Antibody to integrin alpha 11 beta 1

Abstract

The present disclosure includes antibodies that specifically bind to integrin alpha11 beta1 (α11β1), as well as methods of making and using such antibodies.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent 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 by reference in their entireties for all purposes.

[0002] (Sequence Listing) This application has been filed electronically in ASCII format and contains a Sequence Listing, which is incorporated herein by reference in its entirety. This ASCII copy, created on November 19, 2021, is named 2010403_0592_SL.txt and is 440,570 bytes in size. [Background technology]

[0003] Fibrosis is a scarring process that appears in many tissues in the body, typically as a result of inflammation or tissue injury. Increased production of extracellular matrix leads to organ failure and often death. Diseases associated with fibrosis account for approximately 45% of all deaths in industrialized countries (Wynn, TA, 2008, J Pathol. 214:199-210). One such disease is systemic sclerosis (SSc). SSc is a complex autoimmune disease with a chronic progressive course and high interpatient variability. It is characterized by inflammation, vascular dysfunction and fibrosis. Fibrosis in the skin and visceral organs leads to irreversible scarring and ultimately organ failure, causing high mortality. Currently, there are no approved targeted therapies with disease-modifying potential. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure provides novel function-blocking antibodies against the type I collagen receptor integrin alpha11 beta1 (alpha11 beta1, α11β1). The present disclosure also provides uses of such antibodies for treating fibrotic disorders and / or cancer.

[0005] In one aspect, the present 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 NOs: 103 to 443. In another aspect, the present 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 NOs: 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, 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, or an antigen-binding fragment thereof. In another aspect, the disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof comprising a CDR1, CDR2, and CDR3 encompassed in any one of SEQ ID NOs: 103-206 or 413-435. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-114, 207-311, and 312-443.In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NOs: 103-114, 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, 313, 314, 315, 316, 317, 318, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 359, 361, 365, 367, 369, 271, 275, 277, 14, 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 antigen-binding fragment thereof comprises one or more CDR sequences encompassed in any one of SEQ ID NOs: 103-114 or 413-434. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 encompassed in any one of SEQ ID NOs: 103-114 or 413-434.

[0006] In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof reduces the interaction of α11β1 with collagen in human α11β1-expressing cells. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof competes with an antibody or antigen-binding fragment thereof described herein.

[0007] In another aspect, the disclosure provides a nucleic acid comprising a nucleic acid sequence encoding an antibody or antigen-binding fragment thereof described herein, in some embodiments, the nucleic acid sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 1-102.

[0008] In another aspect, the disclosure provides a vector comprising a nucleic acid described herein.

[0009] In another aspect, the disclosure provides a host cell comprising a nucleic acid described herein, or a vector described herein.

[0010] In another aspect, the disclosure provides a method of producing an antibody or antigen-binding fragment thereof, comprising culturing a host cell as described herein under conditions suitable for expression of the antibody or antigen-binding fragment thereof.

[0011] In another aspect, the disclosure provides a method of treating a subject having or at risk for chronic kidney disease, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof described herein. In some embodiments, the chronic kidney disease is or comprises primary glomerular disease (including but not limited to IgA nephropathy and focal segmental glomerulosclerosis), secondary glomerular disease (including but not limited to lupus nephritis), thrombotic microangiopathy, tubulointerstitial disease (including but not limited to obstructive uropathy), diabetic nephropathy, hypertensive nephropathy, ischemic nephropathy, cardiorenal syndrome in CKD, genetic disorders of the glomerulus (including but not limited to Alport syndrome), cystic diseases of the kidney (including but not limited to polycystic kidney disease), or genetic disorders of the renal tubules. In some embodiments, administration of a therapeutically effective amount of an antibody or antigen-binding fragment thereof results in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction in the measured markers, signs, and / or symptoms compared to a control. In some embodiments, the control comprises a constant level of the measured markers, signs, and / or symptoms in a subject prior to administration of the antibody. In some embodiments, the control comprises a constant level of the measured markers, signs, and / or symptoms in a subject suffering from a kidney-related disorder. In some embodiments, the control comprises an average level of the measured markers, signs, and / or symptoms in a population of subjects suffering from a kidney-related disorder. In some embodiments, the measured markers, signs and / or symptoms are or include COL1A1, fibronectin, PAI-1, IL-11, CXCL1, MCP-1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, MMP9, or combinations thereof. [Brief description of the drawings]

[0012] The present teachings set forth herein will be more fully understood from the following description of various exemplary embodiments when read in conjunction with the accompanying drawings, in which: It should be understood that the drawings described below are for illustrative purposes only and are not intended to limit the scope of the present teachings in any way. [Figure 1] FIG. 1 shows a diagram of integrin structure. The panel shows the structure of a collagen-binding integrin, in which three different conformations of the integrin can exist on the surface of a cell. [Figure 2A] 1 shows a chart depicting ELISA analysis of binding of exemplary mouse monoclonal antibodies to human α11β1. [Figure 2B] 1 shows a chart depicting an exemplary ELISA analysis of binding of mouse monoclonal antibodies to mouse α11β1. [Figure 3A] 1 shows a graph depicting ELISA analysis of binding of exemplary rat monoclonal antibodies to human α11β1 I-domain. [Figure 3B] 1 shows a graph depicting ELISA analysis of binding of exemplary mouse monoclonal antibodies to human α11β1 I-domain. [Figure 4A] 1 shows a graph depicting FACS analysis of binding of exemplary rat monoclonal antibodies to CHO-K1 cells expressing human α11β1. [Figure 4B] 1 shows a graph depicting FACS analysis of binding of exemplary mouse monoclonal antibodies to CHO-K1 cells expressing human α11β. [Diagram 5] 1 shows a graph depicting FACS analysis of binding of exemplary mouse monoclonal antibodies to human pulmonary fibroblasts (HPF) and myofibroblasts (MF). [Figure 6A] 1 shows a graph depicting the ability of exemplary rat monoclonal antibodies to inhibit adhesion of CHO-K1 cells expressing human alpha 11 to rat tail type I collagen. [Figure 6B]1 shows a graph depicting the ability of exemplary rabbit monoclonal antibodies to inhibit adhesion of CHO-K1 cells expressing human alpha 11 to rat tail type I collagen. [Figure 6C] 1 shows a graph depicting the ability of exemplary mouse monoclonal antibodies to inhibit adhesion of CHO-K1 cells expressing human alpha 11 to rat tail type I collagen. [Figure 7A] FIG. 1 shows a graph depicting the ability of exemplary rat monoclonal antibodies to inhibit Fibroblast-to-Myofibroblasts Transition (FMT) as measured by percent inhibition of αSMA upregulation. [Figure 7B] 1 shows a graph depicting the ability of exemplary rabbit monoclonal antibodies to inhibit fibroblast to myofibroblast transition (FMT) as measured by percent inhibition of αSMA upregulation. [Figure 7C] 1 shows a graph depicting the ability of exemplary mouse monoclonal antibodies to inhibit fibroblast to myofibroblast transition (FMT) as measured by percent inhibition of αSMA upregulation. [Figure 8] 1 shows a graph depicting the ability of exemplary monoclonal antibodies to inhibit CHO-K1 human α11-mediated rat tail collagen type I gel contraction. [Figure 9] 1 shows a graph depicting the affinity of exemplary monoclonal antibodies to human α11β1 by surface plasmon resonance (SPR). [Figure 10A] 1 shows a graph depicting the affinity of exemplary monoclonal antibodies to human α11β1 by surface plasmon resonance (SPR). [Figure 10B] 1 shows a graph depicting the affinity of exemplary monoclonal antibodies to human α11β1 by surface plasmon resonance (SPR). [Figure 11A] 1 shows a graph depicting the binding ability of selected rabbit, rat, mouse and human monoclonal antibodies to α11β1 expressed on the surface of CHO cells. [Figure 11B]1 shows a graph depicting the binding ability of selected rabbit, rat, mouse and human monoclonal antibodies to α11β1 expressed on the surface of CHO cells. [Figure 12] 1 shows a graph depicting FACS analysis of binding of exemplary monoclonal antibodies to human lung fibroblasts (HPF) and myofibroblasts (MF). [Figure 13] 1 shows graphs and tables depicting FACS analysis of binding of exemplary monoclonal antibodies to human myofibroblasts (MF). [Figure 14] FIG. 1 shows a graph depicting the binding ability of selected monoclonal antibodies to α11β1 expressed on the surface of CHO cells. [Figure 15A] 1 shows a graph depicting the ability of exemplary monoclonal antibodies to inhibit adhesion of CHO cells expressing human alpha 11 to rat tail type I collagen. [Figure 15B] 1 shows a graph depicting the ability of exemplary monoclonal antibodies to inhibit adhesion of CHO cells expressing human alpha 11 to rat tail type I collagen. [Figure 16] 1 shows a graph depicting the effect of exemplary monoclonal antibodies on xenograft growth in SCID mice. [Figure 17A] FIG. 1 shows the effect of an exemplary monoclonal antibody on soluble pro-fibrotic markers in Precision-Cut Liver Slices (PCLS). [Figure 17B] FIG. 1 shows the effect of an exemplary monoclonal antibody on soluble pro-fibrotic markers in Precision-Cut Liver Slices (PCLS). [Figure 17C] FIG. 1 shows the effect of an exemplary monoclonal antibody on soluble pro-fibrotic markers in Precision-Cut Liver Slices (PCLS). [Figure 18A] FIG. 1 shows the effect of an exemplary monoclonal antibody against the soluble pro-fibrotic marker Col1a1 in precision-cut kidney slices (PCKS). [Figure 18B]FIG. 1 shows the effect of an exemplary monoclonal antibody against the soluble pro-fibrotic marker Col1a1 in precision-cut kidney slices (PCKS). [Figure 18C] FIG. 1 shows the effect of an exemplary monoclonal antibody against the soluble pro-fibrotic marker Col1a1 in precision-cut kidney slices (PCKS). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure is based in part on the discovery of novel antibodies that selectively bind to α11β1. The disclosure also relates to nucleic acids encoding such antibodies and methods of use in the treatment of fibrosis and diseases that have a fibrotic component.

[0014] Fibrosis and Disease Fibrosis is a scarring process that appears in many tissues in the body, typically as a result of inflammation or tissue injury. Increased production of extracellular matrix leads to organ failure and often death. Diseases associated with fibrosis account for approximately 45% of all deaths in industrialized countries (Wynn, TA, 2008, J Pathol. 214:199-210). One such disease is Systemic Sclerosis (SSc). SSc is a complex autoimmune disease with a chronic progressive course and high interpatient variability. It is characterized by inflammation, vascular dysfunction and fibrosis. Fibrosis in the skin and visceral organs leads to irreversible scarring and ultimately organ failure, causing high mortality. Currently, there are no approved targeted therapies with disease-modifying potential.

[0015] The cells responsible for the production of extracellular matrix (ECM) for tissue repair (and in fibrosis) are a specialized type of fibroblast called myofibroblast (MF). Although the mechanisms of fibrosis have been extensively studied, this complex process is by no means fully understood. To focus on the most important drivers of fibrosis, published patient-derived datasets (SSc patient data and normal controls) were investigated using a novel data analysis method obtained in-house. This analysis identified the type I collagen-binding integrin alpha11 beta1 (α11β1) as one of the top targets for modulating fibrosis.

[0016] To date, there are no truly disease-modifying therapies for fibrosis. Two of the approved therapies for idiopathic pulmonary fibrosis (IPF), nintedanib and pirfenidone, are ineffective and do not modify the disease, and to date there are no approved therapies for systemic sclerosis (SSc). In some embodiments, the fibrotic disorder is or includes idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis (SSc). In some embodiments, the fibrotic disorder is or includes atrial fibrosis, endomyocardial fibrosis, arthrofibrosis, mediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

[0017] One clinical feature of the tumor microenvironment is the interaction between the tumor and the stroma, which mainly depends on various integrins interacting with ECM components and growth factors. Such interactions can affect tumor survival, progression and ultimately metastasis. α11β1 has been reported to be overexpressed in cancer-associated fibroblasts (CAFs) of metastatic tumors, and its expression correlates with invasive tumors in patients. For example, integrin α11 was overexpressed in the stroma of most head and neck squamous cell carcinomas (HNSCC) and positively correlated with alpha smooth muscle actin expression (Parajuli et al., J. Oral Pathol. Med. 46:267-275 (2017)). Integrin α11 was also overexpressed by CAFs in pancreatic ductal adenocarcinoma (PDAC) stroma (Schnittert et al., FASEB J. 33: 6609-6621 (2019)). In addition, integrin α11β1 overexpression in tumor stroma has been associated with tumor growth and metastatic potential in non-small cell lung cancer (NSCLC), and high expression of ITGA11 (the gene encoding integrin alpha-11 in humans) was associated with lower recurrence-free survival in all NSCLC patients. The same study showed that α11 overexpression in lung cancer cell lines resulted in increased migration and invasion (Ando et al., Cancer Sci. 111: 200-208 (2020)).

[0018] Integrin Integrins are a large family of type I transmembrane heterodimeric glycoprotein receptors that act as the primary receptors for cell adhesion. The integrin family of receptors plays an important role in regulating signaling pathways that control cell adhesion, migration, proliferation, differentiation and apoptosis. There are 18 α subunits and 8 β subunits that combine to form 24 integrin heterodimers. Each integrin receptor contains two non-covalently linked subunits, α and β. Integrins α1β1, α2β1, α10β1 and α11β1 are the major collagen receptors. The α and β subunits are transmembrane proteins with a large modular extracellular domain, a single transmembrane helix, and a short cytoplasmic region that mediate cytoskeletal interactions. The extracellular domain of integrins is generally large, approximately 80-150 kDa in structure. The extracellular domain can be considered to include a headpiece connected to two legs (see Figure 1 for the structure of collagen-binding integrins). Collagen-binding integrins contain an I domain that serves as a ligand-binding site. The αI domain contains a conserved "metal-ion-dependent adhesion site" (MIDAS) that binds divalent metal cations (Mg2+) and plays an important role in ligand binding.

[0019] Integrins can exist in three different conformations: 1) a resting, low affinity state in which the headpiece containing the ligand binding site faces towards the membrane (flexed conformation, Figure 1, panel A), 2) an extended intermediate affinity state in which the integrin is extended but the headpiece remains "closed" (Figure 1, panel B), and 3) an extended high affinity state in which the integrin is fully activated and readily binds ligand. The complexity of the different integrin states allows for both allosteric and ligand blocking methods of inhibiting integrin function. As marked with an asterisk in Figure 1, one allosteric method of blocking integrin function is to generate monoclonal antibodies that prevent the integrin from reaching the fully extended conformation from the extended intermediate conformation. Another allosteric option is to bind to the integrin in its bent / inactive conformation and prevent it from extending into either of the two other states. A non-allosteric method of inhibiting integrin function is to bind to the I-domain and prevent the integrin from attaching to collagen. Binding to the ligand-binding site directly runs the risk of generating a recombinant activator of integrin function.

[0020] As cell surface receptors, integrins can sense the stiffness of the surrounding matrix and trigger cells to produce and remodel additional connective tissue, thus perpetuating the fibrotic phenotype. Many integrins are overexpressed in fibrosis, but it is unclear which alpha subunit is sufficient for the development of fibrosis. α11β1 integrin is specifically expressed in a subset of fibroblasts and myofibroblasts (i.e., terminal scar-producing cells). Recent literature provides strong evidence that α11β1 is one of the major drivers of the fibrotic phenotype in cardiac tissue, liver, lung and kidney (Romaine, A. et.al. Overexpression of integrin alpha11 induces cardiac fibrosis in mice. Acta Physiol Feb 2018,222(2); Bansal, R. et.al. Integrin alpha11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. Exp Mol Med. 2017 Nov 17:49(11)). Blockade of α11β1 function can inhibit myofibroblast differentiation and extracellular matrix deposition (i.e. key events in scar formation) and provide a mechanism for local injury-specific attenuation of fibrosis that could fundamentally alter the fibrotic microenvironment and modify disease progression in all diseases with a fibrotic component.

