Antibodies against integrin alpha 11 beta 1

Abstract

This disclosure includes antibodies that specifically bind to integrin α11β1, and methods for manufacturing and using such antibodies. The present disclosure includes antibodies that specifically bind integrin alpha 11 beta 1 (α11β1), as well as methods of making and using such antibodies.

Description

[Technical Field]

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 127,849, filed December 18, 2020, and U.S. Provisional Patent Application No. 63 / 213,973, filed June 23, 2021, which are incorporated herein by reference in their entirety for all purposes.

[0003] Sequence List

[0004] This application contains a sequence list, which has been submitted electronically in ASCII format and whose full text is incorporated herein by reference. The ASCII copy (created on November 19, 2021) is named MPI6002SL.txt and has a file size of 440,570 bytes. [Previous Technology]

[0005] Fibrosis is a scarring process that manifests in many tissues throughout the body, generally resulting from inflammation or tissue damage. Increased production of extracellular matrix leads to organ failure and often death. Approximately 45% of all deaths in industrialized countries are attributed to fibrosis-related diseases (Wynn, TA, 2008, J Pathol. 214:199-210). One such disease is systemic sclerosis (SSc). SSc is a complex autoimmune disease with a long-term progressive process and high inter-patient variability. It is characterized by inflammation, vascular dysfunction, and fibrosis. Fibrosis of the skin and internal organs leads to irreversible scarring, ultimately resulting in organ failure and high mortality. Currently, there are no approved targeted therapies that may improve the disease. [Summary of the Invention]

[0006] This disclosure provides a novel functional blocking antibody against type I collagen receptor integrin α11β1. This disclosure also provides the use of such antibodies for the treatment of fibrotic conditions and / or cancer.

[0007] In one embodiment, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 443. In another embodiment, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof, comprising a CDR sequence encompassing any of the following: SEQ ID NO: 103 to 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316, 3 18, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443. In another embodiment, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 covered by any one of SEQ ID NO: 103 to 206, or 413 to 435. In some embodiments, the anti-α11β1 antibody or the antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 114, 207 to 311, and 312 to 443.In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises a CDR sequence encompassing any of the following: SEQ ID NO: 103 to 114, 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316 318, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises one or more CDR sequences covered by any one of SEQ ID NO: 103 to 114, or 413 to 434. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises CDR1, CDR2, and CDR3 covered by any one of SEQ ID NO: 103 to 114, or 413 to 434.

[0008] In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment is a monoclonal antibody or its antigen-binding fragment. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment is a humanized antibody or its antigen-binding fragment. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment reduces the interaction between α11β1 and collagen in human α11β1 phenotyped cells. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment competes with the antibodies or their antigen-binding fragments described herein.

[0009] In another embodiment, this disclosure provides a nucleic acid comprising a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the nucleic acid sequence comprises a sequence selected from the group consisting of SEQ ID NO: 1 to 102.

[0010] In another embodiment, this disclosure provides a vector containing the nucleic acid described herein.

[0011] In another embodiment, this disclosure provides a host cell containing the nucleic acid or the vector described herein.

[0012] In another embodiment, this disclosure provides a method for generating an antibody or an antigen-binding fragment thereof, comprising culturing a host cell described herein under conditions suitable for expressing the antibody or the antigen-binding fragment thereof.

[0013] In another embodiment, this disclosure provides a method for treating a subject with or at risk of chronic kidney disease, the method comprising administering to the subject a therapeutically effective amount of the antibody or its antigen-binding fragment described herein. In some embodiments, chronic kidney disease refers to or includes primary glomerular diseases (including but not limited to IgA nephropathy and segmental glomerulosclerosis), secondary glomerular diseases (including but not limited to lupus nephritis), thrombotic microangiopathy, tubulointerstitial diseases (including but not limited to obstructive urinary tract diseases), diabetic nephropathy, hypertensive nephropathy, ischemic nephropathy, cardiorenal syndrome of CKD, hereditary glomerular disorders (including but not limited to Alport syndrome), renal cystic diseases (including but not limited to polycystic kidney disease), or hereditary tubular disorders. In some embodiments, administration of a therapeutically effective amount of an antibody or its antigen-binding fragment results in a reduction of measured markers, signs, and / or symptoms by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% relative to a control group. In some embodiments, the control group comprises the levels of measured markers, signs, and / or symptoms in subjects before antibody administration. In some embodiments, the control group comprises the levels of measured markers, signs, and / or symptoms in subjects with the kidney-related condition. In some embodiments, the control group comprises the average level of measured markers, signs, and / or symptoms in a group of subjects with kidney-related conditions. In some embodiments, the measured markers, signs, and / or symptoms are or comprise: COL1A1, fibronectin, PAI-1, IL-11, CXCL1, MCP-1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, MMP9, or combinations thereof.

Implementation Method

[0015] This disclosure is partly based on the discovery of novel antibodies that selectively bind to α11β1. This disclosure also relates to the nucleic acids encoding these antibodies and methods for treating fibrosis and diseases comprising fibrotic components. Fibrosis and Disease

[0016] Fibrosis is a scarring process that manifests in many tissues throughout the body, generally resulting from inflammation or tissue damage. Increased production of extracellular matrix leads to organ failure and often death. Approximately 45% of all deaths in industrialized countries are attributed to fibrosis-related diseases (Wynn, TA, 2008, J Pathol. 214:199-210). One such disease is systemic sclerosis (SSc). SSc is a complex autoimmune disease with a long-term progressive process and high inter-patient variability. It is characterized by inflammation, vascular dysfunction, and fibrosis. Fibrosis of the skin and internal organs leads to irreversible scarring, ultimately resulting in organ failure and high mortality. Currently, there are no approved targeted therapies that may improve the disease.

[0017] A specialized type of fibroblast, called myofibroblast (MF), is the cell line responsible for producing the extracellular matrix (ECM) for tissue repair (and in fibrosis). Although the mechanisms of fibrosis have been extensively studied, this complex process remains far from fully understood. To focus on the most important drivers of fibrosis, we investigated publicly available patient-derived datasets (SSc patient data and normal controls) using a novel, self-developed data analysis method. The analysis identified type I collagen-binding integrin α11β1 as one of the primary targets for regulating fibrosis.

[0018] To date, there is no truly effective treatment for fibrosis. Two approved therapies for idiopathic pulmonary fibrosis (IPF) (nintedanib and pirfenidone) are ineffective and do not improve the disease, and there is currently no approved therapy for systemic sclerosis (SSc). In some embodiments, fibrotic conditions include or include idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis (SSc). In some embodiments, fibrotic conditions may include atrial fibrosis, endocardial fibrosis, arthrofibrosis, mediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

[0019] One clinical feature of the tumor microenvironment is the interaction between the tumor and the stroma, which relies primarily on various integrins that interact with ECM components and growth factors. These interactions can affect tumor survival, progression, and eventual metastasis. α11β1 has been reported to be overexpressed in cancer-associated fibroblasts (CAF) of metastatic tumors, and its expression is associated with progressive tumors in patients. For example, integrin α11 is overexpressed in the stroma of most head and neck squamous cell carcinomas (HNSCC) and is positively correlated with α-smooth muscle actin expression (Parajuli et al., J. Oral Pathol.Med.46:267-275 (2017)). Integrin α11 is also overexpressed by CAF in the stroma of pancreatic ductal adenocarcinoma (PDAC) (Schnittert et al., FASEB J. 33:6609-6621 (2019)). Furthermore, overexpression of integrin α11β1 in the tumor stroma has been associated with tumor growth and metastasis in non-small cell lung cancer (NSCLC), and high expression of ITGA11 (the gene encoding integrin α11 in humans) is associated with lower relapse-free survival in all NSCLC patients; similar studies have shown that α11 overexpression in lung cancer cell lines leads to increased migration and invasion (Ando et al., Cancer Sci.111:200-208 (2020)). Integrins

[0020] Integrins are type I transmembrane heterodimeric glycoprotein receptors, playing a major role in cell adhesion. The integrin receptor family plays a crucial role in regulating signal transduction pathways that control cell adhesion, migration, proliferation, differentiation, and apoptosis. There are 18 α and 8 β subunits, which combine to form 24 integrin heterodimers. Each integrin receptor contains two non-covalently bound subunits (α and β). Integrins α1β1, α2β1, α10β1, and α11β1 are major collagen receptors. The α and β subunits are transmembrane proteins with a large extracellular domain, a single transmembrane helix, and a short cytoplasmic region (which mediates cytoskeletal interactions). The extracellular domain of an integrin is typically a large structure of approximately 80 to 150 kDa. The extracellular domain can be seen to contain a headpiece that connects to two legs (see Figure 1 for the structure of collagen-binding integrins). Collagen-binding integrins contain an I domain, which serves as the ligand-binding site. The αI domain contains a retained metal-ion-dependent adhesion site (MIDAS), which binds divalent metal cations (Mg2+) and plays a crucial role in ligand binding.

[0021] Integrins can exist in three different conformations: 1) a stationary low-affinity state (bent conformation, Fig. 1, Fig. A), in which the head segment containing the ligand-binding site is a directional membrane; 2) an extended intermediate-affinity state, in which the integrin is extended, but the head segment remains "closed" (Fig. 1, Fig. B); 3) an extended high-affinity state, in which the integrin is fully activated and readily binds to ligands. The complexity of different integrin states allows for the inhibition of integrin function via ectopic and ligand-blocking methods. As shown by the star-shaped marker in Fig. 1, one ectopic method for blocking integrin function is to generate a monoclonal antibody that prevents the integrin from reaching the fully extended conformation from the extended intermediate conformation. Another ectopic option is to bind the integrin in its bent / inactive conformation and prevent it from extending into either of the other two states. A non-ectopic method for inhibiting integrin function is to bind to the I domain, preventing the integrin from attaching to collagen. Binding to the ligand-binding site directly risks generating recombinant activators of integrin function.

[0022] As cell surface receptors, integrins sense the stiffness of the surrounding matrix, triggering cells to further generate and remodel connective tissue, which can perpetuate the fibrotic phenotype. Many integrin lineages are overexpressed in fibrosis, but it is unclear which α subunit is sufficient to cause fibrosis. The α11β1 integrin lineage is specifically expressed in a subset of fibroblasts and myofibroblasts (i.e., the cells that ultimately produce scars). Recent literature has provided strong evidence that α11β1 is one of the major drivers of the fibrotic phenotype in cardiac tissue, liver, lung, and kidney (Romaine, A. et. al. Overexpression of integrin alpha 11 induces cardiac fibrosis in mice. Acta Physiol Feb 2018, 222(2); Bansal, R. et. al. Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. Exp Mol Med. 2017 Nov 17:49(11)). Blocking α11β1 function can inhibit myofibroblast differentiation and extracellular matrix deposition (i.e., the main events in scar formation), and blocking α11β1 function can provide a mechanism for targeted reduction of local damage in fibrosis, which can essentially alter the fibrotic microenvironment and improve disease progression in all diseases with fibrotic components.

[0023] In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment disclosed herein reduces the interaction between α11β1 and collagen in human α11β1 phenotyped cells. In some embodiments, reducing the interaction between α11β1 and collagen in human α11β1 phenotyped cells comprises an anti-α11β1 antibody or its antigen-binding fragment interacting with α11β1, wherein the α11β1 is in a stationary low-affinity state (bent conformation). In some embodiments, reducing the interaction between α11β1 and collagen in human α11β1 phenotyped cells comprises an anti-α11β1 antibody or its antigen-binding fragment interacting with α11β1, wherein the α11β1 is in an extended intermediate-affinity state. In some embodiments, reducing the interaction between α11β1 and collagen in human α11β1 phenotyped cells comprises an anti-α11β1 antibody or its antigen-binding fragment interacting with α11β1, wherein the α11β1 is in an extended high-affinity state. Antibody

[0024] The term "antibody" is used in the broadest sense herein and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and / or antibody fragments (preferably fragments exhibiting the desired antigen-binding activity). Antibodies described herein may be immunoglobulins, heavy chain antibodies, light chain antibodies, LRR-based antibodies, or other protein scaffolds with antibody-like properties, as well as other immunobinding moieties known in the art, including, for example, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, Feb, scFv, SMIP, antibodies, diabody, triabody, tetrabody, minibody, macrobody, tandab, DVD, BiTe, TandAb, or similar, or any combination thereof. The subunit structures and three-dimensional configurations of different classes of antibodies are known in the art.

[0025] A "monoclonal antibody" or "mAb" refers to an antibody derived from a substantially homogeneous group of antibodies, meaning that the individual antibodies in that group are identical and / or bind to the same epitope, with the exception of possible variant antibodies (e.g., those containing naturally occurring mutations or those generated during the production of a monoclonal antibody formulation). Such variants are usually present in small quantities. Polyclonal antibody formulations generally consist of different antibodies targeting different determinants (epitaxes), in contrast to monoclonal antibody formulations where each monoclonal antibody targets a single determinant on the antigen.

[0026] An "antigen-binding fragment" refers to a portion of a complete antibody that binds to the antigen bound by the complete antibody. Antigen-binding fragments of antibodies include any naturally occurring, enzymatically available, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Exemplary antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabody; linear antibody; single-chain antibody molecules (e.g., only scFv or VHH or VH or VL domains); and multispecific antibodies formed from antibody fragments. In some embodiments, the antigen-binding fragment of an antibody described herein is scFv. Like a complete antibody molecule, an antigen-binding fragment may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody may contain at least two different variable domains, each of which can specifically bind to different antigens or different epitopes of the same antigen.

[0027] A "multispecific antibody" refers to an antibody that contains at least two different antigen-binding domains and recognizes and specifically binds to at least two different antigens. A "bispecific antibody" is a type of multispecific antibody and refers to an antibody that contains at least two different antigen-binding domains and recognizes and specifically binds to at least two different antigens.

[0028] "Different antigen" can refer to different and / or distinct proteins, polypeptides or molecules; and different and / or distinct epitopes, which may be contained in a protein, polypeptide or other molecule.

[0029] The term "epitope" refers to an antigenic determinant site that interacts with a specific antigen-binding site (called a complementary site) in the variable region of an antibody molecule. A single antigen may have more than one epitope. Therefore, different antibodies can bind to different regions of the antigen and may have different biological effects. The term "epitope" also refers to an antigenic site to which B and / or T cells respond. It also refers to the region of the antigen to which the antibody binds. An epitope can be defined as structural or functional. Functional epitopes are typically a subset of structural epitopes and contain residues with an affinity that directly facilitates the interaction. Epitopes can also be conformational, i.e., composed of nonlinear amino acids. In some embodiments, an epitope may include: a determinant site that is a molecule belonging to the chemically active surface class, such as an amino acid, a sugar side chain, a phosphoryl group, or a sulfonylurea, and in some embodiments, may have specific three-dimensional structural features and / or specific charge features.

[0030] As used herein, "selective binding," "selectively bind," "specific binding," or "specifically bind" refers to the preferential association between the antigen-binding portion and the antigen target (rather than a non-antigen target entity) with respect to the antigen-binding portion and the antigen target. Some degree of non-specific binding may occur between the antigen-binding portion and the non-target. In some embodiments, the antigen-binding portion selectively binds to the antigen target if the binding affinity between the antigen-binding portion and the antigen target is greater than 2, 5, 10, or 100 times greater than the binding affinity between the antigen-binding portion and the non-target. In some embodiments, the antigen-binding portion selectively binds to the antigen target if the binding affinity is less than about 10⁻⁵ M, less than about 10⁻⁶ M, less than about 10⁻⁷ M, less than about 10⁻⁸ M, or less than about 10⁻⁹ M.

[0031] In some embodiments, antibodies or fragments thereof that selectively bind to the same or overlapping epitopes often cross-compete for binding to antigens. Therefore, in some embodiments, this disclosure provides an antibody or fragment thereof that cross-competes with the exemplary antibodies or fragments thereof disclosed herein. In some embodiments, "cross-compete," "compete," "cross-competition," or "competition" means that the antibody or fragment thereof competes for binding sites on the same epitope or target. Such competition can be determined by a test in which a reference antibody or fragment thereof prevents or inhibits the specific binding of the test antibody or fragment thereof, and vice versa. Many types of competitive binding tests can be used to determine whether a test molecule competes for binding with a reference molecule. Examples of analyses that can be used include solid-phase direct or indirect radioimmunoassay (RIA), solid-phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, for example, Stahli et al. (1983) Methods in Enzymology 9:242-253), solid-phase direct biotin-avidin EIA (see, for example, Kirkland et al., (1986) J. Immunol. 137:3614-9), solid-phase direct labeling assay, solid-phase direct labeling sandwich assay, Luminex (Jia et al. "A novel method of Multiplexed Competitive Antibody Binning for the characterization of monoclonal antibodies" J. Immunological Methods (2004) 288, 91-98), and surface plasma resonance (Song et al. "Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Patients (J. Virol. (2010) 84, 6935-42). Typically, when a competitive antibody or fragment thereof is present in excess, it will inhibit the binding of the reference antibody or fragment thereof to the common antigen by at least 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, the binding system is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more.

[0032] An antibody may be an immunoglobulin molecule having four polypeptide chains, such as two heavy (H) chains and two light (L) chains. In some embodiments, the light chain is a λ light chain. In some embodiments, the light chain is a κ light chain. The heavy chain may include a heavy chain variable domain and a heavy chain constant domain. The heavy chain constant domain may include a CH1 region, a hinge region, a CH2 region, a CH3 region, and in some cases, a CH4 region. The heavy chain may include a light chain variable domain and a light chain constant domain. The light chain constant domain may include a CL.

[0033] The heavy chain variable domains and the light chain variable domains can generally be further subdivided into variant regions called complementarity-determining regions (CDRs), which are interspersed with more reserved regions called framework regions (FRs). Each of these heavy and light chain variable domains may include three CDRs and four framework regions, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, one or more of which may be engineered (as described herein). The CDRs in the heavy chain are referred to as "CDRH1", "CDRH2", and "CDRH3", respectively, and the CDRs in the light chain are referred to as "CDRL1", "CDRL2", and "CDRL3".

[0034] Antibodies are classified into five main classes: IgA, IgD, IgE, IgG, and IgM. Several of these classes can be further subdivided into "subclasses" (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different immunoglobulin classes are respectively called α, δ, ε, γ, and µ. Example antibody

[0035] This disclosure provides antibodies that may include the various heavy and light chains described herein. In some embodiments, the antibody comprises two heavy and light chains. In some embodiments, this disclosure covers antibodies comprising: at least one heavy and / or light chain (as disclosed herein), at least one heavy and / or light chain architecture domain (as disclosed herein), at least one heavy and / or light chain CDR domain (as disclosed herein), and / or any heavy and / or light chain constant domain (as disclosed herein).

