Antibodies against integrin [alpha] 11 [beta] 1 and uses thereof

Abstract

Embodiments provided herein relate to antibodies and compositions that bind to [alpha] 11 [beta] 1. Methods of producing the antibodies of the disclosure are also provided, as well as the use of the provided antibodies and compositions for the treatment of [alpha] 11 [beta] 1 mediated diseases and disorders.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 366,811, filed on June 22, 2022, which is hereby incorporated by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. The XML file named 258199_010202_SL.xml was created on June 22, 2023 and is 312,715 bytes in size. Technical Field

[0005] The field of the invention is immunology, in particular therapeutic antibodies, and the use of these antibodies to treat disease. Background Art

[0006] Fibrosis is a scarring process that manifests itself in many tissues in the body, usually as a result of inflammation or tissue damage. Such a disease involving inflammation and fibrosis is rheumatoid arthritis (RA). RA is a chronic autoimmune disease that typically involves inflammation of the joints, especially the small joints of the hands, wrists, and feet. As the disease progresses, continued inflammation leads to loss of joint mobility and ultimately deformities. In addition, RA may also affect other organs of the body. This may include the lungs, leading to pulmonary fibrosis, in which scarring of the lung tissue occurs. Disclosed herein are compositions for treating RA and other fibrotic, inflammatory, and autoimmune diseases listed herein. Summary of the invention

[0007] In some embodiments, an antibody or an antigen-binding fragment thereof is provided, wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising heavy chain HCDR1, HCDR2 and HCDR3 sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO:1; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO:2; and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO:3; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2 and LCDR3 sequences or a variant of any of the foregoing sequences, wherein the light chain LCDR1 sequence has the amino acid sequence of SEQ ID NO:16; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO:17; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO:18.

[0008] In some embodiments, an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising a heavy chain HCDR1, HCDR2 and HCDR3 sequence, or a variant of any of the foregoing sequences, wherein the heavy chain HCDR1 sequence has an amino acid sequence of SEQ ID NO:23; the heavy chain HCDR2 has an amino acid sequence of SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26 or SEQ ID NO:27, and the heavy chain HCDR3 sequence has an amino acid sequence of SEQ ID NO:28 or SEQ ID NO:29; and (ii) a light chain variable region comprising a light chain LCDR1, LCDR2 and LCDR3 sequence, or a variant of any of the foregoing sequences, wherein the light chain LCDR1 sequence has an amino acid sequence of SEQ ID NO:34; the light chain LCDR2 sequence has an amino acid sequence of SEQ ID NO:35; and the light chain LCDR3 sequence has an amino acid sequence of SEQ ID NO:36.

[0009] In some embodiments, an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising a heavy chain HCDR1, HCDR2 and HCDR3 sequence, or a variant of any of the foregoing sequences, wherein the heavy chain HCDR1 sequence has an amino acid sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40; the heavy chain HCDR2 has an amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42; and the heavy chain HCDR3 sequence has an amino acid sequence of SEQ ID NO:43; and (ii) a light chain variable region comprising a light chain LCDR1, LCDR2 and LCDR3 sequence, or a variant of any of the foregoing sequences, wherein the light chain LCDR1 sequence has an amino acid sequence of SEQ ID NO:58; the light chain LCDR2 sequence has an amino acid sequence of SEQ ID NO:59; and the light chain LCDR3 sequence has an amino acid sequence of SEQ ID NO:60. In some embodiments, the antibody or antigen-binding fragment thereof provided herein is or includes a scFv antibody, a Fab fragment, a Fab' fragment, or a F(ab')2 fragment. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized antibody.

[0010] In some embodiments, the antibody or antigen-binding fragment thereof comprises a constant region selected from SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, or SEQ ID NO:69.

[0011] In some embodiments, a method for producing a polypeptide comprising a heavy chain variable region and / or a light chain variable region is provided, the method comprising: (a) culturing a host cell comprising a polypeptide encoding an antibody provided herein under conditions such that the host cell expresses a polypeptide comprising the heavy chain variable region and / or the light chain variable region; and (b) purifying the polypeptide comprising the heavy chain variable region and / or the light chain variable region.

[0012] In some embodiments, a method for producing an antibody or an antigen-binding fragment thereof that binds to human α11β1 integrin is provided, the method comprising: (a) culturing a host cell comprising a polypeptide encoding an antibody provided herein under conditions such that the host cell expresses one or more polypeptides comprising an immunoglobulin heavy chain variable region and / or an immunoglobulin light chain variable region, thereby producing the antibody or an antigen-binding fragment thereof; and (b) purifying the antibody or the antigen-binding fragment thereof.

[0013] In some embodiments, a method of treating a subject suffering from an α11β1-mediated disorder is provided, the method comprising administering to the subject an antibody or antigen-binding fragment thereof provided herein. In some embodiments, the disorder is a fibrotic disorder, an autoimmune disorder, an inflammatory disorder, or cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Schematic diagram showing the structure of integrin. Panels showing the structure of integrin that binds collagen and the three different conformations of integrin that can exist on the cell surface.

[0015] Figure 2A , Figure 2B and Figure 2C showed that anti-α11β1 antibodies provided inhibition of the secretion of pro-fibrotic and pro-inflammatory mediators by Col1a1. Figure 2A is antibody 1994-01-C07; Figure 2B It is antibody 79E3E3; Figure 2C It is antibody 16E10.

[0016] Figure 3A , Figure 3B and Figure 3C It was shown that anti-α11β1 antibody provided inhibition of secreted pro-fibrotic and pro-inflammatory mediator IL-11. Figure 3Ais antibody 1994-01-C07; Figure 3B It is antibody 79E3E3; Figure 3C It is antibody 16E10.

[0017] FIG. 4A to FIG. 4C Described are assays for 1994-01-C7 antibody variants. Figure 4A The CHO-huα11 binding assay is described; Figure 4B A myofibroblast binding assay is described; and Figure 4C A cell adhesion inhibition assay is described.

[0018] Figure 5A and Figure 5B Assays for 16E10 antibody variants are described. Figure 5A A CHO-huα11 binding assay is described; and Figure 5B A CHO-α11 adhesion inhibition assay is described.

[0019] Fig. 6A and Figure 6B showed that, compared with other cells or cells from subjects with osteoarthritis ( Figure 6B ) compared with α11β1 in stromal cells of subjects with rheumatoid arthritis ( Fig. 6A ) is strongly expressed. Fig. 7A and Figure 7B showed that α11β1 is highly expressed in cells from subjects with an inadequate response to TNF (TNF-IR; Fig. 7A ), and α11β1 is expressed in low-grade, moderate-grade and severe rheumatoid arthritis.

[0020] Figure 8 These results suggest that α11β1 is selectively expressed in sub-inner layer fibroblasts. DETAILED DESCRIPTION

[0021] Provided herein are binding proteins (e.g., antibodies or fragments thereof) that selectively bind to type I collagen receptor integrin α11β1 (α11β1). Also provided herein are nucleic acids encoding antibodies and antibody fragments that bind to α11β1, and methods of using these antibodies and antibody fragments to treat fibrosis and other diseases disclosed herein.

[0022] Before describing the compositions and methods of the present invention, it should be understood that the scope of the present invention is not limited to the specific processes, compositions or methodology described herein, because these can change. It should also be understood that the terms used in this specification are only used to describe the purpose of a specific version or embodiment, and are not intended to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art are generally understood. Although any methods and materials similar or equivalent to those described herein can be used to practice or test the embodiments of the methods and systems disclosed herein, preferred methods, devices and materials are now described.

[0023] The following explanations of terms and methods are provided to better describe the present disclosure and guide those of ordinary skill in the art to practice the present disclosure.

[0024] As used herein, unless the context clearly indicates otherwise, "comprising" means "including", and the singular form "one" or "a kind of" or "the / said" includes plural references. For example, a reference to "comprising a therapeutic agent" includes one or more such therapeutic agents. Unless the context clearly indicates otherwise, the term "or" refers to a single element in the alternative element described. For example, the phrase "A or B" refers to a single A or a single B. The phrase "A, B or a combination thereof" refers to a single A, a single B or a combination of A and B. Similarly, the phrase "one or more of A and B" refers to a combination of A, B or both A and B. In addition, the various elements, features and steps discussed herein and other known equivalents of each such element, feature or step can be mixed and matched by a person of ordinary skill in the art to perform methods according to the principles described herein. Among the various elements, features and steps, some elements, features and steps will be specifically included in a specific example, while other elements, features and steps will be specifically excluded from a specific example.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. In addition, materials, methods and examples are merely illustrative and not intended to be limiting. All references cited herein are incorporated by reference in their entirety.

[0026] As used herein and unless otherwise indicated, the term "about" is intended to mean ±5% of its modified value. Thus, about 100 means 95 to 105.

[0027] As used herein, the term "antibody" refers to any form of antibody that exhibits the desired biological activity. Therefore, it is used in the broadest sense and specifically encompasses, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies, and camelized single domain antibodies. "Parent antibody" is an antibody obtained by exposing the immune system to an antigen before modifying the antibody for an intended use, such as humanization of an antibody for use as a human therapeutic antibody.

[0028] As used herein, unless otherwise indicated, "antibody fragment" or "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability to specifically bind to an antigen that binds to a full-length antibody, such as a fragment that retains one or more CDR regions. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; double-chain antibodies; linear antibodies; single-chain antibody molecules, such as sc-Fv; nanobodies (single-domain antibodies) and multispecific antibodies formed from antibody fragments.

[0029] The "Fab fragment" consists of a light chain and a heavy chain C H The heavy chain of the Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0030] The "Fc" region contains the C H 2 domains and C H The two heavy chain fragments are connected by two or more disulfide bonds and C H The 3 domains are held together by hydrophobic interactions.

[0031] A "Fab' fragment" contains a light chain and a portion or fragment of a heavy chain, which contains V H Domain and C H 1 domain and C H 1 domain and C H The region between the two Fab' domains allows for the formation of an interchain disulfide bond between the two heavy chains of the two Fab' fragments to form the F(ab')2 molecule.

[0032] The "F(ab')2 fragment" contains two light chains and two heavy chains. H 1 domain and C H The F(ab')2 fragment consists of two Fab' fragments held together by the disulfide bonds between the two heavy chains.

[0033] The "Fv region" comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0034] The term "single-chain Fv" or "scFv" antibody refers to an antibody comprising a V H Domain and V L In general, the Fv polypeptide also includes a V H Domain and V L A polypeptide linker between the domains that enables the scFv to form the structure required for antigen binding. For a review of scFv, see Pluckthun (1994), "The Pharmacology of Monoclonal Antibodies", Vol. 113, Rosenburg and Moore, ed., Springer-Verlag, New York, pp. 269-315. See also International Patent Application Publication No. WO 88 / 01649 and U.S. Pat. Nos. 4,946,778 and 5,260,203.

[0035] A "single domain antibody" is an immunologically functional immunoglobulin fragment that contains only the variable region of a heavy chain or a variable region of a light chain. H The two V domains of the bivalent domain antibody are covalently linked to a peptide linker to generate a bivalent domain antibody. H The regions may target the same or different antigens.

[0036] A "bivalent antibody" comprises two antigen binding sites. In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody can be bispecific (see below).

[0037] In certain embodiments, the monoclonal antibodies herein also include camelized single domain antibodies. See, for example, Muyldermans et al. (2001), Trends Biochem. Sci. 26:230; Reichmann et al. (1999), J. Immunol. Methods 231:25; WO 94 / 04678; WO 94 / 25591; U.S. Pat. No. 6,005,079. In one embodiment, the present invention provides a monoclonal antibody comprising two V H The two domains are modified to form a single domain antibody.

[0038] As used herein, the term "diabodies" refers to small antibody fragments with two antigen-binding sites, which are contained in the same polypeptide chain (V H -V L or V L -V H) in the light chain variable domain (V L ) connected to the heavy chain variable domain (V H ). By using a linker that is too short to allow pairing between two domains on the same chain, these domains are forced to pair with the complementary domains of another chain and create two antigen binding sites. Diabodies are more fully described in, for example, EP404,097; WO 93 / 11161; and Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448. For a review of engineered antibody variants, see generally Holliger and Hudson (2005), Nat. Biotechnol. 23:1126-1136.

[0039] Typically, when the binding activity is expressed on a molar basis, the variant antibodies or antigen-binding fragments of antibodies provided herein retain at least 10% of their A11B1 binding activity (compared to the modified parent antibody). In some embodiments, the variant antibodies (or their antigenic fragments) or antigen-binding fragments of antibodies provided herein retain at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the A11B1 binding affinity, which is the same as the parent antibody. As described herein, it is also contemplated that the antibodies or antigen-binding fragments of the present invention may include conservative or non-conservative amino acid substitutions, which may also be referred to as "conservative variants" or "functional conservative variants" of antibodies that do not substantially change their biological activity.

[0040] An "isolated antibody" refers to a purified state of a binding compound, and in this case means that the molecule is substantially free of other biomolecules (such as nucleic acids, proteins, lipids, carbohydrates) or other materials (such as cell debris and growth medium). In general, the term "isolated" is not intended to refer to the complete absence of such substances or the absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with the experimental or therapeutic use of the binding compound as described herein.

[0041] As used herein, the term "monoclonal antibody" refers to a substantially homologous antibody population, that is, except for the possible naturally occurring mutations and / or post-translational modifications that may exist in a small amount, the antibody molecules that constitute this population are identical in amino acid sequence. On the contrary, conventional (polyclonal) antibody preparations typically include a variety of different antibodies with different amino acid sequences in their variable domains (particularly, they typically have specific CDRs for different epitopes). The modifier "monoclonal" represents that the feature of an antibody is obtained from a substantially homologous antibody population, and is not interpreted as requiring antibody to be produced by any ad hoc method. For example, the monoclonal antibody used according to the present invention can be prepared by the hybridoma method described in Kohler et al. (1975), Nature 256:495 for the first time, or can be prepared by a recombinant DNA method (see, for example, U.S. Patent number 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using techniques described in, for example, Clackson et al. (1991), Nature 352:624-628, and Marks et al. (1991), J. Mol. Biol. 222:581-597. See also Presta (2005), J. Allergy Clin. Immunol. 116:731.