[0021] In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof of the present disclosure reduces the interaction between α11β1 and collagen in human α11β1-expressing cells. In some embodiments, the reduction in the interaction between α11β1 and collagen in human α11β1-expressing cells comprises an anti-α11β1 antibody or antigen-binding fragment thereof interacting with α11β1 in a resting low affinity state (bent conformation). In some embodiments, the reduction in the interaction between α11β1 and collagen in human α11β1-expressing cells comprises an anti-α11β1 antibody or antigen-binding fragment thereof interacting with α11β1 in an extended intermediate affinity state. In some embodiments, the reduction in the interaction between α11β1 and collagen in human α11β1-expressing cells comprises an anti-α11β1 antibody or antigen-binding fragment thereof interacting with α11β1 in an extended high affinity state.

[0022] antibody The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and / or antibody fragments (preferably fragments that exhibit the desired antigen-binding activity). The 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 immunological binding moieties known in the art, including, for example, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, Feb, scFv, SMIP, antibodies, diabodies, triabodies, tetrabodies, minibodies, maxibodies, tandab, DVD, BiTe, TandAb, etc., or any combination thereof. The subunit structures and three-dimensional configurations of different classes of antibodies are known in the art.

[0023] A "monoclonal antibody" or "mAb" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies (e.g., containing naturally occurring mutations or arising during production of the monoclonal antibody preparation), which variants are typically present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.

[0024] "Antigen-binding fragment" refers to a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Antigen-binding fragments of antibodies include any naturally occurring, enzymatically obtainable, 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; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or VHH or VH or VL domains only); and multispecific antibodies formed from antibody fragments. In some embodiments, the antigen-binding fragments of antibodies described herein are scFvs. As with complete antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies may include at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope of the same antigen.

[0025] A "multispecific antibody" refers to an antibody that contains at least two different antigen-binding domains that recognize and specifically bind to at least two different antigens. A "bispecific antibody" is a type of multispecific antibody and refers to an antibody that contains two different antigen-binding domains that recognize and specifically bind to at least two different antigens.

[0026] "Different antigens" may refer to different and / or distinct proteins, polypeptides or molecules, as well as different and / or distinct epitopes that may be contained within one protein, polypeptide or other molecule.

[0027] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions of an antigen and have different biological effects. The term "epitope" also refers to the site of an antigen to which B cells and / or T cells respond. It also refers to the region of an antigen that is bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and have residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, i.e., composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groups of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and in certain embodiments may have specific three-dimensional structural characteristics and / or specific charge characteristics.

[0028] As used herein, "selective binding," "selectively binds," "specific binding," or "specifically binds," in reference to an antigen-binding moiety and an antigen target, refers to the antigen-binding moiety preferentially associating with the antigen target and not with entities that are not the antigen target. Some degree of non-specific binding may occur between the antigen-binding moiety and the non-target. In some embodiments, an antigen-binding moiety selectively binds to an antigen target if the binding between the antigen-binding moiety and the antigen target is more than 2-fold, more than 5-fold, more than 10-fold, or more than 100-fold greater than the binding ... has a binding affinity of about 10 -5 Less than M, about 10 -6 Less than M, about 10 -7 Less than M, about 10 -8 Less than M or about 10 -9If M is less than M, it will selectively bind to the antigen target.

[0029] In some embodiments, antibodies or fragments thereof that selectively bind to the same or overlapping epitopes often cross-compete for binding to an antigen. Thus, in some embodiments, the present disclosure provides antibodies or fragments thereof that cross-compete with the exemplary antibodies or fragments thereof disclosed herein. In some embodiments, "cross-compete," "compete," "cross-compete," or "compete" means that an antibody or fragment thereof competes for the same epitope or binding site on a target. Such competition can be determined by an assay in which a reference antibody or fragment thereof prevents or inhibits specific binding of a test antibody or fragment thereof, or vice versa. Many types of competitive binding assays can be used to determine whether a test molecule competes with a reference molecule for binding. Examples of assays that can be utilized include solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competitive assays (see, e.g., Stahli et al. (1983) Methods in Enzymology 9:242-253), solid-phase direct biotin-avidin EIA (see, e.g., Kirkland et al., (1986) J. Immunol. 137:3614-9), solid-phase direct labeling assays, solid-phase direct labeling sandwich assays, 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 plasmon 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 competing antibody or fragment thereof is present in excess, it inhibits binding of a reference antibody or fragment thereof to a common antigen by at least 50%, 55%, 60%, 65%, 70%, or 75%. In some instances, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more.

[0030] An antibody can be an immunoglobulin molecule of four polypeptide chains, e.g., two heavy (H) chains and two light (L) chains. In some embodiments, the light chain is a lambda light chain. In some embodiments, the light chain is a kappa light chain. The heavy chain can comprise a heavy chain variable domain and a heavy chain constant domain. The heavy chain constant domain can comprise a CH1, hinge, CH2, CH3, and optionally a CH4 region. The light chain can comprise a light chain variable domain and a light chain constant domain. The light chain constant domain can comprise a CL.

[0031] The heavy chain variable domain of the heavy chain and the light chain variable domain of the light chain can typically be further subdivided into regions of variability called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Such heavy and light chain variable domains can each comprise three CDRs and four framework regions arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, one or more of which can be engineered as described herein. The CDRs of the heavy chain are referred to as "CDRH1", "CDRH2", and "CDRH3", respectively, and the CDRs of the light chain are referred to as "CDRL1", "CDRL2", and "CDRL3", respectively.

[0032] There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0033] Exemplary Antibodies The present disclosure provides antibodies that may comprise various heavy and light chains as described herein. In some embodiments, the antibodies comprise two heavy and light chains. In some embodiments, the present disclosure encompasses antibodies that comprise at least one heavy and / or light chain as disclosed herein, at least one heavy and / or light chain framework 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.

[0034] In some embodiments, the antibodies disclosed herein are homodimeric monoclonal antibodies. In some embodiments, the antibodies disclosed herein are heterodimeric antibodies. In some embodiments, the antibodies are, for example, typical antibodies or diabodies, triabodies, tetrabodies, minibodies, maxibodies, tandabs, DVDs, BiTe, scFvs, TandAbs, scFvs, Fabs, Fab2s, Fab3s, F(ab')2s, etc., or any combination thereof.

[0035] The present disclosure provides, inter alia, anti-integrin alpha11 beta 1 (α11β1) antibodies or antigen-binding fragments thereof. In some embodiments, the α11β1 antibody or antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-443. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NOs: 103-207, 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, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 359, 361, 365, 367, 369, 271, 275, 277, 279, 281, 283, , 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 435. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof comprises CDR1, CDR2 and CDR3 encompassed by any one of SEQ ID NOs: 103-206 or 413-443. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-114, 207-311, and 312-443.In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NOs: 103-114, 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, 313, 314, 315, 316, 317, 318, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 359, 361, 365, 367, 369, 271, 275, 277, 14, 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 antigen-binding fragment thereof comprises one or more CDR sequences encompassed in any one of SEQ ID NOs: 103-114 or 413-434. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof comprises CDR1, CDR2 and CDR3 encompassed in any one of SEQ ID NOs: 103-114 or 413-434. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof reduces the interaction of α11β1 with collagen in human α11β1-expressing cells. In some embodiments, the present disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof that competes with an antibody or antigen-binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-443.In some embodiments, the disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof that competes with an antibody or antigen-binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-443.

[0036] In some embodiments, the present disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof comprising a heavy chain provided herein and a light chain provided herein. In some embodiments, the present disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof comprising a heavy chain variable domain provided herein and a light chain variable region provided herein. In some embodiments, the present disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof comprising a particular combination of a heavy chain variable domain and a light chain variable domain. For example, in some embodiments, the anti-α11β1 antibody or antigen-binding fragment thereof comprises a combination of a heavy chain variable domain and a light chain variable domain selected from Table 1.

[0037] [Table 1]

[0038] In some embodiments, the disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof that comprises 1-30 (e.g., 1, 2, 3, 4, 5, 10 or more) additions, deletions, or substitutions compared to an anti-α11β1 antibody or antigen-binding fragment thereof, where the anti-α11β1 antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-158, 413, 414, and 421-434, e.g., the antibody or fragment selectively binds to α11β1. In some embodiments, the disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof that comprises 1-30 additions, deletions, or substitutions compared to an anti-α11β1 antibody or antigen-binding fragment thereof, where the anti-α11β1 antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-114, 413, 414, and 421-434, e.g., the antibody or fragment selectively binds to α11β1. In some embodiments, the disclosure provides an anti-α11β1 antibody or 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 to an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-158, 413, 414 and 421-434, e.g., the antibody or fragment selectively binds to α11β1. In some embodiments, the disclosure provides an anti-α11β1 antibody or 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 to an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-114, 413, 414 and 421-434, e.g., the antibody or fragment selectively binds to α11β1.

[0039] In some embodiments, the disclosure provides an anti-α11β1 antibody or antigen-binding fragment thereof that comprises 1 to 90 (e.g., 1 to 50, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) additions, deletions or substitutions compared to an anti-α11β1 antibody or antigen-binding fragment thereof, wherein the anti-α11β1 antibody or antigen-binding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 159-206 and 415-420, e.g., the antibody or fragment selectively binds to α11β1. In some embodiments, the disclosure provides an anti-α11β1 antibody or 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 to an amino acid sequence selected from the group consisting of SEQ ID NOs: 159-206 and 415-420, e.g., the antibody or fragment selectively binds to α11β1.

[0040] In some aspects, the present disclosure provides an antibody or fragment thereof that selectively binds to alpha11beta1, the antibody or fragment comprising one or more CDR sequences set forth in the list of exemplary sequences provided herein. For example, in some embodiments, the antibody or fragment comprises one or more CDRs from SEQ ID NOs: 103-114. In some embodiments, the present disclosure provides an antibody or fragment thereof that selectively binds to alpha11beta1, 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 NOs: 103-114. In some embodiments, the antibody or fragment comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NOs: 103-114, the antibody comprises one or more CDRs set forth in one of SEQ ID NOs: 103-114. For example, the antibody or fragment comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:103, and the antibody comprises one or more CDRs (e.g., one, two or three CDRs) set forth in SEQ ID NO:103.

[0041] In some aspects, the disclosure provides an antibody or fragment thereof that selectively binds to α11β1, wherein the antibody or fragment comprises one or more CDR sequences set forth in the list of exemplary sequences provided herein. For example, in some embodiments, the antibody or fragment comprises one or more CDR sequences set forth in SEQ ID NOs: 103-207, 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, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 3 4, 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 disclosure provides an antibody or fragment thereof that selectively binds to α11β1, the antibody or fragment being selected from the group consisting of SEQ ID NOs: 103-207, 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, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 6, 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 413-443.In some embodiments, the antibody or fragment is selected from the group consisting of SEQ ID NOs: 103-207, 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, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 375, 377, 379, 381, , 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 413-443 and at least 90%, 91%, 92%, 93%, 94%, 95%, or 96% , 97%, 98%, or 99% identity to any of the amino acid sequences set forth in SEQ ID NOs: 103-207, 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 413-443.For example, the antibody or fragment comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:103, and the antibody comprises one or more CDRs (e.g., one, two or three CDRs) set forth in SEQ ID NO:103.

[0042] The present disclosure provides, inter alia, methods for making anti-α11β1 antibodies or antigen-binding fragments thereof. Methods for making antibodies are known in the art. In some embodiments, the present disclosure provides a method for producing an antibody or antigen-binding fragment thereof, comprising culturing a host cell comprising a nucleic acid comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-102 under conditions suitable for expression of the antibody or antigen-binding fragment thereof.

[0043] Exemplary Nucleotide Sequences The present disclosure includes nucleotide sequences encoding one or more heavy chains, heavy chain variable domains, heavy chain framework regions, heavy chain CDRs, heavy chain constant domains, light chains, light chain variable domains, light chain framework 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, e.g., a cell of a subject in need of treatment or a cell for the production of an antibody, e.g., a mammalian cell for the production of an antibody.

[0044] In some embodiments, the disclosure provides a nucleic acid comprising a nucleic acid sequence encoding an antibody or antigen-binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-206. In some embodiments, the disclosure provides a nucleic acid comprising a nucleic acid sequence encoding an antibody or antigen-binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-114. In some embodiments, the disclosure provides a nucleic acid comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-102. In some embodiments, the disclosure provides a vector comprising a nucleic acid comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-102. In some embodiments, the disclosure provides a host cell comprising a nucleic acid comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-102. In some embodiments, the disclosure provides a vector comprising a nucleic acid comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-102.

[0045] In some embodiments, the 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 to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-102.

[0046] Measurement of antibody interaction with α11β1 The binding properties of the antibodies described herein to alpha11beta1 can be measured by methods known in the art, such as one of the following methods: BIACORE analysis, Enzyme Linked Immunosorbent Assay (ELISA), X-ray crystallography, sequence analysis, and scanning mutagenesis. The binding interaction between the antibody and alpha11beta1 can be analyzed using Surface Plasmon Resonance (SPR). SPR, or Biomolecular Interaction Analysis (BIA), detects biospecific interactions in real time without labeling any of the interactants. A change in mass at the binding surface of the BIA chip (indicative of a binding event) results in a change in the refractive index of light near the surface. The change in refractivity generates a detectable signal, which is measured as an indication of a real-time reaction between biological molecules. Methods using SPR are described, for example, in U.S. Patent No. 5,641,640, Raether (1988) Surface Plasmon Springer Verlag, Sjolander and Urbaniczky (1991) Anal.Chem.63:2338-2345, Szabo et al. (1995) Curr.Opin.Struct.Biol.5:699-705, and online resources are provided by BIAcore International AB (Uppsala, Sweden). Additionally, KinExA® (Kinexclusion Assay) assays available from Sapidyne Instruments (Boise, Id.) can also be used.

[0047] Information from SPR was used to determine the equilibrium dissociation constant (K D ), and K on and K offSPR can provide accurate and quantitative measures of kinetic parameters, including the binding affinity, binding affinity, and affinity of the target molecule. Such data can be used to compare different molecules. Information from SPR can also be used to develop structure-activity relationships (SAR). Variant amino acids at given positions that correlate with particular binding parameters, e.g., high affinity, can be identified.

[0048] In certain embodiments, the antibodies described herein exhibit high affinity for binding to α11β1. In various embodiments, the K D is about 10 -4 , 10 -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 , 10 -14 or 10 -15 In a particular example, the K of the antibodies described herein for α11β1 is less than M. D is 0.001 to 1 nM, for example, 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM or 1 nM.

[0049] Treatment method In some embodiments, one or more anti-α11β1 antibodies described herein are used in a method for treating one or more disorders described herein, such as one or more fibrotic disorders and / or one or more cancers. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof described herein. In some embodiments, the fibrotic disorder is or comprises idiopathic pulmonary fibrosis (IPF), chronic kidney disease, diabetic cardiomyopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), nonalcoholic fatty liver disease (NAFLD / NASH), Crohn's disease, ulcerative colitis, or systemic sclerosis.