[0036] In some embodiments, the anti-system disclosed herein is a homodimeric monoclonal antibody. In some embodiments, the anti-system disclosed herein is a heterodimeric antibody. In some embodiments, the anti-system is, for example, a general antibody or bivalent antibody, trivalent antibody, tetravalent antibody, microantibody, large antibody, tandab, DVD, BiTe, scFv, TandAb scFv, Fab, Fab2, Fab3, F(ab')2, or similar, or any combination thereof.

[0037] This disclosure provides, among other things, anti-integrin α11β1 antibodies or antigen-binding fragments thereof. In some embodiments, the α11β1 antibody or its antigen-binding fragment comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 443. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises a CDR sequence encompassing any of the following: SEQ ID NO: 103 to 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316, 3 18, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 435. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises CDR1, CDR2, and CDR3 covered by any one of SEQ ID NO: 103 to 206, or 413 to 443. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 114, 207 to 311, and 312 to 443.In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises a CDR sequence encompassing any of the following: SEQ ID NO: 103 to 114, 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316 318, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises one or more CDR sequences covered by any one of SEQ ID NO: 103 to 114, or 413 to 434. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment comprises CDR1, CDR2, and CDR3 covered by any one of SEQ ID NO: 103 to 114, or 413 to 434. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment is a monoclonal antibody or its antigen-binding fragment. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment is a humanized antibody or its antigen-binding fragment. In some embodiments, the anti-α11β1 antibody or its antigen-binding fragment reduces the interaction between α11β1 and collagen in human α11β1 phenotyped cells. In some embodiments, this disclosure provides an anti-α11β1 antibody or its antigen-binding fragment that competes with: an antibody or its antigen-binding fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 443. In some embodiments, this disclosure provides an anti-α11β1 antibody or its antigen-binding fragment that competes with: an antibody or its antigen-binding fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 443.

[0038] In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof comprising the heavy chain and light chain provided herein. In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof comprising the heavy chain variable domain and light chain variable domain provided herein. In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof comprising a specific combination of heavy chain variable domain and light chain variable domain. For example, in some embodiments, the anti-α11β1 antibody or an antigen-binding fragment thereof comprises a combination of heavy chain variable domain and light chain variable domain selected from Table 1. Table 1. Combinations of heavy chain variable regions and light chain variable regions of 16E10 variant Light chain variable region Heavy chain variable region illustrate 16E10_VL (SEQ ID NO: 428) 16E10_VH (SEQ ID NO: 421) Parental light chain variable region; Parental heavy chain variable region 16E10_VL_1 (SEQ ID NO: 429) 16E10_VH_1 (SEQ ID NO: 422) Conservative humanized light chain variable region; Conservative humanized heavy chain variable region 16E10_VL_2 (SEQ ID NO: 430) 16E10_VH_2 (SEQ ID NO: 423) Humanized light chain variable region; humanized heavy chain variable region 16E10_VL_3 (SEQ ID NO: 431) 16E10_VH_1 (SEQ ID NO: 422) Deimmunized conserved humanized light chain variable region; conserved humanized heavy chain variable region 16E10_VL_4 (SEQ ID NO: 432) 16E10_VH_2 (SEQ ID NO: 423) Deimmunized humanized light chain variable region; humanized heavy chain variable region 16E10_VL_1 (SEQ ID NO: 429) 16E10_VH_3 (SEQ ID NO: 424) Conserved humanized light chain variable region; Deimmunized conserved humanized heavy chain variable region 16E10_VL_2 (SEQ ID NO: 430) 16E10_VH_4 (SEQ ID NO: 425) Humanized light chain variable region; Deimmunized humanized heavy chain variable region 16E10_VL_3 (SEQ ID NO: 431) 16E10_VH_3 (SEQ ID NO: 424) Deimmunized conserved humanized light chain variable region; Deimmunized conserved humanized heavy chain variable region 16E10_VL_4 (SEQ ID NO: 432) 16E10_VH_4 (SEQ ID NO: 425) Deimmunized humanized light chain variable region; Deimmunized humanized heavy chain variable region 16E10_VL_5 (SEQ ID NO: 433) 16E10_VH_3 (SEQ ID NO: 424) De-risking, de-immunization, conserved humanized light chain variable region; de-immunization, conserved humanized heavy chain variable region 16E10_VL_6 (SEQ ID NO: 434) 16E10_VH_4 (SEQ ID NO: 425) De-risking, de-immunization, humanized light chain variable region; de-immunization, humanized heavy chain variable region 16E10_VL_3 (SEQ ID NO: 431) 16E10_VH_5 (SEQ ID NO: 426) Deimmunization of conserved humanized light chain variable regions; deriskization of deimmunization of conserved humanized heavy chain variable regions. 16E10_VL_4 (SEQ ID NO: 432) 16E10_VH_6 (SEQ ID NO: 427) Deimmunized humanized light chain variable region; Derisk-deimmunized humanized heavy chain variable region 16E10_VL_5 (SEQ ID NO: 433) 16E10_VH_5 (SEQ ID NO: 426) De-risking, de-immunizing, conserved humanized light chain variable region; De-risking, de-immunizing, conserved humanized heavy chain variable region 16E10_VL_6 (SEQ ID NO: 434) 16E10_VH_6 (SEQ ID NO: 427) De-risking, de-immunizing, humanized light chain variable region; De-risking, de-immunizing, humanized heavy chain variable region

[0039] In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof, which includes additions, deletions, or substitutions at positions between 1 and 30 (e.g., 1, 2, 3, 4, 5, 10, or more) relative to an anti-α11β1 antibody or an antigen-binding fragment thereof, wherein the anti-α11β1 antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 158, 413, 414, and 421 to 434, and, for example, the antibody or fragment selectively binds to α11β1. In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof, comprising additions, deletions, or substitutions at positions between 1 and 30 relative to an anti-α11β1 antibody or an antigen-binding fragment thereof, wherein the anti-α11β1 antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 103 to 114, 413, 414, and 421 to 434, and, for example, the antibody or fragment selectively binds α11β1. In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof, comprising an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 103 to 158, 413, 414, and 421 to 434, and, for example, the antibody or fragment selectively binds α11β1. In some embodiments, this disclosure provides an anti-α11β1 antibody or its antigen-binding fragment comprising an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 114, 413, 414, and 421 to 434, and, for example, the antibody or fragment selectively binds to α11β1.

[0040] In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof, which includes additions, deletions, or substitutions at positions between 1 and 90 (e.g., between 1 and 50, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) relative to an anti-α11β1 antibody or an antigen-binding fragment thereof, wherein the anti-α11β1 antibody or the antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 159 to 206 and 415 to 420, and, for example, the antibody or fragment selectively binds to α11β1. In some embodiments, this disclosure provides an anti-α11β1 antibody or an antigen-binding fragment thereof, comprising an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 159 to 206 and 415 to 420, and, for example, the antibody or fragment selectively binds to α11β1.

[0041] In some embodiments, this disclosure provides an antibody or fragment thereof that selectively binds α11β1, wherein the antibody or fragment comprises one or more CDR sequences shown in the list of exemplary sequences provided herein. For example, in some embodiments, the antibody or fragment thereof comprises one or more CDRs from SEQ ID NO: 103 to 114. In some embodiments, this disclosure provides an antibody or fragment thereof that selectively binds α11β1, wherein the antibody or fragment comprises an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to one or more CDRs from SEQ ID NO: 103 to 114. In some embodiments, an antibody or fragment comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to one of SEQ ID NO: 103 to 114, wherein the antibody comprises one or more CDRs shown in one of SEQ ID NO: 103 to 114. For example, the antibody or fragment contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 103, wherein the antibody contains one or more CDRs (e.g., 1, 2, or 3 CDRs) shown in SEQ ID NO: 103.

[0042] In some embodiments, this disclosure provides an antibody or fragment thereof that selectively binds to α11β1, wherein the antibody or fragment comprises one or more CDR sequences shown in the list of exemplary sequences provided herein. For example, in some embodiments, an antibody or fragment thereof comprises one or more CDRs from the following: SEQ ID NO: 103 to 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316, 3 18, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443. In some embodiments, this disclosure provides an antibody or fragment thereof that selectively binds to α11β1, wherein the antibody or fragment comprises an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to one or more of the following CDRs: SEQ ID NO: 103 to 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316, 3 18, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443.In some embodiments, the antibody or a fragment thereof comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with one of the following: SEQ ID NO: 103 to 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 32 4, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443, wherein the antibody contains one or more of the following CDRs: SEQ ID NO: 103 to 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316, 3 18, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443. For example, the antibody or fragment contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 103, wherein the antibody contains one or more CDRs (e.g., 1, 2, or 3 CDRs) shown in SEQ ID NO: 103.

[0043] This disclosure provides, among other things, a method for manufacturing an anti-α11β1 antibody or an antigen-binding fragment thereof. Methods for manufacturing antibodies are known in the art. In some embodiments, this disclosure provides a method for producing an antibody or an antigen-binding fragment thereof, comprising culturing host cells under conditions suitable for expressing the antibody or the antigen-binding fragment thereof, the host cells comprising nucleic acid sequences selected from the group consisting of SEQ ID NO: 1 to 102. Exemplary nucleotide sequences

[0044] This disclosure includes nucleotide sequences encoding one or more heavy chains, heavy chain variable domains, heavy chain architecture regions, heavy chain CDRs, heavy chain constant domains, light chains, light chain variable domains, light chain architecture regions, light chain CDRs, light chain constant domains, or other immunoglobulin-like sequences, antibodies, or binding molecules (disclosed herein). In some embodiments, such nucleotide sequences may be present in a vector. In some embodiments, such nucleotides may be present in the genome of a cell line, such as cells of a subject requiring treatment, or cells used to produce antibodies (e.g., mammalian cells used to produce antibodies).

[0045] In some embodiments, this disclosure provides a nucleic acid comprising: a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 206. In some embodiments, this disclosure provides a nucleic acid comprising: a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 114. In some embodiments, this disclosure provides a nucleic acid comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 to 102. In some embodiments, this disclosure provides a vector comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 to 102. In some embodiments, this disclosure provides a host cell comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 to 102. In some embodiments, this disclosure provides a vector comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 to 102.

[0046] In some embodiments, this disclosure provides a nucleic acid comprising a nucleic acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 to 102. Measuring the interaction between the antibody and α11β1.

[0047] The binding properties of the antibody to α11β1 described herein can be measured by methods known in the art, such as one of the following: BIACORE analysis, enzyme-linked immunosorbent assay (ELISA), X-ray crystallography, sequence analysis, and scanning mutagenesis. Surface plasma resonance (SPR) can be used to analyze the binding interaction between the antibody and α11β1. SPR, or biomolecular interaction analysis (BIA), detects immediate, biospecific interactions without labeling any interacting molecules. Mass changes at the binding surface of a BIA wafer (indicating a binding event) cause a change in the refractive index near the surface. This refractive index change generates a detectable signal, which is measured to indicate an immediate reaction between biomolecules. The method using SPR is described, for example, in U.S. Patent No. 5,641,640; Raether (1988) Surface Plasmons Springer Verlag; Sjolander and Urbaniczky (1991) Anal. Chem. 63:2338-2345; Szabo et al. (1995) Curr. Opin. Struct. Biol. 5:699-705; and online resources provided by BIAcore International AB (Uppsala, Sweden). Alternatively, verification can be performed using KinExA® (kinetic exclusion test), which is available from Savidyne Instruments (Boise, Id.).

[0048] Information from SPR can be used to provide accurate quantitative indicators of the following: the equilibrium dissociation constant (KD) for antibody binding to α11β1, and kinetic parameters (including Kon and Koff). This data can be used to compare different molecules. Information from SPR can be used to develop structure-activity relationships (SARs). Variant amino acids at a given position can be identified that are associated with specific binding parameters (e.g., high affinity).

[0049] In some embodiments, the antibodies described herein exhibit high affinity for α11β1. In various embodiments, the KD values ​​of the antibodies described herein for α11β1 are less than about 10⁻⁴, 10⁻⁵, 10⁻⁶, 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³, ​​10⁻¹⁴, or 10⁻¹⁵ M. In some cases, the KD values ​​of the antibodies described herein for α11β1 are between 0.001 and 1 nM, for example, 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM, or 1 nM. Treatment Methods

[0050] In some embodiments, one or more anti-α11β1 anti-systems described herein are used as a method for treating one or more conditions described herein (e.g., one or more fibrotic conditions and / or one or more cancers). In some embodiments, the method includes delivering a therapeutically effective amount of the antibody described herein or its antigen-binding fragment to a subject in need. In some embodiments, the fibrotic condition is or includes idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis.

[0051] In some embodiments, the fibrotic condition may include atrial fibrosis, endocardial fibrosis, arthrofibrosis, mediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

[0052] In some embodiments, one or more of the anti-α11β1 anti-systems described herein are used in a method of treating cancer, the cancer being one or more of the following: head and neck squamous cell carcinoma, pancreatic duct adenocarcinoma, non-small cell lung cancer, adrenocortical carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, invasive breast cancer, cervical squamous cell carcinoma, bile duct carcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, glioblastoma multiforme, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, melanoma of the skin, mesothelioma, ovarian serous cystadenocarcinoma, pheochromocytoma and paraganglioma, prostate cancer, sarcoma, gastric adenocarcinoma, testicular germ cell tumor, thymoma, thyroid cancer, endometrial cancer of the uterine body, uterine carcinosarcoma, uveal melanoma. Melanoma, clear cell renal cell carcinoma, chromophobe renal cell carcinoma, and papillary renal cell carcinoma.

[0053] In some embodiments, one or more of the anti-α11β1 anti-systems described herein are used to treat subjects with chronic kidney disease (CKD) or at risk of developing chronic kidney disease, such as CKD associated with fibrosis. CKD is known in the art (see, for example, Brenner, Barry M. (ed) Brenner & Rector's The Kidney, 11th edition 2019). CKD includes, for example, primary glomerular diseases (including but not limited to IgA nephropathy and segmental glomerulosclerosis), secondary glomerular diseases (including but not limited to lupus nephritis), thrombotic microangiopathy, tubulointerstitial diseases (including but not limited to obstructive urinary tract diseases), diabetic nephropathy, hypertensive nephropathy, ischemic nephropathy, cardiorenal syndrome of CKD, hereditary glomerular diseases (including but not limited to Alport syndrome), renal cystic diseases (including but not limited to polycystic kidney disease), and hereditary tubular diseases (Brenner, Barry M. (ed) Brenner & Rector's The Kidney, 11th edition 2019).

[0054] In some embodiments, the anti-α11β1 antibody described herein, upon administration to a subject, reduces one or more markers, signs, and / or symptoms of kidney-related diseases described herein. Markers, signs, and / or symptoms of kidney-related diseases include, for example, COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, and MMP9. In some embodiments, after administration to a subject, the anti-α11β1 antibody can reduce the measured markers, signs, and / or symptoms by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% relative to a control group (e.g., the levels of measured markers, signs, and / or symptoms in the subject before administration of the antibody; the levels of measured markers, signs, and / or symptoms in subjects with kidney-related conditions; and / or the average level of measured markers, signs, and / or symptoms in a group of subjects with kidney-related conditions).

[0055] In some embodiments, such as measured in models of kidney-related diseases (e.g., human precision-cut kidney slices (PCKS), ReninAAV Unx db / db mouse models, or 5 / 6 nephrectomy models), the anti-α11β1 antibody described herein reduces the levels of COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, MMP9, or combinations thereof by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% relative to the control group. In some embodiments, markers, signs, and / or symptoms of kidney-related diseases can be determined by measuring protein levels, RNA levels, DNA levels, or combinations thereof. In some embodiments, markers, signs, and / or symptoms of kidney-related disorders may be determined by using the following: ELISA, PCR, RNAseq, biochemical assays (e.g., analytical procedures for detecting and quantifying cellular processes (e.g., apoptosis, cell communication) or metabolic responses), cytology, immunohistochemistry, or combinations thereof.

[0056] In some embodiments, markers, signs, and / or symptoms of kidney-related conditions can be determined by testing biological samples from the subject. Examples of suitable biological samples include, but are not limited to, serum, plasma, cerebrospinal fluid, urine, circulating blood cells (e.g., peripheral blood mononuclear cells), and biopsy samples. In some embodiments, the sample comprises cells or tissue. In some embodiments, the provided method further includes the steps of lysing cells or performing a tissue biopsy, and one or more markers include one or more intracellular markers. Biological samples suitable for this disclosure may be fresh or frozen samples collected from the subject, or stock samples with a known history of diagnosis, treatment, and / or outcome. Biological samples may be collected by any invasive or non-invasive means, such as, for example, by aspirating CSF or blood from the subject, or using fine needle aspiration or needle biopsy, or by surgical biopsy. In some embodiments, biological samples may be used without or with limited processing. Combination Therapy

[0057] In some embodiments, the anti-α11β1 anti-system described herein is administered in combination with one or more additional therapeutic agents, such as chemotherapeutic agents or oncolytic agents. As used herein, "combination therapy" refers to a situation in which two or more different agents are administered in an overlapping manner, such that the subject is simultaneously exposed to both agents. When used in combination therapy, the two or more different agents may be administered simultaneously or separately. Combination administration may include simultaneous administration of two or more agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, two or more agents may be co-formulated in the same dosage form and administered simultaneously. Alternatively, two or more agents may be administered simultaneously, wherein the agents are present in separate formulations. In another alternative, a first agent may be administered, followed by one or more additional agents. In separate administration procedures, two or more agents may be administered at intervals of minutes, hours, or days.

