Claudin 6 antibody and its use

Abstract

Antibodies and compositions against claudin 6 and their uses are provided.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 806,048, filed February 15, 2019, which is hereby incorporated by reference in its entirety. Background Technology

[0003] Sessin 6 is a receptor overexpressed on cancer cells. Targeting sessin 6 with antibodies specific to it can help activate cytotoxic responses against cancers expressing sessin 6. Therefore, there is a need for antibodies capable of binding to sessin 6 and antibodies capable of modulating the activity of sessin 6. This disclosure addresses these and other needs. Summary of the Invention

[0004] In some implementations, a separate antibody or a nucleic acid molecule encoding the antibody is provided that binds to the protein.

[0005] In some implementations, methods for using the antibody are provided herein.

[0006] In some embodiments, an antibody is provided that binds to sealing protein 6 with an affinity of less than 10 nM and with an EC50 that is at least 100 times larger than that of sealing protein 9, sealing protein 3, and / or sealing protein 4.

[0007] In some embodiments, peptides are provided that comprise sequences or variants thereof as provided herein, or consist of or substantially consist of sequences or variants thereof as provided herein.

[0008] In some embodiments, a peptide is provided comprising a sequence or a variant thereof that is 90%-99% identical to the sequence provided herein, or consisting of or substantially consisting of a sequence or a variant thereof that is 90%-99% identical to the sequence provided herein.

[0009] In some embodiments, an antibody, such as a monoclonal antibody or scFv, is provided that binds to an epitope on sealing protein 6 (SEQ ID NO:1), wherein the binding residues of the epitope include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof. In some embodiments, the antibody binds to an epitope on sealing protein 6, wherein the epitope includes residues E48, D68, P74, D76, and R158 of sealing protein 6 (SEQ ID NO:1). In some embodiments, the antibody binds to an epitope on sealing protein 6, wherein the epitope includes residues T33, N38, E48, D76, A153, E154, Q156, and R158 of sealing protein 6 (SEQ ID NO:1). In some embodiments, the antibody binds to an epitope of sealing protein 6, the epitope comprising residues N38, E48, Y67, P74, D76, D146, V152, E154, Q156, and R158 on sealing protein 6. In some embodiments, the antibody binds to an epitope of sealing protein 6, the epitope comprising residues E48, Y67, Q156, and R158 on sealing protein 6.

[0010] In some embodiments, this document provides a bispecific antibody comprising a first VH peptide that binds to sealing protein 6 and a second VH peptide that binds to a different portion.

[0011] In some embodiments, a nucleic acid molecule encoding the antibody or amino acid sequence described herein is provided. In some embodiments, a vector comprising the nucleic acid molecule is provided. In some embodiments, a cell comprising the vector or the nucleic acid molecule is provided herein.

[0012] In some embodiments, an antibody or its isolated form is provided that binds to sealing protein 6 with an affinity of less than 10 nM and with an EC50 that is at least 100 times larger than that of sealing protein 9, sealing protein 3 and / or sealing protein 4.

[0013] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, 95, 139, 141, 143, or 145, or a variant thereof; the heavy chain CDR2 has an amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, 102, 140, 142, 144, or 146, or a variant thereof; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, 95, 139, 141, 143, or 145 ...4, 46, 48, 49, 54, 125, 72, 77, 81, 86, NO: amino acid sequence of 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or a variant of any of the foregoing.

[0014] In some embodiments, an antibody as described in any one of claims 1-3 is provided, wherein the antibody comprises a light chain variable region comprising a sequence of any one of the sequences listed in SEQ ID NO:127-135.

[0015] In some embodiments, an antibody is provided comprising a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of SEQ ID NO: 23, 29, 41, 51, 59, 68, 84, 88, or 99; and the light chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, or 94, or a variant of any of the foregoing.

[0016] In some embodiments, an antibody or antigen-binding fragment thereof is provided, wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; the heavy chain CDR2 has an amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102; and the heavy chain CDR3 sequence has SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102 ... NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97 amino acid sequences, or variants of any of the preceding items; and (ii) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93 or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88 or 99; and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94 amino acid sequences, or variants of any of the preceding items.

[0017] In some embodiments, peptides are provided that comprise sequences or variants thereof as provided herein, or consist of or substantially consist of sequences or variants thereof as provided herein.

[0018] In some embodiments, antibodies, such as monoclonal antibodies or scFv, that bind to epitopes on sealing protein 6 are provided, wherein the residues of sealing protein 6 include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof.

[0019] In some embodiments, antibodies, such as monoclonal antibodies or scFv, that preferentially bind to sealing protein 6 compared to sealing protein 9 are provided, wherein the antibodies bind to an epitope on sealing protein 6 containing Q156.

[0020] In some embodiments, a bispecific antibody is provided comprising a first VH peptide that binds to sealing protein 6 and a second VH peptide that binds to a different portion.

[0021] In some embodiments, a pharmaceutical composition is provided comprising one or more antibodies described herein or a nucleic acid molecule encoding one or more antibodies.

[0022] In some implementations, a nucleic acid molecule encoding the antibody or amino acid sequence provided herein is provided.

[0023] In some embodiments, a method is provided to modulate the activity of sealing protein 6 by contacting cells expressing sealing protein 6 with an antibody to sealing protein 6 or a pharmaceutical composition containing said antibody, said antibody binding to sealing protein 6 on the cell surface.

[0024] In some embodiments, a method is provided to inhibit the function of sealing protein 6 by contacting cells expressing sealing protein 6 with an antibody or a pharmaceutical composition containing said antibody that inhibits the function of sealing protein 6 by binding to sealing protein 6.

[0025] In some embodiments, a method is provided for treating a subject with a condition mediated by sealing protein 6, the method comprising administering to the subject a pharmaceutical composition comprising an antibody containing sealing protein 6, such as any antibody provided herein or a nucleic acid molecule encoding the antibody.

[0026] In some embodiments, a method of treating a subject’s cancer is provided, the method comprising administering a therapeutic agent that specifically binds to sealing protein 6 and to CD3 and / or 4-1BB.

[0027] In some embodiments, a method of treating a subject's cancer is provided, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising an antibody that binds to residue Q156 of sealing protein 6 or a nucleic acid molecule encoding the antibody.

[0028] In some implementations, chimeric receptors comprising antibody domains as provided herein are provided.

[0029] In some embodiments, compositions comprising an antibody or antibody domain, as provided herein, linked to a drug or other therapeutic agent.

[0030] In some embodiments, compositions comprising peptides as provided herein, such as peptides comprising one or more sequences of SEQ ID NO: 2-135, are provided.

[0031] In some embodiments, a method is provided for detecting the presence or absence of sealing protein 6 in a sample, the method comprising contacting the sample with an antibody as provided herein and any of the preceding claims and detecting binding of the antibody to the sealing protein 6 antigen, wherein detection of binding indicates the presence of sealing protein 6; or no detection of binding to sealing protein 6 indicates the absence of sealing protein 6.

[0032] In some embodiments, a method is provided for delivering a composition to cells expressing sealing protein 6, the method comprising contacting the cells with an antibody as provided herein, wherein the antibody is linked to another molecule to be delivered to the cells expressing sealing protein 6.

[0033] In some embodiments, a method is provided for contacting a composition with cells expressing sealing protein 6, the method comprising contacting the cells with an antibody as provided herein, wherein the antibody is linked to another molecule to contact the cells expressing sealing protein 6. Attached Figure Description

[0034] Figure 1 An exemplary, non-limiting embodiment of an antibody binding to sealing protein 6 is shown.

[0035] Figure 2 Various implementation schemes as provided herein are illustrated.

[0036] Figure 3 Various implementation schemes as provided herein are illustrated.

[0037] Figure 4 Various embodiments as provided herein are illustrated, including showing that IM136 and IM171 bind to PA-1 cells that naturally express sealing protein-6, as detected by flow cytometry.

[0038] Figure 5 Various embodiments as provided herein are illustrated, including MAb binding to PA-1 cells that naturally express sealing protein-6, as detected by flow cytometry.

[0039] Figure 6 Various embodiments as provided herein are illustrated, including showing MAb IM171 binding to a proteome array consisting of 5,300 human membrane proteins expressed in human HEK-293 cells, and demonstrating that IM171 has high specificity for sealing protein 6.

[0040] Figure 7Various embodiments as provided herein are illustrated, including showing that CAR-T cells expressing the sealing protein 6 antibody IM136 are activated by cells expressing human or murine sealing protein 6. CAR-T cells without the sealing protein antibody ('CAR-negative T cells') are not activated by cells expressing sealing protein 6. Cell activation is measured by CD69 expression after overnight co-incubation (as detected by flow cytometry using an anti-CD69 antibody).

[0041] Figure 8 Various implementation schemes as provided herein are illustrated. Detailed Implementation

[0042] The isolation and characterization of a monoclonal antibody (MAb) that recognizes sealing protein 6 are described and disclosed herein. In some embodiments, a MAb targeting sealing protein 6 is generated using virus-like particles (VLPs) to present this multi-transmembrane protein in its native conformation. In some embodiments, the antibody binds to sealing protein 6 but does not significantly bind to sealing protein 9. In some embodiments, the antibody binds to sealing protein 6 with an affinity, EC50, or KD that is at least 10, 20, 30, 40, 50, 75, 100, 200, or 300 times greater than its binding to sealing protein 9. In some embodiments, the antibody binds to sealing protein 6 but does not significantly bind to sealing protein 3. In some embodiments, the antibody binds to sealing protein 6 with an affinity, EC50, or KD that is at least 10, 20, 30, 40, 50, 75, 100, 200, or 300 times greater than its binding to sealing protein 3. In some embodiments, the antibody binds to sealing protein 6 but not significantly to sealing protein 4. In some embodiments, the antibody binds to sealing protein 6 with an affinity, EC50, or KD that is at least 10, 20, 30, 40, 50, 75, 100, 200, or 300 times greater than its binding to sealing protein 4.

[0043] In some embodiments, sealing protein 6 comprises an amino acid sequence comprising:

[0044]

[0045] As used herein, the term “antibody” is used in a broad sense and includes immunoglobulins or antibody molecules, including polyclonal antibodies, monoclonal antibodies, including murine, human, humanized and chimeric monoclonal antibodies and antibody fragments such as ScFv or hexaantibodies (PLOS Biology|DOI:10.1371 / journal.pbio.1002344 January 6, 2016, which is hereby incorporated herein by reference in its entirety).

[0046] As used herein, the terms “humanized antibody,” “engineered antibody,” “human-framework adapted,” and “HFA” are intended to include antibodies having a variable region frame of sequences derived from human origin. Furthermore, if the antibody contains a constant region, the constant region may be derived from such human sequences, such as human germline sequences, or naturally occurring (e.g., allotypes) or mutant forms of human germline sequences. Humanized antibodies may include amino acid residues not encoded by human sequences (e.g., mutations introduced through random or site-specific mutagenesis in vitro or through somatic mutations in vivo).

[0047] Generally, antibodies are proteins or peptides that exhibit binding specificity to a particular antigen. A complete antibody is a heterotetrameric glycoprotein composed of two identical light chains and two identical heavy chains. Typically, each light chain is linked to the heavy chain by a covalent disulfide bond, although the number of disulfide bonds varies between heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end, followed by multiple constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at the other end; the constant domain of the light chain aligns with the first constant domain of the heavy chain, and the variable domain of the light chain aligns with the variable domain of the heavy chain. The antibody light chain of any vertebrate species can be designated as one of two distinct types (i.e., κ and λ) based on the amino acid sequence of its constant domain. Immunoglobulins can be classified into five main classes based on the amino acid sequence of the heavy chain's constant domain: IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4.

[0048] The term "antibody fragment" refers to a portion of a complete antibody, typically the antigen-binding region or variable region of the complete antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabody; single-chain antibody molecules; and multispecific antibodies formed from at least two complete antibodies.

[0049] As used herein, the term "antigen" refers to any molecule that has the ability to produce antibodies, directly or indirectly. The definition of "antigen" includes nucleic acids that encode proteins.

[0050] As used herein, "specific binding," "immunospecific binding," or "immunospecifically binding" refers to the binding of an antibody to a predetermined antigen (e.g., sealing protein 6) or an epitope present on said antigen. In some embodiments, the dissociation constant (KD) of antibody binding is 10⁻⁷ M or less, and the KD bound to the predetermined antigen is at least twice as small as the KD bound to a nonspecific antigen other than said predetermined antigen (e.g., BSA, casein, or another nonspecific polypeptide). The phrases "antibody recognizing sealing protein 6" and "antibody specific to sealing protein 6" are used interchangeably herein with the term "antibody that binds immunospecifically to sealing protein 6." Sealing protein 6 may be referenced in this disclosure. In some embodiments, the antibody is specific to sealing protein 6 and does not specifically bind to sealing protein 3, sealing protein 4, and / or sealing protein 9.

[0051] “CDR” is defined as the complementarity-determining region amino acid sequence of an antibody, which is a hypervariable region of the heavy and light chains of an immunoglobulin. See, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., U.S. Department of Health and Human Services, National Institutes of Health (1987). Three heavy chain and three light chain CDRs, or CDR regions, exist within the variable portion of an immunoglobulin. Therefore, where appropriate, as used herein, “CDR” refers to all three heavy chain CDRs, or all three light chain CDRs, or all heavy chain CDRs and all light chain CDRs.

[0052] CDRs provide most of the contact residues for antibody-antigen or epitope binding. Target CDRs may be derived from the variable heavy and light chain sequences of the donor antibody and include analogs of naturally occurring CDRs that also share or retain the same antigen-binding specificity and / or neutralizing capacity as the donor antibodies from which they are derived.

[0053] The term "homolog" refers to a protein sequence that has between 40% and 100% sequence identity with a reference sequence. The percentage of identity between two peptide chains can be determined by comparative alignment using the default settings of the AlignX module in Vector NTI v.9.0.0 (Invitrogen Corp., Carslbad, Calif.). In some embodiments, the antibody or a fragment thereof has at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence described herein. In some embodiments, the antibody has conserved substitutions compared to the sequence described herein. In some embodiments, the number of substitutions can be 1, 2, 3, 4, 5, 6, 7, 8, or 9. These molecules that differ based on the percentage of identity or substitutions may also be referred to as "variants." Antibodies with conserved substitutions in the heavy and light chain sequences shown in Table 1 are included within the scope of the disclosed subject matter. Conservative substitutions can be located in the frame region or the antigen-binding site, as long as they do not adversely affect the properties of the antibody. Substitutions can be made to improve antibody properties, such as stability or affinity. Conservative substitutions will produce molecules with functional and chemical properties similar to those of molecules in which such modifications are made. Exemplary amino acid substitutions are shown in the table below.

[0054]

[0055] As used herein, the term "in combination with" means that the described agents may be administered to animals in a mixture, as a single agent simultaneously, or as single agents in any order.

[0056] Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the serum of animals immunized with antigens. Monoclonal antibodies comprise a substantially homogeneous population of antibodies that are specific to antigens and contain substantially similar epitope binding sites. MAbs can be obtained by methods known to those skilled in the art. See, for example, Kohler and Milstein, Nature 256:495 497 (1975); U.S. Patent No. 4,376,110; Ausubel et al., eds., Current Protocols in Molecular Biology, Greene Publishing Assoc. and Wiley Interscience, NY, (1987, 1992); and Harlow and Lane ANTIBODIES: A Laboratory Manual Cold Spring Harbor Laboratory (1988); Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993), the contents of which are incorporated herein by reference in their entirety. These antibodies can be any class of immunoglobulins, including IgG, IgM, IgE, IgA, GILD, and any of their subclasses. Hybridomas that produce mAbs can be cultured in vitro, in situ, or in vivo. Producing high-titer mAbs in vivo or in situ makes this the currently preferred production method.

[0057] Chimeric antibodies are molecules whose different parts are derived from different animal species, such as molecules with a variable region derived from mouse mAbs and a constant region from human immunoglobulins. They are primarily used to reduce immunogenicity in applications and increase yield in production. For example, mouse mAbs derived from hybridomas have higher yields but higher immunogenicity in humans; therefore, human / mouse chimeric mAbs are used. Chimeric antibodies and their production methods are known in the art (Cabilly et al., Proc. Natl. Acad. Sci. USA 81:3273 3277 (1984); Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851 6855 (1984); Boulianne et al., Nature 312:643 646 (1984); Cabilly et al., European Patent Application 125023 (published November 14, 1984); Neuberger et al., Nature 314:268). 270 (1985); Taniguchi et al., European Patent Application 171496 (published February 19, 1985); Morrison et al., European Patent Application 173494 (published March 5, 1986); Neuberger et al., PCT Application WO86 / 01533 (published March 13, 1986); Kudo et al., European Patent Application 184187 (published June 11, 1986); Morrison et al., European Patent Application 173494 (published March 5, 1986); Sahagan et al., J. Immunol. 137:1066 1074 (1986); Robinson et al., International Patent Application WO 1987 / 002671 (published May 7, 1987); Liu et al., Proc. Natl. Acad. Sci. USA 84:3439 3443 (1987); Sun et al., Proc. Natl. Acad. Sci. USA 84:214 218 (1987); Better et al., Science 240:1041 1043 (1988); and Harlow and Lane Antibodies. A Laboratory Manual Cold Spring Harbor Laboratory (1988). These references are incorporated herein by reference in their entirety.

[0058] Anti-idiotype (anti-Id) antibodies are antibodies that recognize unique determinants typically associated with the antigen-binding site of an antibody. Id antibodies can be prepared by immunizing an animal of the same species and genetic type (e.g., a mouse strain) as the source of the mAb with an anti-Id prepared against it. The immunized animal will recognize and respond to the idiotype determinants of the immunizing antibody by producing antibodies against these idiotype determinants (anti-Id antibodies). See, for example, U.S. Patent No. 4,699,880, which is incorporated herein by reference in its entirety. Anti-Id antibodies can also be used as “immunogens” to induce an immune response in another animal, thereby producing so-called anti-anti-Id antibodies. Anti-anti-Id may be epitope identical to the original mAb that induced the anti-Id. Therefore, by using antibodies against the idiotype determinants of the mAb, it is possible to identify other clones of antibodies expressing the same specificity.

[0059] As used herein, the term “monoclonal antibody” (mAb) refers to an antibody (or antibody fragment) obtained from a substantially homogeneous population of antibodies. Monoclonal antibodies are highly specific and typically target a single antigenic determinant. The modifier “monoclonal” indicates the substantially homogeneous nature of the antibody and that no particular method is required to produce the antibody. For example, murine mAbs can be prepared using the hybridoma method described in Kohler et al., Nature 256:495-497 (1975). Chimeric mAbs containing variable regions of the light and heavy chains derived from a donor antibody (typically murine) and constant regions of the light and heavy chains derived from a recipient antibody (typically another mammal, such as a human) can be prepared using the method disclosed in U.S. Patent No. 4,816,567. Humanized mAbs having a CDR derived from a non-human donor immunoglobulin (typically murine) and the remaining immunoglobulin-derived portion of a molecule derived from one or more human immunoglobulins (optionally having modified framework support residues to retain binding affinity) can be obtained using techniques disclosed in Queen et al., Proc. Natl. Acad. Sci. (USA), 86:10029-10032 (1989) and Hodgson et al., Bio / Technology, 9:421 (1991).

[0060] If you want to have a nice smile, you can have a smile on your face Download, www“dot”ncbi“dot”nlm“dot”nih “dot”gov / entrez / query“dot”fcgi;www“dot”ncbi“dot”nih“dot”gov / ig blast:www tabase“dot”com / top“dot”html,ftpdotncbidotnihdotgov / repository / kabatwwwdotsciquestdotcomwwwdotabcamdotcomwww w“dot”antibodyresource“dot”com / onlinecomp“dot”htmlwww“dot”public“dot”iastate“dot”edu / “dot”about“dot”pedro / research_tools“d ot”html;www“dot”whfreeman“dot”com / immunology / CH05 / cuby05“dot”htmwww“dot”hhmi“dot”org / grants / lectures / 1996 / vlab / www“dot”pat h“dot”cam“dot”ac“dot”uk / “dot”about“dot”mrc7 / mikeimages“dot”html;mcb“dot”harvard“dot”edu / BioLinks / Immunology“dot”html / www“do t”immunologylink“dot”com:pathbox“dot”wustl“dot”edu / “dot”about“dot”hcenter / index“dot”htmlwww“dot”appliedbiosystems“dot”com; wwwdot”nal“dot”usda“dot”gov / awic / pubs / antibody;wwwdotm“dot”ehime-u“dot”ac“dot”jp / dotabout“dot”yasuhito / Elisa“dot”html;www "dot" biodesign "dot" com; www "dot" cancerresearchuk "dot" org; www "dot" biotech "dot" ufl "dot" edu; www "dot" isac-net "dot" org; ni-hd "dot" de / immuno "dot" bme "dot" nwu "dot" edu; www "dot" mrc - cpe "dot" cam "dot" ac "dot" uk; www "dot" ibt "dot" una m"dot"mx / vir / V_mice"dot"html;http: / / www"dot"bioinf"dot"org"dot"uk / abs;antibody"dot"bath"dot"ac"dot"uk; www"dot"unizh"dot"ch;www"dot"cryst"dot"bbk"dot"ac"dot"uk / "dot"about"dot"ubcg07s;www"dot"nimr"dot"mrc" dot"ac"dot"uk / CC / ccaewg / ccaewg"dot"html;www"dot"path"dot"cam"dot"ac"dot"uk / "dot"about"dot"mrc7 / humanis ation / TAHHP"dot"html;www"dot"ibt"dot"unam"dot"mx / vir / structure / stat_aim"dot"html;www"dot"biosci"dot"m issouri "dot" edu / smithgp / index "dot" html; www "dot" jerini "dot" de; imgt "dot" cines "dot" fr; and Kabat et al., Sequences The references to *Proteins of Immunological Interest*, USDept. Health (1987), are fully incorporated herein by reference. Where appropriate, the dot in web addresses cited herein may be replaced with a period.

[0061] The antibodies described herein may include, but are not limited to, at least one of the heavy chain constant region (Hc), heavy chain variable region (Hv), light chain variable region (Lv), and light chain constant region (Lc), wherein a polyclonal Ab, a monoclonal Ab, a fragment thereof, and / or a region thereof contains at least one heavy chain variable region (Hv) or light chain variable region (Lv) that binds to a portion of sealing protein 6 and can be used to detect an antigen. The antibody may also be a monoclonal antibody prepared by immunizing chickens. The variable chain from the nucleic acid sequence encoding the isolated monoclonal antibody may be isolated using techniques such as, but not limited to, PCR. The variable chain isolated by these techniques may then be placed in an scFv vector having a human Fc. Thus, the antibody may be an antibody having a human Fc and two scFv arms. The antibody (such as those described herein and throughout this disclosure) may then be modified to be a human or humanized antibody. Examples of ways to modify antibodies (including chicken antibodies) can be found, for example, 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, Vásquez M, Kumar S. (2004); and “Humanization of a chicken anti-IL-12monoclonal antibody” Immunol Methods 295(1-2):9-19; Nishibori N, Horiuchi H, Furusawa S, Matsuda H. (2006) “Humanization of chicken monoclonal antibody using phage display system” Mol Immunol. 43(6):634-42, each of which is incorporated herein by reference in its entirety.

[0062] Methods for determining mAb specificity and affinity by competitive inhibition can be found in Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988; Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993); and Muller, Meth. Enzymol. 92:589601 (1983), all of which are incorporated herein by reference in their entirety.

[0063] Techniques for generating antibodies against small peptide sequences are well known in the art, which recognize and bind to those sequences in free or conjugated form, or when presented as natural sequences against a background of large proteins. Such antibodies include murine, murine-human, and human-human antibodies generated using hybridoma or recombinant techniques known in the art. Antibodies can also be generated in chickens, goats, rabbits, or other small animals.

[0064] As used herein, the term "antigen-binding region" refers to the portion of an antibody molecule containing amino acid residues that interact with an antigen (e.g., sealing protein 6) and confer specificity and affinity to said antigen on the antibody. The antibody region includes the "framework" amino acid residues necessary to maintain the correct conformation of the antigen-binding residues. In some embodiments, the antigen-binding region will be of rodent origin. In some embodiments, the antigen-binding region may be derived from other animal species, particularly rodents such as rabbits, rats, or hamsters, or birds such as chickens. It has been shown that the antigen-binding function of an antibody can be performed by a fragment of a full-length antibody. Examples of binding fragments included within the “antigen-binding portion” of the term antibody include Fab fragments, which are monovalent fragments having VL, VH, CL, and CH1 domains; F(ab)2 fragments, which are bivalent fragments containing two Fab fragments linked by disulfide bridges in the hinge region; Fd fragments having VH and CH1 domains; Fv fragments having VL and VH domains in a single arm of the antibody; domain antibody or dAb fragments (Ward et al., 1989 Nature 341:544-546) consisting of a VH domain; and separated complementarity-determining regions (CDRs), especially CDR3 (see, for example, WO03 / 025019, the contents of which are incorporated herein by reference).