[0050] In some embodiments, the fibrotic disorder is or includes atrial fibrosis, endomyocardial fibrosis, arthrofibrosis, mediastinal fibrosis, myelofibrosis, progressive massive fibrosis, retroperitoneal fibrosis, or skeletal muscle fibrosis.

[0051] In some embodiments, one or more anti-alpha11beta1 antibodies described herein are used in a method to treat cancer, such as one or more of the following: head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, non-small cell lung carcinoma, adrenocortical carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, invasive breast carcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, glioblastoma multiforme, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, skin melanoma, mesothelioma, ovarian serous cystadenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, sarcoma, gastric adenocarcinoma, testicular germ cell tumor, thymoma, thyroid carcinoma, uterine endometrial carcinoma, uterine carcinosarcoma, uveal melanoma, renal clear cell carcinoma, renal carcinosarcoma, and renal papillary cell carcinoma.

[0052] In some embodiments, one or more anti-α11β1 antibodies described herein are used to treat a subject having or at risk for chronic kidney disease (CKD), e.g., CKD associated with fibrosis. CKD is known in the art (see, e.g., Brenner, Barry M. (ed) Brenner & Rector's The Kidney, 11). th (See, for example, Brenner, Barry M. (ed) Brenner & Rector's The Kidney, 11th edition 2019.) CKD includes, for example, primary glomerular disease (including but not limited to IgA nephropathy and focal segmental glomerulosclerosis), secondary glomerular disease (including but not limited to lupus nephritis), thrombotic microangiopathy, tubulointerstitial disease (including but not limited to obstructive uropathy), diabetic nephropathy, hypertensive nephropathy, ischemic nephropathy, cardiorenal syndrome in CKD, genetic disorders of the glomerulus (including but not limited to Alport syndrome), cystic diseases of the kidney (including but not limited to polycystic kidney disease), or genetic disorders of the renal tubule (Brenner, Barry M. (ed) Brenner & Rector's The Kidney, 11th edition 2019.) th edition2019).

[0053] In some embodiments, the anti-α11β1 antibodies described herein, when administered to a subject, reduce one or more markers, signs and / or symptoms of a kidney-related disorder described herein, including, for example, COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, and MMP9. In some embodiments, upon administration to a subject, the anti-α11β1 antibody can reduce a measured marker, sign, and / or symptom by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% compared to a control (e.g., a certain level of the measured marker, sign, and / or symptom in a subject prior to administration of the antibody, a certain level of the measured marker, sign, and / or symptom in a subject suffering from a renal-related disorder, and / or an average level of the measured marker, sign, and / or symptom in a population of subjects suffering from a renal-related disorder).

[0054] In some embodiments, the anti-α11β1 antibodies described herein reduce the levels of COL1A1, IL-6, TIMP-1, hyaluronic acid, TGFβ, CTGF, PDGF, MMP9, or a combination thereof, by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% compared to a control when measured in a model of kidney-related disorder (e.g., human precision cut kidney slice (PCKS), ReninAAV Unx db / db mouse model, or 5 / 6 nephrectomy model). In some embodiments, markers, signs and / or symptoms of kidney-related disorder can be determined by measuring protein levels, RNA levels, DNA levels, or a combination thereof. In some embodiments, markers, signs and / or symptoms of kidney-related disorders may be determined using ELISA, PCR, RNAseq, biochemical assays (e.g., analytical procedures for detecting and quantifying cellular processes (e.g., apoptosis, cell signaling) or metabolic responses), cytology, immunohistochemistry, or combinations thereof.

[0055] In some embodiments, markers, signs and / or symptoms of kidney-related disorders can be determined by testing a biological sample from a subject. Examples of suitable biological samples include, but are not limited to, serum, plasma, cerebrospinal fluid, urine, circulating blood cells (e.g., peripheral blood mononuclear cells), and biopsy specimens. In some embodiments, the sample comprises cells or tissue. In some embodiments, the provided method further comprises lysing cells or performing a tissue biopsy, and the one or more markers comprise one or more intracellular markers. A biological sample suitable for the present disclosure may be a fresh or frozen sample collected from a subject, or an archived sample with a known diagnosis, treatment and / or outcome history. The biological sample may be collected by any invasive or non-invasive means, for example, by withdrawing CSF or blood from the subject, or by using fine needle aspiration or needle biopsy, or by surgical biopsy. In some embodiments, the biological sample may be used without or with limited sample processing.

[0056] Combination therapy In some embodiments, the anti-alpha11beta1 antibodies described herein are administered in combination with one or more additional therapeutic agents, such as chemotherapeutic agents or oncolytic therapeutic agents. As used herein, "combination therapy" refers to a situation in which two or more different pharmaceutical agents are administered in an overlapping regimen such that the subject is exposed to both agents simultaneously. When used in combination therapy, the two or more different agents can be administered simultaneously or separately. Combination administration can 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 can be formulated together in the same dosage form and administered simultaneously. Alternatively, two or more agents can be administered simultaneously, where the agents are in separate formulations. In another alternative, one or more additional agents can be administered immediately after administration of the first agent. In separate administration protocols, two or more agents can be administered minutes apart, or hours apart, or days apart.

[0057] As used herein, the term "chemotherapeutic agent" or "oncolytic therapeutic agent" (e.g., anti-cancer drug, e.g., anti-cancer therapy, e.g., immune cell therapy) has its art-recognized meaning to refer to one or more pro-apoptotic, cytostatic and / or cytotoxic agents and / or hormonal agents, including, for example, agents specifically utilized and / or recommended for use in treating one or more diseases, disorders, or conditions associated with unwanted cell proliferation. In some embodiments, the chemotherapeutic agent and / or oncolytic therapeutic agent is a platinum compound (e.g., cisplatin, carboplatin, and oxaliplatin), an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, and bendamustine), an antitumor antibiotic (e.g., daunorubicin, , doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, and dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogues (e.g., fludarabine, clofarabine, cladocycline, cyclospor ... livine, pentostatin, and nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacytidine and decitabine), proteosome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., bicristine, vindesine, vinorelbine, and vinblastine), Tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, and sunitinib), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide and lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide,The therapeutic agent may be or may include an anti-inflammatory drug, such as cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory drugs, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, and oxaprozin), a selective cyclooxygenase-2 (COX-2) inhibitor, or any combination thereof.

[0058] In certain embodiments, chemotherapeutic and / or oncolytic therapeutic agents for anti-cancer treatment include 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., cytokines, e.g., immunomodulators or biological response modifiers), checkpoint inhibitors, or other immunological agents. In certain embodiments, immunological agents include immunoglobulins, immunostimulants (e.g., bacterial vaccines, colony stimulating factors, interferons, interleukins, therapeutic vaccines, vaccine combinations, viral vaccines), and / or immunosuppressants (e.g., calcineurin inhibitors, interleukin inhibitors, TNF alpha inhibitors). In certain embodiments, hormonal agents include agents for anti-androgen therapy (e.g., ketoconazole, abiraterone, TAK-700, TOK-OOl, bicalutamide, nilutamide, flutamide, enzalutamide, ARN-509).

[0059] Additional chemotherapeutic and / or oncolytic therapeutic agents include immune checkpoint therapeutics (e.g., pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, tremelimumab, or cemiplimab), other monoclonal antibodies (e.g., rituximab, cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamab, isin, 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, WA) Genetics), ado-trastuzumab emtansine (KADCYLA®, Roche), gemtuzumab ozogamicin (Wyeth), CMC-544, SAR3419, CDX-011, PSMA-ADC, BT-062, and IMGN901 (see, e.g., 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.

[0060] In some embodiments, the combined administration of anti-alpha11beta1 antibody and additional therapeutic agent results in the amelioration of cancer to a greater extent than that caused by either anti-alpha11beta1 antibody or additional therapeutic agent alone. The difference between the combined effect and the effect of each agent alone can be a statistically significant difference. In some embodiments, the combined effect can be a synergistic effect. In some embodiments, the combined administration of anti-alpha11beta1 antibody and additional therapeutic agent allows the administration of the additional therapeutic agent at a reduced dose, reduced dosing times, and / or reduced dosing frequency compared to a standard dosing regimen, e.g., an approved dosing regimen for the additional therapeutic agent.

[0061] In some embodiments, the therapeutic methods described herein are administered to subjects who have failed other treatments for a medical condition or have been treated less successfully by other means. Additionally, the therapeutic methods described herein can be administered in conjunction with one or more additional treatments for a medical condition. For example, the method can include administering a cancer regimen, such as non-myeloablative chemotherapy, surgery, hormonal therapy, and / or radiation, before, substantially simultaneously, or after administration of the anti-α11β1 antibody or composition thereof described herein.

[0062] Formulation and Administration In various embodiments, the antibodies described herein can be incorporated into pharmaceutical compositions. Such pharmaceutical compositions can be useful, for example, for the prevention and / or treatment of diseases, such as fibrotic disorders. Pharmaceutical compositions can be formulated by methods known to those skilled in the art (e.g., as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA. (1985)).

[0063] In some embodiments, the pharmaceutical composition can be formulated to include a pharma- ceutically acceptable carrier or excipient. Examples of pharma-ceutically acceptable carriers include, but are not limited to, any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The composition of the present invention can include pharma-ceutically acceptable salts, such as acid addition salts or base addition salts.

[0064] In some embodiments, compositions comprising the antibodies described herein, e.g., sterile preparations for injection, can be formulated according to conventional pharmaceutical practice using distilled water for injection as a vehicle. For example, saline or isotonic solutions containing glucose and other supplements such as D-sorbitol, D-mannose, D-mannitol and sodium chloride, optionally in combination with suitable solubilizers, e.g., alcohols such as ethanol and / or polyhydric alcohols such as propylene glycol or polyethylene glycol and / or non-ionic surfactants such as polysorbate 80™ or HCO-50, can be used as aqueous solutions for injection.

[0065] As disclosed herein, pharmaceutical compositions may be in any form known in the art, including, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.

[0066] The selection or use of any particular form may depend in part on the intended mode of administration and therapeutic application. For example, compositions containing compositions intended for systemic or local delivery may be in the form of an injectable or infusible solution. Thus, the composition may be formulated for administration by parenteral modes (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). As used herein, parenteral administration refers to modes of administration other than enteral and local administration, usually by injection, and includes, but is not limited to, intravenous, intranasal, intraocular, intrapulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion. In some embodiments, the composition may be targeted to the kidney. In some embodiments, the composition may be targeted to renal cells.

[0067] The route of administration may be parenteral, e.g., by injection, nasal, pulmonary, or transdermal. Administration may be systemic or local, such as by intravenous, intramuscular, intraperitoneal, or subcutaneous injection. In some embodiments, the route of administration is or includes dialysis. In some aspects, the route of administration is or includes hemodialysis. In some embodiments, the route of administration is or includes peritoneal dialysis.

[0068] In some embodiments, the pharmaceutical compositions of the present invention can be formulated as solutions, microemulsions, dispersions, liposomes, or other ordered structures suitable for stable storage at high concentrations. Sterile injectable solutions can be prepared by incorporating the required amount of the compositions described herein in an appropriate solvent containing one or a combination of ingredients listed above, as needed, followed by filtered sterilization. In general, dispersions are prepared by incorporating the compositions described herein into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, which yield a powder of the compositions described herein and any additional desired ingredients (see below) from a previously sterile-filtered solution thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0069] Pharmaceutical compositions can be administered parenterally in the form of injectable formulations, including sterile solutions or suspensions in water or another pharma- ceutically acceptable liquid. For example, pharmaceutical compositions can be formulated by suitable combination of therapeutic molecules with pharma- ceutically acceptable vehicles or media, such as sterile water and saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring excipients, diluents, vehicles, preservatives, binders, and then mixed in unit dose forms required by generally accepted pharmaceutical practice. The amount of active ingredient included in the pharmaceutical preparation is such that a suitable dose within the specified range is provided. Non-limiting examples of oily liquids include sesame oil and soybean oil, which can be combined with benzyl benzoate or benzyl alcohol as a solubilizer. Other items that can be included are buffers such as phosphate buffer or sodium acetate buffer, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol or phenol, and antioxidants. Formulated injections can be packaged in suitable ampoules.

[0070] In various embodiments, subcutaneous administration can be accomplished by devices such as a syringe, a pre-filled syringe, an auto-injector (e.g., disposable or reusable), a pen injector, a patch injector, a wearable injector, a portable injector infusion pump with a subcutaneous infusion set, or other devices for combining an antibody drug for subcutaneous injection.

[0071] The injection system of the present disclosure may utilize a delivery pen as described in U.S. Pat. No. 5,308,341. Pen-type devices, most commonly used for self-delivery of insulin to diabetic patients, are well known in the art. Such devices may include at least one injection needle (e.g., a 31-gauge needle having a length of about 5-8 mm) and are typically pre-filled with one or more therapeutic unit doses of a therapeutic solution, useful for rapid delivery of the solution to a subject with as little pain as possible. One drug delivery pen includes a vial holder that can accept a vial of a therapeutic drug or other medication. The pen may be a completely mechanical device or may be combined with electronic circuitry to accurately set and / or indicate the dosage of the medication to be injected to the user. See, for example, U.S. Pat. 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 devices suitable for delivery of any one of the currently characterized compositions are also described in, for example, U.S. Patent No. 6,277,099, U.S. Patent No. 6,200,296, and U.S. Patent No. 6,146,361, the disclosures of each of which are incorporated herein by reference in their entirety.Microneedle-based pen devices are also described in, for example, U.S. Patent No. 7,556,615, the disclosures of which are incorporated herein by reference in their entirety.See also Precision Pen Injector (PPI) device, MOLLY (trademark), manufactured by Scandinavian Health Ltd.

[0072] In some embodiments, the compositions described herein can be therapeutically delivered to a subject by local administration. As used herein, "local administration" or "local delivery" can refer to delivery that does not rely on the transport of the composition or agent to its intended target tissue or site via the vascular system. For example, the composition can be delivered by injection or implantation of the composition or agent, or by injection or implantation of a device containing the composition or agent. In certain embodiments, after local administration near the target tissue or site, the composition or agent, or one or more components thereof, can diffuse to the intended target tissue or site that is not the site of administration.

[0073] In some embodiments, the compositions can be formulated for storage at temperatures below 0° C. (e.g., −20° C. or −80° C.). In some embodiments, the compositions can be formulated for storage at 2-8° C. (e.g., 4° C.) for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 11 / 2 years, or 2 years). Thus, in some embodiments, the compositions described herein are stable upon storage at 2-8° C. (e.g., 4° C.) for at least 1 year.

[0074] In some embodiments, the pharmaceutical composition can be formulated as a solution, e.g., a buffered solution at a concentration suitable for storage at 2-8°C (e.g., 4°C).

[0075] Compositions comprising one or more of the antibodies described herein can be formulated into immunoliposome compositions. Such formulations can be prepared by methods known in the art. Liposomes with improved circulation time are disclosed, for example, in U.S. Patent No. 5,013,556.

[0076] In certain embodiments, the composition can be formulated with a carrier that protects the compound from rapid release, such as controlled release formulations, including implants and microencapsulated delivery systems.Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.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.

