.1nM to about 500nM. For example, the antibody binds to human TMEM106B with a Kd of any of about 500nM, about 400nM, about 300nM, about 200nM, about 100nM, about 75nM, about 50nM, about 25nM, about 10nM, about 9nM, about 8nM, about 7nM, about 6nM, about 5nM, about 4nM, about 3nM, about 2nM, about 1nM, or about 1nM to about 0.1 nM.

(2) Antibody fragments

In some embodiments of any one of the antibodies provided herein, the antibody is an antibody fragment. Antibody fragments include, but are not limited to, fab '-SH, F (ab') ₂ Fv and scFv fragments and other fragments described below. For a review of certain antibody fragments, see Hudson et al Nat. Med.9:129-134 (2003). For reviews of scFv fragments, see for example WO 93/16185; and U.S. patent nos. 5571894 and 5587458. Fab and F (ab') which contain salvage receptor binding epitope residues and have increased in vivo half-life ₂ See U.S. patent No. 5869046 for a discussion of fragments.

Diabodies are antibody fragments having two antigen binding sites, which may be bivalent or bispecific. See, e.g., EP404097; WO 1993/01161; hudson et al Nat. Med.9:129-134 (2003). Trisomy and tetrasomy are also described in Hudson et al Nat. Med.9:129-134 (2003). A single domain antibody is an antibody fragment comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, the single domain antibody is a human single domain antibody (see, e.g., U.S. patent No. 6248516).

As described herein, antibody fragments may be prepared by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., escherichia coli (e.coli) or phage).

(3) Chimeric and humanized antibodies

In some embodiments of any one of the antibodies provided herein, the antibody is a chimeric antibody. Some chimeric antibodies are described, for example, in U.S. patent No. 481657. In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate (such as a monkey)) and a human constant region. In another example, the chimeric antibody is a "class switch" antibody, wherein the class or subclass has been changed from the class or subclass of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In some embodiments of any one of the antibodies provided herein, the antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parent non-human antibody. In certain embodiments, the humanized antibody is substantially non-immunogenic in humans. In certain embodiments, the affinity of the humanized antibody for the target is substantially the same as an antibody from another species from which the humanized antibody was derived. See, for example, U.S. patent nos. 5530101, 5693761;5693762; and 5585089. In certain embodiments, amino acids of antibody variable domains are identified that can be modified without reducing the natural affinity of the antigen binding domain but without reducing immunogenicity. See, for example, U.S. patent nos. 5766886 and 5869619. In general, humanized antibodies comprise one or more variable domains, in which the HVRs (or portions thereof) are derived from a non-human antibody and the FRs (or portions thereof) are derived from a human antibody sequence. The humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., an antibody from which HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

Humanized antibodies and methods for their preparation are reviewed, for example, in Almagro et al front. Biosci.13:1619-1633 (2008), and are further described, for example, in U.S. Pat. Nos. 5821337, 7527791, 6982321, and 7087409. Human framework regions useful for humanization include, but are not limited to: the framework regions were selected using the "best fit" method (see, e.g., sims et al J. Immunol.151:2296 (1993)); the framework regions of the consensus sequences of human antibodies derived from a particular light chain variable region or subgroup of heavy chain variable regions (see, e.g., carter et al Proc. Natl. Acad. Sci. USA 89:4285 (1992); and Presta et al J. Immunol.151:2623 (1993)); human mature (somatic mutation) framework regions or human germline framework regions (see, e.g., almagro and frankson front. Biosci.13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., baca et al J.biol. Chem.272:10678-10684 (1997) and Rosok et al J.biol. Chem.271:22611-22618 (1996)).

(4) Human antibodies

In some embodiments of any one of the antibodies provided herein, the antibody is a human antibody. Human antibodies can be produced using a variety of techniques known in the art. Human antibodies are generally described by van Dijk et al Curr. Opin. Phacol.5:368-74 (2001) and Lonberg Curr. Opin. Immunol.20:450-459 (2008).

Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce a fully human antibody or a fully antibody with human variable regions in response to an antigenic challenge. Mouse strains deficient in mouse antibody production can be engineered with large fragments of the human Ig locus to expect that such mice can produce human antibodies in the absence of mouse antibodies. Human Ig large fragments can retain large variable gene diversity and appropriate regulation of antibody production and expression. By exploiting the antibody diversification and selection mechanisms of mice and the lack of immune tolerance of human proteins, the repertoire of human antibodies replicated in these mouse strains can produce high affinity fully human antibodies against any antigen of interest, including human antigens. Using hybridoma technology, antigen-specific human monoclonal antibodies with the desired specificity can be produced and selected. Some exemplary methods are described in U.S. patent nos. 5545807, EP 546073, and EP 546073. See also, e.g., descriptions xenomouise ^TM U.S. patent nos. 6075181 and 6150584 describe the technologyTechnical U.S. Pat. No. 5770 429; description of K-M->Technical U.S. Pat. No. 7041870 and description->Technical U.S. patent application publication No. US2007/0061900. The human variable region of the whole antibody produced by such animals may also be further modified, for example by combining with different human constant regions.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heterologous myeloma cell lines for the production of human monoclonal antibodies have been described. (see, e.g., kozbor J.Immunol.133:3001 (1984) and Boerner et al J.Immunol.147:86 (1991)). Human antibodies produced via human B cell hybridoma technology are also described in Li et al Proc.Natl. Acad.Sci.USA, 1:3557-3562 (2006). Additional methods include, for example, those described in U.S. patent No. 7189826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines). Human hybridoma technology (triple-source hybridoma technology) is also described in Vollmers et al Histology and Histopathology (3): 927-937 (2005) and Vollmers et al Methods and Findings in Experimental and Clinical Pharmacology (3): 185-91 (2005). Human antibodies can also be produced by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with the desired human constant domain. Techniques for selecting human antibodies from a library of antibodies are described below.

In some embodiments of any one of the antibodies provided herein, the antibody is a human antibody isolated by an in vitro method and/or screening a combinatorial library (to obtain an antibody having one or more desired activities). Suitable examples include, but are not limited to, phage display (CAT, morphosys, dyax, biosite/Medarex, xoma, symphogen, alexion (previously referred to as Proliferon), affimed), ribosome display (CAT), yeast display (Adimab), and the like. In some phage display methods, VH and VL gene libraries are cloned separately by Polymerase Chain Reaction (PCR) and randomly recombined in phage libraries, and antigen-binding phages can then be screened as described in Winter et al ann.rev.immunol.12:433-455 (1994). For example, many methods for generating phage display libraries and screening such libraries for antibodies with desired binding characteristics are known in the art. See also Sidhu et al J.mol.biol.338 (2): 299-310, 2004; lee et al J.mol.biol.340 (5): 1073-1093, 2004; fellouse Proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al J.Immunol. Methods 284 (-2): 1.19-132 (2004). Phage typically display antibody fragments as single chain Fv (scFv) fragments or as Fab fragments. The library of immune sources provides high affinity antibodies to the immunogen without the need to construct hybridomas. Alternatively, an initial repertoire can be cloned (e.g., from humans) to provide a single source of antibodies against a wide range of non-self and self-antigens without any immunization, as described by Griffiths et al, EMBO J.12:725-734 (1993). Finally, the initial library may also be prepared synthetically by: the unrearranged V gene segments were cloned from stem cells using PCR primers containing random sequences to encode highly variable HVR3 regions and to effect the rearrangement in vitro, as described by Hoogenboom et al, J.mol. Biol.,227:381-388, 1992. Patent publications describing human antibody phage libraries include, for example: us patent No. 5750373 and us patent publication nos. 2007/0292936 and 2009/0002360. Antibodies isolated from a human antibody library are considered human antibodies or human antibody fragments herein.

(5) Constant region comprising Fc region

In some embodiments of any one of the antibodies provided herein, the antibody comprises Fc. In some embodiments, the Fc is a human IgG1, igG2, igG3, and/or IgG4 isotype. In some embodiments, the antibody is of the IgG class, igM class, or IgA class.

In certain embodiments of any one of the antibodies provided herein, the antibody has an IgG2 isotype. In some embodiments, the antibody contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region comprises an Fc region. In some embodiments, the antibody induces one or more TMEM106B activities or is not associated with Fc receptor binding. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (fcγiib).

In certain embodiments of any one of the antibodies provided herein, the antibody has an IgG1 isotype. In some embodiments, the antibody contains a mouse IgG1 constant region. In some embodiments, the antibody contains a human IgG1 constant region. In some embodiments, the human IgG1 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (fcγiib).

In certain embodiments of any one of the antibodies provided herein, the antibody has an IgG4 isotype. In some embodiments, the antibody contains a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (fcγiib).

In certain embodiments of any one of the antibodies provided herein, the antibody has a hybrid IgG2/4 isotype. In some embodiments, the antibody comprises an amino acid sequence comprising amino acids 118 to 260 according to the EU numbering of human IgG2 and amino acids 261 to 447 according to the EU numbering of human IgG4 (WO 1997/11971; WO 2007/106585).

In some embodiments, the Fc region increases clustering but does not activate complement as compared to a corresponding antibody comprising the Fc region (not comprising an amino acid substitution). In some embodiments, the antibody induces one or more activities of the target to which the antibody specifically binds. In some embodiments, the antibody binds to TMEM106B.

It is also desirable to modify the anti-TMEM 106B antibodies of the present disclosure to modify effector function and/or increase serum half-life of the antibodies. For example, the Fc receptor binding sites on the constant region may be modified or mutated to remove or reduce binding affinity for certain Fc receptors (such as fcyri, fcyrii, and/or fcyriii) to reduce antibody-dependent cell-mediated cytotoxicity. In some embodiments, effector function is impaired by removing N-glycosylation of the Fc region of the antibody (e.g., in the CH2 domain of IgG). In some embodiments, effector function is impaired by modifying regions such as 233-236, 297 and/or 327-331 of human IgG, such as WO 99/58372 and Armour et al Molecular Immunology, 40:585-593 (2003); reddy et al J.immunology 164:1925-1933 (2000). In other embodiments, it is also desirable to modify the anti-TMEM 106B antibodies of the present disclosure to modify effector function, thereby increasing the selectivity of findings for ITIM-containing fcgrib (CD 32B) without activating the humoral response, increasing clustering of TMEM106B antibodies on neighboring cells, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell phagocytosis.

For example, to increase the serum half-life of an antibody, a salvage receptor binding epitope can be incorporated into the antibody (particularly an antibody fragment), as described in us patent 5739277. As used herein, the term "salvage receptor binding epitope" refers to an IgG molecule responsible for increasing the in vivo serum half-life of an IgG molecule (e.g., igG ₁ 、IgG ₂ 、IgG ₃ Or IgG ₄ ) An epitope of the Fc region of (c). Other amino acid sequence modifications.

(6) Multispecific antibodies

Multispecific antibodies are antibodies that have binding specificities for at least two different epitopes, including those on the same or another polypeptide (e.g., one or more TMEM106B polypeptides of the present disclosure). In some embodiments, the multispecific antibody may be a bispecific antibody. In some embodiments, the multispecific antibody may be a trispecific antibody. In some embodiments, the multispecific antibody may be a tetraspecific antibody. Such antibodies may be derived from full length antibodies or antibody fragments (e.g., F (ab') ₂ Bispecific antibodies). In some embodiments, the multispecific antibody comprises a first antigen-binding region that binds to a first site on TMEM106B, and comprises a first antigen-binding region that binds to a second site on TMEM106B A diaantigen binding region. In a certain embodiment, the multispecific antibody comprises a first antigen-binding region that binds to TMEM106B and a second antigen-binding region that binds to a second polypeptide.

Provided herein are multispecific antibodies comprising a first antigen-binding region comprising six HVRs of an antibody described herein, bound to TMEM106B, and a second antigen-binding region bound to a second polypeptide. In some embodiments, the first antigen binding region comprises V of an antibody described herein _H Or V _L 。

The multivalent antibody may recognize TMEM106B antigen as well as, but not limited to, other antigens, such as viral entry factors of coronaviruses, including angiotensin converting enzyme 2 (ACE 2), which are viral entry receptors for HCoV-NL63, SARS-CoV-1, and SARS-CoV-2.

Multivalent antibodies contain at least one polypeptide chain (and preferably two polypeptide chains), wherein one or more polypeptide chains comprise two or more variable domains. For example, one or more polypeptide chains can comprise VD1- (X1) _n -VD2-(X2) _n -Fc, wherein VD1 is a first variable domain, VD2 is a second variable domain, fc is a polypeptide chain of an Fc region, X1 and X2 represent amino acids or polypeptides, and n is 0 or 1. Similarly, one or more polypeptide chains may comprise V _H -C _H 1-Flexible Joint-V _H -C _H 1-Fc region chain; or V _H -C _H 1-V _H -C _H 1-Fc region chain. The multivalent antibodies herein preferably further comprise at least two (and preferably four) light chain variable domain polypeptides. Multivalent antibodies herein may, for example, comprise about two to about eight light chain variable domain polypeptides. Light chain variable domain polypeptides contemplated herein comprise a light chain variable domain, and optionally further comprise a CL domain.

Techniques for preparing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello Nature 305:537 (1983), WO 93/08829 and Traunecker et al EMBO J.10:3655 (1991)) and "knob-in-hole" engineering (see, e.g., U.S. Pat. No. 5731168). See also WO 2013/026833 (cross mab). Multispecific antibodies can also be prepared by the following techniques: engineering the electrostatic steering effect for the preparation of antibody Fc heterodimer molecules (WO 2009/089004 A1); crosslinking two or more antibodies (see, e.g., U.S. patent No. 4676980); leucine was used; bispecific antibody fragments have been prepared using "diabody" techniques (see, e.g., hollinger et al Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)); single chain Fv (scFv) dimers (see, e.g., gruber et al J. Immunol.152:5368 (1994)); and the preparation of trispecific antibodies as described, for example, in Tutt et al J.Immunol.147:60 (1991).

Also included herein are engineered antibodies having three or more functional antigen binding sites, including "octopus antibodies" (see, e.g., US 2006/0025576). Antibodies herein also include "dual-acting FAb" or "DAF" comprising antigen binding sites that bind to a plurality of TMEMs 106B (see, e.g., US 2008/0069820).

(7) Antibody variants

In some embodiments of any one of the antibodies provided herein, amino acid sequence variants of the antibodies are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of antibodies.

(i) Substitution, insertion and deletion variants

In some embodiments of any one of the antibodies provided herein, an antibody variant having one or more amino acid substitutions is provided. Amino acid sequence variants of antibodies can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues within the amino acid sequence of the antibody.

Table a: amino acid substitutions

Substantial modification of the biological properties of antibodies is achieved by selecting substitutions that differ significantly in their effect in maintaining the following properties: (a) the structure of the polypeptide backbone in the displacement region (e.g., folded or helical conformation), (b) the charge or hydrophobicity of the molecule at the target site, or (c) the side chain volume. Naturally occurring residues are divided into several groups according to common side chain properties:

(1) Hydrophobicity: norleucine, met, ala, val, leu, ile;

(2) Neutral hydrophilicity: cys, ser, thr, asn, gln;

(3) Acid: asp, glu;

(4) Alkaline: his, lys, arg;

(5) Residues that affect chain orientation: gly, pro; and

(6) Aromatic: trp, tyr, phe.

For example, a non-conservative substitution may involve replacing a member of one of these categories with a member of another category. Such substituted residues may be introduced, for example, into regions of a human antibody that are homologous to a non-human antibody, or into non-homologous regions of a molecule.

According to certain embodiments, the hydropathic index of amino acids may be considered when altering the polypeptides or antibodies described herein. Each amino acid has been assigned a hydropathic index based on its hydrophobicity and charge characteristics. They are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamic acid (-3.5); glutamine (-3.5); aspartic acid (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

The importance of the hydrophilic amino acid index in conferring interactive biological functions on a protein is understood in the art. Kyte et al J.mol.biol.,157:105-131 (1982). It is known that certain amino acids may be substituted for other amino acids having similar hydrophilicity indices or scores and still retain similar biological activity. In making the change according to the hydropathic index, in certain embodiments, substitutions of amino acids having hydropathic index within ±2 are included. In certain embodiments, those amino acids within ±1 are included, and in certain embodiments, those amino acids within ±0.5 are included.

It will also be appreciated in the art that similar amino acid substitutions can be made effectively in terms of hydrophilicity, particularly where the biologically functional protein or peptide produced thereby is intended for use in an immunological embodiment, as is currently the case. In certain embodiments, the maximum local average hydrophilicity of a protein, governed by the hydrophilicity of adjacent amino acids of the protein, correlates with the immunogenicity and antigenicity of the protein, i.e., with the biological properties of the protein.

These amino acid residues have been assigned the following hydrophilicity values: arginine (+3.0); lysine (+3.0±1); aspartic acid (+3.0±1); glutamic acid (+3.0±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5±1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4). In making changes according to similar hydrophilicity values, substitutions of amino acids having hydrophilicity values within ±2 are included in certain embodiments, substitutions of those amino acids within ±1 are included in certain embodiments, and substitutions of those amino acids within ±0.5 are included in certain embodiments. Epitopes can also be identified from primary amino acid sequences based on hydrophilicity. These regions are also referred to as "epitope core regions".

In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such changes do not substantially reduce the ability of the antibody to bind to an antigen. For example, conservative changes (e.g., conservative substitutions provided herein) may be made in the HVR that do not substantially reduce binding affinity. Such alterations may be, for example, outside of antigen-contacting residues in the HVR. In certain embodiments of the variant VH and VL sequences provided above, each HVR is unchanged or contains no more than one, two, or three amino acid substitutions.

Amino acid sequence insertions include amino and/or carboxy-terminal fusions ranging in length from one residue to polypeptides comprising one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertional variants of antibody molecules include fusions of the N-terminus or C-terminus of an antibody with an enzyme (e.g., for ADEPT) or a polypeptide that extends the serum half-life of the antibody.

Any cysteine residues that are not involved in maintaining the proper conformation of the antibody may also be replaced, typically with serine, to improve the oxidative stability of the molecule and prevent abnormal cross-linking. Instead, one or more cysteine linkages may be added to the antibody to improve the stability of the antibody (especially where the antibody is an antibody fragment (such as an Fv fragment).

(ii) Glycosylation variants

In some embodiments of any one of the antibodies provided herein, the antibody is altered to increase or decrease the degree of glycosylation of the antibody. The addition or deletion of glycosylation sites of antibodies can be conveniently accomplished by altering the amino acid sequence to create or remove one or more glycosylation sites.

Glycosylation of antibodies is typically N-linked or O-linked. N-linkage refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. Tripeptide sequences asparagine-X-serine and asparagine-X-threonine are recognition sequences for the enzymatic attachment of a carbohydrate moiety to an asparagine side chain, wherein X is any amino acid except proline. Thus, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of a sugar (i.e., one of N-acetylgalactosamine, galactose, or xylose) to a hydroxyamino acid (most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used).

The addition of glycosylation sites to antibodies is conveniently accomplished by altering the amino acid sequence such that the antibody contains one or more of the tripeptide sequences described above (for an N-linked glycosylation site). Alterations (for O-linked glycosylation sites) may also be made by addition of or substitution by one or more serine or threonine residues to the sequence of the original antibody.

Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. The natural antibodies produced by mammalian cells typically comprise branched-chain double-antennary oligosaccharides, which are typically linked by an N-linkage to Asn297 (numbered according to Kabat) of the CH2 domain of the Fc region. Oligosaccharides may include various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and fucose attached to GlcNAc in the "stem" of a double-antennary oligosaccharide structure. In some embodiments, oligosaccharides in the antibodies of the invention may be modified to produce antibody variants with certain improved properties.

In one embodiment, antibody variants are provided having a carbohydrate structure that lacks (directly or indirectly) fucose attached to the Fc region. See, for example, U.S. patent publication nos. 2003/0157108 and 2004/0093621. Examples of disclosures relating to "defucosylation" or "fucose deficient" antibody variants include: US2003/0157108; US 2003/015614; US2002/0164328; US2004/0093621; US 2004/013321; US 2004/010704; US2004/0110282; US2004/0109865; okazaki et al J.Mo l.biol.336:1239-1249 (2004); yamane-Ohnuki et al Biotech.Bioen g.87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3CHO cells deficient in protein fucosylation (described by Ripka et al arch. Biochem. Bi ophs. 249:533-545 (1986); US 2003/0157108), and knockout cell lines such as alpha-1, 6-fucosyltransferase genes, FUT8, knockout CHO cells (see, e.g., yamane-Ohnuki et al biotech. Bioeng.87:614 (2004) and Kanda et al Bio technol. Bioeng.94 (4): 680-688 (2006)).