[0042] As used herein, a "chimeric antibody" is an antibody having a variable domain from a first antibody and a constant domain from a second antibody, wherein the first antibody and the second antibody are from different species. (U.S. Pat. No. 4,816,567, and Morrison et al. (1984), Proc. Natl. Acad. Sci. USA 81:6851-6855). Typically, the variable domains are obtained from antibodies from experimental animals (such as rodents) ("parent antibodies"), and the constant domain sequences are obtained from human antibodies, so that the resulting chimeric antibodies are less likely to cause an adverse immune response in human subjects than the parent (e.g., rodent) antibodies.

[0043] As used herein, the term "humanized antibody" refers to an antibody form containing sequences from both human antibodies and non-human (e.g., mouse, rat) antibodies. In general, a humanized antibody will comprise substantially all of at least one, and usually two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulins, and all or substantially all of the framework regions (FRs) are those of human immunoglobulin sequences. A humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc).

[0044] The term "fully human antibody" refers to an antibody that contains only human immunoglobulin sequences. If produced in mice, in mouse cells, or in hybridomas derived from mouse cells, fully human antibodies may contain mouse carbohydrate chains. Similarly, "mouse antibodies" refer to antibodies that contain only mouse immunoglobulin sequences. Alternatively, if produced in rats, in rat cells, or in hybridomas derived from rat cells, fully human antibodies may contain rat carbohydrate chains. Similarly, "rat antibodies" refer to antibodies that contain only rat immunoglobulin sequences.

[0045] In some embodiments, the basic antibody structural unit includes a tetramer. Each tetramer includes two pairs of identical polypeptide chains, each pair having a "light" chain (about 25kDa) and a "heavy" chain (about 50kDa to 70kDa). The amino terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids, which is primarily responsible for antigen recognition. The carboxyl terminal portion of the heavy chain can define a constant region primarily responsible for effector function. Typically, human light chains are classified as κ and λ light chains. In addition, human heavy chains are typically classified as μ, δ, γ, α or ε, and the isotypes of antibodies are defined as IgM, IgD, IgG, IgA, and IgE, respectively. In the light and heavy chains, the variable and constant regions are connected by a "J" region having about 12 or more amino acids, wherein the heavy chain also includes a "D" region having about 10 or more amino acids. See generally, Fundamental Immunology, Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989).

[0046] The variable regions of each light / heavy chain pair form an antibody binding site. Thus, in general, a complete antibody has two binding sites. However, in bifunctional or bispecific antibodies, these two binding sites are usually different.

[0047] Typically, the variable domains of both the heavy and light chains include three hypervariable regions, also referred to as complementarity determining regions (CDRs), located within relatively conservative framework regions (FRs). CDRs are typically arranged by framework regions to enable binding to specific epitopes. Generally speaking, the light chain variable domain and the heavy chain variable domain both include FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from N-terminal to C-terminal. Generally, the amino acid assignments for each domain are defined according to the following literature: "Sequences of Proteins of Immunological Interest", Kabat et al., National Institutes of Health, Bethesda, Md., 5th edition; NIH Publ. No. 91-3242 (1991); Kabat (1978), Adv. Prot. Chem. 32: 1-75; Kabat et al. (1977), J. Biol. Chem. 252: 6609-6616; Chothia et al. (1987), J Mol. Biol. 196: 901-917; or Chothia et al. (1989), Nature 342: 878-883.

[0048] As used herein, the term "hypervariable region" refers to the amino acid residues of an antibody that are responsible for antigen binding. The hypervariable region comprises amino acid residues from the "complementarity determining region" or "CDR" (i.e., residues 24 to 34 (CDRL1), 50 to 56 (CDRL2), and 89 to 97 (CDRL3) in the light chain variable domain, and residues 31 to 35 (CDRH1), 50 to 65 (CDRH2), and 95 to 102 (CDRH3) in the heavy chain variable domain; Kabat et al. (1991), "Sequences of Proteins of Immunological Importance" Interest), 5th edition, U.S. National Institutes of Health, Public Health Service, Bethesda, Md.) and / or those residues from the "hypervariable loops" (i.e., residues 26 to 32 (CDRL1), 50 to 52 (CDRL2), and 91 to 96 (CDRL3) in the light chain variable domain, and residues 26 to 32 (CDRH1), 53 to 55 (CDRH2), and 96 to 101 (CDRH3) in the heavy chain variable domain; Chothia and Lesk (1987) J. Mol. Biol. 196:901-917). CDRs may also be referenced according to the IMGT system described in Lefranc MP for identifying CDRs. A unique database numbering system is used for immunogenetic analysis. Immunol Today (1997) 18:509. As used herein, the term "framework" or "FR" residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues. CDR provides most of the contact residues for antibody binding to antigen or epitope. Interested CDRs can be derived from donor antibody variable heavy and light chain sequences, and include analogs of naturally occurring CDRs that also share or retain the same antigen binding specificity and / or neutralization ability as the donor antibody from which they are derived.

[0049] As used herein, "specific binding" or "immunospecific binding" or "immunospecifically binds" refers to an antibody that binds to a predetermined antigen with much greater affinity than another antigen (e.g., selectively binds to the active form of complement component A11B1 as compared to the inactive A11B1 (which may also be referred to as proA11B1 zymogen). In some embodiments, the antibody binds to the antigen with a 10 -7 M or less dissociation constant (K D ) binds to a predetermined antigen, and this K D is its K for binding to a nonspecific antigen (e.g., BSA, casein, or another nonspecific polypeptide). D At least 1 / 2 of.

[0050] The phrases "antibodies that recognize A11B1" and "antibodies that are specific for A11B1" are used interchangeably herein with the term "antibodies that immunospecifically bind to A11B1". In some embodiments, the antibody specifically or preferentially binds to A11B1, such as an active form of A11B1, compared to other proteins such as, but not limited to, an inactive form of A11B1 (proA11B1). The degree of specificity necessary for an anti-A11B1 antibody may depend on the intended use of the antibody and is in any case defined by its suitability for the intended purpose. In some embodiments, the antibody of the contemplated method or a binding compound derived from the antigen binding site of the antibody binds to its antigen (active form of A11B1) with an affinity that is at least two times, at least ten times, at least 20 times, or at least 100 times greater than the affinity for any other antigen (including, but not limited to, inactive A11B1).

[0051] Methods for determining mAb specificity and affinity by competitive inhibition can be found in Harlow et al., "Antibodies: A Laboratory Manual", Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988; Colligan et al., eds., "Current Protocols in Immunology", Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993); and Muller, Meth. Enzymol. 92:589 601 (1983), the entirety of which is incorporated herein by reference.

[0052] The term "homolog" refers to a protein sequence with 40% to 100% sequence identity to a reference sequence. The percent identity between two peptide chains can be determined by pairwise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carlsbad, Calif.) or other suitable alignment software (such as BLAST). In some embodiments, the antibody or its antigen-binding fragment has at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homology or identity to the sequence described herein. In some embodiments, the antibody has conservative substitutions compared to the sequence described herein. Exemplary conservative substitutions are shown in Table 1 and are included within the scope of the disclosed subject matter. Conservative substitutions may be present in the framework region or in the antigen binding site, as long as they do not adversely affect the characteristics of the antibody. Substitutions may also be performed to improve antibody properties, such as stability or affinity. Conservative substitutions will produce molecules with similar functional and chemical properties to those molecules undergoing such modifications. Exemplary amino acid substitutions are shown in the table below.

[0053]

[0054]

[0055] In some embodiments, variants of proteins and peptides provided herein are provided. In some embodiments, variants comprise substitutions, deletions or insertions. In some embodiments, variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (e.g., 1 to 10) substitutions. As described herein, substitutions can be conservative substitutions. In some embodiments, substitutions are non-conservative. In some embodiments, variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (e.g., 1 to 10) deletions. In some embodiments, variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (e.g., 1 to 10) insertions. In some embodiments, substitutions, deletions or insertions are present in CDRs provided herein. In some embodiments, substitutions, deletions or insertions are not present in CDRs provided herein.

[0056] As used herein, the term "in combination with" means that the therapeutic agents are administered to an animal or subject together in a mixture, simultaneously as single agents, or sequentially in any order as single agents.

[0057] The term "epitope" means the part of any molecule that can be recognized and bound by an antibody at one or more antigen binding regions of an Ab. An epitope is usually composed of chemically active surface groups of a molecule such as amino acids or sugar side chains, and has specific three-dimensional structural characteristics, as well as specific charge characteristics.

[0058] "Expression vector" refers to a vector comprising a recombinant polynucleotide comprising an expression control sequence operably linked to a nucleotide sequence to be expressed. The expression vector comprises sufficient cis-acting elements for expression; other elements for expression may be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked plasmids or plasmids contained in liposomes), and viruses (e.g., Sendai virus, lentivirus, retrovirus, adenovirus, and adeno-associated virus) to which the recombinant polynucleotide is incorporated.

[0059] Integrins are a large family of type I transmembrane heterodimeric glycoprotein receptors and serve as the main receptors for cell adhesion. The integrin receptor family plays a key role in regulating signal transduction pathways that control cell adhesion, migration, proliferation, differentiation, and apoptosis. There are 18 α subunits and 8 β subunits, which combine to form 24 integrin heterodimers. Each integrin receptor contains two non-covalently bound subunits, α and β. Integrins α1β1, α2β1, α10β1, and α11β1 are the main collagen receptors. α subunits and β subunits are transmembrane proteins with large modular extracellular domains, single transmembrane helices, and short cytoplasmic regions that mediate cytoskeletal interactions. The extracellular domain of integrins is usually large, with a structure of approximately 80 kDa to 150 kDa. The extracellular domain can be considered to include a head connected to two legs (see Figure 1 Structure of collagen-binding integrins). Collagen-binding integrins contain an I domain, which serves as a ligand binding site. The -domain contains a conserved “metal ion-dependent adhesion site” (MIDAS), which binds divalent metal cations (Mg2+) and plays an important role in ligand binding.

[0060] Integrins can exist in three different conformations: 1) a resting low-affinity state (bent conformation, Figure 1 , panel A), in which the head containing the ligand binding site faces the membrane; 2) an extended intermediate affinity state, in which the integrin extends but the head remains "closed" ( Figure 1 , panel B), and 3) an extended high affinity state in which the integrin is fully activated and readily binds ligand. The complexity of the different integrin states allows both allosteric and ligand blocking approaches to inhibit integrin function. Figure 1One of the allosteric ways to block integrin function, marked with an asterisk in the figure, is to generate monoclonal antibodies that prevent the integrin from reaching the fully extended conformation from the moderately extended conformation. Another allosteric option is to bind the integrin in its bent / inactive conformation and prevent it from extending to either of the two other states. A non-allosteric way to inhibit integrin function is to bind to the I domain, preventing the integrin from attaching to collagen. Binding to the ligand binding site directly leads to the risk of generating recombinant activators of integrin function.

[0061] As cell surface receptors, integrins sense the stiffness of the surrounding matrix, triggering cells to further produce and remodel connective tissue, which can perpetuate the fibrotic phenotype. Many integrins are overexpressed in fibrosis, but it is unclear which α subunit is sufficient for fibrosis. α11β1 integrin is specifically expressed on a subpopulation of fibroblasts and myofibroblasts (i.e., cells that produce terminal scars). Recent literature has provided strong evidence that α11β1 is one of the main drivers of the fibrotic phenotype in cardiac tissue, liver, lung, and kidney (Romaine, A. et al., Overexpression of integrin alpha 11 induces cardiac fibrosis in mice. Acta Physiol, February 2018, 222 (2); Bansal, R. et al., Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. Exp Mol Med. November 2017, 17: 49 (11)). Blocking α11β1 function inhibits myofibroblast differentiation and extracellular matrix deposition (i.e., the main events in scar formation), and blocking α11β1 Function may provide a mechanism for local injury-specific mitigation of fibrosis, which could fundamentally alter the fibrotic microenvironment and ameliorate disease progression in all diseases with a fibrotic component.

[0062] In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof of the present disclosure reduces the interaction of α11β1 with collagen in a human cell expressing α11β1. In some embodiments, reducing the interaction of α11β1 with collagen in a human cell expressing α11β1 includes the interaction of an anti-α11β1 antibody or antigen-binding fragment thereof with α11β1 in a resting low-affinity state (bent conformation). In some embodiments, reducing the interaction of α11β1 with collagen in a human cell expressing α11β1 includes the interaction of an anti-α11β1 antibody or antigen-binding fragment thereof with α11β1 in an extended medium-affinity state. In some embodiments, reducing the interaction of α11β1 with collagen in a human cell expressing α11β1 includes the interaction of an anti-α11β1 antibody or antigen-binding fragment thereof with α11β1 in an extended high-affinity state.

[0063] Composition

[0064] The present disclosure also provides an anti-α11β1 antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is a monoclonal antibody or a fragment thereof that binds to α11β1. In some embodiments, the antibody is a homodimeric monoclonal antibody or a fragment thereof that binds to α11β1. In some embodiments, the antibody is a heterodimeric monoclonal antibody or a fragment thereof that binds to α11β1. In some embodiments, the antibody is, for example, a typical antibody or a double-chain antibody, a three-chain antibody, a four-chain antibody, a microantibody, a large antibody, a tetravalent bispecific antibody (tandab), DVD, BiTe, scFv, TandAb scFv, Fab, Fab2, Fab3, F(ab')2, etc., or any combination thereof.

[0065] The term "purified" with respect to an antibody means that the antibody is substantially free of other substances associated with the molecule in its natural environment. For example, a purified protein is substantially free of cellular material or other proteins from the cell or tissue from which it was derived. The term refers to a preparation in which the isolated protein is sufficiently pure for analysis, or is at least 70% to 80% (w / w), at least 80% to 90% (w / w), 90% to 95% pure; and at least 95%, 96%, 97%, 98%, 99% or 100% (w / w) pure. In some embodiments, the antibody is purified.