[0077] In some embodiments, administration of the antibodies described herein is accomplished by administering to the subject a nucleic acid encoding the antibody. Nucleic acids encoding the therapeutic antibodies described herein can be incorporated into genetic constructs used as part of gene therapy protocols to deliver nucleic acids that can be used to express and produce the antibody in cells. Such component expression constructs can be administered in any therapeutically effective carrier, for example, any formulation or composition that can effectively deliver the component genes to cells in vivo. Approaches include viral vectors, including recombinant retroviruses, adenoviruses, adeno-associated viruses, lentiviruses, and herpes simplex virus-1 (HSV-1), or insertion of the gene of interest into recombinant bacterial or eukaryotic plasmids. Viral vectors can directly transfect cells. Plasmid DNA can be delivered with the aid of, for example, cationic liposomes (lipofectin) or derivatized polylysine conjugates, gramicidin S, artificial viral envelopes, or other such intracellular carriers, as well as direct injection or CaPO4 precipitation of the genetic construct (see, for example, WO 04 / 060407).Examples of suitable retroviruses include pLJ, pZIP, pWE, and pEM, which are known to those skilled in the art (see, e.g., 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. (1992) Proc Natl Acad Sci USA 88:8377-8381, and others). (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. Pat. Nos. 4,868,116 and 4,980,286; and WO 89 / 07136, 89 / 02468, 89 / 05345, and 92 / 07573. Another viral gene delivery system utilizes adenovirus-derived vectors (see, e.g., 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 the adenovirus strain Ad type 5 dl324 or other strains of adenovirus (e.g., Ad2, Ad3, Ad7, etc.) are known to those of skill in the art.Yet another viral vector system useful for delivery of a gene of interest is the adeno-associated virus (AAV). See, e.g., 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.

[0078] In some embodiments, the compositions provided herein are in unit dosage form, and this unit dosage form can be suitable for self-administration.Such unit dosage form can be provided in a container, typically, for example, a vial, a cartridge, a pre-filled syringe or a disposable pen.Administration devices, such as the administration device described in U.S. Patent No. 6,302,855, can also be used with, for example, the injection system described herein.

[0079] The suitable dose of the compositions described herein is the dose that can treat or prevent the subject's disorder, and may depend on various factors, including, for example, the age, sex, and weight of the subject being treated, as well as the specific inhibitor compound used. For example, different doses of one composition comprising an antibody described herein may be required to treat a subject with a fibrotic disorder, compared to doses of different formulations of the antibody. Other factors that affect the dose administered to the subject include, for example, the type or severity of the disorder. Other factors may include, for example, other medical disorders that simultaneously or previously affect the subject, the overall health of the subject, the genetic predisposition of the subject, diet, administration time, excretion rate, drug combination, and any other additional therapeutic agents administered to the subject. It should also be understood that the specific dosage and treatment regimen for any particular subject may also be adjusted based on the judgment of the treating physician.

[0080] The compositions described herein can be administered as a fixed dose or in milligram per kilogram (mg / kg) doses. In some embodiments, the dose can also be selected to reduce or avoid the production of antibodies or other host immune responses to one or more of the antigen-binding molecules in the composition. Exemplary dosages of antibodies, such as the compositions described herein, include, for example, 0.0001-100 mg / kg, 0.01-5 mg / kg, 1-1000 mg / kg, 1-100 mg / kg, 0.5-50 mg / kg, 0.1-100 mg / kg, 0.5-25 mg / kg, 1-20 mg / kg, and 1-10 mg / kg of the subject's body weight. For example, dosages can 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 within the range of 1-20 mg / kg body weight. Exemplary treatment regimens entail administration once per week, once per two weeks, once per three weeks, once per four weeks, once per month, once per three months, or once per three to six months, or at short dosing intervals initially (such as once per week to once per three weeks) followed by longer intervals (such as once per month to once per three to six months).

[0081] The pharmaceutical solution may include a therapeutically effective amount of the compositions described herein. Such effective amounts may be readily determined by one of skill in the art based in part on the effect of the administered composition or, if more than one agent is used, on the combined effect of the composition and one or more additional active agents. The therapeutically effective amount of the compositions described herein may also vary according to factors such as the disease state, age, sex, and weight of the individual, 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, e.g., improvement of at least one symptom of a fibrotic disorder. For example, a therapeutically effective amount of the compositions described herein may inhibit (reduce the severity or eliminate the occurrence) and / or prevent a particular disorder, and / or any one of the symptoms of a particular disorder known in the art or described herein. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the composition are outweighed by the therapeutically beneficial effects.

[0082] Suitable human doses of any of the compositions described herein can be further evaluated, for example, in Phase I dose escalation studies. See, e.g., van Gurp et al. (2008) Am J Transplantation 8(8):1711-1718, Hanouska et al. (2007) Clin Cancer Res 13(2,part1):523-531, and Hetherington et al. (2006) Antimicrobial Agents and Chemotherapy 50(10):3499-3500.

[0083] The toxicity and therapeutic efficacy of the compositions can be determined by known pharmaceutical procedures in cell cultures or experimental animals (e.g., animal models of any of the fibrotic disorders described herein). These procedures can be used, for example, in LD 50 (lethal dose for 50% of the population) and ED 50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD50 / ED 50 It can be expressed as a ratio.Preferably, the compositions described herein exhibit high therapeutic index.Compositions that exhibit toxic side effects may be used, but care should be taken to design a delivery system that targets such compounds to the site of affected tissue, minimizing potential damage to normal cells, thereby reducing side effects.

[0084] Those skilled in the art will appreciate that the data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. Appropriate dosages of the compositions described herein will generally be administered at ED 100 mg with little or no toxicity. 50 The circulating concentration of the composition is within a range of 100 mg / kg / day, the range comprising 100 mg / kg / day of administration. Dosages can vary within this range depending on the dosage form used and the route of administration utilized. For compositions described herein, the therapeutically effective dose can be estimated initially from cell culture assays. Doses are based on the IC50 determined in animal models and in cell culture. 50 (i.e., the concentration of antibody that achieves half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. In some embodiments, for example, when local administration (e.g., to the eye or joint) is desired, cell culture or animal modeling can be used to determine the dose required to achieve a therapeutically effective concentration in the local site.

[0085] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In addition, the materials, methods, and examples are merely illustrative and are 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 belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.

[0086] The present disclosure is further illustrated by the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope or content of the present disclosure in any way. EXAMPLES

[0087] method Generation of novel antibodies against α11β1 Rat immunization Wistar rats were immunized with recombinant human α11β1 protein. Enzyme-linked immunosorbent assay (ELISA) was used to test the immune response against the target human and mouse proteins. Cell fusion (by electrofusion) was then performed with animals that generated a good immune response. All fused cells were plated in 96-well plates and the supernatants were screened by ELISA against soluble human and mouse α11β1. Positive clones were counterscreened against human α1β1, α2β1 and α10β1. Clones that specifically bound to human and mouse α11β1, but not to α1β1, α2β1 and α10β1, were selected, subcloned, expanded and cryopreserved. Purified antibodies were then generated from the selected clones and heavy and light chain variable domain sequences were obtained from each purified antibody.

[0088] Rabbit immunization Rabbits were immunized using a cell-based monoclonal antibody platform. Two rabbits were immunized with recombinant human α11β1 protein. To reduce the number of β1-specific B cell clones, splenocytes from the immunized rabbits were sorted and selected against human β1. The sorted splenocytes were then cultured for approximately one week, and the culture supernatants were screened for binding to human α11β1. The top results were sequenced, and rabbit antibodies were subsequently recombinantly produced using HEK cell lines.

[0089] Mouse immunization Ten mice from five different strains were immunized with an appropriate mixture of human α11β1, mouse α11β1 and tolerance breaking proteins. Plasma titers were assessed by ELISA against a mixture of human and mouse α11β1. Popliteal, inguinal and iliac lymph nodes were collected. ELISA positive anti-human / mouse α11β1 hybridomas were expanded and subjected to secondary screening against human and mouse α11β1, control HIS protein and counterscreened against human α11β1, α2β1 and α10β1. Supernatant IgG concentrations were sufficient for functional screening. Selected hybridomas fulfilling all criteria were cloned and clonal hybridomas were confirmed by ELISA against human and mouse α11β1 followed by scale-up and IgG purification. The heavy and light chain variable regions of selected hybridomas were then sequenced.

[0090] Phage library display Phage library display was used for the generation of fully human anti-α11β1 antibodies. Fully human anti-α11β1 antibodies were discovered using single chain fragment variable (scFv) antigen-binding fragments displayed on phage (phage display library). To enrich for α11 subunit-specific antibodies, three rounds of selection against purified human and mouse α11β1 antigens and deselection against α10β1 were performed. The best populations were then subcloned into bacterial soluble expression vectors, recombinant antibody expression was induced, and supernatants were screened for binding by ELISA assay. Antibodies with appropriate binding profiles were sequenced and subsequently converted from scFv to IgG.

[0091] ELISA 0.25 μg / mL of target antigen (recombinant human or mouse α11β1) was plated in 96-well plates overnight at 4°C. Plates were washed (PBS with 0.1% Tween-20), blocked (PBS with 2% BSA and 0.05% Tween-20) for 1 h at room temperature, and incubated with a range of antibody concentrations for 1 h at room temperature. Plates were subsequently washed and incubated with biotinylated anti-rabbit / mouse / human IgG in 1:1000 dilution buffer and incubated for 1 h at room temperature. After washing the plates, streptavidin HRP was added at 1:200 in dilution buffer and incubated for 1 h at room temperature. Ultra TMB ELISA substrate solution was added and the plates were incubated for 5 min on a plate shaker. The reaction was stopped by adding stop solution to each well, and the plates were read at 450 nm.

[0092] FACS Antibody binding to CHO-K1 200,000 cells (wild type CHO-K1 cells or CHO-K1 cells expressing human alpha11) were incubated with the desired concentration of each antibody in FACS buffer for 30 minutes at 4° C. The cells were then washed with FACS buffer and incubated with a 1:100 dilution of secondary antibody for 30 minutes at 4° C. The cells were then washed and fixed with 1% PFA in PBS for 20 minutes at room temperature. They were washed again and read on a cytometer in FACS buffer.

[0093] Antibody binding to HPF / MF Human lung fibroblasts (ScienCell) were cultured in complete fibroblast growth medium (ScienCell) in T-150 flasks until 80% confluent. Cells were washed and harvested using Accutase. Cells were cultured at 7,500 cells / cm in complete FGF. 2 Cells were seeded in T-150 flasks at 4°C 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 harvested using Accutase and seeded into 96-well conical bottom plates. Cells were blocked with heat-inactivated fetal bovine serum (Gibco) for 30 minutes at 4°C. Cells were then incubated with anti-α11 antibodies at the doses indicated in each figure for 30 minutes at 4°C. A human anti-α11 antibody (Creative BioLabs) was included as a positive control, as well as appropriate IgG isotype negative controls. Cells were washed twice and incubated with a PE-conjugated secondary antibody specific for the IgG class of the anti-α11 antibody being tested for 30 minutes at 4°C. Cells were washed twice and fixed in 1% PFA for 30 minutes. Cells were acquired on a FACS Verse (Benton Dickson) conjugate of each antibody. Data was analyzed by gating on single cells and determining the geometric mean fluorescence intensity (gMFI) in the PE channel for each sample.

[0094] Surface Plasmon Resonance (SPR) The affinity of the antibodies for human α11β1 was measured by surface plasmon resonance assay (SPR). The affinity was measured at pH 7.6 and 25° C. using a Biacore T200 instrument. Anti-HIS antibodies were immobilized on the SPR sensor surface using EDC / NHS covalent binding. HIS-tagged human α11β1 was captured on the sensor surface and a single cycle kinetic assay was used. Increasing concentrations of test antibodies were injected sequentially over sensor-bound α11β1. Dissociation was monitored for up to 1000 seconds. Data were double reference subtracted using a sensor surface with anti-HIS antibodies only and a series of blank injections. A 1:1 Langmuir model was fitted to the data to estimate the kinetic association and dissociation constants. The affinity of the interaction (equilibrium dissociation constant) was calculated by dividing the kinetic dissociation constant by the kinetic binding constant. Between injection cycles, α11β1 and bound antibodies were removed by injection of 10 mM glycine at pH 1.5.

[0095] Cell adhesion inhibition 0.6×10 6 Cells / mL were incubated with various concentrations of each antibody for 20 min at 37°C. E-Plate VIEW96 PET plates coated with 100ng / mL type I collagen or PBS overnight at room temperature were blocked in 3% BSA for 1 h at room temperature. After washing the plates with PBS, the cells and antibody mixtures were added to the wells and the plates were placed in the xCelligence instrument. Cell adhesion was recorded over a 6-h period. The time point of maximum cell adhesion was used for relative comparison to the control.

[0096] Fibroblast to myofibroblast transition (FMT) Human lung fibroblasts (ScienCell) were cultured to 80% confluence in complete fibroblast growth medium (ScienCell). Cells were washed and harvested using Accutase. Cells were seeded at 20,000 cells / well in complete fibroblast growth medium on tissue culture treated 96-well plates. After 24 hours, cells were washed and starved for an additional 24 hours in serum reduced medium. After starvation, cells were treated with TGFβ-1 (R&D Systems) with or without anti-α11 antibody. Polyclonal rabbit anti-human α11 antibody was used as a positive control. Appropriate IgG isotype controls were also included. After 48 hours, cells were harvested, fixed, permeabilized, and stained with AlexaFluor488-labeled anti-αSMA (α-smooth muscle actin) (Invitrogen). Cells were acquired on a FACS Verse (Benton Dickson) to determine the expression levels of αSMA. Data was analyzed by gating on single cells and determining the geometric mean fluorescence intensity (gMFI) in the FITC channel for each sample. The gMFI for each sample was normalized to the untreated control and expressed as % inhibition.

[0097] Collagen gel contraction assay 24-well plates were blocked with 2% BSA in PBS overnight at 37°C. The next day, plates were washed three times with PBS before being used for the assay. Human CHO cell lines expressing α11 were harvested and incubated at 1.25 × 10 6 The collagen gel solution was prepared by diluting 3 mg / mL type I collagen stock (Gibco™ Collagen I Rat Protein, Tail Cat. No. A1048301) to 1 mg / mL in the medium containing the CHO cells. Sodium hydroxide was added to the solution to neutralize the pH, and 400 μL of collagen solution was added to each well of a 24-well plate. For wells containing antibodies in collagen gel solution, 2.5×10 CHO cells were added. 6and antibodies were prepared at 2x final concentration in ExpiCHO medium. Cells and antibodies were then combined 1:1 before adding collagen type 1 stock. Gels were polymerized for 60 minutes at 37°C. Antibodies were added to ExpiCHO medium, which was then layered on top of the polymerized gel (400 μL / well). Gels were incubated at 37°C for 6 days before gel contraction was quantified. Images of each well were analyzed using Image J and gel contraction was determined as a percentage of the initial gel area.

[0098] Tumor xenograft models Inject A549 cells (5 × 10 6 The tumor volume was approximately 100 mm 3 Once the tumor reached a mass of 1000 mm, the animals were randomized into seven groups of eight mice each. Mice were then treated intraperitoneally with isotype control or novel mAbs 79E3E3, 16E10 and 9G04 (2 and 20 mg / kg) every 3 days for a total of seven doses, or with docetaxel at 10 mg / kg every 4 days for a total of six doses. Tumor volumes and body weights were recorded twice weekly with an interval of 2-3 days between the two measurements until any of the following defined conditions were observed: a loss of body weight of 20% or more; tumors that inhibit normal physiological functions such as eating, drinking and exercise; ulcerating tumors; tumors that are >2000 mm 3 Larger tumor size and clinical observations of collapse, paralysis, seizures and bleeding.