[0058] As used herein, the terms "chemotherapeutic agent" or "oncolytic therapeutic agent" (e.g., anticancer drugs, anticancer therapies, immunotherapy) have the meaning understood in their respective technical fields and refer to one or more apoptosis-promoting agents, cell growth inhibitors, and / or cytotoxic agents, and / or hormones, including, for example, agents used and / or recommended for the treatment of one or more diseases, conditions, or illnesses associated with undesirable cell proliferation. In some embodiments, the chemotherapeutic agent and / or oncolytic agent may be a platinum compound (e.g., cisplatin, carboplatin, and oxaliplatin), an alkylating agent (e.g., cyclophosphamide, ifosfamide, nitrogen mustard chlorpyrifos, nitrogen mustard gas, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, and bendamustine), or an antitumor antibiotic (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, etc.). plicamycin and actinomycin, taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguanine, fluorouridine, capecitabine, and methotrexate), nucleoside analogs (e.g., fludarabine, clofarabine, cladribine, pentostatin, and nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), and hypomethylating agents.Agents (e.g., azacitidine and decitabine), proteasome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (Vinca) Alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, and sunitinib), nitrosoureas (e.g., carmustine, formostine, and lomustine), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide and lenalidomide), and steroids (e.g., prednisone and dexamethasone). And prednisolone), hormones (e.g., tamoxifen, raloxifene, leuprolide, bicaluatmide, granisetron, and flutamide), aromatase inhibitors (e.g., letrozole and anastrozole), arsenic trioxide, tretinoin, non-selective cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory drugs, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naproxen, diclofenac, tolmetin, ketoprofen, nabumetone, and oxaprozin), selective cyclooxygenase 2 (COX-2) inhibitors, or any combination thereof.

[0059] In some embodiments, the chemotherapeutic agents and / or oncolytic agents used for anticancer treatment comprise biological agents such as tumor-infiltrating lymphocytes, CAR-T cells, antibodies, antigens, therapeutic vaccines (e.g., made from the patient's own tumor cells or other substances such as antigens produced by certain tumors), immunomodulators (e.g., interleukins, such as immunomodulatory drugs or biological response modifiers), checkpoint inhibitors, or other immunomodulators. In some embodiments, immunomodulators include immunoglobulins, immunostimulants (e.g., bacterial vaccines, community-stimulating factors, interferons, interleukins, therapeutic vaccines, vaccine combinations, viral vaccines), and / or immunosuppressants (e.g., calcineurin inhibitors, interleukin inhibitors, TNFα inhibitors). In some embodiments, the hormone agents include agents used for antiandrogen therapy (e.g., ketoconazole, abiraterone, TAK-700, TOK-OOl, bicalutamide, nilutamide, flutamide, enzalutamide, ARN-509).

[0060] Additional chemotherapy agents and / or oncolytic agents include immune checkpoint therapy agents (e.g., pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, tremelimumab, or cemiplimab), other monoclonal antibodies (e.g., rituximab, cetuximab, panetumumab, tositumomab, trastuzumab, aleemtuzumab, gemtuzumab, and ozomicin). ozogamicin), bevacizumab, catumaxomab, denosumab, obinutuzumab, ofatumumab, ramucirumab, pertuzumab, nimotuzumab, lambrolizumab, pidilizumab, siltuximab, BMS-936559, RG7446 / MPDL3280A, MEDI4736, antibody-drug conjugates (e.g., brentuximab vedotin (ADCETRIS®, Seattle Genetics); ado-trastuzumab emtansine (KADCYLA®)). Roche; Gemtuzumab ozogamicin (Wyeth); CMC-544; SAR3419; CDX-011; PSMA-ADC; BT-062; and IMGN901 (see, for example, Sassoon et al., Methods Mol. Biol. 1045:1-27 (2013); Bouchard et al., Bioorganic Med. Chem. Lett. 24: 5357-5363 (2014)), or any combination thereof.

[0061] In some embodiments, the combined administration of the anti-α11β1 antibody and the additional therapeutic agent results in cancer improvement to a greater extent than that produced by the anti-α11β1 antibody or the additional therapeutic agent alone. The difference between the combination effect and the effect of the individual agents alone may be statistically significant. In some embodiments, the combination effect may be a synergistic effect. In some embodiments, the combined administration of the anti-α11β1 antibody and the additional therapeutic agent allows the additional therapeutic agent to be administered at a reduced dose, at a reduced number of doses, and / or at a reduced dose frequency compared to a standard dosing regimen (e.g., a dosing regimen of an approved additional therapeutic agent).

[0062] In some embodiments, the treatment methods described herein are applied to subjects who have experienced failure of other treatments for their medical condition, or who have been treated with limited success by other means. Furthermore, the treatment methods described herein may be performed in conjunction with one or more additional treatments for the medical condition. For example, the method may include administering a cancer regimen, such as non-myeloablative chemotherapy, surgery, hormone therapy, and / or radiation, before, substantially simultaneously with, or after administering the anti-α11β1 antibody or a composition thereof described herein. Formulation and Administration

[0063] In various embodiments, the antibodies described herein may be incorporated into pharmaceutical compositions. Such pharmaceutical compositions may be used, for example, to prevent and / or treat diseases, such as fibrosis. Pharmaceutical compositions may be formulated by methods known to those skilled in the art (such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985)).

[0064] In some embodiments, the pharmaceutical composition may be formulated to include a pharmaceutically acceptable carrier or excipient. Examples of pharmaceutically acceptable carriers include (but are not limited to) any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption delay agents, and physiologically compatible similar agents. The compositions of the present invention may include pharmaceutically acceptable salts, such as acid addition salts or base addition salts.

[0065] In some embodiments, distilled water for injection may be used as a medium, in accordance with conventional pharmaceutical practice, to formulate a composition comprising antibodies as described herein, such as a sterile formulation for injection. For example, physiological saline or an isotonic solution containing glucose and other supplements (such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride) may be used as an aqueous solution for injection, optionally in combination with: suitable co-solvents, such as alcohols, such as ethanol and / or polyols (such as propylene glycol or polyethylene glycol); and / or nonionic surfactants, such as polysorbate 80™ or HCO-50.

[0066] As disclosed herein, pharmaceutical compositions may take any form known in the art. Such forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusionable solutions), dispersions or suspensions, tablets, powders, liposomes, and suppositories.

[0067] The choice or use of any particular form may depend in part on the intended mode of administration and therapeutic application. For example, a composition containing an ingredient intended for systemic or local delivery may be in the form of an injectable or infusionable solution. Thus, the composition may be formulated for administration via parenteral routes (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular). As used herein, parenteral administration refers to a mode of administration other than enteral and local administration, typically administered by injection, and includes (but is not limited to) intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, tracheal, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injections and infusions. In some embodiments, the composition may be targeted to the kidneys. In some embodiments, the composition may target kidney cells.

[0068] The route of administration may be extragastric, such as by injection, nasal administration, pulmonary administration, or percutaneous administration. Administration may be systemic or local, via intravenous injection, intramuscular injection, intraperitoneal injection, or subcutaneous injection. In some embodiments, the route of administration may include dialysis. In some embodiments, the route of administration may include hemodialysis. In some embodiments, the route of administration may include peritoneal dialysis.

[0069] In some embodiments, the pharmaceutical composition of the present invention may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure (suitable for stable storage at high concentrations). A sterile injectable solution may be prepared by incorporating the desired amount of the composition described herein with one or a combination of the ingredients listed above (as needed) into a suitable solvent, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the composition described herein into a sterile medium containing a basic dispersion medium and other necessary components from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method includes vacuum drying and freeze-drying to produce a powder of the composition described herein plus any additional desired components (see below) of its previously sterile filtered solution. Appropriate flowability of the solution may be maintained, for example, by using a coating (such as lecithin), in the case of a dispersion by maintaining a desired particle size, and by using a surfactant. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption (e.g., monostearate and gelatin) in the composition.

[0070] Pharmaceutical compositions may be administered parenterally in the form of injectable formulations comprising a sterile solution or suspension (in water) or another pharmaceutically acceptable liquid. For example, pharmaceutical compositions may be formulated by appropriately combining therapeutic molecules with pharmaceutically acceptable mediators or agents, such as sterile water and physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring excipients, diluents, mordants, preservatives, and binders; followed by mixing in a unit dosage form generally accepted in pharmaceutical practice. The amount of active ingredient included in the pharmaceutical formulation is such that an appropriate dose within a specified range is provided. Non-limiting examples of oily liquids include sesame oil and soybean oil, which may be combined with benzyl benzoate or benzyl alcohol as a cosolvent. Other systems that may be included include buffers (such as phosphate buffers or sodium acetate buffers), soothing agents (such as procaine hydrochloride), stabilizers (such as benzyl alcohol or phenol), and antioxidants. The prepared injectable solution can be packaged in a suitable ampoule.

[0071] In various embodiments, subcutaneous administration may be achieved by means of components of a device, such as a syringe, a prefilled syringe, an auto-injector (e.g., disposable or reusable), a pen syringe, a patch injector, a wearable syringe, a portable syringe infusion pump for subcutaneous infusion kits, or other devices (for combining antibody drugs for subcutaneous injection).

[0072] The injection system disclosed herein may employ a delivery pen as described in U.S. Patent No. 5,308,341. Pen-type devices (most commonly used for self-delivery of insulin to diabetic patients) are well known in the art. Generally, such devices may include at least one injection needle (e.g., a 31-gauge needle about 5 to 8 mm long) prefilled with one or more therapeutic unit doses of therapeutic solution, intended for rapid delivery of the solution to the subject with minimal pain. One drug delivery pen includes a vial holder for receiving vials of therapeutic agents or other medications. The pen may be a fully mechanical device, or it may be combined with electronic circuitry to accurately set and / or indicate the dosage of medication injected into the user. See, for example, U.S. Patent No. 6,192,891. In some embodiments, the needle of the pen-type device is disposable, and the kit includes one or more disposable replacement needles. Pen-shaped devices suitable for delivering any of the principal components of this invention are also described, for example, in U.S. Patent Nos. 6,277,099, 6,200,296, and 6,146,361, the disclosures of which are incorporated herein by reference in their entirety. Microneedle-based pen-shaped devices are described, for example, in U.S. Patent No. 7,556,615, the disclosure of which is incorporated herein by reference in its entirety. See also the MOLLY™ Precision Pen Injector (PPI) device (manufactured by Scandinavian Health Ltd).

[0073] In some embodiments, the composition described herein may be therapeutically delivered to the subject via local administration. As used herein, "local administration" or "local delivery" may refer to delivery independent of the following: delivery of the composition or agent via a vascular system to its intended target tissue or site. For example, the composition may be delivered by: injection or implantation of the composition or agent; or injection or implantation of a device containing the composition or agent. In some embodiments, after local administration in the vicinity of the target tissue or site, the composition or agent, or one or more components thereof, may diffuse to the intended target tissue or site outside the administration site.

[0074] In some embodiments, the composition may be formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the composition may be formulated for storage at 2 to 8°C (e.g., 4°C) for up to 2 years (e.g., one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, eleven and a half years, or two years). Thus, in some embodiments, the composition described herein is stably stored at 2 to 8°C (e.g., 4°C) for at least one year.

[0075] In some embodiments, the pharmaceutical composition may be formulated as a solution. In some embodiments, the composition may be formulated as a buffer solution, for example, with a concentration suitable for storage at 2 to 8°C (e.g., 4°C).

[0076] Compositions comprising one or more antibodies as described herein can be formulated into immunoliposome compositions. Such formulations can be prepared by methods known in the art. Cycle-time-enhanced lipid systems are disclosed, for example, in U.S. Patent No. 5,013,556.

[0077] In some embodiments, the composition may be formulated with a carrier that prevents rapid release of the compound, such as in controlled-release formulations (including implants and microencapsulated delivery systems). Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid may be used. Many methods for preparing such formulations are known in the art. See, for example, JR Robinson (1978), "Sustained and Controlled Release Drug Delivery Systems," Marcel Dekker, Inc., New York.

[0078] In some embodiments, nucleic acid encoding an antibody is delivered to the subject to achieve antibody delivery as described herein. The nucleic acid encoding the therapeutic antibody described herein may be incorporated into a gene construct for use as part of a gene therapy protocol to deliver nucleic acid that can be expressed in cells and generate antibodies. Such a component's expression construct may be delivered to any therapeutically effective carrier, such as any formulation or composition capable of efficiently delivering the component gene to cells in vivo. Methods include inserting the target gene into a viral vector, including recombinant retroviruses, adenoviruses, adeno-associated viruses, lentiviruses, and herpes simplex virus type 1 (HSV-1), or plasmids of recombinant bacteria or eukaryotes. Viral vectors can be directly transfected into cells; plastid DNA can be delivered with the assistance of, for example, cationic liposomes (lipofectin) or derivatized polyisocyanate conjugates, brevicin S, artificial viral sheaths, or other such intracellular carriers, as well as direct injection of gene constructs or CaPO4 precipitates (see, for example, WO04 / 060407).Suitable examples of retroviruses include pLJ, pZIP, pWE, and pEM, which are known to those of ordinary skill in the art (see, for example, Eglitis et al. (1985) Science 230:1395-1398; Danos and Mulligan (1988) Proc Natl Acad Sci USA 85:6460-6464; Wilson et al. (1988) Proc Natl Acad Sci USA 85:3014-3018; Armentano et al. (1990) Proc Natl Acad Sci USA 87:6141-6145; Huber et al. (1991) Proc Natl Acad Sci USA 88:8039-8043; Ferry et al. (1991) Proc Natl Acad Sci USA). 88:8377-8381; Chowdhury et al. (1991) Science 254:1802-1805; van Beusechem et al. (1992) Proc Natl Acad Sci USA 89:7640-7644; Kay et al. (1992) Human Gene Therapy 3:641-647; Dai et al. (1992) Proc Natl Acad Sci USA 89:10892-10895; Hwu et al. (1993) J Immunol 150:4104-4115; U.S. Patents 4,868,116 and 4,980,286; and PCT Publications WO89 / 07136, WO89 / 02468, WO89 / 05345, and WO92 / 07573. Another viral gene delivery system utilizes adenovirus-derived vectors (see, for example, Berkner et al. (1988) BioTechniques 6:616; Rosenfeld et al. (1991) Science 252:431-434; and Rosenfeld et al. (1992) Cell 68:143-155). Suitable adenovirus vectors derived from adenovirus strain Ad 5 dl324 or other adenovirus strains (e.g., Ad2, Ad3, Ad7, etc.) are known to those skilled in the art.Another viral vector system used for delivering target genes is adeno-associated virus (AAV). See, for example, Flotte et al. (1992) Am J Respir Cell Mol Biol 7:349-356; Samulski et al. (1989) J Virol 63:3822-3828; and McLaughlin et al. (1989) J Virol 62:1963-1973.

[0079] In some embodiments, the compositions provided herein are available in unit dosage forms suitable for self-administration. Such unit dosage forms may be provided in containers, typically such as vials, cartridges, pre-filled syringes, or disposable pens. For example, dosing devices (such as the dosing device described in U.S. Patent No. 6,302,855) may also be used with the injection systems described herein.

[0080] The appropriate dosage of the components described herein (the dosage which can treat or prevent the condition of the subject) may depend on various factors, including, for example, the age, sex, and weight of the subject to be treated, and the specific inhibitory compound used. For example, different dosages of one component including an antibody as described herein may be needed to treat a subject with fibrosis (compared to dosages of different formulations of that antibody). Other factors affecting the dosage administered to the subject include, for example, the type or severity of the condition. Other factors may include, for example, other medical conditions that simultaneously or previously affect the subject, the subject's overall health, the subject's genetic disposition, diet, administration time, excretion rate, drug combination, and any other additional therapeutic agents administered to the subject. It should also be understood that specific dosages and treatment regimens may be adjusted for any particular subject based on the judgment of the treating physician.

[0081] The components described herein may be administered at a fixed dose or at a dose of milligrams per kilogram (mg / kg). In some embodiments, the dose may also be selected to reduce or avoid the generation of antibodies or other host immune responses against one or more of the antigen-binding molecules in the components. Exemplary doses of antibodies (such as the components described herein) include, for example, 0.0001 to 100 mg / kg, 0.01 to 5 mg / kg, 1 to 1000 mg / kg, 1 to 100 mg / kg, 0.5 to 50 mg / kg, 0.1 to 100 mg / kg, 0.5 to 25 mg / kg, 1 to 20 mg / kg, and 1 to 10 mg / kg of the subject's body weight. For example, the dosage may be 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg body weight, or in the range of 1 to 20 mg / kg body weight. An illustrative treatment regimen may require administration once weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months, or initially with short intervals (such as once weekly to once every three weeks) followed by longer intervals (such as once a month to once every three to six months).

[0082] A pharmaceutical solution may include a therapeutically effective amount of the composition described herein. Such an effective amount can be readily determined by those skilled in the art, partly based on the effect of administering the composition, or the combined effect of the composition and one or more additional active agents. The therapeutically effective amount of the composition described herein can also vary depending on factors such as an individual's disease state, age, sex, and weight, and the ability of the composition (and one or more additional active agents) to induce a desired response in the individual (e.g., improvement of at least one condition parameter, such as improvement of at least one symptom of fibrotic disease). For example, a therapeutically effective amount of the composition described herein may inhibit (reduce severity or eliminate occurrence) and / or prevent any symptom of a particular disease and / or any symptom of a particular disease known in the art or described herein. A therapeutically effective amount is also an amount in which the beneficial therapeutic effect outweighs any toxic or adverse effects of the composition.

[0083] The appropriate human dose of any of the components described herein may be further evaluated in, for example, a phase I dose escalation study. See, for example, van Gurp et al. (2008) Am J Transplantation 8(8):1711-1718; Hanouska et al. (2007) Clin Cancer Res 13 (2, part 1):523-531; and Hetherington et al. (2006) Antimicrobial Agents and Chemotherapy 50 (10): 3499-3500.

[0084] The toxicity and therapeutic efficacy of the composition can be determined using known pharmaceutical procedures in cell culture or laboratory animals (e.g., animal models of any fibrotic disease described herein). These procedures can be used, for example, to determine the LD50 (the dose that is 50% lethal in a population) and ED50 (the dose that is 50% therapeutically effective in a population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compositions described herein that exhibit a high therapeutic index are preferred. Although compositions exhibiting toxic side effects can be used, delivery systems that target such compounds to the affected tissue site should be carefully designed, and potential damage should be minimized to the level of normal cells to reduce side effects.

[0085] Those skilled in the art will understand that data obtained from cell culture assays and animal studies can be used to determine dosage ranges for human use. Appropriate doses of the components described herein generally fall within the range of circulating concentrations of the components, including ED50s with little or no toxicity. The dose may vary within this range depending on the dosage form and route of administration used. For the components described herein, the therapeutically effective dose can initially be assessed from cell culture assays. Doses can be established in animal models to achieve circulating plasma concentration ranges, including IC50 (i.e., the antibody concentration at which maximum half-inhibition of symptoms is achieved) as determined in cell cultures. Such information can be used to more accurately determine the useful dose in humans. For example, plasma levels can be measured by high-performance liquid chromatography. In some embodiments, such as for local administration (e.g., to the eye or joint), cell cultures or animal modeling can be used to determine the dose required to achieve therapeutically effective concentrations at the local site.