[0066] The antibodies provided herein can also be conjugated with a chemical moiety. The chemical moiety can be (especially) a polymer, a radionuclide or a cytotoxic factor. In some embodiments, this can be referred to as an antibody drug conjugate. In some embodiments, the chemical moiety is a polymer that increases the half-life of the antibody molecule in the subject. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2kDa, 5kDa, 10kDa, 12kDa, 20kDa, 30kDa or 40kDa), dextran and monomethoxy polyethylene glycol (mPEG). Lee et al. (1999) (Bioconj.Chem.10:973-981) disclose single-chain antibodies conjugated with PEG. Wen et al. (2001) (Bioconj.Chem.12:545-553) opened antibodies conjugated with PEG, which is connected to a radioactive metal chelator (diethylenetriaminepentaacetic acid (DTPA)). Examples of chemical moieties include, but are not limited to, anti-mitotic agents such as calicheamicin (e.g., ozogamicin), monomethyl auristatin E, maytansine, and the like. Other examples include, but are not limited to, biologically active anti-microtubule agents, alkylating agents, and DNA minor groove binders. Other examples are provided herein and below. Chemical moieties can be linked to antibodies via linking groups (maleimide), cleavable linkers such as cathepsin cleavable linkers (valine-citrulline), and in some embodiments one or more spacers (e.g., p-aminobenzyl carbamate).

[0067] The antibodies and antibody fragments of the present invention may also be conjugated to labels such as 99 Tc, 90 Y. 111 In, 32 P. 14 C. 125 I. 3 H. 131 I. 11 C. 15 O. 13 N. 18 F. 35 S. 51 Cr, 57 To, 226 Ra, 60 Co. 59 Fe, 57 Se, 152 Eu, 67 CU, 217 Ci, 211 At 212 Pb, 47 Sc, 109 Pd, 234 Th and 40 K.157 Gd, 55 Mn, 52 Tr and 56 Fe.

[0068] Antibodies and antibody fragments may also be conjugated to fluorescent or chemiluminescent labels including: fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluorescamine, 152 Eu, dansyl, umbelliferone, fluorescein, luminal label, isoluminol label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate label, aequorin label, 2,3-dihydrophthalazinedione, biotin / avidin, spin label, and stable free radicals.

[0069] These antibody molecules can also be conjugated to cytotoxic factors such as diphtheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g., fatty acids), dianthus toxins, Phytoiacca americana proteins PAPI, PAPII and PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, milincomycin, restrictocin, phenomycin and enomycin.

[0070] Any method known in the art for conjugating the antibody molecules of the invention to various moieties may be employed, including those described by Hunter et al. (1962), Nature 144:945; David et al. (1974), Biochemistry 13:1014; Pain et al. (1981), J. Immunol. Meth. 40:219; and Nygren, J. (1982), Histochem. and Cytochem. 30:407. Methods for conjugating antibodies are routine and well known in the art.

[0071] In some embodiments, the antibody comprises a heavy chain CDR peptide having one of the following sequences or a variant thereof (Table 2):

[0072]

[0073] In some embodiments, the antibody comprises a light chain CDR peptide having one of the following sequences or a variant thereof (Table 3):

[0074]

[0075] In some embodiments, the antibody or its antibody binding fragment comprises a heavy chain CDR having a sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 29, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, or a combination thereof. In some embodiments, the antibody or its antibody binding fragment comprises a heavy chain CDR having a sequence of SEQ ID NO: 1. In some embodiments, the antibody or its antibody binding fragment comprises a heavy chain CDR having a sequence of SEQ ID NO: 2. In some embodiments, the antibody or its antibody binding fragment comprises a heavy chain CDR having a sequence of SEQ ID NO: 3. In some embodiments, the antibody or its antibody binding fragment comprises a heavy chain CDR having a sequence of SEQ ID NO: 23. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 24. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 25. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 26. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 27. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 29. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 38. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 39. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 40. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 41. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 42. In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 43.

[0076] In some embodiments, the antibody or its antibody binding fragment comprises a light chain CDR having a sequence of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, or a combination thereof. In some embodiments, the antibody or its antibody binding fragment comprises a light chain CDR having a sequence of SEQ ID NO: 16. In some embodiments, the antibody or its antibody binding fragment comprises a light chain CDR having a sequence of SEQ ID NO: 17. In some embodiments, the antibody or its antibody binding fragment comprises a light chain CDR having a sequence of SEQ ID NO: 18. In some embodiments, the antibody or its antibody binding fragment comprises a light chain CDR having a sequence of SEQ ID NO: 34. In some embodiments, the antibody or its antibody binding fragment comprises a light chain CDR having a sequence of SEQ ID NO: 35. In some embodiments, the antibody or its antibody binding fragment comprises a light chain CDR having a sequence of SEQ ID NO: 36. In some embodiments, the antibody or antibody binding fragment thereof comprises a light chain CDR having a sequence of SEQ ID NO: 58. In some embodiments, the antibody or antibody binding fragment thereof comprises a light chain CDR having a sequence of SEQ ID NO: 59. In some embodiments, the antibody or antibody binding fragment thereof comprises a light chain CDR having a sequence of SEQ ID NO: 60.

[0077] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:1, the HCDR2 has the sequence of SEQ ID NO:2, and the HCDR3 has the sequence of SEQ ID NO:3.

[0078] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:24, and the HCDR3 has the sequence of SEQ ID NO:28.

[0079] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:24, and the HCDR3 has the sequence of SEQ ID NO:29.

[0080] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:25, and the HCDR3 has the sequence of SEQ ID NO:28.

[0081] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:25, and the HCDR3 has the sequence of SEQ ID NO:29.

[0082] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:26, and the HCDR3 has the sequence of SEQ ID NO:28.

[0083] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:26, and the HCDR3 has the sequence of SEQ ID NO:29.

[0084] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:27, and the HCDR3 has the sequence of SEQ ID NO:28.

[0085] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:23, the HCDR2 has the sequence of SEQ ID NO:27, and the HCDR3 has the sequence of SEQ ID NO:29.

[0086] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:38, the HCDR2 has the sequence of SEQ ID NO:41, and the HCDR3 has the sequence of SEQ ID NO:43.

[0087] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:38, the HCDR2 has the sequence of SEQ ID NO:42, and the HCDR3 has the sequence of SEQ ID NO:43.

[0088] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:39, the HCDR2 has the sequence of SEQ ID NO:41, and the HCDR3 has the sequence of SEQ ID NO:43.

[0089] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:39, the HCDR2 has the sequence of SEQ ID NO:42, and the HCDR3 has the sequence of SEQ ID NO:43.

[0090] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:40, the HCDR2 has the sequence of SEQ ID NO:41, and the HCDR3 has the sequence of SEQ ID NO:43.

[0091] In some embodiments, the antibody or antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein the HCDR1 has the sequence of SEQ ID NO:40, the HCDR2 has the sequence of SEQ ID NO:42, and the HCDR3 has the sequence of SEQ ID NO:43.

[0092] In some embodiments, the antibody or antibody binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein the LCDR1 has the sequence of SEQ ID NO:16, the LCDR2 has the sequence of SEQ ID NO:17, and the LCDR3 has the sequence of SEQ ID NO:18.

[0093] In some embodiments, the antibody or antibody binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein the LCDR1 has the sequence of SEQ ID NO:34, the LCDR2 has the sequence of SEQ ID NO:35, and the LCDR3 has the sequence of SEQ ID NO:36.

[0094] In some embodiments, the antibody or antibody binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein the LCDR1 has the sequence of SEQ ID NO:58, the LCDR2 has the sequence of SEQ ID NO:59, and the LCDR3 has the sequence of SEQ ID NO:60.

[0095] For clarity, the following tables describing non-limiting exemplary combinations of heavy chain (Table 4) and light chain (Table 5) CDRs are provided.

[0096]

[0097]

[0098] In some embodiments, the antibody or antibody binding fragment thereof comprises: (i) a heavy chain having any one of the foregoing combinations of HCDR1, HCDR2, and HCDR3 sequences; and (ii) a light chain having any one of the foregoing combinations of LCDR1, LCDR2, and LCDR3 sequences. The following combinations are provided with reference to Tables 4 and 5 above.

[0099] So, for example, including V H A and V LThe antibody or antibody binding fragment thereof of A is understood to comprise a heavy chain having HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 17 and LCDR3 of SEQ ID NO: 18.

[0100] Thus, in some embodiments, the antibody or antibody binding fragment thereof comprises V H A and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H A and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H A and V L C.

[0101] In some embodiments, the antibody or antibody binding fragment thereof comprises V H B and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H B and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H B and V L C.

[0102] In some embodiments, the antibody or antibody binding fragment thereof comprises V H C and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H C and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H C and V L C.

[0103] In some embodiments, the antibody or antibody binding fragment thereof comprises V H D and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H D and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H D and V L C.

[0104] In some embodiments, the antibody or antibody binding fragment thereof comprises V H E and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H E and VL B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H E and V L C.

[0105] In some embodiments, the antibody or antibody binding fragment thereof comprises V H F and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H F and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H F and V L C.

[0106] In some embodiments, the antibody or antibody binding fragment thereof comprises V H G and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H G and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H G and V L C.

[0107] In some embodiments, the antibody or antibody binding fragment thereof comprises V H H and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H H and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H H and V L C.

[0108] In some embodiments, the antibody or antibody binding fragment thereof comprises V H I and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H I and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H I and V L C.

[0109] In some embodiments, the antibody or antibody binding fragment thereof comprises V H J and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H J and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H J and V L C.

[0110] In some embodiments, the antibody or antibody binding fragment thereof comprises V H K and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H K and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H K and V L C.

[0111] In some embodiments, the antibody or antibody binding fragment thereof comprises V H M and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H M and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H M and V L C.

[0112] In some embodiments, the antibody or antibody binding fragment thereof comprises V H N and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H N and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H N and V L C.

[0113] In some embodiments, the antibody or antibody binding fragment thereof comprises V H O and V L A. In some embodiments, the antibody or antibody binding fragment thereof comprises V H O and V L B. In some embodiments, the antibody or antibody binding fragment thereof comprises V H O and V L C.

[0114] In some embodiments, the light chain variable region LCDR1 is replaced by any other light chain LCDR1 sequence. In some embodiments, the light chain variable region LCDR2 is replaced by any other light chain LCDR2 sequence. In some embodiments, the light chain variable region LCDR3 is replaced by any other light chain LCDR3 sequence. In some embodiments, the heavy chain variable region HCDR1 is replaced by any other heavy chain HCDR1 sequence. In some embodiments, the heavy chain variable region HCDR2 is replaced by any other heavy chain HCDR2 sequence. In some embodiments, the heavy chain variable region HCDR3 is replaced by any other heavy chain HCDR3 sequence.

[0115] In some embodiments, the antibody comprises a heavy chain variable region peptide having one of the following sequences or a variant thereof (Table 6):

[0116]

[0117]

[0118]

[0119] In some embodiments, the antibody comprises a light chain variable region peptide having one of the following sequences or a variant thereof (Table 7):

[0120]

[0121] In some embodiments, the heavy chain variable region and / or the light chain variable region is described as comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to the sequence identifier, provided that the heavy chain variable region and / or the light chain variable region comprises a specific set of HCDRs and / or LCDRs as indicated by the context. As used herein, the term "provided that the heavy chain variable region and / or the light chain variable region comprises a specific set of HCDRs and / or LCDRs" or similar language used herein means that the HCDRs or LCDRs as indicated by the context are identical to the sequence referenced by the sequence identifier, and the overall percentage identity of the heavy chain variable region and / or the light chain variable region is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the referenced sequence.

[0122] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence selected from one or more of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, or any variant thereof. H Peptide.

[0123] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85% identical to SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, or any variant thereof. H Peptide.

[0124] In some embodiments, the antibody or antigen-binding fragment thereof comprises the residues of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65 NO:57 or any variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to V H Peptide.

[0125] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:4. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:4. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0126] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:5. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:5. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0127] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:6. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 6. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0128] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:7. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:7. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0129] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:8. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:8. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0130] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:9. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:9. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0131] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 10. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 10. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0132] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 11. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 11. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0133] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 12. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 12. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0134] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 13. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 13. HPeptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0135] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 14. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 14. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0136] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 15. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 15. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO:1, the HCDR2 sequence of SEQ ID NO:2 and the HCDR3 sequence of SEQ ID NO:3.

[0137] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 30. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 30. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:23, a HCDR2 sequence of SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26 or SEQ ID NO:27, and a HCDR3 sequence of SEQ ID NO:28 or SEQ ID NO:29.

[0138] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 31. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 31. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:23, a HCDR2 sequence of SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26 or SEQ ID NO:27, and a HCDR3 sequence of SEQ ID NO:28 or SEQ ID NO:29.

[0139] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 32. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 32. HPeptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:23, a HCDR2 sequence of SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26 or SEQ ID NO:27, and a HCDR3 sequence of SEQ ID NO:28 or SEQ ID NO:29.

[0140] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 33. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 33. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:23, a HCDR2 sequence of SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26 or SEQ ID NO:27, and a HCDR3 sequence of SEQ ID NO:28 or SEQ ID NO:29.

[0141] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 44. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 44. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0142] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 45. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 45. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0143] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:46. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 46. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0144] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 47. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 47.H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0145] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 48. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 48. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0146] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 49. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 49. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0147] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:50. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 50. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0148] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:51. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 51. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0149] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:52. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 52.H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0150] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:53. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 53. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0151] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:54. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 54. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0152] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:55. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 55. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0153] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:56. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:56. H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0154] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO:57. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 57.H Peptide, provided that the antibody or antigen-binding fragment thereof comprises a HCDR1 sequence of SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, a HCDR2 sequence of SEQ ID NO:41 or SEQ ID NO:42, and a HCDR3 sequence of SEQ ID NO:43.