[0099] Precision-cut liver slices (PCLS) Precision-cut liver slices (PCLS) were prepared from resected liver tissue and left to rest for 24 h for a post-slicing stress period before the start of the experiment. PCLS were cultured without exogenous challenge (group 1), with 100 μg / mL of control antibody (groups 2 and 3—either mouse IgG2a or rabbit IgG), or with a combination of TGF-β1 (3 ng / mL) and PDGF-ββ (50 ng / mL) (groups 2–10). PCLS were cultured in the presence or absence of 10 μM Alk5i (group 4) as a positive control, or two increasing doses (10 and 100 μg / mL) of novel inhibitors (16E10, 79E3E3, and 9G05) in groups 5–10. Each of the 10 groups contained n=6 human PCLS prepared from a single human liver. PCLS medium containing all stimuli and compounds was refreshed and collected at 24-h intervals. Cell culture supernatants (n=2 / 3 duplicated wells) were collected every 24 hours and flash frozen for quantification of soluble products. All PCLS were harvested at 96 hours.

[0100] Tissue culture levels of markers of liver injury (lactate dehydrogenase (LDH) and aspartate transaminase (AST)) and a marker of hepatocyte function / viability (albumin) were quantified in all PCLS at all time points. Albumin secretion was quantified by ELISA as a marker of PCLS integrity and function. R&D Duoset ELISA kits were used to quantitate levels of collagen 1a1, IL-6, hyaluronic acid, and Timp-1 in cell culture supernatants.

[0101] Total RNA extraction from PCLS was performed for all samples. RNeasy Mini kit (Qiagen) was used for RNA extraction. RNA was reverse transcribed into cDNA and used in qPCR to measure the transcript levels of Col1a1, αSMA, TIMP-1, TGF-β1, IL-6, and β-actin / GAPDH.

[0102] Precision Cut Kidney Slices (PCKS) PCKS were prepared from explanted fibrotic human kidney tissue and allowed to sit for 24 hours for a post-slicing stress period before starting 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 of test anti-α11β1 antibodies (1, 10 and 50 μg / mL), or a single high dose of IgG control antibody. PCKS culture medium was collected every 24 hours for a total of three time points. Levels of type I collagen α1 (col1a1) in tissue culture supernatants were quantified using the R&D Duoset ELISA kit. Statistics were performed using two-way ANOVA followed by Dunnett's multiple comparison test.

[0103] Example 1. Generation of novel monoclonal antibodies against α11β1 and determination of binding affinity Antibody discovery was performed by immunizing rats and rabbits with recombinant human α11β1 and by immunizing mice with both human and mouse α11β1. 51 novel anti-human α11β1 monoclonal antibodies were generated (24 rabbits, 7 rats and 20 mice). Heavy and light chain variable region sequences were determined for the mouse and rat antibodies, while complete heavy and light chain sequences were determined for the rabbit antibodies.

[0104] ELISA results showing exemplary binding of selected mouse monoclonal antibodies to recombinant human α11β1 are shown in Figure 2 A. Three of these mAbs also bound to mouse α11β1, as shown in Figure 2B.

[0105] Data was also collected to determine whether the antibody of interest bound to the I-domain of α11β1. An in-house generated I-domain of α11β1 was used. Rat clones 79E3E3, 8H8E9 and 6E5C11 showed high, medium and low binding, respectively, as determined by ELISA. Mouse antibodies 10-F23, 10-L15, 7-O8, 6-A12, 9-G05 and 9-E16 and rabbit antibodies 7-H12 and 2-D3 were also tested for binding to the in-house generated α11β1 I-domain. Figures 3A and 3B show graphs depicting binding data from exemplary mAbs.

[0106] α11β1 belongs to the collagen receptor family and has relatively high homology with them. Therefore, the novel antibodies of the present invention were counter-screened against α1β1, α2β1 and / or α10β1. Table 2 contains the cross-reactivity results against other receptors.

[0107] [Table 2-1]

[0108] [Table 2-2] N / A = not tested

[0109] Because integrins are large, transmembrane receptors that exist in different conformational shapes, experiments were performed to confirm that the novel antibody also binds to cells expressing α11β1. A CHO-K1 cell line that endogenously expressed high levels of the β1 subunit was engineered to stably express human α11 (CHO-K1 huα11).

[0110] Figures 4A and 4B show selected rat and mouse mAbs that bind to human α11β1 (as tested by ELISA) and also demonstrate the ability to bind to α11β1 expressed on the surface of CHO-K1 cells. Figures 11A and 11B show selected rabbit, rat, mouse and human mAbs that demonstrate the ability to bind to α11β1 expressed on the surface of CHO cells. Additionally, Figure 14 shows selected fully human mAbs that demonstrate the ability to bind to α11β1 expressed on the surface of CHO cells. However, as shown in Table 1, there were several mAbs that were shown to bind to α11β1 by ELISA but did not bind to cell-expressed α11β1.

[0111] Combined EC 50 was estimated using data from fluorescence-activated cell sorting (FACS) performed with CHO-K1 huα11β1 cells. The results are shown in Table 3. Four of the six mAbs tested had EC 50 mAbs had potent binding profiles (8-P20, 8-G15, 8-J17, 8-I14), whereas the remaining two mAbs were less potent (9-G05 and 9-E16, both I-domain binders).

[0112] [Table 3]

[0113] As shown in FIG. 9, when antibodies 16E10, 79E3E3, 9G05 and 1994_01_C07 were tested for their affinity to human α11β1 via surface plasmon resonance (SPR), they showed KDs of 48 pM, 10 pM, 2.85 nM and 0.77 nM, respectively. Interestingly, 16E10 and 1994_01_C07 did not bind to either the I-domain or headpiece domain of α11β1, indicating that both may act as allosteric inhibitors by not binding to the ligand-binding domain but still inhibiting α11β1 function. 9G05 and 79E3E3 bind to the I-domain (ligand-binding domain) and therefore may directly inhibit the ligand-binding site. The binding affinities of the antibodies to α11β1 headpiece and α11β1 I-domain measured by SPR are shown in FIG. 10A and FIG. 10B, respectively.

[0114] Binding to physiologically relevant primary human cell types was also tested. Human lung fibroblasts (HPF) and TGFβ treatment were used to induce fibroblast to myofibroblast transition (FMT) to generate myofibroblasts (MF). HPF do not express α11β1, but significant expression of α11β1 is shown by MF. Additionally, HPF express other collagen binding receptors, α1β1 and α2β1, meaning that HPF can be for testing cross-reactivity of the antibody of interest. Selected mAbs were evaluated for binding to HPF and MF, and as shown in Figure 5, Figure 12 and Figure 13, it is clear that the antibodies tested bound strongly to MF but not to HPF, except for 9-E16, which showed some HPF binding suggesting off-target binding.

[0115] Example 2. Biological activity of novel monoclonal antibodies against α11β1 Because myofibroblasts are involved in the secretion of fibrous matrix, blocking and / or reducing MF accumulation is a critical step to treat and / or prevent fibrosis. This can be achieved by inhibiting fibroblast-to-myofibroblast transition using anti-α11β1 antibodies. Typical functional inhibitors of the receptor block ligand binding, and while prevention of α11β1 binding to type I collagen is a desired feature of anti-α11β1 antibodies, it may not be necessary for therapeutic efficacy. Unlike many other receptors, integrins can both "outside-in" (canonical, ligand-mediated) and "inside-out" signaling. Thus, it may be possible for antibodies to bind to α11β1 in a manner that affects the structure of α11β1 in a manner that prevents inside-out signaling and FMT, but does not affect the ability of α11β1 to bind type I collagen. For this reason, both mAbs that block and do not block ligand binding were included in these studies.

[0116] The CHO-K1 huα11 cell line was used to evaluate the ability of mAbs to block α11β1-mediated binding to type I collagen. As shown in Figure 6A, of the three rat mAbs tested, two significantly inhibited adhesion of CHO-K1 huα11 cells to type I collagen-coated plates. In the "untreated" condition, cells were plated on type I collagen but no antibody was added, and in the "uncoated" condition, cells were seeded on BSA-coated wells that did not contain type I collagen. Statistics were performed using one-way ANOVA followed by Dunnett's multiple comparison test. 79E3E3 is an I-domain binder and was able to block cell adhesion with an IC50 of 9.4 nM. However, 40G10H11, although it strongly inhibited cell adhesion, was not found to be an I-domain binder, despite cross-reacting with other collagen receptors (α1β1, α2β1, and α10β1). 24E4G6 did not bind to the I-domain and did not inhibit cell adhesion to collagen. When rabbit mAbs were tested, eight of nine mAbs potently and significantly inhibited cell adhesion, and none of these mAbs were found to be I-domain binders (Figure 6B). Thus, these mAbs may bind to the α11β1 domain that keeps the integrin in a low or medium affinity state. Figure 6C shows the activity of selected mouse mAbs. Three of 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, although a potent blocker of cell adhesion, 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. Nine human mAbs were also tested for their ability to inhibit the binding of human CHO-α11 cells to type I collagen. As shown in Figures 15A and 15B, all of the human Abs inhibited cell adhesion compared to the control, with 1994-01-C07 having an IC50 of 3.3 nM.As illustrated by these data (and summarized in Table 1), several anti-α11β1 mAbs were found to bind strongly to human α11β1 when tested by ELISA and FACS, but not all of these antibodies were able to block the ligand interaction. Furthermore, it was found that binding to the I-domain (the ligand-binding domain on α11β1) was not required to block the interaction of α11β1 with type I collagen.

[0117] In addition to the above binding abilities, anti-α11β1 antibodies are important in inhibiting fibroblast-to-myofibroblast transition (FMT). It is now recognized that myofibroblasts are a heterogeneous cell population that exists in different activation states with the primary functions of producing and contracting collagen extracellular matrix (ECM). FMT is a multi-step event controlled by the changing mechanical environment in tissues undergoing repair. TGFβ is one of the potent factors enhancing this process, and alpha smooth muscle actin (αSMA) is one of the main markers overexpressed when fibroblasts are undergoing the transition to become myofibroblasts. The presence of αSMA enhances fibroblast contraction and induces myofibroblast activation through an intracellular feedback loop. As αSMA is the primary molecular marker of myofibroblasts, we tested the ability of a novel anti-α11β1 mAb to inhibit αSMA expression in TGFβ-induced FMT.

[0118] As shown in FIG. 7A, two rat mAbs (40G10H11 and 24E4G6) significantly inhibited αSMA expression compared to the control, but neither antibody was found to be an I-domain binder. Statistics were performed using one-way ANOVA followed by Dunnett's multiple comparison test. Furthermore, only 40G10H11 inhibited cell adhesion to type I collagen. Interestingly, 79E3E3 mAb was found to be an I-domain binder and strongly inhibited cell adhesion to collagen, but failed to reduce αSMA expression (a surrogate for myofibroblast generation). As shown in FIG. 7B, two rabbit mAbs significantly inhibited αSMA expression compared to the control, but neither antibody was found to be an I-domain binder. 16E10 was found to inhibit both ligand binding and FMT (% inhibition of αSMA upregulation), while 16G7, although found to inhibit FMT, had no effect on cell adhesion to collagen. Finally, as shown in Figure 7C, five of the six tested mouse mAbs significantly inhibited αSMA expression compared to controls. Three of the 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 and affected ligand binding.

[0119] Example 3. Ability of selected antibodies to inhibit cell-mediated contraction of collagen gels Cell-mediated contraction of CD collagen I gels is a process previously shown to be α11β1-mediated, and more recent studies have shown that α11β1-mediated downstream signaling is essential for gel contraction to occur. Selected exemplary antibodies were tested for their ability to inhibit cell-mediated 3D gel contraction, as this ability is directly related to the functionality of the exemplary antibodies.

[0120] As can be seen in Figure 8, rat 79E3E3, mouse 9E16, 9G05 and 8I14, rabbit 16E10, and human 1994_01_C07, 2004_04_B03, 2004_04_C12 and 1994_01_D12 antibodies all inhibited CHO-huα11-mediated collagen gel contraction. Notably, CHO-huα11 cells were able to contract collagen gels without the addition of TGFβ, as shown in the UT (untreated) condition. In the untreated condition, cells were embedded in collagen gels but no antibodies were added. Statistics were performed using one-way ANOVA followed by Dunnett's multiple comparison test. Each treatment condition was compared to the untreated condition. Asterisks indicate statistical significance and "ns" indicates that the difference was not statistically significant.

[0121] Example 4. Evaluation of the effect of selected antibodies on tumor xenograft growth Previous studies have shown that the growth of A549 cell xenografts in α11 knockout SCID mice is significantly hindered compared to wild-type mice. In this example, studies were performed to determine whether inhibition of α11β1 function by mAb results in xenograft growth inhibition. As shown in Figure 16 and Table 4, blocking α11β1 on mouse CAFs hindered xenograft growth in SCID mice. Specifically, 79E3E3, an effectorless mAb that cross-reacts with mouse α11β1, significantly inhibited tumor growth compared to isotype control, whereas 16E10, a mAb that does not bind to mouse α11β1, did not show significant inhibition of tumor growth. As 16E10 did not show any effect, inhibition of tumor-expressed α11β1 did not affect tumor growth.

[0122] [Table 4]

[0123] Example 5. Effect of anti-α11β1 antibodies on human precision-cut liver slices (PCLS) Precision-cut liver slices (PCLS) from human liver tissue are physiologically and architecturally representative of tissue structure, and testing of therapeutic targets in human PCLS allows for the assessment of their efficacy and relevance to clinical situations, overcoming the limitations of in vivo rodent models and in vitro 2D cell culture methods. The tissue bioreactor technique maintains the viability and functionality of PCLS from human liver tissue for at least 6 days in vitro.

[0124] As shown in Figures 17A-C, all anti-α11-β1 antibodies tested produced partial inhibition of soluble profibrotic markers (COL1A1, hyaluronan, and TIMP1) in a dose-dependent manner or at the highest dose tested. No toxicity was observed after treatment with any of the antibodies (i.e., no elevation of ALT, AST, or albumin, data not shown).

[0125] Example 6. Effect of anti-α11β1 antibodies on human precision-cut kidney slices (PCKS) Human precision cut kidney slices (PCKS) are prepared from human kidney tissue with moderate fibrosis. After 24 hours of rest, PCKS are cultured with a novel anti-α11β1 monoclonal antibody at different doses over time. At each time point, PCKS culture medium is collected. At harvest time points, culture medium is collected and then RNA is extracted from each tissue slice. Various profibrotic mediators are measured in the culture medium 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).

[0126] PCKS were prepared from explanted fibrotic human kidney tissue as described in the methods above and allowed to sit for 24 hours for the post-slicing stress period before starting the experiments. 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 of test anti-α11β1 antibodies (1, 10 and 50 μg / mL), or a single high dose of IgG control antibody. PCKS culture medium was collected every 24 hours for a total of three time points. Levels of collagen type I α1 (col1a1) in tissue culture supernatants were quantified using the R&D Duoset ELISA kit. Statistics were performed using two-way ANOVA followed by Dunnett's multiple comparison test.

[0127] As shown in Figures 18A-C, for each anti-α11-β1 antibody, at least one dose at at least one time point resulted in significant inhibition of col1a1 secretion. There was significant inhibition of col1a1 secretion by the 1994_01_C07 novel mAb at the 72 and 96 hour time points at each dose tested. This is an important finding since type I collagen deposition is a major cause of fibrotic tissue.

[0128] Example 7. Effect of anti-α11β1 antibody on an in vivo renal fibrosis model Two different renal fibrosis models are used: the 5 / 6 nephrectomy model and the ReninAAV Unx db / db mouse model. These two models are characterized by significant renal fibrosis accompanied by measurable loss of renal function. Anti-α11β1 mAbs are tested in these models to determine their effects on renal morphology (fibrosis) and renal function (GFR and albuminuria).

