Antibodies against integrin alpha11 beta1 and uses thereof

Abstract

Embodiments provided herein relate to antibodies and compositions that bind to α11β1. Also provided are methods of producing the antibodies of the disclosure, and uses of the provided antibodies and compositions for the treatment of α11β1-mediated diseases and α11β1-mediated disorders.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 366,881, filed on June 22, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] (Sequence Listing) This application includes a sequence listing that has been electronically submitted in XML file format, the entire disclosure of which is incorporated herein by reference. The XML file has a title of 258199_010202_SL.xml, was created on June 22, 2023, and is 312,715 bytes in size.

[0003] (Field) The field of the present invention is immunology, particularly therapeutic antibodies and the treatment of diseases with such antibodies.

[0004] (Background) Fibrosis is typically a scarring process that appears in many tissues in the body as a result of inflammation or tissue damage. One such disease associated with inflammation and fibrosis is rheumatoid arthritis (RA). RA is typically a chronic autoimmune disease associated with inflammation of joints, particularly the small joints of the hands, wrists, and feet. As the disease progresses, continuous inflammation causes loss of joint mobility and eventually deformation. Furthermore, RA can affect other organs of the body, which may include the lungs, causing pulmonary fibrosis and scarring of lung tissue. Compositions for treating RA, as well as other fibroses, inflammations, and autoimmune diseases listed herein, are disclosed herein.

[0005] (Summary) In some embodiments, an antibody or antigen-binding fragment thereof comprises: (i) a heavy-chain variable region comprising a heavy-chain HCDR1 sequence, a heavy-chain HCDR2 sequence, and a heavy-chain HCDR3 sequence, 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, the heavy-chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 3, or a variant of any of the foregoing; and (ii) a light-chain variable region comprising a light-chain LCDR1 sequence, a light-chain LCDR2 sequence, and a light-chain LCDR3 sequence, 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, the light-chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 18, or a variant of any of the foregoing. An antibody or antigen-binding fragment thereof is provided.

[0006] In some embodiments, an antibody or antigen-binding fragment thereof comprises: (i) a heavy-chain variable region comprising a heavy-chain HCDR1 sequence, a heavy-chain HCDR2 sequence, and a heavy-chain HCDR3 sequence, 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, the heavy-chain HCDR3 sequence has the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 29, or a variant of any of the foregoing; and (ii) a light-chain variable region comprising a light-chain LCDR1 sequence, a light-chain LCDR2 sequence, and a light-chain LCDR3 sequence, 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, the light-chain LCDR3 sequence has the amino acid sequence of SEQ ID NO: 36, or a variant of any of the foregoing. An antibody or antigen-binding fragment thereof is provided.

[0007] In some embodiments, an antibody or antigen-binding fragment thereof comprises: (i) a heavy-chain variable region comprising a heavy-chain HCDR1 sequence, a heavy-chain HCDR2 sequence, and a heavy-chain HCDR3 sequence, wherein the heavy-chain HCDR1 sequence has the amino acid sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, the heavy-chain HCDR2 has the 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, or a variant of any of the foregoing; and (ii) a light-chain variable region comprising a light-chain LCDR1 sequence, a light-chain LCDR2 sequence, and a light-chain LCDR3 sequence, 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 LCDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or a variant of any of the foregoing. In some embodiments, the antibody or antigen-binding fragment thereof provided herein is or comprises an scFv antibody, a Fab fragment, a Fab’ fragment, or an F(ab’)2 fragment. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized antibody.

[0008] 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.

[0009] In some embodiments, provided is a method for producing a polypeptide comprising a heavy-chain variable region and / or a light-chain variable region, the method comprising: (a) growing a host cell comprising a polypeptide encoding an antibody provided herein under conditions such that the host cell expresses a polypeptide comprising a heavy-chain variable region or a light-chain variable region; and (b) purifying the polypeptide comprising a heavy-chain variable region and / or a light-chain variable region.

[0010] In some embodiments, a method of producing an antibody that binds to human α11β1 integrin or an antigen-binding fragment thereof, comprising: (a) growing a host cell comprising a polypeptide encoding an antibody provided herein under conditions such that the host cell expresses a polypeptide(s) 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 (b) purifying the antibody or an antigen-binding fragment thereof.

[0011] In some embodiments, a method of treating a subject having an α11β1-mediated disorder, comprising administering to the subject an antibody or an 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

[0012]

Figure 1-1

Figure 1-2

Figure 1-3

Figure 2A

Figure 2B

Figure 2C

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 4C

Figure 5A

Figure 5B

Figure 6A

Figure 6B

Figure 7A

Figure 7B

Figure 8

[0013] (Detailed description) Provided herein are binding proteins, such as antibodies or fragments thereof, that selectively bind to the type I collagen receptor integrin alpha11 beta1 (α11β1). Also provided herein are nucleic acids encoding antibodies and antibody fragments that bind to α11β1, and methods of treating fibrosis and other diseases disclosed herein using the antibodies and antibody fragments.

[0014] Before describing the compositions and methods, it should be understood that, just as the specific processes, compositions, or methodologies described herein may vary, the scope of the invention is not limited thereto. It should also be understood that the terms used in the description are used only for the purpose of describing a particular type or embodiment and are not intended to limit the scope of the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In practicing or testing the embodiments of the methods and systems disclosed herein, any methods and materials similar or equivalent to those described herein can be used, but the preferred methods, devices, and materials are described below.

[0015] The following explanations regarding terms and methods are provided to more clearly describe the present disclosure and to provide guidance to those skilled in the art in practicing the present disclosure.

[0016] As used herein, "comprising" means "including", and the singular forms "a", "an", or "the" include references to the plural unless the context clearly dictates otherwise. For example, when referring to "a therapeutic agent", one or more such therapeutic agents are included. The term "or" refers to a single one of the recited alternative elements unless the context clearly dictates otherwise. For example, the phrase "A or B" refers to A alone or B alone. The phrase "A, B, or a combination thereof" refers to A alone, B alone, or a combination of A and B. Similarly, "one or more of A and B" refers to A, B, or a combination of both A and B. The phrase "A and B" refers to a combination of A and B. Further, the various elements, features, and steps discussed herein, as well as other known equivalents of such elements, features, or steps, can be mixed and adapted by those skilled in the art to practice the method in accordance with the principles described herein. Among the various elements, features, and steps, in certain instances, some are specifically included and some are specifically excluded.

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure, the preferred methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications cited herein are incorporated by reference in their entirety.

[0018] As used herein, unless otherwise specified, the term "about" is intended to mean ±5% of the value it modifies. Thus, about 100 means 95 - 105.

[0019] As used herein, the term "antibody" refers to any form of antibody that exhibits the desired biological activity. Thus, the term is used in its broadest sense and specifically includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies, and camelized single domain antibodies. A "parent antibody" is an antibody obtained by exposing the immune system to an antigen prior to modification of the antibody for the intended use, such as humanization of an antibody for use as a human therapeutic antibody.

[0020] As used herein, unless otherwise specified, an "antibody fragment" or "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., a fragment that retains the ability to specifically bind to an antigen to which the full-length antibody binds, e.g., a fragment that retains one or more CDR regions. Examples of antibody-binding fragments include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, such as sc-Fv; nanobodies (single domain antibodies) formed from antibody fragments, and multispecific antibodies.

[0021] An "Fab fragment" consists of one light chain and the C H 1 and variable regions of one heavy chain. The heavy chain of an Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0022] The "Fc" region contains two heavy chain fragments, including the C H 2 domain and the C H 3 domain. The two heavy chain fragments are joined by two or more disulfide bonds and by hydrophobic interactions between the C H 3 domains.

[0023] An "Fab'" fragment contains one light chain and a portion or fragment of one heavy chain that includes the V H domain and the C H 1 domain, and further, the CH 1 domain and H also includes the region between the 2 domains, so that an inter-chain disulfide bond can be formed between the two heavy chains of the two Fab’ fragments to form an F(ab’)2 molecule.

[0024] “F(ab’)2 fragment” consists of two light chains and two heavy chains including a part of the constant region between the C H 1 domain and the C H 2 domain, so that an inter-chain disulfide bond is formed between the two heavy chains. Therefore, the F(ab’)2 fragment consists of two Fab’ fragments linked by a disulfide bond between the two heavy chains.

[0025] “Fv region” includes the variable regions derived from both the heavy chain and the light chain, but lacks the constant region.

[0026] The term “single-chain Fv” or “scFv” antibody refers to an antibody fragment that includes the V H domain and the V L domain, and these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further includes a polypeptide linker between the V H domain and the V L domain that enables the scFv to form the desired structure for antigen binding. For an overview of scFv, see Pluckthun (1994) The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds. Springer-Verlag, New York, pp. 269-315. See also International Publication No. 88 / 01649, as well as U.S. Patent Nos. 4,946,778 and 5,260,203.

[0027] “Single-domain antibody” is an immunologically functional immunoglobulin fragment that includes only the variable region of the heavy chain or the variable region of the light chain. In some examples, two or more V HLink the domains with a peptide linker to create a bivalent domain antibody. The two V H domains of the bivalent domain antibody can target the same antigen or different antigens.

[0028] A "bivalent antibody" contains two antigen-binding sites. In some examples, the two binding sites have the same antigen specificity. However, the bivalent antibody may be bispecific (see below).

[0029] 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; International Publication No. 94 / 04678; International Publication No. 94 / 25591; U.S. Patent No. 6,005,079). In one embodiment, the invention provides a single-domain antibody comprising two V H domains having modifications such that a single-domain antibody is formed.

[0030] As used herein, the term "diabody" refers to a small antibody fragment having two antigen-binding sites, the fragment comprising a heavy-chain variable domain (V L ) linked to a light-chain variable domain (V H ) in the same polypeptide chain (V H -V L or V L -V H) By using a short linker such that no pairing occurs between two domains on the same chain, the domains are paired with complementary domains on another chain to create two antigen-binding sites. For diabodies, see, for example, European Patent No. 404,097; International Publication No. 93 / 11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448 for more details. For an overview of engineered antibody variants, generally see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136.

[0031] Typically, the variant antibodies or antigen-binding fragments of the antibodies provided herein retain at least 10% of their A11B1s binding activity (compared to the modified parental antibody) when expressed on a molar basis. In some embodiments, the variant antibodies (or antigen fragments thereof) or antigen-binding fragments of the antibodies provided herein retain at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the A11B1s binding affinity of the parental antibody. As described herein, it is also contemplated that the antibodies or antigen-binding fragments of the invention may include conservative or non-conservative amino acid substitutions, which may also be referred to as "conservative variants" or "functionally conservative variants" of the antibody and which do not substantially alter its biological activity.

[0032] "Isolated antibody" refers to the purified state of the binding compound, and in such context, it means that the molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, etc., and other substances such as cell debris and growth medium. Generally, the term "isolated" is not intended to mean that such substances are absent altogether or that there is no water, buffer or salt present, provided that they are not present in an amount that substantially interferes with the experimental or therapeutic use of the binding compound described herein.

[0033] As used herein, the term "monoclonal antibody" refers to a substantially homogeneous population of antibodies, i.e., the antibody molecules that make up the population are identical in amino acid sequence except for natural mutations and / or post-translational modifications that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically contain a number of different antibodies that often have different amino acid sequences in their variable domains, particularly their CDRs, which are specific for different epitopes. The modifier "monoclonal" indicates the characteristics of an antibody obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the production of an antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using, for example, the techniques described in 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.

[0034] As used herein, a "chimeric antibody" is an antibody having variable domains derived from a first antibody and constant domains derived from a second antibody, where the first antibody and the second antibody are from different species. (See 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 an antibody from an experimental animal such as a rodent ("parent antibody"), and the constant domain sequence is obtained from a human antibody, such that the resulting chimeric antibody is less likely to induce an immune response harmful to a human subject than the parent antibody (e.g., a rodent antibody).