[0155] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence selected from one or more of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 37, SEQ ID NO: 61, SEQ ID NO: 62, or any variant thereof. L Peptide.

[0156] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85% identical to SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 37, SEQ ID NO: 61, SEQ ID NO: 62, or any variant thereof. L Peptide.

[0157] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 37, SEQ ID NO: 61, SEQ ID NO: 62, or any variant thereof. L Peptide.

[0158] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 19. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 19. LPeptide, provided that the antibody or antigen-binding fragment thereof comprises the LCDR1 sequence of SEQ ID NO:16, the LCDR2 sequence of SEQ ID NO:17, and the LCDR3 sequence of SEQ ID NO:18.

[0159] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 20. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 20. L Peptide, provided that the antibody or antigen-binding fragment thereof comprises the LCDR1 sequence of SEQ ID NO:16, the LCDR2 sequence of SEQ ID NO:17, and the LCDR3 sequence of SEQ ID NO:18.

[0160] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 21. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 21. L Peptide, provided that the antibody or antigen-binding fragment thereof comprises the LCDR1 sequence of SEQ ID NO:16, the LCDR2 sequence of SEQ ID NO:17, and the LCDR3 sequence of SEQ ID NO:18.

[0161] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 22. LIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 22. L Peptide, provided that the antibody or antigen-binding fragment thereof comprises the LCDR1 sequence of SEQ ID NO:16, the LCDR2 sequence of SEQ ID NO:17, and the LCDR3 sequence of SEQ ID NO:18.

[0162] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 37. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 37. L Peptide, provided that the antibody or antigen-binding fragment thereof comprises the LCDR1 sequence of SEQ ID NO:34, the LCDR2 sequence of SEQ ID NO:35, and the LCDR3 sequence of SEQ ID NO:36.

[0163] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 61. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 61. L Peptide, provided that the antibody or antigen-binding fragment thereof comprises the LCDR1 sequence of SEQ ID NO:58, the LCDR2 sequence of SEQ ID NO:59, and the LCDR3 sequence of SEQ ID NO:60.

[0164] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical or identical to SEQ ID NO: 62. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 62. L Peptide, provided that the antibody or antigen-binding fragment thereof comprises the LCDR1 sequence of SEQ ID NO:58, the LCDR2 sequence of SEQ ID NO:59, and the LCDR3 sequence of SEQ ID NO:60.

[0165] The VH sequence and VL sequence can be in any format, including but not limited to the scFv format, in which the VH region and the VL region are connected with a peptide linker. Examples of peptide linkers that can be used to connect the various peptides provided herein include but are not limited to: (GGGGS) n (SEQ ID NO:70), (GGGGA) n (SEQ ID NO:71) or any combination thereof, wherein each n is independently 1 to 5. In some embodiments, each n is independently 1. In some embodiments, each n is independently 2. In some embodiments, each n is independently 3. In some embodiments, each n is independently 4. In some embodiments, each n is independently 5. In some embodiments, the variable region is not connected to a peptide linker.

[0166] As provided herein, the various peptides described herein (V H or V L ) may be connected to a peptide linker, or may not be connected to a peptide linker but form a continuous sequence. In some embodiments, the heavy chain variable region and the light chain variable region are not connected by a linker. In some embodiments, the heavy chain variable region and the light chain variable region are connected via a peptide linker. In some embodiments, the peptide linker includes the sequence (GGGGS) n (SEQ ID NO:70), (GGGGA) n (SEQ ID NO: 71) or any combination thereof, wherein each n is independently 1 to 5. In some embodiments, each n is independently 1. In some embodiments, each n is independently 2. In some embodiments, each n is independently 3. In some embodiments, each n is independently 4. In some embodiments, each n is independently 5. The linked peptide format can be represented by Formula V H -ZVL or V L -ZV H In some embodiments, Z is (GGGGS) n (SEQ ID NO:70), (GGGGA) n (SEQ ID NO:71) or any combination thereof, wherein each n is independently 1 to 5. In some embodiments, each n is independently 1. In some embodiments, each n is independently 2. In some embodiments, each n is independently 3. In some embodiments, each n is independently 4. In some embodiments, each n is independently 5.

[0167] In some embodiments, the VH polypeptide and the VL polypeptide are linked to an Fc region, such as “IgG1-AAS constant region”, “IgG4 S228P L235E LS” or “IgG4 S228P L235E YTE”. In some embodiments, the Fc region is as provided herein.

[0168] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14 or SEQ ID NO:15; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 or SEQ ID NO:22.

[0169] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14 or SEQ ID NO:15; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 or SEQ ID NO: 22; provided that the V H The peptide comprises at least one HCDR having a sequence of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3; and / or the V L The peptide comprises at least one LCDR having a sequence of SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18. In some embodiments, V H or V L The CDRs in the chains are as shown in the combinations provided herein.

[0170] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14 or SEQ ID NO:15; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 or SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises LCDR1 having the sequence of SEQ ID NO:16, LCDR2 having the sequence of SEQ ID NO:17, and LCDR3 having the sequence of SEQ ID NO:18.

[0171] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V LThe peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 4. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0172] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 4. H Peptide and V of SEQ ID NO:20 L Peptide.

[0173] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 4. H Peptide and V of SEQ ID NO:21 L Peptide.

[0174] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 4; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 4. H Peptide and V of SEQ ID NO:22 L Peptide.

[0175] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 5. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0176] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 5. H Peptide and V of SEQ ID NO:20 L Peptide.

[0177] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 5. H Peptide and V of SEQ ID NO:21 L Peptide.

[0178] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:5; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V LThe peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 5. H Peptide and V of SEQ ID NO:22 L Peptide.

[0179] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 6. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0180] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 6. H Peptide and V of SEQ ID NO:20 L Peptide.

[0181] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 6. H Peptide and V of SEQ ID NO:21 L Peptide.

[0182] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 6; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 6. H Peptide and V of SEQ ID NO:22 L Peptide.

[0183] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 7. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0184] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 7. H Peptide and V of SEQ ID NO:20 L Peptide.

[0185] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V LThe peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 7. H Peptide and V of SEQ ID NO:21 L Peptide.

[0186] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:7; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 7. H Peptide and V of SEQ ID NO:22 L Peptide.

[0187] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 8. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0188] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 8. H Peptide and V of SEQ ID NO:20 L Peptide.

[0189] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 8. H Peptide and V of SEQ ID NO:21 L Peptide.

[0190] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 8; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 8. H Peptide and V of SEQ ID NO:22 L Peptide.

[0191] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 9. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0192] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V LThe peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 9. H Peptide and V of SEQ ID NO:20 L Peptide.

[0193] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 9. H Peptide and V of SEQ ID NO:21 L Peptide.

[0194] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 9. H Peptide and V of SEQ ID NO:22 L Peptide.

[0195] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 10. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0196] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 10. H Peptide and V of SEQ ID NO: 20 L Peptide.

[0197] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 10. H Peptide and V of SEQ ID NO: 21 L Peptide.

[0198] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 10. H Peptide and V of SEQ ID NO: 22 L Peptide.

[0199] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V LThe peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 11. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0200] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 11. H Peptide and V of SEQ ID NO: 20 L Peptide.

[0201] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 11. H Peptide and V of SEQ ID NO: 21 L Peptide.

[0202] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 11; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 11. H Peptide and V of SEQ ID NO: 22 L Peptide.

[0203] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 12. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0204] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 12. H Peptide and V of SEQ ID NO: 20 L Peptide.

[0205] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 12. H Peptide and V of SEQ ID NO: 21 L Peptide.

[0206] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 12; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 12. H Peptide and V of SEQ ID NO: 22 L Peptide.

[0207] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V LThe peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 13. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0208] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 13. H Peptide and V of SEQ ID NO: 20 L Peptide.

[0209] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 13. H Peptide and V of SEQ ID NO: 21 L Peptide.

[0210] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 13; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 13. H Peptide and V of SEQ ID NO: 22 L Peptide.

[0211] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 14. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0212] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 14. H Peptide and V of SEQ ID NO: 20 L Peptide.

[0213] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 14. H Peptide and V of SEQ ID NO: 21 L Peptide.

[0214] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 14; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 16, a LCDR2 having a sequence of SEQ ID NO: 17, and a LCDR3 having a sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 14. H Peptide and V of SEQ ID NO: 22 L Peptide.

[0215] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 19; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V LThe peptide comprises a LCDR1 having the sequence of SEQ ID NO: 16, a LCDR2 having the sequence of SEQ ID NO: 17, and a LCDR3 having the sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 15. H Peptide and V of SEQ ID NO: 19 L Peptide.

[0216] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 20; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 16, a LCDR2 having the sequence of SEQ ID NO: 17, and a LCDR3 having the sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 15. H Peptide and V of SEQ ID NO: 20 L Peptide.

[0217] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 21; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 16, a LCDR2 having the sequence of SEQ ID NO: 17, and a LCDR3 having the sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 15. H Peptide and V of SEQ ID NO: 21 L Peptide.

[0218] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 15; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 22; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 1, a HCDR2 having the sequence of SEQ ID NO: 2, and a HCDR3 having the sequence of SEQ ID NO: 3; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 16, a LCDR2 having the sequence of SEQ ID NO: 17, and a LCDR3 having the sequence of SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 15. H Peptide and V of SEQ ID NO: 22 L Peptide.

[0219] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32 or SEQ ID NO:33, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:37.

[0220] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H comprising a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32 or SEQ ID NO:33; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37; provided that the V H The peptide comprises at least one HCDR having a sequence of SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29; and / or the V L The peptide comprises at least one LCDR having a sequence of SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36. In some embodiments, V H or V L The CDRs in the chains are as shown in the combinations provided herein.

[0221] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32 or SEQ ID NO:33; and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37; provided that the V H The peptide comprises a HCDR1 having the sequence of SEQ ID NO: 23, a HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and a HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29; and / or the V L The peptide comprises LCDR1 having the sequence of SEQ ID NO:34, LCDR2 having the sequence of SEQ ID NO:35, and LCDR3 having the sequence of SEQ ID NO:36.

[0222] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:30, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 30; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 23, a HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and a HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 34, a LCDR2 having a sequence of SEQ ID NO: 35, and a LCDR3 having a sequence of SEQ ID NO: 36. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 30. H Peptide and V of SEQ ID NO:37 L Peptide.

[0223] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:31, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 31; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 23, a HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and a HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 34, a LCDR2 having a sequence of SEQ ID NO: 35, and a LCDR3 having a sequence of SEQ ID NO: 36. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 31. H Peptide and V of SEQ ID NO:37 L Peptide.

[0224] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:32, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 32; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 23, a HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and a HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 34, a LCDR2 having a sequence of SEQ ID NO: 35, and a LCDR3 having a sequence of SEQ ID NO: 36. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 32. H Peptide and V of SEQ ID NO:37 L Peptide.

[0225] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 33, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 33; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 37; provided that the V HThe peptide comprises a HCDR1 having the sequence of SEQ ID NO: 23, a HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and a HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 34, a LCDR2 having a sequence of SEQ ID NO: 35, and a LCDR3 having a sequence of SEQ ID NO: 36. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 33. H Peptide and V of SEQ ID NO:37 L Peptide.

[0226] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56 or SEQ ID NO:57; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:61 or SEQ ID NO:62.

[0227] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56 or SEQ ID NO:57; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61 or SEQ ID NO: 62; provided that the V H The peptide comprises at least one HCDR having a sequence of SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42 or SEQ ID NO:43; and / or the V L The peptide comprises at least one LCDR having a sequence of SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60. In some embodiments, V H or V L The CDRs in the chains are as shown in the combinations provided herein.

[0228] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56 or SEQ ID NO:57; and / or the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:61 or SEQ ID NO:62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises LCDR1 having the sequence of SEQ ID NO:58, LCDR2 having the sequence of SEQ ID NO:59, and LCDR3 having the sequence of SEQ ID NO:60.

[0229] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 44, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 44; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V HThe peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 44. H Peptide and V of SEQ ID NO:61 L Peptide.

[0230] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 44, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 44; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V LThe peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 44. H Peptide and V of SEQ ID NO:62 L Peptide.

[0231] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 45, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 45; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 45. HPeptide and V of SEQ ID NO:61 L Peptide.

[0232] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 45, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 45; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 45. H Peptide and V of SEQ ID NO:62 L Peptide.

[0233] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 46, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 46; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 46. H Peptide and V of SEQ ID NO:61 L Peptide.

[0234] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 46, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 46; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 46. H Peptide and V of SEQ ID NO:62 L Peptide.

[0235] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 47, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and VL Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 47; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 47. H Peptide and V of SEQ ID NO:61 L Peptide.

[0236] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 47, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 47; and the VL The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 47. H Peptide and V of SEQ ID NO:62 L Peptide.

[0237] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 48, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 48; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V HThe peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 48. H Peptide and V of SEQ ID NO:61 L Peptide.

[0238] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 48, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 48; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V LThe peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 48. H Peptide and V of SEQ ID NO:62 L Peptide.

[0239] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 49, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 49; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 49. HPeptide and V of SEQ ID NO:61 L Peptide.

[0240] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 49, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 49; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 49. H Peptide and V of SEQ ID NO:62 L Peptide.

[0241] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:50, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:50; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having a sequence of SEQ ID NO: 58, a LCDR2 having a sequence of SEQ ID NO: 59, and a LCDR3 having a sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 50. H Peptide and V of SEQ ID NO:61 L Peptide.

[0242] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:50, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:50; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 50. H Peptide and V of SEQ ID NO:62 L Peptide.

[0243] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:51, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and VL Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:51; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 51. H Peptide and V of SEQ ID NO:61 L Peptide.

[0244] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:51, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:51; and the VL The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 51. H Peptide and V of SEQ ID NO:62 L Peptide.

[0245] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:52, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:52; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V HThe peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 52. H Peptide and V of SEQ ID NO:61 L Peptide.