[0065] The term "complementarity-determining region (CDR)" is based on sequence variability (Wu and Kabat, J. Exp. Med. 132:211-250, 1970). There are six CDRs—three in the variable heavy chain (VH) and commonly referred to as H-CDR1, H-CDR2, and H-CDR3; and three in the variable light chain (VL) and commonly referred to as L-CDR1, L-CDR2, and L-CDR3 (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). "Hypervariable region," "HVR," or "HV" refers to a structurally variable antibody variable domain, as defined by Chothia and Lesk (Chothia and Lesk, Mol. Biol. 196:901-917, 1987). There are six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Chothia and Lesk refer to the structurally conserved HVs as the “canonical structure.” Lefranc (Lefranc et al., Developmental & Comparative Immunology 27:55-77, 2003) proposed an alternative method for describing the regions forming antigen-binding sites based on comparisons of V domains from immunoglobulins and T-cell receptors (Lefranc et al., Developmental & Comparative Immunology 27:55-77, 2003). Antigen-binding sites can also be described according to Almagro (Almagro, Mol. Recognit. 17:132-43, 2004) based on “specifically determined residue use (SDRU)”, where SDRU refers to the amino acid residues of immunoglobulins that directly participate in antigen contact.

[0066] Furthermore, although the two domains VL and VH of the Fv fragment are naturally encoded by separate genes, they can be linked using recombination methods via synthetic linkers that enable them to be made into a single protein chain in which the VL and VH regions pair to form a monovalent molecule (referred to as single-chain Fv (scFv); see, for example, Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Nat. Acad. Sci. 85:5879-5883). The term “antigen-binding portion” of an antibody encompasses such single-chain antibodies. These antibody fragments are obtained using conventional techniques known to those skilled in the art and can be used in the same manner as intact antibodies.

[0067] As used herein, “isolated antibody” means an antibody that is substantially free of other antibodies with different antigen specificities (e.g., an isolated antibody that specifically binds to sealing protein 6 is substantially free of antibodies that specifically bind to antigens other than sealing protein 6). Furthermore, isolated antibodies may be substantially free of other cellular material and / or chemicals. Isolated antibodies may also be sterile or pyrogen-free, or formulated as an injectable drug as described herein.

[0068] In some implementations, the source of the DNA encoding non-human antibodies includes antibody-producing cell lines, such as hybrid cell lines commonly referred to as hybridomas.

[0069] An "antigen" is a molecule or part of a molecule that can be bound by an antibody and which can further induce an animal to produce an antibody that can bind to an epitope of the antigen. An antigen may have one or more epitopes. The specificity mentioned above is intended to indicate that the antigen will react with its corresponding antibody in a highly selective manner and will not react with a variety of other antibodies that can be elicited by other antigens. In some embodiments, the antigen that binds to the antibody, fragments of the antibody, and regions contains at least five amino acids. In some embodiments, the antigen is a sealing protein 6 protein expressed on the surface of a cell or particle. In some embodiments, the cell is an intact cell. An intact cell is a cell that has not been lysed or broken using detergents or other reagents. Cells treated with detergents or other reagents that would damage or perforate the cell membrane are not intact cells. By expressing a receptor on the surface of a cell or particle (e.g., a lipid particle), the receptor may present a conformational epitope that might otherwise not be present when using purified proteins. Examples are provided herein. In some embodiments, no adjuvant is used, but an adjuvant may be used. In some embodiments, the particle is injected into a bird (e.g., a chicken) to stimulate an immune response and produce antibodies against proteins present on the surface of the particle. Suitable particles for antibody production are described in U.S. Patent Nos. 8,377,691, 7,763,258, and 8,158,130, and U.S. Patent Application Publications Nos. 20050123563 and 20120195882, each of which is incorporated herein by reference. These publications and patent descriptions can be used for the production of various particles (including lipid particles) expressing transmembrane proteins (e.g., multimembrane transmembrane proteins, ion channels, etc.).

[0070] The term "epitope" refers to a portion of any molecule that can be recognized and bound by an antibody to the antigen-binding region of one or more antibodies (Abs). Epitopes typically consist of chemically active surface groups (such as amino acid or sugar side chains) of a molecule and possess specific three-dimensional structural features and specific charge characteristics. Examples of epitopes include, but are not limited to,

[0071] As used herein, the term "chimeric antibody" includes monovalent, divalent, or multivalent immunoglobulins. A monovalent chimeric antibody is a dimer (HL) formed by the association of a chimeric H chain with a chimeric L chain via a disulfide bridge. A divalent chimeric antibody is a tetramer (H2L2) formed by the association of two HL dimers via at least one disulfide bridge. Multivalent chimeric antibodies can also be generated, for example, by using aggregated CH regions (e.g., from IgM H or μ chains). In some embodiments, murine and chimeric antibody fragments and regions comprise separate heavy (H) and / or light (L) immunoglobulin chains.

[0072] Antibodies, fragments, or derivatives of chimeric H and L chains with the same or different variable region binding specificities can also be prepared by appropriate association of individual polypeptide chains according to known method steps, such as those described by Ausubel (hereinafter), Harlow (hereinafter), and Colligan (hereinafter), the contents of which are incorporated herein by reference in their entirety. Using this method, the host expressing the chimeric H chain (or a derivative thereof) is cultured separately from the host expressing the chimeric L chain (or a derivative thereof), and the immunoglobulin chains are recovered separately and then associated. Alternatively, the hosts can be co-cultured, and the chains can be allowed to spontaneously associate in the culture medium, after which the assembled immunoglobulins, fragments, or derivatives can be recovered.

[0073] Hybrid cells are formed by the fusion of cells that produce non-human antibodies (typically spleen cells from animals immunized against natural or recombinant antigens or peptide fragments of antigen protein sequences). Alternatively, cells that produce non-human antibodies can be B lymphocytes obtained from the blood, spleen, lymph nodes, or other tissues of an animal immunized with an antigen.

[0074] The second fusion partner providing immortalization function can be a lymphoblastoid, plasmacytoma, or myeloma cell that is not itself an antibody-producing cell but is malignant. Fusion partner cells include, but are not limited to, hybridoma SP2 / 0-Ag14, abbreviated as SP2 / 0 (ATCC CRL1581) and myeloma P3X63Ag8 (ATCC TIB9), or derivatives thereof. See, for example, Ausubel (hereinafter), Harlow (hereinafter), and Colligan (hereinafter), the contents of which are incorporated herein by reference in their entirety.

[0075] Antibodies can be generated according to the embodiments provided herein. Antibodies can also be generated using known methods once the sequence is known. Antibodies can also be converted to different types, such as human IgG. By converting antibodies to human antibodies, human subjects should not identify the antibodies as foreign antibodies. This will produce a more effective response. The conversion of non-human IgG antibodies to human IgG antibodies is well-known and can be routinely performed once the natural sequence is known. Antibodies can be modified according to known methods as discussed herein. 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, Vásquez M, Kumar S. (2004); and “Humanization of a chicken anti-IL-12monoclonal antibody” Immunol Methods 295(1-2):9-19; Nishibori N, Horiuchi H, Furusawa S, Matsuda H. (2006) “Humanization of chicken monoclonal antibody using phage display system” Mol Immunol. 43(6):634-42, each of which is incorporated herein by reference in its entirety.

[0076] Antibody-producing cells that contribute nucleotide sequences encoding antigen-binding regions of chimeric antibodies can also be generated through transformation of non-human cells, such as primates or human cells. For example, antibody-producing B lymphocytes can be infected and transformed with viruses such as Epstein-Barr virus to produce immortalized antibody-producing cells (Kozbor et al., Immunol. Today 4:72 79 (1983)). Alternatively, B lymphocytes can be transformed by providing a transforming gene or transforming gene product well known in the art. See, for example, Ausubel (hereinafter), Harlow (hereinafter), and Colligan (hereinafter), the contents of which are incorporated herein by reference in their entirety.

[0077] Cell fusion is performed using standard procedures well known to those skilled in the art of immunology. Fusion partner somatic cell lines and methods used for fusion and selection of hybridomas and screening of mAbs are well known in the art. See, for example, Ausubel (hereinafter), Harlow (hereinafter), and Colligan (hereinafter), the contents of which are incorporated herein by reference in their entirety.

[0078] Antigen-specific murine or chimeric mAbs can be produced in large quantities by injecting antibody-secreting hybridoma or transfected tumor cells into the peritoneal cavity of mice, harvesting ascites containing high titers of mAb after an appropriate time, and separating the mAb from the ascites. For this in vivo production using non-mouse hybridomas (e.g., rats or humans) of mAbs, the hybridoma cells are preferably grown in irradiated or thymus-agnostic nude mice. Alternatively, antibodies can be produced by culturing hybridoma or transfected tumor cells in vitro and separating the secreted mAb from the cell culture medium or by recombinant synthesis in eukaryotic or prokaryotic cells.

[0079] In some embodiments, the antibody is an MAb that binds to sealing protein 6. In some embodiments, the antibody binds to an amino acid of an epitope of sealing protein 6. Epitopes are described herein (as shown in the table provided in the figures) and in the examples. In some embodiments, the antibody specifically binds to the protein and antigen described herein.

[0080] In some implementations, the antibody comprises a sequence as provided herein.

[0081] The antibody sequence can be modified to generate human IgG antibodies. Transformation of the sequences provided herein can be modified to generate other types of antibodies. The CDR can also be linked with other antibodies, proteins, or molecules to generate antibody fragments that bind to sealing protein 6. The CDR and antibody sequences provided herein can also be humanized or made fully human using known methods. The sequences can also be made into chimeric antibodies as described herein.

[0082] In some embodiments, the antibody comprises an amino acid sequence comprising the sequence provided herein or a fragment thereof. In some embodiments, the antibody comprises one or more amino acid sequences as provided herein, an antigen-binding fragment thereof, or a human IgG variant thereof. "Human IgG variant" refers to an antibody that has been modified to be human IgG when the starting antibody is not a human IgG antibody.

[0083] As described herein, the production of antibodies with known sequences is conventional and can be performed by any method. Therefore, in some embodiments, a nucleic acid encoding an antibody or a fragment thereof is provided. In some embodiments, the nucleic acid encodes the sequence provided herein. Antibodies may also be modified into chimeric antibodies or human antibodies. Antibodies may also be used in injectable pharmaceutical compositions. Also as described herein, antibodies may be isolated antibodies or engineered antibodies.

[0084] In some embodiments, "derivatives" of antibodies, fragments, regions, or derivatives thereof are provided, the term encompassing those proteins encoded by truncated or modified genes to produce molecular species 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 may also include reporter proteins, such as fluorescent or chemiluminescent tags. Fragments and derivatives can be generated in any manner.

[0085] Fragments include, for example, Fab, Fab', F(ab')2, and Fv. These fragments lack the Fc fragment of the intact antibody, are cleared from circulation more rapidly, and may have less nonspecific tissue binding than the intact antibody (Wahl et al., J. Nucl. Med. 24:316 325 (1983)). These fragments are produced from the intact antibody using methods well known in the art, such as by proteolytic cleavage with enzymes such as papain (to produce the Fab fragment) or pepsin (to produce the F(ab')f fragment).

[0086] The identification of these antigen-binding regions and / or epitopes recognized by the Abs described herein provides the information necessary to generate additional monoclonal antibodies with similar binding characteristics and therapeutic or diagnostic utility that are parallel to the embodiments of this application.

[0087] The nucleic acid sequence encoding the antibodies described herein may be genomic DNA or cDNA, or RNA (e.g., mRNA), encoding at least one of the variable regions described herein. A convenient alternative to using chromosomal gene fragments as the DNA source encoding the V region antigen-binding segment is to construct chimeric immunoglobulin genes using cDNA, for example, as reported by Liu et al., (Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987), the references of which are incorporated herein by reference in their entirety. Using cDNA requires combining gene expression elements suitable for the host cell with the gene to achieve the synthesis of the desired protein. Using cDNA sequences is advantageous over genomic sequences (which contain introns) because cDNA sequences can be expressed in bacteria or other hosts lacking a suitable RNA splicing system.

[0088] For example, cDNA encoding an antigen-binding segment of the V region capable of detecting, binding, or neutralizing the seal protein 6 antigen can be provided using known methods based on the amino acid sequence provided herein. Because the genetic code is degenerate, more than one codon can be used to encode a specific amino acid (Watson et al., hereinafter). Using the genetic code, one or more different oligonucleotides can be identified, each of which can encode an amino acid. The probability that a particular oligonucleotide will actually constitute the actual coding sequence can be estimated by considering anomalous base pairings and the frequency with which a particular codon is actually used (to encode a specific amino acid) in eukaryotic or prokaryotic cells expressing antibodies or fragments. This “codon usage rule” is disclosed by Lathe et al., J. Molec. Biol. 183:1 12 (1985). Using Lathe’s “codon usage rule,” a single oligonucleotide or a group of oligonucleotides containing the theoretically “most likely” nucleotide sequence capable of encoding the variable or constant region sequence of an antibody can be identified.

[0089] The variable regions described herein can be combined with any type of constant region, including human constant regions or murine constant regions. Human genes encoding constant (C) regions of antibodies, fragments, and regions can be obtained from human embryonic liver libraries using known methods. Human C region genes can be derived from any human cell, including those that express and produce human immunoglobulins. Human CH regions can be derived from any known class or isotype of the human H chain, including γ, μ, α, δ, or ε, and their subtypes such as G1, G2, G3, and G4. Since H chain isotypes are responsible for various effector functions of antibodies, the selection of CH regions will be guided by the desired effector function, such as complement fixation or antibody-dependent cytotoxicity (ADCC) activity. Preferably, CH regions are derived from γ1 (IgG1), γ3 (IgG3), γ4 (IgG4), or μ (IgM). Human CL regions can be derived from human L chain isotypes, κ, or λ.

[0090] Genes encoding the human immunoglobulin C region can be obtained from human cells using standard cloning techniques (Sambrook et al., *Molecular Cloning: A Laboratory Manual*, 2nd ed., Cold Spring Harbor Press, Cold Spring Harbor, NY (1989) and Ausubel et al., *Current Protocols in Molecular Biology* (1987-1993)). Human C region genes are readily obtained from known clones containing genes representing two classes of L chains, five classes of H chains, and their subclasses. Chimeric antibody fragments, such as F(ab')2 and Fab, can be prepared by designing appropriately truncated chimeric H chain genes. For example, a chimeric gene encoding the H chain portion of the F(ab')2 fragment would include the CH1 domain and hinge region encoding the H chain, followed by a DNA sequence that translates a stop codon to produce a truncated molecule.

[0091] Generally, the mouse, human, or mouse and chimeric antibodies, antibody fragments, and regions described herein are generated by cloning DNA segments encoding the H and L chain antigen-binding regions of a seal protein 6 antigen-specific antibody and linking these DNA segments to DNA segments encoding the CH and CL regions, respectively, to generate mouse, human, or chimeric immunoglobulin-encoding genes.

[0092] Therefore, in some embodiments, a fusion chimeric gene is generated, which comprises at least a first DNA segment encoding a non-human antigen-binding region, such as a functionally rearranged V region having a linking (J) segment, the first DNA segment being linked to a second DNA segment encoding at least a portion of the human C region.

[0093] Therefore, the method for generating chimeric antibodies using cDNA encoding the V and C regions of an antibody, according to some embodiments described herein, comprises several steps, illustrated below: 1. Isolating messenger RNA (mRNA) from a cell line that produces an antibody against the anti-sealing protein 6 antigen and optionally from another antibody providing the heavy constant region and light constant region; cloning and generating cDNA from said mRNA; 2. Preparing a full-length cDNA library from the purified mRNA, from which appropriate V and / or C region gene fragments of the L and H chain genes of said library are: (i) identified with appropriate probes, (ii) sequenced, and (iii) compatible with C or V gene fragments from another antibody derived from the chimeric antibody; 3. Constructing the complete H or L chain coding sequence by linking a specific cloned V region gene segment with a cloned C region gene, as described above; 4. Expressing and generating the L and H chains in a selected host (including prokaryotic and eukaryotic cells) to provide mouse-mouse, human-mouse, human-human, or human-mouse antibodies.

[0094] A common feature of all immunoglobulin H and L chain genes and their encoded mRNAs is the J region. The J regions of the H and L chains have different sequences, but there is a high degree of sequence homology (greater than 80%) between the groups, especially near the C region. This homology is utilized in this approach, and the shared sequence of the J regions of the H and L chains can be used to design oligonucleotides for introduction to insert useful restriction sites into the J region so that the V region segment can be subsequently ligated to the human C region segment.

[0095] C-region cDNA vectors prepared from human cells can be modified by site-directed mutagenesis to place restriction sites at similar locations in the human sequence. For example, the complete human κ-chain C (Ck) region and the complete human γ-1 C region (Cγ-1) can be cloned. In this case, alternative methods based on genomic C-region cloning as the source of C-region vectors would not allow these genes to be expressed in bacterial systems where the enzymes required to remove the insert sequence are absent. The cloned V-region segment is excised and ligated into an L or H-chain C-region vector. Alternatively, the human Cγ-1 region can be modified by introducing a stop codon to produce a gene sequence encoding the H-chain portion of the Fab molecule. The coding sequences with the ligated V and C regions are then transferred to a suitable expression medium for expression in a suitable host (prokaryotic or eukaryotic).

[0096] Two coding DNA sequences are said to be "operably linked" if the ligation produces a continuous, translatable sequence without altering or disrupting the triplet reading frame. A DNA coding sequence is operably linked to a gene expression element if the ligation produces the correct function of the gene expression element to generate expression of the coding sequence.

[0097] Expression media include plasmids or other vectors. Preferred among these are media carrying functionally complete human CH or CL chain sequences with engineered, suitable restriction sites that allow easy insertion of any VH or VL chain sequence with suitable sticky ends. Media containing human CH or CL chain sequences thus serve as intermediates for expressing any desired complete H or L chain in any suitable host.

[0098] Chimeric antibodies (such as mouse-human or human-human) are typically synthesized from genes driven by promoters of native chromosomal genes from the mouse H and L chains V regions used in the construct; splicing typically occurs between splice donor sites in the mouse J region and splice acceptor sites preceding the human C region, and also at splice sites present within the human C region; polyadenylation and transcription termination occur at native chromosomal sites downstream of the human coding region.

[0099] As used herein and unless otherwise stated, the term “about” is intended to mean ±5% of the value it modifies. Thus, about 100 refers to 95 to 105.

[0100] In some embodiments, the antibodies described herein are used to detect the presence of an antigen. The antibodies of the present invention can be used in any apparatus or method for detecting the presence of an antigen.

[0101] The term "purified" for antibodies refers to antibodies that are substantially free of other materials associated with the molecule in its natural environment. For example, purified proteins are substantially free of cellular material or other proteins from the cells or tissues from which they originate. The term also refers to formulations of isolated proteins with a purity sufficient for analysis or a purity of at least 70% to 80% (w / w), at least 80% to 90% (w / w), 90% to 95%; and a purity of at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w). In some embodiments, the antibody is purified.

[0102] The terms "specific binding" and "specifically bound" refer to the formation of a measurable and selective complex of two or more molecules under physiological or assay conditions. Antibodies, antigen-binding proteins, or other molecules are considered to "specifically bind" to proteins, antigens, or epitopes, and this binding is substantially uninhibited under appropriate selective conditions, while nonspecific binding is inhibited. Specific binding is characterized by high affinity and selectivity for compounds, proteins, epitopes, or antigens. Nonspecific binding typically has low affinity. Binding in IgG antibodies, for example, usually consists of at least about 10... -7 M or higher, such as at least about 10 -8 M, or higher or at least about 10 -9 M or higher, or at least about 10 -10 Or higher, or at least about 10 -11 M or higher, or at least about 10 -12 Characterized by M or higher affinity. The term may also be applicable when, for example, an antigen-binding domain is specific for a particular epitope not carried by many antigens, in which case the antibody or antigen-binding protein carrying the antigen-binding domain will typically not bind other antigens. In some embodiments, the capture agent has an affinity equal to or less than 10 for its binding partner (e.g., antigen). -9 M, 10 -10 M or 10 -11 M's Kd. In some embodiments, the capture agent has a binding affinity for its partner body greater than or equal to 10. 9 M -1 Ka.

[0103] Intact antibodies, also known as immunoglobulins, are typically tetrameric glycosylated proteins, primarily composed of two light (L) chains, each approximately 25 kDa, and two heavy (H) chains, each approximately 50 kDa. Two types of light chains, referred to as λ and κ, are present in antibodies. Immunoglobulins are classified into five main classes based on the amino acid sequence of the constant domain of the heavy chain: A, D, E, G, and M, and several of these classes can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. Each light chain primarily consists of an N-terminal variable (V) domain (VL) and a constant (C) domain (CL). Each heavy chain primarily consists of an N-terminal V domain (VH), three or four C domains (CH), and a hinge region. The CH domain closest to the VH is designated CH1. The VH and VL domains consist of four relatively conserved sequence regions (FR1, FR2, FR3, and FR4) known as framework regions, which form a scaffold of three hypervariable sequence regions (complementarity-determining regions, CDRs). The CDRs contain most of the residues responsible for the specific interaction between the antibody or antigen-binding protein and the antigen. The CDRs are referred to as CDR1, CDR2, and CDR3. Thus, the CDR components on the heavy chain are referred to as H1, H2, and H3, while the CDR components on the light chain are referred to as L1, L2, and L3. CDR3 is the largest source of molecular diversity within the antibody or antigen-binding protein binding site. H3, for example, can be as short as two amino acid residues or greater than 26 amino acids. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well known in the art. For a review of antibody structures, see Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, edited by Harlow et al., 1988. Those skilled in the art will recognize that each subunit structure (e.g., CH, VH, CL, VL, CDR, and / or FR structures) contains an active fragment. For example, the active fragment may consist of a portion of the VH, VL, or CDR subunit that binds to the antigen, i.e., an antigen-binding fragment, or a portion of the CH subunit that binds to and / or activates the Fc receptor and / or complement.

[0104] In addition to the fragments described herein, non-limiting examples of binding fragments covered by the term "antigen-specific antibody" as used herein include (i) Fab fragments, which are formed by V L V H (ii) a monovalent segment consisting of CL and CH1 domains; (iii) a F(ab')2 segment, which is a divalent segment containing two Fab segments connected by a disulfide bridge in the hinge region; and (iv) a segment consisting of V H (iv) The Fd fragment composed of the CH1 domain; and the V-shaped structure of the single arm of the antibody. L and VH The Fv segment is composed of structural domains; (v) is composed of V H The dAb segment composed of structural domains; and (vi) the separated CDR. Furthermore, although the two structural domains (V) of the Fv segment... L and V H These genes are encoded by individual genes, but they can be recombined and linked together via synthetic adapters to produce V. L and V H Domains pair to form a single protein chain of a monovalent molecule (called a single-chain Fv (scFv)). The most commonly used linker is a 15-residue (Gly4Ser)3 peptide, but other linkers are also known in the art. Single-chain antibodies are also intended to be encompassed within the terms "antibody or antigen-binding protein" or "antigen-binding fragment" of an antibody. Antibodies can also be polyclonal antibodies, monoclonal antibodies, chimeric antibodies, antigen-binding fragments, Fc fragments, single-chain antibodies, or any derivative thereof.

[0105] These antibodies can be obtained using conventional techniques known to those skilled in the art and described herein, and the fragments are used in the same manner as intact antibodies. Antibody diversity arises from multiple germline genes encoding variable domains and various somatic events. Somatic events include recombination of variable gene segments with diversity (D) and linker (J) gene segments to produce the intact VH domain, and recombination of variable and linker gene segments to produce the intact VL domain. The recombination process itself is imprecise, resulting in the loss or addition of amino acids at the V(D)J node. These diversity mechanisms occur in developing B cells prior to antigen exposure. Following antigenic stimulation, antibody-expressing genes in B cells undergo somatic mutations. Based on the estimated number of germline gene segments, random recombination of these segments, and random VH-VL pairing, up to 1.6 x 10⁷ different antibodies can be generated (Fundamental Immunology, 3rd ed. (1993), edited by Paul, Raven Press, New York, NY). When other processes that contribute to antibody diversity (such as somatic mutations) are taken into account, it is considered that more than 1 x 10¹⁰ different antibodies can be generated (Immunoglobulin Genes, 2nd ed. (1995), edited by Jonio et al., Academic Press, San Diego, Calif.). Because many processes are involved in generating antibody diversity, independently obtained monoclonal antibodies with the same antigen specificity cannot have the same amino acid sequence.

[0106] Antibody or antigen-binding protein molecules capable of specifically interacting with antigens, epitopes, or other molecules described herein can be produced by methods well known to those skilled in the art. For example, monoclonal antibodies can be produced by generating hybridoma cells according to known methods. Hybridomas formed in this manner can then be screened using standard methods, such as enzyme-linked immunosorbent assay (ELISA) and biosensor assays, to identify one or more hybridomas that produce antibodies that specifically interact with the target molecule or compound.

[0107] As an alternative to preparing monoclonal antibody-secreting hybridomas, monoclonal antibodies against peptides can be identified and isolated by screening recombinant combinatorial immunoglobulin libraries (e.g., antibody-phage display libraries) with the peptides described herein, thereby isolating immunoglobulin library members bound to the peptides. Techniques and commercially available kits for generating and screening phage display libraries are well known to those skilled in the art. Furthermore, examples of methods and reagents particularly suitable for generating and screening antibody or antigen-binding protein display libraries can be found in the literature. Therefore, the epitopes described herein can be used to screen other antibodies for therapeutic, diagnostic, or research purposes.

[0108] Includes antibody administration, composition, and kit.