[0086] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. Furthermore, materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials may be used in the practice or testing of this invention, suitable methods and materials are described herein.

[0087] This disclosure is further illustrated by the following examples. These examples are provided for illustrative purposes only and should not be construed as limiting the scope or content of this disclosure in any way. Example Method: Immunotherapy of Rat Specimens to Generate Novel Antibodies Against α11β1

[0088] Wistar rats were immunized with recombinant human α11β1 protein. Immunoreactivity against the target human and mouse proteins was tested using enzyme-linked immunosorbent assay (ELISA). Subsequently, cell fusion (by electrofusion) was performed on animals that produced a good immune response. All fused cells were seeded in 96-well plates, and the supernatant was screened using an ELISA assay for soluble human and mouse α11β1. Positive lines were counter-screened for human α1β1, α2β1, and α10β1. Lines that specifically bound to human and mouse α11β1 but not to α1β1, α2β1, and α10β1 were selected, secondary-selected, amplified, and cryopreserved. Purified antibodies were then generated from the selected lines, and heavy and light chain variable domain sequences were obtained from each purified antibody. Rabbit immunization.

[0089] Rabbits were immunized using a cell-based monoclonal antibody platform. Two rabbits were immunized with recombinant human α11β1 protein. Spleen cells from the immunized rabbits were sorted and selected for human β1 to reduce β1-specific B cell colonies. The sorted spleen cells were then cultured for approximately one week, and the culture supernatant was screened for binding to human α11β1. The top results were sequenced, and rabbit antibodies were subsequently generated recombinantly using the HEK cell system. Mouse immunization.

[0090] Ten mice from five different strains were immunized using an appropriate mixture of human α11β1, mouse α11β1, and tolerance-disrupting proteins. Plasma titers were assessed by ELISA against a mixture of human and mouse α11β1. Lymph nodes from the popliteal, inguinal, and iliac crests were collected. ELISA-positive anti-human / mouse α11β1 fusion tumors were amplified and subjected to secondary selection against human and mouse α11β1 (control HIS protein), and reverse selection against human α11β1, α2β1, and α10β1. The supernatant IgG concentration was sufficient for functional screening. Selected fusion tumors meeting all criteria were colonized, and colonization was confirmed by ELISA against human and mouse α11β1. These tumors were then amplified, and IgG was purified. The heavy and light chain variable regions of the selected fusion tumors were then sequenced. Phage library display.

[0091] Phage library display was used to generate complete human anti-α11β1 antibodies. Complete human anti-α11β1 antibodies were identified using single-chain fragment variable (scFv) antigen-binding fragments displayed by phages (phage display library). Three rounds of selection were performed on purified human and mouse α11β1 antigens, with deselection for α10β1, to enrich α11 subunit-specific antibodies. The optimal group was then colonized into a bacterial soluble expression vector, inducing recombinant antibody expression, and the supernatant was screened by ELISA testing for binding. Antibodies with appropriate binding profiles were sequenced and subsequently converted from scFv to IgG. ELISA

[0092] 0.25 µg / mL of the target antigen (recombinant human or mouse α11β1) was seeded into 96-well plates (incubated overnight at 4°C). The plates were washed (PBS with 0.1% Tween-20), blocked at room temperature (PBS with 2% BSA and 0.05% Tween-20) for 1 hour, and incubated at room temperature for 1 hour at a series of antibody concentrations. Subsequently, the plates were washed and incubated with biotinylated anti-rabbit / mouse / human IgG (in 1:1000 dilution buffer) for 1 hour at room temperature. After washing the plates, streptavidin HRP (in 1:200 dilution buffer) was added, and the plates were incubated at room temperature for 1 hour. Ultra TMB ELISA substrate solution was added, and the plates were incubated on a plate shaker for 5 minutes. The stop solution was added to each well to terminate the reaction, and the plates were then read at 450 nm. FACS antibody bound to CHO-K1.

[0093] 200,000 cells (wild-type CHO-K1 cells or CHO-K1 cells expressing human α11) were cultured at 4°C for 30 min with each antibody (at the desired concentration, in FACS buffer). Next, the cells were washed with FACS buffer and cultured at 4°C for 30 min with a secondary antibody (1:100 dilution). Then, the cells were washed again and fixed with 1% PFA (in PBS) at room temperature for 20 min; washed again and read on a cell analyzer in FACS buffer. Antibodies bound to HPF / MF...

[0094] Human lung fibroblasts (ScienCell) were cultured in complete fibroblast growth medium (ScienCell) until 80% confluence was achieved in T-150 culture flasks. Cells were washed and collected using Accutase. Cells were seeded at 7,500 cells / cm² (in complete FGF) into T-150 culture flasks and cultured for 72 hours. Cells were then washed and starved in serum-reduced medium for 24 hours. After starvation, cells were treated with TGFβ-1 (R&D Systems) for 72 hours. Cells were collected using Accutase and seeded in 96-well conical trays. Cells were blocked with heat-inactivated fetal bovine serum (Gibco) at 4°C for 30 minutes. Cells were then cultured with anti-α11 antibody (at the doses described in the figures) at 4°C for 30 minutes. Human anti-α11 antibody (Creative BioLabs) was included as a positive control, and appropriate IgG isotype negative controls were included. Cells were washed twice and conjugated with a secondary antibody specific to the test anti-α11 antibody against IgG class IgG, and cultured at 4°C for 30 minutes. Cells were washed twice and fixed in 1% PFA for 30 minutes. Cells were obtained by binding to the FACS Verse (Benton Dickson) of each antibody. Single cells were gated in the PE channel of each sample, and the geometric mean fluorescence intensity (gMFI) was determined for data analysis. Surface plasma resonance (SPR) was also performed.

[0095] The affinity of the antibody for human α11β1 was measured using surface plasma resonance (SPR). Affinity was measured at pH 7.6 and 25°C using a Biacore T200 instrument. The anti-HIS antibody was immobilized on the surface of the SPR sensor using EDC / NHS covalent attachment. HIS-labeled human α11β1 was captured on the sensor surface and kinetics were determined using a single-cycle assay. Increasing concentrations of the test antibody were sequentially injected onto the α11β1 bound to the sensor. Dissociation was monitored for 1000 seconds. Data were subtracted under dual reference using a sensor surface containing only the anti-HIS antibody and a series of blank injections. A 1:1 Langmuir model was fitted to the data to assess the kinetic association and dissociation constants. The interaction affinity (equilibrium dissociation constant) was calculated by dividing the kinetic dissociation constant by the kinetic association constant. Between injection cycles, α11β1 and the bound antibody system were removed by injection of 10 mM glycine (at pH 1.5). Cell adhesion inhibition

[0096] Cells were cultured at 37°C for 20 minutes at 0.6 × 10⁶ cells / mL with various antibodies (at a series of concentrations). E-Plate VIEW 96 PET plates, spread overnight at room temperature with 100 ng / mL type I collagen or PBS, were then blocked with 3% BSA at room temperature for 1 hour. After washing the plates with PBS, the cell-antibody mixture was added to the wells, and the plates were placed in an xCelligence instrument. Cell adhesion was recorded over 6 hours. The time point of maximum cell adhesion was used for comparison with the control group. Fibroblast-to-myofibroblast transition (FMT)

[0097] Human lung fibroblasts were cultured in complete fibroblast growth medium (ScienCell) until 80% confluence was achieved. Cells were washed and collected using Accutase. Cells were seeded at 20,000 cells / well (in complete fibroblast growth medium) onto tissue culture-treated 96-well plates. After 24 hours, cells were washed and starved in serum-reduced medium for an additional 24 hours. After starvation, cells were treated with TGFβ-1 (R&D Systems) (with or without anti-α11 antibody). Multiple rabbit anti-human α11 antibodies were used as a positive control. An appropriate IgG isotype control group was also included. After 48 hours, cells were collected, fixed, permeabilized, and stained with Alexa Fluor 488 for anti-αSMA (α-smooth muscle actin) (Invitrogen). Cells were obtained using FACS Verse (Benton Dickson) to determine the expression level of αSMA. In the FITC channel of each sample, single cells were selected and the geometric mean fluorescence intensity (gMFI) was determined for data analysis. The gMFI of each sample was normalized relative to the untreated control group and presented as inhibition % . Collagen gel shrinkage assay

[0098] The 24-well discs were blocked overnight at 37°C with 2% BSA (in BSA). The next day, the discs were washed three times with PBS before use for assay. Human CHO cells expressing α11 were collected and resuspended at 1.25 × 10⁶ cells in ExpiCHO expression medium (Gibco™ catalog number A2910002). 3 mg / mL stock collagen type I (Gibco™ collagen I rat protein, tail catalog number A1048301) was diluted to 1 mg / mL in the medium containing CHO cells to prepare a collagen gel solution. Sodium hydroxide was added to the solution to neutralize the pH, and 400 µL of the collagen solution was added to each well of the 24-well disc. In the wells, the collagen gel solution contained antibodies, with the CHO cell line prepared at 2.5 × 10⁶ cells and the antibody system prepared at 2x the final concentration (in ExpiCHO medium). Cells and antibodies were then combined 1:1, followed by the addition of reserve collagen type I. The gel was allowed to polymerize at 37°C for 60 minutes. Antibodies were added to ExpiCHO medium, which was then layered on top of the polymerized gel (400 µL / well). The gel was incubated at 37°C for 6 days, and gel shrinkage was quantified. Image J was used to analyze images of each well, and gel shrinkage was determined as a percentage of the initial gel area. (Tumor xenograft model)

[0099] Fifty-six female CB-17 SCID mice were subcutaneously inoculated with A549 cells (5 × 10⁶ cells / mouse) into the flank. Once the tumor volume reached ~100 mm³, the animals were randomly assigned to 7 groups (n=8 per group). The mice were then treated intraperitoneally with either the isotype control group or novel mAbs 79E3E3, 16E10, and 9G04 (2 and 20 mg / kg) every 3 days for a total of 7 doses; or European paclitaxel (at 10 mg / kg) every 4 days for a total of 6 doses. Tumor volume and body weight were recorded twice a week, with an interval of 2 to 3 days between measurements, until any of the following criteria were observed: a weight loss of 20% or more; a tumor that inhibits normal physiological functions (such as eating and movement); an ulcerative tumor; a tumor size greater than 2000 mm³, and clinical prostration, paralysis, seizures, and hemorrhage were observed. Precision-cut liver slices (PCLS)

[0100] Precisely cut liver sections (PCLS) were prepared from resected liver tissue and allowed to stand for 24 hours to allow the post-slicing stress period to pass before the start of experiments. PCLS were cultured under the following conditions: no exogenous stimulation (Group 1); with 100 µg / mL control antibody (Groups 2 and 3: mouse IgG2a or rabbit IgG); or with a combination of TGF-β1 (3 ng / mL) and PDGF-ββ (50 ng / mL) (Groups 2 to 10). PCLS were cultured with or without 10 µM Alk5i (Group 4) as a positive control or with two incremental doses (10 and 100 µg / mL) of novel inhibitors (16E10, 79E3E3, and 9G05) (in Groups 5 to 10). Each of the 10 groups included n=6 human PCLS prepared from a single human liver. PCLS culture medium (including all stimuli and compounds) was refreshed and collected at 24-hour intervals. Cell culture supernatant was collected every 24 hours (n=2 / 3 of the wells) and rapidly frozen for quantitative soluble output. All PCLS were collected over 96 hours.

[0101] At all time points, tissue culture levels of markers of liver injury (lactate dehydrogenase (LDH) and aspartate transaminase (AST)) and hepatocyte function / viability (albumin) were quantified for all PCLS. Albumin secretion was quantified by ELISA as a marker of PCLS integrity and function. The levels of collagen 1α1, IL-6, hyaluronic acid, and Timp-1 in cell culture supernatant were quantified using the R&D Duoset ELISA kit.

[0102] Total RNA was extracted from all samples using PCLS. RNA was extracted using RNeasy Mini kits (Qiagen). The RNA lines were reverse transcribed into cDNA and used for qPCR to measure transcript levels of Col1a1, αSMA, TIMP-1, TGF-β1, IL-6, and β-actin / GAPDH. Precisely cut kidney sections (PCKS) were then analyzed.

[0103] PCKS were prepared from explanted fibrotic human kidney tissue and allowed to stand for 24 hours to allow the post-section stress period to pass before the start of the experiment. PCKS were cultured with TGF-β1 (3 ng / mL) and PDGFββ (50 ng / mL) in the presence or absence of Alk5i (10 µM, positive control), three doses (1, 10, and 50 µg / mL) of anti-α11β1 antibody, or in the presence of IgG control antibody (single high dose). PCKS culture medium was collected every 24 hours (a total of 3 time points). The level of collagen type I α1 (col1a1) in the tissue culture supernatant was quantified using the R&D Duoset ELISA kit. Statistical analysis was performed using a two-factor ANOVA followed by a Dunnett multiple comparison test. Example 1. Generation of novel monoclonal antibodies against α11β1 and determination of binding affinity.

[0104] Recombinant human α11β1 was used to immunize rats and rabbits, and both human and mouse α11β1 were used to immunize mice for antibody discovery. Fifty-one novel anti-human α11β1 monoclonal antibodies were generated (24 rabbits, 7 rats, and 20 mice). The heavy and light chain variable region sequences of the mouse and rat antibodies were determined, while the complete heavy and light chain sequences of the rabbit antibody were determined.

[0105] The ELISA results illustrating the exemplary binding of selected mouse monoclonal antibodies to recombinant human α11β1 are shown in Figure 2A. The three mAbs also bound to mouse α11β1, as shown in Figure 2B.

[0106] Data were also collected to determine whether the antibody of interest bound to the I domain of α11β1. The self-generated I domain of α11β1 was used. Rat strains 79E3E3, 8H8E9, and 6E5C11 showed high, medium, and low binding, respectively (as determined by ELISA). Binding of mouse antibodies 10-F23, 10-L15, 7-O8, 6-A12, 9-G05, and 9-E16, and rabbit antibodies 7-H12 and 2-D3 to the self-generated I domain of α11β1 was also tested. Figures 3A and 3B illustrate the binding data from the exemplary mAbs.

[0107] α11β1 belongs to the collagen receptor family and is highly homologous to these collagen receptors. Therefore, the novel antibody of this invention underwent reverse screening against α1β1, α2β1, and / or α10β1. Table 2 includes the results of cross-reactivity with other receptors. Table 2. Summary of data from tested monoclonal antibodies propagation ID Humans α11β1 ELISA rodents α11β1 ELISA Deviation Target (Off Target) I domain Combination CHO-K1 FACS HPF FACS MF FACS CHO-K1 Collagen White sticky Wear it inhibition FMT Suppression CHO-K1 Gel contraction inhibition mice 10-L15 yes yes no yes no no no no no 8-I14 yes yes no no yes no yes no yes no 3-G5 yes Yes / Low no no no no no no no 2-A3 yes Yes / Low no no no no no no no 8-G15 yes no no no yes no yes yes yes 8-P20 yes no no no yes no yes no no 10-F23 yes Yes / Low no yes yes no yes yes no 7-O8 yes Yes / Low yes (α10β1) yes yes no yes no no 8-J17 yes no yes (in high) Dosage Down) no yes no yes no yes 9-E16 yes yes no yes yes Low yes yes yes 9-G05 yes yes no yes yes no yes yes yes yes 10-K10 yes Yes / Low no no no no yes no no 6-O12 yes no no no no no no no no 6-A15 yes Yes / Low no no no no no no no 6-B21 yes Yes / Low no no no no no no no 6-A12 yes Yes / Low no yes yes no yes yes no 6-M8 yes no no no no no no no no 6-P20 yes no no no yes no no no no 6-O17 yes Yes / Low no no yes no yes no no 9-B11 yes no no yes yes no yes yes yes no 7-H14 yes Yes / Low no no yes no yes no no rats 24E4G6 yes No / Low no no yes no yes no yes yes 40G10 H11 yes yes yes (all) no yes N / A N / A yes yes 18E10 F10 yes no no no yes N / A N / A yes yes 8H8E9 yes no no no yes N / A N / A yes yes 6E5C11 yes no no no yes N / A N / A no yes 7D8B10 yes no no no yes no yes no yes 79E3E3 yes yes no yes yes no yes yes no yes rabbit 16E10 yes no no no yes no yes yes yes yes 6F9 yes no no no yes no yes yes no 6G4 yes no no no yes no yes yes no 4E1 yes no no no yes no yes yes no 6C7 yes no no no yes no yes yes no 5D7 yes no no no yes no yes yes no 5A7 yes no no no yes no yes yes no 3B1 yes no no no yes no yes yes no 16G7 yes yes no no yes no yes no yes no N / A = Untested

[0108] Since integrins are large transmembrane receptors that exist in different conformations, experiments were conducted to confirm that novel antibodies also bind to α11β1 expressed by cells. The CHO-K1 cell line, which endogenously expresses high levels of the β1 subunit, was engineered to stably express human α11 (CHO-K1 hu α11).

[0109] Figures 4A and 4B show the selected rat and mouse mAbs, which bind human α11β1 (as tested by ELISA) and also demonstrate their binding ability to α11β1 expressed on the surface of CHO-K1 cells. Figures 11A and 11B show the selected rabbit, rat, mouse, and human mAbs, which demonstrate their binding ability to α11β1 expressed on the surface of CHO cells. Furthermore, Figure 14 shows the selected intact human mAbs, which demonstrate their binding ability to α11β1 expressed on the surface of CHO cells. However, as shown in Table 1, several mAbs showed binding to α11β1 by ELISA but not to cellularly expressed α11β1.