[0246] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:52, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:52; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V LThe peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 52. H Peptide and V of SEQ ID NO:62 L Peptide.

[0247] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:53, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:53; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 53. HPeptide and V of SEQ ID NO:61 L Peptide.

[0248] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:53, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:53; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 53. H Peptide and V of SEQ ID NO:62 L Peptide.

[0249] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V HThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:54, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:54; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 54. H Peptide and V of SEQ ID NO:61 L Peptide.

[0250] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:54, and the V LThe peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:54; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 54. H Peptide and V of SEQ ID NO:62 L Peptide.

[0251] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:55, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and VL Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:55; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 55. H Peptide and V of SEQ ID NO:61 L Peptide.

[0252] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:55, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:55; and the VL The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 55. H Peptide and V of SEQ ID NO:62 L Peptide.

[0253] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:56, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:56; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V HThe peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 56. H Peptide and V of SEQ ID NO:61 L Peptide.

[0254] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:56, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:56; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V LThe peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 56. H Peptide and V of SEQ ID NO:62 L Peptide.

[0255] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:57, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:57; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 61; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 57. HPeptide and V of SEQ ID NO:61 L Peptide.

[0256] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:57, and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Peptide and V L Peptide, wherein the V H The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:57; and the V L The peptide comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 62; provided that the V H The peptide comprises a HCDR1 having a sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40, a HCDR2 having a sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and a HCDR3 having a sequence of SEQ ID NO: 43; and / or the V L The peptide comprises a LCDR1 having the sequence of SEQ ID NO: 58, a LCDR2 having the sequence of SEQ ID NO: 59, and a LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V sequence of SEQ ID NO: 57. H Peptide and V of SEQ ID NO:62 L Peptide.

[0257] In some embodiments, the antibody comprises an Fc domain. The Fc domain may be connected to the heavy chain or light chain of the antibody. In some embodiments, the Fc domain comprises a mutation to extend the half-life of the antibody. In some embodiments, the Fc domain comprises a mutation, such as those described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety. In some embodiments, the constant region comprises a mutation at the position of amino acid residue 428 numbered according to the EU numbering index of Kabat relative to the wild-type human IgG constant domain. Without being bound by any particular theory, an antibody comprising a mutation corresponding to residue 428 may have an increased half-life compared to the half-life of an IgG with a wild-type human IgG constant domain. In some embodiments, the mutation is to replace a native residue with threonine, leucine, phenylalanine or serine. In some embodiments, the antibody further comprises one or more amino acid substitutions at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436 numbered according to the Kabat EU numbering index relative to the corresponding wild-type human IgG constant domain. Specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.

[0258] Other mutations can be used for Fc domains, such as those provided in U.S. Patent No. 8,394,925, which is hereby incorporated by reference in its entirety. In some embodiments, the Fc region is a variant Fc region comprising amino acid substitutions at positions 428 and 434, wherein the amino acid substitution is a leucine that is not a wild-type amino acid at position 428 and a serine that is not a wild-type amino acid at position 434, wherein the polypeptide is an antibody and wherein numbering is performed according to the EU index of Kabat et al. In some embodiments, the Fc region comprises human S228P, L235E, M428L or N434S substitutions. In some embodiments, the Fc region comprises M428L substitutions. In some embodiments, the Fc region comprises N434S substitutions. In some embodiments, the Fc region comprises M428L and N434S substitutions. In some embodiments, the Fc region comprises M252Y, S254T and / or T256E substitutions.

[0259] In some embodiments, the antibodies comprise a constant region as shown below, with or without the mutations provided in the list below.

[0260] IgG1-AAS constant region

[0261] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:63)

[0262] IgG4 S228P L235E LS

[0263] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPPAPEFEGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLLSLGK(SEQ ID NO:64)

[0264] IgG4 S228P L235E YTE

[0265] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:65)

[0266] In some embodiments, the antibody comprises a constant region as provided herein, wherein the C-terminal lysine (K) amino acid has been deleted. In some embodiments, the antibody comprises a constant region set as follows:

[0267] IgG1-AAS constant truncation

[0268] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:66)

[0269] IgG4 S228P L235E LS-truncated

[0270] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG(SEQ ID NO:67)

[0271] IgG4 S228P L235E YTE-truncated

[0272] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG(SEQ ID NO:68)

[0273] In some embodiments, an antibody (such as a light chain) comprises a κ constant region, such as a human constant domain that may comprise the following sequence:

[0274] Human kappa constant domain

[0275] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:69)

[0276] In some embodiments, the antibody or antigen-binding fragment thereof of any embodiment as provided herein may include any known constant domain, such as but not limited to IgG constant domain. In some embodiments, the constant domain is as provided herein. In some embodiments, the constant domain is selected from the group including but not limited to SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69 or its variants.

[0277] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 4 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 4 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 4 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 4 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 4 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 4 and a constant domain of SEQ ID NO: 68.

[0278] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 5 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 5 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 5 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 5 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 5 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 5 and a constant domain of SEQ ID NO: 68.

[0279] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 6 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 6 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 6 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 6 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 6 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 6 and a constant domain of SEQ ID NO: 68.

[0280] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 7 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 7 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 7 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 7 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 7 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 7 and a constant domain of SEQ ID NO: 68.

[0281] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 8 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 8 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 8 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 8 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 8 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 8 and a constant domain of SEQ ID NO: 68.

[0282] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 9 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 9 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 9 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 9 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 9 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 9 and a constant domain of SEQ ID NO: 68.

[0283] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 10 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 10 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 10 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 10 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 10 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 10 and a constant domain of SEQ ID NO: 68.

[0284] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 11 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 11 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 11 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 11 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 11 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 11 and a constant domain of SEQ ID NO: 68.

[0285] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 12 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 12 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 12 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 12 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 12 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 12 and a constant domain of SEQ ID NO: 68.

[0286] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 13 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 13 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 13 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 13 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 13 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 13 and a constant domain of SEQ ID NO: 68.

[0287] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 14 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 14 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 14 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 14 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 14 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 14 and a constant domain of SEQ ID NO: 68.

[0288] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 15 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 15 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 15 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 15 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 15 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 15 and a constant domain of SEQ ID NO: 68.

[0289] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 30 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 30 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 30 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 30 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 30 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 30 and a constant domain of SEQ ID NO: 68.

[0290] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 31 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 31 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 31 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 31 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 31 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 31 and a constant domain of SEQ ID NO: 68.

[0291] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 32 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 32 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 32 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 32 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 32 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 32 and a constant domain of SEQ ID NO: 68.

[0292] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 33 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 33 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 33 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 33 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 33 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 33 and a constant domain of SEQ ID NO: 68.

[0293] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 44 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 44 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 44 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 44 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 44 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 44 and a constant domain of SEQ ID NO: 68.

[0294] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 45 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 45 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 45 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 45 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 45 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 45 and a constant domain of SEQ ID NO: 68.

[0295] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 46 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 46 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 46 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 46 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 46 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 46 and a constant domain of SEQ ID NO: 68.

[0296] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 47 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 47 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 47 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 47 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 47 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 47 and a constant domain of SEQ ID NO: 68.

[0297] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 48 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 48 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 48 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 48 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 48 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 48 and a constant domain of SEQ ID NO: 68.

[0298] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 49 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 49 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 64 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 49 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 49 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 49 and a constant domain of SEQ ID NO: 68.

[0299] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 50 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 50 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 50 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 50 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 50 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 50 and a constant domain of SEQ ID NO: 68.

[0300] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 51 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 51 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 51 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 51 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 51 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 51 and a constant domain of SEQ ID NO: 68.

[0301] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 52 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 52 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 52 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 52 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 52 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 52 and a constant domain of SEQ ID NO: 68.

[0302] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 53 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 53 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 53 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 53 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 53 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 53 and a constant domain of SEQ ID NO: 68.

[0303] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 54 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 54 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 54 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 54 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 54 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 54 and a constant domain of SEQ ID NO: 68.

[0304] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 55 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 55 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 55 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 55 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 55 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 55 and a constant domain of SEQ ID NO: 68.

[0305] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 56 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 56 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 56 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 56 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 56 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 56 and a constant domain of SEQ ID NO: 68.

[0306] In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 57 and a constant domain of SEQ ID NO: 63. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 57 and a constant domain of SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 57 and a constant domain of SEQ ID NO: 65. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 57 and a constant domain of SEQ ID NO: 66. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 57 and a constant domain of SEQ ID NO: 67. In some embodiments, the antibody comprises a heavy chain comprising a variable region of SEQ ID NO: 57 and a constant domain of SEQ ID NO: 68.

[0307] In some embodiments, the antibody comprises a light chain comprising a variable region of SEQ ID NO: 19 and a constant domain of SEQ ID NO: 69. In some embodiments, the antibody comprises a light chain comprising a variable region of SEQ ID NO: 20 and a constant domain of SEQ ID NO: 69. In some embodiments, the antibody comprises a light chain comprising a variable region of SEQ ID NO: 21 and a constant domain of SEQ ID NO: 69. In some embodiments, the antibody comprises a light chain comprising a variable region of SEQ ID NO: 22 and a constant domain of SEQ ID NO: 69. In some embodiments, the antibody comprises a light chain comprising a variable region of SEQ ID NO: 37 and a constant domain of SEQ ID NO: 69. In some embodiments, the antibody comprises a light chain comprising a variable region of SEQ ID NO: 61 and a constant domain of SEQ ID NO: 69. In some embodiments, the antibody comprises a light chain comprising a variable region of SEQ ID NO: 62 and a constant domain of SEQ ID NO: 69.

[0308] In some embodiments, the antibody or any antibody fragment thereof comprises a heavy chain selected from Table 8 below.

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346] In some embodiments, the antibody or any antibody fragment thereof comprises a light chain selected from Table 9 below.

[0347]

[0348]

[0349] In some embodiments, the antibodies described herein comprise a heavy chain selected from Table 8 and a light chain selected from Table 9.

[0350] In some embodiments, the antibody comprises a heavy chain selected from SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142 or SEQ ID NO:143;and a light chain selected from SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146 or SEQ ID NO: 147. ;

[0351] In some embodiments, the antibody comprises a heavy chain selected from SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 159, SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, or SEQ ID NO: 171; and a light chain selected from SEQ ID NO: 172.

[0352] In some embodiments, the antibody comprises a sequence selected from SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:242, SEQ IDNO:243, SEQ ID NO:244, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:250, SEQ ID NO:251, SEQ ID NO:252, SEQ ID NO:253, SEQ ID NO:254, SEQ ID NO:255 or SEQ ID NO:256; and a light chain selected from SEQ ID NO:257 or SEQ ID NO:258.

[0353] As provided herein, antibodies or their antigen-binding fragments can be variants of these sequences. Therefore, in some embodiments, variants of antibodies or their antigen-binding fragments provided herein are provided. In some embodiments, the variant comprises a mutation selected from substitution, deletion, insertion or a combination thereof. In some embodiments, the variant comprises 1 to 20 mutations. In some embodiments, the variant comprises 1 to 10 mutations. In some embodiments, the variant comprises 1 to 5 mutations. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mutations. In some embodiments, the variant comprises at least 1 mutation. Therefore, in some embodiments, the variant comprises up to or more than 20 mutations. In some embodiments, the variant comprises 1 to 10 mutations, wherein these mutations are selected from substitution, deletion, insertion or a combination thereof. In some embodiments, the variant comprises 1 to 10 mutations, wherein these mutations are conservative substitutions. Examples of conservative substitutions are provided herein (Table 1). Furthermore, those skilled in the art will recognize and appreciate substitutions encompassed by the term “conservative substitutions.” Such substitutions are within the scope of the present disclosure.

[0354] The antibody or antigen binding fragment may comprise an antibody fragment as defined and provided herein. In some embodiments, the antibody binding fragment is as provided herein. In some embodiments, the antibody fragment is a scFv antibody, a Fab fragment, a Fab' fragment or a F(ab')2 fragment. In some embodiments, the antibody fragment is a scFv antibody. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is a Fab' fragment. In some embodiments, the antibody fragment is a F(ab')2 fragment.

[0355] The sequence of the antibody can be modified to obtain a human IgG antibody. The conversion of the sequence provided herein can be modified to obtain other types of antibodies. The CDR can also be connected to other antibodies, proteins or molecules to produce antibody fragments that bind α11β1. This can be in the form of an antibody drug conjugate ("ADC") or a multispecific molecule. The sequence can also be made into a chimeric antibody as described herein.

[0356] In some embodiments, the antibody comprises an amino acid sequence containing a sequence or a fragment thereof provided herein. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody comprises one or more amino acid sequences, its Fab or its human IgG variant as provided herein. "Its human IgG variant" refers to an antibody that is modified to become human IgG when the starting antibody is not a human IgG antibody.

[0357] As described herein, the production of antibodies with known sequences is conventional and can be carried out by any method. Antibodies can also be modified to be chimeric antibodies or human antibodies. Antibodies can also be used in pharmaceutical compositions that can be injected. As also described herein, antibodies can be isolated antibodies or engineered antibodies.

[0358] In some embodiments, "derivatives" of antibodies, fragments, regions or derivatives thereof are provided, the term including those proteins encoded by truncated or modified genes to obtain molecular species functionally similar to immunoglobulin fragments. These modifications include, but are not limited to, the addition of genetic sequences encoding cytotoxic proteins such as plant toxins and bacterial toxins. The modifications may also include reporter proteins such as fluorescent or chemiluminescent tags. Fragments and derivatives may be produced in any manner.

[0359] Identification of these antibodies or antigen-binding fragments thereof provides the information necessary to generate additional monoclonal antibodies having similar binding characteristics and therapeutic or diagnostic utility as the embodiments of the present application.