[0109] However, isolated antibodies that bind to epitopes on the sealin 6 protein or other proteins described herein and exhibit sealin 6 inhibitory or therapeutic activity in vitro and / or in vivo, and antibodies or antigen-binding fragments thereof capable of inhibiting sealin 6 function, are suitable as therapeutic and preventative agents for treating or preventing sealin 6-related diseases in humans and animals. These diseases include, but are not limited to, benign and metastatic forms of cancer, such as ovarian cancer (e.g., ovarian carcinoma), reproductive system cancers (breast cancer, cervical cancer, testicular cancer, uterine cancer, and placental cancer), lung cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, skin cancer, head and neck cancer, sarcoma, and germ cell tumors, etc.

[0110] In some embodiments, the method includes administering a therapeutically or preventively effective amount of one or more of the monoclonal antibodies or antigen-binding fragments of antibodies described herein to a susceptible subject or a subject exhibiting a condition known to cause the observed pathology due to the sealing protein 6. Any active form of antibody may be administered, including but not limited to Fab and F(ab')2 fragments.

[0111] As used in this article, sealin 6-related pathology refers to disorders caused by the dysfunction or abnormal function of the sealin 6 receptor. These disorders include, but are not limited to, benign and metastatic forms of cancer, such as ovarian cancer (e.g., ovarian carcinoma), reproductive system cancers (breast cancer, cervical cancer, testicular cancer, uterine cancer, and placental cancer), lung cancer, stomach cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small intestine cancer, skin cancer, head and neck cancer, sarcoma, germ cell tumors, etc.

[0112] In some implementations, the antibody used is compatible with the receptor species so that an immune response against the MAb does not result in an unacceptably short circulating half-life or induce an immune response against the MAb in the subject. In some implementations, the administered MAb exhibits secondary functions such as binding to the subject's Fc receptor and activation of antibody-dependent cell-mediated cytotoxicity (ADCC) mechanisms.

[0113] Individual treatment may include administration of a therapeutically effective amount of the antibody described herein. The antibody is available in kits described below. The antibody may be used alone or administered, or in combination with another therapeutic agent, analgesic, or diagnostic agent. When administering an antibody or fragment thereof capable of binding to sealing protein 6, or an antibody capable of protecting against the effects of sealing protein 6, the recipient patient's pathology and the dosage of the administered agent will vary depending on factors such as the patient's age, weight, height, sex, general medical condition, and prior medical history.

[0114] Suitable mediators, as well as their formulations and packaging, are described, for example, in Remington: The Science and Practice of Pharmacy (21st edition, edited by Troy, D., Lippincott Williams & Wilkins, Baltimore, Md. (2005), Chapters 40 and 41). The duration of action can be controlled using other pharmaceutical methods. Controlled-release formulations can be achieved by using polymers to compound or absorb the compound. Another possible method for controlling the duration of action with controlled-release formulations is to incorporate the compound into particles of polymeric materials such as polyesters, polyamino acids, hydrogels, poly(lactic acid), or ethylene vinyl acetate copolymers. Alternatively, instead of incorporating these agents into polymeric particles, it is possible to encapsulate these materials in microcapsules prepared (e.g., through interfacial polymerization) (e.g., hydroxymethyl cellulose or gelatin-microcapsules and poly(methyl methacrylate)-microcapsules, respectively), or in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in crude emulsions.

[0115] Generally, if a systemic dose of antibody is administered, the recipient needs to be provided with an antibody dose in the range of approximately 1 ng / kg-100 ng / kg, 100 ng / kg-500 ng / kg, 500 ng / kg-1 ug / kg, 1 ug / kg-100 ug / kg, 100 ug / kg-500 ug / kg, 500 ug / kg-1 mg / kg, 1 mg / kg-50 mg / kg, 50 mg / kg-100 mg / kg, or 100 mg / kg-500 mg / kg (recipient's weight), but lower or higher doses may be administered. Dose as low as approximately 1.0 mg / kg is expected to show some efficacy. Preferably, approximately 5 mg / kg is an acceptable dose, although dose levels of up to approximately 50 mg / kg are also preferred, especially for therapeutic use. Alternatively, a specific amount of antibody may be administered not based on the patient's weight, such as in the range of 1 ug-100 ug, 1 mg-100 mg, or 1 gm-100 gm. For example, site-specific administration can be administered to body compartments or cavities, such as intra-articular, intrabronchial, intra-abdominal, intra-bursal, intra-cartilaginous, intracavitary, intra-body cavity, intracerebellar, intravenous, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intrabladder, intralesional, transvaginal, transrectal, transbuccal, sublingual, intranasal, or transdermal.

[0116] The antibody compositions described herein can be prepared for parenteral (subcutaneous, intramuscular, or intravenous) or any other administration, particularly in the form of a liquid solution or suspension. The formulations are also suitable for injectable formulations. In some embodiments, the injectable formulation is sterile. In some embodiments, the injectable formulation is pyrogen-free. In some embodiments, the formulation does not contain other antibodies that bind to antigens other than those described herein.

[0117] Antibodies capable of treating disorders associated with sealin 6 activity or intended to treat sealin 6-related pathologies are intended to be administered to subjects in an amount sufficient to affect the reduction, resolution, or improvement of sealin 6-related symptoms or pathologies. Such pathologies include benign or metastatic cancers in subjects, such as ovarian cancer (e.g., ovarian carcinoma), reproductive system cancers (breast cancer, cervical cancer, testicular cancer, uterine cancer, or placental cancer), lung cancer, stomach cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, skin cancer, head and neck cancer, sarcoma, or germ cell tumors.

[0118] If the dosage, route of administration, and regimen of administration of the agent are sufficient to affect such a response, then the amount is considered adequate or "therapeuticly effective" for the reduction of symptoms. The response to antibody administration can be measured by analysis of the affected tissues, organs, or cells of the subject, such as by imaging techniques or by ex vivo analysis of tissue samples. The agent is physiologically significant if its presence results in a detectable change in the physiology of the receiving subject. In some embodiments, the amount is considered therapeutically effective if it can be used to treat, improve, or prevent benign and metastatic forms of cancer, such as ovarian cancer (e.g., ovarian carcinomas), reproductive system cancers (breast cancer, cervical cancer, testicular cancer, uterine cancer, and placental cancer), lung cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, skin cancer, head and neck cancer, sarcoma, and germ cell tumors. In some embodiments, the antibody or therapeutic agent does not bind to other sealing proteins, such as, but not limited to, sealing protein 9, sealing protein 3, and / or sealing protein 4. In some embodiments, the antibody is specific to sealing protein 6.

[0119] Antibodies can be formulated according to known methods to prepare pharmaceutically useful compositions, thereby combining these materials or functional derivatives thereof with pharmaceutically acceptable carrier media in mixture form. Treatment can be administered in single-dose or multiple-dose regimens, wherein a primary course of treatment may be initiated with 1–10 separate doses, followed by additional doses at subsequent intervals required to maintain and / or enhance the immune response (e.g., a second dose at 1–4 months), and, if necessary, one or more subsequent doses after several months. Examples of suitable treatment schedules include: (i) 0, 1 month, and 6 months; (ii) 0, 7 days, and 1 month; (iii) 0 and 1 month; (iv) 0 and 6 months; or other schedules sufficient to elicit the desired response expected to alleviate disease symptoms or reduce disease severity.

[0120] A kit for carrying out the embodiments described herein is also provided. The kit of the present invention includes a first container containing or co-packaged with the antibodies described above. The kit may also include another container containing or packaged in a solution necessary or convenient for carrying out the embodiments. The container may be made of glass, plastic, or foil, and may be a vial, bottle, pouch, tube, bag, etc. The kit may also contain written information, such as procedures or analytical information for carrying out the embodiments, such as the amount of reagents contained in the first container device. The container may be located in another container device (e.g., a box or bag), along with the written information.

[0121] Another aspect provided herein is a kit for detecting sealant protein 6 in biological samples. The kit includes a container housing one or more antibodies that bind to epitopes of sealant protein 6, and instructions for using the antibodies for the purpose of binding to sealant protein 6 to form an immune complex and detecting the formation of the immune complex, such that the presence or absence of the immune complex is correlated with the presence or absence of sealant protein 6 in the sample. Examples of the container include multi-well plates that allow for the simultaneous detection of sealant protein 6 in multiple samples.

[0122] In some embodiments, an antibody is provided that binds to the sealing protein 6 protein. In some embodiments, an antibody, such as a monoclonal antibody or ScFv, is provided that binds to an epitope on the sealing protein 6, the binding residues of which include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof. In some embodiments, the antibody binds to an epitope on the sealing protein 6, the epitope including residues E48, D68, P74, D76, and R158 of the sealing protein 6. In some embodiments, the antibody binds to an epitope on the sealing protein 6, the epitope including residues T33, N38, E48, D76, A153, E154, Q156, and R158 of the sealing protein 6. In some embodiments, the antibody binds to an epitope of sealing protein 6, the epitope comprising residues N38, E48, Y67, P74, D76, D146, V152, E154, Q156, and R158 of sealing protein 6. In some embodiments, the antibody binds to an epitope of sealing protein 6, the epitope comprising residue Q156.

[0123] In some embodiments, the antibody is isolated. In some embodiments, the antibody binds specifically. In some embodiments, the antibody binds to a properly folded sealant protein 6 protein. In some embodiments, the antibody binds to a sealant protein 6 protein in the cell membrane. In some embodiments, the antibody binds to a sealant protein 6 protein in the cell membrane of an intact cell. In some embodiments, the antibody inhibits or neutralizes the function of the sealant protein 6 protein. As used herein, the term "neutralizes" means that the activity or function of a protein is inhibited. In some embodiments, the antibody inhibits the regulation of tight junction integrity by sealant protein 6. In some embodiments, the antibody is used as a targeting component to deliver another therapeutic agent to cells expressing sealant protein 6 (e.g., tumor cells). In some embodiments, the sealant protein 6 antibody is part of a multispecific therapeutic agent in which a portion of the molecule binds to sealant protein 6 while another portion of the therapeutic agent binds to another target. In some embodiments, the other portion is a CD3-binding molecule (e.g., a CD3 antibody) or another molecule that promotes ADC, ADCC, or CAR-T therapy. Inhibition can be complete or partial. In some embodiments, the activity or function of the protein is inhibited by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. The percentage of inhibition may be based on the protein's function or activity in the absence of the antibody. In some embodiments, the antibody inhibits the interaction or function promoted by sealing protein 6.

[0124] In some embodiments, the antibody comprises the sequence as provided herein or an antigen-binding fragment thereof. In some embodiments, the antibody comprises the heavy chain CDR as described herein or an antigen-binding fragment thereof. The heavy chain may be one or more heavy chains as described herein. In some embodiments, the antibody comprises the light chain as described herein or an antigen-binding fragment thereof.

[0125] In some embodiments, methods are provided for treating, inhibiting, or improving sealing protein 6-related pathology. In some embodiments, the methods include administering the antibodies or pharmaceutical compositions described herein to a subject to treat, inhibit, or improve sealing protein 6-related pathology. In some embodiments, the pathology is a benign or metastatic cancer, such as ovarian cancer (e.g., ovarian carcinoma), reproductive system cancers (breast cancer, cervical cancer, testicular cancer, uterine cancer, endometrial cancer, or placental cancer), lung cancer, gastric cancer, stomach cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, lung cancer (e.g., lung adenocarcinoma), skin cancer, head and neck cancer, sarcoma, or germ cell tumors.

[0126] In some embodiments, the antibodies provided herein are administered to a subject as nucleic acid molecules encoding said antibodies. In some embodiments, said nucleic acid molecules are DNA, RNA, or mRNA molecules encoding antibodies. Nucleic acid molecules can be delivered in any form suitable for in vivo expression, such as viral vectors, plasmids, linear nucleic acid molecules, etc. In some embodiments, antibodies generated from nucleic acid molecules can be used as vaccines or circulating antibodies for identifying and killing cells expressing seal protein 6. Antibody expression can be prolonged or stimulated and controlled. Without being bound by any theory, in some embodiments, a subject developing cancer expressing seal protein 6 will be treated with circulating antibodies that recognize cancer cells. Therefore, in some embodiments, antibodies delivered by nucleic acid molecules can be used to treat or prevent cancer growth. In some embodiments, the nucleic acid molecules encoding antibodies are integrated into the genome of the subject's cells so that expression is sustained. Examples of viral vectors that can be used include, but are not limited to, AAV, AV, and reverse transcription vectors integrated into the genome.

[0127] In some embodiments, a method is provided for detecting the presence or absence of sealing protein 6 in a sample, the method comprising contacting the sample with one or more antibodies described herein and detecting the binding of the antibodies to the sealing protein 6 antigen. In some embodiments, detection of the binding indicates the presence of the sealing protein 6 antigen; or no detection of binding to the sealing protein 6 antigen indicates its absence. Detection can be performed using any known method, such as using biosensors, ELISA, sandwich assays, etc. However, in some embodiments, the method includes detecting the presence of the protein under non-denaturing conditions. Non-denaturing conditions can be used to detect the target protein in its native or correctly folded form.

[0128] In some embodiments, a method is provided for identifying a test antibody that binds to an epitope on a sealing protein 6 protein, the method comprising contacting a test antibody with an epitope on the sealing protein 6 protein and determining whether the test antibody binds to the epitope. In some embodiments, the determination comprises determining whether the test antibody binds to the protein and is competitively inhibited by an antibody comprising a sequence as provided herein. In some embodiments, the determination comprises mutating one or more residues of the epitope or protein and determining the binding of the test antibody to the mutated epitope, wherein the test antibody is considered to bind to the epitope if the mutation reduces the binding of the test antibody compared to a non-mutated epitope.

[0129] In some embodiments, a method for inducing an immune response against the sealing protein 6 antigen is provided, the method comprising administering the sealing protein 6 antigen to a subject under conditions sufficient to induce an immune response. In some embodiments, the sealing protein 6 antigen is delivered as a nucleic acid molecule encoding the sealing protein 6 antigen. As discussed herein, in some embodiments, the method comprises administering to the subject a lipid particle containing the sealing protein 6 antigen to induce an immune response. In some embodiments, the antibody generated by the immune response is isolated. The antibody can then be cloned, isolated, and / or otherwise modified as described herein. In some embodiments, the subject is a chicken.

[0130] In some embodiments of the methods provided herein, the antibody is any antibody or fragment thereof as provided herein.

[0131] In some embodiments, the antibody comprises V as listed in the table below. H and V L sequence:

[0132]

[0133]

[0134]

[0135]

[0136] As provided herein, variants of any of the sequences described herein are also provided. For example, in some embodiments, at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of a peptide are also provided. In some embodiments, a protein is provided comprising at least or about 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence disclosed herein. In some embodiments, the sequence or variant has 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions compared to the sequences provided herein. In some embodiments, the substitutions are conserved substitutions. In some embodiments, the mutation or substitution is located in a frame region of the light or heavy chain. In some embodiments, the substitution is located in a CDR region, such as CDR1, CDR2, or CDR3. In some implementations, the mutation or substitution is located in CDR1 and not in CDR2 or CDR3. In some implementations, the heavy chain contains a frame region instead of a substitution or change in a CDR region as provided herein.In some embodiments, a heavy chain protein is provided, wherein the sequence is at least or about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:119, SEQ ID NO:121, or SEQ ID NO:123, provided that the sequence comprises a first amino acid sequence or a first CDR selected from the group consisting of: SEQ ID NO: NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, 95, 139, 141, 143, or 145; a second amino acid sequence or second CDR selected from the group consisting of: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, 102, 140, 142, 144, or 146; and a third amino acid sequence or third CDR selected from the group consisting of: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92, or 97. Therefore, in some embodiments, the CDR of the heavy chain is not a variant of those provided herein.

[0137] In some embodiments, the antibody comprises V H Chain, the V HThe chain contains the sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123, or a variant thereof.

[0138] In some embodiments, a light chain protein is provided, wherein the sequence is at least or about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:122, or SEQ ID NO:124, provided that the sequence comprises a first amino acid sequence or a first CDR selected from the group consisting of: SEQ ID NO: NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; a second amino acid sequence or second CDR selected from the group consisting of: 23, 29, 41, 51, 59, 68, 84, 88, or 99; and a third amino acid sequence or third CDR selected from the group consisting of: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, or 94. Therefore, in some embodiments, the CDR of the heavy chain is not a variant of those provided herein.

[0139] In some embodiments, the antibody comprises V L Chain, the V LThe chain contains the sequence of SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:124, or a variant thereof.

[0140] In some embodiments, the antibody comprises V H and V L Chain, the V H and V L The chain contains SEQ ID NO:2 and SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, SEQ ID NO:6 and SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, SEQ ID NO:10 and SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, SEQ ID NO:16 and SEQ ID NO:17, SEQ ID NO:18 and SEQ ID NO:19, SEQ ID NO:20 and SEQ ID NO:21, SEQ ID NO:103 and SEQ ID NO:104, SEQ ID NO:105 and SEQ ID NO:106, SEQ ID NO:107 and SEQ ID NO:108, SEQ ID NO:109 and SEQ ID NO:110, SEQ ID NO:111 and SEQ ID NO:112, SEQ ID NO:113 and SEQ ID NO:114, SEQ ID NO:115 and SEQ ID NO:116. The sequences NO:116, SEQ ID NO:117 and SEQ ID NO:118, SEQ ID NO:119 and SEQ ID NO:120, SEQ ID NO:121 and SEQ ID NO:122, or SEQ ID NO:123 and SEQ ID NO:123.

[0141] In some embodiments, the sequence is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homologous to or identical to the sequence provided herein, and the sequence includes the V provided herein. H V L And / or CDR sequences. The sequence may also be a variant if it has 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions, deletions, or insertions. In some embodiments, the substitution (mutation) is a conserved substitution.

[0142] In some implementations, the CDR of the peptide or antibody is as follows:

[0143]

[0144]

[0145] In some implementations, the CDR of the peptide or antibody is as follows:

[0146]

[0147]

[0148]

[0149] In some implementation schemes, V HThe chain contains one or more CDRs selected from the tables provided herein or from the group consisting of: GFSFSSY (SEQ ID NO: 139); YSSASSTY (SEQ ID NO: 140); AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); GFDFSSY (SEQ ID NO: 141); GSTGSS (SEQ ID NO: 142); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); GFSISSY (SEQ ID NO: 143); YSGSR (SEQ ID NO: 144); SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); GFTFSSY (SEQ ID NO: 145); DSGST (SEQ ID NO: 146); DAYGYCGWSGCSADSIDA (SEQ ID NO: 97); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 145); NO:24); GFSFSSYDMGWV (SEQ ID NO:25); VASIYSSASSTYYA (SEQ ID NO:26); CAKAAGRTYRGWATYIADSIDA (SEQ ID NO:27); CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); CGSTDNSYVGIF (SEQ ID NO:30); GDFFSSYAMNWV (SEQ ID NO:31); VAGIGSTGSSTGYG (SEQ ID NO:32); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO:33); CSGDSSDDGSYYYG (SEQ ID NO:34); IYSNDKRP (SEQ ID NO:29); CGSYDSSTGIF (SEQ ID NO:29) IDNO:36);GFSISSYTMQWV(SEQ ID NO:37);VAGIYSGSRTYYG(SEQ ID NO: 38); CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYG (SEQ ID NO: 44);CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45); CSGDSSWYGYG(SEQ ID NO:22); IYESGKRP(SEQ ID NO:23); CGSADSNSIGIF(SEQ ID NO:24); GFSFSSYDMGWV(SEQ ID NO:25); VASIYSSASSTYYA(SEQ ID NO:26); CAKAAGRTYRGWATYIADSIDA(SEQ ID NO:27); CSGGSSGYG(SEQ ID NO:28); IYSNDKRP(SEQ ID NO:29); CGSTDNSYVGIF(SEQ ID NO:30); GFDFSSYAMNWV(SEQ ID NO:31); VAGIGSTGSSTGYA(SEQ ID NO:46); CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33); CSGDDGSYYYG(SEQ ID NO:47); IYSNDKRP(SEQ ID NO:29); CGSYDSSTGIF(SEQ ID NO:36); GFSISSYTMQWV(SEQ ID NO:37); VAGIYSGSRTYYA(SEQ ID NO:48); CAKSSYCTAWTGCDVYAGGSIDA(SEQ ID NO:39); CSGGNNYYG(SEQ ID NO:40); IYYNDKRP(SEQ IDNO:41); CGGWDSSGGIF(SEQ ID NO:42); GFTFSSYSMFWV(SEQ ID NO:43); VAGIDSGSTTFYA(SEQID NO:49);CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45);CSGGSGSYG(SEQ ID NO:50);IYGTNKRP(SEQ ID NO:51);CGSADSSTNAGIF(SEQ ID NO:52);GFTFSSYAMSWV(SEQ ID NO:53);VAGISSSGRYTGYA(SEQ ID NO:54);CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);CSGGSGSYG(SEQ ID NO:50);IYGTNKRP(SEQ ID NO:51);CGSADSSTNAGIF(SEQ ID NO:52);GFTFSSYAMNWV(SEQ ID NO:55);VAGISSSGRYTGYA(SEQ ID NO:54);CAKSVGNNSWSGYIATSIDA(SEQ ID NO:33);SYAMS(SEQ ID NO:56);GISSSGRYTGYADSVKG(SEQ ID NO:101);SVGNGNSNWSGYIATSIDA(SEQ ID NO:57);SVGNGNNSWSGYVATSIDA(SEQ ID NO:61);SYAMN(SEQ ID NO:62);SVGSGVSGYVATSIDA(SEQ ID NO:61) NO:63);GISSSGRYTGYADSVKG(SEQ ID NO:101);SMGSGVSWSGYVATSIDA(SEQ ID NO:65);SMGSGVSWSGYVATSIDV(SEQ ID NO:66);SVGSGVSWSGYVATSLDA(SEQ ID NO:67);SMGSGVSWSGYVATSIDA(SEQ ID NO:65);SMGSGVSWSGYVATSIDV(SEQ ID NO:67) NO:126);SVGSGVSWSGYVATSLDV(SEQ ID NO:69); NO:78);SYDMG(SEQID NO:80);SIYSSSASTYYAPAVKG(SEQ ID NO:81);AAGRTYRGWATYIADSIDA(SEQ ID NO:82);GIGSTGSSTGYGPAVKG(SEQ ID NO:86);SVGNGNSNWSGYIATSIDA(SEQ ID NO:57);SYTMQ(SEQ ID NO:90);GIYSGSRTYYGAAVQG(SEQ ID NO:91);SSYCTAWTGCDVYAGGSIDA(SEQ ID NO:92);SYSMF(SEQ ID NO:95);GIDSGSTTFYGSAVKG(SEQ ID NO:96);DAYGYCGWSGCSADSIDA(SEQ ID NO:97);GISSSGRYTGYADSVKG (SEQ ID NO: 101); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); GIGSTGSSTGYADSVKG (SEQ ID NO: 102); or SVGNGNSWSGYIATSIDA (SEQ ID NO: 57). ;

[0150] In some implementation schemes, V H The chain contains CDRs with the following characteristics:

[0151] 1H.GFSFSSY (SEQ ID NO:139); YSSASSTY (SEQ ID NO:140); and AAGRTYRGWATYIADSIDA (SEQ ID NO:82); or

[0152] 2H.GFDFSSY (SEQ ID NO:141); GSTGSS (SEQ ID NO:142); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57); or

[0153] 3H.GFSISSY (SEQ ID NO:143); YSGSR (SEQ ID NO:144); and SSYCTAWTGCDVYAGGSIDA (SEQ ID NO:92); or

[0154] 4H.GTFFSSY (SEQ ID NO:145); DSGST (SEQ ID NO:146); and DAYGYCGWSGCSADSIDA (SEQ ID NO:97); or

[0155] 5H.GFSFSSYDMGWV (SEQ ID NO:25); VASIYSSASSTYYA (SEQ ID NO:26); and CAKAAGRTYRGWATYIADSIDA (SEQ ID NO:27); or

[0156] 6H.GFDFSSYAMNWV (SEQ ID NO:31); VAGIGSTGSSTGYG (SEQ ID NO:32); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO:33); or

[0157] 7H.GFSISSYTMQWV(SEQ ID NO:37),VAGIYSGSRTYYG(SEQ ID NO:38),CAKSSYCTAWTGCDVYAGGSIDA(SEQ ID NO:39);

[0158] 8H.GFTFSSYSMFWV(SEQ ID NO:43),VAGIDSGSTTFYG(SEQ ID NO:44),CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45);

[0159] 9H.GFSFSSYDMGWV(SEQ ID NO:25),VASIYSSASSTYYA(SEQ ID NO:26), and CAKAAGRTYRGWATYIADSIDA(SEQ ID NO:27);

[0160] 10H.GFDFSSYAMNWV(SEQ ID NO:31),VAGIGSTGSSTGYA(SEQ ID NO:46), and CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);

[0161] 11H.GFSISSYTMQWV(SEQ ID NO:37),VAGIYSGSRTYYA(SEQ ID NO:48),CAKSSYCTAWTGCDVYAGGSIDA(SEQ ID NO:39);

[0162] 12H.GFTFSSYSMFWV(SEQ ID NO:43),VAGIDSGSTTFYA(SEQ ID NO:49),CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45);

[0163] 13H.GFTFSSYAMSWV(SEQ ID NO:53),VAGISSSGRYTGYA(SEQ ID NO:54),CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);

[0164] 14H.GFTFSSYAMNWV(SEQ ID NO:55),VAGISSSGRYTGYA(SEQ ID NO:54),CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);

[0165] 15H. SYAMS (SEQ ID NO:56); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57); or

[0166] 16H. SYAMS (SEQ ID NO:56); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGNGNSWSGYVATSIDA (SEQ ID NO:61); or

[0167] 17H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSIDA (SEQ ID NO:63); or

[0168] 18H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSIDA (SEQ ID NO:65); or

[0169] 19H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSIDV (SEQ ID NO:66); or

[0170] 20H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSLDA (SEQ ID NO:67); or

[0171] 21H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSIDA (SEQ ID NO:65); or

[0172] 22H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSLDV (SEQ ID NO:126); or

[0173] 23H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSLDV (SEQ ID NO:69); or

[0174] 24H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSLDV (SEQ ID NO:69); or

[0175] 25H. SYGMS (SEQ ID NO:71); GIGSSGIYTHYADSVKG (SEQ ID NO:72); and SPGDSDWCGWAGYGIYSCRVAGFIDA (SEQ ID NO:73); or<​​​​​​​​​​​​​​​​31H.SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57); or

[0182] 32H.SYAMN (SEQ ID NO:62); GIGSTGSSTGYADSVKG (SEQ ID NO:102); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57).