[0035] As used herein, the term "humanized antibody" refers to an antibody in a form that contains sequences derived from both human antibodies and non-human (e.g., mouse, rat) antibodies. Generally, a humanized antibody will substantially comprise at least one, typically two, entire variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. A humanized antibody may optionally include at least a portion of a human immunoglobulin constant region (Fc).

[0036] The term "fully human antibody" refers to an antibody that contains only human immunoglobulin protein sequences. A fully human antibody may contain mouse sugar chains when produced in a mouse, in mouse cells, or in a hybridoma derived from mouse cells. Similarly, a "mouse antibody" refers to an antibody that contains only mouse immunoglobulin sequences. Alternatively, a fully human antibody may contain rat sugar chains when produced in a rat, in rat cells, or in a hybridoma derived from rat cells. Similarly, a "rat antibody" refers to an antibody that contains only rat immunoglobulin sequences.

[0037] In some embodiments, the basic antibody structural unit comprises a tetramer. Each tetramer comprises two pairs of identical polypeptide chains, and each pair has one "light" chain (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain comprises a variable region consisting of about 100-110 or more amino acids that primarily serves the role of antigen recognition. The carboxy-terminal portion of the heavy chain may define a constant region that primarily serves the role of effector function. Typically, human light chains are classified as kappa and lambda light chains. Further, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody isotypes as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are joined by a "J" region consisting of about 12 or more amino acids, and the heavy chain also includes a "D" region consisting of about 10 or more amino acids. In general, see Fundamental Immunology Ch.7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)).

[0038] The variable regions of each light / heavy chain pair form the antibody binding sites. Thus, generally, intact antibodies have two binding sites. However, in bispecific or dual - specificity antibodies, the two binding sites are generally not the same.

[0039] Typically, both the variable domains of the heavy and light chains contain three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FRs). The CDRs are usually aligned by the framework regions and enable binding to specific epitopes. Generally, proceeding from the N-terminus to the C-terminus, both the light chain variable domain and the heavy chain variable domain contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid assignments to each domain generally follow the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5 th ed.; 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.

[0040] As used herein, the term "hypervariable region" refers to the amino acid residues of an antibody that are involved in antigen binding. Hypervariable regions include amino acid residues derived from "complementary determining regions" or "CDRs" (i.e., residues 24-34 (CDRL1), 50-56 (CDRL2), and 89-97 (CDRL3) in the light chain variable domain, and residues 31-35 (CDRH1), 50-65 (CDRH2), and 95-102 (CDRH3) in the heavy chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.) and / or residues derived from "hypervariable loops" (i.e., residues 26-32 (CDRL1), 50-52 (CDRL2), and 91-96 (CDRL3) in the light chain variable domain, and residues 26-32 (CDRH1), 53-55 (CDRH2), and 96-101 (CDRH3) in the heavy chain variable domain; Chothia and Lesk (1987) J. Mol. Biol. 196:901-917). CDRs can also be referred to according to the IMGT system for the identification of CDRs, as described in Lefranc MP. Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509. As used herein, the term "framework" residue or "FR" residue refers to variable domain residues other than the hypervariable region residues defined herein as CDR residues. CDRs account for most of the contact residues for an antibody to bind an antigen or epitope. The CDRs of interest are derived from the variable heavy chain and variable light chain sequences of a donor antibody and may include analogs of naturally occurring CDRs, which share or retain the same antigen binding specificity and / or neutralizing capacity as the donor antibody from which they are derived.

[0041] As used herein, "specific binding" or "immunospecific binding" or "immunologically binds specifically" refers to an antibody that binds to a given antigen with a much higher affinity than to other antigen(s) (e.g., selectively binds to the active complement component A11B1s rather than the inactive A11B1s, which may also be called proA11B1s). In some embodiments, the antibody binds to the given antigen with a dissociation constant (K -7 ) of 10 D M or less, and such K D is at least 2-fold smaller than K D for binding to its non-specific antigen (e.g., BSA, casein, or another non-specific polypeptide).

[0042] The phrases "antibody that recognizes A11B1s" and "antibody specific for A11B1s" are used interchangeably herein with the term "antibody that immunospecifically binds to A11B1s". In some embodiments, the antibody binds specifically or preferentially to A11B1s, such as the active form of A11B1s, over other proteins, such as but not limited to the inactive form of A11B1s (proA11B1s). The degree of specificity required for an anti-A11B1s antibody can depend on the intended use of the antibody, and in any case, is determined by its suitability for the intended purpose of use. In some embodiments, the binding compound derived from the antibody or the antigen-binding site of the antibody for the intended method binds to that antigen (the active form of A11B1s) with an affinity that is at least 2-fold greater, at least 10-fold greater, at least 20-fold greater, or at least 100-fold greater than its affinity for any other antigen, such as but not limited to the inactive A11B1s.

[0043] Additional methods for determining the specificity and affinity of mAbs by competitive inhibition are described, for example, in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589-601 (1983), which are hereby incorporated by reference in their entirety.

[0044] The term "homolog" means a protein sequence having a sequence identity of 40% to 100% with 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, Carlsbad, Calif.) or other suitable alignment software such as BLAST. In some embodiments, the antibody or antigen-binding fragment thereof has at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology or identity with the sequences described herein. In some embodiments, the antibody has conservative substitutions compared to the sequences 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 within the framework region or within the antigen-binding site as long as they do not adversely affect the properties of the antibody. The substitutions can be made, for example, for the purpose of improving properties of the antibody such as stability or affinity. By like substitution, molecules are generated that have functional and chemical properties similar to those of the molecules thus modified. Exemplary amino acid substitutions are shown in the following table.

[0045]

Table 1

[0046] In some embodiments, variants of the proteins and peptides provided herein are provided. In some embodiments, the variants include substitutions, deletions, or insertions. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) substitutions. As described herein, the substitutions can be conservative substitutions. In some embodiments, the substitutions are non-conservative. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) deletions. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) insertions. In some embodiments, there are substitutions, deletions, or insertions in the CDRs provided herein. In some embodiments, there are no substitutions, deletions, or insertions in the CDRs provided herein.

[0047] As used herein, the term "in combination with" means that the recited agent can be administered to an animal or subject together as a mixture, simultaneously as a single agent, or sequentially in any order as a single agent.

[0048] The term "epitope" shall refer to a portion of any molecule that can be recognized and bound by an antibody in the antigen-binding region of one or more Abs. Epitopes usually consist of chemically active surface atomic groups of a molecule, such as amino acids or sugar side chains, etc., and have specific three-dimensional structural characteristics and specific charge characteristics.

[0049] The term "expression vector" refers to a vector containing a recombinant polynucleotide that includes an expression control sequence operably linked to a nucleotide sequence to be expressed. The expression vector contains cis-acting elements sufficient for expression, and other elements for expression can be supplied by the host cell or in an in vitro expression system. Examples of expression vectors include any vectors known in the art such as cosmids, plasmids (e.g., naked or contained in liposomes) into which the recombinant polynucleotide has been incorporated, and viruses (e.g., Sendai virus, lentivirus, retrovirus, adenovirus, and adeno-associated virus).

[0050] "Integrin" is a large family of type I transmembrane heterodimeric glycoprotein receptors that act as major receptors for cell adhesion. The integrin family of receptors plays an important 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 associated subunits, α and β. Integrin α1β1, α2β1, α10β1, and α11β1 are major collagen receptors. The α and β subunits are transmembrane proteins having large modular extracellular domains, a single transmembrane helix, and short cytoplasmic regions, and mediate cytoskeletal interactions. The extracellular domain of integrin is generally a large structure of about 80 - 150 kDa. The extracellular domain is thought to include a head connected to two legs (see Figure 1 for the structure of collagen-binding integrin). Collagen-binding integrin contains an I domain that serves as a ligand-binding site. The ai domain binds to a divalent metal cation (Mg2+) and contains a conserved "metal-ion-dependent adhesion site" (MIDAS) that plays an important role in ligand binding.

[0051] Integrins can exist in three different conformations: 1) a resting, low-affinity state (bent conformation, panel A of FIG. 1) in which the head containing the ligand-binding site faces the membrane; 2) an extended, intermediate-affinity state in which the integrin is extended but the head remains "closed" (panel B of FIG. 1); 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 for both allosteric and ligand-blocking methods of inhibiting integrin function. As indicated by the asterisks in FIG. 1, one allosteric method of blocking integrin function is to generate monoclonal antibodies that prevent the integrin from reaching its fully extended conformation from the extended intermediate conformation. Another allosteric option is to bind to the integrin in its bent / inactive conformation and prevent it from extending into either of the two other states. A non-allosteric method of inhibiting integrin function is to bind to the I domain and prevent the integrin from attaching to collagen. Binding to the ligand-binding site directly risks generating a recombinant activating factor for integrin function.

[0052] As a cell surface receptor, integrin can sense the stiffness of the surrounding matrix, induce cells to produce and remodel connective tissue, and thereby perpetuate the fibrotic phenotype. Although many integrins are overexpressed in fibrosis, it is not clear which alpha subunit is sufficient for the development of fibrosis. α11β1 integrin is specifically expressed in subsets of fibroblasts and myofibroblasts (i.e., terminal scar-producing cells). Recent literature provides strong evidence that α11β1 is one of the major 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 Feb 2018, 222(2), Bansal, R. et al. Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. Exp Mol Med. 2017 Nov 17:49(11)). Blocking α11β1 function can inhibit the differentiation of myofibroblasts and the deposition of the extracellular matrix (i.e., a major event in scar formation), and blocking al Ibi function can bring about a mechanism for local and injury-specific fibrosis attenuation that can fundamentally change the fibrotic microenvironment and modify disease progression in any disease with fibrotic components.

[0053] In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof of the present disclosure reduces the interaction between α11β1 and collagen in human α11β1-expressing cells. In some embodiments, the reduction of the interaction between α11β1 and collagen in human α11β1-expressing cells involves an anti-α11β1 antibody or antigen-binding fragment thereof that interacts with α11β1 in a resting low-affinity state (bent conformation). In some embodiments, the reduction of the interaction between α11β1 and collagen in human α11β1-expressing cells involves an anti-α11β1 antibody or antigen-binding fragment thereof interacting with α11β1 in an extended intermediate-affinity state. In some embodiments, the reduction of the interaction between α11β1 and collagen in human α11β1-expressing cells involves an anti-α11β1 antibody or antigen-binding fragment thereof interacting with α11β1 in an extended high-affinity state.

[0054] Composition The present disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof. In some embodiments, the antibody is a monoclonal antibody or fragment thereof that binds to α11β1. In some embodiments, the antibody is a homodimeric monoclonal antibody or fragment thereof that binds to α11β1. In some embodiments, the antibody is a heterodimeric monoclonal antibody or fragment thereof that binds to α11β1. In some embodiments, the antibody is, for example, a typical antibody or diabody, triabody, tetrabody, minibody, maxibody, tandab, DVD, BiTe, scFv, TandAb, scFv, Fab, Fab2, Fab3, F(ab’)2, etc., or any combination thereof.

[0055] The term "purified" with respect to an antibody refers to an antibody that is substantially free of other substances that associate with the molecule in its natural environment. For example, a purified protein is substantially free of cellular material or other proteins from the cells or tissue from which it is derived. This term refers to preparations in which the isolated protein is pure enough for analysis or has a purity of at least 70% - 80% (w / w), at least 80% - 90% (w / w), 90 - 95%, and at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w). In some embodiments, the antibody is purified.