[0110] Data obtained from fluorescence-activated cell sorting (FACS) of CHO-K1 hu α11β1 cells were used to evaluate EC50 binding. The results are shown in Table 3. Of the six tested mAbs, four had low nemerore EC50 results (8-P20, 8-G15, 8-J17, 8-l14), while the remaining two mAbs were not so effective (9-G05 and 9-E16; both are I-domain binders). Table 3. CHO-K1 binding EC50 evaluated against mouse mAbs mAb Concentration (µg / mL) mole concentration (nM) 9-G05 21.03 140.2 8-P20 0.12 0.8 8-G15 0.22 1.5 8-J17 0.33 2.2 8-I14 1.22 8.1 9-E16 42.80 285.3

[0111] As shown in Figure 9, when antibodies 16E10, 79E3E3, 9G05, and 1994_01_C07 were tested for their affinity for human α11β1 via surface plasma resonance (SPR), they exhibited KD values ​​of 48 pM, 10 pM, 2.85 nM, and 0.77 nM, respectively. Interestingly, 16E10 and 1994_01_C07 did not bind to the I domain or head domain of α11β1, indicating that they may bind to the ligand-binding domain but still inhibit α11β1 function, acting as ectopic inhibitors. 9G05 and 79E3E3 did not bind to the I domain (ligand-binding domain), and therefore could directly inhibit the ligand binding site. The antibodies' affinity for the α11β1 head domain and α11β1 I domain (as measured by SPR) are shown in Figures 10A and 10B, respectively.

[0112] Binding to physiologically relevant primary human cell types was also tested. Human lung fibroblasts (HPF) were treated with TGFβ to induce fibroblast-to-myofibroblast transition (FMT), resulting in myofibroblasts (MF). Although HPF did not express α11β1, MF showed significant expression of α11β1. Furthermore, HPF expressed α1β1 and α2β1 (other collagen-binding receptors), meaning that HPF could be used to test the cross-reactivity of the antibody of interest. The binding of the selected mAb to HPF and MF was evaluated, and as shown in Figures 5, 12, and 13, it is evident that the test antibody strongly bound MF but not HPF (except for 9-E16), showing some HPF binding (indicating deviated binding). Example 2. Bioactivity of novel monoclonal antibodies against α11β1

[0113] Myofibroblasts are responsible for secreting fibrotic matrix (MF), therefore blocking and / or reducing MF accumulation is an important step in the treatment and / or prevention of fibrosis. This can be achieved by using anti-α11β1 antibodies to inhibit the fibroblast-to-myofibroblast transition. General functional inhibitors of receptors block ligand binding, and while preventing α11β1 binding to type I collagen is the desired feature of anti-α11β1 antibodies, it may not be necessary for therapeutic efficacy. Unlike many other receptors, integrins are capable of both "outside-in" (typically ligand-mediated) and "inside-out" communication. Therefore, antibodies may bind to α11β1 in a way that affects the structure of α11β1 in a manner that prevents inside-out communication and MF, without affecting α11β1's ability to bind to type I collagen. Therefore, these studies include both mAbs that block ligand binding and mAbs that do not block ligand binding.

[0114] The ability of mAbs to block α11β1-mediated binding to type I collagen was evaluated using the CHO-K1 hu α11 cell line. As shown in Figure 6A, two of the three tested rat mAbs significantly inhibited the adhesion of CHO-K1 hu α11 cells to discs coated with type I collagen. In the "untreated" condition, cells were seeded onto type I collagen without antibody addition, while in the "uncoated" condition, cells were seeded into wells coated with BSA (without type I collagen). Statistical analysis was performed using a single-factor ANOVA followed by a Dunnett multiple comparison test. 79E3E3 (its type I domain binder) blocked cell adhesion with an IC50 of 9.4 nM. However, 40G10H11 strongly inhibited cell adhesion, despite its cross-reactivity with other collagen receptors (α1β1, α2β1, and α10β1), but it was not found to be an I-domain binder. 24E4G6 did not bind to the I-domain and did not inhibit cell adhesion to collagen. When rabbit mAbs were tested, eight of the nine mAbs strongly and significantly inhibited cell adhesion, and none of these mAbs were found to be I-domain binders (Figure 6B). Therefore, these mAbs may bind to the α11β1 domain, keeping integrins in a low or intermediate affinity state. Figure 6C shows the activity of the selected mouse mAbs. Three of the six mAbs significantly blocked cell adhesion, and two of these mAbs were found to be I-domain binders (9-G05 and 9-E16). However, 8-G15 was a strong inhibitor of cell adhesion, but it was not found to bind to the I-domain. 8-P20, 8-J17, and 8-I14 did not block cell adhesion to type I collagen. The ability of nine human mAbs to inhibit the binding of human CHO-α11 cells to type I collagen was also tested. As shown in Figures 15A and 15B, all human Abs inhibited cell adhesion compared to the control group, with 1994-01-C07 exhibiting an IC50 of 3.3 nM. These data (and the summary in Table 1) indicate that some anti-α11β1 mAb lines were found to bind strongly to human α11β1 (when tested by ELISA and FACS), but not all of these antibodies were able to block ligand interactions. Furthermore, binding to the I domain (the ligand-binding domain on α11β1) was found to be unnecessary for blocking the interaction between α11β1 and type I collagen.

[0115] In addition to the binding ability mentioned above, the ability of anti-α11β1 antibodies to inhibit fibroblast-to-myofibroblast transition (FMT) is important. Myofibroblasts are understood to be a heterogeneous cell population existing in various activation states, whose main function is the production and contraction of collagen extracellular matrix (ECM). FMT is a multi-step event controlled by changes in the mechanical environment within tissues undergoing repair. TGFβ is an effective factor enabling this process, while α-smooth muscle actin (αSMA) is a major marker that becomes overexpressed during the transition from fibroblasts to myofibroblasts. The presence of αSMA enhances fibroblast contraction and guides myofibroblast activation (through intracellular feedback loops). Because αSMA is a major molecular marker of myofibroblasts, the ability of novel anti-α11β1 mAb to inhibit αSMA expression in TGFβ-induced FMT was tested.

[0116] As shown in Figure 7A, compared to the control, both rat mAbs (40G10H11 and 24E4G6) significantly inhibited αSMA expression, but neither antibody was found to be a domain I binder. Statistical analysis was performed using a single-factor ANOVA followed by a Dunnett multiple comparison test. Furthermore, only 40G10H11 inhibited cell adhesion to type I collagen. Interestingly, 79E3E3 mAb was found to be a domain I binder and strongly inhibited cell adhesion to collagen, but it did not reduce αSMA expression (targeting myofibroblast-produced substitutes). As shown in Figure 7B, compared to the control, both rat mAbs significantly inhibited αSMA expression, but neither antibody was found to be a domain I binder. The 16E10 line was found to inhibit ligand binding and FMT (inhibition of αSMA upregulation %), while the 16G7 line was found to inhibit FMT but did not affect cell adhesion to collagen. Finally, as shown in Figure 7C, five of the six tested mouse mAbs significantly inhibited αSMA expression compared to the control group. Three FMT inhibitors (9-G05, 8-G15, 9-E16) were also found to reduce cell adhesion to collagen, and two of them (9-G05, 9-E16) also bound to the I domain. Mouse antibodies 8-J17 and 8-I14 only inhibited FMT, but had an effect on ligand binding. Example 3. The ability of selected antibodies to inhibit cell-mediated collagen gel contraction.

[0117] Cell-mediated CD collagen I gel contraction is, as previously shown, an α11β1-mediated process, and more recent studies have shown that α11β1-mediated downstream signaling is indispensable for gel contraction. The ability of the selected exemplary antibody to inhibit cell-mediated 3D gel contraction was tested (because this ability is directly related to the functionality of the exemplary antibody).

[0118] As shown in Figure 8, antibodies against rat 79E3E3, mouse 9E16, 9G05, and 8I14, rabbit 16E10, and human 1994_01_C07, 2004_04_B03, 2004_04_C12, and 1994_01_D12 all inhibited CHO-hu α11-mediated collagen gel contraction. Notably, CHO-hu α11 cells were able to induce collagen gel contraction without the addition of TGFβ, as shown in the UT (untreated) condition. In the untreated condition, cells were embedded in collagen gel without the addition of antibodies. Statistical analysis was performed using a single-factor ANOVA followed by a Dunnett multiple comparison test; each treated condition was compared with the untreated condition. An asterisk indicates statistical significance, and "ns" indicates no statistical significance. Example 4. Evaluation of the effect of selected antibodies on tumor xenograft growth.

[0119] Previous studies have shown that A549 cell xenograft growth in α11 knockout SCID mice is significantly inhibited compared to wild-type mice. In this case, an investigation was conducted to determine whether inhibition of α11β1 function with mAbs leads to xenograft growth inhibition. As shown in Figure 16 and Table 4, blocking α11β1 on mouse CAFs inhibited xenograft growth in SCID mice. Specifically, compared to the isotype control group, 79E3E3 (an effectless mAb that cross-reacts with mouse α11β1) significantly inhibited tumor growth, while 16E10 (an mAb that does not inhibit mouse α11β1) did not show significant inhibition of tumor growth. Since 16E10 showed no effect, inhibition of α11β1 in the tumor did not affect tumor growth. Table 4. Days to achieve volume doubling after mAb treatment treat Number of days to achieve volume doubling (average, 95% CI) mouse IgG2a 7.6 (7.3, 8.0) European paclitaxel 11.0 (10.0, 12.0) 79E3E3 2mpk 8.5 (8.0, 9.0) 79E3E3 20mpk 8.5 (8.0, 9.0) 16E10 2mpk 7.9 (7.5, 8.3) 16E10 20mpk 7.9 (7.5, 8.3) Example 5. Effect of anti-α11β1 antibody on precision-cut human liver sections (PCLS)

[0120] Precision cut liver slices (PCLS) from human liver tissue are physiologically and histologically representative of tissue structure, and testing therapeutic targets in human PCLS allows for the assessment of their effectiveness and relevance to clinical situations, overcoming the limitations of in vivo rodent models and in vitro 2D cell culture methods. Tissue bioreactor technology enables PCLS from human liver tissue to maintain viability and function in vitro for at least 6 days.

[0121] As shown in Figures 17A to 17C, all tested anti-α11-β1 antibodies provided partial inhibition of soluble fibrillary markers (COL1A1, hyaluronic acid, and TIMP1) in a dose-dependent manner or at the highest tested dose. No toxicity was observed after treatment with any antibody (i.e., no increase in ALT, AST, or albumin; data not shown). Example 6. Effect of anti-α11β1 antibodies on human precision-cut kidney sections (PCKS).

[0122] Precision cut kidney sections (PCKS) were prepared from human kidney tissue with moderate fibrosis. After standing for 24 hours, PCKS were cultured with a novel anti-α11β1 monoclonal antibody at different doses over time. The PCKS culture medium was collected at each time point. RNA was subsequently extracted from each tissue section. In the culture medium, a series of profibrotic mediators were measured as secreted proteins (including but not limited to COL1A1, fibronectin, PAI-1, IL-11, CXCL1, MCP-1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, and MMP9), and also at the transcriptional level (including but not limited to COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, aSMA, and ITGA11).

[0123] As described above, PCKS were prepared from explanted fibrotic human kidney tissue and allowed to stand for 24 hours to allow the post-section stress period to pass before the start of the experiment. PCKS were cultured with TGF-β1 (3 ng / mL) and PDGFββ (50 ng / mL), with or without Alk5i (10 µM, positive control), at three doses (1, 10, and 50 µg / mL) of anti-α11β1 antibody, or in the presence of IgG control antibody (single high dose). PCKS culture medium was collected every 24 hours (a total of 3 time points). The level of collagen type I α1 (col1a1) in the tissue culture supernatant was quantified using the R&D Duoset ELISA kit. Statistical analysis was performed using a two-factor ANOVA followed by a Dunnett multiple comparison test.

[0124] As shown in Figures 18A to 18C, each anti-α11-β1 antibody provided significant inhibition of col1a1 secretion at at least one time point at at least one dose. The novel mAb 1994_01_C07 significantly inhibited col1a1 secretion at 72 and 96 hours at each tested dose. This is an important finding because type I collagen deposition is a major cause of fibrotic tissue. Example 7. Effect of anti-α11β1 antibody on an in vivo model of renal fibrosis.