[0129] Exemplary Sequences DNA sequence of anti-α11β1 monoclonal antibody Rat mAb sequence

[0130] [Table 5]

[0131] [Table 6]

[0132] [Table 7]

[0133] [Table 8]

[0134] Mouse mAb sequence 9-G05 Heavy chain variable region GAGGTCCAGCTGCAACAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATACCCTGCAAGGCTTCTGGATACACATTCCCTGACTACAACATGGACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATATTAATCCTGACAATGGTGGTACTATCTACAACCAGA AGTTCAAGGGCAAGGCCACATTGACTGTAGACAAGTCCTCCAGCACAGCCTACATGGAGCTCCGCAGCCTGACATCTGAGGACACTGCAGTCTATTACTGTGCAAGATTAGACAGCTCAGGCTACGGTTACTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 15) 9-G05 Light chain variable region GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATCTCCTGCAGAGCCAGCGAAAGTGTTGATAATTATGGCATTAGTTTTATGCACTGGTACCAGCAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCGTGCATCCAACCTAGACTCTGAGATCCCTGCCAGGTTCAGTGGCAGTGGGTCTAGGACAGACTTCACCCTCACCATTGATCCTGTGGAGACTGATGATGTTGCAACCTATTACTGTCAGCAAAGTTATAAGGATCCTCGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA(SEQ ID NO: 16) 8-P20 Heavy Chain Variable Region AAAGTGATGCTGGTGGAGTCTGGGGGAGCCTTAGTGAAGCCTGGAGGGTCCCTGAAACTCTCCTGTGTAGCCTCTGGATTCACTTTCAGTAACTATGCCATGTCTTGGGTTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCAACCATTAGTAGTGGTGGTTATTACACTTACTATCCAGACAGTGTGAAGGGTCGATTCACCATCTCCAGAGACAATGCCAGGAACACCCTGTTCCTGCAAATGAGCAGTCTGAGGTCTGAGGACACGGCCATGTTTTACTGTGCAAGAGAGGATGATTACGGAAGATATTCCTATACTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA(SEQ ID NO: 17) 8-P20 Light Chain Variable Region GATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGTCTCCATCTCTTGCAGATGTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCACAGCTCCTGATCTACAAAATTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTACACGTTCGGAGGGGGGACCGAGCTGGAAATAAAA(SEQ ID NO:18) 8-G15 Heavy Chain Variable Region GAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAGGATATCCTGCAAGGCTTCTGGATACACATTCACTGACTACTACATACACTGGGTGAAGCAGAAGCCTGGGCAGGGCCTTGAATGCATTGGAGAGATTTATCCTGGAACTGATAATACTTACTACAGTAAAAAATTCAGGGGCAAGGCCACACTGACTGCAGACAAATCCTCCGACACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTTCTGTGCAAGAGGAGACTACTATAGGGGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA(SEQ ID NO:19) 8-G15 Light Chain Variable Region GATGTTGTGATGACTCAGACCTCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTACATAGTAATGGAAAGACATATTTGAATTGGTTATTACAGAGGCCAGGCCAGTCTCCAAAGTTCCTAATCTATCTGGTGTCTAAACTGGAATCTGGAGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGGGTTTATTACTGCTTGCAATCTACACATTTTCCTTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA(SEQ ID NO: 20) 8-I14 heavy chain variable region GAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAAGAAATCCTGCAAGGCTTCTGGATACACATTCACTGACTACTACATGCACTGGGTGAAGCAGAAGCCTGGGCAGGGCCTTGAGTGGATTGGAAAGATTTATCCTGGAAGTGGTAATACTCACTACAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTTCTGTGCAACCAATTACTACGGCTACAGGGCAATGAACTATTGGGGTCAAGGATCCTCAGTCACCGTCTCCTCA(SEQ ID NO: 21) 8-I14 light chain variable region GACATCCATTTGACCCAGTCTCCATCCTCCTTATCTGCCTCTCTGGGAGAAAGAATCAGTCTCACTTGCCGGGCAAGTCAGGACATTTATATTAGCTTAAACTGGTTTCAGCAGAAACCAGATGGAACTATTAAACTCCTGATCTACGGCACATCCAGTTTAGATTCTGGTGTCCCCAAAAGGTTCAGTGGCAGTAGGTCTGGGTCAGATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGATTTTGCAGACTATTACTGTCTACAATATGCTAGTTCTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA(SEQ ID NO: 22) 9-E16 heavy chain variable region GAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGGCTTCTGGATACACATTCACTGACTACTACATGCACTGGGTGAAGCAGAAGCCTGGGCAGGGCCTTGAGTGGATTGGAGAGATTTATCCTGGAAGTGGTAATCCTTACTACAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACAAATCATCCAGCTCAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTTCTGTGCAAGAACCTCCTACGGTAGAGTAGGGACAGGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(SEQ ID NO: 23) 9-E16 light chain variable region AATTTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTCTACACAGTAACGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAACAGAGTGGAGACTGAGGATCTGGGAATTTATTTCTGCTCTCAAAGTTCACATGTTCCCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA(SEQ ID NO: 24) 8-J17 Heavy Chain Variable Region CAGGTCCAGCTGCAGCAGTCTGGGGCTGAACTGGCAAAACCTGGGGCCTCAGTGAAGATGTCCTGCAAGGCTTCTGGCTACACCTTTACTAACTACTGGATGCACTGGGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGATACATTAATCCTAACAATGGTTATACTGAGTACAATCAGCGATTCAAGGACAAGGCCACATTGACTGCAGACAGATCCTCCACCACAGCCTACATGCAACTAAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGATCCGATATCATTACGACAGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID NO: 25) 8-J17 Light Chain Variable Region GATGTTGTGATCCAAACTCCACTTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTATATAGTAATGGAAATACCTATTTACATTGGATACCTGCAGAAGCCAGCCAGTCTCCAAAGCTCCGATCTACAAAGTTCCCAACCGATTTTCTGGGGTCCCCAGACAGGTTCAGTGGCAGTGGCAGTGGGATCAGGGACATTTCACACTCAAGATAAGCAGAGTGGAGGCTGGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGACGTTCCGGTGGAGCACCAAGCTGGAAATCAAA (sequence number 26) 6-O12 variable region GAAGTGAAGCTTGAGGAGTCTGGAGGAGGCTTGGTGCAACCTGGAGGATCCATGAAACTCTCTTGTGCTGCCTGGATTCACTTTTAGTGACGCCTGGATGGACTGGGTCCGCAGTCTCCAGAGGCGGGCTTGAGTGGGTTGCTGAAATTAGAACAAAGCCATAATCCTGCAACATACTATGCTGAGTCCTTGAAAGGGAGATTCACCATCTCAAAAGTAGTGTCTACCTGCAAATGAACAGCTTAAGAGCTGAAGACACTGGCATTTATTACTGTACCTTAGTAGCCCTGATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA(sequence number 27) 6-O12 variable region GACATTGTGATGTCACTGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGGTTACTATGAGCTGCAAGTCCAGTCAGAGCCTTTTATATAGTCGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTACTGGGCATCCACTAGGGCATCTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGCTATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA(SEQ ID NO: 28) 10-L15 Heavy Chain Variable Region CAGGTCCAACTGCAGCAGTCTGGGCCTGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCAGGCTATACCTTCACCAGCTACTGGATGCACTGGGTGAAACAGAGGCCTGGACAAGGCCTTGAGTGGATTGGCATGATTGATCCTTCCAATAGTGAAACTTGGTTAAATCAGAAGTTCAAGGACAAGGCCACATTGAATGTAGACAAATCCTCCAACACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGATATGATGGTTACTACGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID NO: 29) 10-L15 Light Chain Variable Region AACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTTCTCTAGGGCAGAGGCCACCATATCCTGCAGAGCCAGTGAAAGTGTGATAGTTATGGCAATAGTTTTATGCACTGGTACCAGCAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCTTGCATCCAACGTAGAATCTGGGTCCTGCCAGGTTCAGTGGCAGTGGTCTAGGACAGACTTCACCTTCACCATTGATCCTGTGGAGGCTGATGATGCTGCAACCTATTACTGTCAGCAAAATAATGAGGATCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA(sequence number 30) 7-H14 variable region CAGGTCCAACTGCAGCAGCTGGGGCTGGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGCCTTCTGGCTACACCTTCACCAGCTACTGGATGAACTGGGTGAAGCAGAGGCCTGGACAAGGCCTTGAATGGATTGGTATGATTGATCCTTCAGACAGTGAAACTCACTACAATCAAATGTTCAAGGACAAGGCCCACATTGACTGACTGATTGACAAATCCTCCAACACAGCCTACATGCAGCTCAGCCTGACATCTGAGGACTCTCGGTCTATTACTTGGCGAGATCTCATGCCTATGCTCTCTGCA (sequence number 31) 7-H14 variable region GACATTGTGATGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGGTTACTATGAGCTGCAAGTCCAGTCAGAGCCTTTTATATAGTAGCCATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTTCTCCTAAACTGCTGATTTACTGGGCATCCACTAGGGAATCTGGGTCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCAGTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGGAATATTATAGCTGGACGTTTCGGTGGAGCACCAAGCTGGAAATCAAA (sequence number 32) 6-B21 variable region GAGGTCCAGCTGCAACAATCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGGAAGATATCCTGTAAGGCTTCTGGATACACGTTTCACTGACTACATGAACTGGGTGAAGCAGAGCCATGGAAAGACCTTGAGTGATTGGAGATATTAATCCTCACAATGGTGGTACTAGCTTCATCCCAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAGTCCTCCAGCCAGCCCTACATGGAGCTCCGCAGCCTGACATCTGAGGACTCTGCAGTCTATTATTGTGCCCCTCTGGGACGAAAGGAGGGGTTTGCTTACTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(sequence number 33) 6-B22 GACACTGTGCTGACACAGTCTCCTGCTTCCTTAGTTGTATCTCTGGGGCAGAGGGCCACCATCTCATGCAGGGCCAGCAAAAGTGTCAGTACATCTGGCTATAGTTATATGCACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCTTGCATCCAACCTAGAATCTGGGGTCCCTGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGCCTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCACAGTAGGGAGCTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA(SEQ ID NO: 34) 10-F23 Heavy Chain Variable Region CAGGTTACTCTGAAAGAGTCTGGCCCTGGGATATTGCAGCCCTCCCAGACCCTCAGTCTGACTTGTTCTTTCTCTGGGTTTTCACTGAGCACTTTTGCTATGGGTGTAGGCTGGATTCGTCAGCCTTCAGGGAAGGGTCTGGAGTGGCTGGCACACATTTGGTGGGATGATGATAAGTACTATAACCCAGCCCTGAAGAGCCGGCTCACAATCTCCAAGGATACCTCCAAAAACCATGTATTCCTCAAGATCGCCAATGTGGACACTGCAGATACTGCCACATACTACTGTGCTCGAATGCCGCTAACTTTCTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID NO: 35) 10-F23 Light Chain Variable Region GATGTTTTGCTGACCCAAACTCCACTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCATTGTACATAGTAATGGACACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCCGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGGAGTTCGGGAGTTTATTACTGCTTTCAAGGTTCACATGTTTCCGTTCACGTTCGGAGGGGGACCAAGCTGGAAATAAAA (sequence number 36) 6-A12 variable region CAGGTTACTCTGAAAAGAGTCTGGCCCTGGGATATTGCAGCCCTCCAGACCCTCAGTCTGACTTGTTCTTCTGGGTTTTTCACTGAGAACTTTTGCTATGGGTGGTGTAGGCTGGATTCGTCAGCCTTCAGGGAAGGGTCTGGAGTGGCTGGCACACATTTGGTGGGGATGATGATGATATGACTATAACCCAGCCCTGAAGACCCGGCTCACAATCTCCAAGGATACCTCCAAAAACCAGGTATTCCCTCAAAGATCGCCAATGTGGACACTGCAGATACTGCCACATACTACTGTGCTCGAATGCCGCTAACTTTCTACTTTGACTACTGGGCCAAGGCACCACTCTCACAGTCTCCTCA(sequence number 37) 6-A12 variable area GATGTTTTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGTAGATCTAGTCAGAGCATTGTACATAGTAATGGAAACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCACCCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGCTTTCAAGGTTCACATGTTCCGTTCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA(SEQ ID NO: 38) 6-M8 Heavy Chain Variable Region CAGGTCCAACTGCAGCAGCCTGGGGCTGAACTTGTGATGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAACTACTGGATGCACTGGGTGAAACAGAGGCCTGGACAAGGCCTTGAGTGGATCGGAGAGATTGATCCTTCTGATAGTTATACTAACTACAATCAAAAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGACAGGGTAGTACCTACGCGTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA(SEQ ID NO: 39) 6-M8 Light Chain Variable Region GATATTGTGATGACGCAGGCTGCATTCTCCAATCCAGTCACTCTTGGAACATCAGCTTCCATCTCCTGCAGGTCTAGTAAGAGTCTCCTACATAGTAATGGCATCACTTATTTGTATTGGTATCTGCAGAAGCCAGGCCAGTCTCCTCAGCTCCTGATTTATCAGATGTCCAACCTTGCCTCAGGAGTCCCAGACAGGTTCAGTAGCAGTGGGTCAGGAACTGATTTCACACTGAGAATCAGCAGAGTGGAGGCTGAGGATGTGGGTGTTTATTACTGTGCTCAAAATCTAGAACTTCCTCCGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA(SEQ ID NO: 40) 2-A3 Heavy Chain Variable Region GAGGTCCAGCTGCAACAATCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGTAAGGCTTCTGGATACACATTCACTGACTACTACATGATGTGGGTGAAGCAGAGTCATGGAAAGAGCCTTGAGTGGATTGGAGATATTAATCCTTACAATGGTGGTTCTAGCTACAACCCGAAGTTCAAGGGCAGGGCCACATTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAACAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGAGGGACTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(SEQ ID NO: 41) 2-A3 Light Chain Variable Region GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGCTGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATGTATCTGGTGTCTAAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGCGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA(SEQ ID NO: 42) 6-O17 Heavy Chain Variable Region CAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTTGTGAAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTACTGGATGCACTGGATAAAGCAGAGACCTGGACAAGGCCTTGAGTGGATTGGAGAGATTAACCCTAGCAATGGTGGTTCTAACTACAATGAGAAGTTCAAGAGCAAGGCCACACTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAACTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTATCACTGTAAAAGCAGAGGCTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID NO: 43) 6-O17 Light Chain Variable Region GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTTATGGAAAGACATATTTGAATTGGTTGTTACAGCGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAATTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAATTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA(SEQ ID NO: 44) 3-G5 heavy chain variable region CAGGTTCAGCTGCAGCAGTCTGGAGCTGAGCTGGCGAGGCCTGGGGCTTCAGTGAAACTGTCCTGCAAGGCTTCTGGCTACACCTTCACAAGCTATGGTATAAGCTGGGTGAAACAGAGAACTGGACAGGGCCTTGAGTGGATTGGAGAGATTTTTCCTAGAAGTAGTAATACTTACTATAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACAAGTCCTCCAGCACAGTGTACATGGAGTTCCGCAGCCTGACATCTGAGGACTCTGCGGTCTATTTCTGTGCAAGAGAGGGGGGCCTGGCCTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(SEQ ID NO: 45) 3-G5 light chain variable region GATGTTGTGATCCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCTTCCATCTCTTGCAAGTCAAGTCAGAGCCTTTATATACTAATGGAAACACCTATTTGAATTGGTTATTACAGAGGCCAGGCCAGTCTCCAAAACCCTAATCTAATCTGGTGTCTAAATTGGACTCTGGTAATCCCTGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTGAGAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTATTACTGCTGCAGAGTACACATTTTCCATTCACGTTCCATTCACGTTCGCTCGGGGACAAAGTTGGAAATAAAA (sequence number 46) 6-A15 variable area GAGGTCCAGCTGCAACAATCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGAGTGTCCTGTAAGGCTTCTGGATACACAATCACTGACTACATGATGTGGTTGGAAGCAGAGTCATGGAAAGCCTTGAATGGATTGGAGATATTAATCCTTACACTGGTGGTACTAGCTACAACCAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAATCCTCCAGCACAGCCTACCTGCAGCTCCAGAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGAGGGGCCTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(sequence number 47) 6-A15 variable area GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA(SEQ ID NO: 48) 10-K10 heavy chain variable region GAGGTCCAGCTGCAACAATCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGTAAGGCTTCTGGATACACAATCACTGACTACTACATGATGTGGTTGAAGCAGAGTCATGGAAAGAGCCTTGAATGGATTGGAGATATTAATCCTTACACTGGTGGTACTAGCTACAACCAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAACAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGAGGGGCCTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID NO: 49) 10-K10 light chain variable region GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA(SEQ ID NO: 50) 6-P20 heavy chain variable region GAGGTCCAGCTGCAACAATCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGTAAGGCTTCTGGATACACGTTCACTGACTACTACATGAACTGGGTGAAGCAGAGCCATGGCAGGAGCCTTGAGTTGATTGGAGATATTAATCCTAACAATGGTGGTTCTAACTTCAACCAGAAGTTCAGGGGCAAGGCCACATTGACTGTAGACAAGTCCTCCAGCACAGCCTATATGGAGCTCCGCAGCCTGACATCTGAGGACTCTGCAATCTATTACTGTGCAAGAATGGGTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(SEQ ID NO: 51) 6-P20 light chain variable region GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTACATAGTGATGGAAAGACATATTTGAATTGGATGTTCCAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAACTGGACTCTGGAGTCCCTTACAGGTTCACTGGCGGTGGATCAGGGACAGATTTCACACTGCAAATCAGCAGAGTGGAGACTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCTCGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA(SEQ ID NO: 52) 7-O8 heavy chain variable region GAGGTCCAGCTGCAGCAGTCTGGACCTGAACTGGTCAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTCACTGACTACTACATACACTGGGTGAAGCAGAAGCCTGGGCAGGGCCTTGAGTACATTGGAGAGATTTATCCTGGAAGTGGTAATACTTACTACAATGGGAAGTTCAGGGGCAAGGCCACACTGACTGCAGACAAGTCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTTCTGTGGTAGTGGCTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID NO: 53) 7-O8 light chain variable region GATGTTGTGATGACCCAGACTCCACTCACTTTGTCTGTTACCATTGGACAGCCAGCTTCCATTTCTTGCAAGTCAAGTCAGAGCCTCTTATATAGTAATGGAAAAACCTATTTGAATTGGTTATTACAGAGTCCAGGCCAGTCTCCAAAGCTCCTAATCTATCTGGTGTCTA AACTGGAATCTGGAGTCCCTGACAGATTCAGTGGCAGTGGATCAGGGACAGATTTTACACTGAAACTCAGCAGAGTGGAGGCTGAGGATTTGGGAGTATATTACTGCGTGCAAGGTACACATTTCCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA (SEQ ID NO: 54) Rabbit mAb sequence A11B1_16G7 heavy chain A11B1_16G7 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTACTGCTCTGGCTCCCAGGTGCCAGATGTGCTGACATTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTGGCAATGCATTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGCAGCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGTGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAAGCTATTATTTTACTAGTGTTAGTAGTTATGGCAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 56) A11B1_16E10 heavy chain A11B1_16E10 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCGTTCGAATTGACCCAGACTCCATCCTCCGTGGAGGCTGCTGTGGGAGGCACGCCCACCATCAAGTGCCAGGCCAGTCAGACCATTTACAGTTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGAAGCGTCCAAACTGGCCTCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGACTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAGCTATCATGGTACTGCTAGTACTGAATATAATACTTTCGGCGGGGGGACCGAGGTGGTGGTCAGAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 58) A11B1_15G10 heavy chain A11B1_15 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCATTCGAATTGACGCAGACTCCATCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGTTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGAATCTGGGGTCCCATCGCGGTTTAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTTCTGTCAAAGCTATTATGGTGTTACTTTTAGTGGTTTTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 60) A11B1_14 heavy chain A11B1_14H1 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCACAAGTGCTGACCCAGACTGCATCGTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAATAATTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGACATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTATAGTGGTAATATTTACGTAAATGATTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 62) A11B1_13G4 heavy chain A11B1_13 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCGATGTTGTGATGACCCAGACTCCATCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGCTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATCTGGAGTCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAAACTATTATGCTATTGATACTTATGGTCATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 64) A11B1_13 heavy chain A11B1_13C3 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCATATGTGACCCTGTGCTGACCCAGACTCCATCCTCCGTGTCTGCGGCTGTGGGAGTCACAGTCACCATCAACTGCCAGTCCAGTCCGAGTGTTTATAGTAACTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTCATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCACTTATAGTGGTAATATTTGGTCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 66) A11B1_12F2 heavy chain A11B1_12F2 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGCAACTACTTTTCTTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCGTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATTCTGCCACTTACTACTGTCAGTGCACTTATGGTAGTAGTAGTACTGGTTTTGGTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCCCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 68) A11B1_11D10 heavy chain A11B1_11D10 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGACTCCTACTGCTCTGGCTCCCAGGTGCCAGATGTGCTGACATTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGTTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTACAGGGCATCCACTCTAAAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTATTATTGTCAAGCGTATTATCTTAGTAGTAGTATCAGTTATGGTAATACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 70) A11B1_10F9 heavy chain A11B1_10F9 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTACTGCTCTGGCTCCCAGGTGCCAGATGTGCTGACATTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGCTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGACATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTATTGTCAAAGCTATGCTTATAGTAGTAGTAGCAGTTATGGTAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 72) A11B1_7H12 heavy chain A11B1_7H12 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCTGACATTGTGCTGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAATGTTTATAGTAACAATGCCTTAGCCTGGCATCAGCAGAAACCAGGGCAGCGTCCCAACCTCCTGATCTACAAGGCTTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTTACTCTCACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGAATTTAGTTGTAGTAGTGGTGATTGTTTTGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 74) A11B1_7G12 heavy chain A11B1_7G12 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGACTCCTACTGCTCTGGCTCCCAGGTGCCAGATGTGCTGACATTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGTTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTACAGGGCATCCACTCTAAAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTATTATTGTCAAGCGTATTATCTTAGTAGTAGTATCAGTTATGGTAATACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 76) A11B1_6G4 heavy chain A11B1_6G4 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCGACATCGTGGTGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGCAACTACTTTTCTTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCGTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGCACTTACGGTAGAAGTAATAGTAATTTTTTTTATGGTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 78) A11B1_6F9 heavy chain A11B1_6F9 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTGCATCCCCTGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGTCAGTCCAGTCAGAGTGTTTATGATAACAACTGGTTAGCCTGGTATCAGCAAAAACCAGGGCAGCCTCCCAAACTCTTGATCGACGATGCATCCAAATTGACATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACGCAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCGCTTATTATAGTAGTGGTTGGTACTGGGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 80) A11B1_6C7 heavy chain A11B1_6C7 light chain ATGGACACGAGCACCTCCACTGCGCTCCTGGGGCTCCTGCTGCTCTGGCTCACAGGTGCCAGATGTGCCATCGAGATGACCCAGTCTCCACCCTCCCTGTCTGCATCTGTGGGAGAAACTGTCAGGATTAGGTGCCTGGCCAGTGAGGACATTTACAGTGGTATATCCTGGTACCAACAGAAGCCAGAGAAACCTCCTACACTCCTGATCTCTGGTGCATCCAATTTAGAATCTGGGGTCCCACCACGGTTCAGTGGCGGTGGATCCGGGACAGATTACACCCTCACCATCGGCGGCGTGCAGGCTGAAGATGTTGCCACCTACTACTGTCTAGGCGGTTATAGTTTCAGTAGTACCGGTTTGACTTTTGGAGCTGGCACCAAGGTGGAAATCAAACGTGATCCAGTTGCGCCTTCTGTCCTCCTCTTCCCACCATCTAAGGAGGAGCTGACAACTGGAACAGCCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 82) A11B1_6B6 heavy chain A11B1_6B6 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCACGTGCCAGGCCAGTCAGAGCATTAGCAACTACTTTTCTTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCGTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATTCTGCCACTTACGCCTGTCAGTGCACTTATGGTAGTAGTAGTACTGGTTTTGGTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 84) A11B1_5F7 heavy chain A11B1_5F7 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCATATGTGACCCTGTGATGACCCAGACTCCATCTTCCACGTCTGCGGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAACAACTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAACGCCTGATCTACGAATCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGAGGCAGTGGATCTGGGGCACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGCATATTATACTACTCTTGATTTCGGCGGAGGGACCGAGGTGGTGGTCAGAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 86) A11B1_5D7 heavy chain A11B1_5D7 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGCCACCATCAACTGCCAGGCCAGTCAGAGTCTTTATAGTCCCAAGAATTTAGCCTGGTATCAGCAGACACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCGAAACTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCAATTTACTACTGTCAAGGCGAATTTAGTTGTACTACTGCTGCTTGTTTTGCTTTTGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 88) A11B1_5A7 heavy chain A11B1_5A7 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCGCAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTGGTAGTAATTTAGCCTGGTATCAGCACAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTTTGCATCCAGCCTGGCATCTGGGGTCTCGTCGCGGTTCAAGGGCGGTAGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCACTGTACTTATTATCCTCTTAGTTATGTTACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 90) A11B1_4E1 heavy chain A11B1_4E1 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCATTCGAATTGACCCAGACTCCATCCTCCGTGTCTGAACCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTTACAGCTACTTTTCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATTTACCAGGCATCCACTCTGGCTTCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAACAATTATGGTAGGGGTAGTGGTAGTTATTTTTTTGGTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 92) A11B1_3H9 heavy chain A11B1_3H9 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGACTCCTACTGCTCTGGCTCCCAGGTGCCAGATGTGCTGACATTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGTTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGACTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTATTATTGTCATACCTATTATCTTAGTAGTAGTATCAGTTATGGTAATACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 94) A11B1_3G2 heavy chain A11B1_3G2 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGGGACTTATCCTGGTATCAGCAGAAACCTGGACAGCCTCCCAAGCGCCTAATCTACAAGGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTAGTATTGATGTTGATAATGATTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 96) A11B1_3B1 heavy chain A11B1_3B1 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTACTGCTCTGGCTCCCAGGTGCCAGATGTGCTGACATTGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCACAGTCACCATCAAGTGTCAGGCCAGTCAGAACATTAATAGCGGCTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAACCTATTATTATAGTAGTAGTAGTAGTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 98) A11B1_2D3 heavy chain A11B1_2D3 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAAGCACAGTCACCATCAATTGCCAGGCCAGTCAGAGTGTTTATAAAGACAACAATTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCTTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGAAGATGCTGCCACTTACTACTGTCAAGGCGAATTCAGTTGTGGTAGTGCTGATTGTATTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 100) A11B1_2A7 heavy chain A11B1_2A7 light chain ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACTCCGGCTTCCACGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGTCAGTCCAGTCAGAGCGTGTATCGTAGCAACTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATGTATTTAATTTGGCATCTGGGGTCCCATCCCGGTTCAAGGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGCCGATGCTGCCACTTACTACTGTCAAGGCAGTTATTATAGTGGTAATTGGTACAGTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG (SEQ ID NO: 102)