[0056] The antibodies provided herein may also be conjugated to a chemical moiety. The chemical moiety can be, inter alia, a polymer, a radionuclide, or a cytotoxic agent. In some embodiments, this may 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 body of the subject. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., PEG having a molecular weight of 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa, or 40 kDa), dextran, and monomethoxypolyethylene glycol (mPEG). Lee, et al., (1999) (Bioconj.Chem. 10:973-981) disclose PEG-conjugated single-chain antibodies. Wen, et al., (2001) (Bioconj.Chem. 12:545-553) disclose conjugating an antibody with PEG conjugated to a radioactive metal chelating agent (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, mertansine, 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. The chemical moiety can be linked to the antibody via a linking group (maleimide), a cleavable linker such as a cathepsin-cleavable linker (valine-citrulline), and in some embodiments, one or more spacers (e.g., para-aminobenzyl carbamate).

[0057] Also, the antibodies and antibody fragments of the present invention can be labeled, 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 It may be conjugated with Fe or the like.

[0058] In addition, the antibody and antibody fragments may be conjugated with a fluorophore, such as a rare earth chelate, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluorescamine, 152 Eu, dansyl, umbelliferone, luciferin, luminol label, isoluminol label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate ester label, aequorin label, 2,3-dihydrophthalazinedione, biotin / avidin, spin label, and a fluorescent label or chemiluminescent label including a stable free radical.

[0059] Alternatively, the antibody molecule may be conjugated with a cytotoxic factor such as diphtheria toxin, the A chain of Pseudomonas aeruginosa exotoxin, the A chain of ricin, the A chain of abrin, the A chain of modeccin, alpha-sarcin, the protein and compound (e.g., fatty acid) of Aleurites fordii, dianthin protein, the protein PAPI, PAPII and PAP-S of Phytolacca americana, the inhibitor of Momordica charantia, curcin, crocin, the inhibitor of Saponaria officinalis, mitogelin, restrictocin, phenomycin, and enomycin.

[0060] Any method known in the art for conjugating the antibody molecules of the present invention with various moieties may be used, and the methods 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 are included herein. The methods for conjugating antibodies are conventional and well known in the art.

[0061] In some embodiments, the antibody comprises a heavy chain CDR peptide having one of the following sequences, or a variant thereof (Table 2):

[0062]

Table 2

[0063] In some embodiments, the antibody comprises a light chain CDR peptide having one of the following sequences, or a variant thereof (Table 3):

[0064]

Table 3

[0065] In some embodiments, the antibody or an antibody binding fragment thereof 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 an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 1. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 2. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 3. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 23. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 24. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 25. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 26. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 27. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 28. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 29. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 38. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 39. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 40. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 41. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 42. In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 43.

[0066] In some embodiments, the antibody or an antibody binding fragment thereof 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 an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 16. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 17. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 18. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 34. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 35. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 36. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 58. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 59. In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain CDR having the sequence of SEQ ID NO: 60.

[0067] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 1, HCDR2 has the sequence of SEQ ID NO: 2, and HCDR3 has the sequence of SEQ ID NO: 3.

[0068] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 24, and HCDR3 has the sequence of SEQ ID NO: 28.

[0069] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 24, and HCDR3 has the sequence of SEQ ID NO: 29.

[0070] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 25, and HCDR3 has the sequence of SEQ ID NO: 28.

[0071] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 25, and HCDR3 has the sequence of SEQ ID NO: 29.

[0072] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 26, and HCDR3 has the sequence of SEQ ID NO: 28.

[0073] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 26, and HCDR3 has the sequence of SEQ ID NO: 29.

[0074] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 27, and HCDR3 has the sequence of SEQ ID NO: 28.

[0075] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 23, HCDR2 has the sequence of SEQ ID NO: 27, and HCDR3 has the sequence of SEQ ID NO: 29.

[0076] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 38, HCDR2 has the sequence of SEQ ID NO: 41, and HCDR3 has the sequence of SEQ ID NO: 43.

[0077] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 38, HCDR2 has the sequence of SEQ ID NO: 42, and HCDR3 has the sequence of SEQ ID NO: 43.

[0078] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 39, HCDR2 has the sequence of SEQ ID NO: 41, and HCDR3 has the sequence of SEQ ID NO: 43.

[0079] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 39, HCDR2 has the sequence of SEQ ID NO: 42, and HCDR3 has the sequence of SEQ ID NO: 43.

[0080] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 40, HCDR2 has the sequence of SEQ ID NO: 41, and HCDR3 has the sequence of SEQ ID NO: 43.

[0081] In some embodiments, the antibody or an antibody binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 40, HCDR2 has the sequence of SEQ ID NO: 42, and HCDR3 has the sequence of SEQ ID NO: 43.

[0082] In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 16, LCDR2 has the sequence of SEQ ID NO: 17, and LCDR3 has the sequence of SEQ ID NO: 18.

[0083] In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 34, LCDR2 has the sequence of SEQ ID NO: 35, and LCDR3 has the sequence of SEQ ID NO: 36.

[0084] In some embodiments, the antibody or an antibody binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 58, LCDR2 has the sequence of SEQ ID NO: 59, and LCDR3 has the sequence of SEQ ID NO: 60.

[0085] For clarity, the following table shows non-limiting exemplary combinations of heavy chain CDRs (Table 4) and light chain CDRs (Table 5).

[0086]

Table 4

[0087]

Table 5

[0088] In some embodiments, the antibody or an antibody-binding fragment thereof comprises: (i) a heavy chain having any one of the combinations of the above HCDR1, HCDR2, and HCDR3 sequences; and (ii) a light chain having any one of the combinations of the above LCDR1, LCDR2, and LCDR3 sequences. Referring to Tables 4 and 5 above, the following combinations are provided.

[0089] Thus, for example, an antibody or an antibody-binding fragment thereof comprising H V L V 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.

[0090] Thus, in some embodiments, the antibody or an antibody-binding fragment thereof comprises H V L V. In some embodiments, the antibody or an antibody-binding fragment thereof comprises H V L V. In some embodiments, the antibody or an antibody-binding fragment thereof comprises H V L V.

[0091] In some embodiments, the antibody or an antibody-binding fragment thereof comprises H V L V. In some embodiments, the antibody or an antibody-binding fragment thereof comprises H V L V. In some embodiments, the antibody or an antibody-binding fragment thereof comprises H V L V.

[0092] In some embodiments, the antibody or an antibody-binding fragment thereof comprises H V L V. In some embodiments, the antibody or an antibody-binding fragment thereof comprises H V LIt includes B. In some embodiments, the antibody or its antibody-binding fragment is V H C and V L C.

[0093] In some embodiments, the antibody or its antibody-binding fragment is V H D and V L A. In some embodiments, the antibody or its antibody-binding fragment is V H D and V L B. In some embodiments, the antibody or its antibody-binding fragment is V H D and V L C.

[0094] In some embodiments, the antibody or its antibody-binding fragment is V H E and V L A. In some embodiments, the antibody or its antibody-binding fragment is V H E and V L B. In some embodiments, the antibody or its antibody-binding fragment is V H E and V L C.

[0095] In some embodiments, the antibody or its antibody-binding fragment is V H F and V L A. In some embodiments, the antibody or its antibody-binding fragment is V H F and V L B. In some embodiments, the antibody or its antibody-binding fragment is V H F and V L C.

[0096] In some embodiments, the antibody or its antibody-binding fragment is V H G and V L A. In some embodiments, the antibody or its antibody-binding fragment is V H G and V L B. In some embodiments, the antibody or its antibody-binding fragment is V H G and V L C.

[0097] In some embodiments, the antibody or an antibody binding fragment thereof comprises VH and H VH and L VA. In some embodiments, the antibody or an antibody binding fragment thereof comprises VH and H VH and L VB. In some embodiments, the antibody or an antibody binding fragment thereof comprises VH and H VH and L VC.

[0098] In some embodiments, the antibody or an antibody binding fragment thereof comprises VI and H VI and L VA. In some embodiments, the antibody or an antibody binding fragment thereof comprises VI and H VI and L VB. In some embodiments, the antibody or an antibody binding fragment thereof comprises VI and H VI and L VC.

[0099] In some embodiments, the antibody or an antibody binding fragment thereof comprises VJ and H VJ and L VA. In some embodiments, the antibody or an antibody binding fragment thereof comprises VJ and H VJ and L VB. In some embodiments, the antibody or an antibody binding fragment thereof comprises VJ and H VJ and L VC.

[0100] In some embodiments, the antibody or an antibody binding fragment thereof comprises VK and H VK and L VA. In some embodiments, the antibody or an antibody binding fragment thereof comprises VK and H VK and L VB. In some embodiments, the antibody or an antibody binding fragment thereof comprises VK and H VK and L VC.

[0101] In some embodiments, the antibody or an antibody binding fragment thereof comprises VM and H VM and L VA. In some embodiments, the antibody or an antibody binding fragment thereof comprises VM andH M and V L including B. In some embodiments, the antibody or its antibody-binding fragment is V H M and V L including C.

[0102] In some embodiments, the antibody or its antibody-binding fragment is V H N and V L including A. In some embodiments, the antibody or its antibody-binding fragment is V H N and V L including B. In some embodiments, the antibody or its antibody-binding fragment is V H N and V L including C.

[0103] In some embodiments, the antibody or its antibody-binding fragment is V H O and V L including A. In some embodiments, the antibody or its antibody-binding fragment is V H O and V L including B. In some embodiments, the antibody or its antibody-binding fragment is V H O and V L including C.

[0104] In some embodiments, the light chain variable region LCDR1 is replaced with any of the other light chain LCDR1 sequences. In some embodiments, the light chain variable region LCDR2 is replaced with any of the other light chain LCDR2 sequences. In some embodiments, the light chain variable region LCDR3 is replaced with any of the other light chain LCDR3 sequences. In some embodiments, the heavy chain variable region HCDR1 is replaced with any of the other heavy chain HCDR1 sequences. In some embodiments, the heavy chain variable region HCDR2 is replaced with any of the other heavy chain HCDR2 sequences. In some embodiments, the heavy chain variable region HCDR3 is replaced with any of the other heavy chain HCDR3 sequences.

[0105] In some embodiments, the antibody comprises a heavy chain variable region peptide having one of the following sequences, or a variant thereof (Table 6):

[0106]

Table 6-1

[0107]

Table 6-2

[0108] In some embodiments, the antibody comprises a light chain variable region peptide having one of the following sequences, or a variant thereof (Table 7):

[0109]

Table 7

[0110] In some embodiments, the heavy chain variable region and / or the light chain variable region are described as comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the recited sequence identifier, or being identical thereto, provided that the heavy chain variable region and / or the light chain variable region comprise a particular set of HCDR and / or LCDR as the context indicates. As used herein, the phrase "provided that the heavy chain variable region and / or the light chain variable region comprise a particular set of HCDR and / or LCDR" or similar expressions used herein means that the recited HCDR or LCDR is identical to the sequence referred to by the sequence identifier as the context indicates, and that the overall percent 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 reference sequence.

[0111] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide 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 variants thereof. H comprises a peptide.

[0112] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85% identity with 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 variants thereof. H comprises a peptide.

[0113] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with 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 variants thereof. H comprises a peptide.

[0114] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 4. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 4, 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. H

[0115] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 5. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 5, 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. H

[0116] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 6. HIt contains a peptide. In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 6 or is identical thereto, V H It contains a peptide, provided that the antibody or antigen-binding fragment thereof contains 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.

[0117] In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 7 or is identical thereto, V H It contains a peptide. In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 7 or is identical thereto, V H It contains a peptide, provided that the antibody or antigen-binding fragment thereof contains 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.

[0118] In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 8 or is identical thereto, V H It contains a peptide. In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 8 or is identical thereto, V H It contains a peptide, provided that the antibody or antigen-binding fragment thereof contains 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.

[0119] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 9. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 9. H 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.