[0360] These antibodies can be produced according to the examples provided herein. Once the sequence is known, antibodies can also be produced according to known methods. These antibodies can also be converted into different types, such as into human IgG, etc. By converting the antibody into a human antibody, the human subject will not recognize the antibody as exogenous. The conversion of non-human IgG antibodies to human IgG antibodies is well known, and once the native sequence is known, the conversion can be routinely performed. As discussed herein, antibodies can be modified according to known methods. Such methods are described in, for example, the following documents: Riechmann L, Clark M, Waldmann H, Winter G (1988), "Reshaping human antibodies for therapy", Nature 332 (6162): 332-323; Tsurushita N, Park M, Pakabunto K, Ong K, Avdalovic A, FuH, Jia A, Vásquez M, Kumar S. (2004), which are incorporated by reference in their entirety.

[0361] In some embodiments, a host cell is provided. In some embodiments, the host cell comprises an antibody or antigen binding fragment thereof as provided herein. In some embodiments, the host cell comprises a nucleic acid molecule encoding an antibody or antigen binding fragment thereof as provided herein. In some embodiments, the host cell comprises a vector comprising a nucleic acid molecule encoding an antibody or antigen binding fragment thereof as provided herein.

[0362] In some embodiments, the host cell produces an antibody or antigen binding fragment thereof as provided herein. In some embodiments, an antibody or antigen binding fragment thereof as provided herein is provided, wherein the antibody or antigen binding fragment thereof as provided herein is produced by a host cell.

[0363] In some embodiments, a method for producing a polypeptide is provided. In some embodiments, the polypeptide comprises a heavy chain variable region as provided herein, a light chain variable region as provided herein, or a combination thereof. In some embodiments, the method comprises cultivating a host cell under conditions such that the host cell expresses a polypeptide comprising a heavy chain variable region, a light chain variable region, or a combination thereof, and purifying the polypeptide comprising a heavy chain variable region, a light chain variable region, or a combination thereof, thereby producing a polypeptide. In some embodiments, the host cell is a host cell as provided herein.

[0364] In some embodiments, a method for producing an antibody or an antigen-binding fragment thereof is provided. In some embodiments, the antibody binds to human α11β1. In some embodiments, the antigen-binding fragment binds to human α11β1. In some embodiments, the method includes cultivating a host cell under conditions such that the host cell expresses one or more polypeptides comprising an immunoglobulin heavy chain variable region and / or an immunoglobulin light chain variable region, thereby producing an antibody or an antigen-binding fragment of the antibody, and purifying the antibody or the antigen-binding fragment of the antibody. In some embodiments, the one or more polypeptides comprise an immunoglobulin heavy chain variable region. In some embodiments, the one or more polypeptides comprise an immunoglobulin light chain variable region. In some embodiments, the one or more polypeptides comprise an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region. In some embodiments, the host cell is a host cell as provided herein. In some embodiments, an antibody or an antigen-binding fragment thereof is as provided herein.

[0365] Providing the nucleotide sequence encoding the antigen-binding region of the chimeric antibody to produce polypeptides or antibody cells can also be produced by transforming non-human (such as primate) cells or human cells. For example, B lymphocytes producing antibodies can be infected and transformed with viruses such as Epstein-Barr virus to obtain cells producing immortal antibodies (Kozbor et al., Immunol. Today 4: 72 79 (1983)). Alternatively, B lymphocytes can be transformed by providing a transforming gene or a transforming gene product, as is well known in the art. See, for example, Ausubel (see below), Harlow (see below) and Colligan (see below), the contents of which are incorporated herein by reference in their entirety. Cell fusion is completed by standard procedures well known to those skilled in the art of immunology, such as producing cells that can also be hybridomas, which are produced by fusing B cells with immortal myeloma cells. Fusion partner cell lines and methods for fusing and selecting hybridomas and screening mAbs are well known in the art. See, e.g., Ausubel (vide infra), Harlow (vide infra), and Colligan (vide infra), the contents of which are incorporated herein by reference in their entireties.

[0366] The nucleic acid sequence encoding the antibodies described herein may be genomic DNA or cDNA, or RNA (e.g., mRNA) encoding at least one of the variable regions described herein. A convenient alternative to using chromosomal gene fragments as a source of DNA encoding V region antigen binding fragments is to use cDNA to construct chimeric immunoglobulin genes, for example, as reported by Liu et al., Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987), which are hereby incorporated by reference in their entirety. The use of cDNA requires gene expression elements suitable for host cells combined with genes to achieve the synthesis of the desired protein. The use of cDNA sequences is superior to genomic sequences (which contain introns) because cDNA sequences can be expressed in bacteria or other hosts lacking a suitable RNA splicing system.

[0367] For example, known methods based on the use of the amino acid sequences provided herein can be used to provide a cDNA encoding a V region antigen binding fragment that can detect, bind or neutralize A11B1. Since the genetic code is degenerate, more than one codon can be used to encode a specific amino acid (Watson et al., see below). Using the genetic code, one or more different oligonucleotides can be identified, each of which can encode an amino acid. In fact, the probability that a specific oligonucleotide constitutes an actual coding sequence can be estimated by considering the frequency of abnormal base pairing relationships and the actual use of specific codons (encoding specific amino acids) in eukaryotic or prokaryotic cells expressing antibodies or fragments. Such "codon usage rules" are disclosed in Lathe et al., J.Molec.Biol.183:1 12 (1985). Using Lathe's "codon usage rules", a single oligonucleotide or a group of oligonucleotides containing the theoretically "most likely" nucleotide sequence that can encode an antibody variable region or constant region sequence is identified.

[0368] The variable regions described herein can be combined with any type of constant region, including human constant regions or mouse constant regions. Human genes encoding constant (C) regions of antibodies, fragments, and regions can be obtained from human fetal liver libraries by known methods. Human C region genes can be derived from any human cell, including cells that express and produce human immunoglobulins. Human C H The C region may be derived from any known class or isotype of human H chain, including γ, μ, α, δ or ε and subtypes thereof, such as G1, G2, G3 and G4. Since the H chain isotype is responsible for various effector functions of antibodies, as well as antibody circulation through interaction with FcRn, the C H The choice of region will be guided by the desired effector function, such as activity in complement fixation or antibody-dependent cellular cytotoxicity (ADCC).H The region is derived from γ1 (IgG1), γ3 (IgG3), γ4 (IgG4) or μ (IgM). L The region may be derived from a human L chain isotype, kappa or lambda.

[0369] Methods for purifying polypeptides or proteins (including antibodies or antigen-binding fragments thereof) are known in the art, and any such methods are within the scope of the present application. In addition, host cells are not limited to the above examples. Any suitable cell can be used to produce polypeptides or proteins of the present disclosure.

[0370] Pharmaceutical composition

[0371] In some embodiments, a pharmaceutical composition is provided. In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof as provided herein.

[0372] In some embodiments, to prepare a pharmaceutical or sterile composition of an anti-α11β1 antibody or other protein provided herein, the antibody or antigen-binding fragment thereof or other protein provided herein is mixed with a pharmaceutically acceptable carrier or excipient. See, for example, "Remington's Pharmaceutical Sciences" and "US Pharmacopeia: National Formulary", Mack Publishing Company, Easton, PA (1984).

[0373] Formulations of the therapeutic agents or antibodies provided herein can be prepared by mixing with an acceptable carrier, excipient or stabilizer in the form of, for example, a lyophilized powder, a slurry, an aqueous solution or a suspension (see, e.g., Hardman et al. (2001), "Goodman and Gilman's The Pharmacological Basis of Therapeutics", McGraw-Hill, New York, NY; Gennaro (2000), "Remington: The Science and Practice of Pharmacy", Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993), "Pharmaceutical Dosage Forms: Parenteral Medications", Marcel Dekker, NY; Lieberman et al. (eds.) (1990), "Pharmaceutical Dosage Forms: Tablets", Marcel Dekker, NY; Lieberman et al. (eds.) (1990), "Pharmaceutical Dosage Forms: Disperse Systems", Marcel Dekker, NY; Weiner and Kotkoskie (2000), "Excipient Toxicity and Safety", Marcel Dekker, Inc., New York, NY). In some embodiments, the antibody is diluted to an appropriate concentration in sodium acetate solution at pH 5-6, and NaCl or sucrose is added to adjust tonicity. Additional agents such as polysorbate 20 or polysorbate 80 may be added to enhance stability.

[0374] Toxicity and therapeutic effects of the antibody compositions, administered alone or in combination with another agent, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, on LD 50 (the dose that is lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index (LD 50 / ED 50). In certain aspects, antibodies that exhibit high therapeutic indices are desired. The data obtained from these cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds is preferably within the range that includes the ED with little or no toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration employed.

[0375] In some embodiments, the composition is administered to a subject in accordance with "Physicians' Desk Reference 2003" (Thomson Healthcare; 57th Edition (November 1, 2002)).

[0376] The mode of administration may vary. Suitable routes of administration include oral, rectal, transmucosal, enteral, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, directly intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal or intraarterial. In some embodiments, the composition is an injectable pharmaceutical composition. In some embodiments, the composition is formulated for intravenous or subcutaneous injection. In some embodiments, the composition is formulated for intravenous injection. In some embodiments, the composition is formulated for subcutaneous injection.

[0377] In some embodiments, the antibody or its antigen-binding fragment can be administered by an invasive route such as by injection. In some embodiments, the antibody or its antigen-binding fragment or its pharmaceutical composition is administered intravenously, subcutaneously, intramuscularly, intraarterially, intraarticularly (e.g., in an arthritic joint), intratumorally, or by inhalation, aerosol delivery. Administration by a non-invasive route (e.g., oral; e.g., in the form of a pill, capsule, or tablet) is also within the scope of the present embodiment.

[0378] In some embodiments, an anti-α11β1 antibody or antigen-binding fragment thereof is administered in combination with at least one additional therapeutic agent, such as, but not limited to, any therapeutic agent for treating a disorder provided herein. In some embodiments, an antibody is administered in combination with another therapeutic agent for a disorder provided herein.

[0379] The compositions can be administered using medical devices known in the art. For example, the pharmaceutical compositions of the invention can be administered by injection using a hypodermic needle (including, for example, a prefilled syringe or an autoinjector).

[0380] The pharmaceutical composition may also be administered using a needle-free subcutaneous injection device; such as the devices disclosed in US Pat. Nos. 6,620,135, 6,096,002, 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556.

[0381] The pharmaceutical composition can also be administered by infusion. Examples of well-known implants and module forms for administering pharmaceutical compositions include: U.S. Pat. No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Pat. No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system with multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0382] Alternatively, one can administer the antibody, usually in the form of a depot or sustained release formulation, in a local rather than systemic manner, for example, by injecting the antibody directly into an arthritic joint or pathogen-induced lesion characterized by immunopathology. In addition, one can administer the antibody in the form of a targeted drug delivery system, for example, in the form of liposomes coated with tissue-specific antibodies, targeting, for example, an arthritic joint or pathogen-induced lesion characterized by immunopathology. These liposomes will be targeted to and selectively taken up by the diseased tissue.

[0383] The administration regimen depends on several factors, including the serum or tissue renewal rate of the therapeutic antibody, the severity of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of target cells in the biomatrix. Preferably, the administration regimen delivers enough therapeutic antibodies to achieve improvement in the target disease state while minimizing undesirable side effects. Therefore, the amount of the delivered biologic depends in part on the severity of the specific therapeutic antibody and the condition being treated. Guidance for selecting appropriate doses of therapeutic antibodies is available (see, e.g., Wawrzynczak (1996), "Antibody Therapy", Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991), "Monoclonal Antibodies, Cytokines and Arthritis", Marcel Dekker, New York, NY; Bach (ed.) (1993), "Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases", Marcel Dekker, New York, NY; Baert et al. (2003), New Engl. J. Med. 348:601-608; Milgrom et al. (1999), New Engl. J. Med. 341: 1966-1973; Slamon et al. (2001), New Engl. J. Med. 344: 783-792; Beniaminovitz et al. (2000), New Engl. J. Med. 342: 613-619; Ghosh et al. (2003), New Engl. J. Med. 348: 24-32; Lipsky et al. (2000), New Engl. J. Med. 343: 1594-1602).

[0384] The determination of the appropriate dosage can be performed by a clinician, for example, using parameters or factors known in the art or suspected of affecting treatment. Generally speaking, the dosage starts with an amount slightly lower than the optimal dosage and is then increased in small increments until the desired or optimal effect is achieved relative to any adverse side effects. Important diagnostic measures include, for example, those for the symptoms of inflammation or the levels of inflammatory cytokines produced. Generally speaking, it is desirable that the biological preparation to be used is derived from the same species as the animal of the targeted therapy, thereby minimizing any immune response to the agent. For example, in the case of a human subject, chimeric antibodies, humanized antibodies, and fully human antibodies may be desirable.

[0385] The antibody or antigen-binding fragment thereof can be provided by continuous infusion or by dosages administered, for example, daily, 1 to 7 times per week, weekly, biweekly, monthly, bimonthly, or quarterly. In some embodiments, the total weekly dose is typically at least 0.05 μg / kg body weight, more typically at least 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / kg, 0.25 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 5.0 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg or more (see, e.g., Yang et al. (2003), New Engl. J. Med. 349:427-434; Herold et al. (2002), New Engl. J. Med. 346:1692-1698; Liu et al. (1999), J. Neurol. Neurosurg. Psych. 67:451-456; Portielji et al. (20003) Cancer Immunol. Immunother. 52: 133-144). Doses may also be provided to achieve a predetermined target concentration of antibody in the subject's serum, such as 0.1 μg / ml, 0.3 μg / ml, 1 μg / ml, 3 μg / ml, 10 μg / ml, 30 μg / ml, 100 μg / ml, 300 μg / ml or higher. In other embodiments, fully human antibodies are administered subcutaneously or intravenously at a dose of 10 mg, 20 mg, 50 mg, 80 mg, 100 mg, 200 mg, 500 mg, 1000 mg or 2500 mg / subject on a weekly, biweekly, "every 4 weeks", monthly, bimonthly or quarterly basis.