[0135] Protein sequence of anti-α11β1 monoclonal antibody Rat mAb sequence

[0136]

Table 9

[0137]

Table 10

[0138] [Table 11]

[0139] [Table 12]

[0140] [Table 13]

[0141] [Table 14]

[0142] [Table 15]

[0143] Rabbit mAb sequence A11B1_16G7 heavy chain METGLRWLLLVAVFKGVQCQEQLVESGGDLVKPGASLTLTCTASGFSFNKNYWMCWVRQAPGKGLEWIGCIYNGDGNTYYASWVNGRFTISKTSSTTVTLQMTSLTVADTAIY FCARLLNMWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:159) A11B1_16G7 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYTAATLASGVPSRFSGSGSGTEFTLTISGVQCDDAATYYCQSYYFTSV SSYGNAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:160) A11B1_16E10 Heavy Chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCRVSGFSFSSSYYMCWVRQAPGKGLEWIACIGTTRGSTYYATWAKGRFTISKISSTTVTLQMTSLTDADTATYFCAR DATGYRINTIGLYFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTK VDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPA PIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:161) A11B1_16E10 light chain MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVEAAVGGTPTIKCQASQTIYSYLSWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISDLECADAATYYCQSYHGTAS TEYNTFGGGTEVVVRGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:162) A11B1_15G10 heavy chain METGLRWLLLVAVLKGVQCQQQLVESGGGLVKPGAALTFTCTASGFSFSGNYWICWVRQAPGKGLEWIACIGTITSRTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCA RGAVVSSGNAPYYFTLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTK VDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPA PIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:163) A11B1_15G10 light chain MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVEAAVGGTVTIKCQASQSISSYLSWYQQKPGQPPKLLIYRASTLESGVPSRFKGSGSGTEFTLTISDLECADAATYFCQSYYGVTF SGFAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:164) A11B1_14H1 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCKASGIDFNNYWITWVRQAPGKGLEWIACIYVGITGRTWYANWAKGRFTISKASSTVDLKMTSLTAADTATYFCAR NGDGGIYALNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDK TVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPI EKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:165) A11B1_14H1 light chain MDTRAPTQLLGLLLLWLPGATFAQVLTQTASSVSAAVGGTVTISCQSSQSVYNNNWLAWYQQKPGQPPKLLIYRASTLTSGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGYSGN IYVNDFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:166) A11B1_13G4 heavy chain METGLRWLLLVAVLKGVQCQEQLEESGGDLVKPGGSLTLTCKASGFSFSNTYWACWVRQAPGKGLEWIACMNPASSGSSYYASWAKGRFTISKTSSTTVTLHMPSLTAADTATY FCAKWDTAFDVWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDK TVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPI EKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:167) A11B1_13G4 light chain MDTRAPTQLLGLLLLWLPGARCADVVMTQTPSSVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKLLIYGASNLESGVPSRFKGSGSGTEYTLTISGVQCDDAATYYCQNYYAID TYGHAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:168) A11B1_13C3 heavy chain METGLRWLLLVAVLKGVQCQEQLEESGGDLVKPGASLTLTCTASGFSFSSNYHICWVRQAPGKGLELIACIYVGDGSTYYASWAKGRFTISKSSSTTVALQMTSLTAADTATY FCGRMFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:169) A11B1_13C3 light chain MDTRAPTQLLGLLLLWLPGAICDPVLTQTPSSVSAAVGVTVTINCQSSPSVYSNYLSWYQQKPGQPPKLLIYLASTLASGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAGTYSG NIWSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:170) A11B1_12F2 heavy chain METGLRWLLLVAVLKGVQCQQQLVESGGGLVKPGASLTLTCTASGFSFSSGYHMCWVRQAPGKGLEWIACFGVYTGTTTYASWAKGRFTISKTSSTTVTLQMTSLTVADTATYFC ARISAENGGDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDK TVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPI EKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:171) A11B1_12F2 light chain MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASQSISNYFSWYQQKPGQPPKLLIYRASTLASGVPSRFSGSGSGTEFTLTISDLECADSATYYCQCTYGSSS TGFGFGGGTEVVVKGDPVAPTVPIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:172) A11B1_11D10 Heavy Chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCMASGIDFSSGYGMWWVRQAPGKGLEYIGYIDTGDDNTYYANWAKGRFTISKTSSTTVTLQMTSLTVADTATYFC AKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:173) A11B1_11D10 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQRPKLLIYRASTLKSGVPSRFKGSGSGTEYTLTISDLECADAATYYCQAYYLSSS ISYGNTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:174) A11B1_10F9 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGFSLSSGYGMCWVRQAPGKGLEWIGYTDTATGTIHYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFC AKGGAMDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:175) A11B1_10F9 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKLLIYRTSTLASGVPSRFKGSGSGTEYTLTISDLECADAATYYCQSYAYSSS SSYGNAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:176) A11B1_7H12 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTGSGIDFSSSYWICWVRQAPGKGLEWIACIDGSDGNTYYASWARGRFTISKTSSTTVTLQMASLTAADTATYF CTRDLRLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVA PSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:177) A11B1_7H12 light chain MDTRAPTQLLGLLLLWLPGARCADIVLTQTPASVSAAVGGTVTINCQASQNVYSNNALAWHQQKPGQRPNLLIYKASTLASGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCLGEFSCS SGDCFVFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:178) A11B1_7G12 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCMASGIDFSSGYGMWWVRQAPGKGLEYIGYIDTGDDNTYYANWAKGRFTISKTSSTTVTLQMTSLTVADTATYFC AKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:179) A11B1_7G12 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQRPKLLIYRASTLKSGVPSRFKGSGSGTEYTLTISDLECADAATYYCQAYYLSSS ISYGNTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:180) A11B1_6G4 heavy chain METGLRWLLLVAVLKGVQCQQQLEESGGGLVKPGGTLLTTCKASGVALNPYYYMCWVRQAPGKGLEWIACVDADSSGSTYYASWAKGRFTISKTSSTTVTLKMTSLTAADTATYFCA RESVDYSSVGIGYVHGTDGLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPAT NTKVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALP APIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:181) A11B1_6G4 light chain MDTRAPTQLLGLLLLWLPGARCADIVVTQTPSSVSAAVGGTVTIKCQASQSISNYFSWYQQKPGQPPKLLIYRASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGRSN SNFFYGFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:182) A11B1_6F9 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGSSFSSTYWNCWVRQAPGKGLEWIACINAGSGTTYYASWAKGRFTVSKTSSTTVTLQMTSLTAADTATYFCTR DSDGRFSSGYYFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKV DKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAP IEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:183) A11B1_6F9 light chain MDTRAPTQLLGLLLLWLPGATFAQVLTQTASPVSAAVGGTVTINCQSSQSVYDNNWLAWYQQKPGQPPKLLIDDASKLTSGVSSRFKGSGSGTQFTLTISGVQCDDAATYYCQGAYYSS GWYWAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:184) A11B1_6C7 heavy chain METGLRWLLLVAVLKGVQCQQQLEESGGGLVKPGGTLTLTCKASGIDFSSYYYMCWVRQAPGKGLELIVCIYTSSGGTWYASWVNGRLTISRSTSLNTVDLKMTSLTAADTATYFC ARGVYSGSSDYPTRLDLWGQGTLVTVSLGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNT KVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPA PIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:185) A11B1_6C7 light chain MDTSTSTALLGLLLLWLTGARCAIEMTQSPPSLSASVGETVRIRCLASEDIYSGISWYQQKPEKPPTLLISGASNLESGVPPRFSGGGSGTDYTLTIGGVQAEDVATYYCLGGYSFSS TGLTFGAGTKVEIKRDPVAPSVLLFPPSKEELTTGTATIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:186) A11B1_6B6 heavy chain METGLRWLLLVAVLKGVQCQQHLVESGGGLVKPGASLTLTCTASGFSFTTGYHMCWVRQAPGKGLEWIACFGVYTSTTTYASWAKGRFTISKTSSTTVTLQMTSLTVADTATYFC ARISAEDGGDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDK TVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPI EKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:187) A11B1_6B6 light chain MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTITCQASQSISNYFSWYQQKPGQPPKLLIYRASTLASGVPSRFSGSGSGTQFTLTISDLECADSATYACQCTYGSSS TGFGFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:188) A11B1_5F7 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLLTTCKASGFSFSSYFWICWVRQAPGKGLEWSACIYGDSSGSSYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFC ASYGSSSYYYSNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVD KTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAP IEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:189) A11B1_5F7 light chain MDTRAPTQLLGLLLLWLPGAICDPVMTQTPSSTSAAVGGTVTISCQSSQSVYNNNYLAWYQQKPGQPPKRLIYESSKLASGVPSRFRGSGSGAQFTLTISDLECDDAATYYCLGAYY TTLDFGGGTEVVVRGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:190) A11B1_5D7 heavy chain METGLRWLLLVAVLKGVQCQEQLVESGGGLVQPEGSLTLTCKASGFDFSSNAMCWVRQAPGKGLEWIACIYNGDGSTYYASWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCA RGLSNWNRDNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDK TVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPI EKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:191) A11B1_5D7 light chain MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSSVSAAVGGTATINCQASQSLYSPKNLAWYQQTPGQPPKLLIYSASKLASGVPSRFKGSGSGTQFTLTISGVQCDDAAIYYCQGEFSCT TAACFAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:192) A11B1_5A7 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGGLVQPEGSLTLACTASGFSFSYYYICWVRQAPGTGLEWIGCINTGSDDTHYASWLKGRFTFSKASSTTLTLQMTSLTAADTATYFCA RSSGSSDDAYDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVD KTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAP IEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:193) A11B1_5A7 light chain MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVSEPVGGAVTIKCQASQSIGSNLAWYQHKPGQPPKLLIYFASSLASGVSSRFKGGRSGTQFTLTISDLECADAATYYCHCTYYPL SYVTGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:194) A11B1_4E1 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGTSLTLSCTASGFSFGSYYYMCWVRQAPGKGLEWIACIDVGSSGDTYYASWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCA RDDTAAGGFGNLELWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKV DKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAP IEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:195) A11B1_4E1 light chain MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVSEPVGGTVTIKCQASQSIYSYFSWYQQKPGQPPKRLIYQASTLASGVPSRFKGSGSGTDFTLTISDLECADAATYYCQNNYGRGSG SYFFGFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:196) A11B1_3H9 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCKASGIDFSSGYGMWWVRQAPGKGLEYIGYIDTGSGSTYYANWAKGRFTISKTSSTMVTLQMTSLTVADTATYFC AKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:197) A11B1_3H9 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQRPKLLIYRASTLASGVPSRFKGSGSGTDYTLTISDLECADAATYYCHTYYLSSS ISYGNTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO:198) A11B1_3G2 heavy chain METGLRWLLLVAVLKGVQCQEQLEESGGDLVKPEGSLTLTCKASGFSFSSIYWICWVRQAPGKGLEWIACTTVVKSGRTYYANWAKGRFTISKTSSTTVTLQMTSLTAADTATYFC AREFVDGGGSSGRDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTK VDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPA PIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO:199) A11B1_3G2 light chain MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEAAVGGTVTIKCQASQSISRDLSWYQQKPGQPPKRLIYKASTLASGVPSRFKGSGSGTDFTLTISDLECADAATYYCQQGYSSID VDNDFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (Sequence number 200) A11B1_3B1 heavy chain METGLRWLLLVAVLKGVQCQEQLEESGGGLVKPEGSLLTTCKASGFDLSSGYDMCWVRQAPGKGLEWIACIYADYSGSTYYASWVNGRFTISSSTSLNTVDLKMTSLTAADTATYF CARGATGNGGYGYYFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNT KVDKTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPA PIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (Sequence number 201) A11B1_3B1 light chain MDTRAPTQLLGLLLLWLPGARCADIVMTQTPASVSEPVGGTVTIKCQASQNINSGLAWYQQKPGQPPKLLIYKASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQTYYYSSS SSDNAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO: 202) A11B1_2D3 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGFSFSSSYWICWVRQAPGKGLEWIACIYGGSSSGNIAYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFC ARDIPSDAFTLDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVD KTVAPSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAP IEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO: 203) A11B1_2D3 light chain MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSSVSAAVGSTVTINCQASQSVYKDNNLAWYQQKPGQPPKLLIYKASTLASGVPSRFKGSGSGTQFTLTISGVQCEDAATYYCQGEFSCG SADCIAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO: 204) A11B1_2A7 heavy chain METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCKGSGIDFSGYGMWWVRQAPGKGLEYIGYIDTGYGSTYYASWAKGRFTISKTSSTTVTLQMTSLTVADTATYFC AKGGAIDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPMCPPPELPGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPTVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK * (SEQ ID NO: 205) A11B1_2A7 light chain MDTRAPTQLLGLLLLWLPGATFAAVLTQTPASTSAAVGGTVTINCQSSQSVYRSNWLAWYQQKPGQPPKLLIYDVFNLASGVPSRFKGSGSGTQFTLTISGVQCADAATYYCQGSYYSG NWYSAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC * (SEQ ID NO: 206)

[0144] Human mAb sequence Heavy and light chain variable region sequences

[0145] [Table 16]

[0146] [Table 17]

[0147]

Table 18

[0148]

Table 19

[0149]

Table 20

[0150]

Table 21

[0151]

Table 22

[0152]

Table 23

[0153]

Table 24

[0154]

Table 25

[0155]

Table 26

[0156]

Table 27

[0157]

Table 28

[0158]

Table 29

[0159]

Table 30

[0160]

Table 31

[0161]

Table 32

[0162]

Table 33

[0163]

Table 34

[0164]

Table 35

[0165]

Table 36

[0166]

Table 37

[0167] [Table 38]

[0168] [Table 39]

[0169] [Table 40]

[0170] [Table 41]

[0171] [Table 42]

[0172] 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)

[0173] [Table 43]

[0174] [Table 44] 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_4 EVQLLESGGGLVKPGGSLRLSCAVSGFSFSSSYYMCWVRQAPGKGLEWVSCIGTTRGSTYYADSAKGRFTISKDNSKNTVYLQMSSLRAEDTAVYFCARDATGYRINTIGLYFNLWGQGTLVTVSS (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_3 QLTQSPSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDTATYYCQSYHGTASTEYNTFGGGTKVEIK (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 QLTQSPSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDTATYYCQSYHGTASTEYQTFGGGTKVEIK (SEQ ID NO: 433) Humanized 16E10 light chain variable region VL_6 DIQLTQSPSSLSASVGDRVTITCQASQTIYSYLSWYQQKPGKPPKLLIYEASKLASGVPSRFSGSGSGTDYTLTISSLQPEDTATYYCQSYHGTASTEYQTFGGGTKVEIK (SEQ ID NO: 434)

[0175] Equivalent While the present invention has been described in connection with its detailed description, it is understood that the foregoing description is illustrative of the scope of the invention and is not intended to limit the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. 1. A pharmaceutical composition for use in a method of treating a subject having or at risk of chronic kidney disease, comprising an anti-integrin alpha11 beta 1 (α11β1) antibody or an antigen-binding fragment thereof, The method includes administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof; The antibody or antigen-binding fragment thereof comprises: (1) a heavy chain comprising heavy chain complementarity determining region 1 (CDRH1), heavy chain complementarity determining region 2 (CDRH2), and heavy chain complementarity determining region 3 (CDRH3); and (2) a light chain comprising light chain complementarity determining region 1 (CDRL1), light chain complementarity determining region 2 (CDRL2), and light chain complementarity determining region 3 (CDRL3); said CDRH1 comprising the sequence GYTFTSYG (SEQ ID NO:439); said CDRH2 comprising the sequence ISAYNGNT (SEQ ID NO:265); said CDRH3 comprising the sequence VTGITGTTIDP (SEQ ID NO:267); said CDRL1 comprising the sequence QSISSY (SEQ ID NO:216); said CDRL2 comprises the sequence DAS (SEQ ID NO:269); and said CDRL3 comprises the sequence QQYNNWPQT (SEQ ID NO:271); Pharmaceutical compositions.

2. The antibody or antigen-binding fragment thereof further comprises: (3) a heavy chain further comprising heavy chain framework region 1 (FRH1), heavy chain framework region 2 (FRH2), heavy chain framework region 3 (FRH3), and heavy chain framework region 4 (FRH4); and (4) a light chain further comprising light chain framework region 1 (FRL1), light chain framework region 2 (FRL2), light chain framework region 3 (FRL3), and light chain framework region 4 (FRL4); said FRH1 comprising the sequence QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 263); said FRH2 comprising the sequence ISWVRQAPGQGLEWMGW (SEQ ID NO: 264); said FRH3 comprises the sequence NYAQKLQGRVTMTTDTSSTAYMELRSLRSDDTAAYYCAR (SEQ ID NO: 266); said FRH4 comprising the sequence WGQGTMVTVSS (SEQ ID NO:268); said FRL1 comprises the sequence DIQMTQSPSSLSASVGDRVTITCRAS (SEQ ID NO: 227); said FRL2 comprises the sequence LNWYQQKPGKAPKLLIY (SEQ ID NO:217); The FRL3 comprises the sequence SLESGVPSRFSGSGSGTEFTLTISSLQPDDFAVYYC (SEQ ID NO: 270); and The FRL4 comprises the sequence FGQGTKVEIK (SEQ ID NO: 272); The pharmaceutical composition of claim 1. (i) the heavy chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSSTAYMELRSLRSDDTAAYYCARVTGITGTTIDPWGQGTMVTVSS; and (ii) the light chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the sequence of DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFAVYYCQQYNNWPQTFGQGTKVEIK; The pharmaceutical composition according to claim 1 or claim 2. (i) the heavy chain variable region comprises the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSSTAYMELRSLRSDDTAAYYCARVTGITGTTIDPWGQGTMVTVSS; and (ii) the light chain variable region comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFAVYYCQQYNNWPQTFGQGTKVEIK; The pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical composition described in any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or an antigen-binding fragment thereof.

6. The pharmaceutical composition described in any one of claims 1 to 5, wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.

7. A pharmaceutical composition described in any one of claims 1 to 6, wherein the antibody or antigen-binding fragment thereof reduces the interaction between α11β1 and collagen in human α11β1-expressing cells.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the chronic kidney disease is or comprises primary glomerular disease (including but not limited to IgA nephropathy and focal segmental glomerulosclerosis), secondary glomerular disease (including but not limited to lupus nephritis), thrombotic microangiopathy, tubulointerstitial disease (including but not limited to obstructive uropathy), diabetic nephropathy, hypertensive nephropathy, ischemic nephropathy, cardiorenal syndrome in CKD, genetic disorders of the glomerulus (including but not limited to Alport syndrome), cystic diseases of the kidney (including but not limited to polycystic kidney disease), or genetic disorders of the renal tubules.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein administering the therapeutically effective amount of the antibody or antigen-binding fragment thereof results in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% reduction in a measured marker, sign and / or symptom compared to a control.

10. The pharmaceutical composition of claim 9 , wherein the control comprises a constant level of a measured marker, sign and / or symptom in the subject prior to administration of the antibody.

11. 10. The pharmaceutical composition of claim 9, wherein the control comprises a constant level of a measured marker, sign and / or symptom in a subject suffering from a kidney-related disorder.

12. 10. The pharmaceutical composition of claim 9, wherein the control comprises average levels of measured markers, signs and / or symptoms in a population of subjects suffering from a kidney-related disorder.

13. 13. The pharmaceutical composition of any one of claims 9 to 12, wherein 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.

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