[0120] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 10. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 10. H 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.

[0121] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 11. HIt contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 11, V H It contains a peptide, provided that the antibody or its antigen-binding fragment contains 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.

[0122] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 12, V H It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 12, V H It contains a peptide, provided that the antibody or its antigen-binding fragment contains 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.

[0123] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 13, V H It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 13, V H It contains a peptide, provided that the antibody or its antigen-binding fragment contains 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.

[0124] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 14. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 14. H wherein 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.

[0125] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 15. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 15. H wherein 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 peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 30. HIt contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 30, V H It contains a peptide, provided that the antibody or its antigen-binding fragment contains the HCDR1 sequence of SEQ ID NO: 23, the HCDR2 sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and the HCDR3 sequence of SEQ ID NO: 28 or SEQ ID NO: 29.

[0127] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 31, V H It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 31, V H It contains a peptide, provided that the antibody or its antigen-binding fragment contains the HCDR1 sequence of SEQ ID NO: 23, the HCDR2 sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and the HCDR3 sequence of SEQ ID NO: 28 or SEQ ID NO: 29.

[0128] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 32, V H It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 32, V HComprising a peptide, provided that the antibody or its antigen-binding fragment comprises the HCDR1 sequence of SEQ ID NO: 23, the HCDR2 sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and the HCDR3 sequence of SEQ ID NO: 28 or SEQ ID NO: 29.

[0129] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to the V H Comprising a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to the V H Comprising a peptide, provided that the antibody or its antigen-binding fragment comprises the HCDR1 sequence of SEQ ID NO: 23, the HCDR2 sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and the HCDR3 sequence of SEQ ID NO: 28 or SEQ ID NO: 29.

[0130] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to the V H Comprising a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to the V H Comprising a peptide, provided that the antibody or its antigen-binding fragment comprises the HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, the HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and the HCDR3 sequence of SEQ ID NO: 43.

[0131] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 45. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 45, provided that the antibody or antigen-binding fragment thereof comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43. H

[0132] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 46. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 46, provided that the antibody or antigen-binding fragment thereof comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43. H

[0133] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 47. HIt contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 47, V H It contains a peptide, provided that the antibody or its antigen-binding fragment contains the HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, the HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and the HCDR3 sequence of SEQ ID NO: 43.

[0134] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 48, V H It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 48, V H It contains a peptide, provided that the antibody or its antigen-binding fragment contains the HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, the HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and the HCDR3 sequence of SEQ ID NO: 43.

[0135] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 49, V H It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with or is identical to SEQ ID NO: 49, V HComprising a peptide, provided that the antibody or its antigen-binding fragment comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43.

[0136] In some embodiments, the antibody or its antigen-binding fragment comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 50. H Comprising a peptide. In some embodiments, the antibody or its antigen-binding fragment comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 50. H Comprising a peptide, provided that the antibody or its antigen-binding fragment comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43.

[0137] In some embodiments, the antibody or its antigen-binding fragment comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 51. H Comprising a peptide. In some embodiments, the antibody or its antigen-binding fragment comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 51. H Comprising a peptide, provided that the antibody or its antigen-binding fragment comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43.

[0138] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 52. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 52. H wherein the antibody or antigen-binding fragment thereof comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43.

[0139] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 53. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 53. H wherein the antibody or antigen-binding fragment thereof comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43.

[0140] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 54. HIt comprises a peptide. In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or is identical to SEQ ID NO: 54, V H It comprises a peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, the HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and the HCDR3 sequence of SEQ ID NO: 43.

[0141] In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or is identical to SEQ ID NO: 55, V H It comprises a peptide. In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or is identical to SEQ ID NO: 55, V H It comprises a peptide, provided that the antibody or antigen-binding fragment thereof comprises the HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, the HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and the HCDR3 sequence of SEQ ID NO: 43.

[0142] In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or is identical to SEQ ID NO: 56, V H It comprises a peptide. In some embodiments, the antibody or antigen-binding fragment thereof has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or is identical to SEQ ID NO: 56, V HComprising a peptide, provided that the antibody or antigen-binding fragment thereof comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43.

[0143] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 57. H Comprising a peptide. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to or being identical to SEQ ID NO: 57. H Comprising a peptide, provided that the antibody or antigen-binding fragment thereof comprises an HCDR1 sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 sequence of SEQ ID NO: 43.

[0144] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide 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 variants thereof. L Comprising a peptide.

[0145] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85% identity 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 variants thereof. L Comprising a peptide.

[0146] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being 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 It contains a peptide.

[0147] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 19. L It contains a peptide. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 19. L It contains a 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.

[0148] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 20. L It contains a peptide. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 20. L It contains a 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.

[0149] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 21. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 21. L wherein 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.

[0150] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 22. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 22. L wherein 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.

[0151] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V peptide having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or being identical to, SEQ ID NO: 37. LIt contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 37, or is identical thereto, V L It contains a peptide, provided that the antibody or its antigen-binding fragment contains 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.

[0152] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 61, or is identical thereto, V L It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 61, or is identical thereto, V L It contains a peptide, provided that the antibody or its antigen-binding fragment contains 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.

[0153] In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 62, or is identical thereto, V L It contains a peptide. In some embodiments, the antibody or its antigen-binding fragment has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 62, or is identical thereto, V LComprising a peptide, provided that the antibody or its antigen-binding fragment 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.

[0154] The VH and VL sequences can be of any type, including but not limited to the scFv type in which the VH region and the VL region are linked by a peptide linker. Examples of peptide linkers that can be used to link the various peptides provided herein include, but are not limited to, the following: (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 regions are not linked by a peptide linker.

[0155] As provided herein, the different peptides (V H or V L ) described herein can be linked by a peptide linker or can form a continuous sequence instead of being linked by a peptide linker. In some embodiments, the heavy-chain variable region and the light-chain variable region are not linked by a linker. In some embodiments, the heavy-chain variable region and the light-chain variable region are linked by a peptide linker. In some embodiments, the peptide linker is (GGGGS) n (SEQ ID NO: 70), (GGGGA) n(SEQ ID NO: 71), or an array of 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 type is V H -Z-V L or V L -Z-V H and can be represented by the formula, where Z is a peptide linker. 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.

[0156] 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.

[0157] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V H peptide and a V L peptide, and the V H peptide comprises a sequence that is at least 85%, 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.

[0158] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H peptide and V L peptide comprises at least one HCDR having the sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, and / or at least one LCDR having the sequence of SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18. In some embodiments, V H the CDRs in the chain or V L the CDRs in the chain are as described in the combinations provided herein.

[0159] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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.

[0160] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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, 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 is V H the peptide and V L the peptide, and 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, 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H the peptide and V L the peptide.

[0161] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H the peptide and V L the peptide, and 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, 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 the peptide and V L the peptide, and 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, 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 V HThe peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide.

[0162] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or V LThe 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide.

[0163] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or V L 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof comprises V HA peptide and V of SEQ ID NO: 22 L comprises a peptide and V

[0164] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 is V H peptide and V L peptide, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or V L 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V of SEQ ID NO: 5 H peptide and V of SEQ ID NO: 19 L peptide

[0165] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and VL comprising a peptide, and 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 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 is V H the peptide and V L comprising a peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 5 and V L the peptide of SEQ ID NO: 20.

[0166] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L comprising a peptide, and 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, 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, V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 5 and V L the peptide of SEQ ID NO: 21.

[0167] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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, 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 22.

[0168] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 6 and V L peptide of SEQ ID NO: 19.

[0169] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 20.

[0170] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 6 and V L peptide of SEQ ID NO: 21.

[0171] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 22.

[0172] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 7 and V L peptide of SEQ ID NO: 19.

[0173] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 20.

[0174] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 7 and V L peptide of SEQ ID NO: 21.

[0175] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 22.

[0176] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 19.

[0177] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 8 and V L peptide of SEQ ID NO: 20.

[0178] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 21.

[0179] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 8 and V L peptide of SEQ ID NO: 22.

[0180] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 9 and V L peptide of SEQ ID NO: 19.

[0181] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 20.

[0182] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 9 and V L peptide of SEQ ID NO: 21.

[0183] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 22.

[0184] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 10 and V L peptide of SEQ ID NO: 19.

[0185] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 10 and V L peptide of SEQ ID NO: 20.

[0186] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 21.

[0187] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 10 and V L peptide of SEQ ID NO: 22.

[0188] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 19.

[0189] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 11 and V L peptide of SEQ ID NO: 20.

[0190] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V of SEQ ID NO: 11 H peptide and V of SEQ ID NO: 21 L peptide.

[0191] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 22.

[0192] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V of SEQ ID NO: 12 H peptide and V of SEQ ID NO: 19 L peptide.

[0193] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 12 and V L peptide of SEQ ID NO: 20.

[0194] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 12 and V L peptide of SEQ ID NO: 21.

[0195] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 12 and V L peptide of SEQ ID NO: 22.

[0196] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 13 and V L peptide of SEQ ID NO: 19.

[0197] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 13 and V L peptide of SEQ ID NO: 20.

[0198] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 13 and V L peptide of SEQ ID NO: 21.

[0199] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 22.

[0200] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 14 and V L peptide of SEQ ID NO: 19.

[0201] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide of SEQ ID NO: 20.

[0202] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 14 and V L peptide of SEQ ID NO: 21.

[0203] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 14 and V L peptide of SEQ ID NO: 22.

[0204] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 15 and V L peptide of SEQ ID NO: 19.

[0205] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 15 and V L peptide of SEQ ID NO: 20.

[0206] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 15 and V L peptide of SEQ ID NO: 21.

[0207] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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 is V H peptide and V L peptide, and 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 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 1, HCDR2 having the sequence of SEQ ID NO: 2, and HCDR3 having the sequence of SEQ ID NO: 3, and / or 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: 28. In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide of SEQ ID NO: 15 and V L peptide of SEQ ID NO: 22.

[0208] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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 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.

[0209] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V H peptide and a V L peptide, and the V H peptide comprises a sequence that is at least 85%, 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 peptide comprises a sequence that is at least 85%, 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 peptide and the V L peptide comprise at least one HCDR having the 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 at least one LCDR having the sequence of SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36. In some embodiments, the CDRs in the V H chain or the V L chain are as described in the combinations provided herein.

[0210] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V H peptide and a V L peptide, and the V H peptide comprises a sequence that is at least 85%, 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 peptide comprises a sequence that is at least 85%, 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 an HCDR1 having the sequence of SEQ ID NO: 23, an HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and an HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29, and / or V L The peptide comprises an LCDR1 having the sequence of SEQ ID NO: 34, an LCDR2 having the sequence of SEQ ID NO: 35, and an LCDR3 having the sequence of SEQ ID NO: 36.

[0211] In some embodiments, the antibody or antigen-binding fragment thereof is V H peptide and V L peptide, and 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, 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 is V H peptide and V L peptide, and 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, 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 V H The peptide comprises an HCDR1 having the sequence of SEQ ID NO: 23, an HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27, and an HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29, and / or V LThe 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. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide.

[0212] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide, wherein V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H peptide comprises HCDR1 having the sequence of SEQ ID NO: 23, HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29, and / or V LThe 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. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide.

[0213] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H peptide comprises HCDR1 having the sequence of SEQ ID NO: 23, HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29, and / or V LThe 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. In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide.

[0214] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H peptide and V L peptide, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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, and V H peptide comprises a sequence that is at least 85%, 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 V L peptide comprises a sequence that is at least 85%, 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 V H peptide comprises HCDR1 having the sequence of SEQ ID NO: 23, HCDR2 having the sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and HCDR3 having the sequence of SEQ ID NO: 28 or SEQ ID NO: 29, and / or V LThe 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. In some embodiments, the antibody or antigen-binding fragment thereof comprises the V of SEQ ID NO: 33 H peptide and the V of SEQ ID NO: 37 L peptide.