[0126] In SEQ ID NO: 117 to 144, CDR3 is indicated in bold and underlined. 6-O12 Heavy chain variable region EVKLEESGGGLVQPGGSMKLSCAASGFTFSDAWMDWVRQSPEAGLEWVAEIRNKAHNPATYYAESVKGRFTISRDDSKSSVYLQMNSLRAEDTGIYYCTLVAPDAMDYWGQGTSVTVSS (SEQ ID NO: 117) 6-O12 Light chain variable region DIVMSLSPSSLAVSVGEKVTMSCKSSQSLLYSRNQKNYLAWYQQKPGQSPKLLIYWASTRASGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPYTFGGGTKLEIK (SEQ ID NO: 118) 10-L15 heavy chain variable region QVQLQQSGPELVRPGASVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGMIDPSNSETWLNQKFKDKATLNVDKSSNTAYMQLSSLTSEDSAVYYCARYDGYYDYWGQGTTLTVSS (SEQ ID NO: 119) 10-L15 light chain variable regionNIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNVESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQNNEDPWTFGGGTKLEIK (SEQ ID NO: 120) 7-H14 Heavy chain variable region QVQLQQPGAELVRPGASVKLSCKPSGYTFTSYWMNWVKQRPGQGLEWIGMIDPSDSETHYNQMFKDKATLTVDKSSNTAYMQLSSLTSEDSAVYYCAQIYYAYDKAYWGQGTLVTVSA (SEQ ID NO: 121) 7-H14 Light chain variable region DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSSHQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFSLTISSVKAEDLAVYYCQEYYSWTFGGGTKLEIK (SEQ ID NO: 122) 6-B21 Heavy chain variable regionEVQLQQSGPELVKPGASVKISCKASGYTFTDYYMNWVKQSHGKSLEWIGDINPHNGGTSFIQKFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYCAPLGRKEGFAYWGQGTLVTVSA (SEQ ID NO: 123) 6-B21 variable region of light chain DTVLTQSPASLVVSLGQRATISCRASKSVSTSGYSYMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSGTAFTLNIHPVEEEDAATYYCQHSRELPYTFGGGTKLEIK (SEQ ID NO: 124) 10-F23 variable region of heavy chain QVTLKESGPGILQPSQTLSLTCSFSGFSLSTFAMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPALKSRLTISKDTSKNHVFLKIANVDTADTATYYCARMPLTFYFDYWGQGTTLTVSS (SEQ ID NO: 125) 10-F23 variable region of light chain DVLLTQTPLSLPVSLGDQASISCRSSQSIVHSNGHTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPFTFGGGTKLEIK (SEQ ID NO: 126) 6-A12 variable region of heavy chain QVTLKESGPGILQPSQTLSLTCSFSGFSLRTFAMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPALKSRLTISKDTSKNQVFLKIANVDTADTATYYCARMPLTFYFDYWGQGTTLTVSS (SEQ ID NO: 127) 6-A12 variable region of light chain DVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSTRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPFTFGGGTKLEIK (SEQ ID NO: 128) 6-M8 variable region of heavy chain QVQLQQPGAELVMPGASVKLSCKASGYTFTNYWMHWVKQRPGQGLEWIGEIDPSDSYTNYNQKFKGKATLTVDKSSSTAYMQLSSLTSEDSAVYYCTRQGSTYAWGQGTSVTVSS (SEQ ID NO: 129)6-M8 light chain variable region: DIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLELPPTFGGGTKLEIK (SEQ ID NO: 130) 2-A3 heavy chain variable region: EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMMWVKQSHGKSLEWIGDINPYNGGSSYNPKFKGRATLTVDKSSSTAYMQLNSLTSEDSAVYYCARGTYWGQGTLVTVSA (SEQ ID NO: 131) 2-A3 light chain variable region: DVVMTQTPLTLSVTIGQPASISCKSSQSLLDSAGKTYLNWLLQRPGQSPKRLMYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPYTFGGGTKLEIK (SEQ ID NO: 132) 6-O17 heavy chain variable region: QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWIKQRPGQGLEWIGEINPSNGGSNYNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYHCKSRGYWGQGTTLTVSS (SEQ ID NO: 133) 6-O17 light chain variable region: DVVMTQTPLTLSVTIGQPASISCKSSQSLLDSYGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPHTFGSGTKLEIK (SEQ ID NO: 134) 3-G5 heavy chain variable region: QVQLQQSGAELARPGASVKLSCKASGYTFTSYGISWVKQRTGQGLEWIGEIFPRSSNTYYNEKFKGKATLTADKSSSTVYMEFRSLTSEDSAVYFCAREGGLAWFAYWGQGTLVTVSA (SEQ ID NO: 135) 3-G5 light chain variable region: DVVMTQTPLTLSVTIGQPASISCKSSQSLLYTNGNTYLNWLLQRPGQSPKRLIYLVSKLDSGIPDRFSGSGSGTDFTLRISRVEAEDLGVYYCLQSTHFPFTFGSGTKLEIK (SEQ ID NO: 136) 6-A15 heavy chain variable regionEVQLQQSGPELVKPGASVKMSCKASGYTITDYYMMWLKQSHGKSLEWIGDINPYTGGTSYNQKFKGKATLTVDKSSSTAYLQLHSLTSEDSAVYYCARGAYWGQGTTLTVSS (SEQ ID NO: 137) 6-A15 light chain variable region DVVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPYTFGGGTKLEIK (SEQ ID NO: 138) 10-K10 heavy chain variable region EVQLQQSGPELVKPGASVKMSCKASGYTITDYYMMWLKQSHGKSLEWIGDINPYTGGTSYNQKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARGAYWGQGTTLTVSS (SEQ ID NO: 139) 10-K10 light chain variable region DVVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPYTFGGGTKLEIK (SEQ ID NO: 140) 6-P20 heavy chain variable region EVQLQQSGPELVKPGASVKISCKASGYTFTDYYMNWVKQSHGRSLELIGDINPNNGGSNFNQKFRGKATLTVDKSSSTAYMELRSLTSEDSAIYYCARMGYWGQGTLVTVSA (SEQ ID NO: 141) 6-P20 light chain variable region DVVMTQTPLTLSVTIGQPASISCKSSQSLLHSDGKTYLNWMFQRPGQSPKRLIYLVSKLDSGVPYRFTGGGSGTDFTLQISRVETEDLGVYYCWQGTHFPRTFGGGTKLEIK (SEQ ID NO: 142) 7-O8 heavy chain variable region EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYIHWVKQKPGQGLEYIGEIYPGSGNTYYNGKFRGKATLTADKSSSTAYMQLSSLTSEDSAVYFCGSGYFDYWGQGTTLTVSS (SEQ ID NO: 143) 7-O8 light chain variable regionDVVMTQTPLTLSVTIGQPASISCKSSQSLLYSNGKTYLNWLLQSPGQSPKLLIYLVSKLESGVPDRFSGSGSGTDFTLKLSRVEAEDLGVYYCVQGTHFPFTFGSGTKLEIK (SEQ ID NO: 144) Rabbit mAb sequence A11B1_16G7 heavy chain METGLRWLLLVAVFKGVQCQEQLVESGGDLVKPGASLTLTCTASGFSFNKNYWMCWVRQAPGKGLEWIGCIYNGDGNTYYASWVNGRFTISKTSSTTVTLQMTSLTVADTAIYFCARLLNMWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 159) A11B1_16G7 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYTAATLASGVPSRFSGSGSGTEFTLTISGVQCDDAATYYCQSYYFTSVSSYGNAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 160) A11B1_16E10 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCRVSGFSFSSSYYMCWVRQAPGKGLEWIACIGTTRGSTYYATWAKGRFTISKISSTTVTLQMTSLTDADTATYFCARDATGYRINTIGLYFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 161) A11B1_16E10 light chain MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVEAAVGGTPTIKCQASQTIYSYLSWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISDLECADAATYYCQSYHGTASTEYNTFGGGTEVVVRGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 162) A11B1_15G10 heavy chainMETGLRWLLLVAVLKGVQCQQQLVESGGGLVKPGAALTFTCTASGFSFSGNYWICWVRQAPGKGLEWIACIGTITSRTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGAVVSSGNAPYYFTLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 163) A11B1_15G10 light chain MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVEAAVGGTVTIKCQASQSISSYLSWYQQKPGQPPKLLIYRASTLESGVPSRFKGSGSGTEFTLTISDLECADAATYFCQSYYGVTFSGFAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 164) A11B1_14H1 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCKASGIDFNNYWITWVRQAPGKGLEWIACIYVGITGRTWYANWAKGRFTISKASSTVDLKMTSLTAADTATYFCARNGDGGIYALNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 165) Light chain of A11B1_14H1 MDTRAPTQLLGLLLLWLPGATFAQVLTQTASSVSAAVGGTVTISCQSSQSVYNNNWLAWYQQKPGQPPKLLIYRASTLTSGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGYSGNIYVNDFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 166) Heavy chain of A11B1_13G4METGLRWLLLVAVLKGVQCQEQLEESGGDLVKPGGSLTLTCKASGFSFSNTYWACWVRQAPGKGLEWIACMNPASSGSSYYASWAKGRFTISKTSSTTVTLHMPSLTAADTATYFCAKWDTAFDVWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 167) Light chain of A11B1_13G4 MDTRAPTQLLGLLLLWLPGARCADVVMTQTPSSVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKLLIYGASNLESGVPSRFKGSGSGTEYTLTISGVQCDDAATYYCQNYYAIDTYGHAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 168) Heavy chain of A11B1_13C3METGLRWLLLVAVLKGVQCQEQLEESGGDLVKPGASLTLTCTASGFSFSSNYHICWVRQAPGKGLELIACIYVGDGSTYYASWAKGRFTISKSSSTTVALQMTSLTAADTATYFCGRMFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 169) A11B1_13C3 light chain MDTRAPTQLLGLLLLWLPGAICDPVLTQTPSSVSAAVGVTVTINCQSSPSVYSNYLSWYQQKPGQPPKLLIYLASTLASGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAGTYSGNIWSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 170) A11B1_12F2 heavy chainMETGLRWLLLVAVLKGVQCQQQLVESGGGLVKPGASLTLTCTASGFSFSSGYHMCWVRQAPGKGLEWIACFGVYTGTTTYASWAKGRFTISKTSSTTVTLQMTSLTVADTATYFCARISAENGGDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 171) A11B1_12F2 light chain MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASQSISNYFSWYQQKPGQPPKLLIYRASTLASGVPSRFSGSGSGTEFTLTISDLECADSATYYCQCTYGSSSTGFGFGGGTEVVVKGDPVAPTVPIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 172) A11B1_11D10 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCMASGIDFSSGYGMWWVRQAPGKGLEYIGYIDTGDDNTYYANWAKGRFTISKTSSTTVTLQMTSLTVADTATYFCAKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 173) A11B1_11D10 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQRPKLLIYRASTLKSGVPSRFKGSGSGTEYTLTISDLECADAATYYCQAYYLSSSISYGNTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 174) A11B1_10F9 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGFSLSSGYGMCWVRQAPGKGLEWIGYTDTATGTIHYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAKGGAMDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 175) Light chain of A11B1_10F9 MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKLLIYRTSTLASGVPSRFKGSGSGTEYTLTISDLECADAATYYCQSYAYSSSSSYGNAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 176) Heavy chain of A11B1_7H12METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTGSGIDFSSSYWICWVRQAPGKGLEWIACIDGSDGNTYYASWARGRFTISKTSSTTVTLQMASLTAADTATYFCTRDLRLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 177) A11B1_7H12 light chain MDTRAPTQLLGLLLLWLPGARCADIVLTQTPASVSAAVGGTVTINCQASQNVYSNNALAWHQQKPGQRPNLLIYKASTLASGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCLGEFSCSSGDCFVFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 178) A11B1_7G12 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCMASGIDFSSGYGMWWVRQAPGKGLEYIGYIDTGDDNTYYANWAKGRFTISKTSSTTVTLQMTSLTVADTATYFCAKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 179) A11B1_7G12 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQRPKLLIYRASTLKSGVPSRFKGSGSGTEYTLTISDLECADAATYYCQAYYLSSSISYGNTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 180) A11B1_6G4 heavy chainMETGLRWLLLVAVLKGVQCQQQLEESGGGLVKPGGTLTLTCKASGVALNPYYYMCWVRQAPGKGLEWIACVDADSSGSTYYASWAKGRFTISKTSSTTVTLKMTSLTAADTATYFCARESVDYSSVGIGYVHGTDGLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 181) A11B1_6G4 light chain MDTRAPTQLLGLLLLWLPGARCADIVVTQTPSSVSAAVGGTVTIKCQASQSISNYFSWYQQKPGQPPKLLIYRASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGRSNSNFFYGFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 182) A11B1_6F9 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGSSFSSTYWNCWVRQAPGKGLEWIACINAGSGTTYYASWAKGRFTVSKTSSTTVTLQMTSLTAADTATYFCTRDSDGRFSSGYYFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 183) A11B1_6F9 light chain MDTRAPTQLLGLLLLWLPGATFAQVLTQTASPVSAAVGGTVTINCQSSQSVYDNNWLAWYQQKPGQPPKLLIDDASKLTSGVSSRFKGSGSGTQFTLTISGVQCDDAATYYCQGAYYSSGWYWAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 184) A11B1_6C7 heavy chainMETGLRWLLLVAVLKGVQCQQQLEESGGGLVKPGGTLTLTCKASGIDFSSYYYMCWVRQAPGKGLELIVCIYTSSGGTWYASWVNGRLTISRSTSLNTVDLKMTSLTAADTATYFCARGVYSGSSDYPTRLDLWGQGTLVTVSLGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 185) A11B1_6C7 light chain MDTSTSTALLGLLLLWLTGARCAIEMTQSPPSLSASVGETVRIRCLASEDIYSGISWYQQKPEKPPTLLISGASNLESGVPPRFSGGGSGTDYTLTIGGVQAEDVATYYCLGGYSFSSTGLTFGAGTKVEIKRDPVAPSVLLFPPSKEELTTGTATIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 186) A11B1_6B6 heavy chainMETGLRWLLLVAVLKGVQCQQHLVESGGGLVKPGASLTLTCTASGFSFTTGYHMCWVRQAPGKGLEWIACFGVYTSTTTYASWAKGRFTISKTSSTTVTLQMTSLTVADTATYFCARISAEDGGDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 187) A11B1_6B6 light chain MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTITCQASQSISNYFSWYQQKPGQPPKLLIYRASTLASGVPSRFSGSGSGTQFTLTISDLECADSATYACQCTYGSSSTGFGFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 188) A11B1_5F7 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCKASGFSFSSYFWICWVRQAPGKGLEWSACIYGDSSGSSYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCASYGSSSYYYSNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 189) A11B1_5F7 light chain MDTRAPTQLLGLLLLWLPGAICDPVMTQTPSSTSAAVGGTVTISCQSSQSVYNNNYLAWYQQKPGQPPKRLIYESSKLASGVPSRFRGSGSGAQFTLTISDLECDDAATYYCLGAYYTTLDFGGGTEVVVRGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 190) A11B1_5D7 heavy chainMETGLRWLLLVAVLKGVQCQEQLVESGGGLVQPEGSLTLTCKASGFDFSSNAMCWVRQAPGKGLEWIACIYNGDGSTYYASWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCARGLSNWNRDNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 191) A11B1_5D7 light chain MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSSVSAAVGGTATINCQASQSLYSPKNLAWYQQTPGQPPKLLIYSASKLASGVPSRFKGSGSGTQFTLTISGVQCDDAAIYYCQGEFSCTTAACFAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 192) A11B1_5A7 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGGLVQPEGSLTLACTASGFSFSSYYYICWVRQAPGTGLEWIGCINTGSDDTHYASWLKGRFTFSKASSTTLTLQMTSLTAADTATYFCARSSGSSDDAYDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 193) A11B1_5A7 light chain MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVSEPVGGAVTIKCQASQSIGSNLAWYQHKPGQPPKLLIYFASSLASGVSSRFKGGRSGTQFTLTISDLECADAATYYCHCTYYPLSYVTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 194) A11B1_4E1 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGTSLTLSCTASGFSFGSYYYMCWVRQAPGKGLEWIACIDVGSSGDTYYASWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCARDDTAAGGFGNLELWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 195) Light chain of A11B1_4E1 MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVSEPVGGTVTIKCQASQSIYSYFSWYQQKPGQPPKRLIYQASTLASGVPSRFKGSGSGTDFTLTISDLECADAATYYCQNNYGRGSGSYFFGFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 196) Heavy chain of A11B1_3H9METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCKASGIDFSSGYGMWWVRQAPGKGLEYIGYIDTGSGSTYYANWAKGRFTISKTSSTMVTLQMTSLTVADTATYFCAKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 197) A11B1_3H9 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQRPKLLIYRASTLASGVPSRFKGSGSGTDYTLTISDLECADAATYYCHTYYLSSSISYGNTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 198) A11B1_3G2 heavy chainMETGLRWLLLVAVLKGVQCQEQLEESGGDLVKPEGSLTLTCKASGFSFSSIYWICWVRQAPGKGLEWIACTTVVKSGRTYYANWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAREFVDGGGSSGRDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 199) A11B1_3G2 light chain MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEAAVGGTVTIKCQASQSISRDLSWYQQKPGQPPKRLIYKASTLASGVPSRFKGSGSGTDFTLTISDLECADAATYYCQQGYSSIDVDNDFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 200) A11B1_3B1 heavy chainMETGLRWLLLVAVLKGVQCQEQLEESGGGLVKPEGSLTLTCKASGFDLSSGYDMCWVRQAPGKGLEWIACIYADYSGSTYYASWVNGRFTISSSTSLNTVDLKMTSLTAADTATYFCARGATGNGGYGYYFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 201) A11B1_3B1 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVSEPVGGTVTIKCQASQNINSGLAWYQQKPGQPPKLLIYKASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQTYYYSSSSSDNAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 2) A11B1_2D3 heavy chainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGFSFSSSYWICWVRQAPGKGLEWIACIYGGSSGNIAYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARDIPSDAFTLDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 203) A11B1_2D3 Light Chain MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSSVSAAVGSTVTINCQASQSVYKDNNLAWYQQKPGQPPKLLIYKASTLASGVPSRFKGSGSGTQFTLTISGVQCEDAATYYCQGEFSCGSADCIAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 204) A11B1_2A7 Heavy ChainMETGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCKGSGIDFSSGYGMWWVRQAPGKGLEYIGYIDTGYGSTYYASWAKGRFTISKTSSTTVTLQMTSLTVADTATYFCAKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK* (SEQ ID NO: 205) A11B1_2A7 light chain MDTRAPTQLLGLLLLWLPGATFAAVLTQTPASTSAAVGGTVTINCQSSQSVYRSNWLAWYQQKPGQPPKLLIYDVFNLASGVPSRFKGSGSGTQFTLTISGVQCADAATYYCQGSYYSGNWYSAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC* (SEQ ID NO: 206) Human mAb sequence Heavy and light chain variable region sequences 2004_04_B03 Heavy chain FR1 QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 208) Heavy chain CDR1 GFTFSNYG (SEQ ID NO: 209) Heavy chain FR2 MNWVRQAPGKGLEWVSY (SEQ ID NO: 210) Heavy chain CDR2 ISSSGSTV (SEQ ID NO: 211) Heavy chain FR3 YYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCAS (SEQ ID NO: 212) Heavy chain CDR3 GQLDTSDAFDI (SEQ ID NO: 213) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Heavy chain V Gene segments IGHV3-48 Light chain FR1 DIEMTQSPSSPSSASVGDRVTITCRAS (SEQ ID NO: 215) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 219) Light chain CDR3 QQSYSTPLT (SEQ ID NO: 220) Light chain FR4 FGGGTKVEIK (SEQ ID NO: 221) Light chain V Gene segments IGKV1-39; IGKV1D-39 Light chain locus κ 2004_05_A06 Heavy chain FR1 EVQLLESGGGVVQSGRSLRVSCAAS (SEQ ID NO: 222) Heavy chain CDR1 GFSFSSYG (SEQ ID NO: 223) Heavy chain FR2 MHWVRQAPGKGLEWVSY (SEQ ID NO: 224) Heavy chain CDR2 ISSSGSTI (SEQ ID NO: 225) Heavy chain FR3 YYADSVKGRFTISRDNAENSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 226) Heavy chain CDR3 DLGHFDSGSSYFDY (SEQ ID NO: 442) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Heavy chain V Gene segments IGHV3-48 Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QGISNY (SEQ ID NO: 228) Light chain FR2 LAWYQQKPGKVPKLLIY (SEQ ID NO: 229) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 TLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 230) Light chain CDR3 QQSYSTPLT (SEQ ID NO: 220) Light chain FR4 FGGGTKVEVK (SEQ ID NO: 231) Light chain V Gene segments IGKV1-27 Light chain locus κ 2004_04_C12 Heavy chain FR1 EVQLLESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 232) Heavy chain CDR1 GFTFSNYG (SEQ ID NO: 209) Heavy chain FR2 MNWVRQAPGKGLEWVSY (SEQ ID NO: 210) Heavy chain CDR2 ISSSSSTI (SEQ ID NO: 233) Heavy chain FR3 YYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCAS (SEQ ID NO: 212) Heavy chain CDR3 GQXDXSDAFDI (SEQ ID NO: 234) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Heavy chain V Gene segments IGHV3OR16-8 Light chain FR1 DIEMTQSPSSPSSASVGDRVTITCRAS (SEQ ID NO: 215) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNXYQQKPGKAPKLLXY (SEQ ID NO: 235) Light chain CDR2 XAS (SEQ ID NO: 236) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDXATYYC (SEQ ID NO: 237) Light chain CDR3 QQSYSTPLT (SEQ ID NO: 220) Light chain FR4 FGGGXKXEIK (SEQ ID NO: 238) Light chain V Gene segments IGKV1-39; IGKV1D-39 Light chain locus κ 2002_02_B07 Heavy chain FR1 EVQLLESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 232) Heavy chain CDR1 GFTFSTYG (SEQ ID NO: 436) Heavy chain FR2 MHWVRQAPGKGLEWVSY (SEQ ID NO: 224) Heavy chain CDR2 ISSSGSTI (SEQ ID NO: 225) Heavy chain FR3 YYADSVKGRFAISRDNAKNTLYLQMNSLRAEDTALYYCAK (SEQ ID NO: 239) Heavy chain CDR3 ATRYDILTGYSDGVDYFDY (SEQ ID NO: 240) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Heavy chain V Gene segments IGHV3-48 Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 219) Light chain CDR3 HQSYSTPYT (SEQ ID NO: 241) Light chain FR4 FGQGTKLEIK (SEQ ID NO: 242) Light chain V Gene segments IGKV1-39; IGKV1D-39 Light chain locus κ 2004_05_B04 Heavy chain FR1 QVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 243) Heavy chain CDR1 GFTFSSYW (SEQ ID NO: 437) Heavy chain FR2 MSWVRQAPGKGLEWVAN (SEQ ID NO: 244) Heavy chain CDR2 IKQDGSEK (SEQ ID NO: 245) Heavy chain FR3 YYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 246) Heavy chain CDR3 VTSPHAFDI (SEQ ID NO: 247) Heavy chain FR4 WGRGTLVTVSS (SEQ ID NO: 248) Heavy chain V Gene segments IGHV3-7 Light chain FR1 DIQMTQSPSAMSSVGDRVTITCRAS (SEQ ID NO: 249) Light chain CDR1 QGISNY (SEQ ID NO: 228) Light chain FR2 LAWFQQKPGKVPKRLIY (SEQ ID NO: 250) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 219) Light chain CDR3 QQSYSTPLT (SEQ ID NO: 220) Light chain FR4 FGGGTKVEVK (SEQ ID NO: 231) Light chain V Gene segments IGKV1-39; IGKV1D-17; IGKV1D-39 Light chain locus κ 2003_03_E12 Heavy chain FR1 QVQLVESGGGVVRPGGSLRLSCAAS (SEQ ID NO: 251) Heavy chain CDR1 GFTFDDYG (SEQ ID NO: 438) Heavy chain FR2 MSWVRQAPGKGLEWVSG (SEQ ID NO: 252) Heavy chain CDR2 INWNGGST (SEQ ID NO: 253) Heavy chain FR3 GYADSVKGRFTISRDNSKNTLYLQMNSLRGEDTAVYYCVT (SEQ ID NO: 254) Heavy chain CDR3 QGSAFDI (SEQ ID NO: 255) Heavy chain FR4 WGRGTLVTVSS (SEQ ID NO: 248) Heavy chain V Gene segments IGHV3-20 Light chain FR1 SYELTQPPSLSVSPGQTARITCSGD (SEQ ID NO: 256) Light chain CDR1 ALAKQY (SEQ ID NO: 257) Light chain FR2 AYWYQQTPGQAPVLVIY (SEQ ID NO: 258) Light chain CDR2 KDT (SEQ ID NO: 259) Light chain FR3 ERPSGIPERFSGSSSGTTVTLTISGVQAEDEVDYYC (SEQ ID NO: 260) Light chain CDR3 QSTDSSGTYQV (SEQ ID NO: 261) Light chain FR4 FGGGTKLTVL (SEQ ID NO: 262) Light chain V Gene segments IGLV3-25 Light chain locus λ 1994_01_C07 Heavy chain FR1 QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 