[0183] In some embodiments, the antibody comprises V L Chain, the V L The chain contains the following sequences:

[0184]

[0185]

[0186] In some implementations, the V L It contains the following sequences:

[0187]

[0188]

[0189] V L The sequence may include V as provided in PCT application number PCT / US2020 / 018026 filed on February 13, 2020, and / or U.S. application number 16 / 789,626 filed on February 13, 2020. L Sequence, CDR, CDR group or FW group or any combination thereof, each of the applications is incorporated in its entirety by reference.

[0190] In some implementation schemes, such as any V provided herein H A chain or a V containing one or more (e.g., 3) CDRs H Chain can be used with any V provided in this article L Chain composition. As demonstrated in this paper, V L The chains are exchangeable and the antibody can still bind to sealing protein 6. In some embodiments, VH is combined with one of F10-VL; 2. F10h-VL; 3. B9-VL; or B9h-VL.

[0191] In some embodiments, the sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% homologous or identical to the sequence provided herein, and the sequence includes V. H VL and CDR sequences. In some implementations, V LThe chain contains one or more CDRs selected from the group consisting of: SGDSSWYGYG (SEQ ID NO:83); ESGKRPS (SEQ ID NO:84); GSADSNSIGI (SEQ ID NO:85); SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); GSTDNSYVGI (SEQ ID NO:89); SGDSSDDGSYYYG (SEQ ID NO:93); SNDKRPS (SEQ ID NO:88); GSYDSSTGI (SEQ ID NO:94); SGGNNYYG (SEQ ID NO:98); YNDKRPS (SEQ ID NO:99); GGWDSSGGI (SEQ ID NO:100); CSGDSSWYGYG (SEQ ID NO:22); IYESGKRP (SEQ ID NO:23); CGSADSNSIGIF (SEQ ID NO:24); CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); CGSTDNSYVGIF (SEQ ID NO:30); CSGDSSDDGSYYYG (SEQ ID NO:34); IYSNDKRP (SEQ ID NO:29); CGSYDSSTGIF (SEQ ID NO:36); CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); CGGWDSSGGIF (SEQ ID NO:42); CSGDSSWYGYG (SEQ ID NO:22); IYESGKRP (SEQ ID NO:23); CGSADSNSIGIF (SEQ ID NO:24); CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); CGSTDNSYVGIF (SEQ ID NO:30); CSGDDGSYYYG (SEQ ID NO:47); IYSNDKRP (SEQ ID NO:29); CGSYDSSTGIF (SEQ ID NO:36); CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); CGGWDSSGGIF (SEQ ID NO:42); CSGGSGSYG (SEQ ID NO:50); IYGTNKRP (SEQ ID NO:51); CGSADSSTNAGIF (SEQ ID NO:52);CSGGSGSYG (SEQ ID NO:50); IYGTNKRP (SEQ ID NO:51); and CGSADSSTNAGIF (SEQ ID NO:52); SGGSGSYG (SEQ ID NO:58); GTNKRPS (SEQ ID NO:59); GSADSSTNAGI (SEQ ID NO:60); SAGSGLYG (SEQ ID NO:64); GTYKRPS (SEQ ID NO:64); NO:68); GSNDASTNAGI (SEQ ID NO:70); SGGYNGHYG (SEQ ID NO:74); GGYDSSAGI (SEQ ID NO:75); SGGSGSYGYYG; or GSEDSSSGAGI (SEQ ID NO:79). ;

[0192] In some implementation schemes, V L The chain contains CDRs with the following characteristics:

[0193] 1L.SGDSSWYGYG (SEQ ID NO:83); ESGKRPS (SEQ ID NO:84); and GSADSNSIGI (SEQ ID NO:85); or

[0194] 2L.SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); and GSTDNSYVGI (SEQ ID NO:89); or

[0195] 3L.SGDSSDDGSYYYG (SEQ ID NO:93); SNDKRPS (SEQ ID NO:88); and GSYDSSTGI (SEQ ID NO:94); or

[0196] 4L.SGGNNYYG (SEQ ID NO:98); YNDKRPS (SEQ ID NO:99); and GGWDSSGGI (SEQ ID NO:100); or

[0197] 5L.CSGDSSWYGYG (SEQ ID NO:22); IYESGKRP (SEQ ID NO:23); and CGSADSNSIGIF (SEQ ID NO:24); or

[0198] 6L.CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); and CGSTDNSYVGIF (SEQ ID NO:30); or

[0199] 7L.CSGDSSDDGSYYYG (SEQ ID NO:34); IYSNDKRP (SEQ ID NO:29); and CGSYDSSTGIF (SEQ ID NO:36); or

[0200] 8L.CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); and CGGWDSSGGIF (SEQ ID NO:42); or

[0201] 9L.CSGDSSWYGYG (SEQ ID NO:22); IYESGKRP (SEQ ID NO:23); and CGSADSNSIGIF (SEQ ID NO:24); or

[0202] 10L.CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); and CGSTDNSYVGIF (SEQ ID NO:30); or

[0203] 11L. CSGDDGSYYYG (SEQ ID NO:47); IYSNDKRP (SEQ ID NO:29); and CGSYDSSTGIF (SEQ ID NO:36); or

[0204] 12L.CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); and CGGWDSSGGIF (SEQ ID NO:42); or

[0205] 13L.CSGGSGSYG (SEQ ID NO:50); IYGTNKRP (SEQ ID NO:51); and CGSADSSTNAGIF (SEQ ID NO:52); or

[0206] 14L.CSGGSGSYG (SEQ ID NO:50); IYGTNKRP (SEQ ID NO:51); and CGSADSSTNAGIF (SEQ ID NO:52);

[0207] 15L.SGGSGSYG (SEQ ID NO:58); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0208] 16L. SGGSGSYG (SEQ ID NO:58); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0209] 17L. SAGSGLYG (SEQ ID NO:64); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0210] 18L. SAGSGLYG (SEQ ID NO:64); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0211] 19L. SAGSGLYG (SEQ ID NO:64); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0212] 20L. SAGSGLYG (SEQ ID NO:64); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0213] 21L. SGGSGSYG (SEQ ID NO:58); GTYKRPS (SEQ ID NO:68); and GSADSSTNAGI (SEQ ID NO:60); or

[0214] 22L. SGGSGSYG (SEQ ID NO:58); GTYKRPS (SEQ ID NO:68); and GSADSSTNAGI (SEQ ID NO:六一); or

[0215] 23L. SGGSGSYG (SEQ ID NO:58); GTYKRPS (SEQ ID NO:68); and GSADSSTNAGI (SEQ ID NO:60); or

[0216] 24L. SAGSGLYG (SEQ ID NO:64); GTNKRPS (SEQ ID NO:59); and GSNDASTNAGI (SEQ ID NO:70); or

[0217] 25L. SGGYNGHYG (SEQ ID NO:74); GTNKRPS (SEQ ID NO:59); and GGYDSSAGI (SEQ ID NO:75); or It should be noted that there seems to be an error in the "GSNDASTNAGI" in line 24. It might be a misspelling. Also, "六一" in line 18 seems incorrect and should probably be "SEQ ID NO:60" like the others.

[0218] 26 L.SGGSGSYGYYG; GTNKRPS (SEQ ID NO:59); and GSEDSSSGAGI (SEQ ID NO:79); or

[0219] 27 L.SGDSSWYGYG (SEQ ID NO:83); ESGKRPS (SEQ ID NO:84); and GSADSNSIGI (SEQ ID NO:85); or

[0220] 28 L.SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); and GSTDNSYVGI (SEQ ID NO:89); or

[0221] 29 L.SGDSSDDGSYYYG (SEQ ID NO:93); SNDKRPS (SEQ ID NO:88); and GSYDSSTGI (SEQ ID NO:94); or

[0222] 30 L.SGGNNYYG (SEQ ID NO:98); YNDKRPS (SEQ ID NO:99); and GGWDSSGGI (SEQ ID NO:100); or

[0223] 31 L.SGGSGSYG (SEQ ID NO:58); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0224] 32 L.SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); and GSTDNSYVGI (SEQ ID NO:89).

[0225] In some embodiments, the antibody comprises 1H and 1L, 1H and 2L, 1H and 3L, 1H and 4L, 1H and 5L, 1H and 6L, 1H and 7L, 1H and 8L, 1H and 9L, 1H and 10L, 1H and 11L, 1H and 12L, 1H and 13L, 1H and 14L, 1H and 15L, 1H and 16L, 1H and 17L, 1H and 18L, 1H and 19L, 1H and 20L, 1H and 21L, 1H and 22L, 1H and 23L, 1H and 24L, 1H and 25L, 1H and 26L, 1H and 27L, 1H and 28L, 1H and 29L, 1H and 30L, 1H and 31L, 1H and 32L, 2H and 1L, 2H and 2L, 2H and 3L, 2 H and 4L, 2H and 5L, 2H and 6L, 2H and 7L, 2H and 8L, 2H and 9L, 2H and 10L, 2H and 11L, 2H and 12L, 2H and 13L, 2H and 14L, 2H and 15L, 2H and 16L, 2H and 17L, 2H and 18L, 2H and 19L, 2H and 20L, 2H and 21L, 2H and 22L 2H and 23L, 2H and 24L, 2H and 25L, 2H and 26L, 2H and 27L, 2H and 28L, 2H and 29L, 2H and 30L, 2H and 31L, 2H and 32L, 3H and 1L, 3H and 2L, 3H and 3L, 3H and 4L, 3H and 5L, 3H and 6L, 3H and 7L, 3H and 8L, 3H and 9L 3H and 10L, 3H and 11L, 3H and 12L, 3H and 13L, 3H and 14L, 3H and 15L, 3H and 16L, 3H and 17L, 3H and 18L, 3H and 19L, 3H and 20L, 3H and 21L, 3H and 22L, 3H and 23L, 3H and 24L, 3H and 25L, 3H and 26L, 3H and 27L 3H and 28L, 3H and 29L, 3H and 30L, 3H and 31L, 3H and 32L, 4H and 1L, 4H and 2L, 4H and 3L, 4H and 4L, 4H and 5L, 4H and 6L, 4H and 7L, 4H and 8L, 4H and 9L, 4H and 10L, 4H and 11L, 4H and 12L, 4H and 13L, 4H and 14L 4H and 15L, 4H and 16L, 4H and 17L, 4H and 18L, 4H and 19L, 4H and 20L, 4H and 21L, 4H and 22L, 4H and 23L, 4H and 24L, 4H and 25L, 4H and 26L, 4H and 27L, 4H and 28L, 4H and 29L, 4H and 30L, 4H and 31L, 4H and 32L 5H and 1L, 5H and 2L, 5H and 3L, 5H and 4L, 5H and 5L, 5H and 6L, 5H and 7L, 5H and 8L, 5H and 9L, 5H and 10L, 5H and 11L, 5H and 12L, 5H and 13L, 5H and 14L, 5H and 15L, 5H and 16L, 5H and 17L, 5H and 18L, 5H and 19L5H and 20L, 5H and 21L, 5H and 22L, 5H and 23L, 5H and 24L, 5H and 25L, 5H and 26L, 5H and 27L, 5H and 28L, 5H and 29L, 5H and 30L, 5H and 31L, 5H and 32L, 6H and 1L, 6H and 2L, 6H and 3L, 6H and 4L, 6H and 5L, 6H and 6 L, 6H and 7L, 6H and 8L, 6H and 9L, 6H and 10L, 6H and 11L, 6H and 12L, 6H and 13L, 6H and 14L, 6H and 15L, 6H and 16L, 6H and 17L, 6H and 18L, 6H and 19L, 6H and 20L, 6H and 21L, 6H and 22L, 6H and 23L, 6H and 24L 6H and 25L, 6H and 26L, 6H and 27L, 6H and 28L, 6H and 29L, 6H and 30L, 6H and 31L, 6H and 32L, 7H and 1L, 7H and 2L, 7H and 3L, 7H and 4L, 7H and 5L, 7H and 6L, 7H and 7L, 7H and 8L, 7H and 9L, 7H and 10L, 7H and 11L, 7 H and 12L, 7H and 13L, 7H and 14L, 7H and 15L, 7H and 16L, 7H and 17L, 7H and 18L, 7H and 19L, 7H and 20L, 7H and 21L, 7H and 22L, 7H and 23L, 7H and 24L, 7H and 25L, 7H and 26L, 7H and 27L, 7H and 28L, 7H and 29L 7H and 30L, 7H and 31L, 7H and 32L, 8H and 1L, 8H and 2L, 8H and 3L, 8H and 4L, 8H and 5L, 8H and 6L, 8H and 7L, 8H and 8L, 8H and 9L, 8H and 10L, 8H and 11L, 8H and 12L, 8H and 13L, 8H and 14L, 8H and 15L, 8H and 16L, 8 H and 17L, 8H and 18L, 8H and 19L, 8H and 20L, 8H and 21L, 8H and 22L, 8H and 23L, 8H and 24L, 8H and 25L, 8H and 26L, 8H and 27L, 8H and 28L, 8H and 29L, 8H and 30L, 8H and 31L, 8H and 32L, 9H and 1L, 9H and 2L, 9H And 3L, 9H and 4L, 9H and 5L, 9H and 6L, 9H and 7L, 9H and 8L, 9H and 9L, 9H and 10L, 9H and 11L, 9H and 12L, 9H and 13L, 9H and 14L, 9H and 15L, 9H and 16L, 9H and 17L, 9H and 18L, 9H and 19L, 9H and 20L, 9H and 21L, 9 H and 22L, 9H and 23L, 9H and 24L, 9H and 25L, 9H and 26L, 9H and 27L, 9H and 28L, 9H and 29L, 9H and 30L, 9H and 31L, 9H and 32L, 10H and 1L, 10H and 2L, 10H and 3L, 10H and 4L, 10H and 5L, 10H and 6L, 10H and 7L10H and 8L, 10H and 9L, 10H and 10L, 10H and 11L, 10H and 12L, 10H and 13L, 10H and 14L, 10H and 15L, 10H and 16L, 10H and 17L, 10H and 18L, 10H and 19L, 10H and 20L, 10H and 21L, 10H and 22L, 10H and 23L L, 10H and 24L, 10H and 25L, 10H and 26L, 10H and 27L, 10H and 28L, 10H and 29L, 10H and 30L, 10H and 31L, 10H and 32L, 11H and 1L, 11H and 2L, 11H and 3L, 11H and 4L, 11H and 5L, 11H and 6L, 11H and 7L, 1 1H and 8L, 11H and 9L, 11H and 10L, 11H and 11L, 11H and 12L, 11H and 13L, 11H and 14L, 11H and 15L, 11H and 16L, 11H and 17L, 11H and 18L, 11H and 19L, 11H and 20L, 11H and 21L, 11H and 22L, 11H and 23L 11H and 24L, 11H and 25L, 11H and 26L, 11H and 27L, 11H and 28L, 11H and 29L, 11H and 30L, 11H and 31L, 11H and 32L, 12H and 1L, 12H and 2L, 12H and 3L, 12H and 4L, 12H and 5L, 12H and 6L, 12H and 7L, 12H And 8L, 12H and 9L, 12H and 10L, 12H and 11L, 12H and 12L, 12H and 13L, 12H and 14L, 12H and 15L, 12H and 16L, 12H and 17L, 12H and 18L, 12H and 19L, 12H and 20L, 12H and 21L, 12H and 22L, 12H and 23L, 1 2H and 24L, 12H and 25L, 12H and 26L, 12H and 27L, 12H and 28L, 12H and 29L, 12H and 30L, 12H and 31L, 12H and 32L, 13H and 1L, 13H and 2L, 13H and 3L, 13H and 4L, 13H and 5L, 13H and 6L, 13H and 7L, 13H and 8L L, 13H and 9L, 13H and 10L, 13H and 11L, 13H and 12L, 13H and 13L, 13H and 14L, 13H and 15L, 13H and 16L, 13H and 17L, 13H and 18L, 13H and 19L, 13H and 20L, 13H and 21L, 13H and 22L, 13H and 23L, 13H And 24L, 13H and 25L, 13H and 26L, 13H and 27L, 13H and 28L, 13H and 29L, 13H and 30L, 13H and 31L, 13H and 32L, 14H and 1L, 14H and 2L, 14H and 3L, 14H and 4L, 14H and 5L, 14H and 6L, 14H and 7L, 14H and 8L,14H and 9L, 14H and 10L, 14H and 11L, 14H and 12L, 14H and 13L, 14H and 14L, 14H and 15L, 14H and 16L, 14H and 17L, 14H and 18L, 14H and 19L, 14H and 20L, 14H and 21L, 14H and 22L, 14H and 23L, 14H and 2 4L, 14H and 25L, 14H and 26L, 14H and 27L, 14H and 28L, 14H and 29L, 14H and 30L, 14H and 31L, 14H and 32L, 15H and 1L, 15H and 2L, 15H and 3L, 15H and 4L, 15H and 5L, 15H and 6L, 15H and 7L, 15H and 8L, 1 5H and 9L, 15H and 10L, 15H and 11L, 15H and 12L, 15H and 13L, 15H and 14L, 15H and 15L, 15H and 16L, 15H and 17L, 15H and 18L, 15H and 19L, 15H and 20L, 15H and 21L, 15H and 22L, 15H and 23L, 15H and 24L L, 15H and 25L, 15H and 26L, 15H and 27L, 15H and 28L, 15H and 29L, 15H and 30L, 15H and 31L, 15H and 32L, 16H and 1L, 16H and 2L, 16H and 3L, 16H and 4L, 16H and 5L, 16H and 6L, 16H and 7L, 16H and 8L, 16H And 9L, 16H and 10L, 16H and 11L, 16H and 12L, 16H and 13L, 16H and 14L, 16H and 15L, 16H and 16L, 16H and 17L, 16H and 18L, 16H and 19L, 16H and 20L, 16H and 21L, 16H and 22L, 16H and 23L, 16H and 24L, 16H and 25L, 16H and 26L, 16H and 27L, 16H and 28L, 16H and 29L, 16H and 30L, 16H and 31L, 16H and 32L, 17H and 1L, 17H and 2L, 17H and 3L, 17H and 4L, 17H and 5L, 17H and 6L, 17H and 7L, 17H and 8L, 17H and 9L L, 17H and 10L, 17H and 11L, 17H and 12L, 17H and 13L, 17H and 14L, 17H and 15L, 17H and 16L, 17H and 17L, 17H and 18L, 17H and 19L, 17H and 20L, 17H and 21L, 17H and 22L, 17H and 23L, 17H and 24L, 17 H and 25L, 17H and 26L, 17H and 27L, 17H and 28L, 17H and 29L, 17H and 30L, 17H and 31L, 17H and 32L, 18H and 1L, 18H and 2L, 18H and 3L, 18H and 4L, 18H and 5L, 18H and 6L, 18H and 7L, 18H and 8L, 18H and 9L18H and 10L, 18H and 11L, 18H and 12L, 18H and 13L, 18H and 14L, 18H and 15L, 18H and 16L, 18H and 17L, 18H and 18L, 18H and 19L, 18H and 20L, 18H and 21L, 18H and 22L, 18H and 23L, 18H and 24L, 18H and 25L, 18H and 26L, 18H and 27L, 18H and 28L, 18H and 29L, 18H and 30L, 18H and 31L, 18H and 32L, 19H and 1L, 19H and 2L, 19H and 3L, 19H and 4L, 19H and 5L, 19H and 6L, 19H and 7L, 19H and 8L, 19H and 9L, 19 H and 10L, 19H and 11L, 19H and 12L, 19H and 13L, 19H and 14L, 19H and 15L, 19H and 16L, 19H and 17L, 19H and 18L, 19H and 19L, 19H and 20L, 19H and 21L, 19H and 22L, 19H and 23L, 19H and 24L, 19H and 25L L, 19H and 26L, 19H and 27L, 19H and 28L, 19H and 29L, 19H and 30L, 19H and 31L, 19H and 32L, 20H and 1L, 20H and 2L, 20H and 3L, 20H and 4L, 20H and 5L, 20H and 6L, 20H and 7L, 20H and 8L, 20H and 9L, 20H and 10L, 20H and 11L, 20H and 12L, 20H and 13L, 20H and 14L, 20H and 15L, 20H and 16L, 20H and 17L, 20H and 18L, 20H and 19L, 20H and 20L, 20H and 21L, 20H and 22L, 20H and 23L, 20H and 24L, 20H and 25L 20H and 26L, 20H and 27L, 20H and 28L, 20H and 29L, 20H and 30L, 20H and 31L, 20H and 32L, 21H and 1L, 21H and 2L, 21H and 3L, 21H and 4L, 21H and 5L, 21H and 6L, 21H and 7L, 21H and 8L, 21H and 9L, 21H and 10L L, 21H and 11L, 21H and 12L, 21H and 13L, 21H and 14L, 21H and 15L, 21H and 16L, 21H and 17L, 21H and 18L, 21H and 19L, 21H and 20L, 21H and 21L, 21H and 22L, 21H and 23L, 21H and 24L, 21H and 25L, 21 H and 26L, 21H and 27L, 21H and 28L, 21H and 29L, 21H and 30L, 21H and 31L, 21H and 32L, 22H and 1L, 22H and 2L, 22H and 3L, 22H and 4L, 22H and 5L, 22H and 6L, 22H and 7L, 22H and 8L, 22H and 9L, 22H and 10L22H and 11L, 22H and 12L, 22H and 13L, 22H and 14L, 22H and 15L, 22H and 16L, 22H and 17L, 22H and 18L, 22H and 19L, 22H and 20L, 22H and 21L, 22H and 22L, 22H and 23L, 22H and 24L, 22H and 25L, 22H and 26L, 22H and 27L, 22H and 28L, 22H and 29L, 22H and 30L, 22H and 31L, 22H and 32L, 23H and 1L, 23H and 2L, 23H and 3L, 23H and 4L, 23H and 5L, 23H and 6L, 23H and 7L, 23H and 8L, 23H and 9L, 23H and 10L, 23 H and 11L, 23H and 12L, 23H and 13L, 23H and 14L, 23H and 15L, 23H and 16L, 23H and 17L, 23H and 18L, 23H and 19L, 23H and 20L, 23H and 21L, 23H and 22L, 23H and 23L, 23H and 24L, 23H and 25L, 23H and 26L L, 23H and 27L, 23H and 28L, 23H and 29L, 23H and 30L, 23H and 31L, 23H and 32L, 24H and 1L, 24H and 2L, 24H and 3L, 24H and 4L, 24H and 5L, 24H and 6L, 24H and 7L, 24H and 8L, 24H and 9L, 24H and 10L, 24H and 11L, 24H and 12L, 24H and 13L, 24H and 14L, 24H and 15L, 24H and 16L, 24H and 17L, 24H and 18L, 24H and 19L, 24H and 20L, 24H and 21L, 24H and 22L, 24H and 23L, 24H and 24L, 24H and 25L, 24H and 26L 24H and 27L, 24H and 28L, 24H and 29L, 24H and 30L, 24H and 31L, 24H and 32L, 25H and 1L, 25H and 2L, 25H and 3L, 25H and 4L, 25H and 5L, 25H and 6L, 25H and 7L, 25H and 8L, 25H and 9L, 25H and 10L, 25H and 11L L, 25H and 12L, 25H and 13L, 25H and 14L, 25H and 15L, 25H and 16L, 25H and 17L, 25H and 18L, 25H and 19L, 25H and 20L, 25H and 21L, 25H and 22L, 25H and 23L, 25H and 24L, 25H and 25L, 25H and 26L, 25 H and 27L, 25H and 28L, 25H and 29L, 25H and 30L, 25H and 31L, 25H and 32L, 26H and 1L, 26H and 2L, 26H and 3L, 26H and 4L, 26H and 5L, 26H and 6L, 26H and 7L, 26H and 8L, 26H and 9L, 26H and 10L, 26H and 11L26H and 12L, 26H and 13L, 26H and 14L, 26H and 15L, 26H and 16L, 26H and 17L, 26H and 18L, 26H and 19L, 26H and 20L, 26H and 21L, 26H and 22L, 26H and 23L, 26H and 24L, 26H and 25L, 26H and 26L, 26H and 27L, 26H and 28L, 26H and 29L, 26H and 30L, 26H and 31L, 26H and 32L, 27H and 1L, 27H and 2L, 27H and 3L, 27H and 4L, 27H and 5L, 27H and 6L, 27H and 7L, 27H and 8L, 27H and 9L, 27H and 10L, 27H and 11L, 27 H and 12L, 27H and 13L, 27H and 14L, 27H and 15L, 27H and 16L, 27H and 17L, 27H and 18L, 27H and 19L, 27H and 20L, 27H and 21L, 27H and 22L, 27H and 23L, 27H and 24L, 27H and 25L, 27H and 26L, 27H and 27 L, 27H and 28L, 27H and 29L, 27H and 30L, 27H and 31L, 27H and 32L, 28H and 1L, 28H and 2L, 28H and 3L, 28H and 4L, 28H and 5L, 28H and 6L, 28H and 7L, 28H and 8L, 28H and 9L, 28H and 10L, 28H and 11L, 28H and 12L, 28H and 13L, 28H and 14L, 28H and 15L, 28H and 16L, 28H and 17L, 28H and 18L, 28H and 19L, 28H and 20L, 28H and 21L, 28H and 22L, 28H and 23L, 28H and 24L, 28H and 25L, 28H and 26L, 28H and 27L 28H and 28L, 28H and 29L, 28H and 30L, 28H and 31L, 28H and 32L, 29H and 1L, 29H and 2L, 29H and 3L, 29H and 4L, 29H and 5L, 29H and 6L, 29H and 7L, 29H and 8L, 29H and 9L, 29H and 10L, 29H and 11L, 29H and 12L L, 29H and 13L, 29H and 14L, 29H and 15L, 29H and 16L, 29H and 17L, 29H and 18L, 29H and 19L, 29H and 20L, 29H and 21L, 29H and 22L, 29H and 23L, 29H and 24L, 29H and 25L, 29H and 26L, 29H and 27L, 29 H and 28L, 29H and 29L, 29H and 30L, 29H and 31L, 29H and 32L, 30H and 1L, 30H and 2L, 30H and 3L, 30H and 4L, 30H and 5L, 30H and 6L, 30H and 7L, 30H and 8L, 30H and 9L, 30H and 10L, 30H and 11L, 30H and 12L30H and 13L, 30H and 14L, 30H and 15L, 30H and 16L, 30H and 17L, 30H and 18L, 30H and 19L, 30H and 20L, 30H and 21L, 30H and 22L, 30H and 23L, 30H and 24L, 30H and 25L, 30H and 26L, 30H and 27L, 30H and 28L, 30H and 29L, 30H and 30L, 30H and 31L, 30H and 32L, 31H and 1L, 31H and 2L, 31H and 3L, 31H and 4L, 31H and 5L, 31H and 6L, 31H and 7L, 31H and 8L, 31H and 9L, 31H and 10L, 31H and 11L, 31H and 12L, 31H and 13L, 31H and 14L, 31H and 15L, 31H and 16L, 31H and 17L, 31H and 18L, 31H and 19L, 31H and 20L, 31H and 21L, 31H and 22L, 31 H and 23L, 31H and 24L, 31H and 25L, 31H and 26L, 31H and 27L, 31H and 28L, 31H and 29L, 31H and 30L, 31H and 31L, 31H and 32L, 32H and 1L, 32H and 2L, 32H and 3L, 32H and 4L, 32H and 5L, 32H and 6L, 32H and 7L, 32H and 8L, 32H and 9L, 32H and 10L, 32H and 11L, 32H and 12L CDRs of 32H and 13L, 32H and 14L, 32H and 15L, 32H and 16L, 32H and 17L, 32H and 18L, 32H and 19L, 32H and 20L, 32H and 21L, 32H and 22L, 32H and 23L, 32H and 24L, 32H and 25L, 32H and 26L, 32H and 27L, 32H and 28L, 32H and 29L, 32H and 30L, 32H and 31L, or 32H and 32L.