[0215] In some embodiments, the antibody or antigen-binding fragment thereof comprises the V H peptide and the V L peptide, and the V H peptide comprises a sequence that is at least 85%, 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 peptide comprises a sequence that is at least 85%, 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.

[0216] In some embodiments, the antibody or antigen-binding fragment thereof comprises the V H peptide and the V L peptide, and the V H peptide comprises a sequence that is at least 85%, 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 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 V H the peptide and V L The peptide comprises at least one HCDR having the 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 at least one LCDR having the sequence of SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60. In some embodiments, V H in the chain or V L the CDRs in the chain are as described in the combinations provided herein.

[0217] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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.

[0218] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V H peptide and a V L peptide, and the V H peptide comprises a sequence that is at least 85%, 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 peptide comprises a sequence that is at least 85%, 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 a V H peptide and a V L peptide, and the V H peptide comprises a sequence that is at least 85%, 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 peptide comprises a sequence that is at least 85%, 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 peptide comprises an HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 having the sequence of SEQ ID NO: 43, and / or the V L peptide comprises an LCDR1 having the sequence of SEQ ID NO: 58, an LCDR2 having the sequence of SEQ ID NO: 59, and an LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof comprises the V H peptide of SEQ ID NO: 44 and the V L peptide of SEQ ID NO: 61.

[0219] In some embodiments, the antibody or antigen-binding fragment thereof comprises a V H peptide and a V Lcomprising a peptide, 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, 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 is V H the peptide and V L comprising a peptide, 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, 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 V H The peptide comprises an HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, an HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and an HCDR3 having the sequence of SEQ ID NO: 43, and / or V L The peptide comprises an LCDR1 having the sequence of SEQ ID NO: 58, an LCDR2 having the sequence of SEQ ID NO: 59, and an LCDR3 having the sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment thereof is the V of SEQ ID NO: 44 H the peptide and the V of SEQ ID NO: 62 L comprising the peptide.

[0220] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L comprising a peptide, 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: 45, and 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 is V H comprises the peptide and V L comprises the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 45 and V L the peptide of SEQ ID NO: 61.

[0221] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprises the peptide and V L comprises the peptide, and 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: 45, 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 is V H comprising the peptide and V L comprising the peptide and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 45 and V L the peptide of SEQ ID NO: 62.

[0222] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprising the peptide and V L comprising the peptide and 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 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 is V H comprised of the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 46 and V L the peptide of SEQ ID NO: 61.

[0223] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, and 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 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 is V H the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V of SEQ ID NO: 46 H the peptide and V of SEQ ID NO: 62 L the peptide.

[0224] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 47, 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 is V H comprised of the peptide and V L the peptide, 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is the V of SEQ ID NO: 47 H peptide and the V of SEQ ID NO: 61 L peptide.

[0225] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, 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: 47, 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 is V H comprised of the peptide and V L the peptide, 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is the V of SEQ ID NO: 47 H peptide and the V of SEQ ID NO: 62 L peptide.

[0226] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, 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: 48, 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 is V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 48 and V L the peptide of SEQ ID NO: 61.

[0227] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 48, 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 is V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 48 and V L the peptide of SEQ ID NO: 62.

[0228] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 49, 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 is V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is the V of SEQ ID NO: 49 H peptide and the V of SEQ ID NO: 61 L peptide.

[0229] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 49, 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, V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof, V H the peptide of SEQ ID NO: 49 and V L the peptide of SEQ ID NO: 62.

[0230] In some embodiments, the antibody or antigen-binding fragment thereof, V H the peptide and V L the peptide, and 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 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 is V H comprised of the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 50 and V L the peptide of SEQ ID NO: 61.

[0231] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, and 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 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 is V H comprises the peptide and V L comprises the peptide and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 50 and V L the peptide of SEQ ID NO: 62.

[0232] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprises the peptide and V L comprises the peptide and 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: 51, and 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 is V H comprised of the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 51 and V L the peptide of SEQ ID NO: 61.

[0233] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, and 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: 51, 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 is V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V of SEQ ID NO: 51 H the peptide and V of SEQ ID NO: 62 L the peptide.

[0234] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 52, and 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 is V H the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 52 and V L the peptide of SEQ ID NO: 61.

[0235] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 52, 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 is V H the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 52 and V L the peptide of SEQ ID NO: 62.

[0236] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 53, and 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 is V H comprised of the peptide and V L comprised of the peptide and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide of SEQ ID NO: 53 and V L comprised of the peptide of SEQ ID NO: 61.

[0237] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L comprised of the peptide and 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: 53, and 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 is V H comprised of the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 53 and V L the peptide of SEQ ID NO: 62.

[0238] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, and 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 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 is V H comprised of the peptide and V L comprised of the peptide and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide of SEQ ID NO: 54 and V L comprised of the peptide of SEQ ID NO: 61.

[0239] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L comprised of the peptide and 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 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 is V H comprised of the peptide and V L comprised of the peptide and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide of SEQ ID NO: 54 and V L comprised of the peptide of SEQ ID NO: 62.

[0240] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L comprised of the peptide and 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: 55, 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 is V H comprised of the peptide and V L the peptide, and 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 55 and V L the peptide of SEQ ID NO: 61.

[0241] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, and 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: 55, and 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 is V H the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 55 and V L the peptide of SEQ ID NO: 62.

[0242] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 56, 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 is V H comprised of the peptide and V L the peptide, 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 56 and V L the peptide of SEQ ID NO: 61.

[0243] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, 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: 56, and 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 is V H the peptide and V L the peptide, and 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 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 56 and V L the peptide of SEQ ID NO: 62.

[0244] In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide and V L the peptide, and 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: 57, 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 is V H comprised of the peptide and V L the peptide, 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, 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 V H the peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V of SEQ ID NO: 57 H the peptide and V of SEQ ID NO: 61 L the peptide.

[0245] In some embodiments, the antibody or antigen-binding fragment thereof is V H comprised of the peptide and V L the peptide, 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: 57, 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, V H the peptide and V L the peptide, and 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, 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 V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, HCDR2 having the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and HCDR3 having the sequence of SEQ ID NO: 43, and / or 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. In some embodiments, the antibody or antigen-binding fragment thereof is V H the peptide of SEQ ID NO: 57 and V L the peptide of SEQ ID NO: 62.

[0246] In some embodiments, the antibody comprises an Fc domain. The Fc domain may be linked to the heavy or light chain of the antibody. In some embodiments, the Fc domain comprises a mutation that extends 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 Kabat EU numbering index, as compared to the wild-type human IgG constant domain. Without being bound by any particular theory, antibodies comprising a mutation corresponding to residue 428 may exhibit an increase in half-life as compared to the half-life of an IgG having a wild-type human IgG constant domain. In some embodiments, the mutation is a substitution of the 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, amino acid residues 285-290, amino acid residues 308-314, amino acid residues 385-389, and amino acid residues 429-436 numbered according to the Kabat EU numbering index, as compared 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.

[0247] Other mutations may be used in the Fc domain, such as those provided in U.S. Patent No. 8,394,925, which is incorporated herein by reference in its entirety. In some embodiments, the Fc region is a mutant Fc region comprising amino acid substitutions at positions 428 and 434, the amino acid substitutions being leucine, which is not the wild-type amino acid at position 428, and serine, which is not the wild-type amino acid at position 434, the polypeptide is an antibody, and the numbering follows the EU index of Kabat et al. In some embodiments, the Fc region comprises an S228P substitution, an L235E substitution, an M428L substitution, or an N434S substitution. In some embodiments, the Fc region comprises an M428L substitution. In some embodiments, the Fc region comprises an N434S substitution. In some embodiments, the Fc region comprises both an M428L substitution and an N434S substitution. In some embodiments, the Fc region comprises an M252Y substitution, an S254T substitution, and / or a T256E substitution.

[0248] In some embodiments, the antibody comprises the constant regions described below, regardless of the presence or absence of the mutations provided in the following list.

[0249] IgG1-AAS constant region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 63)

[0250] IgG4 S228P L235E LS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLGK (SEQ ID NO: 64)

[0251] IgG4 S228P L235E YTE ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 65)

[0252] In some embodiments, the antibody comprises a constant region provided herein, wherein the C-terminal lysine (K) amino acid is deleted. In some embodiments, the antibody comprises a constant region as described below:

[0253] IgG1-AAS shortened constant region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 66)

[0254] IgG4 S228P L235E LS - truncated type ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG (SEQ ID NO: 67)

[0255] IgG4 S228P L235E YTE - truncated type ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 68)

[0256] In some embodiments, an antibody, such as a light chain, may include a kappa constant region, such as a human constant domain, that includes the following sequence:

[0257] Human kappa constant domain RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 69)

[0258] In some embodiments, any antibody or antigen-binding fragment thereof of any of the embodiments provided herein may include any known constant domain, such as, but not limited to, an IgG constant domain. In some embodiments, the constant domain is as provided herein. In some embodiments, the constant domain is selected from the group consisting of, 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 variants thereof.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] In some embodiments, the antibody or any antibody fragment thereof comprises a heavy chain selected from Table 8 below.

[0291]

Table 8-1

[0292]

Table 8-2

[0293]

Table 8-3

[0294]

Table 8-4

[0295]

Table 8-5

[0296]

Table 8-6

[0297]

Table 8-7

[0298]

Table 8-8

[0299]

Table 8-9

[0300]

Table 8-10

[0301]

Table 8-11

[0302]

Table 8-12

[0303]

Table 8-13

[0304]

Table 8-14

[0305]

Table 8-15

[0306]

Table 8-16

[0307]

Table 8-17

[0308]

Table 8-18

[0309]

Table 8-19

[0310]

Table 8-20

[0311]

Table 8-21

[0312]

Table 8-22

[0313]

Table 8-23

[0314]

Table 8-24

[0315]

Table 8-25

[0316]

Table 8-26

[0317]

Table 8-27

[0318]

Table 8-28

[0319]

Table 8-29

[0320]

Table 8-30

[0321] In some embodiments, the antibody or any antibody fragment thereof comprises a light chain selected from Table 9 below.

[0322]

Table 9

[0323] In some embodiments, the antibodies described herein include a heavy chain selected from Table 8 and a light chain selected from Table 9.

[0324] In some embodiments, the antibody includes 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.

[0325] In some embodiments, the antibody includes 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.

[0326] In some embodiments, the antibody comprises a heavy chain 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 ID NO: 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.

[0327] When provided herein, an antibody or antigen-binding fragment thereof can be a variant of these sequences. Accordingly, in some embodiments, variants of the antibodies or antigen-binding fragments thereof provided herein are provided. In some embodiments, the variant comprises a mutation selected from a substitution, deletion, insertion, or a combination thereof. In some embodiments, the variant comprises from 1 to 20 mutations. In some embodiments, the variant comprises from 1 to 10 mutations. In some embodiments, the variant comprises from 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. Accordingly, in some embodiments, the variant comprises up to 20 mutations or more than 20 mutations. In some embodiments, the variant comprises from 1 to 10 mutations, and the mutations are selected from a substitution, deletion, insertion, or a combination thereof. In some embodiments, the variant comprises from 1 to 10 mutations, and the mutations are conservative substitutions. Examples of conservative substitutions are provided herein (Table 1). Further, those skilled in the art will recognize and understand the substitutions encompassed by the term "conservative substitution." Such substitutions are within the scope of the present disclosure.

[0328] An antibody or antigen-binding fragment can include 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, Fab fragment, Fab' fragment, or 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 an F(ab')2 fragment.