[0386] As used herein, "inhibiting" or "treating" or "treating" includes delaying the development of symptoms associated with a disorder and / or reducing the severity of symptoms of such a disorder. These terms also include ameliorating existing uncontrolled or undesirable symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms. Thus, these terms indicate that a beneficial result has been produced in a vertebrate subject having a disorder, disease or symptom or at risk of such a disorder, disease or symptom.

[0387] As used herein, the terms "therapeutically effective amount", "therapeutically effective dose" and "effective amount" refer to an amount that effectively causes a measurable improvement in one or more symptoms of a disease or condition or the progression of such a disease or condition when an antibody or antigen-binding fragment thereof is administered alone or in combination with another therapeutic agent to a cell, tissue or subject. A therapeutically effective dose also refers to an amount of a binding compound sufficient to cause at least a partial improvement in symptoms (e.g., treatment, cure, prevention or improvement of a related medical condition, or to accelerate the rate of treatment, cure, prevention or improvement of such a condition). When applied to a single active ingredient administered alone, a therapeutically effective dose refers only to that ingredient. When applied to a combination, a therapeutically effective dose refers to the combined amount of active ingredients that produces a therapeutic effect, whether administered in combination, sequentially or simultaneously. An effective amount of a therapeutic agent will result in an improvement in a diagnostic measure or parameter of at least 10%; typically at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably at least 50%. In the case where a subjective measure is used to assess the severity of the disease, an effective amount may also result in an improvement in the subjective measure. In some embodiments, an amount is a therapeutically effective amount if it is an amount that can be used to treat or ameliorate a tumor or gastric tumor.

[0388] The term "subject" used throughout the text includes any organism, such as an animal, including mammals (e.g., rats, mice, dogs, cats, rabbits), and for example, humans. In one embodiment, the subject is a human. The subject may also be referred to as a patient. In some embodiments, the subject is a subject in need thereof. A subject in need thereof refers to a subject that has been determined to need treatment of a condition to be treated and is treated for a specific purpose of treating such a condition. These conditions may be, for example, any of the conditions described herein.

[0389] method

[0390] In some embodiments, these methods include administering a therapeutically effective amount or a prophylactically effective amount of one or more antibodies described herein or antigen-binding fragments of these antibodies to a susceptible subject or a subject exhibiting a condition in which the observed pathology is known to be caused by α11β1. Any active form of the antibody may be administered, including but not limited to scFv, Fab and F(ab')2 fragments, and other forms of antibodies provided herein.

[0391] The binding properties of antibodies described herein to α11β1 can be measured by methods known in the art, such as one of the following methods: BIACORE analysis, enzyme-linked immunosorbent assay (ELISA), x-ray crystallography, sequence analysis, and scanning mutagenesis. The binding interactions of antibodies to α11β1 can be analyzed using surface plasmon resonance (SPR). SPR or biomolecular interaction analysis (Biomolecular Interaction Analysis, BIA) detects biospecific interactions in real time without labeling any interaction factors. The mass change at the binding surface of the BIA chip (indicating a binding event) causes a change in the refractive index of light near the surface. The change in refractive index produces a detectable signal, which is measured as an indication of a real-time reaction between biomolecules. Methods for using SPR are described, for example, in U.S. Pat. No. 5,641,640; Raether (1988), Surface Plasmons Springer Verlag; Sjolander and Urbaniczky (1991), Anal. Chem. 63:2338-2345; Szabo et al. (1995), Curr. Opin. Struct. Biol. 5:699-705, and online resources provided by BIAcore International AB (Uppsala, Sweden). Alternatively, Sapidyne Instruments (Boise, Id.) may be used. (Kinetic Exclusion Assay) assay.

[0392] Information from SPR can be used to provide the equilibrium dissociation constant (K) for antibody binding to α11β1. D ) and kinetic parameters (including K on and K off SPR can be used to accurately and quantitatively measure the binding activity of a given site. Such data can be used to compare different molecules. Information from SPR can also be used to generate structure-activity relationships (SAR). Variant amino acids associated with specific binding parameters (e.g., high affinity) at a given site can be identified.

[0393] In certain embodiments, the antibodies described herein exhibit high affinity for binding to α11β1. In various embodiments, the K of the antibodies described herein against α11β1 is D Less than about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10-10 M, 10 -11 M, 10 -12 M, 10 -13 M, 10 -14 M or 10 -15 M. In some cases, the K of an antibody as described herein directed against α11β1 D It is 0.001 nM to 1 nM, for example 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM or 1 nM.

[0394] In some embodiments, the use of an antibody or antigen binding fragment as provided herein or a pharmaceutical composition as provided herein is provided. In some embodiments, the use is for treating α11β1-mediated conditions. In some embodiments, the use of an antibody or antigen binding fragment as provided herein is provided, and the use is used to treat α11β1-mediated conditions. In some embodiments, the use of a pharmaceutical composition comprising an antibody or antigen binding fragment as provided herein is provided, and the use is used to treat Α11Β1a-mediated conditions. In some embodiments, the pharmaceutical composition is as provided herein. The antibody or pharmaceutical composition of any one of these embodiments inhibits complement α11β1 activity in an individual suffering from a complement-mediated disease or condition.

[0395] The present disclosure provides the use of an anti-α11β1 antibody or a pharmaceutical composition thereof according to any of these embodiments in the preparation of a medicament for inhibiting complement α11β1 activity. In some embodiments, the present disclosure provides the use of an anti-α11β1 antibody or a pharmaceutical composition thereof according to any of these embodiments in the preparation of a medicament for inhibiting complement α11β1 activity in an individual suffering from an α11β1-mediated disease or condition.

[0396] The present disclosure provides an anti-α11β1 antibody or a pharmaceutical composition thereof according to any of these embodiments for use in medical therapy.

[0397] Treatment of an individual may include administering a therapeutically effective amount of an antibody as described herein. The antibody may be provided in a kit, such as those provided herein. The antibody may be used or administered alone, or mixed with another therapeutic agent, analgesic, or diagnostic agent (such as provided herein) for use or administration. When providing an antibody or fragment thereof capable of binding to α11β1 or an antibody capable of protecting a recipient patient from α11β1, the dosage of the administered agent will vary according to factors such as the patient's age, weight, height, sex, general medical condition, and previous medical history.

[0398] Antibodies capable of treating conditions associated with α11β1 activity or for treating α11β1-associated pathologies are intended to be provided to a subject in an amount sufficient to achieve reduction, regression or amelioration of α11β1-associated symptoms or pathologies. Examples of such pathologies are provided herein.

[0399] Thus, in some embodiments, a method of treating a subject suffering from an α11β1-mediated disorder is provided. In some embodiments, the method comprises administering a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as provided herein. In some embodiments, the disorder is as provided herein.

[0400] As provided herein, antibodies or antigen-binding fragments thereof can be administered together with other therapeutic agents. These antibodies or antigen-binding fragments thereof and other therapeutic agents can be administered simultaneously or sequentially.

[0401] Also provided are kits that can be used to implement the embodiments described herein. The kit of the present invention may include a first container that contains or is packaged with the above-mentioned antibodies. The kit may also include another container that contains or is packaged with solutions necessary or applicable to implement these embodiments. The container may be made of glass, plastic, or foil, and may be a vial, bottle, pouch, tube, bag, etc. The kit may also include written information, such as procedural or analytical information for implementing these embodiments, such as the amount of reagents contained in the first container device. The container may be placed in another container device (e.g., a box or bag) together with the written information.

[0402] In some embodiments, antibodies that bind to α11β1 protein are provided. In some embodiments, the antibody is an antibody or antigen-binding fragment as provided herein. In some embodiments, the antibody or antigen-binding fragment comprises an amino acid sequence as provided herein or a variant thereof as provided herein. In some embodiments, the antibody is alone. In some embodiments, the antibody specifically binds to an active form of α11β1.

[0403] In some embodiments, the antibody inhibits or neutralizes the function of the active form of the α11β1 protein. As used herein, the term "neutralize" means that the activity or function of the protein is inhibited. The inhibition can be complete or partial. In some embodiments, the activity or function of the protein is inhibited by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%. The inhibition percentage can be based on the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits the function promoted by α11β1.

[0404] In some embodiments, one or more anti-α11β1 antibodies described herein are used in a method of treating one or more disorders described herein. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof described herein.

[0405] In some embodiments, one or more anti-α11β1 antibodies described herein are used in methods for treating fibrotic disorders. Fibrosis is a scarring process that manifests itself in many tissues in the body, usually as a result of inflammation or tissue damage. Increased production of extracellular matrix leads to organ failure and often death. In industrialized countries, diseases associated with fibrosis account for about 45% of all deaths (Wynn, TA, 2008, J Pathol. 214: 199-210). The cells responsible for producing extracellular matrix (ECM) for tissue repair (and fibrosis) are specialized types of fibroblasts called myofibroblasts (MF). Although the mechanisms of fibrosis have been extensively studied, this complex process is not yet fully understood. In order to focus on the most important drivers of fibrosis, a new data analysis method derived internally was used to interrogate a publicly available patient-derived data set (SSc patient data and normal controls). This analysis led to the identification of type I collagen-binding integrin α11β1 as one of the main targets for regulating fibrosis.

[0406] In some embodiments, the fibrotic disorder is or includes idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis (SSc). In some embodiments, the fibrotic disorder is or includes atrial fibrosis, endomyocardial fibrosis, arthrofibrosis, intramediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

[0407] In some embodiments, the fibrotic disorder is or includes idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis. In some embodiments, the fibrotic disorder is or includes atrial fibrosis, endomyocardial fibrosis, arthrofibrosis, intramediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

[0408] In some embodiments, the anti-α11β1 antibodies described herein reduce one or more markers, signs and / or symptoms of kidney-related disorders described herein after administration to a subject. Markers, signs and / or symptoms of kidney-related disorders include, for example, COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF and MMP9. In some embodiments, following administration to a subject, an anti-α11β1 antibody may reduce a measured marker, sign, and / or symptom by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% relative to a control (e.g., the level of a marker, sign, and / or symptom measured in a subject prior to administration of the antibody, the level of a marker, sign, and / or symptom measured in a subject with a kidney-related disorder, and / or the average level of a marker, sign, and / or symptom measured in a population of subjects with a kidney-related disorder).

[0409] In some embodiments, the anti-α11β1 described herein reduces the level of COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, MMP9, or a combination thereof by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, relative to a control, as measured in a kidney-related disorder model (e.g., human precision kidney slices (PCKS), ReninAAV Unx db / db mouse model, or 5 / 6 nephrectomy model). In some embodiments, markers, signs, and / or symptoms of kidney-related disorders can be determined by measuring protein levels, RNA levels, DNA levels, or a combination thereof. In some embodiments, markers, signs and / or symptoms of kidney-related disorders may be determined using ELISA, PCR, RNAseq, biochemical assays (e.g., analytical procedures that detect and quantify cellular processes (e.g., apoptosis, cell signaling) or metabolic reactions), cytology, immunohistochemistry, or a combination thereof.

[0410] In some embodiments, the markers, signs and / or symptoms of kidney-related disorders can be measured by testing biological samples from subjects. Examples of suitable biological samples include, but are not limited to, serum, plasma, cerebrospinal fluid, urine, circulating blood cells (e.g., peripheral blood mononuclear cells) and biopsy specimens. In some embodiments, the sample comprises cells or tissues. In some embodiments, the method provided also includes the step of lysing cells or performing a tissue biopsy, and one or more markers include one or more intracellular markers. Biological samples suitable for the present disclosure can be fresh or frozen samples collected from subjects, or samples with known diagnosis, treatment and / or result resume. Biological samples can be collected by any invasive or non-invasive means, such as by extracting CSF or blood from subjects, or using fine needle aspiration or needle puncture biopsy, or by surgical biopsy. In some embodiments, biological samples can be used without or with limited sample processing.

[0411] In some embodiments, the anti-α11β1 antibodies described herein can be used to promote the catabolism and clearance of pathogenic antibodies (e.g., IgG and IgG autoantibodies) in the subject after administration to the subject, reduce the immune response, such as blocking the activation of immune responses based on immune complexes in the subject, and treat the immunological conditions or diseases of the subject. Specifically, the anti-α11β1 antibodies described herein can be used to reduce or treat acute or chronic immune response activation based on immune complexes. The acute immune response can be activated by a medical condition selected from the following items: pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barre syndrome, antibody-mediated rejection, catastrophic antiphospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulitis, ion channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), immune neutropenia, dilated cardiomyopathy and serum sickness. The chronic immune response may be activated by a medical condition selected from the group consisting of chronic inflammatory demyelinating polyneuropathy (CIDP), systemic lupus, chronic forms of the condition suitable for acute treatment, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA).

[0412] In some embodiments, the anti-α11β1 antibodies described herein can be used to reduce or treat an immune response activated by an autoimmune disease. The autoimmune disorder can be selected from alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Schwartz syndrome, cicatricial pemphigoid, localized scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune Lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff-man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, or Wegener's granulomatosis. In some embodiments, the anti-α11β1 antibodies described herein can be used to reduce or treat an immune response activated by systemic lupus erythematosus, antiphospholipid syndrome, pemphigus vulgaris / bullous pemphigoid, vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), myasthenia gravis, or neuromyelitis optica.

[0413] In some embodiments, the anti-α11β1 antibodies described herein can be used to reduce or treat inflammatory diseases or conditions. In some embodiments, the inflammatory disease or condition is also an autoimmune disease or condition as described herein. In some embodiments, the inflammatory disease or condition includes hidradenitis suppurativa, also known as acne inverse or Verneuil's disease.