(iii) Modified constant regions

In some embodiments of any one of the antibodies provided herein, the antibody Fc is an antibody Fc isotype and/or modified. In some embodiments, the antibody Fc isotype and/or modification is capable of binding to an fcγ receptor.

In some embodiments of any one of the antibodies provided herein, the modified antibody Fc is an IgG1 modified Fc. In some embodiments, the IgG1 modified Fc comprises one or more modifications. For example, in some embodiments, an IgG1 modified Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from N297A (Bolt S et al (1993) Eur J Immunol 23:403-411), D265A (Shields et al (2001) R.J. biol. Chem.276, 6591-6604), L234A, L235A (Hutchins et al (1995) Proc Natl Acad Sci USA,92:11980-11984; alegre et al, (1994) transfer 57:1537-1543.31; xu et al, (2000) Cell Immunol, 200:16-26), G237A (Alegre et al (1994) transfer 57:1537-1543.31; xu et al (2000) Immunol, 200:16-26), C226S, C229S, E233P, L234V, L234F, L235E (Mc 118et al, (1994) transfer 57:1537-1543.31; xu et al (2000) C226S, C229-35, E234V, L234E (Mc 1186) and so forth, (2008) 35:35:2007-35) and so forth, wherein amino acid positions are according to the EU numbering convention.

In some embodiments of any of the IgG1 modified Fc, the Fc comprises an N297A mutation according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises D265A and N297A mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises a D270A mutation according to EU numbering. In some embodiments, the IgG1 modified Fc comprises L234A and L235A mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises L234A and G237A mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises L234A, L235A and G237A mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises one or more (including all) of the P238D, L328E, E233, G237D, H268D, P271G and a330R mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises one or more of the S267E/L328F mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises P238D, L328E, E233D, G237D, H268D, P271G and a330R mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises P238D, L328E, G237D, H268D, P271G and a330R mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises P238D, S267E, L328E, E233D, G237D, H268D, P271G and a330R mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises P238D, S267E, L328E, G237D, H268D, P271G and a330R mutations according to EU numbering. In some embodiments of any of the IgG1 modified fcs, the Fc comprises C226S, C229S, E233P, L234V and L235A mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises L234F, L235E and P331S mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises S267E and L328F mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the Fc comprises an S267E mutation according to EU numbering. In some embodiments of any of the IgG1 modified fcs, the Fc comprises a constant heavy chain 1 (CH 1) and hinge region substitution with CH1 and a kappa light chain hinge region substitution of IgG2 (amino acids 118-230 of IgG2 according to EU numbering).

In some embodiments of any of the IgG1 modified fcs, the Fc comprises two or more amino acid substitutions that increase antibody clustering but do not activate complement, as compared to a corresponding antibody having an Fc region (not comprising two or more amino acid substitutions). Thus, in some embodiments of any of the IgG1 modified Fc, the IgG1 modified Fc is an antibody comprising an Fc region, wherein the antibody comprises an amino acid substitution at position E430G and one or more amino acid substitutions in the Fc region, the residue positions of the amino acid substitutions being selected from the group consisting of: L234F, L235A, L E, S267E, K322A, L328F, A330S, P331S according to EU numbering and any combination thereof. In some embodiments, the IgG1 modified Fc comprises amino acid substitutions at positions E430G, L243A, L a and P331S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid substitutions at positions E430G and P331S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid substitutions at positions E430G and K322A according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid substitutions at positions E430G, A S and P331S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid substitutions at positions E430G, K322A, A S and P331S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid substitutions at positions E430G, K a and a330S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid substitutions at positions E430G, K a and P331S according to EU numbering.

In some embodiments of any of the IgG1 modified Fc, the IgG1 modified Fc may additionally be included herein in combination with one or more of the a330L mutation (Lazar et al Proc Natl Acad Sci USA,103:4005-4010 (2006)) or the L234F, L E and/or P331S mutation (Sazinsky et al Proc Natl Acad Sci USA,105:20167-20172 (2008)) according to EU numbering convention to eliminate complement activation. In some embodiments of any of the IgG1 modified Fc, the IgG1 modified Fc may further comprise one or more of a330L, A330S, L234F, L235E and/or P331S according to EU numbering. In some embodiments of any of the IgG1 modified Fc, the IgG1 modified Fc may additionally comprise one or more mutations to enhance antibody half-life in human serum (e.g., one or more (including all) of the M252Y, S T and T256E mutations according to EU numbering convention). In some embodiments of any of the IgG1 modified Fc, the IgG1 modified Fc may further comprise one or more of E430G, E430S, E430F, E T, E345K, E345R, E345Y, S440Y and/or S440W according to EU numbering.

Other aspects of the disclosure relate to antibodies having modified constant regions (i.e., fc regions). If the antibody is engineered to eliminate FcgR binding, the agonist activity may be lost from the antibody binding to FcgR receptor to activate the targeted receptor (see, e.g., wilson et al Cancer Cell 19:101-113 (2011); armouret al Immunology 40:585-593 (2003); White et al. Cancer Cell 27:138-148 (2015)). Thus, it is believed that when an antibody has an Fc domain (CH 1 and hinge region) from a human IgG2 isotype or another type of Fc domain that is capable of preferentially binding to the inhibitory fcgrriib r receptor or variant thereof, the anti-TMEM 106B antibody of the present disclosure with the correct epitope specificity can activate the target antigen with minimal adverse effects.

In some embodiments of any one of the antibodies provided herein, the modified antibody Fc is an IgG2 modified Fc. In some embodiments, the IgG2 modified Fc comprises one or more modifications. For example, in some embodiments, an IgG2 modified Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments of any of the IgG2 modified Fc, the one or more amino acid substitutions are selected from V234A according to the EU numbering convention (Alegre et al translation 57:1537-1543 (1994); xu et al Cell Immunol,200:16-26 (2000)); G237A (Cole et al, transformation, 68:563-571 (1999)); H268Q, V309L, A330S, P331S (US 2007/0148167; armour et al Eur J Immunol 29:2613-2624 (1999); armour et al The Haematology Journal (suppl.1): 27 (2000); armour et al The Haematology Journal (suppl.1): 27 (2000)), C219S and/or C220S (White et al Cancer Cell 27, 138-148 (2015)); S267E, L328F (Chu et al Mol Immunol 45:3926-3933 (2008)); and M252Y, S T and/or T256E. In some embodiments of any of the IgG2 modified Fc, the Fc comprises amino acid substitutions at positions V234A and G237A according to EU numbering. In some embodiments of any of the IgG2 modified fcs, the Fc comprises amino acid substitutions at positions C219S or C220S according to EU numbering. In some embodiments of any of the IgG2 modified fcs, the Fc comprises amino acid substitutions at positions a330S and P331S according to EU numbering. In some embodiments of any of the IgG2 modified Fc, the Fc comprises amino acid substitutions at positions S267E and L328F according to EU numbering.

In some embodiments of any of the IgG2 modified Fc, the Fc comprises a C127S amino acid substitution according to EU numbering convention (White et al, (2015) Cancer Cell 27, 138-148; described by light et al Protein Sci.19:753-762 (2010), and WO 2008/079246). In some embodiments of any of the IgG2 modified fcs, the antibody has an IgG2 isotype with a kappa light chain constant domain comprising a C214S amino acid substitution according to EU numbering convention (White et al Cancer Cell 27:138-148 (2015); light et al Protein sci.19:753-762 (2010), and WO 2008/079246).

In some embodiments of any of the IgG2 modified fcs, the Fc comprises a C220S amino acid substitution according to EU numbering convention. In some embodiments of any of the IgG2 modified fcs, the antibody has an IgG2 isotype with a kappa light chain constant domain comprising a C214S amino acid substitution according to EU numbering convention.

In some embodiments of any of the IgG2 modified Fc, the Fc comprises a C219S amino acid substitution according to EU numbering convention. In some embodiments of any of the IgG2 modified fcs, the antibody has an IgG2 isotype with a kappa light chain constant domain comprising a C214S amino acid substitution according to EU numbering convention.

In some embodiments of any of the IgG2 modified Fc, the Fc comprises IgG2 isotype heavy chain constant domain 1 (CH 1) and a hinge region (White et al Cancer Cell27:138-148 (2015)). In certain embodiments of any of the IgG2 modified fcs, the IgG2 isotype CH1 and the hinge region comprise amino acid sequences 118-230 according to EU numbering. In some embodiments of any of the IgG2 modified Fc, the antibody Fc region comprises an S267E amino acid substitution, an L328F amino acid substitution, or both, and/or an N297A or N297Q amino acid substitution according to EU numbering convention.

In some embodiments of any of the IgG2 modified Fc, the Fc further comprises one or more amino acid substitutions at positions E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S Y and S440W according to EU numbering. In some embodiments of any of the IgG2 modified fcs, the Fc may additionally comprise one or more mutations to enhance the antibody half-life in human serum (e.g., one or more (including all) of the M252Y, S254T and T256E mutations according to the EU numbering convention). In some embodiments of any of the IgG2 modified fcs, the Fc may further comprise a330S and P331S.

In some embodiments of any of the IgG2 modified Fc, the Fc is an IgG2/4 hybrid Fc. In some embodiments, the IgG2/4 hybrid Fc comprises IgG2 aa 118 to 260 and IgG4 aa 261 to 447. In some embodiments of any of the IgG2 modified fcs, the Fc comprises one or more amino acid substitutions at positions H268Q, V309L, A S and P331S according to EU numbering.

In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises one or more amino acids selected from a330L, L234F, L E or P331S according to EU numbering; and additional amino acid substitutions of any combination thereof.

In certain embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises one or more amino acid substitutions at residue positions selected from C127S, L234A, L234F, L235A, L235E, S267E, K A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises amino acid substitutions at positions E430G, L243A, L235A and P331S according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified Fc, the Fc comprises amino acid substitutions at positions E430G and P331S according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises amino acid substitutions at positions E430G and K322A according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises amino acid substitutions at positions E430G, A330S and P331S according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises amino acid substitutions at positions E430G, K322A, A330S and P331S according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises amino acid substitutions at positions E430G, K322A and a330S according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises amino acid substitutions at positions E430G, K322A and P331S according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified Fc, the Fc comprises amino acid substitutions at positions S267E and L328F according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified fcs, the Fc comprises an amino acid substitution at position C127S according to EU numbering. In some embodiments of any of the IgG1 and/or IgG2 modified Fc, the Fc comprises amino acid substitutions at positions E345R, E430G and S440Y according to EU numbering.

In some embodiments of any one of the antibodies provided herein, the modified antibody Fc is an IgG4 modified Fc. In some embodiments, the IgG4 modified Fc comprises one or more modifications. For example, in some embodiments, an IgG4 modified Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments of any of the IgG4 modified Fc, the one or more amino acid substitutions are selected from L235A, G237A, S229P, L E (Reddy et al JImmunol 164:1925-1933 (2000)), S267E, E318A, L328F, M Y, S254T and/or T256E according to EU numbering convention. In some embodiments of any of the IgG4 modified fcs, the Fc may additionally comprise L235A, G237A and E318A according to EU numbering convention. In some embodiments of any of the IgG4 modified fcs, the Fc may additionally comprise S228P and L235E according to EU numbering convention. In some embodiments of any of the IgG4 modified Fc, the IgG4 modified Fc may further comprise S267E and L328F according to EU numbering convention.

In some embodiments of any of the IgG4 modified Fc, the IgG4 modified Fc comprises one or more mutations that can be combined with the S228P mutation according to EU numbering convention (Angal et al, mol immunol.30:105-108 (1993)) and/or with (Peters et al J Biol chem.287 (29): 24525-33 (2012)) to enhance antibody stability.

In some embodiments of any of the IgG4 modified Fc, the IgG4 modified Fc may additionally comprise one or more mutations to enhance antibody half-life in human serum (e.g., one or more (including all) of the M252Y, S T and T256E mutations according to EU numbering convention).

In some embodiments of any of the IgG4 modified fcs, the Fc comprises L235E according to EU numbering. In certain embodiments of any of the IgG4 modified fcs, the Fc comprises one or more amino acid substitutions at residue positions selected from C127S, F234A, L235A, L235E, S267E, K322A, L328F, E345R, E430G, S440Y, and any combination thereof, according to EU numbering. In some embodiments of any of the IgG4 modified fcs, the Fc comprises amino acid substitutions at positions E430G, L243A, L235A and P331S according to EU numbering. In some embodiments of any of the IgG4 modified fcs, the Fc comprises amino acid substitutions at positions E430G and P331S according to EU numbering. In some embodiments of any of the IgG4 modified fcs, the Fc comprises amino acid substitutions at positions E430G and K322A according to EU numbering. In some embodiments of any of the IgG4 modified fcs, the Fc comprises an amino acid substitution at position E430 according to EU numbering. In some embodiments of any of the IgG4 modified Fc, the Fc region comprises amino acid substitutions at positions E430G and K322A according to EU numbering. In some embodiments of any of the IgG4 modified fcs, the Fc comprises amino acid substitutions at positions S267E and L328F according to EU numbering. In some embodiments of any of the IgG4 modified fcs, the Fc comprises an amino acid substitution at position C127S according to EU numbering. In some embodiments of any of the IgG4 modified fcs, the Fc comprises amino acid substitutions at positions E345R, E G and S440Y according to EU numbering.

(8) Other antibody modifications

In some embodiments of any of the antibodies, the antibody is a derivative. The term "derivative" refers to a molecule that comprises a chemical modification other than an insertion, deletion, or substitution of an amino acid (or nucleic acid). In certain embodiments, the derivative comprises a covalent modification, including but not limited to chemical bonding to a polymer, lipid, or other organic or inorganic moiety. In certain embodiments, the chemically modified antigen binding protein may have a longer circulatory half-life than the non-chemically modified antigen binding protein. In certain embodiments, the chemically modified antigen binding protein may have improved targeting ability to a desired cell, tissue, and/or organ. In some embodiments, the derivative antigen binding protein is covalently modified to comprise one or more water-soluble polymer attachments, including but not limited to polyethylene glycol, polyethylene oxide glycol, or polypropylene glycol. See, for example, U.S. patent nos. 4640835, 4496689, 4301144, 4670417, 4791192, and 4179337. In certain embodiments, the derivative antigen binding protein comprises one or more polymers including, but not limited to, monomethoxy-polyethylene glycol, dextran, cellulose, ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymers, polyaminoacids (homopolymers or random copolymers), poly- (N-vinylpyrrolidone) -polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, and mixtures of such polymers.

In certain embodiments, the derivative is covalently modified with a polyethylene glycol (PEG) subunit. In certain embodiments, one or more water-soluble polymers are bonded at one or more specific positions (e.g., at the amino terminus) of the derivative. In certain embodiments, one or more water-soluble polymers are randomly attached to one or more side chains of the derivative. In certain embodiments, PEG is used to improve the therapeutic ability of antigen binding proteins. In certain embodiments, PEG is used to improve the therapeutic ability of the humanized antibodies. Some such methods are discussed, for example, in U.S. patent No. 6133426, which is hereby incorporated by reference for any purpose.

Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs, which are similar in nature to those of the template peptide. These types of non-peptide compounds are known as "peptide mimetics" or "peptide mimetics". Fauchere, J.Adv.drug Res.,15:29 (1986); and Evans et al J.Med.chem.,30:1229 (1987), which are incorporated herein by reference for any purpose. Such compounds are typically developed by means of computerized molecular modeling. Peptide mimics that are structurally similar to the peptides used in therapy may be used to produce similar therapeutic or prophylactic effects. In general, a mimetic is similar in structure to an exemplary polypeptide (i.e., a polypeptide having biochemical or pharmacological activity), such as a human antibody, but has one or more peptide bonds optionally replaced by bonds selected from the group consisting of: -CH ₂ NH-、-CH ₂ S-、-CH ₂ -CH ₂ -, -CH ═ CH- (cis and trans), -COCH ₂ -、-CH(OH)CH ₂ -and-CH ₂ SO-. Systematic substitution of one or more amino acids of the consensus sequence with the same type of D-amino acid (e.g., D-lysine for L-lysine) may be used in certain embodiments to produce a more stable peptide. Furthermore, constrained peptides comprising a consensus sequence or substantially identical consensus sequence variations can be produced by methods known in the art (Rizo and giaasch ann.rev. Biochem.,61:387 (1992), incorporated herein by reference for any purpose); for example, peptides are cyclized by the addition of internal cysteine residues capable of forming intramolecular disulfide bridges.

Drug conjugation involves coupling a biologically active cytotoxic (anti-cancer) payload or drug to an antibody that specifically targets a certain tumor marker (e.g., a polypeptide that is ideally present only within or on tumor cells). Antibodies track these proteins in vivo and attach themselves to the surface of cancer cells. The biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the tumor cells, which then absorbs or internalizes the antibody along with the cytotoxin. Upon internalization of the ADC, the cytotoxic drug is released and kills the cancer. Due to this targeting, drugs ideally have lower side effects and provide a broader therapeutic window than other chemotherapeutic agents. Techniques for conjugating antibodies have been disclosed and are known in the art (see, e.g., jane de Lartigue QncLive, 2012, 7, 5, ADC Review on antibody-drug conjugates; and Ducry et al Bioconjugate Chemistry 21 (1): 5-13 (2010).

Nucleic acids, vectors and host cells

The anti-TMEM 106B antibodies of the present disclosure may be produced using recombinant methods and compositions, for example, as described in us patent No. 4817567. In some embodiments, an isolated nucleic acid having a nucleotide sequence encoding any one of the anti-TMEM 106B antibodies of the present disclosure is provided. Such nucleic acids may encode anti-TMEM 106B antibodies comprising V _L Amino acid sequence of (c) and/or comprising V _H (e.g., the light chain and/or the heavy chain of an antibody). In some embodiments, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In some embodiments, host cells comprising such nucleic acids are also provided. In some embodiments, the host cell comprises (e.g., has been transduced with): (1) A vector comprising a nucleic acid encoding V comprising an antibody _L Amino acid sequences of (2) and V comprising antibodies _H (2) a first vector comprising a sequence encoding a V comprising an antibody _L And a second vector comprising a nucleic acid encoding an antibody comprising V _H Is a nucleic acid of an amino acid sequence of (a). In some embodiments, the host cell is a eukaryotic cell, such as a Chinese Hamster Ovary (CHO) cell or lymphocyte (e.g., Y0, NS0, sp20 cell). Host cells of the present disclosure also include, but are not limited to, isolated cells, in vitro cultured cells, and ex vivo cultured cells.

Methods of making anti-TMEM 106B antibodies of the present disclosure are provided. In some embodiments, the methods comprise culturing a host cell of the present disclosure comprising a nucleic acid encoding an anti-TMEM 106B antibody under conditions suitable for expression of the antibody. In some embodiments, the antibody is subsequently recovered from the host cell (or host cell culture medium).

For recombinant production of anti-TMEM 106B antibodies of the present disclosure, nucleic acids encoding anti-TMEM 106B antibodies are isolated and inserted into one or more vectors for further cloning and/or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of an antibody).

Suitable vectors comprising a nucleic acid sequence encoding any of the anti-TMEM 106B antibodies of the present disclosure, or cell surface expressed fragments or polypeptides thereof (including antibodies) described herein include, but are not limited to, cloning vectors and expression vectors. Suitable cloning vectors may be constructed according to standard techniques or may be selected from a large number of cloning vectors available in the art. Although the cloning vector selected may vary depending on the host cell desired to be used, useful cloning vectors generally have self-replicating capabilities, may have a single target for a particular restriction endonuclease, and/or may carry genes for markers that may be used to select for clones containing the vector. Suitable examples include plasmids and bacterial viruses, such as pUC18, pUC19, bluescript (e.g., pBS SK+) and derivatives thereof, mpl8, mpl9, pBR322, pMB9, colE1, pCR1, RP4, phage DNA and shuttle vectors such as pSA3 and pAT 28. These and many other cloning vectors are available from commercial suppliers such as BioRad, strategene and Invitrogen.