[0329] The sequence of the antibody can be modified to obtain a human IgG antibody. The sequence conversions provided herein can be modified to obtain other types of antibodies. Also, the CDRs can be linked to other antibodies, proteins, or molecules to create antibody fragments that bind to α11β1. This can be in the form of an antibody-drug conjugate ("ADC") or a multispecific molecule. Also, the sequence can be made into the chimeric antibodies described herein.

[0330] In some embodiments, the antibody comprises an amino acid sequence that includes the sequence provided herein or a fragment thereof. 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 of the amino acid sequences provided herein, an antigen-binding fragment thereof, or a human IgG variant thereof. "The human IgG variant thereof" refers to an antibody that has been modified to be human IgG when the starting antibody is not a human IgG antibody.

[0331] As described herein, the production of antibodies with known sequences is routine and can be carried out by any method. Also, the antibody can be modified to be a chimeric or human antibody. Also, the antibody may be used in an injectable pharmaceutical composition. As also described herein, the antibody can be an isolated or engineered antibody.

[0332] In some embodiments, "derivatives" of the antibody, fragments, regions, or derivatives thereof are provided, and this term includes proteins encoded by genes that have been cleaved or modified to yield molecular species that are functionally similar to immunoglobulin fragments. Modifications include, but are not limited to, the addition of gene sequences encoding cytotoxic proteins such as plant and bacterial toxins. Modifications can also include reporter proteins such as fluorescent or chemiluminescent tags. Fragments and derivatives can be produced by any method.

[0333] By identifying these antibodies or antigen-binding fragments thereof, information necessary to generate additional monoclonal antibodies having similar binding characteristics and therapeutic or diagnostic utility comparable to embodiments of the present application is obtained.

[0334] Antibodies can be generated according to the examples provided herein. If the sequence is known, antibodies can also be generated according to known methods. Also, they can be converted into different types, such as converting the antibody into human IgG. By converting the antibody into a human antibody, it should be the case that a human subject does not recognize the antibody as a foreign substance. The conversion of a non-human IgG antibody into a human IgG antibody is well-known and can be carried out by routine methods if the native sequence is known. As described herein, antibodies can be modified according to known methods. Such methods are described, for example, in 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, Fu H, Jia A, Vasquez M, Kumar S. (2004), and the above literature is incorporated herein by reference in its entirety.

[0335] In some embodiments, host cells are provided. In some embodiments, the host cells comprise an antibody or antigen-binding fragment thereof provided herein. In some embodiments, the host cells comprise a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof provided herein. In some embodiments, the host cells comprise a vector, and this vector comprises a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof provided herein.

[0336] In some embodiments, the host cell produces an antibody or an antigen-binding fragment thereof provided herein. In some embodiments, an antibody or an antigen-binding fragment thereof provided herein is provided, and the antibody or an antigen-binding fragment thereof provided herein is produced by a host cell.

[0337] In some embodiments, a method of producing a polypeptide is provided. In some embodiments, the polypeptide comprises a heavy chain variable region provided herein, a light chain variable region provided herein, or a combination thereof. In some embodiments, the method comprises growing 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 the heavy chain variable region, the light chain variable region, or a combination thereof, thereby producing the polypeptide. In some embodiments, the host cell is the host cell provided herein.

[0338] In some embodiments, a method of 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 comprises growing a host cell under conditions such that the host cell expresses a polypeptide(s) 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 polypeptide(s) comprises an immunoglobulin heavy chain variable region. In some embodiments, the polypeptide(s) comprises an immunoglobulin light chain variable region. In some embodiments, the polypeptide(s) comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region. In some embodiments, the host cell is the host cell provided herein. In some embodiments, the antibody or an antigen-binding fragment thereof is as provided herein.

[0339] In addition, non-human cells such as primate cells or human cells can be transformed to produce polypeptide-producing cells or antibody-producing cells that contribute to the nucleotide sequence encoding the antigen-binding region of a chimeric antibody. For example, B lymphocytes that produce antibodies can be infected with a virus such as Epstein-Barr virus and transformed to obtain immortal antibody-producing cells (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. For example, reference is made to Ausubel (below), Harlow (below), and Colligan (below), the contents of these references being incorporated herein by reference in their entirety. Cell fusion is achieved by standard procedures well known to those skilled in the immunology art. For example, the producing cells can also be, for example, hybridomas generated by fusing B cells with immortal myeloma cells. Methods for fusing and selecting fusion partner cell lines, as well as hybridomas, and screening for mAbs are well known in the art. For example, reference is made to Ausubel (below), Harlow (below), and Colligan (below), the contents of these references being incorporated herein by reference in their entirety.

[0340] The nucleic acid sequences encoding the antibodies described herein are genomic DNA, cDNA, or RNA (e.g., it may be 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 segments is the use of cDNA for chimeric immunoglobulin gene construction, which has been reported, for example, by Liu et al. (Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987), and these references are hereby incorporated by reference in their entirety. The use of cDNA requires the combination of the gene with gene expression elements suitable for the host cell to achieve the synthesis of the desired protein. The use of cDNA sequences is advantageous over genomic sequences (including introns) in that cDNA sequences can be expressed in bacteria or other hosts lacking an appropriate RNA splicing system.

[0341] For example, based on the use of the amino acid sequences provided herein, cDNA encoding a V-region antigen-binding segment capable of detecting, binding, or neutralizing A11B1s can be obtained using known methods. Since the genetic code is degenerate, more than one codon can be used to encode a particular amino acid (Watson et al., below). Using the genetic code, one or more different oligonucleotides that can each encode that amino acid can be identified. The probability that a particular oligonucleotide actually constitutes the actual coding sequence can be estimated by taking into account abnormal base pairing relationships and the frequency with which a particular codon is actually used (to encode a particular amino acid) in eukaryotic or prokaryotic cells expressing the antibody or fragment. Such "codon usage rules" are disclosed by Lathe, et al., J. Molec. Biol. 183:112 (1985). Using Lathe's "codon usage rules", a single oligonucleotide or set of oligonucleotides is identified that includes the theoretically "most likely" nucleotide sequence capable of encoding the variable region sequence or constant region sequence of an antibody.

[0342] The variable regions described herein can be combined with any type of constant region, including human or mouse constant regions. Human genes encoding the constant (C) regions of antibodies, fragments, and regions can be obtained from a human fetal liver library by known methods. The human C region gene can be from any human cell, such as one that expresses and produces human immunoglobulins. The human C H region can be from any known class or isotype of human H chain, including gamma, mu, alpha, delta, or epsilon, and its subtypes, such as G1, G2, G3, and G4. Since the isotype of the H chain is responsible for various effector functions of the antibody and antibody recycling through interaction with FcRn, the desired effector function, such as activity in complement fixation or antibody-dependent cellular cytotoxicity (ADCC), etc., is C Hwill serve as a guide for the selection of regions. Preferably, C H regions are derived from gamma 1 (IgG1), gamma 3 (IgG3), gamma 4 (IgG4), or mu (IgM). Human C L regions may be derived from either the human L-chain isotype, kappa or lambda.

[0343] Methods for purifying polypeptides or proteins (including antibodies or antigen-binding fragments thereof) are known in the art, and any such method is within the scope of the present application. Further, the host cells are not limited by the above examples. Any suitable cells can be used to produce the polypeptides or proteins of the present disclosure.

[0344] Pharmaceutical compositions In some embodiments, pharmaceutical compositions are provided. In some embodiments, the pharmaceutical compositions comprise an antibody or an antigen-binding fragment thereof provided herein.

[0345] In some embodiments, an antibody or an antigen-binding fragment thereof, or another protein provided herein is mixed with a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical composition or a sterile composition of the anti-α11β1 antibody or another protein provided herein. See, for example, Remington’s Pharmaceutical Sciences and U.S.Pharmacopeia:National Formulary,Mack Publishing Company,Easton,PA (1984).

[0346] The formulations of the therapeutic agents or antibodies provided herein can be prepared, for example, in the form of lyophilized powders, slurries, aqueous solutions, or suspensions, by mixing with acceptable carriers, excipients, or stabilizers (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 with a sodium acetate solution at pH 5-6, and NaCl or sucrose is added for isotonicity. Additional agents such as polysorbate 20 or polysorbate 80 may be added to enhance stability.

[0347] The toxicity and therapeutic efficacy of the antibody compositions administered alone or in combination with another agent can be determined, for example, by standard pharmaceutical procedures using cell cultures or experimental animals to determine the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the therapeutically effective dose for 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index LD50 / ED 50 ) is. In certain embodiments, antibodies with a high therapeutic index are desirable. To formulate the dosage range for use in humans, data obtained from cell culture assays and animal studies can be used. The dosage of such a compound is preferably within the range of circulating concentrations that have little or no toxicity of ED 50 and is included. The dosage can vary within this range depending on the dosage form used and the route of administration employed.

[0348] In some embodiments, the composition is administered to a subject according to the Physicians’ Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0349] The modes of administration can be various. Suitable routes of administration include oral, rectal, transmucosal, enteral, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct 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 injection or subcutaneous injection. In some embodiments, the composition is formulated for intravenous injection. In some embodiments, the composition is formulated for subcutaneous injection.

[0350] In some embodiments, the antibody or its antigen-binding fragment can be administered by an invasive route such as injection. In some embodiments, the antibody or its antigen-binding fragment, or its pharmaceutical composition, is administered intravenously, subcutaneously, intramuscularly, intraarterially, intraarticularly (e.g., into the joints of arthritis), intratumorally, or by inhalation, aerosol delivery. Administration by a non-invasive route (e.g., oral; e.g., tablets, capsules, or pills) is also within the scope of this embodiment.

[0351] In some embodiments, the 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 used to treat the disorders described herein. In some embodiments, the antibody is administered in combination with another treatment for the disorders described herein.

[0352] The composition can be administered using medical devices known in the art. For example, the pharmaceutical composition of the present invention can be administered by injection with a hypodermic needle, such as a pre-filled syringe or autoinjector.

[0353] Alternatively, the pharmaceutical composition can be administered with a needleless subcutaneous injection device, such as, for example, the devices disclosed in U.S. Patent 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.

[0354] Alternatively, the pharmaceutical composition can be administered by infusion. Examples of well-known implants and modules for administering pharmaceutical compositions include U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for dispensing a drug at a controlled rate; U.S. Patent No. 4,447,233, which discloses a drug infusion pump for delivering a drug at an accurate infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; and U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multiple chambers and compartments. Numerous other such implants, delivery systems, and modules are well known to those of skill in the art.

[0355] Alternatively, the antibody may be administered, often in the form of a depot or sustained release formulation, by direct injection in a local rather than a systemic manner, for example, into joints of arthritis characterized by immunopathology or pathogen-induced lesions. Further, in a targeted drug delivery system, for example, in the form of liposomes coated with a tissue-specific antibody, the antibody may be administered by targeting, for example, joints of arthritis or pathogen-induced lesions characterized by immunopathology. The liposomes are targeted to and selectively taken up by the diseased tissue.

[0356] The dosing regimen depends on several factors including the metabolic turnover rate of the therapeutic antibody in serum or tissue, the level of the symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix. Preferably, the dosing regimen delivers a sufficient amount of the therapeutic antibody to effect improvement of the target disease state while minimizing undesirable side effects. Thus, the amount of biologic agent to be delivered is partially dependent on the particular therapeutic antibody and the severity of the condition being treated. There are guidelines for selecting an appropriate dosage of a therapeutic antibody (see, for example, 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).

[0357] Determination of an appropriate dosage can be carried out by a clinician using, for example, parameters or factors known or suspected in the art to affect the treatment. Generally, the dosage is started at a level slightly less than the optimal dosage and then increased in small increments until the desired or optimal effect is obtained for any negative side effects. Important diagnostic measures include, for example, measures such as symptoms of inflammation or levels of inflammatory cytokines produced. Generally, it is desirable to use a biologic agent derived from the same species as the animal being targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric antibodies, humanized antibodies, and fully human antibodies may be desirable.