[0414] A clinical feature of the tumor microenvironment is the interaction between the tumor and the stroma, which mainly depends on various integrins that interact with ECM components and growth factors. Such interactions can affect tumor survival, progression, and ultimately metastasis. It has been reported that α11β1 is overexpressed in cancer-associated fibroblasts (CAFs) of metastatic tumors, and its expression has been associated with invasive tumors in patients. For example, integrin al 1 is overexpressed in the stroma of most head and neck squamous cell carcinomas (HNSCCs) and is positively correlated with the expression of α smooth muscle actin (Parajuli et al., J. Oral Pathol. Med. 46: 267-275 (2017)). Integrin al 1 is also overexpressed by CAFs in the stroma of pancreatic ductal adenocarcinoma (Pancreatic Ductal Adenocarcinoma, PDAC) (Schnittert et al., FASEB J. 33: 6609-6621 (2019)). Furthermore, integrin α11β1 overexpression in the tumor stroma has been associated with tumor growth and metastatic potential of non-small cell lung cancer (NSCLC), and high expression of ITGA11 (the gene encoding integrin α-11 in humans) is associated with lower recurrence-free survival in all NSCLC patients; the same study showed that α11β1 overexpression in lung cancer cell lines led to increased migration and invasion (Ando et al., Cancer Sci. Ill:200-208 (2020)).

[0415] Thus, in some embodiments, one or more anti-α11β1 antibodies described herein are used in a method of treating cancer, such as one or more of the following: head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, non-small cell lung cancer, adrenocortical carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, invasive breast cancer, cervical squamous cell carcinoma, bile duct carcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, glioblastoma multiforme, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, skin melanoma, mesothelioma, ovarian serous cystadenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, sarcoma, gastric adenocarcinoma, testicular germ cell tumor, thymoma, thyroid cancer, uterine corpus endometrial carcinoma, uterine carcinosarcoma, uveal melanoma, renal clear cell carcinoma, renal chromophobe cell carcinoma, and renal papillary cell carcinoma.

[0416] In some embodiments, the anti-α11β1 antibodies described herein are administered in combination with one or more additional therape...

Claims

1. An antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising a heavy chain HCDR1, HCDR2 and HCDR3 sequence or a variant of any of the foregoing sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 1; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 2; and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2 and LCDR3 sequences or a variant of any one of the foregoing sequences, wherein the light chain LCDR1 sequence has the amino acid sequence of SEQ ID NO: 16; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO: 17; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO:

18.

2. The antibody or antigen-binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to or identical to SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14 or SEQ ID NO:15, provided that the heavy chain variable region comprises the sequences of HCDR1, HCDR2 and HCDR3 of claim 1.

3. The antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the light chain variable region comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 or SEQ ID NO: 22, provided that the light chain variable region comprises the sequences of LCDR1, LCDR2 and LCDR3 according to claim 1.

4. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 11, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:21, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

5. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:4, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:1, HCDR2 of SEQ ID NO:2 and HCDR3 of SEQ ID NO:3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:22, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

6. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:4, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:1, HCDR2 of SEQ ID NO:2 and HCDR3 of SEQ ID NO:3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:21, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

7. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 10, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:22, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

8. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity or identical to SEQ ID NO:9, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:1, HCDR2 of SEQ ID NO:2 and HCDR3 of SEQ ID NO:3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:21, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

9. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity or identical to SEQ ID NO: 14, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:22, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

10. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity or identical to SEQ ID NO: 13, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:21, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

11. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity or identical to SEQ ID NO: 12, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:21, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:16, LCDR2 of SEQ ID NO:17 and LCDR3 of SEQ ID NO:

18.

12. An antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising a heavy chain HCDR1, HCDR2 and HCDR3 sequence, or a variant of any of the foregoing sequences, wherein the heavy chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 23; the heavy chain HCDR2 has the amino acid sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 29; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2 and LCDR3 sequences or a variant of any one of the foregoing sequences, wherein the light chain LCDR1 sequence has the amino acid sequence of SEQ ID NO:34; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO:35; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO:

36.

13. The antibody or antigen-binding fragment thereof according to claim 12, wherein the HCDR2 is SEQ ID NO: 24, and the HCDR3 is SEQ ID NO:

28. 14 . The antibody or antigen-binding fragment thereof according to claim 12 , wherein the HCDR2 is SEQ ID NO: 24, and the HCDR3 is SEQ ID NO:

29.

15. The antibody or antigen-binding fragment thereof according to claim 12, wherein the HCDR2 is SEQ ID NO: 25, and the HCDR3 is SEQ ID NO:

28.

16. The antibody or antigen-binding fragment thereof according to claim 12, wherein the HCDR2 is SEQ ID NO: 25, and the HCDR3 is SEQ ID NO:

29.

17. The antibody or antigen-binding fragment thereof according to claim 12, wherein the HCDR2 is SEQ ID NO: 26, and the HCDR3 is SEQ ID NO:

28.

18. The antibody or antigen-binding fragment thereof according to claim 12, wherein the HCDR2 is SEQ ID NO: 26, and the HCDR3 is SEQ ID NO:

29.

19. The antibody or antigen-binding fragment thereof according to claim 12, wherein the HCDR2 is SEQ ID NO: 27, and the HCDR3 is SEQ ID NO:

28.

20. The antibody or antigen-binding fragment thereof according to claim 12, wherein the HCDR2 is SEQ ID NO: 27, and the HCDR3 is SEQ ID NO:

29.

21. The antibody or antigen-binding fragment thereof according to any one of claims 12 to 20, wherein the heavy chain variable region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32 or SEQ ID NO: 33, provided that the heavy chain variable region comprises the sequences of HCDR1, HCDR2 and HCDR3 according to claim 12.

22. The antibody or antigen-binding fragment thereof according to any one of claims 12 to 21, wherein the light chain variable region comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 37, provided that the light chain variable region comprises the sequences of LCDR1, LCDR2 and LCDR3 according to claim 12.

23. The antibody or antigen-binding fragment thereof according to any one of claims 12 to 22, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:30, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24 and HCDR3 of SEQ ID NO:28; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:37, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:34, LCDR2 of SEQ ID NO:35 and LCDR3 of SEQ ID NO:

36.

24. The antibody or antigen-binding fragment thereof according to any one of claims 12 to 22, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:31, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:25 and HCDR3 of SEQ ID NO:28; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:37, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:34, LCDR2 of SEQ ID NO:35 and LCDR3 of SEQ ID NO:

36.

25. The antibody or antigen-binding fragment thereof according to any one of claims 12 to 22, comprising: (i) a heavy chain variable region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO: 33, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 27 and HCDR3 of SEQ ID NO: 28; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:37, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:34, LCDR2 of SEQ ID NO:35 and LCDR3 of SEQ ID NO:

36.

26. An antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising a heavy chain HCDR1, HCDR2 and HCDR3 sequence, or a variant of any of the foregoing sequences, wherein the heavy chain HCDR1 sequence has an amino acid sequence of SEQ ID NO: 38, SEQ ID NO: 39 or SEQ ID NO: 40; and the heavy chain HCDR2 has an amino acid sequence of SEQ ID NO: 41 or SEQ ID NO: 42; and the heavy chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 43; and (ii) a light chain variable region comprising light chain LCDR1, LCDR2 and LCDR3 sequences or a variant of any one of the foregoing sequences, wherein the light chain LCDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain LCDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain LCDR3 sequence has the amino acid sequence of SEQ ID NO:

60.

27. The antibody or antigen-binding fragment thereof according to claim 26, wherein the HCDR1 is SEQ ID NO: 38 and the HCDR2 is SEQ ID NO:

41.

28. The antibody or antigen-binding fragment thereof according to claim 26, wherein the HCDR1 is SEQ ID NO: 38 and the HCDR2 is SEQ ID NO:

42.

29. The antibody or antigen-binding fragment thereof according to claim 26, wherein the HCDR1 is SEQ ID NO: 39, and the HCDR2 is SEQ ID NO:

41.

30. The antibody or antigen-binding fragment thereof according to claim 26, wherein the HCDR1 is SEQ ID NO: 39 and the HCDR2 is SEQ ID NO:

42.

31. The antibody or antigen-binding fragment thereof according to claim 26, wherein the HCDR1 is SEQ ID NO: 40 and the HCDR2 is SEQ ID NO:

41.

32. The antibody or antigen-binding fragment thereof of claim 26, wherein the HCDR1 is SEQ ID NO: 40 and the HCDR2 is SEQ ID NO:

42.

33. The antibody or antigen-binding fragment thereof of any one of claims 26 to 32, wherein the heavy chain variable region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56 or SEQ ID NO:57, provided that the heavy chain variable region comprises the sequences of HCDR1, HCDR2 and HCDR3 according to claim 26.

34. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 33, wherein the light chain variable region comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 61 or SEQ ID NO: 62, provided that the light chain variable region comprises the sequences of LCDR1, LCDR2 and LCDR3 according to claim 26.

35. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:52, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:39, HCDR2 of SEQ ID NO:42, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

36. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:49, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:39, HCDR2 of SEQ ID NO:42, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

37. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:50, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:39, HCDR2 of SEQ ID NO:42, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

38. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:56, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:40, HCDR2 of SEQ ID NO:41, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

39. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:45, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:38, HCDR2 of SEQ ID NO:41, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

40. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:53, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:40, HCDR2 of SEQ ID NO:41, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

41. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) a heavy chain variable region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:47, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:38, HCDR2 of SEQ ID NO:41, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

42. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:55, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:40, HCDR2 of SEQ ID NO:41, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

43. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) comprising a heavy chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:46, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:38, HCDR2 of SEQ ID NO:41, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

44. The antibody or antigen-binding fragment thereof according to any one of claims 26 to 34, comprising: (i) a heavy chain variable region comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:54, provided that the heavy chain variable region comprises HCDR1 of SEQ ID NO:40, HCDR2 of SEQ ID NO:41, and HCDR3 of SEQ ID NO:43; and (ii) comprising a light chain variable region that has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical or identical to SEQ ID NO:61, provided that the light chain variable region comprises LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

45. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is a scFv antibody, a Fab fragment, a Fab' fragment or a F(ab')2 fragment.

46. ​​The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody is a monoclonal antibody.

47. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody is a humanized antibody.

48. The antibody or antigen binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof comprises a constant region such as provided herein.

49. The antibody or antigen-binding fragment thereof of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a constant region comprising the amino acid sequence of SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68 or SEQ ID NO:

69.

50. The antibody or antigen-binding fragment thereof of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 63 and a light chain constant region comprising the amino acid sequence of SEQ ID NO:

69.

51. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the heavy chain variable region and the light chain variable region are not connected by a linker.

52. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the heavy chain variable region and the light chain variable region are connected with a peptide linker.

53. The antibody or antigen-binding fragment thereof of claim 52, wherein the peptide linker comprises the sequence of: (GGGGS) n (SEQ ID NO:70); (GGGGA) n (SEQ ID NO: 71) or any combination thereof, wherein each n is independently 1 to 5.

54. A recombinant antibody or antigen-binding fragment thereof that binds to human α11β1 integrin, wherein the antibody or antigen-binding fragment thereof comprises an amino acid sequence as provided herein or a variant thereof, or an amino acid sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence.

55. An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, heavy chain variable region, light chain variable region, heavy chain or light chain according to any one of the preceding claims.

56. An expression vector comprising the nucleic acid molecule according to claim 55.

57. A host cell comprising the nucleic acid molecule according to claim 55 or the vector according to claim 56.

58. An antibody or antigen-binding fragment produced by the host cell of claim 57.

59. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 54.

60. The pharmaceutical composition of claim 59, wherein the composition is formulated for intravenous or subcutaneous injection.

61. The pharmaceutical composition of claim 59, wherein the composition is an injectable pharmaceutical composition.

62. A method for producing a polypeptide comprising a heavy chain variable region and / or a light chain variable region, the method comprising: (a) cultivating or culturing the host cell according to claim 57 under conditions such that the host cell expresses a polypeptide comprising the heavy chain variable region and / or the light chain variable region; and (b) purifying the polypeptide comprising the heavy chain variable region and / or the light chain variable region.

63. A method for producing an antibody or an antigen-binding fragment thereof that binds to human α11β1 integrin, the method comprising: (a) cultivating or culturing the host cell according to claim 57 under conditions such that the host cell expresses one or more polypeptides comprising an immunoglobulin heavy chain variable region and / or an immunoglobulin light chain variable region, thereby producing the antibody or the antigen-binding fragment of the antibody; as well as (b) purifying the antibody or antigen-binding fragment thereof.

64. A method of treating a subject suffering from an α11β1 integrin-mediated disorder, the method comprising administering to the subject the antibody or antigen-binding fragment thereof according to any one of claims 1 to 54 or the pharmaceutical composition according to any one of claims 59 to 61.

65. The method of claim 64, wherein the disorder is a fibrotic disorder, an autoimmune disorder, an inflammatory disorder, or cancer.

66. The method of claim 65, wherein the fibrotic disorder is or comprises idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis. In some embodiments, the fibrotic disorder is or comprises atrial fibrosis, endomyocardial fibrosis, arthrofibrosis, mediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

67. The method of claim 65, wherein the autoimmune disorder is or comprises alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism , inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff-man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, or Wegener's granulomatosis.

68. The method of claim 65, wherein the inflammatory disorder is hidradenitis suppurativa.

69. The method of claim 65, wherein the cancer is or comprises squamous cell carcinoma of the head and neck, pancreatic ductal adenocarcinoma, non-small cell lung cancer, adrenocortical carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, invasive breast cancer, cervical squamous cell carcinoma, bile duct carcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, glioblastoma multiforme, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, skin melanoma, mesothelioma, ovarian serous cystadenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, sarcoma, gastric adenocarcinoma, testicular germ cell tumor, thymoma, thyroid cancer, uterine corpus endometrial carcinoma, uterine carcinosarcoma, uveal melanoma, renal clear cell carcinoma, renal chromophobe cell carcinoma, or renal papillary cell carcinoma 70. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 54 or the pharmaceutical composition according to any one of claims 59 to 61 for use in treating an α11β1 integrin-mediated disorder such as provided herein.

71. An antibody or binding fragment thereof according to any one of claims 1 to 54 or a pharmaceutical composition according to any one of claims 59 to 61 for use as a medicament.

72. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 54 or a pharmaceutical composition according to any one of claims 59 to 61 for treating an α11β1 integrin-mediated disorder such as provided herein.

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