Suitable host cells for cloning or expressing the antibody-encoding vector include prokaryotic or eukaryotic cells. For example, the anti-TMEM 106B antibodies of the present disclosure may be produced in bacteria, particularly when glycosylation and Fc effector function are not required. With respect to expression of antibody fragments and polypeptides in bacteria (e.g., U.S. Pat. nos. 5648237, 5789199 and 5840523). After expression, the antibodies may be isolated from the bacterial cell slurry in a soluble fraction, and may be further purified.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized" to produce antibodies with a partial or complete human glycosylation pattern (e.g., as described by Gerngross Nat. Biotech.22:1409-1414 (2004; and Li et al Nat. Biotech.24:210-215 (2006)).

Suitable host cells for expressing glycosylated antibodies may also be derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Many baculovirus strains have been identified which can be used in combination with insect cells, in particular for transfection of Spodoptera frugiperda (Spodoptera frugiperda) cells. Plant cell cultures may also be used as hosts (e.g., U.S. Pat. nos. 5959177, 6040498, 6420548, 7125978 and 6417429, which describe the use of PLANTIBODIES for the production of antibodies in transgenic plants) ^TM Technology).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for growth in suspension may be useful. Other examples of useful mammalian host cell lines are the monkey kidney CV1 line (COS-7) transformed by SV 40; human embryonic kidney cell lines (293 or 293 cells, such as, for example, graham et al J.Gen. Virol.36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (TM 4 cells, as described, for example, by Mather, biol. Reprod.23:243-251 (1980)); monkey kidney cells (CV 1); african green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); buffalo rat hepatocytes (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, for example, in Mather et al Annals N.Y. Acad. Sci.383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese Hamster Ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0, and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., yazaki and Wu, methods in Molecular Biology, volume 248 (b.k.c. editions, humana Press, totowa, NJ), pages 255-268 (2003).

Pharmaceutical composition/formulation

Provided herein are pharmaceutical compositions and/or pharmaceutical formulations comprising an anti-TMEM 106B antibody of the present disclosure and a pharmaceutically acceptable carrier, which are useful, for example, in the treatment, prevention, or reduction of risk of a coronavirus infection.

In some aspects, the antibody or antigen binding fragment thereof of the desired purity is present in a formulation comprising, for example, a physiologically acceptable carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences (1990) Mack Publishing co., easton, PA). In some embodiments, the pharmaceutically acceptable carrier is preferably non-toxic to the recipient at the dosage and concentration employed.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizers, thickening agents, stabilizers and preservatives.

In some aspects, the pharmaceutical composition comprises an anti-TMEM 106B antibody or antigen binding fragment thereof as described herein, and a pharmaceutically acceptable carrier (see, e.g., gennaro, remington: the Science and Practice of Pharmacy with Facts and Comparisons: drugs Plus, 20 th edition (2003); ansel et al Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 th edition, lippencott Williams and Wilkins (2004); kibbe et al Handbook of Pharmaceutical Excipients, 3 rd edition, pharmaceutical Press (2000)). In some aspects, the pharmaceutical compositions described herein are used as medicaments. The composition to be used for in vivo administration may be sterile. This is easily achieved by filtration (through, for example, a sterile filtration membrane).

The pharmaceutical compositions described herein may be used to exert an in vivo biological effect, e.g., to treat, prevent, or reduce the risk of a coronavirus infection.

Therapeutic use

In some embodiments, the present disclosure provides methods for treating, preventing, or reducing the risk of a coronavirus infection by administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to TMEM106B protein. In some embodiments, the coronavirus infection is a SARS-CoV-2 coronavirus infection, and the methods provided herein are effective in treating, preventing, or reducing the risk of a SARS-CoV-2 coronavirus infection.

In some embodiments, the present disclosure provides methods for preventing or reducing coronavirus transmission, wherein the methods comprise administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to TMEM106B protein, thereby preventing or reducing coronavirus transmission. In some embodiments, the coronavirus is a SARS-CoV-2 coronavirus, and the methods provided herein are effective to prevent or reduce transmission of the SARS-CoV-2 coronavirus.

The anti-TMEM 106B antibodies of the present disclosure are effective in treating coronavirus infections over a range of clinical manifestations of coronavirus infections including asymptomatic or pre-symptomatic infections, mild disease, moderate disease, severe disease, and critical disease.

In some embodiments, the subject or individual is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the subject or individual is a human.

The antibodies provided herein (and any other therapeutic agent) can be administered by any suitable means, including parenteral, intrapulmonary, intranasal, intralesional, intracerebral spinal, intracranial, intraspinal, intrasynovial, intrathecal, oral, topical, or inhalation routes. Parenteral infusion includes intramuscular, intravenous administration as bolus or continuous infusion over a period of time, intraarterial, intra-articular, intraperitoneal or subcutaneous administration. In some embodiments, the administration is intravenous administration. In some embodiments, the administration is subcutaneous administration. Administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is brief or chronic. Various dosing schedules are contemplated herein, including but not limited to single administration or multiple administrations at various time points, bolus administration, and pulse infusion.

The antibodies provided herein will be formulated, administered, and administered in a manner consistent with good medical practice. Factors considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to the practitioner. The antibodies need not be, but are optionally formulated with one or more agents currently used to prevent or treat the condition in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These agents are generally used at the same dosages as described herein and by the routes of administration as described herein, or at about 1% to 99% of the dosages described herein, or at any dosages empirically/clinically determined to be appropriate and by any routes empirically/clinically determined to be appropriate.

The present disclosure also contemplates the use of anti-TMEM 106B antibodies in combination with other therapies for treating, preventing, or reducing the risk of a coronavirus infection, including, for example, dexamethasone (dexamethasone), rituximab (remdesivir), baratinib (baricitinib), casirizumab (casiriumab), idevezumab (immovimab), bani Wei Shankang (bamlanivimab), or any combination thereof.

In some embodiments, the antibodies of the present disclosure reduce the cytopathic effect in SARS-CoV-2 infected cells, optionally wherein the cells are VeroE6 cells or NCI-H1975 cells.

For the prevention or treatment of a disease, the appropriate dosage of the antibodies of the invention (when used alone or in combination with one or more other therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for prophylactic or therapeutic purposes, past therapy, patient history and response to the antibody, and the discretion of the attendant physician. The antibody is suitably administered to the patient at one time or through a series of treatments.

Article of manufacture

Provided herein are articles of manufacture (e.g., kits) comprising an anti-TMEM 106B antibody described herein. The article of manufacture may comprise one or more containers comprising an antibody as described herein. The container may have any suitable packaging including, but not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. The container may be a unit dose, a bulk package (e.g., a multi-dose package) or a subunit dose.

In some embodiments, the kit may additionally include a second reagent. In some embodiments, the second agent is a pharmaceutically acceptable buffer or diluent, including but not limited to, aqueous Bacteriostatic (BWFI) for injection, phosphate buffered saline, ringer's solution, and dextrose solution, for example. In some embodiments, the second agent is a pharmaceutically active agent.

In some embodiments of any of the articles, the article further comprises instructions for use of the methods according to the present disclosure. The instructions typically include information about the dosage, schedule, and route of administration of the intended treatment. In some embodiments, these instructions include administering an isolated antibody of the present disclosure (e.g., an anti-TMEM 106B antibody described herein) according to any of the methods of the present disclosure to prevent, reduce the risk of, or treat a subject suffering from a disease, disorder, or injury selected from the group consisting of frontotemporal lobar degeneration, frontotemporal lobar dementia, frontotemporal dementia with a mutation in progranulin, frontotemporal lobar dementia with a mutation in C9orf72, frontotemporal lobar degeneration with TDP-43 inclusion bodies, TDP-43 proteinopathies, hippocampal sclerosis (hpcl), aged hippocampal sclerosis (HS-aging), various disorder-related cognitive defects (including but not limited to cognitive defects in amyotrophic lateral sclerosis), and hypomyelination disorders (including but not limited to hypomyelinated leukodystrophy). In some embodiments, the instructions comprise instructions for use of the anti-TMEM 106B antibody and a second agent (e.g., a second pharmaceutically active agent).

The present disclosure will be more fully understood with reference to the following examples. However, it should not be construed as limiting the scope of the present disclosure. All references throughout this disclosure are hereby expressly incorporated by reference.

Examples

Example 1: identification of anti-TMEM 106B antibodies

Monoclonal antibodies targeting human TMEM106B were generated as described above (see international patent application publication WO2019/133512, the disclosure of which is incorporated herein by reference in its entirety).

Briefly, NZB/W mice (JAX 100008, jackson Laboratory, bar Harbor, ME), SJL mice (JAX 000686, jackson Laboratory), or TMEM106B knockout mice (Tacouc, rensselaaer, NY) were co-immunized weekly with 50 μg of each of plasmid DNA encoding full-length human, cynomolgus monkey (cyno), or mouse TMEM106B in the presence or absence of mFlt3 ligand (DNA) and mGM-CSF (DNA) (Invitrogen, san Diego, calif.) diluted in ringer's solution. A total of 5-7 TMEM106B expression plasmid injections were performed for each mouse for DNA immunization. Three days after final DNA immunization, spleens were harvested from mice. Serum from mice was analyzed for reactivity with TMEM106B by FACS analysis using HEK293 cells overexpressing human, cynomolgus monkey and/or mouse TMEM106B. Spleen cells from mice whose serum showed strong binding to HEK293 cells overexpressing human, cynomolgus and/or mouse TMEM106B were fused with p3x63ag8.653 mouse myeloma cells (CRL-1580, american type culture collection (American Type Culture Collection), rockville, MD) via electrofusion (ECM 2001, btx, holiston, ma) and incubated overnight in Clonacell-HY medium C (StemCell Technologies, vancouver, BC, canada) at 37 ℃/5% CO 2. Three rounds of fusion were performed: fusion a, using spleen cells obtained from immunized tmem106b knockout mice; fusion B, using spleen cells obtained from immunized SJL mice; and fusion C, using spleen cells obtained from immunized NZB/W mice.

The next day, the fused cells were centrifuged and resuspended in 10ml of Clonacell-HY Medium C (Jackson Immunoresearch, west Grove, pa.) with anti-mouse IgG Fc-FITC, and then gently mixed with 90ml of methylcellulose-based Clonacell-HY Medium D (Stemcell Technologies) containing HAT components. Cells were plated into Nunc omnitalys (Thermo Fisher Scientific, rochester, NY) and grown at 37 ℃/5% CO2 for seven days. The fluorescent colonies were selected and transferred to 96-well plates containing Clonacell-HY medium E (StemCell Technologies) using Clonepix 2 (Molecular Devices, sunnyvale, calif.), and screened for TMEM106B reactivity after 5 days.

Preliminary screening of anti-TMEM 106B hybridomas was performed as follows. The ability of the differential tissue culture supernatants obtained from hybridomas to bind to transiently transfected HEK293 cells of human TMEM106B was initially screened by comparison with the extent of binding of parental (untransfected) HEK293 cells by transfected cells. Over-expressing TMEM106B cells were generated by transiently transfecting HEK293 cells using lipofectamine systems. To ensure reproducibility of the entire screening experiment, large transfected cell pools (about 1×10) were prepared in a single round of transient transfection ⁹ ) And aliquoted and frozen for all further screening experiments.

To screen hybridoma cell culture supernatants, human TMEM106B transfected HEK293 cells were aliquoted in 96-well round bottom plates (2 x10 per well ⁵ Individual cells) and incubated with 50 μl of hybridoma cell culture supernatant on ice for 30 minutes. After the initial incubation, the supernatant was removed via centrifugation, and the cells were washed twice with 175. Mu.L of ice-cold FACS buffer (PBS+1% FBS+2mM EDTA) and then incubated with anti-mouse IgG Fc-APCs (Jackson Labs, catalog number 115-136-071) (1:500 dilution) for a further 20 minutes on ice. After this secondary incubation, the cells were washed twice again with ice-cold FACS buffer and resuspended in 30 μl final volume of FACS buffer+0.25 μl/well of propidium iodide (BD Biosciences catalog number 556463). Cell sorting was performed on FACS Canto system (BD Biosciences) or iQue (Intellicyt), and sorting gates were set to exclude death (i.e., propidium iodidePositive) cells. Median Fluorescence Intensity (MFI) of anti-mouse APC MFI on TMEM106b+hek293 cells was calculated for each clone, and those clones showing at least 2-fold signal over background compared to wells of secondary antibody only were used for further analysis and characterization.

Example 2: antibody heavy and light chain variable domain sequences

The amino acid sequence of the identified anti-TMEM 106B antibody as described above was determined. Amino acid sequences encoding the light chain variable region and the heavy chain variable region of the produced antibodies are determined using standard techniques. The Kabat heavy chain CDR (HVR) amino acid sequences and Kabat light chain CDR (HVR) amino acid sequences of the antibodies are shown in tables 1, 2, 3, and 4 below. The amino acid sequences of the heavy chain variable region and the light chain variable region of the anti-TMEM 106B antibody are shown in tables 5 and 6 below. In both tables 5 and 6, CDR (HVR) regions defined by Kabat are underlined.

TABLE 1

TABLE 2

TABLE 3 Table 3

TABLE 4 Table 4

TABLE 5

TABLE 6

Example 3: antiviral Activity of anti-TMEM 106B antibodies

TMEM106B has been identified as a host factor for SARS-CoV-2 coronavirus infection. Antiviral activity of anti-TMEM 106B antibodies against infection and/or replication of SARS-CoV-2 coronavirus is determined by a variety of in vitro and in vivo methods known to those skilled in the art and useful for assessing the antiviral activity of antibodies.

For example, veroE6 cells (african green monkey kidney epithelial cells) are incubated with an anti-TMEM 106B antibody for a period of time, such as one hour. Cells are then infected with a series of dilutions covering a series of multiple infections (MOI) of SARS-CoV-2 virus (such as, for example, the SARS-CoV-2 coronavirus Washington 2019 strain) and incubated for a period of time (e.g., 1-3 days). Then, the cells were fixed and stained with neutral red. Cytotoxicity was assessed using standard methods. Cell viability is measured using methods known to those skilled in the art, such as, for example, fixing and staining surviving cells with crystal violet.

In addition, viral cytopathic effect (CPE) was determined. The use of RT-qPCR quantification to determine intracellular SARS-CoV-2 virus levels in non-fixed cells further provides a measure of the effect of anti-TMEM 106B antibodies on SARS-CoV-2 virus replication.

Alternatively, other cell types are used in these studies, such as cell lines derived from the human liver (e.g., huh7 cells, hep3B cells) or cell lines derived from the human lung (e.g., a549 cells, NCI-H1975 cells, NCI-H2110 cells).

The results from these in vitro experiments provided an antiviral effect of anti-TMEM 106B antibodies on SARS-CoV-2 virus infection and/or SARS-CoV-2 virus replication, including an assessment of the effect of anti-TMEM 106B antibodies on SAR-CoV-2 induced cytopathic effect (CPE).

VeroE6 cells were incubated with the anti-TMEM 106B antibodies of the present disclosure (about 100 μg/ml) for 1 hour. Cells were then incubated with serial dilutions of SARS-CoV-2 coronavirus (Washington 2019 strain) as described above. Viral cytopathic effect (CPE) was assessed as described above and measured by cell viability/survival. The results of these studies are shown in figure 1.

The data in figure 1 are provided as fold-changes in cell survival compared to observations in the control. As shown in fig. 1, the anti-TMEM 106B antibodies of the present disclosure are effective in maintaining cell viability following infection with SARS-CoV-2 virus, indicating that the anti-TMEM 106B antibodies of the present disclosure are effective in reducing the viral cytopathic effects. Specifically, the anti-TMEM 106B antibodies TM3, TM11, TM24, TM32, TM34, TM39, TM42, TM51, TM63, TM65, TM71 and TM84 showed about 1.5-fold or higher cell survival compared to the observations in the virus-infected control cells. In addition, the anti-TMEM 106B antibodies TM11, TM24, TM32 and TM51 showed about 2-fold or higher cell survival compared to the observations in the virus-infected control cells. These results demonstrate that the anti-TMEM 106B antibodies of the present disclosure can effectively reduce the viral cytopathic effects in SARS-CoV-2 coronavirus infected cells.

Example 4: epitope frame of anti-TMEM 106b antibody

The epitope box of certain anti-TMEM 106B antibodies of the present disclosure was performed by cartera (Salt Lake City, nevada, USA) using a premixed epitope box and method. Monoclonal anti-TMEM 106B antibodies were immobilized to CMD50M chips (xantec#spmxcmd50M lot number SCCMD50M 0416). The running buffer was HBS-EP+ with 1mg/mL BSA. GST-TMEM106B (truncated, comprising amino acids 122-210 of SEQ ID NO: 1) antigen was prepared at a final concentration of 55nM (equivalent to 2. Mu.g/ml) and mixed with the competitive analyte anti-TMEM 106B antibody at a final concentration of 333nM (equivalent to 50. Mu.g/ml) or compared to a buffer control. Samples were injected onto the array for 5 minutes and regenerated after each cycle with 1 minute of two Pierce IgG-elution buffers (ThermoFisher catalog No. 21004) and 1 part 10mM glycine pH2.0 (Carterra).

anti-TMEM 106B antibodies were sorted into different competition boxes and generated box-and-spectrum. Some anti-TMEM 106B antibodies did not show the ability to block binding to any of the other anti-TMEM 106B antibodies because they were unable to bind to these boxes and the truncated GST-TMEM106B fusion proteins used in the experiments, suggesting that these anti-TMEM 106B antibodies bind to the C-terminal domain of TMEM 106B; these anti-TMEM 106B antibodies were assigned to box 5 (see table 7 below). Other anti-TMEM 106B antibodies showed box-and-spectrum identified as box 1 and box 2. Box 2 shows two closely related sub-boxes (box 3 and box 4). The antibody portion within box 3 or box 4 blocks the box 2 antibody.

The epitope box of certain other anti-TMEM 106B antibodies of the present disclosure was performed by Lake Pharma (Salt Lake City, nevada, USA) using a premixed epitope box and method. Monoclonal anti-TMEM 106B antibodies were immobilized to CMD50M chips (xantec#spmxcmd50M lot number SCCMD50M 0416). The running buffer was HBS-EP+ with 1mg/ml BSA. GST-TMEM106B (truncated) antigen was prepared at a final concentration of 55nM (equivalent to 2. Mu.g/ml) and mixed with the competitive analyte anti-TMEM 106B antibody at a final concentration of 333nM (equivalent to 50. Mu.g/ml) or compared to a buffer control. Samples were injected onto the array for 5 minutes and regenerated after each cycle with 1 minute of two Pierce IgG-elution buffers (ThermoFisher catalog No. 21004) and 1 part 10mM glycine pH2.0 (Carterra). See table 7 below.

These results show that the anti-TMEM 106B antibodies of the present disclosure are framed to different populations (e.g., the anti-TMEM 106B antibodies framed to a particular population bind to the same or overlapping epitopes) based on the assays used as described above.

Example 5: effect of anti-TMEM 106B antibodies on cytopathic effect (CPE) after in vitro SARS-CoV-2 infection

The ability of the anti-TMEM 106B antibodies of the present disclosure to affect cell viability and CPE in vitro was tested as follows. NCI-H1975 cells (human lung epithelial cells) were isolated at 4X 10 ⁴ Cell density of individual cells/ml (100 μl/well) was plated in RPMI medium containing 8% heat-inactivated FBS in 96-well plates. anti-TMEM 106B antibody was serially diluted (see below for final antibody concentration) and added to each well; cells were incubated overnight in the presence of anti-TMEM 106B antibody.

The next day, SARS-CoV-2 virus (SARS-CoV-2 Belgium p6 25-1) was added to the cells; after virus addition to the wells, final serial dilutions of antibody concentrations were 20,000ng/ml, 2,000ng/ml, 200ng/ml and 20ng/ml. The cells were then incubated for three days in the presence of anti-TMEM 106B antibody and SARS-CoV-2 virus. The cells were visually observed for their effect by virus-induced cytopathic effect (CPE) and the effect of anti-TMEM 106B antibodies. Cell viability was assessed by the MTS assay, a colorimetric method for determining cell viability. In these studies, the antiviral compound, adefovir (1. Mu.M), was used as a positive control known to inhibit SARS-CoV-2-induced CPE in NCI-H1975 cells. Hamster anti-SARS-CoV-2 antisera were also used as positive controls in these experiments. These experiments were performed independently twice.