263) Heavy chain CDR1 GYTFTSYG (SEQ ID NO: 439) Heavy chain FR2 ISWVRQAPGQGLEWMGW (SEQ ID NO: 264) Heavy chain CDR2 ISAYNGNT (SEQ ID NO: 265) Heavy chain FR3 NYAQKLQGRVTMTTDTSTAYMELRSLRSDDTAAYYCAR (SEQ ID NO: 266) Heavy chain CDR3 VTGITGTTIDP (SEQ ID NO: 267) Heavy chain FR4 WGQGTMVTVSS (SEQ ID NO: 268) Heavy chain V Gene segments IGHV1-18 Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 DAS (SEQ ID NO: 269) Light chain FR3 SLESGVPSRFSGSGSGTEFTLTISSLQPDDFAVYYC (SEQ ID NO: 270) Light chain CDR3 QQYNNWPQT (SEQ ID NO: 271) Light chain FR4 FGQGTKVEIK (SEQ ID NO: 272) Light chain V Gene segments IGKV1-13; IGKV1D-13 Light chain locus κ 1995_01_G07 Heavy chain FR1 QVQLVESGGGLVKPGGSLRLSCAAS (SEQ ID NO: 273) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MSWVRQAPGKGLEWVSA (SEQ ID NO: 274) Heavy chain CDR2 ISGSGGST (SEQ ID NO: 275) Heavy chain FR3 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 276) Heavy chain CDR3 DYGGYDGVYFDY (SEQ ID NO: 277) Heavy chain FR4 WGRGTLVTVSS (SEQ ID NO: 248) Heavy chain V Gene segments IGHV3-23 Light chain FR1 SYELTQDPAVSVALGQTVRITCQGD (SEQ ID NO: 278) Light chain CDR1 SLRSYY (SEQ ID NO: 279) Light chain FR2 ASWYQQKPGQAPVLVIY (SEQ ID NO: 280) Light chain CDR2 GKN (SEQ ID NO: 281) Light chain FR3 NRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYC (SEQ ID NO: 282) Light chain CDR3 NSRDSSGNHVV (SEQ ID NO: 283) Light chain FR4 FGGGTKVTVL (SEQ ID NO: 284) Light chain V Gene segments IGLV3-19 Light chain locus λ 1995_01_G05 Heavy chain FR1 EVQLLESGGGLVKPGGSLRLSCAAS (SEQ ID NO: 285) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MHWVRQAPGKGLEWVAV (SEQ ID NO: 286) Heavy chain CDR2 ISYDGSNK (SEQ ID NO: 287) Heavy chain FR3 YYADSVKGRFAISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288) Heavy chain CDR3 DRDVGPTYYYYGMDV (SEQ ID NO: 289) Heavy chain FR4 WGQGTMVTVSS (SEQ ID NO: 268) Heavy chain V Gene segments IGHV3-30 Light chain FR1 SYELTQPPSLSVSPGQTARITCSGH (SEQ ID NO: 290) Light chain CDR1 ALPKQY (SEQ ID NO: 291) Light chain FR2 AYWYQQTPGQAPVLVIY (SEQ ID NO: 258) Light chain CDR2 KDT (SEQ ID NO: 259) Light chain FR3 ERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYC (SEQ ID NO: 292) Light chain CDR3 QSADSSGPYQV (SEQ ID NO: 293) Light chain FR4 FGGGTQLTVL (SEQ ID NO: 294) Light chain V Gene segments IGLV3-25 Light chain locus λ 2004_03_G10 Heavy chain FR1 EVQLLESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 232) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MSWVRQAPGKGLEWVSA (SEQ ID NO: 274) Heavy chain CDR2 ISGSGGST (SEQ ID NO: 275) Heavy chain FR3 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK (SEQ ID NO: 295) Heavy chain CDR3 DREYIAVAADY (SEQ ID NO: 296) Heavy chain FR4 WGQGTTVTVSS (SEQ ID NO: 297) Heavy chain V Gene segments IGHV3-23 Light chain FR1 DIQMTQSPSSSLSASVGDTISITCRAS (SEQ ID NO: 298) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 SLQSGVPSRFSGSGSSRTDFTLTISSVQPEDFATYYC (SEQ ID NO: 299) Light chain CDR3 QQSYSTPFT (SEQ ID NO: 300) Light chain FR4 FGPGTKVEIK (SEQ ID NO: 301) Light chain V Gene segments IGKV1-39; IGKV1D-39 Light chain locus κ 2002_02_B05 Heavy chain FR1 EVQLLESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 232) Heavy chain CDR1 GFTFSTYG (SEQ ID NO: 436) Heavy chain FR2 MHWVRQAPGKGLEWVSY (SEQ ID NO: 224) Heavy chain CDR2 ISSSGSTI (SEQ ID NO: 225) Heavy chain FR3 YYADSVKGRFAISRDNAKNTLYLQMNSLRAEDTALYYCAK (SEQ ID NO: 239) Heavy chain CDR3 ATRYDILTGYSDGVDYFDY (SEQ ID NO: 240) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Heavy chain V Gene segments IGHV3-48 Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 219) Light chain CDR3 QQSYSTPFT (SEQ ID NO: 300) Light chain FR4 FGPGTKVEIK (SEQ ID NO: 301) Light chain V Gene segments IGKV1-39; IGKV1D-39 Light chain locus κ 2003_03_F05 Heavy chain FR1 EVQLVESGAEVKKPGASVKVSCKAS (SEQ ID NO: 302) Heavy chain CDR1 GYTFTRYY (SEQ ID NO: 441) Heavy chain FR2 MHWVRQAPGQGLEWMGI (SEQ ID NO: 303) Heavy chain CDR2 INPSGGST (SEQ ID NO: 304) Heavy chain FR3 IYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR (SEQ ID NO: 305) Heavy chain CDR3 SLRDGYNYIGSLGY (SEQ ID NO: 306) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Heavy chain V Gene segments IGHV1-46 Light chain FR1 QSELTQPPSASGTPGQRVTISCSGS (SEQ ID NO: 307) Light chain CDR1 SSNIGSNY (SEQ ID NO: 308) Light chain FR2 VYWYQQLPGTAPKLLIY (SEQ ID NO: 309) Light chain CDR2 RNN (SEQ ID NO: 310) Light chain FR3 QRPSGVPDRFSGSKSGTSASLAIRGLQSEDEAGYYC (SEQ ID NO: 311) Light chain CDR3 AAWDDSLNGLNWV (SEQ ID NO: 207) Light chain FR4 FGGGTQLTVL (SEQ ID NO: 294) Light chain V Gene segments IGLV1-44; IGLV1-47 Light chain locus λ 1994_01_A07 Heavy chain FR1 QVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 243) Heavy chain CDR1 GFTFDDYA (SEQ ID NO: 312) Heavy chain FR2 MHWVRQAPGKGLEWVSG (SEQ ID NO: 313) Heavy chain CDR2 ISWNSGST (SEQ ID NO: 314) Heavy chain FR3 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAG (SEQ ID NO: 315) Heavy chain CDR3 GSRRYDSSGYYYESFDY (SEQ ID NO: 316) Heavy chain FR4 WGQGTTVTVSS (SEQ ID NO: 297) Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 DAS (SEQ ID NO: 269) Light chain FR3 NLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 317) Light chain CDR3 QQSYHTPYT (SEQ ID NO: 318) Light chain FR4 FGQGTKVEIK (SEQ ID NO: 272) Light chain locus κ 1994_01_A09 Heavy chain FR1 QMQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 319) Heavy chain CDR1 GGTFSSYA (SEQ ID NO: 320) Heavy chain FR2 ISWVRQAPGQGLEWMGR (SEQ ID NO: 321) Heavy chain CDR2 IIPILGIA (SEQ ID NO: 322) Heavy chain FR3 NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 323) Heavy chain CDR3 DINRYNWNFRAFDI (SEQ ID NO: 324) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 DIVMTQSPDSLAVSLGERATINCKSS (SEQ ID NO: 435) Light chain CDR1 QSVLYSSNNKNY (SEQ ID NO: 325) Light chain FR2 LAWYQQKPRQPPKLLIY (SEQ ID NO: 326) Light chain CDR2 WAS (SEQ ID NO: 327) Light chain FR3 TRESGVPDRFSSGNGSGTDFTLTISSLQAEDVAAYYC (SEQ ID NO: 328) Light chain CDR3 QQHYSTPLT (SEQ ID NO: 329) Light chain FR4 FGPGTKVEIK (SEQ ID NO: 301) Light chain locus κ 1994_01_D12 Heavy chain FR1 QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 330) Heavy chain CDR1 GYTFTSYG (SEQ ID NO: 439) Heavy chain FR2 ISWVRQAPGQGLEWMGW (SEQ ID NO: 264) Heavy chain CDR2 ISAYNGNT (SEQ ID NO: 265) Heavy chain FR3 NYAQKLQGRVTMTNTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 331) Heavy chain CDR3 VTGITGTTIDP (SEQ ID NO: 267) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYRQKPGKAPKLLIY (SEQ ID NO: 332) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDAATYYC (SEQ ID NO: 333) Light chain CDR3 QQYDSQSGT (SEQ ID NO: 334) Light chain FR4 FGQGTKLEIK (SEQ ID NO: 242) Light chain locus κ 1995_01_F05 Heavy chain FR1 EVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 335) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MHWVRQAPGKGLEWVAV (SEQ ID NO: 286) Heavy chain CDR2 ISYDGVKK (SEQ ID NO: 336) Heavy chain FR3 YYADSVKGRFTISRDNSKSTLYLQMNSLRVDDTAVYYCAK (SEQ ID NO: 337) Heavy chain CDR3 DLGWQNDY (SEQ ID NO: 338) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 QSVLTQPASVSGSPGQSITISCTGT DLGWQNDY (SEQ ID NO: 339) Light chain CDR1 SSDVGGHNY (SEQ ID NO: 340) Light chain FR2 VSWYQQHPGKAPKLMIY (SEQ ID NO: 341) Light chain CDR2 DVS (SEQ ID NO: 342) Light chain FR3 NRPSGVSNRFSGSSKSGNTASLTISGLQAEDEADYYC (SEQ ID NO: 343) Light chain CDR3 SSYTSSSPWV (SEQ ID NO: 344) Light chain FR4 FGGGTKLTVLG (SEQ ID NO: 345) Light chain locus λ 1995_01_F09 Heavy chain FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 346) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MSWVRQAPGKGLEWVSA (SEQ ID NO: 274) Heavy chain CDR2 ISGSGGST (SEQ ID NO: 275) Heavy chain FR3 YYADSVKGRFTISRDNSKNALYLQMNSLRAEDTAVYYCRG (SEQ ID NO: 347) Heavy chain CDR3 YCSSTCYGRRGAFDI (SEQ ID NO: 348) Heavy chain FR4 SGQGTLVTVSS (SEQ ID NO: 349) Light chain FR1 QAVLTQPPSASGTPGQRVTISCSGR (SEQ ID NO: 350) Light chain CDR1 NSNIGSNN (SEQ ID NO: 351) Light chain FR2 VNWYQHLPGTAPKLLIY (SEQ ID NO: 352) Light chain CDR2 SNN (SEQ ID NO: 353) Light chain FR3 QRPSGVPDRFSASKSGTSASLAISGLQSEDEADYYC (SEQ ID NO: 354) Light chain CDR3 AAWDDRMNGPV (SEQ ID NO: 355) Light chain FR4 IGGGTKVTVLG (SEQ ID NO: 356) Light chain locus λ 1996_01_H07 Heavy chain FR1 QVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 243) Heavy chain CDR1 GFTFSSYW (SEQ ID NO: 437) Heavy chain FR2 MHWVRQAPAKGLVWVSR (SEQ ID NO: 357) Heavy chain CDR2 INSDGSST (SEQ ID NO: 358) Heavy chain FR3 SYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 359) Heavy chain CDR3 DFWSGRPYYYYMDV (SEQ ID NO: 360) Heavy chain FR4 WGQGTTVTVSS (SEQ ID NO: 297) Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QDIGDD (SEQ ID NO: 361) Light chain FR2 LAWFQQKPGKAPKRLIY (SEQ ID NO: 362) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 TLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 363) Light chain CDR3 QQSYSTPRT (SEQ ID NO: 364) Light chain FR4 FGPGTKVEIK (SEQ ID NO: 301) Light chain locus κ 1997_02_B01 Heavy chain FR1 EVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 335) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MHWVRQAPGKGLEWVAV (SEQ ID NO: 286) Heavy chain CDR2 ISYDGSNK (SEQ ID NO: 287) Heavy chain FR3 YYADSVKGRFTISRDNSKNTLYLQMNSRRAEDTAVYYCAR (SEQ ID NO: 365) Heavy chain CDR3 WGIVAARPNYYYGMDV (SEQ ID NO: 366) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 QSALTQPRSVSGSPGQSVTISCTGT (SEQ ID NO: 367) Light chain CDR1 SSDVGGYNY (SEQ ID NO: 368) Light chain FR2 VSWYQQHPGKAPKLMIY (SEQ ID NO: 341) Light chain CDR2 DVS (SEQ ID NO: 342) Light chain FR3 KRPSGVPDRFSGSSKSGNTASLTISGLQAEDEADYHC (SEQ ID NO: 443) Light chain CDR3 SSYANNSPWV (SEQ ID NO: 369) Light chain FR4 FGGGTKVTVLG (SEQ ID NO: 370) Light chain locus λ 2002_02_E01 Heavy chain FR1 QVQLVQSGAEVRKPGASVKVSCKAS (SEQ ID NO: 371) Heavy chain CDR1 GYTFTSYG (SEQ ID NO: 439) Heavy chain FR2 ISWVRQAPGQGLEWMGW (SEQ ID NO: 264) Heavy chain CDR2 ISAYNGNT (SEQ ID NO: 265) Heavy chain FR3 NYAQKLQGRVTMTTDTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 372) Heavy chain CDR3 VTGITGTTIDP (SEQ ID NO: 267) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCQAS (SEQ ID NO: 373) Light chain CDR1 QDISNY (SEQ ID NO: 374) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 DAS (SEQ ID NO: 269) Light chain FR3 NLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYC (SEQ ID NO: 375) Light chain CDR3 QQYANLPLT (SEQ ID NO: 376) Light chain FR4 FGGGTKVEIK (SEQ ID NO: 221) Light chain locus κ 2002_02_G11 Heavy chain FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 346) Heavy chain CDR1 GFTVSSNY (SEQ ID NO: 377) Heavy chain FR2 MSWVRQAPGKGLEWVSV (SEQ ID NO: 378) Heavy chain CDR2 IYSGGST (SEQ ID NO: 379) Heavy chain FR3 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 276) Heavy chain CDR3 GGLTGDDAFDI (SEQ ID NO: 380) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QSISSF (SEQ ID NO: 381) Light chain FR2 LNWYQQKPGTAPKLLIY (SEQ ID NO: 382) Light chain CDR2 TTS (SEQ ID NO: 383) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 219) Light chain CDR3 QQGNSLPLT (SEQ ID NO: 384) Light chain FR4 FGGGTKVEIK (SEQ ID NO: 221) Light chain locus κ 2003_03_A09 Heavy chain FR1 QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 208) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MHWVRQAPGKGLEWVAV (SEQ ID NO: 286) Heavy chain CDR2 ISYDGSNK (SEQ ID NO: 287) Heavy chain FR3 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 276) Heavy chain CDR3 DKELSY (SEQ ID NO: 385) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 QSGLTQPASVSGSPGQSITISCTGT (SEQ ID NO: 386) Light chain CDR1 SSDVGGYNY (SEQ ID NO: 368) Light chain FR2 VSWYQQHPGKAPKLMIY (SEQ ID NO: 341) Light chain CDR2 EVS (SEQ ID NO: 387) Light chain FR3 NRPSGVPDRFSGSSKSGNTASLTISGLQAEDEADYYC (SEQ ID NO: 388) Light chain CDR3 SSYTSSSPWV (SEQ ID NO: 344) Light chain FR4 FGGGTKLTVLG (SEQ ID NO: 345) Light chain locus λ 2004_04_D03 Heavy chain FR1 QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 208) Heavy chain CDR1 GFTFSNYG (SEQ ID NO: 209) Heavy chain FR2 MNWVRQAPGKGLEWVSY (SEQ ID NO: 210) Heavy chain CDR2 ISSSSSTI (SEQ ID NO: 233) Heavy chain FR3 YYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCAS (SEQ ID NO: 212) Heavy chain CDR3 GQLDTSDAFDI (SEQ ID NO: 213) Heavy chain FR4 WGQGTTVTVSS (SEQ ID NO: 297) Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 227) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 KTS (SEQ ID NO: 389) Light chain FR3 NLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 390) Light chain CDR3 QQSYSTPLT (SEQ ID NO: 220) Light chain FR4 FGGGTKVEIK (SEQ ID NO: 221) Light chain locus κ 2004_04_F01 Heavy chain FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 346) Heavy chain CDR1 GFTFSSYA (SEQ ID NO: 440) Heavy chain FR2 MSWVRQAPAKGLEWVSA (SEQ ID NO: 391) Heavy chain CDR2 ISGSGGST (SEQ ID NO: 275) Heavy chain FR3 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK (SEQ ID NO: 295) Heavy chain CDR3 DRPYSYGKNDAFDI (SEQ ID NO: 392) Heavy chain FR4 WGQGTTVTVSS (SEQ ID NO: 297) Light chain FR1 DIQMTQSPSSSLSASVGDRVTITCQAS (SEQ ID NO: 373) Light chain CDR1 QDVSNY (SEQ ID NO: 393) Light chain FR2 LNWYRQKPGKAPKLLIY (SEQ ID NO: 332) Light chain CDR2 AAS (SEQ ID NO: 218) Light chain FR3 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 219) Light chain CDR3 QQSYSTPLT (SEQ ID NO: 220) Light chain FR4 FGGGTKLEIK (SEQ ID NO: 394) Light chain locus κ 2005_05_E05 Heavy chain FR1 EVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 395) Heavy chain CDR1 GYTFTSYY (SEQ ID NO: 396) Heavy chain FR2 MHWVRQAPGQGLEWMGI (SEQ ID NO: 303) Heavy chain CDR2 INPSGGST (SEQ ID NO: 304) Heavy chain FR3 SYAQKFQGRVTMTRDTSTVYMELSSLRSEDTAVYYCAR (SEQ ID NO: 397) Heavy chain CDR3 SPWLITFGGVIAMGY (SEQ ID NO: 402) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 QSVLTQPPSASGTPGQRVTISCSGS (SEQ ID NO: 403) Light chain CDR1 SSNIGSNY (SEQ ID NO: 308) Light chain FR2 VYWYQQLPGTAPKLLIY (SEQ ID NO: 309) Light chain CDR2 RNN (SEQ ID NO: 310) Light chain FR3 QRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC (SEQ ID NO: 404) Light chain CDR3 AAWDDSLSGVV (SEQ ID NO: 405) Light chain FR4 FGGGTQLTVLG (SEQ ID NO: 406) Light chain locus λ 1994_01_D04 Heavy chain FR1 QVQLVQSGAEVRKPGASVKVSCKAS (SEQ ID NO: 371) Heavy chain CDR1 GYTFTSYG (SEQ ID NO: 439) Heavy chain FR2 ISWVRQAPGQGLEWMGW (SEQ ID NO: 264) Heavy chain CDR2 ISAYNGNT (SEQ ID NO: 265) Heavy chain FR3 NYAQKLQGRVTMTTDTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 372) Heavy chain CDR3 VTGITGTTIDP (SEQ ID NO: 267) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 DIVMTQSPSSSLSASVGDRVTITCRAS (SEQ ID NO: 407) Light chain CDR1 QSISSY (SEQ ID NO: 216) Light chain FR2 LNWYQQKPGKAPKLLIY (SEQ ID NO: 217) Light chain CDR2 DAS (SEQ ID NO: 269) Light chain FR3 NLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 317) Light chain CDR3 QQFNNYPLT (SEQ ID NO: 408) Light chain FR4 FGGGTKLEIK (SEQ ID NO: 394) Light chain locus κ 1997_02_B03 Heavy chain FR1 QVQLVESGAEVKKPGASVKVSCKAS (SEQ ID NO: 409) Heavy chain CDR1 GYTFTSYY (SEQ ID NO: 396) Heavy chain FR2 MHWVRQAPGQGLEWMGI (SEQ ID NO: 303) Heavy chain CDR2 INPSGGST (SEQ ID NO: 304) Heavy chain FR3 SYAQKFQGRVTMTRDTSTVYMELSSLRSEDTAVYYCAR (SEQ ID NO: 397) Heavy chain CDR3 AGGYYYYYMDV (SEQ ID NO: 398) Heavy chain FR4 WGQGTLVTVSS (SEQ ID NO: 214) Light chain FR1 QSGLTQPPSASGTPGQRVTISCSGS (SEQ ID NO: 399) Light chain CDR1 GPNIGNNY (SEQ ID NO: 400) Light chain FR2 VYWYQQLPGTAPKLLMY (SEQ ID NO: 401) Light chain CDR2 RNN (SEQ ID NO: 310) Light chain FR3 QRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYC (SEQ ID NO: 410) Light chain CDR3 AAWDDSLNGYV (SEQ ID NO: 411) Light chain FR4 FGTGTKLTVLG (SEQ ID NO: 412) Light chain locus λ Humanized mAb sequence: Humanized 79E3E3 heavy chain variable region QIQLVQSGAEVKKPGESLKISCKASGYTFTDYAIGWVRQMPGKGLEWMGIINTQTGKPKYSPSFQGQFIFSLDTSINTTYLQWSSLKASDTAIYFCTRLGTGNTKGFAYWGQGTTVTVSS (SEQ ID NO: 413) Humanized 79E3E3 light chain variable region DIQITQSPSSLSASLGDKVTITCRSSQSLLYSENNQDYLAWYQQKPGKAPKLLIYGASNLQSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCEQTYRYPFTFGPGTKVDIKR (SEQ ID NO: 414) Humanized 9-G05 heavy chain VH_1 leader sequence -VH-hIgG1CH-stop codon* MGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKASGYTFPDYNMDWVRQAPGQRLEWMGYINPDNGGTIYNQKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARL DSSGYGYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK* (SEQ ID NO: 415) Humanized 9-G05 heavy chain VH_2 leader sequence -VH-hIgG1CH-stop codon*MGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKASGYTFPDYNMDWVRQAPGQRLEWIGYINPDNGGTIYNQKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARLDSSGYGYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK* (SEQ ID NO: 416) Humanized 9-G05 heavy chain VH_3 leader sequence - VH - hIgG1CH - stop codon* MGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKASGYTFPDYNMDWVRQAPGQRLEWMGYINPDNGGTIYNQKFKGRATLTVDTSASTAYMELSSLRSEDTAVYYCARLDSSGYGYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*(SEQ ID NO: 417) Humanized 9-G05 heavy chain VH_4 leader sequence -VH-hIgG1CH-stop codon* MGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKASGYTFPDYNMDWVRQAPGQSLEWIGYINPDNGGTIYNQKFKGRATLTVDTSASTAYMELSSLRSEDTAVYYCARLDSSGYGYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK* (SEQ ID NO: 418) Humanized 9-G05 light chain VL_1 Leader sequence -VL-hIgKCL-stop codon* MGWSCIILFLVATATGVHSDIVMTQSPDSLAVSLGERATINCRASESVDNYGISFMHWYQQKPGQPPKLLIYRASNLDSGVPDRFSGSGSGTDFTLTISSLQAEDVATYYCQQSYKDPRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 419) Humanized 9-G05 light chain VL_2 Leader sequence -VL-hIgKCL-stop codon*MGWSCIILFLVATATGVHSDIVLTQSPASLAVSPGQRATITCRASESVDNYGISFMHWYQQKPGQPPKLLIYRASNLDSEVPARFSGSGSRTDFTLTINPVEANDTATYYCQQSYKDPRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 420) 16E10 heavy chain variable region QSLEESGGDLVKPGASLTLTCRVSGFSFSSSYYMCWVRQAPGKGLEWIACIGTTRGSTYYATWAKGRFTISKISSTTVTLQMTSLTDADTATYFCARDATGYRINTIGLYFNLWGPGTLVTVSS (SEQ ID NO: 421) Humanized 16E10 heavy chain variable region VH_1 QSLLESGGGLVKPGGSLRLSCAVSGFSFSSSYYMCWVRQAPGKGLEWVSCIGTTRGSTYYADSAKGRFTISKISKNTVYLQMTSLRAEDTAVYFCARDATGYRINTIGLYFNLWGPGTLVTVSS (SEQ ID NO: 422) Humanized 16E10 heavy chain variable region VH_2 EVQLLESGGGLVKPGGSLRLSCAVSGFSFSSSYYMCWVRQAPGKGLEWVSCIGTTRGSTYYADSAKGRFTISKDNSKNTVYLQMTSLRAEDTAVYFCARDATGYRINTIGLYFNLWGQGTLVTVSS (SEQ ID NO: 423) Humanized 16E10 heavy chain variable region VH_3 QSLLESGGGLVKPGGSLRLSCAVSGFSFSSSYYMCWVRQAPGKGLEWVSCIGTTRGSTYYADSAKGRFTISKESKNTVYLQMSSLRAEDTAVYFCARDATGYRINTIGLYFNLWGPGTLVTVSS (SEQ ID NO: 424) Humanized 16E10 heavy chain variable region VH_4EVQLLESGGGLVKPGGSLRLSCAVSGFSFSSSYYMCWVRQAPGKGLEWVSCIGTTRGSTYYADSAKGRFTISKDNSKNTVYLQMSSLRAEDTAVYFCARDATGYRINTIGLYFNLWGQGTLVTVSS (SEQ ID NO: 425) Humanized 16E10 heavy chain variable region VH_5 QSLLESGGGLVKPGGSLRLSCAVSGFSFSSSYYMCWVRQAPGKGLEWVSCIGTTRGSTYYADSAKGRFTISKESKNTVYLQMSSLRAEDTAVYFCARDATGYRIQTIGLYFNLWGPGTLVTVSS (SEQ ID NO: 426) Humanized 16E10 heavy chain variable region VH_6 EVQLLESGGGLVKPGGSLRLSCAVSGFSFSSSYYMCWVRQAPGKGLEWVSCIGTTRGSTYYADSAKGRFTISKDNSKNTVYLQMSSLRAEDTAVYFCARDATGYRIQTIGLYFNLWGQGTLVTVSS (SEQ ID NO: 427) 16E10 Light Chain Variable Region ELTQTPSSVEAAVGGTPTIKCQASQTIYSYLSWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISDLECADAATYYCQSYHGTASTEYNTFGGGTEVVVK (SEQ ID NO: 428) Humanized 16E10 Light Chain Variable Region VL_1 QLTQSPSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQSYHGTASTEYNTFGGGTKVEIK (SEQ ID NO: 429) Humanized 16E10 Light Chain Variable Region VL_2 DIQLTQSPSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQSYHGTASTEYNTFGGGTKVEIK (SEQ ID NO: 430) Humanized 16E10 Light Chain Variable Region VL_3QLTQSPSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDTATYYCQSYHGTASTEYNTFGGGTKVEIK (SEQ ID NO: 431) Humanized 16E10 Light Chain Variable Region VL_4 DIQLTQSPSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDTATYYCQSYHGTASTEYNTFGGGTKVEIK (SEQ ID NO: 432) Humanized 16E10 Light Chain Variable Region VL_5 QLTQSPSSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDTATYYCQSYHGTASTEYQTFGGGTKVEIK (SEQ ID NO: 433) Humanized 16E10 light chain variable region VL_6 DIQLTQSPSSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDTATYYCQSYHGTASTEYQTFGGGTKVEIK (SEQ ID NO: 434) Equivalent