[0358] An antibody or antigen-binding fragment thereof can be provided by continuous infusion or by a dosage administered, for example, daily, once to seven times a week, weekly, bi-weekly, monthly, bi-monthly, or quarterly. In some embodiments, the total weekly dosage is generally at least 0.05 μg / kg body weight, more generally 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 / ml, 10 mg / kg, 25 mg / kg, 50 mg / kg, or more (see, for example, 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). Also, the dosage may be provided such that a predetermined target concentration of the antibody in the serum of the subject, 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 more, is achieved. In other embodiments, a fully human antibody is administered subcutaneously or intravenously at 10 mg / subject, 20 mg / subject, 50 mg / subject, 80 mg / subject, 100 mg / subject, 200 mg / subject, 500 mg / subject, 1000 mg / subject, or 2500 mg / subject, weekly, bi-weekly, "every four weeks", monthly, bi-monthly, or quarterly.

[0359] As used herein, "inhibit" or "treat" or "treatment" includes delaying the onset of symptoms associated with a disorder and / or reducing the severity of symptoms of such a disorder. These terms further include ameliorating existing uncontrolled or undesirable symptoms, preventing additional symptoms, and ameliorating or preventing the underlying cause of such symptoms. Thus, these terms indicate that a beneficial result has been provided to a vertebrate subject having or at risk of developing such a disorder, disease or symptom.

[0360] As used herein, the terms "therapeutically effective amount," "therapeutically effective dose," and "effective amount," alone or in combination with additional therapeutic agents, when administered to a cell, tissue, or subject, refer to an amount of an antibody or antigen-binding fragment thereof effective to cause a measurable improvement in one or more symptoms of a disease or condition, or in the progression of such a disease or condition. A therapeutically effective dose further refers to an amount of a binding compound sufficient to effect at least a partial improvement of symptoms, an increase in the rate of treatment, cure, prevention, or amelioration of a related medical condition, or treatment, cure, prevention, or amelioration of such a condition. When applied to an individual active ingredient administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to the total amount of active ingredients that produces a therapeutic effect, whether administered in combination, sequentially, or simultaneously. An effective amount of a therapeutic agent produces at least a 10% improvement, usually at least a 20% improvement, preferably at least about a 30% improvement, more preferably at least a 40% improvement, and most preferably at least a 50% improvement in a diagnostic measure or diagnostic parameter. An effective amount can also produce an improvement in a subjective measure when evaluating disease severity using a subjective measure. In some embodiments, an amount is a therapeutically effective amount if it can be used to treat or ameliorate a tumor or gastric tumor.

[0361] The term "subject" as used throughout refers to any organism, including mammals (e.g., rats, mice, dogs, cats, rabbits) and animals including, for example, humans. In one embodiment, the subject is a human. A subject may also be referred to as a patient. In some embodiments, the subject is a subject in need of its treatment. A subject "in need thereof" refers to a subject who has been determined to be in need of treatment for a condition to be treated and who is being treated with the specific intention of treating such a condition. The condition can be, for example, any of the conditions described herein.

[0362] Method In some embodiments, the method comprises administering to a subject susceptible or known to be in a condition where α11β1 is the cause of the observed pathology, a therapeutically effective amount or a prophylactically effective amount of one or more of the antibodies or antigen-binding fragments of antibodies described herein. Any active form of antibody can be administered, including but not limited to scFv fragments, Fab fragments, and F(ab’)2 fragments of the antibodies provided herein, as well as other forms of antibodies.

[0363] The binding characteristics of the 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 site-directed mutagenesis. The binding interaction between the antibody and α11β1 can be analyzed using surface plasmon resonance (SPR). SPR or biomolecular interaction analysis (BIA) detects biospecific interactions in real time without labeling either of the interacting substances. A change in mass at the binding surface of the BIA chip (indicating a binding event) results in a change in the refractive index of light near the surface. A signal detectable by the change in refractive index is generated, which is measured as an indicator of the real-time reaction between biological molecules. Methods using SPR are described, for example, in U.S. Patent 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 are provided by BIAcore International AB (Uppsala, Sweden). Additionally, the KinExA® (equilibrium exclusion binding assay) assay available from Sapidyne Instruments (Boise, ID) can also be used.

[0364] Using the information from SPR, for the binding of the antibody to α11β1, the equilibrium dissociation constant (K D ), as well as K on and K off can provide an accurate and quantitative measure of kinetic parameters including them. Such data can be used to compare different molecules. The information from SPR can also be used to develop a structure-activity relationship (SAR). Mutant amino acids at a given position that correlate with high affinity, for example, can be identified for specific binding parameters.

[0365] In certain embodiments, the antibodies described herein exhibit high affinity for binding to α11β1. In various embodiments, the K D of the antibodies described herein for α11β1 is about 10 -4 , 10 -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 , 10 -14 or 10 -15 M or less. In certain examples, the K D of the antibodies described herein for α11β1 is 0.001 - 1 nM, such as 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM or 1 nM.

[0366] In some embodiments, provided herein is the use of an antibody or antigen-binding fragment, or a pharmaceutical composition provided herein. In some embodiments, the use is for the treatment of an α11β1-mediated disorder. In some embodiments, provided is the use of an antibody or antigen-binding fragment provided herein for the treatment of an α11β1-mediated disorder. In some embodiments, provided is the use of a pharmaceutical composition comprising an antibody or antigen-binding fragment provided herein, which use is for the treatment of an A11B1a-mediated disorder. In some embodiments, the pharmaceutical composition is as provided herein. The antibody or its pharmaceutical composition according to any of the embodiments inhibits complement α11β1 activity in an individual having a complement-mediated disease or disorder.

[0367] The present disclosure provides the use of an anti-α11β1 antibody or its pharmaceutical composition according to any of the embodiments in the manufacture of a medicament for inhibiting complement α11β1 activity. In some embodiments, the present disclosure provides the use of an anti-α11β1 antibody or its pharmaceutical composition according to any of the embodiments in the manufacture of a medicament for inhibiting complement α11β1 activity in an individual having an α11β1-mediated disease or disorder.

[0368] The present disclosure provides an anti-α11β1 antibody or its pharmaceutical composition of any of the embodiments for use in medical therapy.

[0369] Treatment of an individual can include administering a therapeutically effective amount of an antibody described herein. The antibody can be provided in a kit, such as a kit as described below. The antibody can be used alone or in combination with another therapeutic, analgesic, or diagnostic agent. In providing an antibody or fragment thereof that can bind to α11β1, or an antibody that can protect a recipient patient from α11β1, the dosage of the administered agent will vary depending on factors such as the patient's age, weight, gender, overall medical condition, medical history, and the like.

[0370] Antibodies capable of treating conditions related to α11β1 activity, or uses for treating α11β1-related pathologies, are intended to be provided to a subject in an amount sufficient to affect a reduction, dissipation, or improvement of symptoms or pathologies related to α11β1. Examples of such pathologies are provided herein.

[0371] Accordingly, in some embodiments, methods of treating a subject having an α11β1-mediated disorder are provided. In some embodiments, the method comprises administering a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof provided herein. In some embodiments, the disorder is as provided herein.

[0372] As provided herein, an antibody or an antigen-binding fragment thereof can be administered together with other therapeutic agents. These can be administered simultaneously or sequentially.

[0373] Also provided are kits useful for practicing the embodiments described herein. The kit can include a first container containing or packaged together with the antibody described above. The kit may also include another container containing or packaged therein related solutions necessary or convenient for practicing the embodiments. The containers can be made of glass, plastic, or foil, and can be vials, bottles, pouches, tubes, bags, etc. The kit may also include written information such as procedures for practicing the embodiments, or information regarding analysis such as the amount of reagent contained in the first container means. The containers together with the written information can be placed in another container device, such as a box or a bag.

[0374] In some embodiments, an antibody that binds to the α11β1 protein is provided. In some embodiments, the antibody is an antibody or antigen-binding fragment provided herein. In some embodiments, the antibody or antigen-binding fragment comprises an amino acid sequence provided herein or a variant thereof provided herein. In some embodiments, the antibody is isolated. In some embodiments, the antibody specifically binds to active α11β1.

[0375] In some embodiments, the antibody inhibits or neutralizes the function of the active α11β1 protein. As used herein, the term "neutralize" means that the activity or function of the protein is inhibited. The inhibition may 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 percent inhibition may be based on the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits a function promoted by α11β1.

[0376] 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.

[0377] In some embodiments, one or more anti-α11β1 antibodies described herein are used in a method of treating a fibrotic disorder. Fibrosis is a scarring process that typically occurs in many tissues in the body as a result of inflammation or tissue damage. Increased production of the extracellular matrix leads to organ failure and often death. In industrialized countries, diseases associated with fibrosis account for approximately 45% of all deaths (Wynn, T.A., 2008, J Pathol. 214:199-210). The cells involved in the production of the extracellular matrix (ECM) for tissue repair (and in fibrosis) are a special type of fibroblast called myofibroblasts (MF). Although the mechanisms of fibrosis have been extensively studied, this complex process is not yet fully understood. To focus on the most important drivers of fibrosis, we examined publicly available patient-derived datasets (SSc patient data and normal controls) using a novel data analysis method developed in-house. This analysis identified type I collagen-binding integrin α11β1 as one of the top targets for regulating fibrosis.

[0378] In some embodiments, the fibrotic disorder is 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), or includes any of these. In some embodiments, the fibrotic disorder is atrial fibrosis, endomyocardial fibrosis, articular fibrosis, mediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis, or includes any of these.

[0379] 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), nonalcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis. In some embodiments, the fibrotic disorder is, or includes, atrial fibrillation, endomyocardial fibrosis, articular fibrosis, mediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

[0380] In some embodiments, when administered to a subject, the anti-α11β1 antibody described herein reduces one or more markers, signs, and / or symptoms of the kidney-related disorders described herein. 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, upon administration to a subject, the anti-α11β1 antibody can reduce the measured markers, signs, and / or symptoms by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% compared to a control (e.g., a certain level of the measured markers, signs, and / or symptoms in the subject prior to administration of the antibody, a certain level of the measured markers, signs, and / or symptoms in a subject suffering from a kidney-related disorder, and / or the average level of the measured markers, signs, and / or symptoms in a population of subjects suffering from a kidney-related disorder).

[0381] In some embodiments, the anti-α11β1 antibodies described herein reduce the levels of COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, MMP9, or combinations thereof by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% when measured in a model of kidney-related disorder (e.g., human precision-cut kidney slices (PCKS), ReninAAV Unx db / db mouse model, or 5 / 6 nephrectomy model) compared to a control. In some embodiments, markers, signs, and / or symptoms of kidney-related disorders can be determined by measuring protein levels, RNA levels, DNA levels, or combinations thereof. In some embodiments, markers, signs, and / or symptoms of kidney-related disorders can be determined using ELISA, PCR, RNAseq, biochemical assays (e.g., analytical procedures for detecting and quantifying cellular processes (e.g., apoptosis, cell signaling) or metabolic reactions), cytology, immunohistochemistry, or combinations thereof.

[0382] In some embodiments, markers, signs and / or symptoms of kidney-related disorders can be determined by testing a biological sample from a subject. 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 contains cells or tissue. In some embodiments, the provided method further includes a step of lysing cells or performing a tissue biopsy, and one or more markers include one or more intracellular markers. A biological sample suitable for the present disclosure may be a fresh or frozen sample collected from a subject, or a stored sample having a known diagnosis, treatment and / or outcome history. The biological sample can be collected by any invasive or non-invasive means, for example, by collecting CSF or blood from the subject, or by using fine needle aspiration or needle biopsy, or by surgical biopsy. In some embodiments, the biological sample can be used without sample processing or with limited sample processing.