As shown in fig. 2A, 2B, 2C, 2D, 2E, and 2F, the addition of the positive control adefovir (Rem) to virus-infected cells resulted in approximately 75% -80% cell viability compared to the percentage of cell viability in the absence of added virus. In addition, the addition of hamster anti-SARS-CoV-2 antiserum (HP) to virus-infected cells resulted in approximately 75% -80% cell viability compared to the percent cell viability without virus addition, similar to that observed after the Ruidexivir treatment. Note that the addition of PBS in the presence of virus produced a significant viral cytopathic effect as demonstrated by less than 20% cell viability.

Figures 2A-2C show that the anti-TMEM 106B antibodies of the present disclosure are at least as effective as adefovir in reducing the viral cytopathic effects (as measured by cell viability) in NCI-H1975 human lung epithelial cells infected with SARS-CoV-2. Specifically, the addition of anti-TMEM 106B antibodies TM3, TM9, TM10, TM11, TM18, TM19, TM21, TM24, TM25, TM28, TM29, TM30, TM32, TM35, TM37, TM48, TM56, TM59, TM60, TM61, TM63, TM64, TM72, TM76, TM78, TM80, TM86 and TM88 resulted in a cell viability of about 80% or more, as compared to the percent cell viability in the absence of added virus.

Example 6: correlation between epitope frame of anti-TMEM 106B antibody and prevention of SARS-CoV-2 coronavirus cytopathic effect

As described in example 4 above, epitope-frame and analysis revealed a different frame and profile of the anti-TMEM 106B antibodies of the present disclosure for binding to TMEM106B polypeptides. The correlation of the effectiveness of the anti-TMEM 106B antibodies of each of the antibody frame profiles with prevention of cell death (as determined by CPE) following coronavirus infection was determined and the results are shown in table 7 below. As shown below, non-conjugate means an anti-TMEM 106B antibody that is unable to fusion bind to the GST-TMEM106B polypeptide used in these boxes and experiments (designated box 5), which lacks the C-terminal portion of TMEM 106B.

TABLE 7

As shown in table 7, anti-TMEM 106B antibodies belonging to box 2 (and related sub-boxes 3 and 4) were effective in preventing viral cytopathic effects (as measured by cell death), whereas anti-TMEM 106B antibodies belonging to box 1 or box 5 were not effective in preventing viral cytopathic effects. In particular, anti-TMEM 106B antibodies belonging to boxes 2, 3 and 4 provided greater than 50% prevention of cytopathic effects associated with coronavirus infection. In particular, most anti-TMEM 106B antibodies belonging to boxes 2, 3 and 4 showed greater than 80% prevention of cytopathic effects (TM-25, TM-32, TM30, TM18, TM19, TM3, TM9, TM12, TM60, TM61, TM11, TM21, TM10, TM72, TM29, TM59, TM78, TM86, TM35, TM37, TM56, TM24, TM48, TM63, TM64, TM76, TM28, TM72 and TM 13) following coronavirus infection. Taken together, these results demonstrate that anti-TMEM 106B antibodies exhibiting a frame-by-frame profile (as shown above) overlapping frames 2, 3, and 4 may bind to epitopes of TMEM106B polypeptides that prevent or reduce coronavirus infection.

Example 7: dose titration of anti-TMEM 106B antibodies against SARS-CoV-2 infection

NCI-H1975 cells were treated overnight with four different concentrations (20 μg/mL, 2 μg/mL, 0.2 μg/mL and 0.02 μg/mL) of the anti-TMEM 106B antibodies of the present disclosure or adefovir, and then infected with SARS-CoV-2 virus for 3 days. At the end of the experiment, cytopathic effects were assessed visually and cell viability was measured by the MTS assay. Cell viability was normalized to that observed in untreated/uninfected cells, as shown in figures 3A-D. As shown in fig. 3A-D, certain anti-TMEM 106B antibodies of the present disclosure can be effective in reducing cytopathic effects associated with SARS-CoV-2 infection in vitro at concentrations as low as 200 ng/mL.

Sequence listing

<110> Alicker Limited liability company (ALECTOR LLC)

<120> anti-TMEM 106B antibodies for the treatment and prevention of coronavirus infection

<130> 4503.015PC03

<150> US 63/318,068

<151> 2022-03-09

<150> US 63/239,498

<151> 2021-09-01

<150> US 63/164,873

<151> 2021-03-23

<160> 534

<170> PatentIn version 3.5

<210> 1

<211> 274

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> human TMEM106B

<400> 1

Met Gly Lys Ser Leu Ser His Leu Pro Leu His Ser Ser Lys Glu Asp

1 5 10 15

Ala Tyr Asp Gly Val Thr Ser Glu Asn Met Arg Asn Gly Leu Val Asn

20 25 30

Ser Glu Val His Asn Glu Asp Gly Arg Asn Gly Asp Val Ser Gln Phe

35 40 45

Pro Tyr Val Glu Phe Thr Gly Arg Asp Ser Val Thr Cys Pro Thr Cys

50 55 60

Gln Gly Thr Gly Arg Ile Pro Arg Gly Gln Glu Asn Gln Leu Val Ala

65 70 75 80

Leu Ile Pro Tyr Ser Asp Gln Arg Leu Arg Pro Arg Arg Thr Lys Leu

85 90 95

Tyr Val Met Ala Ser Val Phe Val Cys Leu Leu Leu Ser Gly Leu Ala

100 105 110

Val Phe Phe Leu Phe Pro Arg Ser Ile Asp Val Lys Tyr Ile Gly Val

115 120 125

Lys Ser Ala Tyr Val Ser Tyr Asp Val Gln Lys Arg Thr Ile Tyr Leu

130 135 140

Asn Ile Thr Asn Thr Leu Asn Ile Thr Asn Asn Asn Tyr Tyr Ser Val

145 150 155 160

Glu Val Glu Asn Ile Thr Ala Gln Val Gln Phe Ser Lys Thr Val Ile

165 170 175

Gly Lys Ala Arg Leu Asn Asn Ile Thr Ile Ile Gly Pro Leu Asp Met

180 185 190

Lys Gln Ile Asp Tyr Thr Val Pro Thr Val Ile Ala Glu Glu Met Ser

195 200 205

Tyr Met Tyr Asp Phe Cys Thr Leu Ile Ser Ile Lys Val His Asn Ile

210 215 220

Val Leu Met Met Gln Val Thr Val Thr Thr Thr Tyr Phe Gly His Ser

225 230 235 240

Glu Gln Ile Ser Gln Glu Arg Tyr Gln Tyr Val Asp Cys Gly Arg Asn

245 250 255

Thr Thr Tyr Gln Leu Gly Gln Ser Glu Tyr Leu Asn Val Leu Gln Pro

260 265 270

Gln Gln

<210> 2

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-1、TM-14、TM-23、TM-26、TM-27、TM-82、TM-89

<400> 2

Asn Tyr Leu Ile Glu

1 5

<210> 3

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CRD-H1 -- TM-2

<400> 3

Glu Tyr Pro Met His

1 5

<210> 4

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-3

<400> 4

Thr Leu Gly Arg Gly Val Gly

1 5

<210> 5

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-4、TM-18、TM-87

<400> 5

Asp Tyr Tyr Met Asn

1 5

<210> 6

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-5

<400> 6

Thr Tyr Gly Ile Thr

1 5

<210> 7

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-6

<400> 7

Glu Tyr Thr Ile His

1 5

<210> 8

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-7、TM-28、TM-86

<400> 8

Asp Tyr Tyr Ile His

1 5

<210> 9

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-8

<400> 9

Asp Tyr Pro Met His

1 5

<210> 10

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-9、TM-25

<400> 10

Gly Tyr Gly Met Ser

1 5

<210> 11

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-10、TM-31

<400> 11

Ser Tyr Trp Met Asn

1 5

<210> 12

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-11、TM-24

<400> 12

Asp Tyr Gly Val His

1 5

<210> 13

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-12、TM-19、TM-32

<400> 13

Asp Tyr Tyr Met Tyr

1 5

<210> 14

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-13、TM-84

<400> 14

Thr Phe Pro Ile Glu

1 5

<210> 15

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-15

<400> 15

Asn Tyr Trp Ile Thr

1 5

<210> 16

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-16、TM-20

<400> 16

Asp Tyr Tyr Met His

1 5

<210> 17

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-17

<400> 17

Asp Tyr Leu Ile Glu

1 5

<210> 18

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-21、TM-66、TM-70、TM-71

<400> 18

Asn Tyr Ala Met Ser

1 5

<210> 19

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-22

<400> 19

Ser Tyr Tyr Ile His

1 5

<210> 20

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-29、TM-88

<400> 20

Asp Tyr Tyr Ile Asn

1 5

<210> 21

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-30

<400> 21

Asn Tyr Asp Val Asn

1 5

<210> 22

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-33

<400> 22

Asp Tyr Asn Met Asn

1 5

<210> 23

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-34

<400> 23

Asp Ser Gly Met Asp

1 5

<210> 24

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-35

<400> 24

Arg His Trp Met Gln

1 5

<210> 25

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-37、TM-56、TM-59、TM-64、TM-81

<400> 25

Ser Tyr Trp Met His

1 5

<210> 26

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-39

<400> 26

Asp Tyr Trp Met His

1 5

<210> 27

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-41

<400> 27

Asp Cys Tyr Met His

1 5

<210> 28

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-42、TM-45、TM-52、TM-72

<400> 28

Asn Tyr Trp Met His

1 5

<210> 29

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-44

<400> 29

Asp Tyr Gly Met His

1 5

<210> 30

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-46

<400> 30

Ser Phe Trp Met Asn

1 5

<210> 31

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-47、TM-50

<400> 31

Asn Tyr Gly Val His

1 5

<210> 32

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-48、TM-60、TM-90

<400> 32

Ser Tyr Asp Ile Asn

1 5

<210> 33

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-49

<400> 33

Arg Phe Trp Met His

1 5

<210> 34

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-51

<400> 34

Thr Tyr Trp Ile Asp

1 5

<210> 35

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-1

<400> 35

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

1 5 10 15

Gly

<210> 36

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-2

<400> 36

Met Ile Tyr Thr Asn Thr Gly Glu Pro Thr Tyr Ala Ala Glu Phe Lys

1 5 10 15

Gly

<210> 37

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-3

<400> 37

Lys Ile Trp Trp Asn Asp Asp Lys Phe Tyr Tyr Pro Ala Leu Lys Ser

1 5 10 15

<210> 38

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-4

<400> 38

Val Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr His Gln Lys Phe Lys

1 5 10 15

Gly

<210> 39

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-5

<400> 39

Glu Ile Tyr Pro Arg Ser Asp Asn Thr Tyr Tyr Asn Glu Lys Phe Lys

1 5 10 15

Asp

<210> 40

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-6

<400> 40

Trp Phe Tyr Pro Gly Ser Thr Tyr Ile Asp Tyr Asn Glu Lys Phe Lys

1 5 10 15

Asp

<210> 41

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-7

<400> 41

Leu Val Tyr Pro Tyr Asn Gly Asp Thr Asp Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 42

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-8

<400> 42

Val Ile Tyr Thr Asp Thr Gly Glu Pro Lys Tyr Ala Glu Val Phe Lys

1 5 10 15

Gly

<210> 43

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-9

<400> 43

Thr Ile Ser Ser Gly Ser Phe Tyr Ile Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 44

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-10

<400> 44

Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys

1 5 10 15

Gly

<210> 45

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-11、TM-24

<400> 45

Val Ile Trp Asn Asn Gly Asn Thr Asp Tyr Asn Ala Ala Phe Ile Ser

1 5 10 15

<210> 46

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-12

<400> 46

Arg Ile Asp Pro Glu Asp Gly Asp Ala Glu Tyr Ala Pro Lys Phe Gln

1 5 10 15

Gly

<210> 47

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-13、TM-84

<400> 47

Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 48

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-14

<400> 48

Val Ile Asn Pro Gly Gly Gly Asn Thr Asp Tyr Ser Glu Lys Phe Lys

1 5 10 15

Asp

<210> 49

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-15

<400> 49

Asp Ile Tyr Pro Gly Ser Gly Asn Ser Asn Tyr Asn Glu Ser Phe Lys

1 5 10 15

Arg

<210> 50

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-16、TM-20

<400> 50

Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Glu Phe Gln

1 5 10 15

Gly

<210> 51

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-17

<400> 51

Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 52

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-18

<400> 52

Asn Ile Asn Pro Asn Asn Gly Asp Ala Phe Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 53

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-19

<400> 53

Arg Ile Asp Pro Glu Asp Gly Asp Thr Glu Asn Ala Pro Lys Phe Arg

1 5 10 15

Gly

<210> 54

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-21

<400> 54

Phe Ile Ser Asp Gly Gly Gly Tyr Ile Tyr Tyr Ala Asp Asn Val Lys

1 5 10 15

Asp

<210> 55

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-22

<400> 55

Trp Ile Tyr Pro Gly Asn Gly Ile Thr Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 56

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-23、TM-26

<400> 56

Val Ile Asn Pro Gly Ser Gly Ile Thr Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 57

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-25

<400> 57

Thr Ile Ser Ser Gly Gly Arg Tyr Thr Val Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 58

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-27

<400> 58

Val Ile Asn Pro Gly Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 59

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-28

<400> 59

Leu Val Tyr Pro Tyr Asn Gly Gly Thr Asn Tyr Asn Gln Asn Phe Lys

1 5 10 15

Gly

<210> 60

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-29

<400> 60

Arg Ile Tyr Pro Gly Ser Gly Tyr Thr Tyr Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 61

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-30

<400> 61

Trp Ile Tyr Pro Arg Asp Gly Thr Thr Ile Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 62

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-31

<400> 62

Tyr Ile Asn Pro Thr Ser Gly Tyr Thr Arg Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 63

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-32

<400> 63

Arg Ile Asp Pro Glu Asp Gly Asp Thr Glu Tyr Val Pro Lys Phe Gln

1 5 10 15

Gly

<210> 64

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-33

<400> 64

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

1 5 10 15

Gly

<210> 65

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-34

<400> 65

Tyr Ile Ser Ser Gly Ser Ser Thr Thr His Tyr Ala Asp Thr Val Lys

1 5 10 15

Gly

<210> 66

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-35

<400> 66

Glu Ile Leu Pro Gly Ser Asn Asn Ile Tyr Tyr Asn Glu Lys Val Lys

1 5 10 15

Gly

<210> 67

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-37、TM-59

<400> 67

Tyr Val Asn Pro Ser Ser Gly Tyr Thr Lys Asn Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 68

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-39

<400> 68

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

1 5 10 15

Asp

<210> 69

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-41

<400> 69

Arg Ile Asp Pro Glu Asp Gly Thr Thr Asn Phe Ala Pro Lys Phe Gln

1 5 10 15

Asp

<210> 70

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-42、TM-45

<400> 70

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

1 5 10 15

Asp

<210> 71

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-44

<400> 71

Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asp Thr Val Lys

1 5 10 15

Gly

<210> 72

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-46

<400> 72

Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys

1 5 10 15

Asp

<210> 73

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-47、TM-50

<400> 73

Val Ile Trp Ala Gly Gly Asn Thr Asn Tyr Asn Ser Ala Leu Met Ser

1 5 10 15

<210> 74

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-48、TM-60

<400> 74

Trp Ile Tyr Pro Arg Asp Gly Asn Thr Gln Tyr Ile Glu Lys Leu Lys

1 5 10 15

Gly

<210> 75

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-49

<400> 75

Asn Ile Asp Pro Ser Asp Ser Gln Thr His Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 76

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-51

<400> 76

Asn Met Phe Pro Gly Ser Ser Arg Thr Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Ser

<210> 77

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-52

<400> 77

Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 78

<211> 13

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-1

<400> 78

Arg Gly Tyr Thr Ile Tyr Asp Phe Tyr Ala Met Asp Tyr

1 5 10

<210> 79

<211> 3

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-2

<400> 79

Ala Gly Tyr

1

<210> 80

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-3

<400> 80

Ile Ala Gly Gly Thr Gly Ala Ala Tyr

1 5

<210> 81

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-4

<400> 81

Ala Ala Thr Val Val Ala Gly Phe Asp Tyr

1 5 10

<210> 82

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-5

<400> 82

Ser Lys Gly Ser Gly Thr Gly Asp Tyr

1 5

<210> 83

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-6

<400> 83

His Glu Glu Asp Tyr Ser Asn Trp Phe Pro Phe

1 5 10

<210> 84

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-7

<400> 84

Thr Tyr Tyr Ala Asn Ser Pro Asp Tyr

1 5

<210> 85

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-8

<400> 85

Arg Leu Ala Tyr

1

<210> 86

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-9

<400> 86

Gln Asn Phe Tyr Tyr Gly Cys Glu Asp Tyr

1 5 10

<210> 87

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-10

<400> 87

Trp Gly His Tyr Asp Glu Ala Met Asp Asp

1 5 10

<210> 88

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-11、TM-24

<400> 88

Ser Leu Arg Pro Leu His Phe Asp Tyr

1 5

<210> 89

<211> 13

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-12

<400> 89

Arg Val Ile Tyr Asp Gly Tyr Tyr Arg Thr Met Asp Cys

1 5 10

<210> 90

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-13、TM-84

<400> 90

Tyr Phe Tyr Gly Gly Met Asp Tyr

1 5

<210> 91

<211> 13

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-14

<400> 91

Ser Pro Tyr Ser Ser Tyr Val Gly Tyr Ala Val Asp Tyr

1 5 10

<210> 92

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-15

<400> 92

Lys Ala Tyr Gly Gly Phe Pro Tyr

1 5

<210> 93

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-16、TM-20

<400> 93

Ser Gln Pro Phe Thr Tyr

1 5

<210> 94

<211> 13

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-17

<400> 94

Ser Ser Tyr Gly Val Tyr Val Ala Tyr Pro Met Asp Tyr

1 5 10

<210> 95

<211> 14

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-18

<400> 95

Glu Gly Gln Leu Arg Leu Arg Arg Val Tyr Ala Met Asp Tyr

1 5 10

<210> 96

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-19

<400> 96

Arg Ile Gly Asn Leu Tyr His Val Met Asp Tyr

1 5 10

<210> 97

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-21

<400> 97

Asp Gly Gly Thr Gly Phe Thr Tyr

1 5

<210> 98

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-22

<400> 98

Pro Tyr Tyr Gly Ile Arg Asn Cys Tyr Phe Asp Val

1 5 10

<210> 99

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-23、TM-26

<400> 99

Ser Asp Phe Ile Thr Thr Val Val Ala Asp Tyr

1 5 10

<210> 100

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-25

<400> 100

Asp Asn Phe Tyr Ser Tyr Ala Met Asp Tyr

1 5 10

<210> 101

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-27

<400> 101

Ile Ile Tyr Asp His Asp Trp Tyr Phe Asp Val

1 5 10

<210> 102

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-28

<400> 102

Ser Tyr Phe Ser Asn Pro Ile Gly Tyr

1 5

<210> 103

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-29

<400> 103

His Tyr Thr Asn Pro Phe Ala Tyr

1 5

<210> 104

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-30

<400> 104

Thr Leu Pro Gln Ala Met Asp Tyr

1 5

<210> 105

<211> 13

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-31

<400> 105

Ser Pro Pro Thr Val Val Leu Ile Gly Tyr Phe Asp Tyr

1 5 10

<210> 106

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-32

<400> 106

Arg Thr Trp Asp Leu Tyr Tyr Ala Val Asp Asn

1 5 10

<210> 107

<211> 2

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-33

<400> 107

Ser Tyr

1

<210> 108

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-34

<400> 108

Arg Asp Gly Asn Tyr Trp Tyr Phe Asp Val

1 5 10

<210> 109

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-35

<400> 109

Ser Leu Tyr Asp Tyr Asp Gly Val Phe Ala Tyr

1 5 10

<210> 110

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-37、TM-42、TM-45、TM-56、TM-59

<400> 110

Glu Gly Gly Ser Ile Ser Asp Trp Tyr Phe Asp Val

1 5 10

<210> 111

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-39

<400> 111

Glu Ala Gly Ser Ile Ser Asp Trp Tyr Phe Asp Val

1 5 10

<210> 112

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-41

<400> 112

Glu Trp Asp Ser Gly Ala Tyr

1 5

<210> 113

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-44

<400> 113

Asn Tyr Gly Ser Pro Tyr Ala Met Asp Tyr

1 5 10

<210> 114

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-46

<400> 114

Gly Asp Gly Phe Ser Tyr Phe Asp Tyr

1 5

<210> 115

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-47、TM-50

<400> 115

Glu Ala Lys Leu Leu Arg Ser Tyr Ala Met Asp Tyr

1 5 10

<210> 116

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-48、TM-60

<400> 116

Trp Ile Phe Tyr Ala Met Asp Tyr

1 5

<210> 117

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-49

<400> 117

Leu Ile Thr Val Asp Tyr Ala Met Asp Tyr

1 5 10

<210> 118

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-51

<400> 118

Lys Glu Gly Leu Trp Thr Tyr Gly Tyr Asp Gly Gly Ala Trp Phe Ala

1 5 10 15

Tyr

<210> 119

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-52

<400> 119

Arg Gly Tyr Tyr Gly Arg Ser Pro Phe Ala Tyr

1 5 10

<210> 120

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-1

<400> 120

Arg Ser Ser Gln Ser Ile Val Tyr Asn Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 121