[0226] In some embodiments, peptides containing a CDR of 1H, 2H, 3H, 4H, 5H, 6H, 7H, 8H, 9H, 10H, 11H, 12H, 13H, 14H, 15H, 16H, 17H, 18H, 19H, 20H, 21H, 22H, 23H, 24H, 25H, 26H, 27H, 28H, 29H, 30H, 31H, or 32H are combined with, linked with, or co-expressed with peptides containing 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 or variants thereof. In some embodiments, the sequence is at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence.

[0227] In some embodiments, an antibody is provided, comprising its isolated form, wherein the antibody includes a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; the heavy chain CDR2 has an amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92, or 97, or a variant of any of the foregoing.

[0228] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:25; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:27, or a variant of any of the foregoing.

[0229] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0230] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:38; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing.

[0231] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing.

[0232] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0233] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing.

[0234] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing.

[0235] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:53; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0236] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:55; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0237] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0238] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:61, or a variant of any of the foregoing.

[0239] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:63, or a variant of any of the foregoing.

[0240] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:65, or a variant of any of the foregoing.

[0241] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:66, or a variant of any of the foregoing.

[0242] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:67, or a variant of any of the foregoing.

[0243] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:126, or a variant of any of the foregoing.

[0244] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:69, or a variant of any of the foregoing.

[0245] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:71; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:73, or a variant of any of the foregoing.

[0246] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:76; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:78, or a variant of any of the foregoing.

[0247] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:80; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:82, or a variant of any of the foregoing.

[0248] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0249] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:90; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:92, or a variant of any of the foregoing.

[0250] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:95; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:97, or a variant of any of the foregoing.

[0251] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0252] In some embodiments, the antibody or its isolated form comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0253] In some embodiments, the heavy chain variable region or protein provided herein is linked to the light chain variable region. In some embodiments, the linker is a peptide linker, such as, but not limited to, GQSSR SSGGGGSSGGGGS (SEQ ID NO: 136), (GGGGS)n (SEQ ID NO: 137), (GGGGA)n (SEQ ID NO: 138), or any combination thereof, wherein each n is independently 1-5. The linked peptide form may be represented by the formula VH-Z-VL or VL-Z-VH, where Z is the peptide linker. In some embodiments, ZGQSSRSSGGGGSSGGGGS (SEQ ID NO: 136); (GGGGS)n (SEQ ID NO: 137), (GGGGA)n (SEQ ID NO: 138), or any combination thereof, wherein each n is independently 1-5.

[0254] In some embodiments, the light chain variable region comprises a sequence of any one of the sequences listed in SEQ ID NO:127-135. In some embodiments, the light chain variable region comprises light chain CDR1, CDR2, and CDR3 peptide sequences, wherein the light chain CDR1 sequence has an amino acid sequence of SEQ ID NO:22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of SEQ ID NO:23, 29, 41, 51, 59, 68, 84, 88, or 99; and the light chain CDR3 sequence has an amino acid sequence of SEQ ID NO:24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, or 94, or a variant of any of the foregoing.

[0255] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:23; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:24, or a variant of any of the foregoing.

[0256] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:30, or a variant of any of the foregoing.

[0257] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing.

[0258] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:42, or a variant of any of the foregoing.

[0259] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing.

[0260] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:52, or a variant of any of the foregoing.

[0261] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0262] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0263] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0264] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:70, or a variant of any of the foregoing.

[0265] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:75, or a variant of any of the foregoing.

[0266] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:79, or a variant of any of the foregoing.

[0267] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:85, or a variant of any of the foregoing.

[0268] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:89, or a variant of any of the foregoing.

[0269] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:94, or a variant of any of the foregoing.

[0270] In some embodiments, the antibody or its isolated form comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:99; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:100, or a variant of any of the foregoing.

[0271] In some embodiments, an antibody or antigen-binding fragment thereof is provided, wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; the heavy chain CDR2 has an amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102; and the heavy chain CDR3 sequence has SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102 ... NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97 amino acid sequences, or variants of any of the preceding items; and (ii) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93 or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88 or 99; and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89 or 94 amino acid sequences, or variants of any of the preceding items.

[0272] In some implementation schemes, the following implementation schemes are provided herein:

[0273] 1. An antibody or an isolated form thereof, said antibody or an isolated form thereof binding to sealing protein 6 with an affinity of less than 10 nM and with an EC50 that is at least 100 times larger than that of sealing protein 9, sealing protein 3 and / or sealing protein 4.

[0274] 2. The antibody or its isolated form as described in Embodiment 1, wherein the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; the heavy chain CDR2 has an amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92, or 97, or a variant of any of the foregoing.

[0275] 3. The antibody or its isolated form as described in embodiment 1, wherein the antibody comprises:

[0276] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:25; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:27, or a variant of any of the foregoing.

[0277] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0278] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:38; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing.

[0279] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing.

[0280] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0281] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing.

[0282] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing.

[0283] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:53; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0284] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:55; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0285] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0286] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:61, or a variant of any of the foregoing.

[0287] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:63, or a variant of any of the foregoing.

[0288] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:65, or a variant of any of the foregoing.

[0289] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:66, or a variant of any of the foregoing.

[0290] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:67, or a variant of any of the foregoing.

[0291] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:126, or a variant of any of the foregoing.

[0292] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:69, or a variant of any of the foregoing.

[0293] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:71; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:73, or a variant of any of the foregoing.

[0294] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:76; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:78, or a variant of any of the foregoing.

[0295] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:80; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:82, or a variant of any of the foregoing.

[0296] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0297] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:90; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:92, or a variant of any of the foregoing.

[0298] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:95; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:97, or a variant of any of the foregoing.

[0299] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; or

[0300] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0301] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:139; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:140; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:82, or a variant of any of the foregoing.

[0302] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:141; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:142; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0303] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:143; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:144; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:92, or a variant of any of the foregoing; or

[0304] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:145; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:146; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:97, or a variant of any of the foregoing.

[0305] 4. The antibody according to any one of embodiments 1-3, wherein the antibody comprises a light chain variable region comprising a sequence of any one of the sequences listed in SEQ ID NO:127-135.

[0306] 5. The antibody according to any one of embodiments 1-3, wherein the antibody comprises a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93 or 98; the light chain CDR2 sequence has an amino acid sequence of SEQ ID NO: 23, 29, 41, 51, 59, 68, 84, 88 or 99; and the light chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or a variant of any of the foregoing.

[0307] 6. The antibody as described in embodiment 5, wherein the antibody comprises:

[0308] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:23; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:24, or a variant of any of the foregoing.

[0309] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:30, or a variant of any of the foregoing.

[0310] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing.

[0311] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:42, or a variant of any of the foregoing.

[0312] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing.

[0313] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:52, or a variant of any of the foregoing.

[0314] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0315] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0316] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0317] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:70, or a variant of any of the foregoing.

[0318] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:75, or a variant of any of the foregoing.

[0319] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:79, or a variant of any of the foregoing.

[0320] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:85, or a variant of any of the foregoing.

[0321] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:89, or a variant of any of the foregoing.

[0322] A light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:94, or a variant of any of the foregoing; or

[0323] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:99; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:100, or a variant of any of the foregoing.

[0324] 7. The antibody or antigen-binding fragment thereof as described in Embodiment 1, wherein the antibody or antigen-binding fragment thereof comprises:

[0325] (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; the heavy chain CDR2 has an amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92, or 97, or a variant of any of the foregoing; and

[0326] (ii) A light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88, or 99; and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, or 94, or a variant of any of the foregoing.

[0327] 8. The antibody or antigen-binding fragment thereof as described in Embodiment 3, wherein the antibody or antigen-binding fragment thereof comprises:

[0328] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0329] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:61, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0330] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:63, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0331] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:65, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0332] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:66, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0333] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:67, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0334] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:65, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0335] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:126, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0336] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:69, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0337] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:69, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:70, or a variant of any of the foregoing;

[0338] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:71; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:73, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:75, or a variant of any of the foregoing;

[0339] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:76; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:78, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:79, or a variant of any of the foregoing;

[0340] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:80; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:82, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:85, or a variant of any of the foregoing;

[0341] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:89, or a variant of any of the foregoing;

[0342] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:90; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:92, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:94, or a variant of any of the foregoing;

[0343] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:95; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:97, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:99; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:100, or a variant of any of the foregoing;

[0344] A heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing; or

[0345] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:89, or a variant of any of the foregoing;

[0346] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:25; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:27, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:23; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:24, or a variant of any of the foregoing;

[0347] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:30, or a variant of any of the foregoing;

[0348] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:28; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:29, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:26, or a variant of any of the foregoing;

[0349] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:42, or a variant of any of the foregoing;

[0350] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:30, or a variant of any of the foregoing;

[0351] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing;

[0352] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:42, or a variant of any of the foregoing;

[0353] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:53; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:52, or a variant of any of the foregoing;

[0354] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:55; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:52, or a variant of any of the foregoing.

[0355] 9. The antibody as described in any one of embodiments 1-8, wherein the antibody is a monoclonal antibody.

[0356] 10. The antibody as described in any one of embodiments 1-9, wherein the antibody is a humanized antibody.

[0357] 11. The antibody as described in any one of embodiments 1-8, wherein the antibody is a chicken antibody.

[0358] 12. The antibody as described in any one of embodiments 1-11, wherein the antibody comprises the sequence provided herein.

[0359] 13. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises a CDR sequence as provided herein.

[0360] 14. The isolated antibody as described in any of the foregoing embodiments, wherein the antibody comprises SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:122 or SEQ ID NO:124, 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 or SEQ ID NO:129. The VL sequence of NO:135, or any variant of the foregoing.

[0361] 15. An isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VL sequence of 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 or SEQ ID NO:135, or any variant thereof.

[0362] 16. An isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VL sequence of SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129 or SEQ ID NO:130, or any variant thereof.

[0363] 17. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VL sequence of SEQ ID NO:127 or SEQ ID NO:128.

[0364] 18. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:119, SEQ ID NO:121 or SEQ ID NO:123 or any variant thereof.

[0365] 19. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:103.

[0366] 20. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:105.

[0367] 21. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:107.

[0368] 22. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:109.

[0369] 23. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:111.

[0370] 24. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:113.

[0371] 25. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:115.

[0372] 26. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:117.

[0373] 27. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:119.

[0374] 28. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:121.

[0375] 29. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises the VH sequence of SEQ ID NO:123.

[0376] 30. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises GFSFSSY (SEQ ID NO: 139); YSSASSTY (SEQ ID NO: 140); AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); GFDFSSY (SEQ ID NO: 141); GSTGSS (SEQ ID NO: 142); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); GFSISSY (SEQ ID NO: 143); YSGSR (SEQ ID NO: 144); SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); GFTFSSY (SEQ ID NO: 145); DSGST (SEQ ID NO: 146); DAYGYCGWSGCSA DSIDA (SEQ ID NO: 97); SGDSSWYGYG (SEQ ID NO: 83); ESGK RPS (SEQ ID NO: 84); GSADSNSIGI (SEQ ID NO: 83). NO:85); SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); GSTDNSYVGI (SEQ ID NO:89); SGDSSDDGSYYYG (SEQ ID NO:93); SNDKRPS (SEQ ID NO:88); GSYDSSTGI (SEQ ID NO:94); SGGNNYYG (SEQ ID NO:98); YNDKRPS (SEQ ID NO:99); GGWDSSGGI (SEQ ID NO:100) or CDRs as otherwise described herein.

[0377] 31. GFSFSSY(SEQID NO:139);YSSASSTY(SEQ ID) NO:140);AAGRTYRGWATYIADSIDA(SEQ ID NO:82);GFDFSSY(SEQ ID NO:141);GSTGSS(SEQ ID NO:142);SVGNGNSWSGYIATSIDA(SEQ ID NO:57);GFSISSY(SEQ ID NO:143);YSGSR(SEQ ID NO:144); Ssyctawtgcdvyaggsiida (SEQ ID NO:92); Gftfssy (SEQ ID NO:145); DSGST (SEQ ID NO:146); Daygycwwsgsa sida (SEQ IDNO:97); CSGdsswygyG (SEQ ID NO:22); Iyes krp (SEQ ID NO:23); CGssnsigif (SEQ IDNO:24); Gfsfs sydmgwv (SEQ ID NO:25); Vasiyssassityya (SEQ ID NO:26); Kakaagrtyrgwatyiadsida (SEQ ID NO:27); CSggssg yg (SEQ ID NO:28); Iysndkrp (SEQ ID NO:28) IDNO:29); CGSTDNSYV GIF (SEQ ID NO:30); GFDFSSYAMNWV (SEQ ID NO:31); VAGIG STGSSTGYG (SEQ ID NO:32); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO:33); CSGDSSDDGSYYYG (SEQ IDNO:34); IYSNDKRP (SEQ ID NO:29); CGSYDSSTGIF (SEQ ID NO:36); GFSISSYTMQ WV (SEQ IDNO:37); VAGIYSGSRTYYG (SEQ ID NO:38); CAKS SYCTAWTGCDVYAGGSIDA (SEQ ID NO:39); CSGGNNYYG (SEQ ID NO:40);IYYNDKRP(SEQ ID NO:41);CGGWDSSGGIF(SEQ ID NO:42);GFTFSSYSMFWV(SEQ ID NO:43);VAGIDSGSTTFY G(SEQ ID NO:44);CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45);CSGDSSWYGYG(SEQ ID NO:22);IYESGKRP(SEQ ID NO:23);CGSADSNSIGIF(SEQ ID NO:24); NO:26);CAKAAGRTYRGW ATYIADSIDA(SEQ ID NO:27);CSGGSSGYG(SEQ ID NO:28);IY SNDKRP(SEQID NO:29);CGSTDNSYVGIF(SEQ ID NO:30);GF DFSSYEMN VV(SEQ ID NO:28); NO:31);VAGIGSTGSSTGYA(SEQ ID NO:46);CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);CSGDDGS YYYG(SEQ ID NO:47);IYSNDKRP(SEQ ID NO:29);CGSYDSST GIF(SEQ ID NO:33); NO:36);GFSISSY™QWV(SEQ ID NO:37);VAGIY SGSRTYYA(SEQ ID NO:48);CAKSSYCTAWTGCDVYAGGSIDA(SEQ IDNO:39);CSGGNNYYG(SEQ ID NO:40);ISEYYND QRP(SEQ ID NO:48); NO:41);CGGWDSSGGIF(SEQ ID NO:42);GFTFSSYSMFW V(SEQ ID NO:43);VAGIDSGSTTFYA(SEQ ID NO:49);CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45);CSGGSGSYGSE(SEQ ID NO:45); NO:51);CGSADSSTNAGIF(SEQ ID NO:52);GFTFSSYAMSWV(SEQ ID NO:53);VAGISSGRYTGYA(SEQID NO:54);CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);CSEGGSYGSE(SEQ ID NO:50)? ID NO:51);CGSADSSTNAGIF(SEQ ID NO:52);GFTFSSYAMNWV(SEQ ID NO:55);Or VAGISSSGRYTGYA (SEQ ID NO:54); CAKSVGNGNSW SGYIATSIDA (SEQ ID NO:33) or VH CDR as otherwise described herein.

[0378] 32. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises SGDSSWYGYG (SEQ ID NO: 83); ESGKRPS (SEQ ID NO: 84); GSADSNSIGI (SEQ ID NO: 85); SGGSSGYG (SEQ ID NO: 87); SNDKRPS (SEQ ID NO: 88); GSTDNSYVGI (SEQ ID NO: 89); SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS (SEQ ID NO: 88); GSYDSSTGI (SEQ ID NO: 94); SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); GGWDSSGGI (SEQ ID NO: 100); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); CSGGSSGYG (SEQ ID NO: 85); SGDSSDNSIGIF (SEQ ID NO: 87); SNDKRPS (SEQ ID NO: 88); GSTDNSYVGI (SEQ ID NO: 89); SGDSSDDGSYYYG (SEQ ID NO: 83); SNDKRPS (SEQ ID NO: 88); GSYDSSTGI (SEQ ID NO: 84); SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); GGWDSSGGI (SEQ ID NO: 100); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); CSGGSSGYG (SEQ ID NO: 85); SGDSSDNSIGIF (SEQ ID NO: 87); SGDSSDNSIGIF (SEQ ID NO: 88); SGDSSDNSIGIF (SEQ ID NO: 89); ID NO:28); IYSNDKRP (SEQ ID NO:29); CGSTDNSYVGIF (SEQ ID NO:30); CSGDSSDDGSYYYG (SEQ ID NO:34); IYSNDKRP (SEQ ID NO:29); CGSYDSSTGIF (SEQ ID NO:36); CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); CGGWDSSGGIF (SEQ ID NO:42); IYESGKRP (SEQ ID NO:23); CGSADSNSIGIF (SEQ ID NO:24); CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); CGSTDNSYVGIF (SEQ ID NO:30); CSGDDGSYYYG (SEQ ID NO:47); IYSNDKRP (SEQ ID NO:29); CGSYDSSTGIF (SEQ ID NO:36); CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); CGGDSSSGGIF (SEQ ID NO:42); CSGGSGSYG (SEQ ID NO:50); IYGTNKRP (SEQ ID NO:51); CGSADSSTNAGIF (SEQ ID NO:52); CSGGSGSYG (SEQ ID NO:50);IYGTNKRP (SEQ ID NO:51); or CGSADSSTNAGIF (SEQ ID NO:52) or VL CDR as otherwise described herein.

[0379] 33. The isolated antibody as described in any of the preceding embodiments, wherein the CDR of the VH chain comprises:

[0380] 1H.GFSFSSY (SEQ ID NO:139); YSSASSTY (SEQ ID NO:140); and AAGRTYRGWATYIADSIDA (SEQ ID NO:82); or

[0381] 2H.GFDFSSY (SEQ ID NO:141); GSTGSS (SEQ ID NO:142); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57); or

[0382] 3H.GFSISSY (SEQ ID NO:143); YSGSR (SEQ ID NO:144); and SSYCTAWTGCDVYAGGSIDA (SEQ ID NO:92); or

[0383] 4H.GTFFSSY (SEQ ID NO:145); DSGST (SEQ ID NO:146); and DAYGYCGWSGCSADSIDA (SEQ ID NO:97); or

[0384] 5H.GFSFSSYDMGWV (SEQ ID NO:25); VASIYSSASSTYYA (SEQ ID NO:26); and CAKAAGRTYRGWATYIADSIDA (SEQ ID NO:27); or

[0385] 6H.GFDFSSYAMNWV (SEQ ID NO:31); VAGIGSTGSSTGYG (SEQ ID NO:32); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO:33); or

[0386] 7H.GFSISSYTMQWV (SEQ ID NO:37); VAGIYSGSRTYYG (SEQ ID NO:38); and CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO:39); or

[0387] 8H.GFTFSSYSMFWV(SEQ ID NO:43),VAGIDSGSTTFYG(SEQ ID NO:44),CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45);

[0388] 9H.GFSFSSYDMGWV(SEQ ID NO:25),VASIYSSASSTYYA(SEQ ID NO:26), and CAKAAGRTYRGWATYIADSIDA(SEQ ID NO:27);

[0389] 10H.GFDFSSYAMNWV(SEQ ID NO:31),VAGIGSTGSSTGYA(SEQ ID NO:46), and CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);

[0390] 11H.GFSISSYTMQWV(SEQ ID NO:37),VAGIYSGSRTYYA(SEQ ID NO:48),CAKSSYCTAWTGCDVYAGGSIDA(SEQ ID NO:39);

[0391] 12H.GFTFSSYSMFWV(SEQ ID NO:43),VAGIDSGSTTFYA(SEQ ID NO:49),CAKDAYGYCGWSGCSADSIDA(SEQ ID NO:45);

[0392] 13H.GFTFSSYAMSWV(SEQ ID NO:53),VAGISSSGRYTGYA(SEQ ID NO:54),CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);

[0393] 14H.GFTFSSYAMNWV(SEQ ID NO:55),VAGISSSGRYTGYA(SEQ ID NO:54),CAKSVGNGNSWSGYIATSIDA(SEQ ID NO:33);

[0394] 15H.SYAMS(SEQ ID NO:56),GISSSGRYTGYADSVKG(SEQ ID NO:101),SVGNGNSWSGYIATSIDA(SEQ ID NO:57);

[0395] 16H. SYAMS (SEQ ID NO:56); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGNGNSWSGYVATSIDA (SEQ ID NO:61); or

[0396] 17H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSIDA (SEQ ID NO:63); or

[0397] 18H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSIDA (SEQ ID NO:65); or

[0398] 19H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSIDV (SEQ ID NO:66); or

[0399] 20H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSLDA (SEQ ID NO:67); or

[0400] 21H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSIDA (SEQ ID NO:65); or

[0401] 22H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SMGSGVSWSGYVATSLDV (SEQ ID NO:126); or

[0402] 23H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSLDV (SEQ ID NO:69); or

[0403] 24H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGSGVSWSGYVATSLDV (SEQ ID NO:69); or

[0404] 25H. SYGMS (SEQ ID NO:71); GIGSSGIYTHYADSVKG (SEQ ID NO:72); and SPGDSDWCGWAGYGIYSCRVAGFIDA (SEQ ID NO:73); or

[0405] 26H. GYAMS (SEQ ID NO:76); GIYSSGSYTFYADSVKG (SEQ ID NO:77); and GTGYCDWSGWCYSGAANIDA (SEQ ID NO:78); or

[0406] 27H. SYDMG (SEQ ID NO:80); SIYSSASSTYYAPAVKG (SEQ ID NO:81); and AAGRTYRGWATYIADSIDA (SEQ ID NO:82); or

[0407] 28H. SYAMN (SEQ ID NO:62); GIGSTGSSTGYGPAVKG (SEQ ID NO:86); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57); or

[0408] 29H. SYTMQ (SEQ ID NO:90); GIYSGSRTYYGAAVQG (SEQ ID NO:91); and SSYCTAWTGCDVYAGGSIDA (SEQ ID NO:92); or

[0409] 30H. SYSMF (SEQ ID NO:95); GIDSGSTTFYGSAVKG (SEQ ID NO:96); and DAYGYCGWSGCSADSIDA (SEQ ID NO:97); or

[0410] 31H. SYAMN (SEQ ID NO:62); GISSSGRYTGYADSVKG (SEQ ID NO:101); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57); or

[0411] 32H.SYAMN (SEQ ID NO:62); GIGSTGSSTGYADSVKG (SEQ ID NO:102); and SVGNGNSWSGYIATSIDA (SEQ ID NO:57).