[0383] In some embodiments, the anti-α11β1 antibodies described herein, when administered to a subject, are useful for reducing the immune response in the subject, for example, blocking the activation of immune response mainly composed of immune complexes, for promoting the catabolism and clearance of pathogenic antibodies in the subject, such as IgG and IgG autoantibodies, and for treating the immunological state or immune disease in the subject. In particular, the anti-α11β1 antibodies described herein are useful for reducing or treating the activation of acute or chronic immune responses mainly composed of immune complexes. The acute immune response can be activated by medical conditions selected from the group consisting of pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-related rejection reaction, catastrophic antiphospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulus, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenia purpura (ITP), autoimmune haemolytic anaemia (AIHA), immune neutropenia, dilated cardiomyopathy, and serum sickness. The chronic immune response can be activated by medical conditions selected from the group consisting of chronic inflammatory demyelinating polyneuropathy (CIDP), systemic lupus, chronic forms of disorders adapted for acute treatment, reactive arthritis, primary biliary cirrhosis, ulcerative colitis, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

[0384] In some embodiments, the anti-α11β1 antibodies described herein are useful for reducing or treating an immune response activated by an autoimmune disease. Autoimmune diseases can be selected from the group consisting of alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyalgia syndrome, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes, 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, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. In some embodiments, the anti-α11β1 antibodies described herein are useful for reducing or treating an immune response activated by systemic lupus erythematosus, antiphospholipid antibody syndrome, pemphigus vulgaris / bullous pemphigoid, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis, or neuromyelitis optica.

[0385] In some embodiments, the anti-α11β1 antibodies described herein are useful for reducing or treating an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is also an autoimmune disease or disorder described herein. In some embodiments, the inflammatory disease or disorder includes hidradenitis suppurativa, also known as inverse acne or Verneuil's disease.

[0386] One 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 and progression and ultimately metastasis. Alpha11beta1 has been reported to be overexpressed in cancer-associated fibroblasts (CAFs) of metastatic tumors, and its expression has been found to correlate with invasive tumors in patients. For example, integrin alpha11 is overexpressed in the stroma of most head and neck squamous cell carcinomas (HNSCC) and is positively correlated with alpha-smooth muscle actin expression (Parajuli et al., J. Oral Pathol. Med. 46:267-275 (2017)). Integrin alpha11 is also overexpressed by CAFs in the stroma of pancreatic ductal adenocarcinoma (PDAC) (Schnittert et al., FASEB J. 33:6609-6621 (2019)). Furthermore, overexpression of integrin alpha11beta1 in the tumor stroma has been found to be associated with tumor growth and metastatic potential in non-small cell lung cancer (NSCLC). Also, in any NSCLC patients, high expression of ITGA11 (the gene encoding integrin alpha-11 in humans) was associated with a lower recurrence-free survival rate. In the same study, overexpression of alpha11beta1 in lung cancer cell lines was shown to result in increased migration and invasion (Ando et al., Cancer Sci. 111:200-208 (2020)).

[0387] Accordingly, in some embodiments, one or more anti-α11β1 antibodies described herein are used in methods of treating cancer, such as one or more of the following: squamous cell carcinoma of the head and neck, pancreatic ductal adenocarcinoma, non-small cell lung cancer, adrenocortical carcinoma, acute myeloid leukemia, urothelial carcinoma of the bladder, invasive breast cancer, squamous cell carcinoma of the cervix, cholangiocarcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, glioblastoma multiforme, hepatocellular carcinoma of the liver, lung adenocarcinoma, squamous cell carcinoma of the lung, cutaneous melanoma, mesothelioma, serous cystadenocarcinoma of the ovary, pheochromocytoma and paraganglioma, prostate ad...

Claims

1. An antibody or its antigen-binding fragment, (i) A heavy chain variable region comprising a heavy chain HCDR1 sequence, a heavy chain HCDR2 sequence, and a heavy chain HCDR3 sequence, wherein the heavy chain HCDR1 sequence comprises the amino acid sequence of SEQ ID NO: 23, the heavy chain HCDR2 sequence comprises the amino acid sequence of SEQ ID NO: 25, and the heavy chain HCDR3 sequence comprises the amino acid sequence of SEQ ID NO: 28, or a variant of any of the above, (ii) A light chain variable region comprising a light chain LCDR1 sequence, a light chain LCDR2 sequence, and a light chain LCDR3 sequence, wherein the light chain LCDR1 sequence comprises the amino acid sequence of SEQ ID NO: 34, the light chain LCDR2 sequence comprises the amino acid sequence of SEQ ID NO: 35, and the light chain LCDR3 sequence comprises the amino acid sequence of SEQ ID NO: 36, or a variant of any of the above, An antibody or its antigen-binding fragment, including the above.

2. The antibody or antigen-binding fragment according to claim 1, wherein the heavy chain variable region comprises an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with or is identical to SEQ ID NO: 31, provided that the heavy chain variable region comprises the sequences of HCDR1, HCDR2, and HCDR3 as described in claim 1.

3. The antibody or antigen-binding fragment according to claim 1, wherein the light chain variable region comprises an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with or is identical to SEQ ID NO: 37, provided that the light chain variable region comprises the sequences of LCDR1, LCDR2, and LCDR3 according to claim 1.

4. A heavy chain variable region comprising the amino acid sequence of Sequence ID No. 31, The antibody or antigen-binding fragment according to claim 1, comprising a light chain variable region containing the amino acid sequence of SEQ ID NO:

37.

5. An antibody or an antigen-binding fragment thereof, (i) A heavy chain variable region comprising a heavy chain HCDR1 sequence, a heavy chain HCDR2 sequence, and a heavy chain HCDR3 sequence, wherein the heavy chain HCDR1 sequence comprises the amino acid sequence of SEQ ID NO: 23, the heavy chain HCDR2 sequence comprises the amino acid sequence of SEQ ID NO: 26, and the heavy chain HCDR3 sequence comprises the amino acid sequence of SEQ ID NO: 29, or a variant of any of the above, (ii) A light chain variable region comprising a light chain LCDR1 sequence, a light chain LCDR2 sequence, and a light chain LCDR3 sequence, wherein the light chain LCDR1 sequence comprises the amino acid sequence of SEQ ID NO: 34, the light chain LCDR2 sequence comprises the amino acid sequence of SEQ ID NO: 35, and the light chain LCDR3 sequence comprises the amino acid sequence of SEQ ID NO: 36, or a variant of any of the above, An antibody or its antigen-binding fragment, including the above.

6. The antibody or antigen-binding fragment according to claim 5, wherein the heavy chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with or identical to SEQ ID NO: 32, provided that the heavy chain variable region comprises the sequences of HCDR1, HCDR2, and HCDR3 as described in claim 5.

7. The antibody or antigen-binding fragment according to claim 5, wherein the light chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with or identical to SEQ ID NO: 37, provided that the light chain variable region comprises the sequences of LCDR1, LCDR2, and LCDR3 according to claim 5.

8. (i) A heavy chain variable region comprising the amino acid sequence of Sequence ID No. 32 (ii) The antibody or antigen-binding fragment according to claim 5, comprising a light chain variable region containing the amino acid sequence of SEQ ID NO:

37.

9. The antibody or its antigen-binding fragment is an scFv antibody, a Fab fragment, a Fab' fragment, or F(ab') ２ A fragment of the antibody or antigen-binding fragment thereof as described in claim 1.

10. The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody is a monoclonal antibody.

11. The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody is a humanized antibody.

12. The antibody or antigen-binding fragment thereof according to claim 1, comprising a constant region such as a constant region provided herein.

13. The antibody or antigen-binding fragment according to claim 1, comprising a constant region containing 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.

14. The antibody or antigen-binding fragment according to claim 1, comprising a heavy chain constant region containing the amino acid sequence of SEQ ID NO: 63 and a light chain constant region containing the amino acid sequence of SEQ ID NO:

69.

15. The antibody or antigen-binding fragment according to claim 1, wherein the heavy chain variable region and the light chain variable region are not linked by a linker.

16. The antibody or antigen-binding fragment thereof according to claim 1, wherein the heavy chain variable region and the light chain variable region are linked by a peptide linker.

17. The aforementioned peptide linker is (GGGGS) ｎ (Sequence ID 70), (GGGGGA) ｎ The antibody or antigen-binding fragment according to claim 16, comprising the sequence (SEQ ID NO: 71), or any combination thereof, wherein each n is independently 1 to 5.

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

19. An isolated nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof, a heavy chain variable region, a light chain variable region, a heavy chain, or a light chain, as described in any one of claims 1 to 18.

20. An expression vector comprising the nucleic acid molecule described in claim 19.

21. A host cell comprising the nucleic acid molecule described in claim 19.

22. An antibody or antigen-binding fragment produced by a host cell according to claim 21.

23. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 18.

24. The pharmaceutical composition according to claim 23, which is formulated for intravenous or subcutaneous injection.

25. The pharmaceutical composition according to claim 23, which is an injectable pharmaceutical composition.

26. A method for producing a polypeptide containing a heavy chain variable region and / or a light chain variable region, (a) Growing or culturing the host cells described in claim 21 under conditions such that the host cells express a polypeptide comprising the heavy chain variable region and / or the light chain variable region, (b) Purifying the polypeptide containing the heavy chain variable region and / or the light chain variable region, Methods that include...

27. A method for producing an antibody that binds to human α11β1 integrin or an antigen-binding fragment thereof, (a) Growing or culturing the host cells described in claim 21 under conditions such that the host cells express a polypeptide (or more) comprising an immunoglobulin heavy chain variable region and / or an immunoglobulin light chain variable region, thereby producing the antibody or an antigen-binding fragment of the antibody, (b) Purifying the antibody or its antigen-binding fragment, Methods that include...

28. A pharmaceutical composition according to claim 23 for use in a method for treating a subject having an α11β1 integrin-mediated disorder, wherein the method comprises administering the pharmaceutical composition to the subject.

29. The pharmaceutical composition according to claim 28, wherein the disorder is a fibrous disorder, an autoimmune disorder, an inflammatory disorder, or cancer.

30. (a) The fibrous disorder is or includes idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), nonalcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis, or (b) The pharmaceutical composition according to claim 29, wherein the fibrotic disorder is atrial fibrosis, endocardial fibrosis, articular fibrosis, mediastinal fibrosis, myelofibrosis, progressive mass fibrosis, retroperitoneal fibrosis, or skeletal muscular fibrosis, or comprises the same.

31. The aforementioned autoimmune disorders include alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, focal scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, lupus discoid, essential mixed cryoglobulinemia, fibromyalgia, fibromyalgia, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, and idiopathic lung disease. The pharmaceutical composition according to claim 29, comprising or relating to 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, sarcomatoid, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis.

32. The pharmaceutical composition according to claim 29, wherein the inflammatory disorder is hidradenitis suppurativa.

33. The pharmaceutical composition according to claim 29, wherein the cancer is 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 cancer, colorectal adenocarcinoma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, glioblastoma pleomorphicum, hepatocellular carcinoma of the liver, lung adenocarcinoma, lung squamous cell carcinoma, cutaneous melanoma, mesothelioma, ovarian serous cystadenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, sarcoma, gastric adenocarcinoma, testicular germ cell tumor, thymoma, thyroid cancer, endometrial cancer of the uterine body, uterine carcinosarcoma, uveal melanoma, renal clear cell carcinoma, renal chromophobe, or renal papillary cell carcinoma, or includes the same.

34. The pharmaceutical composition according to claim 23, for use in the treatment of α11β1 integrin-mediated disorders, such as those described herein.

35. A pharmaceutical composition according to claim 23, for use as a pharmaceutical product.

Images