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-2

<400> 121

Arg Ala Ser Ser Ser Val Ser Tyr Ile His

1 5 10

<210> 122

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-3、TM-9

<400> 122

Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr

1 5 10 15

<210> 123

<211> 14

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-4

<400> 123

Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn

1 5 10

<210> 124

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-5

<400> 124

Arg Ala Ser Glu Asn Ile Tyr Ile Tyr Leu Ala

1 5 10

<210> 125

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-6

<400> 125

Lys Ala Ser Asp His Ile Asn Asn Trp Leu Ala

1 5 10

<210> 126

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-7

<400> 126

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Arg Asn Tyr Leu

1 5 10 15

Ala

<210> 127

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-8、TM-31

<400> 127

Lys Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser

1 5 10

<210> 128

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-10

<400> 128

Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Lys Thr Tyr Leu His

1 5 10 15

<210> 129

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-11

<400> 129

Lys Ser Ser Gln Ser Leu Leu Asn Ser Asn Asn Leu Gln Asn Tyr Leu

1 5 10 15

Ala

<210> 130

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-12

<400> 130

Arg Ser Ser Gln Thr Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 131

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-13、TM-84

<400> 131

Arg Ala Ser Glu Asn Ile Tyr Ser Ser Leu Gly

1 5 10

<210> 132

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-14、TM-17

<400> 132

Arg Ala Ser Gln Asp Ile Gly Ser Asn Leu Asn

1 5 10

<210> 133

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-15

<400> 133

Arg Val Ser Glu Asn Ile Tyr Asn Asn Leu Ala

1 5 10

<210> 134

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-16、TM-20

<400> 134

Ser Ala Ser Ser Ser Leu Asn Tyr Met Tyr

1 5 10

<210> 135

<211> 15

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-18

<400> 135

Arg Ala Ser Lys Ser Val Ser Ile Ser Val Tyr Thr Tyr Val His

1 5 10 15

<210> 136

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-19

<400> 136

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 137

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-21、TM-25

<400> 137

Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Phe

1 5 10 15

<210> 138

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-22

<400> 138

Arg Ser Gly Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 139

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-23、TM-26

<400> 139

Arg Ser Ser Gln Ser Leu Thr Asn Tyr Tyr Gly Asn Thr Tyr Leu Ser

1 5 10 15

<210> 140

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-24

<400> 140

Lys Ser Ser Gln Ser Leu Leu Asn Ser Asn Asn Gln Gln Asn Tyr Leu

1 5 10 15

Ala

<210> 141

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-27

<400> 141

Ser Ala Ser Ser Ser Ile Ser Tyr Met Tyr

1 5 10

<210> 142

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-28、TM-61、TM-86

<400> 142

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 143

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-29

<400> 143

Arg Ser Ser Lys Ser Leu Leu His Tyr Asn Gly Ile Thr Tyr Leu Tyr

1 5 10 15

<210> 144

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-30

<400> 144

Arg Ser Ser Gln Thr Ile Val His Arg Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 145

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-32

<400> 145

Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 146

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-33

<400> 146

Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala

1 5 10

<210> 147

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-34

<400> 147

Arg Ala Thr Ser Ser Val Thr Tyr Met His

1 5 10

<210> 148

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-35

<400> 148

Arg Ser Ser Gln Ser Ile Val His Arg Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 149

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-37、TM-59

<400> 149

Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Ser Tyr

1 5 10 15

<210> 150

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-39

<400> 150

Arg Ser Ser Lys Thr Leu Leu Asn Ser Asn Gly Asn Thr Tyr Leu Tyr

1 5 10 15

<210> 151

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-41、TM-44

<400> 151

Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 152

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-42、TM-45

<400> 152

Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr

1 5 10 15

<210> 153

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-46

<400> 153

Cys Ala Ser Ser Arg Val Asn Tyr Met His

1 5 10

<210> 154

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-47

<400> 154

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

1 5 10 15

Thr

<210> 155

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-48、TM-54、TM-60

<400> 155

Arg Ser Ser Gln Ser Ile Val His Gly Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 156

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-49、TM-62

<400> 156

Ser Ala Ser Ser Ser Val Ser Tyr Met Tyr

1 5 10

<210> 157

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-50

<400> 157

Arg Ala Ser Gln Asp Ile Asn Asn Tyr Leu Tyr

1 5 10

<210> 158

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-51

<400> 158

Lys Ser Ser Gln Ser Leu Arg Asn Ser Arg Thr Arg Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 159

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-52

<400> 159

Ser Ala Ser Ser Ser Val Ser Tyr Met His

1 5 10

<210> 160

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-1、TM-22、TM-30、TM-32、TM-35、TM-48、TM-54、TM-60、

TM-69、TM-83、TM-94

<400> 160

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 161

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-2、TM-34

<400> 161

Ala Thr Ser Asn Leu Ala Ser

1 5

<210> 162

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-3

<400> 162

Gln Met Ser Ser Leu Ala Ser

1 5

<210> 163

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-4

<400> 163

Gly Thr Asn Asn Arg Ala Pro

1 5

<210> 164

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-5

<400> 164

Asn Gly Lys Met Leu Ala Glu

1 5

<210> 165

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-6

<400> 165

Gly Ala Thr Ser Leu Glu Thr

1 5

<210> 166

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-7、TM-28、TM-61、TM-86

<400> 166

Gly Ala Ser Thr Arg Glu Ser

1 5

<210> 167

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-8

<400> 167

Arg Ala Asn Arg Leu Val Asp

1 5

<210> 168

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-9、TM-21、TM-25、TM-29

<400> 168

Gln Met Ser Asn Leu Ala Ser

1 5

<210> 169

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-10、TM-12

<400> 169

Lys Ile Ser Asn Arg Phe Ser

1 5

<210> 170

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-11、TM-24

<400> 170

Phe Ala Ser Ile Arg Glu Ser

1 5

<210> 171

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-13、TM-15、TM-84

<400> 171

Ala Ala Thr Asn Leu Ala Asp

1 5

<210> 172

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-14、TM-17、TM-89

<400> 172

Ala Thr Ser Ser Leu Asp Ser

1 5

<210> 173

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-16、TM-20、TM-73

<400> 173

Asp Thr Ser Asn Leu Ala Ser

1 5

<210> 174

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-18

<400> 174

Leu Ala Ser Asn Leu Glu Ser

1 5

<210> 175

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-19

<400> 175

Lys Val Phe Asn Arg Phe Ser

1 5

<210> 176

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-23、TM-26、TM-66、TM-82

<400> 176

Gly Ile Ser Asn Arg Phe Ser

1 5

<210> 177

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-27

<400> 177

Arg Thr Ser Thr Leu Ala Ser

1 5

<210> 178

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-31

<400> 178

Arg Gly Asn Gly Leu Val Asp

1 5

<210> 179

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-33

<400> 179

Ser Ala Ser Asn Arg Tyr Thr

1 5

<210> 180

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-37、TM-39、TM-42、TM-45、TM-56、TM-59、TM-63、TM-64、

TM-68、TM-78、TM-80

<400> 180

Arg Met Ser Asn Leu Ala Ser

1 5

<210> 181

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-41、TM-44、TM-47、TM-51

<400> 181

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 182

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-46、TM-49、TM-52、TM-62

<400> 182

Asp Thr Ser Lys Leu Ala Ser

1 5

<210> 183

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-50

<400> 183

Tyr Thr Ser Met Leu His Ser

1 5

<210> 184

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-1

<400> 184

Phe Gln Val Ser His Val Pro Phe Thr

1 5

<210> 185

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-2

<400> 185

Gln Gln Trp Ser Ser Asn Pro Ser Thr

1 5

<210> 186

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-3、TM-9

<400> 186

Ala Gln Asn Leu Glu Leu Pro Trp Thr

1 5

<210> 187

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-4

<400> 187

Val Leu Trp Tyr Ser Asn His Leu Val

1 5

<210> 188

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-5

<400> 188

Gln His His Tyr Gly Ser Pro Pro Ala

1 5

<210> 189

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-6

<400> 189

Gln Gln Tyr Trp Ser Ser Pro Tyr Thr

1 5

<210> 190

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-7、TM-28、TM-86

<400> 190

Gln Asn Asp His Ser Tyr Pro Leu Thr

1 5

<210> 191

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-8

<400> 191

Leu Gln Tyr Asp Glu Phe Pro Leu Thr

1 5

<210> 192

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-10

<400> 192

Ser Gln Ile Thr His Val Pro Trp Thr

1 5

<210> 193

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-11

<400> 193

Gln Gln His Tyr Asn Thr Pro Phe Thr

1 5

<210> 194

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-12、TM-35

<400> 194

Phe Gln Gly Ser His Val Pro Tyr Thr

1 5

<210> 195

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-13

<400> 195

Gln His Leu Trp Ser Ile Pro Trp Thr

1 5

<210> 196

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-14、TM-17、TM-89

<400> 196

Leu Gln Tyr Ala Ser Ser Pro Arg Thr

1 5

<210> 197

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-15

<400> 197

Gln His Phe Trp Asp Thr Pro Phe Thr

1 5

<210> 198

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-16、TM-20

<400> 198

Gln Gln Trp Thr Ser Phe Pro Pro Thr

1 5

<210> 199

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-18

<400> 199

Gln His Ser Arg Glu Leu Pro Tyr Thr

1 5

<210> 200

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-19、TM-32

<400> 200

Phe Gln Gly Ser His Val Pro Phe Thr

1 5

<210> 201

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-21

<400> 201

Val Gln Asn Leu Glu Leu Pro Tyr Thr

1 5

<210> 202

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-22、TM-54

<400> 202

Phe Gln Gly Ser His Val Pro Trp Thr

1 5

<210> 203

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-23、TM-26

<400> 203

Leu Gln Gly Thr His Gln Pro Arg Thr

1 5

<210> 204

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-24、TM-81

<400> 204

Gln Gln His Tyr Ser Thr Pro Phe Thr

1 5

<210> 205

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-25

<400> 205

Ala Gln Asn Leu Glu Leu Trp Thr

1 5

<210> 206

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-27

<400> 206

Gln Gln Tyr His Ser Tyr Pro Arg Thr

1 5

<210> 207

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-29

<400> 207

Ala Gln Asn Leu Glu Leu Pro Tyr Thr

1 5

<210> 208

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-30

<400> 208

Phe Gln Gly Ser His Leu Pro Trp Thr

1 5

<210> 209

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-31

<400> 209

Leu Gln Tyr Asp Glu Phe Pro Phe Thr

1 5

<210> 210

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-33

<400> 210

Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr

1 5

<210> 211

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-34

<400> 211

Gln Gln Trp Ser Ser Asn Pro Tyr Thr

1 5

<210> 212

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-37、TM-42、TM-45、TM-56、TM-59

<400> 212

Met Gln His Leu Glu Tyr Pro Tyr Thr

1 5

<210> 213

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-39

<400> 213

Met Gln His Leu Asp Tyr Pro Tyr Thr

1 5

<210> 214

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-41

<400> 214

Gln Gln Tyr Tyr Ser Tyr Pro Tyr Thr

1 5

<210> 215

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-44

<400> 215

Gln Gln Tyr Tyr Ser Tyr Pro Thr

1 5

<210> 216

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-46

<400> 216

Gln Gln Trp Ser Ser Asn Pro Pro Thr

1 5

<210> 217

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-47

<400> 217

Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

1 5

<210> 218

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-48、TM-60

<400> 218

Phe Gln Gly Ser His Leu Pro Tyr Thr

1 5

<210> 219

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-49、TM-62

<400> 219

Gln Gln Tyr His Ser Tyr Pro Pro Thr

1 5

<210> 220

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-50

<400> 220

Gln Gln Gly Ser Thr Leu Met Tyr Thr

1 5

<210> 221

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-51

<400> 221

Lys Gln Ser Tyr Asn Leu Leu Thr

1 5

<210> 222

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-52

<400> 222

Phe Gln Gly Ser Gly Tyr Pro Leu Thr

1 5

<210> 223

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-54

<400> 223

Thr Tyr Asp Leu Asn

1 5

<210> 224

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-61

<400> 224

Asn Tyr Trp Met Asn

1 5

<210> 225

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-62

<400> 225

Arg Tyr Trp Met His

1 5

<210> 226

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-63

<400> 226

Ser Phe Trp Met His

1 5

<210> 227

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-65

<400> 227

Ser Ser Trp Met His

1 5

<210> 228

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-68

<400> 228

Asp Asp Tyr Met His

1 5

<210> 229

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-69

<400> 229

Ser Tyr Gly Val His

1 5

<210> 230

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-73

<400> 230

Ser His Trp Met His

1 5

<210> 231

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-74

<400> 231

Ser Tyr Val Ile His

1 5

<210> 232

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-75

<400> 232

Ser Tyr Val Met His

1 5

<210> 233

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-76

<400> 233

Thr Ser Gly Met Gly Val Ser

1 5

<210> 234

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-77

<400> 234

Asp Tyr Glu Met His

1 5

<210> 235

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-78

<400> 235

Asn His Trp Met His

1 5

<210> 236

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-79

<400> 236

Asn Tyr Val Met His

1 5

<210> 237

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-80

<400> 237

Thr Phe Trp Met His

1 5

<210> 238

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-83

<400> 238

Thr Tyr Trp Ile His

1 5

<210> 239

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-85

<400> 239

Gly Tyr Trp Met His

1 5

<210> 240

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-91

<400> 240

Ser Gly Tyr Tyr Trp Asp

1 5

<210> 241

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-92

<400> 241

Asp Tyr Thr Met Asp

1 5

<210> 242

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-93

<400> 242

Ser Tyr Gly Ile Ser

1 5

<210> 243

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H1 -- TM-94

<400> 243

Asp Tyr Asn Met Asp

1 5

<210> 244

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-54

<400> 244

Trp Ile Tyr Pro Arg Gly Gly Ser Thr Glu Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 245

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-56

<400> 245

Tyr Ile Asn Pro Ser Ser Gly Tyr Ser Lys Tyr Asn Gln Arg Phe Lys

1 5 10 15

Asp

<210> 246

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-61

<400> 246

Tyr Ile Asn Pro Ser Ser Asp Tyr Thr Lys Tyr Asn Gln Asn Phe Lys

1 5 10 15

Asp

<210> 247

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-62

<400> 247

Asn Ile Asp Pro Ser Asp Ser Glu Thr Gln Tyr Asn Pro Lys Phe Lys

1 5 10 15

Asp

<210> 248

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-63

<400> 248

Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Ser Gln Lys Phe Lys

1 5 10 15

Asp

<210> 249

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-64

<400> 249

Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn Gln Asn Phe Arg

1 5 10 15

Gly

<210> 250

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-65

<400> 250

Glu Ile Asn Pro Lys Asn Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Thr

<210> 251

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-66

<400> 251

Thr Ile Gly Ser Val Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 252

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-68

<400> 252

Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Ser Lys Phe Gln

1 5 10 15

Gly

<210> 253

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-69

<400> 253

Ile Met Gly Trp Asp Asp Lys Lys Tyr Tyr Asn Ser Ala Leu Lys Ser

1 5 10 15

<210> 254

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-70、TM-71

<400> 254

Thr Ile Gly Tyr Gly Gly Ser Tyr Ser Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 255

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-72

<400> 255

Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 256

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-73

<400> 256

Glu Ile Asp Pro Ser Asp Ser Tyr Thr Tyr Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 257

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-74

<400> 257

Phe Ile Asn Pro Asn Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Arg

1 5 10 15

Gly

<210> 258

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-75

<400> 258

Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 259

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-76

<400> 259

His Ile Phe Trp Asp Asp Asp Lys Arg Tyr Asn Leu Phe Leu Lys Ser

1 5 10 15

<210> 260

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-77

<400> 260

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

1 5 10 15

Gly

<210> 261

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-78

<400> 261

Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn His Lys Phe Lys

1 5 10 15

Asp

<210> 262

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-79

<400> 262

His Ile Thr Pro His Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 263

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-80

<400> 263

Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Glu Phe Lys

1 5 10 15

Asp

<210> 264

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-81

<400> 264

Asn Ile Asp Pro Ser Asp Ser Glu Ile His Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 265

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-82

<400> 265

Val Ile Asn Pro Gly Ser Gly Ile Thr Asp Tyr Ser Glu Lys Phe Lys

1 5 10 15

Gly

<210> 266

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-83

<400> 266

Asn Ile Asn Pro Ser Asn Gly Asn Thr Lys Asn Asn Glu Arg Phe Lys

1 5 10 15

Thr

<210> 267

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-85

<400> 267

Arg Ile Asp Pro Tyr Ser Gly Asp Thr Arg Tyr Asn Glu Lys Phe Lys

1 5 10 15

Asn

<210> 268

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-86

<400> 268

Val Ile Ser Pro Tyr Asn Asp Asn Thr Asn Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 269

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-87

<400> 269

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

1 5 10 15

Asp

<210> 270

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-88

<400> 270

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

1 5 10 15

Gly

<210> 271

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-89

<400> 271

Val Ile Asn Pro Gly Ser Gly Gly Thr Asp Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 272

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-90

<400> 272

Trp Ile Tyr Pro Arg Asp Gly Asn Ala Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 273

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-91

<400> 273

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

1 5 10 15

<210> 274

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-92

<400> 274

His Ile Asn Pro Asn Asp Gly Gly Thr Phe Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 275

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-93

<400> 275

Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Glu Ser

1 5 10 15

<210> 276

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H2 -- TM-94

<400> 276

Asp Ile Asn Pro Tyr Asn Gly Gly Thr Leu Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 277