[0127] It should be understood that although the present invention has been described in conjunction with its embodiments, the above description is intended to be illustrative only and not to limit the scope of the invention, which is defined by the scope of the appended claims. Other features, advantages and modifications fall within the scope of the following claims. [Simplified Explanation of the Diagram]

[0014] The teachings described herein will be more fully understood when read in conjunction with the accompanying drawings through the following description of various illustrative embodiments. It should be understood that the drawings described below are for illustrative purposes only and are not intended to limit the scope of the teachings in any way. [Figure 1] shows a diagram of integrin structures. Each figure illustrates the structure of collagen-bound integrins and the three different conformations in which integrins can exist on the cell surface. [Figure 2A] shows an ELISA analysis illustrating the binding of an exemplary mouse monoclonal antibody to human α11β1. [Figure 2B] shows an exemplary ELISA analysis illustrating the binding of a mouse monoclonal antibody to mouse α11β1. [Figure 3A] shows an exemplary ELISA analysis illustrating the binding of a rat monoclonal antibody to the I domain of human α11β1. [Figure 3B] shows an exemplary ELISA analysis illustrating the binding of a mouse monoclonal antibody to the I domain of human α11β1. [Figure 4A] Shows FACS analysis of the binding of an exemplary rat monoclonal antibody to CHO-K1 cells expressing human α11β1. [Figure 4B] Shows FACS analysis of the binding of an exemplary mouse monoclonal antibody to CHO-K1 cells expressing human α11β1. [Figure 5] Shows FACS analysis of the binding of an exemplary mouse monoclonal antibody to human pulmonary fibroblasts (HPF) and myofibroblasts (MF). [Figure 6A] Shows the ability of an exemplary rat monoclonal antibody to inhibit the adhesion of CHO-K1 cells expressing human α11 to type I collagen in the rat tail. [Figure 6B] Shows the ability of an exemplary rabbit monoclonal antibody to inhibit the adhesion of CHO-K1 cells expressing human α11 to type I collagen in the rat tail. [Figure 6C] illustrates the ability of a mouse monoclonal antibody to inhibit the adhesion of human α11-mediated CHO-K1 cells to rat tail type I collagen. [Figure 7A] illustrates the ability of a rat monoclonal antibody to inhibit fibroblast-to-myofibroblast transition (FMT), measured as the percentage inhibition by αSMA upregulation. [Figure 7B] illustrates the ability of a rabbit monoclonal antibody to inhibit fibroblast-to-myofibroblast transition (FMT), measured as the percentage inhibition by αSMA upregulation. [Figure 7C] illustrates the ability of a mouse monoclonal antibody to inhibit fibroblast-to-myofibroblast transition (FMT), measured as the percentage inhibition by αSMA upregulation. [Figure 8] illustrates the ability of a monoclonal antibody to inhibit CHO-K1-mediated human α11-mediated gel contraction of rat tail type I collagen.[Figure 9] shows the affinity of an exemplary monoclonal antibody for human α11β1 via surface plasmon resonance (SPR). [Figures 10A and 10B] show the affinity of an exemplary monoclonal antibody for human α11β1 via surface plasmon resonance (SPR). [Figures 11A and 11B] show the binding affinity of selected rabbit, rat, mouse, and human monoclonal antibodies for α11β1 expressed on the surface of CHO cells. [Figure 12] shows the FACS analysis of the binding of an exemplary monoclonal antibody to human lung fibroblasts (HPF) and myofibroblasts (MF). [Figure 13] shows the FACS analysis of the binding of an exemplary monoclonal antibody to human myofibroblasts (MF). [Figure 14] shows the binding affinity of selected monoclonal antibodies for α11β1 expressed on the surface of CHO cells. [Figures 15A and 15B] illustrate the ability of the illustrated monoclonal antibody to inhibit the adhesion of human α11 CHO cells to rat tail type I collagen. [Figure 16] illustrates the effect of the illustrated monoclonal antibody on xenograft growth in SCID mice. [Figures 17A, 17B, and 17C] illustrate the effect of the illustrated monoclonal antibody on soluble pro-fibrogenic markers from precision-cut liver slices (PCLS). [Figures 18A, 18B, and 18C] illustrate the effect of the illustrated monoclonal antibody on the soluble pro-fibrogenic marker Col1a1 from precision-cut kidney slices (PCKS). [Sequence List]

Claims

1. An anti-integrin α11β1 antibody or an antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 443.

2. An anti-α11β1 antibody or an antigen-binding fragment thereof, comprising a CDR sequence encompassing any of the following: SEQ ID NO: 103 to 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316, 3 18, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443.

3. An anti-α11β1 antibody or an antigen-binding fragment thereof, comprising CDR1, CDR2, and CDR3 covered by any one of SEQ ID NO: 103 to 206, or 413 to 435.

4. The anti-α11β1 antibody or its antigen-binding fragment as described in claim 1, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 103 to 114, 207 to 311, and 312 to 443.

5. The anti-α11β1 antibody or its antigen-binding fragment as described in claim 2, comprising a CDR sequence encompassing any of the following: SEQ ID NO: 103 to 114, 207, 209, 211, 213, 216, 218, 220, 223, 225, 228, 233, 234, 236, 240, 241, 245, 247, 253, 255, 257, 259, 261, 265, 267, 269, 271, 275, 277, 279, 281, 283, 287, 289, 291, 293, 296, 300, 304, 306, 308, 310, 312, 314, 316 318, 320, 322, 324, 325, 327, 329, 334, 336, 338, 340, 342, 344, 348, 351, 353, 355, 358, 360, 361, 364, 366, 368, 369, 374, 376, 377, 379, 380, 381, 383, 384, 385, 387, 389, 392, 393, 396, 398, 400, 402, 405, 408, 411, or 413 to 443.

6. The anti-α11β1 antibody or its antigen-binding fragment as described in claim 2, comprising one or more CDR sequences covered by any one of SEQ ID NO: 103 to 114, or 413 to 434.

7. The anti-α11β1 antibody or its antigen-binding fragment as described in claim 3, comprising CDR1, CDR2, and CDR3 covered by any one of SEQ ID NO: 103 to 114, or 413 to 434.

8. An anti-α11β1 antibody or an antigen-binding fragment thereof as described in any one of claims 1 to 7, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or an antigen-binding fragment thereof.

9. An anti-α11β1 antibody or an antigen-binding fragment thereof as described in any one of claims 1 to 7, wherein the antibody or the antigen-binding fragment thereof is a humanized antibody or an antigen-binding fragment thereof.

10. An anti-α11β1 antibody or an antigen-binding fragment thereof as described in any one of claims 1 to 7, wherein the antibody or the antigen-binding fragment thereof reduces the interaction between α11β1 and collagen in human α11β1 phenotyped cells.

11. An anti-α11β1 antibody or an antigen-binding fragment thereof, which competes with an antibody or an antigen-binding fragment thereof as described in any one of claims 1 to 10.

12. A nucleic acid comprising a nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof as described in any one of claims 1 to 11.

13. The nucleic acid of claim 12, wherein the nucleic acid sequence comprises a sequence selected from the group consisting of SEQ ID NO: 1 to 102.

14. A vector comprising the nucleic acid as described in claim 12 or 13.

15. A host cell comprising a nucleic acid as described in claim 12 or 13 or a vector as described in claim 14.

16. A method for producing an antibody or an antigen-binding fragment thereof, comprising culturing a host cell as described in claim 14 under conditions suitable for expressing the antibody or the antigen-binding fragment thereof.

17. Use of an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 11 for the preparation of a medicament for treating a person suffering from or at risk of chronic kidney disease.

18. The use as described in claim 17, wherein the chronic kidney disease is or includes primary glomerular disease (including but not limited to IgA nephropathy and segmental glomerulosclerosis), secondary glomerular disease (including but not limited to lupus nephritis), thrombotic microangiopathy, tubulointerstitial disease (including but not limited to obstructive urinary tract disease), diabetic nephropathy, hypertensive nephropathy, ischemic nephropathy, cardiorenal syndrome of CKD, hereditary glomerular disease (including but not limited to Alport syndrome), renal cystic disease (including but not limited to polycystic kidney disease), or hereditary tubular disease.

19. The use as described in claim 17 or 18, wherein administration of a therapeutically effective amount of the antibody or its antigen-binding fragment results in a reduction of measured markers, signs, and / or symptoms by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% relative to the control group.

20. The use as described in claim 19, wherein the control group comprises the levels of markers, signs, and / or symptoms measured in the subject prior to administration of the antibody.

21. The use as described in claim 19, wherein the control group comprises the levels of markers, signs, and / or symptoms measured in subjects suffering from the kidney-related condition.

22. The use as described in claim 19, wherein the control group comprises the average level of markers, signs, and / or symptoms measured in a population of subjects with the kidney-related disease.

23. The use as described in claim 17 or 18, wherein the measured marker, sign, and / or symptom is or comprises: COL1A1, Fibronectin, PAI-1, IL-11, CXCL1, MCP-1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, MMP9, or a combination thereof.

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