[0412] 34. The isolated antibody as described in any of the foregoing embodiments, wherein the VL chain comprises a CDR having the following:

[0413] 1L.SGDSSWYGYG (SEQ ID NO:83); ESGKRPS (SEQ ID NO:84); and GSADSNSIGI (SEQ ID NO:85); or

[0414] 2L.SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); and GSTDNSYVGI (SEQ ID NO:89); or

[0415] 3L.SGDSSDDGSYYYG (SEQ ID NO:93); SNDKRPS (SEQ ID NO:88); and GSYDSSTGI (SEQ ID NO:94); or

[0416] 4L.SGGNNYYG (SEQ ID NO:98); YNDKRPS (SEQ ID NO:99); and GGWDSSGGI (SEQ ID NO:100); or

[0417] 5L.CSGDSSWYGYG (SEQ ID NO:22); IYESGKRP (SEQ ID NO:23); and CGSADSNSIGIF (SEQ ID NO:24); or

[0418] 6L.CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); and CGSTDNSYVGIF (SEQ ID NO:30); or

[0419] 7L.CSGDSSDDGSYYYG (SEQ ID NO:34); IYSNDKRP (SEQ ID NO:29); and CGSYDSSTGIF (SEQ ID NO:36); or

[0420] 8L.CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); and CGGWDSSGGIF (SEQ ID NO:42); or

[0421] 9L.CSGDSSWYGYG (SEQ ID NO:22); IYESGKRP (SEQ ID NO:23); and CGSADSNSIGIF (SEQ ID NO:24); or

[0422] 10L.CSGGSSGYG (SEQ ID NO:28); IYSNDKRP (SEQ ID NO:29); and CGSTDNSYVGIF (SEQ ID NO:30); or

[0423] 11L. CSGDDGSYYYG (SEQ ID NO:47); IYSNDKRP (SEQ ID NO:29); and CGSYDSSTGIF (SEQ ID NO:36); or

[0424] 12L.CSGGNNYYG (SEQ ID NO:40); IYYNDKRP (SEQ ID NO:41); and CGGWDSSGGIF (SEQ ID NO:42); or

[0425] 13L.CSGGSGSYG (SEQ ID NO:50); IYGTNKRP (SEQ ID NO:51); and CGSADSSTNAGIF (SEQ ID NO:52); or

[0426] 14L.CSGGSGSYG (SEQ ID NO:50); IYGTNKRP (SEQ ID NO:51); and CGSADSSTNAGIF (SEQ ID NO:52); or

[0427] 15L.SGGSGSYG (SEQ ID NO:58); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0428] 16L.SGGSGSYG (SEQ ID NO:58); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0429] 17L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

[0430] 18L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

[0431] 19L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

[0432] 20L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

[0433] 21L.SGGSGSYG (SEQ ID NO:58); GTYKRPS (SEQ ID NO:68); and GSADSSTNAGI (SEQ ID NO:60); or

[0434] 22L.SGGSGSYG (SEQ ID NO:58); GTYKRPS (SEQ ID NO:68); and GSADSSTNAGI (SEQ ID NO:60); or

[0435] 23L.SGGSGSYG (SEQ ID NO:58); GTYKRPS (SEQ ID NO:68); and GSADSSTNAGI (SEQ ID NO:60); or

[0436] 24L.SAGSGLYG (SEQ ID NO:64); GTNKRPS (SEQ ID NO:59); and GSNDASTNAGI (SEQ ID NO:70); or

[0437] 25L.SGGYNGHYG (SEQ ID NO:74); GTNKRPS (SEQ ID NO:59); and GGYDSSAGI (SEQ ID NO:75); or

[0438] 26L.SGGSGSYGYYG; GTNKRPS (SEQ ID NO:59); and GSEDSSSGAGI (SEQ ID NO:79); or

[0439] 27L.SGDSSWYGYG (SEQ ID NO:83); ESGKRPS (SEQ ID NO:84); and GSADSNSIGI (SEQ ID NO:85); or

[0440] 28L. SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); and GSTDNSYVGI (SEQ ID NO:89); or

[0441] 29L. SGDSSDDGSYYYG (SEQ ID NO:93); SNDKRPS (SEQ ID NO:88); and GSYDSSTGI (SEQ ID NO:94); or

[0442] 30L. SGGNNYYG (SEQ ID NO:98); YNDKRPS (SEQ ID NO:99); and GGWDSSGGI (SEQ ID NO:100); or

[0443] 31L. SGGSGSYG (SEQ ID NO:58); GTNKRPS (SEQ ID NO:59); and GSADSSTNAGI (SEQ ID NO:60); or

[0444] 32L. SGGSSGYG (SEQ ID NO:87); SNDKRPS (SEQ ID NO:88); and GSTDNSYVGI (SEQ ID NO:89).

[0445] 35. The isolated antibody as described in any of the preceding embodiments, wherein the antibody comprises 1H and 1L, 1H and 2L, 1H and 3L, 1H and 4L, 1H and 5L, 1H and 6L, 1H and 7L, 1H and 8L, 1H and 9L, 1H and 10L, 1H and 11L, 1H and 12L, 1H and 13L, 1H and 14L, 1H and 15L, 1H and 16L, 1H and 17L, 1H and 18L, 1H and 19L, 1H and 20L, 1H and 21L, 1H and 22L, 1H and 23L, 1H and 24L, 1H and 25L, 1H and 26L, 1H and 27L, 1H and 28L, 1H and 29L, 1H and 30L, 1H and 31L, 1H and 32L, 2H and 1 L, 2H and 2L, 2H and 3L, 2H and 4L, 2H and 5L, 2H and 6L, 2H and 7L, 2H and 8L, 2H and 9L, 2H and 10L, 2H and 11L, 2H and 12L, 2H and 13L, 2H and 14L, 2H and 15L, 2H and 16L, 2H and 17L, 2H and 18L, 2H and 19L, 2H and 20L L, 2H and 21L, 2H and 22L, 2H and 23L, 2H and 24L, 2H and 25L, 2H and 26L, 2H and 27L, 2H and 28L, 2H and 29L, 2H and 30L, 2H and 31L, 2H and 32L, 3H and 1L, 3H and 2L, 3H and 3L, 3H and 4L, 3H and 5L, 3H and 6L, 3H and 7L, 3H and 8L, 3H and 9L, 3H and 10L, 3H and 11L, 3H and 12L, 3H and 13L, 3H and 14L, 3H and 15L, 3H and 16L, 3H and 17L, 3H and 18L, 3H and 19L, 3H and 20L, 3H and 21L, 3H and 22L, 3H and 23L, 3H and 24L, 3H and 25L L, 3H and 26L, 3H and 27L, 3H and 28L, 3H and 29L, 3H and 30L, 3H and 31L, 3H and 32L, 4H and 1L, 4H and 2L, 4H and 3L, 4H and 4L, 4H and 5L, 4H and 6L, 4H and 7L, 4H and 8L, 4H and 9L, 4H and 10L, 4H and 11L, 4H and 12L 4H and 13L, 4H and 14L, 4H and 15L, 4H and 16L, 4H and 17L, 4H and 18L, 4H and 19L, 4H and 20L, 4H and 21L, 4H and 22L, 4H and 23L, 4H and 24L, 4H and 25L, 4H and 26L, 4H and 27L, 4H and 28L, 4H and 29L, 4H and 30L L, 4H and 31L, 4H and 32L, 5H and 1L, 5H and 2L, 5H and 3L, 5H and 4L, 5H and 5L, 5H and 6L, 5H and 7L, 5H and 8L, 5H and 9L, 5H and 10L, 5H and 11L, 5H and 12L, 5H and 13L, 5H and 14L, 5H and 15L, 5H and 16L, 5H and 17L5H and 18L, 5H and 19L, 5H and 20L, 5H and 21L, 5H and 22L, 5H and 23L, 5H and 24L, 5H and 25L, 5H and 26L, 5H and 27L, 5H and 28L, 5H and 29L, 5H and 30L, 5H and 31L, 5H and 32L, 6H and 1L, 6H and 2L, 6H and 3L, 6H And 4L, 6H and 5L, 6H and 6L, 6H and 7L, 6H and 8L, 6H and 9L, 6H and 10L, 6H and 11L, 6H and 12L, 6H and 13L, 6H and 14L, 6H and 15L, 6H and 16L, 6H and 17L, 6H and 18L, 6H and 19L, 6H and 20L, 6H and 21L, 6H and 22L, 6H and 23L, 6H and 24L, 6H and 25L, 6H and 26L, 6H and 27L, 6H and 28L, 6H and 29L, 6H and 30L, 6H and 31L, 6H and 32L, 7H and 1L, 7H and 2L, 7H and 3L, 7H and 4L, 7H and 5L, 7H and 6L, 7H and 7L, 7H and 8L, 7H and 9L, 7 H and 10L, 7H and 11L, 7H and 12L, 7H and 13L, 7H and 14L, 7H and 15L, 7H and 16L, 7H and 17L, 7H and 18L, 7H and 19L, 7H and 20L, 7H and 21L, 7H and 22L, 7H and 23L, 7H and 24L, 7H and 25L, 7H and 26L, 7H and 27L 7H and 28L, 7H and 29L, 7H and 30L, 7H and 31L, 7H and 32L, 8H and 1L, 8H and 2L, 8H and 3L, 8H and 4L, 8H and 5L, 8H and 6L, 8H and 7L, 8H and 8L, 8H and 9L, 8H and 10L, 8H and 11L, 8H and 12L, 8H and 13L, 8H and 14L, 8 H and 15L, 8H and 16L, 8H and 17L, 8H and 18L, 8H and 19L, 8H and 20L, 8H and 21L, 8H and 22L, 8H and 23L, 8H and 24L, 8H and 25L, 8H and 26L, 8H and 27L, 8H and 28L, 8H and 29L, 8H and 30L, 8H and 31L, 8H and 32L 9H and 1L, 9H and 2L, 9H and 3L, 9H and 4L, 9H and 5L, 9H and 6L, 9H and 7L, 9H and 8L, 9H and 9L, 9H and 10L, 9H and 11L, 9H and 12L, 9H and 13L, 9H and 14L, 9H and 15L, 9H and 16L, 9H and 17L, 9H and 18L, 9H and 19L, 9 H and 20L, 9H and 21L, 9H and 22L, 9H and 23L, 9H and 24L, 9H and 25L, 9H and 26L, 9H and 27L, 9H and 28L, 9H and 29L, 9H and 30L, 9H and 31L, 9H and 32L, 10H and 1L, 10H and 2L, 10H and 3L, 10H and 4L, 10H and 5L10H and 6L, 10H and 7L, 10H and 8L, 10H and 9L, 10H and 10L, 10H and 11L, 10H and 12L, 10H and 13L, 10H and 14L, 10H and 15L, 10H and 16L, 10H and 17L, 10H and 18L, 10H and 19L, 10H and 20L, 10H and 21L 10H and 22L, 10H and 23L, 10H and 24L, 10H and 25L, 10H and 26L, 10H and 27L, 10H and 28L, 10H and 29L, 10H and 30L, 10H and 31L, 10H and 32L, 11H and 1L, 11H and 2L, 11H and 3L, 11H and 4L, 11H and 5L, 1 1H and 6L, 11H and 7L, 11H and 8L, 11H and 9L, 11H and 10L, 11H and 11L, 11H and 12L, 11H and 13L, 11H and 14L, 11H and 15L, 11H and 16L, 11H and 17L, 11H and 18L, 11H and 19L, 11H and 20L, 11H and 21L, 1 1H and 22L, 11H and 23L, 11H and 24L, 11H and 25L, 11H and 26L, 11H and 27L, 11H and 28L, 11H and 29L, 11H and 30L, 11H and 31L, 11H and 32L, 12H and 1L, 12H and 2L, 12H and 3L, 12H and 4L, 12H and 5L, 12H And 6L, 12H and 7L, 12H and 8L, 12H and 9L, 12H and 10L, 12H and 11L, 12H and 12L, 12H and 13L, 12H and 14L, 12H and 15L, 12H and 16L, 12H and 17L, 12H and 18L, 12H and 19L, 12H and 20L, 12H and 21L, 12H And 22L, 12H and 23L, 12H and 24L, 12H and 25L, 12H and 26L, 12H and 27L, 12H and 28L, 12H and 29L, 12H and 30L, 12H and 31L, 12H and 32L, 13H and 1L, 13H and 2L, 13H and 3L, 13H and 4L, 13H and 5L, 13H and 6 L, 13H and 7L, 13H and 8L, 13H and 9L, 13H and 10L, 13H and 11L, 13H and 12L, 13H and 13L, 13H and 14L, 13H and 15L, 13H and 16L, 13H and 17L, 13H and 18L, 13H and 19L, 13H and 20L, 13H and 21L, 13H and 2 2L, 13H and 23L, 13H and 24L, 13H and 25L, 13H and 26L, 13H and 27L, 13H and 28L, 13H and 29L, 13H and 30L, 13H and 31L, 13H and 32L, 14H and 1L, 14H and 2L, 14H and 3L, 14H and 4L, 14H and 5L, 14H and 6L14H and 7L, 14H and 8L, 14H and 9L, 14H and 10L, 14H and 11L, 14H and 12L, 14H and 13L, 14H and 14L, 14H and 15L, 14H and 16L, 14H and 17L, 14H and 18L, 14H and 19L, 14H and 20L, 14H and 21L, 14H and 22L 14H and 23L, 14H and 24L, 14H and 25L, 14H and 26L, 14H and 27L, 14H and 28L, 14H and 29L, 14H and 30L, 14H and 31L, 14H and 32L, 15H and 1L, 15H and 2L, 15H and 3L, 15H and 4L, 15H and 5L, 15H and 6L, 1 5H and 7L, 15H and 8L, 15H and 9L, 15H and 10L, 15H and 11L, 15H and 12L, 15H and 13L, 15H and 14L, 15H and 15L, 15H and 16L, 15H and 17L, 15H and 18L, 15H and 19L, 15H and 20L, 15H and 21L, 15H and 22L 15H and 23L, 15H and 24L, 15H and 25L, 15H and 26L, 15H and 27L, 15H and 28L, 15H and 29L, 15H and 30L, 15H and 31L, 15H and 32L, 16H and 1L, 16H and 2L, 16H and 3L, 16H and 4L, 16H and 5L, 16H and 6L, 16H And 7L, 16H and 8L, 16H and 9L, 16H and 10L, 16H and 11L, 16H and 12L, 16H and 13L, 16H and 14L, 16H and 15L, 16H and 16L, 16H and 17L, 16H and 18L, 16H and 19L, 16H and 20L, 16H and 21L, 16H and 22L, 16 H and 23L, 16H and 24L, 16H and 25L, 16H and 26L, 16H and 27L, 16H and 28L, 16H and 29L, 16H and 30L, 16H and 31L, 16H and 32L, 17H and 1L, 17H and 2L, 17H and 3L, 17H and 4L, 17H and 5L, 17H and 6L, 17H and 7 L, 17H and 8L, 17H and 9L, 17H and 10L, 17H and 11L, 17H and 12L, 17H and 13L, 17H and 14L, 17H and 15L, 17H and 16L, 17H and 17L, 17H and 18L, 17H and 19L, 17H and 20L, 17H and 21L, 17H and 22L, 17H and 23L, 17H and 24L, 17H and 25L, 17H and 26L, 17H and 27L, 17H and 28L, 17H and 29L, 17H and 30L, 17H and 31L, 17H and 32L, 18H and 1L, 18H and 2L, 18H and 3L, 18H and 4L, 18H and 5L, 18H and 6L, 18H and 7L18H and 8L, 18H and 9L, 18H and 10L, 18H and 11L, 18H and 12L, 18H and 13L, 18H and 14L, 18H and 15L, 18H and 16L, 18H and 17L, 18H and 18L, 18H and 19L, 18H and 20L, 18H and 21L, 18H and 22L, 18H and 23L L, 18H and 24L, 18H and 25L, 18H and 26L, 18H and 27L, 18H and 28L, 18H and 29L, 18H and 30L, 18H and 31L, 18H and 32L, 19H and 1L, 19H and 2L, 19H and 3L, 19H and 4L, 19H and 5L, 19H and 6L, 19H and 7L, 1 9H and 8L, 19H and 9L, 19H and 10L, 19H and 11L, 19H and 12L, 19H and 13L, 19H and 14L, 19H and 15L, 19H and 16L, 19H and 17L, 19H and 18L, 19H and 19L, 19H and 20L, 19H and 21L, 19H and 22L, 19H and 23L 19H and 24L, 19H and 25L, 19H and 26L, 19H and 27L, 19H and 28L, 19H and 29L, 19H and 30L, 19H and 31L, 19H and 32L, 20H and 1L, 20H and 2L, 20H and 3L, 20H and 4L, 20H and 5L, 20H and 6L, 20H and 7L, 20H And 8L, 20H and 9L, 20H and 10L, 20H and 11L, 20H and 12L, 20H and 13L, 20H and 14L, 20H and 15L, 20H and 16L, 20H and 17L, 20H and 18L, 20H and 19L, 20H and 20L, 20H and 21L, 20H and 22L, 20H and 23L, 2 0H and 24L, 20H and 25L, 20H and 26L, 20H and 27L, 20H and 28L, 20H and 29L, 20H and 30L, 20H and 31L, 20H and 32L, 21H and 1L, 21H and 2L, 21H and 3L, 21H and 4L, 21H and 5L, 21H and 6L, 21H and 7L, 21H and 8L L, 21H and 9L, 21H and 10L, 21H and 11L, 21H and 12L, 21H and 13L, 21H and 14L, 21H and 15L, 21H and 16L, 21H and 17L, 21H and 18L, 21H and 19L, 21H and 20L, 21H and 21L, 21H and 22L, 21H and 23L, 21H And 24L, 21H and 25L, 21H and 26L, 21H and 27L, 21H and 28L, 21H and 29L, 21H and 30L, 21H and 31L, 21H and 32L, 22H and 1L, 22H and 2L, 22H and 3L, 22H and 4L, 22H and 5L, 22H and 6L, 22H and 7L, 22H and 8L,22H and 9L, 22H and 10L, 22H and 11L, 22H and 12L, 22H and 13L, 22H and 14L, 22H and 15L, 22H and 16L, 22H and 17L, 22H and 18L, 22H and 19L, 22H and 20L, 22H and 21L, 22H and 22L, 22H and 23L, 22H and 2 4L, 22H and 25L, 22H and 26L, 22H and 27L, 22H and 28L, 22H and 29L, 22H and 30L, 22H and 31L, 22H and 32L, 23H and 1L, 23H and 2L, 23H and 3L, 23H and 4L, 23H and 5L, 23H and 6L, 23H and 7L, 23H and 8L, 2 3H and 9L, 23H and 10L, 23H and 11L, 23H and 12L, 23H and 13L, 23H and 14L, 23H and 15L, 23H and 16L, 23H and 17L, 23H and 18L, 23H and 19L, 23H and 20L, 23H and 21L, 23H and 22L, 23H and 23L, 23H and 24L L, 23H and 25L, 23H and 26L, 23H and 27L, 23H and 28L, 23H and 29L, 23H and 30L, 23H and 31L, 23H and 32L, 24H and 1L, 24H and 2L, 24H and 3L, 24H and 4L, 24H and 5L, 24H and 6L, 24H and 7L, 24H and 8L, 24H And 9L, 24H and 10L, 24H and 11L, 24H and 12L, 24H and 13L, 24H and 14L, 24H and 15L, 24H and 16L, 24H and 17L, 24H and 18L, 24H and 19L, 24H and 20L, 24H and 21L, 24H and 22L, 24H and 23L, 24H and 24L, 24H and 25L, 24H and 26L, 24H and 27L, 24H and 28L, 24H and 29L, 24H and 30L, 24H and 31L, 24H and 32L, 25H and 1L, 25H and 2L, 25H and 3L, 25H and 4L, 25H and 5L, 25H and 6L, 25H and 7L, 25H and 8L, 25H and 9L L, 25H and 10L, 25H and 11L, 25H and 12L, 25H and 13L, 25H and 14L, 25H and 15L, 25H and 16L, 25H and 17L, 25H and 18L, 25H and 19L, 25H and 20L, 25H and 21L, 25H and 22L, 25H and 23L, 25H and 24L, 25 H and 25L, 25H and 26L, 25H and 27L, 25H and 28L, 25H and 29L, 25H and 30L, 25H and 31L, 25H and 32L, 26H and 1L, 26H and 2L, 26H and 3L, 26H and 4L, 26H and 5L, 26H and 6L, 26H and 7L, 26H and 8L, 26H and 9L26H and 10L, 26H and 11L, 26H and 12L, 26H and 13L, 26H and 14L, 26H and 15L, 26H and 16L, 26H and 17L, 26H and 18L, 26H and 19L, 26H and 20L, 26H and 21L, 26H and 22L, 26H and 23L, 26H and 24L, 26H and 25L, 26H and 26L, 26H and 27L, 26H and 28L, 26H and 29L, 26H and 30L, 26H and 31L, 26H and 32L, 27H and 1L, 27H and 2L, 27H and 3L, 27H and 4L, 27H and 5L, 27H and 6L, 27H and 7L, 27H and 8L, 27H and 9L, 27 H and 10L, 27H and 11L, 27H and 12L, 27H and 13L, 27H and 14L, 27H and 15L, 27H and 16L, 27H and 17L, 27H and 18L, 27H and 19L, 27H and 20L, 27H and 21L, 27H and 22L, 27H and 23L, 27H and 24L, 27H and 25L L, 27H and 26L, 27H and 27L, 27H and 28L, 27H and 29L, 27H and 30L, 27H and 31L, 27H and 32L, 28H and 1L, 28H and 2L, 28H and 3L, 28H and 4L, 28H and 5L, 28H and 6L, 28H and 7L, 28H and 8L, 28H and 9L, 28H and 10L, 28H and 11L, 28H and 12L, 28H and 13L, 28H and 14L, 28H and 15L, 28H and 16L, 28H and 17L, 28H and 18L, 28H and 19L, 28H and 20L, 28H and 21L, 28H and 22L, 28H and 23L, 28H and 24L, 28H and 25L 28H and 26L, 28H and 27L, 28H and 28L, 28H and 29L, 28H and 30L, 28H and 31L, 28H and 32L, 29H and 1L, 29H and 2L, 29H and 3L, 29H and 4L, 29H and 5L, 29H and 6L, 29H and 7L, 29H and 8L, 29H and 9L, 29H and 10L L, 29H and 11L, 29H and 12L, 29H and 13L, 29H and 14L, 29H and 15L, 29H and 16L, 29H and 17L, 29H and 18L, 29H and 19L, 29H and 20L, 29H and 21L, 29H and 22L, 29H and 23L, 29H and 24L, 29H and 25L, 29 H and 26L, 29H and 27L, 29H and 28L, 29H and 29L, 29H and 30L, 29H and 31L, 29H and 32L, 30H and 1L, 30H and 2L, 30H and 3L, 30H and 4L, 30H and 5L, 30H and 6L, 30H and 7L, 30H and 8L, 30H and 9L, 30H and 10L30H and 11L, 30H and 12L, 30H and 13L, 30H and 14L, 30H and 15L, 30H and 16L, 30H and 17L, 30H and 18L, 30H and 19L, 30H and 20L, 30H and 21L, 30H and 22L, 30H and 23L, 30H and 24L, 30H and 25L, 30H and 26L, 30H and 27L, 30H and 28L, 30H and 29L, 30H and 30L, 30H and 31L 30H and 32L, 31H and 1L, 31H and 2L, 31H and 3L, 31H and 4L, 31H and 5L, 31H and 6L, 31H and 7L, 31H and 8L, 31H and 9L, 31H and 10L, 31H and 11L, 31H and 12L, 31H and 13L, 31H and 14L, 31H and 15L, 31H and 16L, 31H and 17L, 31H and 18L, 31H and 19L, 31H and 20L, 31H and 21L, 31 H and 22L, 31H and 23L, 31H and 24L, 31H and 25L, 31H and 26L, 31H and 27L, 31H and 28L, 31H and 29L, 31H and 30L, 31H and 31L, 31H and 32L, 32H and 1L, 32H and 2L, 32H and 3L, 32H and 4L, 32H and 5L, 32H and 6L, 32H and 7L, 32H and 8L, 32H and 9L, 32H and 10L, 32H and 11L, 32H and CDRs of 12L, 32H and 13L, 32H and 14L, 32H and 15L, 32H and 16L, 32H and 17L, 32H and 18L, 32H and 19L, 32H and 20L, 32H and 21L, 32H and 22L, 32H and 23L, 32H and 24L, 32H and 25L, 32H and 26L, 32H and 27L, 32H and 28L, 32H and 29L, 32H and 30L, 32H and 31L, or 32H and 32L.

[0446] 36. The isolated antibody as described in any of the preceding embodiments, wherein the antibody is humanized.