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-54

<400> 277

Tyr Ser Ile Tyr Ala Met Asp Tyr

1 5

<210> 278

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-61

<400> 278

Trp Gly Gly Ser Arg Ser Tyr Trp Tyr Phe Asp Val

1 5 10

<210> 279

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-62

<400> 279

Leu Thr Thr Leu Asp Tyr Ala Met Asp Tyr

1 5 10

<210> 280

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-63、TM-80

<400> 280

Ser Ser Asn Trp Asp Asn Phe Asp Tyr

1 5

<210> 281

<211> 14

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-64

<400> 281

Ser Arg Gly Gly Thr Tyr Asp Tyr Gly Glu Ala Met Asp Tyr

1 5 10

<210> 282

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-65

<400> 282

Pro Thr Trp Phe Thr Tyr

1 5

<210> 283

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-66

<400> 283

Gln Glu Gly Ser Ser His Phe Asp Tyr

1 5

<210> 284

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-68

<400> 284

Pro Gln Thr Ala Thr Thr Cys

1 5

<210> 285

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-69

<400> 285

Glu Ala Gly Pro Tyr Gly Met Asp Tyr

1 5

<210> 286

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-70、TM-71

<400> 286

Gln Asp Ser Asn Tyr Glu Gly Val Trp Phe Ala Tyr

1 5 10

<210> 287

<211> 14

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-72、TM-78

<400> 287

Ser Arg Gly Gly Tyr Tyr Asp Tyr Gly Glu Ala Met Asp Tyr

1 5 10

<210> 288

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-73

<400> 288

Asn Tyr His Gly Ser Gly Pro Pro Phe Ala His

1 5 10

<210> 289

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-74

<400> 289

Pro Tyr Tyr Asp Tyr Glu Gly Tyr Thr Met Asp Tyr

1 5 10

<210> 290

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-75

<400> 290

Gly Gly Trp Phe Pro Tyr Ala Met Asp Tyr

1 5 10

<210> 291

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-76

<400> 291

Met Gly Arg Gln Arg Asp Tyr Phe Asp Tyr

1 5 10

<210> 292

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-77

<400> 292

Tyr Gly Ile Glu Gly Tyr

1 5

<210> 293

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-79

<400> 293

Ser Gly Gln Phe Gly Arg Gly Asp Tyr Phe His Tyr

1 5 10

<210> 294

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-81

<400> 294

Ser Pro Ala Gly Gln Ile Leu Asp Tyr

1 5

<210> 295

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-82

<400> 295

Ser Pro Phe Ile Thr Thr Val Val Ala Asp Tyr

1 5 10

<210> 296

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-83

<400> 296

Gly Asp Tyr Tyr Gly Thr Ser Tyr Pro Phe

1 5 10

<210> 297

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-85

<400> 297

Tyr Gly Leu Gly His Ala Met Asp Tyr

1 5

<210> 298

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-86

<400> 298

Thr Tyr Tyr Ser Asn Tyr Phe Asp Tyr

1 5

<210> 299

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-87

<400> 299

Gly Asn Tyr Asp Trp Tyr Phe Asp Val

1 5

<210> 300

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-88

<400> 300

Gly Gly Tyr Asp Tyr Gly His Trp Tyr Phe Asp Val

1 5 10

<210> 301

<211> 13

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-89

<400> 301

Asp Pro Tyr Ser Lys Tyr Val His Tyr Pro Met Asp Tyr

1 5 10

<210> 302

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-90

<400> 302

Val Ser Asp Tyr His Gly Gly Tyr Gly Met Asp Tyr

1 5 10

<210> 303

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-91

<400> 303

Ala Val Tyr Ser Val Gly Phe Ala Tyr

1 5

<210> 304

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-92

<400> 304

Trp Val Tyr Tyr Tyr Gly Ile Ser Tyr Glu Gly Gly Ala Met Asp Tyr

1 5 10 15

<210> 305

<211> 15

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-93

<400> 305

Asn Pro Pro Lys Ile Phe Tyr Asp Tyr Leu Met Tyr Phe Asp Tyr

1 5 10 15

<210> 306

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-H3 -- TM-94

<400> 306

Val Gly Tyr His Gly Thr Pro Asp Tyr

1 5

<210> 307

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-56

<400> 307

Arg Ser Ser Lys Ser Leu Leu Gln Asn Asn Gly Asn Thr Tyr Leu Tyr

1 5 10 15

<210> 308

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-63

<400> 308

Arg Ser Ser Gln Ser Leu Leu His Val Asn Gly Asn Thr Tyr Leu Tyr

1 5 10 15

<210> 309

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-64、TM-71、TM-72

<400> 309

Arg Ser Ser Lys Ser Leu Leu His Thr Asn Gly Asn Thr Tyr Leu Phe

1 5 10 15

<210> 310

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-65

<400> 310

Arg Ala Ser Gln Asn Ile Asn Ile Trp Leu Ser

1 5 10

<210> 311

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-66

<400> 311

Arg Ser Ser Gln Ser Leu Val Asn Ser Tyr Gly Lys Thr Phe Leu Ser

1 5 10 15

<210> 312

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-68

<400> 312

Ser Ser Ser Lys Ser Leu Leu His Ser Ser Gly Ile Thr Tyr Leu Tyr

1 5 10 15

<210> 313

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-69

<400> 313

Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 314

<211> 15

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-70

<400> 314

Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn

1 5 10 15

<210> 315

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-73

<400> 315

Ser Ala Ser Ser Gly Ile Ser Tyr Ile Tyr

1 5 10

<210> 316

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-74

<400> 316

Lys Ala Ser Gln Asn Val Arg Ser Ala Val Ala

1 5 10

<210> 317

<211> 15

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-75

<400> 317

Arg Ala Ser Gln Ser Val Asp Tyr Asn Gly Ile Ser Tyr Met His

1 5 10 15

<210> 318

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-76

<400> 318

Ser Ala Ser Leu Ser Ile Ser Tyr Val His

1 5 10

<210> 319

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-77

<400> 319

Lys Ser Ser Gln Ser Leu Phe His Ser Asn Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 320

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-78

<400> 320

Arg Ser Ser Lys Ser Leu Leu His Val Asn Gly Asn Thr Tyr Leu Phe

1 5 10 15

<210> 321

<211> 15

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-79

<400> 321

Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Ser Ile Tyr Ile His

1 5 10 15

<210> 322

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-80

<400> 322

Arg Ser Ser Gln Ser Leu Leu His Val Asn Gly His Thr Tyr Leu Tyr

1 5 10 15

<210> 323

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-81

<400> 323

Lys Ser Ser Gln Ser Leu Leu Asn Ser Lys Asn Gln Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 324

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-82

<400> 324

Arg Ser Ser Gln Ser Leu Ala Asn Thr Tyr Gly Asn Thr Tyr Leu Ser

1 5 10 15

<210> 325

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-83

<400> 325

Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Ile Thr Tyr Leu His

1 5 10 15

<210> 326

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-85

<400> 326

Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala

1 5 10

<210> 327

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-87

<400> 327

Arg Ala Ser Arg Ser Ile Ser Lys Tyr Leu Ala

1 5 10

<210> 328

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-88

<400> 328

Ile Thr Ser Ser Asp Ile Asp Asp His Met Asn

1 5 10

<210> 329

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-89

<400> 329

Arg Ala Ser Gln Asp Ile Gly Ser Ser Leu Asn

1 5 10

<210> 330

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-90

<400> 330

Arg Ser Ser Gln Ser Phe Val His Gly Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 331

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-91

<400> 331

Lys Ala Ser Gln Asn Val Tyr Thr Asn Val Ala

1 5 10

<210> 332

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-92

<400> 332

Arg Ala Ser Lys Ser Ile Ser Lys Tyr Leu Ala

1 5 10

<210> 333

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-93

<400> 333

Lys Ala Ser Gln Asp Val Gly Ser Ala Val Ala

1 5 10

<210> 334

<211> 16

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L1 -- TM-94

<400> 334

Arg Ser Ser Gln Ser Leu Val Tyr Ser Asn Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 335

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-65

<400> 335

Lys Ala Ser Asn Leu His Thr

1 5

<210> 336

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-70

<400> 336

Ala Ala Ser Asn Gln Gly Ser

1 5

<210> 337

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-71、TM-72

<400> 337

Arg Lys Ser Asn Leu Ala Ser

1 5

<210> 338

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-74

<400> 338

Leu Ala Ser Asn Arg His Thr

1 5

<210> 339

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-75

<400> 339

Ala Ala Ser Asn Leu Glu Ser

1 5

<210> 340

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-76

<400> 340

Gly Thr Ser Asn Leu Ala Ser

1 5

<210> 341

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-77

<400> 341

Met Val Ser Lys Leu Glu Ser

1 5

<210> 342

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-79

<400> 342

Leu Thr Ser Asn Leu Glu Ser

1 5

<210> 343

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-81

<400> 343

Phe Ala Phe Phe Arg Glu Ser

1 5

<210> 344

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-85、TM-91

<400> 344

Ser Ala Ser Tyr Arg Tyr Ser

1 5

<210> 345

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-87、TM-92

<400> 345

Ser Gly Ser Thr Leu Gln Ser

1 5

<210> 346

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-88

<400> 346

Glu Gly Asn Ala Leu Arg Pro

1 5

<210> 347

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-90

<400> 347

Lys Val Ser His Arg Phe Ser

1 5

<210> 348

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L2 -- TM-93

<400> 348

Trp Ser Ser Thr Arg Leu Pro

1 5

<210> 349

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-61

<400> 349

Gln Asn Asp Ser Asn Tyr Pro Phe Thr

1 5

<210> 350

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-63

<400> 350

Met Gln His Leu Gln Tyr Pro Phe Ser

1 5

<210> 351

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-64、TM-71、TM-72、TM-78

<400> 351

Met Gln His Leu Glu Tyr Pro Phe Thr

1 5

<210> 352

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-65

<400> 352

Leu Gln Gly Gln Ser Tyr Pro Tyr Thr

1 5

<210> 353

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-66

<400> 353

Leu Gln Gly Thr His Pro Pro Leu Thr

1 5

<210> 354

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-68

<400> 354

Ala Gln Met Leu Glu Arg Pro Trp Thr

1 5

<210> 355

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-69

<400> 355

Ser Gln Asn Thr His Val Pro Leu Thr

1 5

<210> 356

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-70

<400> 356

Gln Gln Ser Lys Asp Val Pro Trp Thr

1 5

<210> 357

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-73

<400> 357

His Gln Trp Arg Ser Tyr Pro Pro Thr

1 5

<210> 358

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-74

<400> 358

Leu Gln His Trp Lys Tyr Pro Phe Thr

1 5

<210> 359

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-75

<400> 359

Gln Gln Ser Ile Glu Asp Pro Trp Thr

1 5

<210> 360

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-76

<400> 360

His Gln Trp Ser Ile Tyr Arg Thr

1 5

<210> 361

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-77

<400> 361

Leu Gln Val Thr His Phe Pro Leu Thr

1 5

<210> 362

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-79

<400> 362

Gln His Ser Gly Glu Leu Pro Trp Thr

1 5

<210> 363

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-80

<400> 363

Met Gln His Leu Gln Tyr Pro Phe Thr

1 5

<210> 364

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-82

<400> 364

Leu Gln Gly Thr His Pro Pro Arg Thr

1 5

<210> 365

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-83

<400> 365

Ser Gln Ser Thr His Val Pro Tyr Thr

1 5

<210> 366

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-84

<400> 366

Gln His Leu Trp Ser Val Pro Trp Thr

1 5

<210> 367

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-85、TM-91

<400> 367

Gln Gln Tyr Asn Ser Tyr Pro Leu Thr

1 5

<210> 368

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-87

<400> 368

Gln Gln His Asn Glu Tyr Pro Leu Thr

1 5

<210> 369

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-88

<400> 369

Leu Gln Ser Asp Asn Leu Pro Leu Thr

1 5

<210> 370

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-90

<400> 370

Phe Gln Asn Ser His Val Pro His Thr

1 5

<210> 371

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-92

<400> 371

Gln Gln His Asn Glu Tyr Pro Trp Thr

1 5

<210> 372

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-93

<400> 372

Gln Gln Tyr Thr Ser Tyr Pro Leu Thr

1 5

<210> 373

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> CDR-L3 -- TM-94

<400> 373

Ser Gln Ser Thr His Val Tyr Thr

1 5

<210> 374

<211> 122

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-1

<400> 374

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys

85 90 95

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

100 105 110

Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 375

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-2

<400> 375

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

1 5 10 15

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

20 25 30

Pro Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Phe Arg Trp Met

35 40 45

Gly Met Ile Tyr Thr Asn Thr Gly Glu Pro Thr Tyr Ala Ala Glu Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Gly Tyr

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Ser Ala Thr Tyr Phe Cys

85 90 95

Val Thr Ala Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala

100 105 110

<210> 376

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-3

<400> 376

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Asn Thr Leu

20 25 30

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

35 40 45

Trp Leu Ala Lys Ile Trp Trp Asn Asp Asp Lys Phe Tyr Tyr Pro Ala

50 55 60

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

65 70 75 80

Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Ser Ala Thr Tyr Tyr

85 90 95

Cys Ala Arg Ile Ala Gly Gly Thr Gly Ala Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Leu Thr Val Ser Ser

115

<210> 377

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-4

<400> 377

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

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile

35 40 45

Gly Val Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr His Gln Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Ala Thr Val Val Ala Gly Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Leu Thr Val Ser Ser

115

<210> 378

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-5

<400> 378

Gln Val Gln Leu Gln Gln Ser Gly Thr Glu Leu Ala Arg Pro Gly Ala

1 5 10 15

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

20 25 30

Gly Ile Thr Trp Val Lys Gln Arg Gly Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Tyr Pro Arg Ser Asp Asn Thr Tyr Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Ser Lys Gly Ser Gly Thr Gly Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 379

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-6

<400> 379

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

1 5 10 15

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

20 25 30

Thr Ile His Trp Val Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Phe Tyr Pro Gly Ser Thr Tyr Ile Asp Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Leu Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg His Glu Glu Asp Tyr Ser Asn Trp Phe Pro Phe Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 380

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-7

<400> 380

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

1 5 10 15

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

20 25 30

Tyr Ile His Trp Val Lys Leu Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Leu Val Tyr Pro Tyr Asn Gly Asp Thr Asp Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Thr Tyr Tyr Ala Asn Ser Pro Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 381

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-8

<400> 381

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

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Pro Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Phe Lys Trp Met

35 40 45

Gly Val Ile Tyr Thr Asp Thr Gly Glu Pro Lys Tyr Ala Glu Val Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Val Arg Arg Leu Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ala

<210> 382

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-9

<400> 382

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

1 5 10 15

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

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val

35 40 45

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

50 55 60

Lys Gly Arg Leu Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Gln Asn Phe Tyr Tyr Gly Cys Glu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Leu Thr Val Ser Ser

115

<210> 383

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-10

<400> 383

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

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr

65 70 75 80

Ile His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Trp Gly His Tyr Asp Glu Ala Met Asp Asp Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 384

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-11, TM-24

<400> 384

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

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Asn Asn Gly Asn Thr Asp Tyr Asn Ala Ala Phe Ile

50 55 60

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

65 70 75 80

Lys Met Thr Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Val

85 90 95

Arg Ser Leu Arg Pro Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 385

<211> 122

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-12

<400> 385

Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Met Arg Pro Gly Ala

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Asp Pro Glu Asp Gly Asp Ala Glu Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Thr Arg Val Ile Tyr Asp Gly Tyr Tyr Arg Thr Met Asp Cys Trp

100 105 110

Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 386

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-13

<400> 386

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

1 5 10 15

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

20 25 30

Pro Ile Glu Trp Met Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Leu Asp Leu Ser Arg Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Phe Tyr Gly Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 387

<211> 122

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-14

<400> 387

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Asn Pro Gly Gly Gly Asn Thr Asp Tyr Ser Glu Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr

65 70 75 80

Ile Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Ser Pro Tyr Ser Ser Tyr Val Gly Tyr Ala Val Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 388

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-15

<400> 388

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Phe Val Arg Pro Gly Ala

1 5 10 15

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

20 25 30

Trp Ile Thr Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile

35 40 45

Gly Asp Ile Tyr Pro Gly Ser Gly Asn Ser Asn Tyr Asn Glu Ser Phe

50 55 60

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

65 70 75 80

Met His Leu Ser Ser Gln Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

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

100 105 110

Val Thr Val Ser Ala

115

<210> 389

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-16, TM-20

<400> 389

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

1 5 10 15

Ser Val Lys Leu Ser Cys Thr Thr Ser Gly Phe Asn Ile Lys Asp Tyr

20 25 30

Tyr Met His Trp Val Lys Gln Arg Thr Glu Gln Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Glu Phe

50 55 60

Gln Gly Lys Ala Thr Ile Thr Ser Asp Thr Ser Ser Asn Thr Ala Phe

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Ser Gln Pro Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ala

115

<210> 390

<211> 122

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-17

<400> 390

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Lys Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Val Arg Ser Ser Tyr Gly Val Tyr Val Ala Tyr Pro Met Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 391

<211> 123

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-18

<400> 391

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

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Val Asn Ile Asn Pro Asn Asn Gly Asp Ala Phe Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Leu Asp Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Gln Leu Arg Leu Arg Arg Val Tyr Ala Met Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 392

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-19

<400> 392

Asp Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Glu Asn Ala Pro Lys Phe

50 55 60

Arg Gly Met Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu Gln Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Thr Arg Ile Gly Asn Leu Tyr His Val Met Asp Tyr Trp Gly His

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 393

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-21

<400> 393

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

1 5 10 15

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

20 25 30

Ala Met Ser Trp Val Arg Glu Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Phe Ile Ser Asp Gly Gly Gly Tyr Ile Tyr Tyr Ala Asp Asn Val

50 55 60

Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr

65 70 75 80

Leu Gln Met Arg His Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Gly Thr Gly Phe Thr Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Val

115

<210> 394

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-22

<400> 394

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Tyr Pro Gly Asn Gly Ile Thr Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Thr Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 395

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-23, TM-26

<400> 395

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Asn Pro Gly Ser Gly Ile Thr Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

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

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 396

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-25

<400> 396

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr

20 25 30

Gly Met Ser Trp Ile Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val

35 40 45

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

50 55 60

Lys Gly Arg Phe Thr Met Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Asp Asn Phe Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Leu Gly

100 105 110

Thr Ser Val Thr Val Ser Ala

115

<210> 397

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-27

<400> 397

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Asn Pro Gly Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Ile Ile Tyr Asp His Asp Trp Tyr Phe Asp Val Trp Gly Thr

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 398

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-28

<400> 398

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

1 5 10 15

Ser Val Lys Ile Ser Cys Met Ala Ser Val Phe Thr Phe Asn Asp Tyr

20 25 30

Tyr Ile His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Leu Val Tyr Pro Tyr Asn Gly Gly Thr Asn Tyr Asn Gln Asn Phe

50 55 60

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

65 70 75 80

Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Leu Val Thr Val Ser Glu

115

<210> 399

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-29

<400> 399

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

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Glu Gly Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Asn His Tyr Thr Asn Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ala

115

<210> 400

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-30

<400> 400

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

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Asp Asn Thr Phe Thr Asn Tyr

20 25 30

Asp Val Asn Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Arg Asp Gly Thr Thr Ile Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Phe Phe Cys

85 90 95

Ala Arg Thr Leu Pro Gln Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 401

<211> 122

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-31

<400> 401

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

1 5 10 15

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

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Thr Ser Gly Tyr Thr Arg Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Tyr Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Pro Thr Val Val Leu Ile Gly Tyr Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Thr Leu Thr Val Ser Ser

115 120

<210> 402

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-32

<400> 402

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Ile Gly Val Tyr Tyr Cys

85 90 95

Thr Thr Arg Thr Trp Asp Leu Tyr Tyr Ala Val Asp Asn Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 403

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-33

<400> 403

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

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr

20 25 30

Asn Met Asn Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile

35 40 45

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

50 55 60

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

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala

100 105 110

<210> 404

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-34

<400> 404

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

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asp Ser

20 25 30

Gly Met Asp Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Phe

35 40 45

Ala Tyr Ile Ser Ser Gly Ser Ser Thr Thr His Tyr Ala Asp Thr Val

50 55 60

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

65 70 75 80

Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Val Arg Arg Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Thr Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 405

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-35

<400> 405

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Pro Gly Tyr Thr Phe Thr Arg His

20 25 30

Trp Met Gln Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Leu Pro Gly Ser Asn Asn Ile Tyr Tyr Asn Glu Lys Val

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Ser Leu Tyr Asp Tyr Asp Gly Val Phe Ala Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 406

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-37

<400> 406

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Val Asn Pro Ser Ser Gly Tyr Thr Lys Asn Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Tyr Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Gly Ser Ile Ser Asp Trp Tyr Phe Asp Val Trp Gly

100 105 110

Thr Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 407

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-39

<400> 407

His Val Gln Arg Gln Gln Ser Gly Thr Glu Leu Ala Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

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

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Tyr Glu Asp Ser Ala Val Phe Tyr Cys

85 90 95

Ala Arg Glu Ala Gly Ser Ile Ser Asp Trp Tyr Phe Asp Val Trp Gly

100 105 110

Thr Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 408

<211> 116

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-41

<400> 408

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Lys Gln Arg Thr Glu Gln Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Glu Asp Gly Thr Thr Asn Phe Ala Pro Lys Phe

50 55 60

Gln Asp Arg Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu Gln Leu Thr Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Trp Asp Ser Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

<210> 409

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-42, TM-45

<400> 409

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Lys Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

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

50 55 60

Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Tyr Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Glu Gly Gly Ser Ile Ser Asp Trp Tyr Phe Asp Val Trp Gly

100 105 110

Thr Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 410

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-44

<400> 410

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

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

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

35 40 45

Ala Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asp Thr Val

50 55 60

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

65 70 75 80

Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Asn Tyr Gly Ser Pro Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 411

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-46

<400> 411

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

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Phe

20 25 30

Trp Met Asn Trp Val Lys Leu Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Asp Gly Phe Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ile Leu Thr Val Ser Ser

115

<210> 412

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-47

<400> 412

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

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ala Gly Gly Asn Thr Asn Tyr Asn Ser Ala Leu Met

50 55 60

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

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Lys Glu Ala Lys Leu Leu Arg Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 413

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-48, TM-60

<400> 413

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

1 5 10 15

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

20 25 30

Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Arg Asp Gly Asn Thr Gln Tyr Ile Glu Lys Leu

50 55 60

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

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

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

100 105 110

Val Thr Val Ser Ser

115

<210> 414

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-49

<400> 414

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Ile Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Gln Thr His Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 415

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-50

<400> 415

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

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ala Gly Gly Asn Thr Asn Tyr Asn Ser Ala Leu Met

50 55 60

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

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Lys Glu Ala Lys Leu Leu Arg Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 416

<211> 126

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-51

<400> 416

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Asn Met Phe Pro Gly Ser Ser Arg Thr Asn Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Lys Glu Gly Leu Trp Thr Tyr Gly Tyr Asp Gly Gly Ala Trp

100 105 110

Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala

115 120 125

<210> 417

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-52

<400> 417

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Asp Trp Ile

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Tyr Tyr Gly Arg Ser Pro Phe Ala Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 418

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-1

<400> 418

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp His Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Asn

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Val

85 90 95

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

100 105 110

<210> 419

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-2

<400> 419

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

1 5 10 15

Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile

20 25 30

His Trp Phe Leu Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr

35 40 45

Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Phe Arg Phe Ile Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Val Glu Ala Glu

65 70 75 80

Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Ser Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 420

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-3

<400> 420

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Phe Tyr Cys Ala Gln Asn

85 90 95

Leu Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 421

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-4

<400> 421

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

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly

35 40 45

Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala

65 70 75 80

Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn

85 90 95

His Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 422

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-5

<400> 422

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

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ile Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Thr Pro Gln Leu Leu Val

35 40 45

Tyr Asn Gly Lys Met Leu Ala Glu Asn Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Ser Pro Pro

85 90 95

Ala Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 423

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-6

<400> 423

Asp Ile Gln Met Ser Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly

1 5 10 15

Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp

20 25 30

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

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Ser Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 424

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-7

<400> 424

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

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

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

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Asn Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn

85 90 95

Asp His Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

100 105 110

Lys

<210> 425

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-8

<400> 425

Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile

35 40 45

Phe Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr

65 70 75 80

Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Met Lys

100 105

<210> 426

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-9

<400> 426

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser

20 25 30

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

35 40 45

Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn

85 90 95

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

100 105 110

<210> 427

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-10

<400> 427

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Asn Gly Lys Thr Tyr Leu His Trp Tyr Val Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ile

85 90 95

Thr His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ser Lys

100 105 110

<210> 428

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-11

<400> 428

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Met Ser Val Gly

1 5 10 15

Gln Lys Val Thr Met His Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

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

35 40 45

Ser Pro Thr Leu Leu Val Tyr Phe Ala Ser Ile Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln

85 90 95

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

100 105 110

Arg

<210> 429

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-12

<400> 429

Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Lys Lys Pro Gly Gln Ser

35 40 45

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

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 430

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-13

<400> 430

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

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His Leu Trp Ser Ile Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 431

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-14

<400> 431

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ser Asn

20 25 30

Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Val Val Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Arg

85 90 95

Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 432

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-15

<400> 432

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

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Val Ser Glu Asn Ile Tyr Asn Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Gln Glu Lys Ser Pro Gln Leu Leu Val

35 40 45

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

50 55 60

Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His Phe Trp Asp Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 433

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-16

<400> 433

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

1 5 10 15

Glu Lys Leu Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu

65 70 75 80

Asp Gly Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Phe Pro Pro Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 434

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-17

<400> 434

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ser Asn

20 25 30

Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Arg

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 435

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-18

<400> 435

Asp Ile Val Leu Ala Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys Ser Val Ser Ile Ser

20 25 30

Val Tyr Thr Tyr Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

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

85 90 95

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

100 105 110

<210> 436

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-19

<400> 436

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ala

35 40 45

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

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

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

100 105 110

<210> 437

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-20

<400> 437

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

1 5 10 15

Glu Lys Leu Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu

65 70 75 80

Asp Gly Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Phe Pro Pro Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 438

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-21

<400> 438

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser

20 25 30

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

35 40 45

Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Asn

85 90 95

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

100 105 110

<210> 439

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-22

<400> 439

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp His Ala Ser Ile Ser Cys Arg Ser Gly Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 440

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-23, TM-26

<400> 440

Asp Ile Val Val Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Phe Gly

1 5 10 15

Asp Gln Val Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Thr Asn Tyr

20 25 30

Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu His Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Thr Ile Lys Pro Glu Asp Leu Gly Met Tyr Tyr Cys Leu Gln Gly

85 90 95

Thr His Gln Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 441

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-24

<400> 441

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Met Ser Val Gly

1 5 10 15

Gln Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

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

35 40 45

Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Ile Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Asn Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln

85 90 95

His Tyr Ser Thr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile

100 105 110

Arg

<210> 442

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-25

<400> 442

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser

20 25 30

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

35 40 45

Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn

85 90 95

Leu Glu Leu Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 443

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-27

<400> 443

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

1 5 10 15

Glu Lys Val Thr Ile Ser Cys Ser Ala Ser Ser Ser Ile Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr

35 40 45

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

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Tyr Pro Arg Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 444

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-28

<400> 444

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Val Gly

1 5 10 15

Glu Lys Val Thr Val Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

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

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn

85 90 95

Asp His Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

100 105 110

Lys

<210> 445

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-29

<400> 445

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Tyr

20 25 30

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

35 40 45

Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn

85 90 95

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

100 105 110

<210> 446

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-30

<400> 446

Asp Val Leu Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Val Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Arg

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 447

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-31

<400> 447

Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Thr Phe Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile

35 40 45

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

50 55 60

Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr

65 70 75 80

Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Phe

85 90 95

Thr Phe Ala Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 448

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-32

<400> 448

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

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

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr Cys Phe Gln Gly

85 90 95

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

100 105 110

<210> 449

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-33

<400> 449

Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Thr Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 450

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-34

<400> 450

Gln Ile Val Leu Ser Gln Ser Pro Val Ile Leu Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Arg Ala Thr Ser Ser Val Thr Tyr Met

20 25 30

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

35 40 45

Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Tyr Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 451

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-35

<400> 451

Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Arg

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 452

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-37, TM-59

<400> 452

Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser

20 25 30

Asn Gly Asn Thr Tyr Ser Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

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

100 105 110

<210> 453

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-39

<400> 453

Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Thr Leu Leu Asn Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Pro

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

Leu Asp Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Gln Leu Glu Ile Lys

100 105 110

<210> 454

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-41

<400> 454

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly

1 5 10 15

Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Lys Thr Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln

85 90 95

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

100 105 110

Lys

<210> 455

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-42, TM-45

<400> 455

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

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

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

100 105 110

<210> 456

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-44

<400> 456

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln

85 90 95

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

100 105 110

<210> 457

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-46

<400> 457

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

1 5 10 15

Glu Arg Val Thr Met Thr Cys Cys Ala Ser Ser Arg Val Asn Tyr Met

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 458

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-47

<400> 458

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

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 459

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-48

<400> 459

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asn Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Gly

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 460

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-49

<400> 460

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

1 5 10 15

Glu Lys Val Thr Ile Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile His

35 40 45

Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Tyr Pro Pro Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 461

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-50

<400> 461

Asp Val Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn Asn Tyr

20 25 30

Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Met Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Ser Thr Leu Met Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 462

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-51

<400> 462

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Arg Asn Ser

20 25 30

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

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asn Leu Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 463

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-52

<400> 463

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

1 5 10 15

Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Ser Asn Thr Ser Pro Lys Leu Trp Ile Tyr

35 40 45

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

50 55 60

Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Ala Glu Ala Glu

65 70 75 80

Asp Val Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Leu Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 464

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-54

<400> 464

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

1 5 10 15

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

20 25 30

Asp Leu Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Arg Gly Gly Ser Thr Glu Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Lys Tyr Ser Ile Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 465

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-56

<400> 465

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Ser Lys Tyr Asn Gln Arg Phe

50 55 60

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

65 70 75 80

Met His Leu Ser Ser Leu Thr Tyr Ala Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Glu Gly Gly Ser Ile Ser Asp Trp Tyr Phe Asp Val Trp Gly

100 105 110

Thr Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 466

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-59

<400> 466

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

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Val Asn Pro Ser Ser Gly Tyr Thr Lys Asn Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Tyr Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Gly Ser Ile Ser Asp Trp Tyr Phe Asp Val Trp Gly

100 105 110

Thr Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 467

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-61

<400> 467

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

1 5 10 15

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

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Ser Ser Asp Tyr Thr Lys Tyr Asn Gln Asn Phe

50 55 60

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

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Tyr Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Gly Gly Ser Arg Ser Tyr Trp Tyr Phe Asp Val Trp Gly

100 105 110

Ala Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 468

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-62

<400> 468

Gln Val Gln Leu Gln Gln Pro Gly Thr Glu Leu Val Arg Pro Gly Ser

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Ile Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr Gln Tyr Asn Pro Lys Phe

50 55 60

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

65 70 75 80

Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Thr Thr Leu Asp Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 469

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-63

<400> 469

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Ser Gln Lys Phe

50 55 60

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

65 70 75 80

Ile Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Asn Trp Asp Asn Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 470

<211> 123

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-64

<400> 470

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn Gln Asn Phe

50 55 60

Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Phe Ser Thr Thr Ala Tyr

65 70 75 80

Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Gly Gly Thr Tyr Asp Tyr Gly Glu Ala Met Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 471

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-65

<400> 471

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

1 5 10 15

Ser Val Arg Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Ser

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Lys Asn Gly Gly Thr Asn Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Pro Thr Trp Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 472

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-66

<400> 472

Glu Val Met Leu Val Glu Ser Gly Gly Ala Leu Val Glu Pro Gly Gly

1 5 10 15

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

20 25 30

Ala Met Ser Trp Ile Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Gly Ser Val Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Gln Glu Gly Ser Ser His Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Leu Thr Val Ser Ser

115

<210> 473

<211> 116

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-68

<400> 473

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Ser Lys Phe

50 55 60

Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Lys Pro Gln Thr Ala Thr Thr Cys Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 474

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-69

<400> 474

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Phe Thr Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Ile Met Gly Trp Asp Asp Lys Lys Tyr Tyr Asn Ser Ala Leu Lys

50 55 60

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

65 70 75 80

Lys Leu Ser Ser Leu Gln Thr Glu Asp Thr Ala Met Tyr Tyr Cys Thr

85 90 95

Arg Glu Ala Gly Pro Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 475

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-70

<400> 475

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

1 5 10 15

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

20 25 30

Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Gly Tyr Gly Gly Ser Tyr Ser Tyr Tyr Pro Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Ser Gly Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Gln Asp Ser Asn Tyr Glu Gly Val Trp Phe Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr

115

<210> 476

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-71

<400> 476

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

1 5 10 15

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

20 25 30

Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Gly Tyr Gly Gly Ser Tyr Ser Tyr Tyr Pro Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Gln Asp Ser Asn Tyr Glu Gly Val Trp Phe Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 477

<211> 123

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-72

<400> 477

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Gly Gly Tyr Tyr Asp Tyr Gly Glu Ala Met Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 478

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-73

<400> 478

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys His Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Tyr Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Tyr His Gly Ser Gly Pro Pro Phe Ala His Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 479

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-74

<400> 479

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

1 5 10 15

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

20 25 30

Val Ile His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Phe Ile Asn Pro Asn Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Arg Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Tyr Tyr Asp Tyr Glu Gly Tyr Thr Met Asp Tyr Gly Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 480

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-75

<400> 480

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

1 5 10 15

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

20 25 30

Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Trp Phe Pro Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 481

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-76

<400> 481

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser

20 25 30

Gly Met Gly Val Ser Trp Ile Arg Lys Pro Ser Gly Lys Gly Leu Glu

35 40 45

Trp Leu Ala His Ile Phe Trp Asp Asp Asp Lys Arg Tyr Asn Leu Phe

50 55 60

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

65 70 75 80

Phe Leu Met Ile Thr Ser Val Asp Thr Thr Asp Thr Ala Thr Tyr Tyr

85 90 95

Cys Ala Arg Met Gly Arg Gln Arg Asp Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Leu Thr Val Ser Ser

115 120

<210> 482

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-77

<400> 482

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

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Met Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Val Lys Tyr Gly Ile Glu Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr

100 105 110

Val Ser Ser

115

<210> 483

<211> 123

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-78

<400> 483

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn His Lys Phe

50 55 60

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

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Phe Tyr Cys

85 90 95

Ala Arg Ser Arg Gly Gly Tyr Tyr Asp Tyr Gly Glu Ala Met Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 484

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-79

<400> 484

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

1 5 10 15

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

20 25 30

Val Met His Trp Leu Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Ala His Ile Thr Pro His Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ser Asp Arg Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Gln Phe Gly Arg Gly Asp Tyr Phe His Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 485

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-80

<400> 485

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Glu Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ser Asn Trp Asp Asn Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ala Val Thr Val Ser Ser

115

<210> 486

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-81

<400> 486

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

1 5 10 15

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

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asp Pro Ser Asp Ser Glu Ile His Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Ile Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Pro Ala Gly Gln Ile Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 487

<211> 120

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-82

<400> 487

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Asn Pro Gly Ser Gly Ile Thr Asp Tyr Ser Glu Lys Phe

50 55 60

Lys Gly Lys Ala Arg Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Arg Ser Pro Phe Ile Thr Thr Val Val Ala Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 488

<211> 119

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-83

<400> 488

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Asn Ile Asn Pro Ser Asn Gly Asn Thr Lys Asn Asn Glu Arg Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Val Arg Gly Asp Tyr Tyr Gly Thr Ser Tyr Pro Phe Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 489

<211> 117

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-84

<400> 489

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

1 5 10 15

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

20 25 30

Pro Ile Glu Trp Met Lys Gln Asn His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Glu Lys Ser Ser Ser Thr Val Tyr

65 70 75 80

Leu Glu Leu Ser Arg Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Phe Tyr Gly Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 490

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-85

<400> 490

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Ala Gly Thr

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Gly Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Arg Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Tyr Ser Gly Asp Thr Arg Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Gly Leu Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser

115

<210> 491

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-86

<400> 491

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

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

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

35 40 45

Gly Val Ile Ser Pro Tyr Asn Asp Asn Thr Asn Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Val Arg Thr Tyr Tyr Ser Asn Tyr Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Leu Thr Val Ser Ser

115

<210> 492

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-87

<400> 492

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

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

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

50 55 60

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

65 70 75 80

Met Gly Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Gly Asn Tyr Asp Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 493

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-88

<400> 493

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

1 5 10 15

Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

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

50 55 60

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

65 70 75 80

Met Glu Leu Asn Ser Gln Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Tyr Asp Tyr Gly His Trp Tyr Phe Asp Val Trp Gly

100 105 110

Thr Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 494

<211> 122

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-89

<400> 494

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asp Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Asp Pro Tyr Ser Lys Tyr Val His Tyr Pro Met Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 495

<211> 121

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-90

<400> 495

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

1 5 10 15

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

20 25 30

Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Arg Asp Gly Asn Ala Lys Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asn Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Val Ser Asp Tyr His Gly Gly Tyr Gly Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 496

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-91

<400> 496

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

1 5 10 15

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

20 25 30

Tyr Tyr Trp Asp Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp

35 40 45

Met Gly Tyr Ile Ser Tyr Asp Gly Asn Asn Asn Tyr Asn Pro Ser Leu

50 55 60

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

65 70 75 80

Leu Lys Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Arg Ala Val Tyr Ser Val Gly Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 497

<211> 125

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-92

<400> 497

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

1 5 10 15

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

20 25 30

Thr Met Asp Trp Val Lys Gln Ser Pro Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly His Ile Asn Pro Asn Asp Gly Gly Thr Phe Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Trp Val Tyr Tyr Tyr Gly Ile Ser Tyr Glu Gly Gly Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120 125

<210> 498

<211> 123

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-93

<400> 498

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

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr

20 25 30

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

35 40 45

Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Glu

50 55 60

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

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala

85 90 95

Arg Asn Pro Pro Lys Ile Phe Tyr Asp Tyr Leu Met Tyr Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 499

<211> 118

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable heavy chain- -TM-94

<400> 499

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

1 5 10 15

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

20 25 30

Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asp Ile Asn Pro Tyr Asn Gly Gly Thr Leu Tyr Asn Gln Lys Phe

50 55 60

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

65 70 75 80

Met Glu Ile Arg Ser Leu Thr Tyr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Gly Tyr His Gly Thr Pro Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 500

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-54

<400> 500

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Gly

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys

100 105 110

<210> 501

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-56

<400> 501

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

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Gln Asn

20 25 30

Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Pro

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

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

100 105 110

<210> 502

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-60

<400> 502

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Gly

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 503

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-61

<400> 503

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

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

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

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn

85 90 95

Asp Ser Asn Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Met

100 105 110

Lys

<210> 504

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-62

<400> 504

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

1 5 10 15

Glu Lys Val Thr Ile Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Ala Gly Ser Ser Pro Lys Pro Trp Ile His

35 40 45

Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Arg Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Tyr Pro Pro Thr

85 90 95

Phe Gly Val Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 505

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-63

<400> 505

Asp Ile Val Met Thr Gln Ala Ser Pro Ser Val Ser Val Thr Pro Gly

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Val

20 25 30

Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Arg Ser

35 40 45

Pro Arg Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

Leu Gln Tyr Pro Phe Ser Phe Gly Ser Gly Thr Lys Leu Glu Met Lys

100 105 110

<210> 506

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-64

<400> 506

Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly

1 5 10 15

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

20 25 30

Asn Gly Asn Thr Tyr Leu Phe Trp Phe Leu Gln Arg Pro Gly Arg Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

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

100 105 110

<210> 507

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-65

<400> 507

Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Thr Ile Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Asn Ile Trp

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Val Pro Lys Leu Leu Ile

35 40 45

Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Gly Gln Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Gly Ile Lys

100 105

<210> 508

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-66

<400> 508

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

1 5 10 15

Asp Gln Val Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Asn Ser

20 25 30

Tyr Gly Lys Thr Phe Leu Ser Trp Tyr Leu His Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Thr Ile Lys Pro Glu Asp Leu Gly Met Tyr Tyr Cys Leu Gln Gly

85 90 95

Thr His Pro Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Met Lys

100 105 110

<210> 509

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-68

<400> 509

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Val Ser Ile Ser Cys Ser Ser Ser Lys Ser Leu Leu His Ser

20 25 30

Ser Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Met

85 90 95

Leu Glu Arg Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 510

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-69

<400> 510

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Asn

85 90 95

Thr His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 511

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-70

<400> 511

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr

20 25 30

Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His

65 70 75 80

Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys

85 90 95

Asp Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Ala Ile Lys

100 105 110

<210> 512

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-71, TM-72

<400> 512

Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly

1 5 10 15

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

20 25 30

Asn Gly Asn Thr Tyr Leu Phe Trp Phe Ile Gln Arg Pro Gly Gln Ser

35 40 45

Pro His Leu Leu Ile Tyr Arg Lys Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

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

100 105 110

<210> 513

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-73

<400> 513

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

1 5 10 15

Glu Lys Val Thr Leu Thr Cys Ser Ala Ser Ser Gly Ile Ser Tyr Ile

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Glu Thr Ser Tyr Ser Leu Thr Ile Ser Arg Leu Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys His Gln Trp Arg Ser Tyr Pro Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg

100 105

<210> 514

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-74

<400> 514

Asp Val Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Glu

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Arg Ser Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile

35 40 45

Tyr Leu Ala Ser Asn Arg His Thr Gly Val Pro Asp Arg Phe Ala Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Leu Gln His Trp Lys Tyr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 515

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-75

<400> 515

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Phe Cys Arg Ala Ser Gln Ser Val Asp Tyr Asn

20 25 30

Gly Ile Ser Tyr Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Ile

85 90 95

Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 516

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-76

<400> 516

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

1 5 10 15

Glu Glu Ile Thr Leu Thr Cys Ser Ala Ser Leu Ser Ile Ser Tyr Val

20 25 30

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

35 40 45

Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Phe Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu

65 70 75 80

Asp Ala Ala Asp Tyr Tyr Cys His Gln Trp Ser Ile Tyr Arg Thr Phe

85 90 95

Gly Gly Gly Thr Lys Leu Glu Met Lys

100 105

<210> 517

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-77

<400> 517

Asp Val Val Met Thr Gln Ile Pro Leu Thr Leu Ser Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Phe His Ser

20 25 30

Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Met Val Ser Lys Leu Glu Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Val

85 90 95

Thr His Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 518

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-78

<400> 518

Asp Ile Val Met Thr Gln Ala Thr Pro Ser Ile Pro Val Thr Pro Gly

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Val

20 25 30

Asn Gly Asn Thr Tyr Leu Phe Trp Phe Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

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

100 105 110

<210> 519

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-79

<400> 519

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser

20 25 30

Gly Ser Ile Tyr Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Gly

85 90 95

Glu Leu Pro Trp Thr Phe Gly Gly Gly Ala Arg Leu Glu Ile Lys

100 105 110

<210> 520

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-80

<400> 520

Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Val

20 25 30

Asn Gly His Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Thr Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln His

85 90 95

Leu Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 521

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-81

<400> 521

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

1 5 10 15

Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

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

35 40 45

Ser Pro Lys Phe Leu Val Tyr Phe Ala Phe Phe Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln

85 90 95

His Tyr Ser Thr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 522

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-82

<400> 522

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

1 5 10 15

Asp Gln Val Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ala Asn Thr

20 25 30

Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu His Thr Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Phe Gly Ile Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Thr Ile Lys Pro Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Gly

85 90 95

Thr His Pro Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys

100 105 110

<210> 523

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-83

<400> 523

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

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

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser

85 90 95

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

100 105 110

<210> 524

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-84

<400> 524

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

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Ser

20 25 30

Leu Gly Trp Tyr His Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His Leu Trp Ser Val Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 525

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-85

<400> 525

Asp Ile Ala Met Ser Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Met Lys

100 105

<210> 526

<211> 113

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-86

<400> 526

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

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

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

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

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

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn

85 90 95

Asp His Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

100 105 110

Lys

<210> 527

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-87

<400> 527

Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly

1 5 10 15

Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Arg Ser Ile Ser Lys Tyr

20 25 30

Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile

35 40 45

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

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 528

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-88

<400> 528

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

1 5 10 15

Glu Lys Val Thr Ile Arg Cys Ile Thr Ser Ser Asp Ile Asp Asp His

20 25 30

Met Asn Trp Tyr Arg Gln Lys Pro Gly Glu Pro Pro Glu Phe Leu Ile

35 40 45

Ser Glu Gly Asn Ala Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Ser

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Glu Asn Ile Leu Ser

65 70 75 80

Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 529

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-89

<400> 529

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ser Ser

20 25 30

Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Arg

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 530

<211> 112

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-90

<400> 530

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Phe Val His Gly

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser His Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Thr Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Asn

85 90 95

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

100 105 110

<210> 531

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-91

<400> 531

Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Tyr Thr Asn

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 532

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-92

<400> 532

Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly

1 5 10 15

Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr

20 25 30

Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile

35 40 45

Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser 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 Met Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 533

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-93

<400> 533

Asp Ile Val Met Thr Gln Ser His Lys Leu Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ser Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

Glu Val Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Thr Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 534

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> variable light chain- -TM-94

<400> 534

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser

85 90 95

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

100 105 110

Claims (29)

1. A pharmaceutical composition for treating, preventing or reducing the risk of a coronavirus infection, the pharmaceutical composition comprising an antibody that binds to TMEM106B protein and a pharmaceutically acceptable carrier.

2. An antibody that binds to TMEM106B protein for use in the treatment, prevention or reduction of the risk of a coronavirus infection.

3. A method for treating, preventing, or reducing the risk of a coronavirus infection, the method comprising administering to an individual in need thereof an effective amount of an antibody that binds to TMEM106B protein.

4. The pharmaceutical composition, antibody or method of any one of claims 1-3, wherein the antibody reduces coronavirus replication.

5. The pharmaceutical composition, antibody or method of any one of claims 1-4, wherein the antibody reduces coronavirus transmission.

6. The pharmaceutical composition, antibody, or method of any one of claims 1-5, wherein the antibody reduces coronavirus genome translation.

7. The pharmaceutical composition, antibody or method of any one of claims 1-6, wherein the antibody reduces coronavirus cell entry.

8. The pharmaceutical composition, antibody or method of any one of claims 1-7, wherein the antibody reduces release of coronavirus from an infected cell.

9. The pharmaceutical composition, antibody or method of any one of claims 1-8, wherein the coronavirus is SARS-CoV-2 coronavirus.

10. The pharmaceutical composition, antibody or method of any one of claims 1-9, wherein the TMEM106B protein is a mammalian protein or a human protein.

11. The pharmaceutical composition, antibody or method of any one of claims 1-10, wherein the antibody binds to a cytoplasmic domain of TMEM106B protein.

12. The pharmaceutical composition, antibody or method of any one of claims 1-10, wherein the antibody binds to a luminal domain of TMEM106B protein.

13. The pharmaceutical composition, antibody, or method of any one of claims 1-12, wherein the antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39 TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-54, TM-56, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65, TM-66, TM-67, TM-68, TM-69, TM-70, TM-71, TM-72, TM-73, TM-74, TM-75, TM-76, TM-77, TM-78, TM-79, TM-80.TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93 and TM-94, optionally wherein the HVR is Kabat, abM, chothia or Contact HVR.

14. The pharmaceutical composition, antibody, or method of claim 13, wherein the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3 and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprises the amino acid sequences:

(a) SEQ ID NOs 2, 35, 78, 120, 160 and 184, respectively;

(b) SEQ ID NOs 3, 36, 79, 121, 161 and 185, respectively;

(c) SEQ ID NOs 4, 37, 80, 122, 162 and 186, respectively;

(d) SEQ ID NOs 5, 38, 81, 123, 163 and 187, respectively;

(e) SEQ ID NOS 6, 39, 82, 124, 164 and 188, respectively;

(f) SEQ ID NOS 7, 40, 83, 125, 165 and 189, respectively;

(g) SEQ ID NOS 8, 41, 84, 126, 166 and 190, respectively;

(h) SEQ ID NOs 9, 42, 85, 127, 167 and 191, respectively; (i) SEQ ID NOs 10, 43, 86, 122, 168 and 186, respectively; (j) 11, 44, 87, 128, 169, and 192, respectively; (k) SEQ ID NOs 12, 45, 88, 129, 170 and 193, respectively;

(l) SEQ ID NOs 13, 46, 89, 130, 169 and 194, respectively;

(m) SEQ ID NOS 14, 47, 90, 131, 171 and 195, respectively;

(n) SEQ ID NOs 2, 48, 91, 132, 172 and 196, respectively;

(o) SEQ ID NOs 15, 49, 92, 133, 171 and 197, respectively;

(p) SEQ ID NOs 16, 50, 93, 134, 173 and 198, respectively;

(q) SEQ ID NOs 17, 51, 94, 132, 172 and 196, respectively;

(r) SEQ ID NOs 5, 52, 95, 135, 174 and 199, respectively;

(s) SEQ ID NOs 13, 53, 96, 136, 175 and 200, respectively;

(t) SEQ ID NOS 16, 50, 93, 134, 173 and 198, respectively;

(u) SEQ ID NOs 18, 54, 97, 137, 168 and 201, respectively;

(v) SEQ ID NOs 19, 55, 98, 138, 160 and 202, respectively;

(w) SEQ ID NOs 2, 56, 99, 139, 176 and 203, respectively;

(x) SEQ ID NOs 12, 45, 88, 140, 170 and 204, respectively;

(y) SEQ ID NOs 10, 57, 100, 137, 168 and 205, respectively;

(z) SEQ ID NOs 2, 56, 99, 139, 176 and 203, respectively;

(aa) SEQ ID NOs 2, 58, 101, 141, 177 and 206, respectively; (bb) SEQ ID NOs 8, 59, 102, 142, 166 and 190, respectively; (cc) SEQ ID NOS 20, 60, 103, 143, 168 and 207, respectively; (dd) SEQ ID NOS.21, 61, 104, 144, 160 and 208, respectively; (ee) SEQ ID NOs 11, 62, 105, 127, 178 and 209, respectively; (ff) SEQ ID NOS 13, 63, 106, 145, 160 and 200, respectively; (gg) SEQ ID NOS: 22, 64, 107, 146, 179 and 210, respectively; (hh) SEQ ID NOS 23, 65, 108, 147, 161 and 211, respectively; (ii) 24, 66, 109, 148, 160 and 194, respectively; (jj) SEQ ID NOS 25, 67, 110, 149, 180 and 212, respectively; (kk) SEQ ID NOS 26, 68, 111, 150, 180 and 213, respectively; (ll) SEQ ID NOS 27, 69, 112, 151, 181 and 214, respectively; (mm) SEQ ID NOS 28, 70, 110, 152, 180 and 212, respectively; (nn) SEQ ID NOs 29, 71, 113, 151, 181 and 215, respectively;

(oo) SEQ ID NOS 28, 70, 110, 152, 180 and 212, respectively;

(pp) SEQ ID NOs 30, 72, 114, 153, 182 and 216, respectively;

(qq) SEQ ID NOS: 31, 73, 115, 154, 181 and 217, respectively;

(rr) SEQ ID NOS 32, 74, 116, 155, 160 and 218, respectively;

(ss) SEQ ID NOS: 33, 75, 117, 156, 182 and 219, respectively;

(tt) SEQ ID NOS: 31, 73, 115, 157, 183 and 220, respectively;

(uu) SEQ ID NOS 34, 76, 118, 158, 181 and 221, respectively;

(v) SEQ ID NOS 28, 77, 119, 159, 182 and 222, respectively;

(ww) SEQ ID NOS 223, 244, 277, 155, 160, and 202, respectively; (xx) 25, 245, 110, 307, 180 and 212, respectively; (yy) SEQ ID NOS 25, 67, 110, 149, 180 and 212, respectively;

(zz) SEQ ID NOS 32, 74, 116, 155, 160, and 218, respectively;

(aaa) SEQ ID NOS 224, 246, 278, 142, 166, and 349, respectively; (bbb) SEQ ID NOs 225, 247, 279, 156, 182 and 219, respectively; (ccc) SEQ ID NOS 226, 248, 280, 308, 180 and 350, respectively; (ddd) SEQ ID NOS 25, 249, 281, 309, 180, and 351, respectively; (eee) SEQ ID NOS 227, 250, 282, 310, 335 and 352, respectively; (fff) SEQ ID NOS: 18, 251, 283, 311, 176 and 353, respectively; (ggg) SEQ ID NOs 228, 252, 284, 312, 180 and 354, respectively; (hhh) SEQ ID NOs 229, 253, 285, 313, 160 and 355, respectively; (iii) 18, 254, 286, 314, 336 and 356, respectively;

(jjj) SEQ ID NOs 18, 254, 286, 309, 337 and 351, respectively;

(kkk) SEQ ID NOS 28, 255, 287, 309, 337 and 351, respectively; (lll) SEQ ID NOs 230, 256, 288, 315, 173 and 357, respectively; (mmm) SEQ ID NOS 231, 257, 289, 316, 338 and 358, respectively; (nnn) SEQ ID NOs 232, 258, 290, 317, 339 and 359, respectively; (ooo) SEQ ID NOS 233, 259, 291, 318, 340 and 360, respectively; (ppp) SEQ ID NOS 234, 260, 292, 319, 341 and 361, respectively; (qqq) SEQ ID NOS 235, 261, 287, 320, 180 and 351, respectively; (rrr) SEQ ID NOs 236, 262, 293, 321, 342 and 362, respectively; (sss) SEQ ID NOS 237, 263, 280, 322, 180 and 363, respectively; (ttt) SEQ ID NOS 25, 264, 294, 323, 343 and 204, respectively;

(uuu) SEQ ID NOs 2, 265, 295, 324, 176 and 364, respectively;

(vvv) SEQ ID NOS 238, 266, 296, 325, 160 and 365, respectively; (www) SEQ ID NOS 14, 47, 90, 131, 171 and 366, respectively; (xxx) SEQ ID NOs 239, 267, 297, 326, 344 and 367, respectively; (yyy) SEQ ID NOs 8, 268, 298, 142, 166 and 190, respectively;

(zzz) SEQ ID NOs 5, 269, 299, 327, 345 and 368, respectively;

(aaaa) SEQ ID NOS 20, 270, 300, 328, 346 and 369, respectively;

(bbbb) SEQ ID NOs 2, 271, 301, 329, 172 and 196, respectively;

(cccc) SEQ ID NOs 32, 272, 302, 330, 347 and 370, respectively;

(dddd) SEQ ID NOS 240, 273, 303, 331, 344 and 367, respectively;

(eeee) SEQ ID NOs 241, 274, 304, 332, 345 and 371, respectively;

(ffff) SEQ ID NOS 242, 275, 305, 333, 348 and 372, respectively; or alternatively

(gggg) SEQ ID NOS 243, 276, 306, 334, 160 and 373, respectively.

15. The pharmaceutical composition, antibody or method of claim 14, wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences:

(a) SEQ ID NOS 374 and 418, respectively;

(b) SEQ ID NOS 375 and 419, respectively;

(c) SEQ ID NOS 376 and 420, respectively;

(d) SEQ ID NOS 377 and 421, respectively;

(e) SEQ ID NOS 378 and 422, respectively;

(f) SEQ ID NOS 379 and 423, respectively;

(g) SEQ ID NOS 380 and 424, respectively;

(h) SEQ ID NOS 381 and 425, respectively;

(i) SEQ ID NOS 382 and 426, respectively; (j) SEQ ID NOS: 383 and 427, respectively; (k) SEQ ID NOS 384 and 428, respectively; (l) SEQ ID NOS 385 and 429, respectively; (m) SEQ ID NOS 386 and 430, respectively; (n) SEQ ID NOS 387 and 431, respectively; (o) SEQ ID NOS 388 and 432, respectively; (p) SEQ ID NOS 389 and 433, respectively; (q) SEQ ID NOS 390 and 434, respectively; (r) SEQ ID NOS 391 and 435, respectively; (s) SEQ ID NOS 392 and 436, respectively; (t) SEQ ID NOS 389 and 437, respectively; (u) SEQ ID NOS 393 and 438, respectively; (v) SEQ ID NOS 394 and 439, respectively; (w) SEQ ID NOS 395 and 440, respectively; (x) SEQ ID NOS 384 and 441, respectively; (y) SEQ ID NOS 396 and 442, respectively; (z) SEQ ID NOS 395 and 440, respectively; (aa) SEQ ID NOS 397 and 443, respectively; (bb) SEQ ID NOS 398 and 444, respectively; (cc) SEQ ID NOS 399 and 445, respectively; (dd) SEQ ID NOS 400 and 446, respectively; (ee) SEQ ID NOs 401 and 447, respectively; (ff) SEQ ID NOS 402 and 448, respectively; (gg) SEQ ID NOS 403 and 449, respectively; (hh) SEQ ID NOS 404 and 450, respectively;

(ii) SEQ ID NOS 405 and 451, respectively; (jj) SEQ ID NOS 406 and 452, respectively; (kk) SEQ ID NOS 407 and 453, respectively; (ll) SEQ ID NOS 408 and 454, respectively; (mm) SEQ ID NOS 409 and 455, respectively; (nn) SEQ ID NOS 410 and 456, respectively; (oo) SEQ ID NOS 409 and 455, respectively; (pp) SEQ ID NOS 411 and 457, respectively; (qq) SEQ ID NOS 412 and 458, respectively; (rr) SEQ ID NOS 413 and 459, respectively; (ss) SEQ ID NOS 414 and 460, respectively; (tt) SEQ ID NOS 415 and 461, respectively; (uu) SEQ ID NOS 416 and 462, respectively; (v) SEQ ID NOS 417 and 463, respectively; (ww) SEQ ID NOS 464 and 500, respectively; (xx) SEQ ID NOS 465 and 501, respectively; (yy) SEQ ID NOS 466 and 452, respectively; (zz) SEQ ID NOS 413 and 502, respectively; (aaa) SEQ ID NOS 467 and 503, respectively; (bbb) SEQ ID NOS 468 and 504, respectively; (ccc) SEQ ID NOS 469 and 505, respectively; (ddd) SEQ ID NOS 470 and 506, respectively; (eee) SEQ ID NOS 471 and 507, respectively; (fff) SEQ ID NOS 472 and 508, respectively; (ggg) SEQ ID NOS 473 and 509, respectively; (hhh) SEQ ID NOS 474 and 510, respectively;

(iii) SEQ ID NOS 475 and 511, respectively; (jjj) SEQ ID NOS 476 and 512, respectively; (kkk) SEQ ID NOs 477 and 512, respectively; (lll) SEQ ID NOS 478 and 513, respectively; (mmm) SEQ ID NOS 479 and 514, respectively; (nnn) SEQ ID NOS 480 and 515, respectively;

(ooo) SEQ ID NOS 481 and 516, respectively;

(ppp) SEQ ID NOS 482 and 517, respectively;

(qqq) SEQ ID NOS 483 and 518, respectively;

(rrr) SEQ ID NOS 484 and 519, respectively;

(sss) SEQ ID NOS 485 and 520, respectively;

(ttt) SEQ ID NOS 486 and 521, respectively;

(uuu) SEQ ID NOS 487 and 522, respectively;

(vvv) SEQ ID NOs 488 and 523, respectively;

(www) SEQ ID NOS 489 and 524, respectively;

(xxx) SEQ ID NOS 490 and 525, respectively;

(yyy) SEQ ID NOS 491 and 526, respectively;

(zzz) SEQ ID NOS 492 and 527, respectively;

(aaaa) SEQ ID NOS 493 and 528, respectively;

(bbbb) SEQ ID NOS 494 and 529, respectively;

(cccc) SEQ ID NOs 495 and 530, respectively;

(dddd) SEQ ID NOS 496 and 531, respectively;

(eeee) SEQ ID NOs 497 and 532, respectively;

(ffff) SEQ ID NOS 498 and 533, respectively; or (gggg) SEQ ID NOs 499 and 534, respectively.

16. The pharmaceutical composition, antibody or method of any one of claims 1-14, wherein the antibody competitively inhibits binding of TMEM106B to an antibody comprising the heavy chain variable region and the light chain variable region of any one of the antibodies of clauses (a) - (ggg) of claim 15.

17. The pharmaceutical composition, antibody or method of any one of claims 1-16, wherein the antibody binds to a truncated TMEM106B protein comprising amino acids 122-210 of SEQ ID No. 1.

18. The pharmaceutical composition, antibody or method of any one of claims 1-17, wherein the antibody is in box 2.

19. The pharmaceutical composition, antibody or method of any one of claims 1-17, wherein the antibody is in box 3.

20. The pharmaceutical composition, antibody or method of any one of claims 1-17, wherein the antibody is in box 4.

21. The pharmaceutical composition of any one of claims 1-20, wherein the antibody is not in frame 1.

22. The pharmaceutical composition, antibody or method of any one of claims 1-21, wherein the antibody is not in box 5.

23. The pharmaceutical composition, antibody or method of any one of claims 1-22, wherein the antibody reduces cytopathic effects in SARS-CoV-2 infected cells, optionally wherein the cells are VeroE6 cells or NCI-H1975 cells.

24. The pharmaceutical composition, antibody or method of any one of claims 1-23, wherein the antibody is a monoclonal antibody.

25. The pharmaceutical composition, antibody or method of any one of claims 1-24, wherein the antibody is of the IgG class, igM class or IgA class.

26. The pharmaceutical composition, antibody or method of claim 25, wherein the antibody is of the IgG class and has an IgG1, igG2 or IgG4 isotype.

27. The pharmaceutical composition, antibody or method of any one of claims 1-26, wherein the antibody is an antibody fragment.

28. The pharmaceutical composition, antibody or method of claim 27, wherein the fragment is a Fab, fab '-SH, F (ab') 2, fv or scFv fragment.

29. The pharmaceutical composition, antibody or method of any one of claims 1-26, wherein the antibody is a full length antibody.