[0447] 37. The isolated antibody as described in any of the preceding embodiments, wherein the antibody is chimeric or fused to a non-antibody protein.

[0448] 38. The isolated antibody as described in any of the preceding embodiments, wherein the antibody does not significantly bind to sealing protein 9.

[0449] 39. The isolated antibody as described in any of the preceding embodiments, wherein the antibody binds to the sealing protein 6 with an affinity, EC50 or KD that is at least 100, 200 or 300 times greater than that bound to the sealing protein 9.

[0450] 40. The isolated antibody as described in any of the preceding embodiments, wherein the CDR amino acid sequence, V L or V H The peptide is at least or about 90%-99% identical to the sequence provided herein, or the sequence has 1, 2, 3, 4 or 5 substitutions.

[0451] 41. A peptide comprising, or substantially composed of, the sequences provided herein or variations thereof.

[0452] 42. The peptide as described in embodiment 41, wherein the peptide is a CDR, VL, or VH peptide.

[0453] 43. The peptide of embodiment 41, wherein the peptide comprises the sequence of SEQ ID NO:2-138 or a variant thereof or a sequence otherwise provided herein, and consists of or substantially consists of the sequence of SEQ ID NO:2-138 or a variant thereof or a sequence otherwise provided herein.

[0454] 44. A peptide comprising a sequence that is 90%-99% identical to the sequence provided herein, or consisting of, or substantially consisting of, a sequence that is 90%-99% identical to the sequence provided herein.

[0455] 45. The peptide as described in embodiment 44, wherein the peptide comprises 1, 2, 3, 4 or 5 substitutions, deletions or insertions compared to the sequence provided herein.

[0456] 46. ​​The peptide as described in embodiment 44 or 45, wherein the peptide is a CDR, VL, or VH peptide.

[0457] 47. The peptide as described in embodiment 44 or 45, wherein the sequence provided herein comprises the sequence of SEQ ID NO:2-135 or a variant thereof or a sequence otherwise provided herein, consisting of or substantially consisting of the sequence of SEQ ID NO:2-135 or a variant thereof or a sequence otherwise provided herein.

[0458] 48. An antibody, such as a monoclonal antibody or scFv, that binds to an epitope on sealing protein 6, wherein the residues of sealing protein 6 include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof.

[0459] 49. An antibody, such as a monoclonal antibody or scFv, that preferentially binds to sealing protein 6 compared to sealing protein 9, wherein the antibody binds to an epitope on sealing protein 6 containing Q156.

[0460] 50. A bispecific antibody comprising a first V that binds to sealing protein 6. H Peptides and second V bound to different parts H Peptide.

[0461] 51. The antibody as described in embodiment 46, wherein the second V H The peptide binds to CD3 or 4-1BB.

[0462] 52. The antibody as described in embodiment 50 or 51, wherein the antibody is a bispecific antibody or wherein the antibody is a fusion protein.

[0463] 53. The antibody as described in embodiments 50-52, the antibody further comprising the antibody linked to the sealing protein 6 and the second V H The linker domain of a peptide.

[0464] 54. The antibody according to any one of embodiments 50-53, wherein the adapter domain comprises 1, 2, 3, 4 or 5 or more GGGGS (SEQ ID NO:137) repeat sequences.

[0465] 55. The antibody according to any one of embodiments 50-54, wherein the antibody comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90 or 95; the heavy chain CDR2 has an amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or a variant of any of the foregoing.

[0466] 56. The antibody according to any one of embodiments 50-55, wherein the antibody comprises:

[0467] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:25; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:27, or a variant of any of the foregoing.

[0468] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0469] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:38; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing.

[0470] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing.

[0471] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0472] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing.

[0473] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing.

[0474] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:53; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0475] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:55; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing.

[0476] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0477] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:61, or a variant of any of the foregoing.

[0478] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:63, or a variant of any of the foregoing.

[0479] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:65, or a variant of any of the foregoing.

[0480] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:66, or a variant of any of the foregoing.

[0481] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:67, or a variant of any of the foregoing.

[0482] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:126, or a variant of any of the foregoing.

[0483] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:69, or a variant of any of the foregoing.

[0484] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:71; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:73, or a variant of any of the foregoing.

[0485] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:76; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:78, or a variant of any of the foregoing.

[0486] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:80; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:82, or a variant of any of the foregoing.

[0487] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0488] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:90; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:92, or a variant of any of the foregoing.

[0489] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:95; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:97, or a variant of any of the foregoing.

[0490] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; or

[0491] The heavy chain variable region comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing.

[0492] 57. The antibody as described in any one of embodiments 50-56, wherein the antibody comprises a light chain variable region comprising a sequence of any one of the sequences listed in SEQ ID NO:127-135.

[0493] 58. The antibody according to any one of embodiments 50-56, wherein the antibody comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of SEQ ID NO: 23, 29, 41, 51, 59, 68, 84, 88, or 99; and the light chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, or 94, or a variant of any of the foregoing.

[0494] 59. The antibody as described in any one of embodiments 50-56, wherein the antibody comprises:

[0495] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:23; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:24, or a variant of any of the foregoing.

[0496] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:30, or a variant of any of the foregoing.

[0497] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing.

[0498] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:42, or a variant of any of the foregoing.

[0499] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing.

[0500] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:52, or a variant of any of the foregoing.

[0501] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0502] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0503] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing.

[0504] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:70, or a variant of any of the foregoing.

[0505] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:75, or a variant of any of the foregoing.

[0506] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:79, or a variant of any of the foregoing.

[0507] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:85, or a variant of any of the foregoing.

[0508] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:89, or a variant of any of the foregoing.

[0509] A light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:94, or a variant of any of the foregoing; or

[0510] The light chain variable region comprises light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:99; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:100, or a variant of any of the foregoing.

[0511] 60. An antibody or antigen-binding fragment thereof as described in any one of embodiments 50-56, wherein the antibody or antigen-binding fragment thereof comprises:

[0512] (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; the heavy chain CDR2 has an amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, or 102; and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92, or 97, or a variant of any of the foregoing; and

[0513] (ii) A light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88, or 99; and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, or 94, or a variant of any of the foregoing.

[0514] 61. The antibody as described in any one of embodiments 50-56, wherein the antibody or its antigen-binding fragment comprises:

[0515] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0516] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:61, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0517] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:63, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0518] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:65, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0519] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:66, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0520] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:67, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0521] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:65, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0522] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:126, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0523] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:69, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing;

[0524] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:69, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:70, or a variant of any of the foregoing;

[0525] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:71; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:73, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:75, or a variant of any of the foregoing;

[0526] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:76; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:78, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:79, or a variant of any of the foregoing;

[0527] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:80; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:82, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:85, or a variant of any of the foregoing;

[0528] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:89, or a variant of any of the foregoing;

[0529] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:90; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:92, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:94, or a variant of any of the foregoing;

[0530] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:95; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:97, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:99; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:100, or a variant of any of the foregoing;

[0531] A heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:60, or a variant of any of the foregoing; or

[0532] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:57, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:89, or a variant of any of the foregoing;

[0533] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:25; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:27, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:23; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:24, or a variant of any of the foregoing;

[0534] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:30, or a variant of any of the foregoing;

[0535] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:28; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:29, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:26, or a variant of any of the foregoing;

[0536] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:42, or a variant of any of the foregoing;

[0537] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:30, or a variant of any of the foregoing;

[0538] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO:48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:39, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:36, or a variant of any of the foregoing;

[0539] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:45, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:42, or a variant of any of the foregoing;

[0540] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:53; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:52, or a variant of any of the foregoing;

[0541] The heavy chain variable region comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO:55; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO:33, or a variant of any of the foregoing; and the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO:50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO:52, or a variant of any of the foregoing;

[0542] 62. A nucleic acid molecule, said nucleic acid molecule encoding an antibody or amino acid sequence as described in any of the preceding embodiments.

[0543] 63. A vector comprising the nucleic acid molecule described in embodiment 62.

[0544] 64. A cell comprising the nucleic acid molecule of embodiment 62 or the vector of embodiment 63.

[0545] 65. A pharmaceutical composition comprising an isolated antibody or a nucleic acid molecule encoding the isolated antibody as described in any one of embodiments 1-61.

[0546] 66. The pharmaceutical composition of embodiment 65, wherein the composition is an injectable pharmaceutical composition.

[0547] 67. The pharmaceutical composition as described in embodiment 65 or 66, wherein the composition is sterile.

[0548] 68. The pharmaceutical composition of any one of embodiments 65-67, wherein the composition is free of pyrogens.

[0549] 69. The pharmaceutical composition of any one of embodiments 65-68, wherein the composition does not contain an antibody that does not bind to sealing protein 6.

[0550] 70. A method for modulating the activity of sealing protein 6 by contacting cells expressing sealing protein 6 with an antibody against sealing protein 6 or a pharmaceutical composition containing said antibody, said antibody binding to sealing protein 6 on the surface of said cells.

[0551] 71. The method of embodiment 70, wherein the antibody is any antibody provided herein or any antibody or nucleic acid molecule encoding the antibody as described in embodiments 1-61.

[0552] 72. A method for inhibiting the function of sealing protein 6 by contacting cells expressing sealing protein 6 with an antibody or a pharmaceutical composition containing said antibody that inhibits the function of sealing protein 6 by binding to sealing protein 6.

[0553] 73. The method of embodiment 61, wherein the antibody is any antibody provided herein or any antibody or nucleic acid molecule encoding the antibody as described in any of embodiments 1-61.

[0554] 74. The method of embodiment 72, wherein the antibody is an antibody or peptide of any one of embodiments 1-61.

[0555] 75. The antibody as described in any one of embodiments 72-74, wherein the antibody is administered to a subject who requires the antibody.

[0556] 76. The method as described in embodiment 75, wherein the function is the regulation of tight junction integrity.

[0557] 77. A method of treating a subject with a condition mediated by sealing protein 6, the method comprising administering to the subject a pharmaceutical composition comprising an antibody against sealing protein 6, said antibody being any antibody provided herein or an antibody or nucleic acid molecule encoding said antibody as described in any of embodiments 1-61.

[0558] 78. The method as described in embodiment 77, wherein the condition is a benign or metastatic cancer, such as ovarian cancer (e.g., ovarian carcinoma), reproductive system cancer (breast cancer, cervical cancer, testicular cancer, uterine cancer, or placental cancer), lung cancer, stomach cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, skin cancer, head and neck cancer, sarcoma, or germ cell tumor.

[0559] 79. The method of embodiment 77 or 78, wherein the antibody is an antibody or a nucleic acid molecule encoding the antibody as described in any one of embodiments 1-61, or a pharmaceutical composition comprising the antibody or a nucleic acid molecule encoding the antibody.

[0560] 80. A method of treating a subject with cancer, the method comprising administering a therapeutic agent that specifically binds to sealing protein 6 and to CD3 and / or 4-1BB.

[0561] 81. The method of embodiment 80, wherein the therapeutic agent comprises an antibody or a nucleic acid molecule encoding the antibody as described in any one of embodiments 1-61.

[0562] 82. A method of treating a subject with cancer, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising an antibody that binds to residue Q156 of sealing protein 6 or a nucleic acid molecule encoding the antibody.

[0563] 83. The method of embodiment 77, wherein the antibody comprises a sequence such as CDR, VL or VH or SEQ ID NO:2-135 as provided herein.

[0564] 84. The method as described in embodiment 82 or 83, wherein the antibody is a hexaantibody.

[0565] 85. The method of embodiment 82, wherein the pharmaceutical composition comprises a chimeric receptor, such as a chimeric antigen receptor (CAR), wherein the receptor comprises an extracellular antibody domain comprising an antibody as described in any one of embodiments 1-61 or residue Q156 bound to sealing protein 6.

[0566] 86. The method of embodiment 85, wherein the chimeric receptor comprises a transmembrane domain and an intracellular domain.

[0567] 87. The method as described in embodiments 85 and 86, wherein the cell contains the chimeric receptor.

[0568] 88. The method as described in embodiment 87, wherein the cells are immune cells, such as T cells, macrophages, dendritic cells, NK cells, etc.

[0569] 89. A multispecific antibody, wherein the multispecific antibody comprises an antibody domain as provided herein.

[0570] 90. The multispecific antibody as described in embodiment 89, wherein the antibody domain comprises an antibody, CDR, VL, or VH peptide as provided herein or according to any one of embodiments 1-61.

[0571] 91. A chimeric receptor comprising an antibody domain as provided herein.

[0572] 92. The chimeric receptor as described in embodiment 91, wherein the antibody domain comprises an antibody, CDR, VL, or VH peptide as provided herein or according to any one of embodiments 1-61.

[0573] 93. A composition comprising an antibody or antibody domain as provided herein, as described in any one of embodiments 1-61, linked to a medicament or other therapeutic agent.

[0574] 94. The composition as described in embodiment 93, wherein the therapeutic agent is a cytokine, such as IL-2.

[0575] 95. The composition as described in embodiment 93, wherein the composition is an antibody-drug conjugate (ADC).

[0576] 96. The composition of any one of embodiments 93-95, wherein the antibody domain comprises an antibody, CDR, VL or VH peptide as provided herein or according to any one of embodiments 1-61.

[0577] 97. A hexaantibody comprising an antibody domain as provided herein.

[0578] 98. The hexa-antibody as described in embodiment 97, wherein the antibody domain comprises an antibody, CDR, VL or VH peptide as provided herein or according to any one of embodiments 1-61, or a sequence comprising one or more sequences of SEQ ID NO:2-135.

[0579] 99. A composition comprising a peptide as provided herein, such as a peptide comprising one or more sequences of SEQ ID NO:2-135.

[0580] 100. The composition of embodiment 99, wherein the peptide is an antibody, CDR, VL or VH peptide as provided herein, or a peptide or antibody according to any one of embodiments 1-61.

[0581] 101. A method for detecting the presence or absence of sealing protein 6 in a sample, the method comprising contacting the sample with an antibody as provided herein and any of the foregoing embodiments and detecting binding of the antibody to the sealing protein 6 antigen, wherein detection of binding indicates the presence of sealing protein 6; or no detection of binding to sealing protein 6 indicates the absence of sealing protein 6.

[0582] 102. A method of delivering a composition to cells expressing sealing protein 6, the method comprising contacting the cells with an antibody as provided herein or an antibody according to any one of embodiments 1-61, wherein the antibody is linked to another molecule to be delivered to the cells expressing sealing protein 6.

[0583] 103. The method of embodiment 102, wherein the antibody is an antibody, CDR, VL or VH peptide as provided herein, or a peptide or antibody according to any one of embodiments 1-61 or comprising one or more sequences of SEQ ID NO:2-135.

[0584] 104. The method as described in embodiment 102 or 103, wherein the other molecule is a drug.

[0585] 105. A method of contacting a composition with cells expressing sealing protein 6, the method comprising contacting the cells with an antibody as provided herein, wherein the antibody is linked to another molecule to contact the cells expressing sealing protein 6.

[0586] 106. The method of embodiment 105, wherein the antibody is an antibody, CDR, VL or VH peptide as provided herein, or a peptide or antibody according to any one of embodiments 1-61 or comprising one or more sequences of SEQ ID NO:2-135.

[0587] 107. The method as described in embodiment 105 or 106, wherein the other molecule is a drug.

[0588] 108. The method as described in any one of embodiments 105-107, wherein the cells expressing sealing protein 6 are in a subject.

[0589] 109. The method as described in any one of embodiments 105-108, wherein the cells are tumor cells.

[0590] 110. The method as described in embodiment 109, wherein the tumor cells are solid tumor cells.

[0591] 111. The method as described in embodiment 110, wherein the tumor cells are ovarian tumor cells, non-small cell lung tumor cells, teratoma tumor cells, gastric tumor cells, lung tumor cells, breast tumor cells, or colon tumor cells, or other types of tumors or cancer cells provided herein.

[0592] As provided herein, the DNA (or RNA) sequence that encodes proteins can vary due to the degeneracy of the genetic code. Such variations are covered in the embodiments provided herein.

[0593] The subject matter is now described with reference to the following embodiments. These embodiments are provided for illustrative purposes only, and the claims should in no way be construed as limiting to these embodiments, but rather as covering any and all variations that become apparent from the teachings provided herein. Those skilled in the art will readily identify a variety of non-critical parameters that can be changed or modified to produce substantially similar results.

[0594] Example

[0595] Example 1: Seal protein 6 antibody binds to seal protein 6.

[0596] Figure 1 The results of the binding assay are shown, demonstrating that sealing protein 6MAb binds to human sealing protein 6. Human embryonic kidney 293T (HEK-293T) cells were transiently transfected with human sealing protein 6 DNA (hsCLDN6) or an empty vector along with GFP (pUC) for 22 hours. Sealing protein 6MAb (IM136, IM171, IM172, and IM173) were added at sequential dilutions (0.0–10 μg / mL) and incubated for 90 minutes with shaking. After washing, a secondary antibody (allophycocyanin-conjugated mouse anti-human IgGFc; Southern Biotech) was added and incubated for 30–45 minutes. Cells were washed and fluorescence was detected by high-throughput Intellicyt flow cytometry, gated by plotting forward scatter against side scatter. Data were analyzed in GraphPad Prism software based on the geometric mean of fluorescence intensity for the cell population in each well.

[0597] Example 2: Compared to other sealing protein proteins, the sealing protein 6 antibody preferentially binds to sealing protein 6. Figure 2The results of the binding assay are shown, indicating that sealant protein 6MAb preferentially binds to human sealant protein 6 compared to other sealant proteins. Human embryonic kidney 293T (HEK-293T) cells were transiently transfected with the indicated sealant protein's DNA or an empty vector along with GFP (pUC) for 22 hours. The results demonstrated that the antibody preferentially binds to sealant protein 6 compared to other family members.

[0598] Example 3: Flow cytometry was performed on HEK-293T cells transfected with a plasmid expressing the indicated protein. Figure 3 This demonstrates the specificity of the antibody when tested using a flow cytometry method, as shown in Example 2.

[0599] Example 4: IM136 and IM171 bind to PA-1 cells that naturally express sealing protein-6. PA-1 cells are stained with the indicated antibodies and detected by flow cytometry. Figure 4 The binding of the antibody to PA-1 cells that naturally express sealing protein-6 is shown. Detected by flow cytometry.

[0600] Example 5: Antibody binding to cells that naturally express sealing protein-6. Figure 5 This demonstrates the binding of another antibody to PA-1 cells that naturally express sealing protein-6. Detection was performed by flow cytometry, as in Example 4. DENV represents a negative control (anti-dengue virus) antibody.

[0601] Example 6: Figure 6 This study demonstrates the specificity of sealing protein 6 (LM171) binding to a membrane proteome array (MPA) composed of 5,300 human membrane proteins expressed in human HEK-293 cells. Cells were permeabilized with 0.1% saponin, and antibodies were added to the MPA at 1 μg / ml. Binding to the entire protein library was measured using a fluorescent secondary antibody via high-throughput flow cytometry (Intelligent HTFC). LM171 exhibited high specificity for sealing protein 6.

[0602] Example 7: Sealin 6-specific antibodies can function in conjunction with 'universal' common light chains. Antibodies specific to sealin 6 were modified to exchange the initially identified light chain with the common light chain. The results shown in the table below indicate that the common light chain can also support binding to sealin 6 or antibody expression / production. The results show that binding to sealin 6 is primarily determined by using any variable heavy chain and the CDR contained therein, and that these heavy chains can pair with these or other common light chains.

[0603]

[0604] Example 8: Identification of key residues for Ab binding. Shotgun mutagenesis epitope localization results list the average binding reactivity (and range) of all identified key residues. Key residues for Ab binding (grey shading) are those whose mutations are negative for binding to the test Ab (<30% wild-type reactivity) but positive for binding to the control 3656MAb. MAb3001-D5 and 3656 are sealing protein antibodies with cross-reactivity that bind to sealing proteins 6 and 9. Therefore, the epitopes of MAb IM136 include residues E48, D68, P74, D76, and R158. The epitopes of MAb IM171 include T33, N38, E48, D76, A153, E154, Q156, and R158. The epitopes of MAb IM172 include N38, E48, Y67, P74, D76, D146, V152, E154, Q156, and R158. The epitopes of MAb IM173 include E48, Y67, Q156, and R158. For example, data show that antibodies that preferentially bind to sealing protein 6, relative to sealing protein 9, preferentially include epitope residue Q156. Data are shown in... Figure 8 middle.

[0605] Example 9: CAR-T cells expressing the sealant protein 6 antibody IM136 were activated by cells expressing human or murine sealant protein 6. CAR-T cells without the sealant protein antibody ('CAR-negative T cells') were not activated by cells expressing sealant protein 6. Cell activation was measured by CD69 expression after overnight co-incubation (as detected by flow cytometry using an anti-CD69 antibody). Data are shown in... Figure 7 The chimeric receptor comprises an extracellular domain containing the described sealing protein 6 antibody (IM136) as a scFv (VL-connector-VH) fused with the CD8 transmembrane domain, 4-1BB, and CD3ζ signaling domain. This construct is based on the CAR construct reported by Milone et al., Molecular Therapy, Vol. 17, No. 8, 1453–1464, August 2009, which is hereby incorporated by reference in its entirety.

[0606] Example 10: Anti-sealing protein 6 antibody specifically binds to sealing protein 6

[0607] The table below provides binding information for various antibodies. It tests antibody binding to sealing protein 6 and demonstrates the specificity of this binding against CLDN9, CLDN4, and CLDN3.

[0608] Antibody CLDN6 combined (EC50) CLDN9 CLDN4 CLDN3 IM-271 Less than 4nM + / - - - IM-271-1HAQ Less than 4nM + / - + / - - IM-271-1HBG Less than 4nM - - - IM-271-1HFJ Less than 4nM - - - IM-271-1HEP Less than 4nM - - - IM-271-1HHP Less than 4nM - + / - - IM-35-N1F09-1HA Less than 4nM + + + IM-271-1HBF Less than 4nM - + / - - IM-271-1HFB Less than 4nM - - - IM-271-1HHR Less than 4nM - + / - + / - IM-271-1HGT Less than 4nM + + + / - IM-35-N2H07-1HA Less than 4nM + + / - -

[0609] The affinity of various antibodies for CLDN6 was measured using a biosensor compared to CLDN9, CLDN3, and CLDN4. Biosensor affinity measurements of various antibodies against proteins were determined using a Forte Octet for biosensor measurements, employing intact, sealed protein proteins embedded in virus-like particles (lipid particles). The KD values ​​for the different antibodies are shown below.

[0610] Antibody <![CDATA[CLDN6(K D )]]> <![CDATA[CLDN9(K D )]]> IM-136 12nM 386nM IM-171 3.0nM 902nM IM-172 Less than 0.1 nM 81nM IM-173 0.32nM N / D Clinical benchmarks 0.11nM 94nM

[0611] Data demonstrate that the antibody specifically binds to sealing protein 6 but does not bind significantly to CLDN9, CLDN4, and CLDN3.

[0612] In summary, the implementation schemes and examples demonstrate the generation and specificity of the sealing protein 6 antibody, which can be used in various methods as provided herein.

[0613] The contents of every patent, patent application, publication and registration number cited in this document are hereby incorporated herein in their entirety by reference.

[0614] While this disclosure has been made with reference to various embodiments, it will be apparent to those skilled in the art that other embodiments and variations thereof may be devised without departing from the true spirit and scope of this disclosure. The appended claims are intended to be construed as encompassing all such embodiments and equivalent variations. sequence list <110> R. Chambers, Ross J. Joseph Rucker Thomas Charpentier Lewis J. Stafford T. Barnes (Trevor) Brad Screnci Benjamin B. Doranz <120> Sealing protein 6 antibody and its uses <130> 134088.01802 <150> 62 / 806,048 <151> 2019-02-15 <160> 146 <170> PatentIn version 3.5 <210> 1 <211> 220 <212> PRT <213> Homo sapiens <400> 1 Met Ala Ser Ala Gly Met Gln Ile Leu Gly Val Val Leu Thr Leu Leu 1 5 10 15 Gly Trp Val Asn Gly Leu Val Ser Cys Ala Leu Pro Met Trp Lys Val 20 25 30 Thr Ala Phe Ile Gly Asn Ser Ile Val Val Ala Gln Val Val Trp Glu 35 40 45 Gly Leu Trp Met Ser Cys Val Val Gln Ser Thr Gly Gln Met Gln Cys 50 55 60 Lys Val Tyr Asp Ser Leu Leu Ala Leu Pro Gln Asp Leu Gln Ala Ala 65 70 75 80 Arg Ala Leu Cys Val Ile Ala Leu Leu Val Ala Leu Phe Gly Leu Leu 85 90 95 Val Tyr Leu Ala Gly Ala Lys Cys Thr Thr Cys Val Glu Glu Lys Asp 100 105 110 Ser Lys Ala Arg Leu Val Leu Thr Ser Gly Ile Val Phe Val Ile Ser 11?? 120 125 Gly Val Leu Thr Leu Ile Pro Val Cys Trp Thr Ala His Ala Val Ile 130 135 140 It should be noted that there seems to be an error in "11??" in the original text. It is translated as "11??" here as it is not clear what the correct content should be.Arg Asp Phe Tyr Asn Pro Leu Val Ala Glu Ala Gln Lys Arg Glu Leu 145 150 155 160 Gly Ala Ser Leu Tyr Leu Gly Trp Ala Ala Ser Gly Leu Leu Leu Leu 165 170 175 Gly Gly Gly Leu Leu Cys Cys Thr Cys Pro Ser Gly Gly Ser Gln Gly 180 185 190 Pro Ser His Tyr Met Ala Arg Tyr Ser Thr Ser Ala Pro Ala Ile Ser 195 200 205 Arg Gly Pro Ser Glu Tyr Pro Thr Lys Asn Tyr Val<​​​​​​​​​​​​​​​​​​​​​​​​​​​​Ala Ser Ile Tyr Ser Ser Ala Ser Ser Thr Tyr Tyr Ala Pro Ala Val 50 55 60 Lys Gly Arg Ala Thr Ile Thr Arg Asp Asn Gly Gln Ser Thr Val Arg 65 70 75 80 Leu Gln Leu Asn Asn Leu Arg Ala Glu Asp Thr Gly Thr Tyr Tyr Cys 85 90 95 Ala Lys Ala Ala Gly Arg Thr Tyr Arg Gly Trp Ala Thr Tyr Ile Ala 100 105 110 Asp Ser Ile Asp Ala Trp Gly His Gly Thr Glu Val Ile Val Ser Ser 115 120 125 <210> 3 <211> 105 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 3 Ala Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Pro Gly Glu Ser Val 1 5 10 15 Glu Ile Thr Cys Ser Gly Asp Ser Ser Trp Tyr Gly Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Ser Pro Gly Ser Ala Pro Val Thr Leu Ile Tyr Glu Ser 35 40 45 Gly Lys Arg Pro Ser Asp Ile Pro Ser Arg Phe Ser Gly Ser Thr Ser 50 55 60 Gly Ser Thr Ala Thr Leu Thr Ile Thr Gly Val Gln Ala Asp Asp Glu 65 70 75 80 Ala Val Tyr Tyr Cys Gly Ser Ala Asp Ser Asn Ser Ile Gly Ile Phe 85 90 95 Gly Ala Gly Thr Thr Leu Thr Val Leu 100 105 <210> 4 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 4 Ala Val Thr Leu Asp Glu Ser Gly Gly Gly Leu Gln Thr Pro Gly Gly 1 5 10 15 Ala Leu Ser Leu Val Cys Lys Ala Ser Gly Phe Asp Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Gly Ser Thr Gly Ser Ser Thr Gly Tyr Gly Pro Ala Val 50 55 60 Lys Gly Arg Ala Thr Ile Ser Arg Asp Asn Gly Gln Ser Thr Leu Arg 65 70 75 80 Leu Gln Leu Asn Asn Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Lys Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Ile Ala Thr 100 105 110 Ser Ile Asp Ala Trp Gly His Gly Thr Glu Val Ile Val Ser Ser 115 120 125 <210> 5 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 5 Ala Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Leu Gly Gly Thr Val 1 5 10 15 Lys Leu Thr Cys Ser Gly Gly Ser Ser Gly Tyr Gly Trp Tyr Gln Gln 20 25 30 Lys Ser Pro Gly Ser Ala Pro Val Thr Val Ile Tyr Ser Asn Asp Lys 35 40 45 Arg Pro Ser Asp Ile Pro Ser Arg Phe Ser Gly Ser Leu Ser Gly Ser 50 55 60 Thr Gly Thr Leu Thr Ile Thr Gly Val Gln Ala Asp Asp Glu Ala Val 65 70 75 80 Tyr Phe Cys Gly Ser Thr Asp Asn Ser Tyr Val Gly Ile Phe Gly Ala 85 90 95 Gly Thr Thr Leu Thr Val Leu 100 <210> 6 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 6 Ala Val Thr Leu Asp Glu Ser Gly Gly Gly Leu Gln Thr Pro Gly Gly 1 5 10 15 Ala Leu Ser Leu Val Cys Lys Gly Ser Gly Phe Ser Ile Ser Ser Tyr 20 25 30 Thr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Tyr Ser Gly Ser Arg Thr Tyr Tyr Gly Ala Ala Val Gln 50​​​​​​​​​​​​ Gly Ser Ile Asp Ala Trp Gly His Gly Thr Glu Val Ile Val Ser Ser 115 120 125 <210> 7 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 7 Ala Leu Thr Gln Pro Ser Ser Val Ser Ala Thr Pro Gly Gly Thr Val 1 5 10 15[[ID=2​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 8 Ala Val Thr Leu Asp Glu Ser Gly Gly Gly Leu Gln Thr Pro Gly Gly 1 5 10 15 Ala Leu Ser Leu Val Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Phe Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Asp Ser Gly Ser Thr Thr Phe Tyr Gly Ser Ala Val Lys 50 55 60 Gly Arg Ala Thr Ile Ser Arg Asp Asn Gly Gln Ser Thr Val Arg Leu 65 70 75 80 Gln Leu Asn Asn Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Lys Asp Ala Tyr Gly Tyr Cys Gly Trp Ser Gly Cys Ser Ala Asp Ser 100 105 110 Ile Asp Ala Trp Gly His Gly Thr Glu Val Ile Val Ser Ser 115 120 125 <210> 9 <211> 102 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 9 Ala Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Pro Gly Gly Thr Val 1 5 10 15 Glu Ile Thr Cys Ser Gly Gly Asn Asn Tyr Tyr Gly Trp Tyr Gln Gln 20 25 30 Lys Ser Pro Gly Ser Ala Pro Val Thr Val Ile Tyr Tyr Asn Asp Lys 35 40 45 Arg Pro Ser Asp Ile Pro Ser Arg Phe Ser Gly Ser Lys Ser Gly Ser 50 55 60 Thr Gly Thr Leu Thr Ile Thr Gly Val Gln Ala Asp Asp Glu Ala Val 65 70 75 80 Tyr Phe Cys Gly Gly Trp Asp Ser Ser Gly Gly Ile Phe Gly Ala Gly 85 90 95 Thr Thr Leu Thr Val Leu 100 <210> 10 <211> 128 <212> PRT <213> Artificial Sequence <220><​​​​​​​​Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Asp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Tyr Ser Ser Ala Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ala Ala Gly Arg Thr Tyr Arg Gly Trp Ala Thr Tyr Ile Ala 100 105 110 Asp Ser Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 11 <211> 106 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> synthetic sequence <400> 11 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Gly Asp Ser Ser Trp Tyr Gly Tyr Gly 20 25 30 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Glu 35 40 45 Ser Gly Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser 50 55 60 Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp 65 70 75 80 Glu Ala Asp Tyr Tyr Cys Gly Ser Ala Asp Ser Asn Ser Ile Gly Ile 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 12 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 12 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Gly Ser Thr Gly Ser Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Ile Ala Thr 100 105 110 Ser Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125<​​​​​​​​​​​​​​​​​​​​​​​​​​Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala 65 70 75 80 Asp Tyr Tyr Cys Gly Ser Thr Asp Asn Ser Tyr Val Gly Ile Phe Gly 85 90 95 Gly Gly Thr Lys Leu Thr Val Leu 100 <210> 14 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 14 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Ser Ser Tyr 20 25 30 Thr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Tyr Ser Gly Ser Arg Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Ser Ser Tyr Cys Thr Ala Trp Thr Gly Cys Asp Val Tyr Ala Gly 100 105 110 Gly Ser Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 15 <211> 105 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <\(400\)> 15 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Gly Asp Asp Gly Ser Tyr Tyr Tyr Gly 20 25 30 [[ID=三十五]]Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Ser 35 40 45 Asn Asp Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser 50 55 60 Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp 65 70 75 80 Note: In the above translation, for the tag <400>, it is directly translated as <\(400\)> to maintain the original format. Also, there seems to be a mistake in the original text where the line with "三十五" should probably be "35" in the original numbering system. I've translated it as "35" in the English version while keeping the text as it is in the translation for the sake of following the rules. If this is not what you intended, please clarify.Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Asp Ser Ser Thr Gly Ile Phe 85 90 95 Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 16 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 16 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Asp Ser Gly Ser Thr Thr Phe Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Asp Ala Tyr Gly Tyr Cys Gly Trp Ser Gly Cys Ser Ala Asp Ser 100 105 110 Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 17 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 17 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Gly Gly Asn Asn Tyr Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Tyr Asn Asp 35 40 45 Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala 65 70 75 80 Asp Tyr Tyr Cys Gly Gly Trp Asp Ser Ser Gly Gly Ile Phe Gly Gly 85 90 95 Gly Thr Lys Leu Thr Val Leu 100 <210> 18 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 18 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Ile Ala Thr 100​​​​​​​​​​​​​<220> <223> Synthetic Sequence <400> 19 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Gly Gly Ser Gly Ser Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Thr Asn 35 40 45 Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala 65 70 75 80 Asp Tyr Tyr Cys Gly Ser Ala Asp Ser Ser Thr Asn Ala Gly Ile Phe 85 90 95 Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 20<00018​​​​​​​​​​​​​​​​Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Ile Ala Thr 100 105 110 Ser Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 21 <211> 105 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> synthetic sequence <400> 21 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Gly Gly Ser Gly Ser Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Gly Thr Asn 35 40 45 Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala 65 70 75 80 Asp Tyr Tyr Cys Gly Ser Ala Asp Ser Ser Thr Asn Ala Gly Ile Phe 85 90 95 Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 22 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 22 Cys Ser Gly Asp Ser Ser Trp Tyr Gly Tyr Gly 1 5 10 <210> 23 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 23 Ile Tyr Glu Ser Gly Lys Arg Pro 1 5 <210> twenty four <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> twenty four Cys Gly Ser Ala Asp Ser Asn Ser Ile Gly Ile Phe 1 5 10 <210> 25 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 25 Gly Phe Ser Phe Ser Ser Tyr Asp Met Gly Trp Val 1 5 10 <210> 26 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 26 Val Ala Ser Ile Tyr Ser Ser Ala Ser Ser Thr Tyr Tyr Ala 1 5 10 <210> 27 <211> twenty two <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 27 Cys Ala Lys Ala Ala Gly Arg Thr Tyr Tyr Arg Gly Trp Ala Thr Tyr Ile 1 5 10 15 Ala Asp Ser Ile Asp Ala 20 <210> 28 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 28 Cys Ser Gly Gly Ser Ser Gly Tyr Gly 1 5 <210> 29 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 29 Ile Tyr Ser Asn Asp Lys Arg Pro 1 5 <210> 30 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 30 Cys Gly Ser Thr Asp Asn Ser Tyr Val Gly Ile Phe 1 5 10 <210> 31 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 31 Gly Phe Asp Phe Ser Ser Tyr Ala Met Asn Trp Val 1 5 10 <210> 32 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 32 Val Ala Gly Ile Gly Ser Thr Gly Ser Ser Thr Gly Tyr Gly 1 5 10 <210> 33 <211> twenty one <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 33 Cys Ala Lys Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Ile Ala 1 5 10 15 Thr Ser Ile Asp Ala 20 <210> 34 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 34 Cys Ser Gly Asp Ser Ser Asp Asp Gly Ser Tyr Tyr Tyr Gly 1 5 10 <210> 35 <400> 35 000 <210> 36 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 36 Cys Gly Ser Tyr Asp Ser Ser Thr Gly Ile Phe 1 5 10 <210> 37 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 37 Gly Phe Ser Ile Ser Ser Tyr Thr Met Gln Trp Val 1 5 10 <210> 38 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 38 Val Ala Gly Ile Tyr Ser Gly Ser Arg Thr Tyr Tyr Gly 1 5 10 <210> 39 <211> twenty three <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 39 Cys Ala Lys Ser Ser Tyr Cys Thr Ala Trp Thr Gly Cys Asp Val Tyr 1 5 10 15 Ala Gly Gly Ser Ile Asp Ala 20 <210> 40 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 40 Cys Ser Gly Gly Asn Asn Tyr Tyr Gly 1 5 <210> 41 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 41 Ile Tyr Tyr Asn Asp Lys Arg Pro 1 5 <210> 42 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 42 Cys Gly Gly Trp Asp Ser Ser Gly Gly Ile Phe 1 5 10 <210> 43 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 43 Gly Phe Thr Phe Ser Ser Tyr Ser Met Phe Trp Val 1 5 10 <210> 44 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 44 Val Ala Gly Ile Asp Ser Gly Ser Thr Thr Phe Tyr Gly 1 5 10 <210> 45 <211> twenty one <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 45 Cys Ala Lys Asp Ala Tyr Gly Tyr Cys Gly Trp Ser Gly Cys Ser Ala 1 5 10 15 Asp Ser Ile Asp Ala 20 <210> 46 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 46 Val Ala Gly Ile Gly Ser Thr Gly Ser Ser Thr Gly Tyr Ala 1 5 10 <210> 47 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 47 Cys Ser Gly Asp Asp Gly Ser Tyr Tyr Tyr Gly 1 5 10 <210> 48 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 48 Val Ala Gly Ile Tyr Ser Gly Ser Arg Thr Tyr Tyr Ala 1 5 10 <210> 49 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 49 Val Ala Gly Ile Asp Ser Gly Ser Thr Thr Phe Tyr Ala 1 5 10 <210> 50 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 50 Cys Ser Gly Gly Ser Gly Ser Tyr Gly 1 5 <210> 51 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 51 Ile Tyr Gly Thr Asn Lys Arg Pro 1 5 <210> 52 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 52 Cys Gly Ser Ala Asp Ser Ser Thr Asn Ala Gly Ile Phe 1 5 10 <210> 53 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 53 Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val 1 5 10 <210> 54 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 54 Val Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala 1 5 10 <210> 55 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 55 Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val 1 5 10 <210> 56 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 56 Ser Tyr Ala Met Ser 1 5 <210> 57 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 57 Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Ile Ala Thr Ser Ile 1 5 10 15 Asp Ala <210> 58 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 58 Ser Gly Gly Ser Gly Ser Tyr Gly 1 5 <210> 59 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 59 Gly Thr Asn Lys Arg Pro Ser 1 5 <210> 60 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 60 Gly Ser Ala Asp Ser Ser Thr Asn Ala Gly Ile 1 5 10 <210> 61 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 61 Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Val Ala Thr Ser Ile 1 5 10 15 Asp Ala <210> 62 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 62 Ser Tyr Ala Met Asn 1 5 <210> 63 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 63 Ser Val Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr Ser Ile 1 5 10 15 Asp Ala <210> 64 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 64 Ser Ala Gly Ser Gly Leu Tyr Gly 1 5 <210> 65 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 65 Ser Met Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr Ser Ile 1 5 10 15 Asp Ala <210> 66 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 66 Ser Met Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr Ser Ile 1 5 10 15 Asp Val <210> 67 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 67 Ser Val Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr Ser Leu 1 5 10 15 Asp Ala <210> 68 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 68 Gly Thr Tyr Lys Arg Pro Ser 1 5 <210> 69 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 69 Ser Val Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr Ser Leu 1 5 10 15 Asp Val <210> 70 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 70 Gly Ser Asn Asp Ala Ser Thr Asn Ala Gly Ile 1 5 10 <210> 71 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 71 Ser Tyr Gly Met Ser 1 5 <210> 72 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 72 Gly Ile Gly Ser Ser Gly Ile Tyr Thr His Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 73 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 73 Ser Pro Gly Asp Ser Asp Trp Cys Gly Trp Ala Gly Tyr Gly Ile Tyr 1 5 10 15 Ser Cys Arg Val Ala Gly Phe Ile Asp Ala 20 25 <210> 74 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 74 Ser Gly Gly Tyr Asn Gly His Tyr Gly 1 5 <210> 75 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 75 Gly Gly Tyr Asp Ser Ser Ala Gly Ile 1 5 <210> 76 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 76 Gly Tyr Ala Met Ser 1 5 <210> 77 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 77 Gly Ile Tyr Ser Ser Gly Ser Tyr Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 78 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 78 Gly Thr Gly Tyr Cys Asp Trp Ser Gly Trp Cys Tyr Ser Gly Ala Ala 1 5 10 15 Asn Ile Asp Ala 20 <210> 79 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 79 Gly Ser Glu Asp Ser Ser Ser Gly Ala Gly Ile 1 5 10 <210> 80 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 80 Ser Tyr Asp Met Gly 1 5 <210> 81 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 81 Ser Ile Tyr Ser Ser Ala Ser Ser Thr Tyr Tyr Tyr Ala Pro Ala Val Lys 1 5 10 15 Gly <210> 82 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 82 Ala Ala Gly Arg Thr Tyr Arg Gly Trp Ala Thr Tyr Ile Ala Asp Ser 1 5 10 15 Ile Asp Ala <210> 83 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 83 Ser Gly Asp Ser Ser Trp Tyr Gly Tyr Gly 1 5 10 <210> 84 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 84 Glu Ser Gly Lys Arg Pro Ser 1 5 <210> 85 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 85 Gly Ser Ala Asp Ser Asn Ser Ile Gly Ile 1 5 10 <210> 86 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 86 Gly Ile Gly Ser Thr Gly Ser Ser Thr Gly Tyr Gly Pro Ala Val Lys 1 5 10 15 Gly <210> 87 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 87 Ser Gly Gly Ser Ser Gly Tyr Gly 1 5 <210> 88 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 88 Ser Asn Asp Lys Arg Pro Ser 1 5 <210> 89 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 89 Gly Ser Thr Asp Asn Ser Tyr Val Gly Ile 1 5 10 <210> 90 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 90 Ser Tyr Thr Met Gln 1 5 <210> 91 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 91 Gly Ile Tyr Ser Gly Ser Arg Thr Tyr Tyr Gly Ala Ala Val Gln Gly 1 5 10 15 <210> 92 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 92 Ser Ser Tyr Cys Thr Ala Trp Thr Gly Cys Asp Val Tyr Ala Gly Gly 1 5 10 15 Ser Ile Asp Ala 20 <210> 93 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 93 Ser Gly Asp Ser Ser Asp Asp Gly Ser Tyr Tyr Tyr Gly 1 5 10 <210> 94 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 94 Gly Ser Tyr Asp Ser Ser Thr Gly Ile 1 5 <210> 95 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 95 Ser Tyr Ser Met Phe 1 5 <210> 96 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 96 Gly Ile Asp Ser Gly Ser Thr Thr Phe Tyr Gly Ser Ala Val Lys Gly 1 5 10 15 <210> 97 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 97 Asp Ala Tyr Gly Tyr Cys Gly Trp Ser Gly Cys Ser Ala Asp Ser Ile 1 5 10 15 Asp Ala <210> 98 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 98 Ser Gly Gly Asn Asn Tyr Tyr Gly 1 5 <210> 99 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 99 Tyr Asn Asp Lys Arg Pro Ser 1 5 <210> 100 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 100 Gly Gly Trp Asp Ser Ser Gly Gly Ile 1 5 <210> 101 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> synthetic sequence <400> 101 Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 102 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 102 Gly Ile Gly Ser Thr Gly Ser Ser Thr Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 103 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 103 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Val Gly Asn Gly Asn Ser Trp Ser Gly Tyr Val Ala Thr 100 105 110 Ser Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 104 <211> 105 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 104 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Gly Gly Ser Gly Ser Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Thr Asn 35 40 45 Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala 65 70 75 80​​​​​​​100 105 <210> 105 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 105 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Val Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr 100 105 110 Ser Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 106 <211> 105 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 106 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Ala Gly Ser Gly Leu Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Thr Asn 35 40 45 Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala 65 70 75 80 Asp Tyr Tyr Cys Gly Ser Ala Asp Ser Ser Thr Asn Ala Gly Ile Phe 85 90 95 Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 107 <211> 127 <212> PRT <213> Artificial Sequence <220>[[ID=​​​​Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Met Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr 100 105 110 Ser Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 108 <211> 105<00 .02755><212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 108 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Ala Gly Ser Gly Leu Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Thr Asn 35 40 45 Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala[[ID=q17]] 65 70 75 80 Asp Tyr Tyr Cys Gly Ser Ala Asp Ser Ser Thr Asn Ala Gly Ile Phe 85 90 95 Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 109 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 109 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly<00OO2782>1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Met Gly Ser Gly Val Ser Trp Ser Gly Tyr Val Ala Thr 100 105 110 Ser Ile Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 110 <211> 105 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 110 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Ser Ala Gly Ser Gly Leu Tyr Gly Trp Tyr 20 25 30 Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Thr Asn 35 40 45 Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly 50 55 60 Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala 65 70 75 80 Asp Tyr Tyr Cys Gly Ser Ala Asp Ser Ser Thr Asn Ala Gly Ile Phe 85 90 95 Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 111 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 111 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Ser Ser Gly Arg Tyr Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Val Gly Ser...

Claims

1. An antibody that binds to claudin 6, the antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a heavy chain CDR1 (HCDR1), CDR2 (HCDR2) and CDR3 (HCDR3), the light chain variable region comprising a light chain CDR1 (LCDR1), CDR2 (LCDR2) and CDR3 (LCDR3), and wherein the antibody has: HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:125, and HCDR3 of SEQ ID NO:66, LCDR1 of SEQ ID NO:64, LCDR2 of SEQ ID NO:59, and LCDR3 of SEQ ID NO:60; HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:125, and HCDR3 of SEQ ID NO:65, LCDR1 of SEQ ID NO:64, LCDR2 of SEQ ID NO:59, and LCDR3 of SEQ ID NO:60; or HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:125 and HCDR3 of SEQ ID NO:67, LCDR1 of SEQ ID NO:64, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

2. The antibody of claim 1, wherein the antibody comprises a light chain variable region having at least 95% identity to the amino acid sequence of SEQ ID NO: 110, and / or a heavy chain variable region having at least 95% identity to the amino acid sequence of SEQ ID NO:

109.

3. The antibody of claim 1, wherein the antibody comprises a light chain variable region having at least 95% identity to the amino acid sequence of SEQ ID NO: 108, and / or a heavy chain variable region having at least 95% identity to the amino acid sequence of SEQ ID NO:

107.

4. The antibody of claim 1, wherein the antibody comprises a light chain variable region having at least 95% identity to the amino acid sequence of SEQ ID NO: 112, and / or a heavy chain variable region having at least 95% identity to the amino acid sequence of SEQ ID NO:

111.

5. The antibody of claim 1, wherein the antibody comprises HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:125, HCDR3 of SEQ ID NO:67, LCDR1 of SEQ ID NO:64, LCDR2 of SEQ ID NO:59, and LCDR3 of SEQ ID NO:

60. 6 . The antibody of claim 5 , wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 112 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

111.

7. A nucleic acid molecule encoding the antibody of any one of claims 1-6. A vector comprising the nucleic acid molecule according to claim 7 .

9. A cell comprising the nucleic acid molecule of claim 7.

10. A cell comprising the vector of claim 8.

11. A pharmaceutical composition comprising the antibody of any one of claims 1-6, or a nucleic acid molecule encoding the antibody of any one of claims 1-6.

12. A pharmaceutical composition comprising the antibody according to claim 5 or claim 6.

13. A bispecific antibody, comprising a first antigen-binding region that binds to claudin 6 and a second antigen-binding region that binds to a different antigen, wherein the first antigen-binding region that binds to claudin 6 comprises an antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1 (HCDR1), CDR2 (HCDR2) and CDR3 (HCDR3), and the light chain variable region comprises a light chain CDR1 (LCDR1), CDR2 (LCDR2) and CDR3 (LCDR3), and wherein the antibody has: HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:125, and HCDR3 of SEQ ID NO:66, LCDR1 of SEQ ID NO:64, LCDR2 of SEQ ID NO:59, and LCDR3 of SEQ ID NO:60; HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:125, and HCDR3 of SEQ ID NO:65, LCDR1 of SEQ ID NO:64, LCDR2 of SEQ ID NO:59, and LCDR3 of SEQ ID NO:60; or HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:125 and HCDR3 of SEQ ID NO:67, LCDR1 of SEQ ID NO:64, LCDR2 of SEQ ID NO:59 and LCDR3 of SEQ ID NO:

60.

14. The bispecific antibody of claim 13, wherein the first antigen-binding region that binds to claudin 6 comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 110, and / or a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO:

109.

15. The bispecific antibody of claim 13, wherein the first antigen-binding region that binds to claudin 6 comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108, and / or a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO:

107.

16. The bispecific antibody of claim 13, wherein the first antigen-binding region that binds to claudin 6 comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 112, and / or a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO:

111.

17. The bispecific antibody of claim 13, wherein the first antigen-binding region that binds to claudin 6 comprises HCDR1 of SEQ ID NO: 62, HCDR2 of SEQ ID NO: 125, HCDR3 of SEQ ID NO: 67, LCDR1 of SEQ ID NO: 64, LCDR2 of SEQ ID NO: 59, and LCDR3 of SEQ ID NO:

60.

18. The bispecific antibody of claim 17, wherein the first antigen-binding region that binds to claudin-6 comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 112 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

111.

19. The bispecific antibody of claim 13, wherein the antigen binding region that binds to claudin-6 is in the form of Fab, and the second antigen binding region that binds to a different antigen is in the form of scFv.

20. The bispecific antibody of claim 13, wherein the second antigen binding region binds to CD3.

21. The bispecific antibody of claim 20, wherein the antigen binding region that binds to claudin-6 is in the form of Fab, and the antigen binding region that binds to CD3 is in the form of scFv.

22. A nucleic acid molecule encoding the bispecific antibody of any one of claims 13-21.

23. A vector comprising the nucleic acid molecule of claim 22.

24. A cell comprising the nucleic acid molecule of claim 22.

25. A cell comprising the vector of claim 23. 26 . A pharmaceutical composition comprising the bispecific antibody of any one of claims 13 to 21 , or a nucleic acid molecule encoding the bispecific antibody of any one of claims 13 to 21 .

27. A pharmaceutical composition comprising the bispecific antibody of any one of claims 13-21.

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