WO2022212836A1

WO2022212836A1 - Gpnmb antibodies and methods of use

Info

Publication number: WO2022212836A1
Application number: PCT/US2022/023041
Authority: WO
Inventors: Ronald Herbst; Daniel FELITSKY; Jianwen Feng; Nicolas SEVERE; Ona MILLER
Original assignee: Pyxis Oncology, Inc.
Priority date: 2021-04-01
Filing date: 2022-04-01
Publication date: 2022-10-06

Abstract

The disclosure relates to immunoglobulins, or antigen-binding fragments thereof, that specifically bind to glycoprotein nonmetastatic melanoma protein B (GPNMB). Such immunoglobulins, or antigen-binding fragments thereof, are useful for various therapeutic or diagnostic purposes, including treatment of cancers and to increase the effectiveness of vaccines.

Description

GPNMB ANTIBODIES AND METHODS OF USE

RELATED APPLICATION

[0001] The present application claims the benefit of U.S. Provisional Application No. 63/169,574 filed on April 1, 2021, the entire contents of which are incorporated herein by reference.

REFERENCE TO A SEQUENCE LISTING

[0002] This application contains a Sequence Listing in computer readable form. The computer readable form is incorporated herein by reference. Said ASCII copy, created on March 23, 2022, is named 764549_000115_SL.txt and is 68,805 bytes in size.

BACKGROUND

[0003] Surface protein co-inhibitory receptors expressed on tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are believed to drive immunosuppression in the tumor microenvironment through two distinct mechanisms: i) direct binding to T cells and inhibition of their function, and ii) immunosuppressive polarization of myeloid cells (TAMs and MDSCs). The action of co-inhibitory receptors is generally carried out by binding of a ligand to the extracellular domain of the co-inhibitory receptor followed by recruitment of intracellular phosphatases by an immunoreceptor tyrosine-based inhibition motif (ITIM) located in the intracellular domain of the co-inhibitory receptor. The action of co- inhibitory receptors is generally to dampen the immune response of T-cell receptor (TCR) engagement. In recent years it has been shown that agents that block the activity of co-inhibitory receptors may be used to as efficacious treatments for cancer and infectious diseases, but clinical responses to solid tumors in patients who are refractory or resistant to checkpoint inhibitors due to an immunosuppressive myeloid cell compartment are lacking.

SUMMARY OF THE INVENTION

[0004] This disclosure relates to a human immunoglobulin, or antigen binding fragment thereof, having binding specificity for glycoprotein nonmetastatic melanoma protein B (GPNMB), as described herein in Table 1. Specifically, the human anti-GPNMB immunoglobulin or antigen binding fragment thereof may comprise amino acid sequences of heavy chain complementary determining regions (CDRs) and/or light chain CDRs described herein in Table 2. The human anti-GPNMB immunoglobulin or antigen binding fragment thereof may comprise heavy chain variable domain and light chain variable domain sequences as described herein in Table 3.

[0005] In one aspect, the disclosure relates to a human immunoglobulin or antigen binding fragment thereof having binding specificity for glycoprotein nonmetastatic melanoma protein B (GPNMB) comprising a heavy chain and a light chain: wherein the heavy chain comprises: a CDR1 selected from the group consisting of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; a CDR2 selected from the group consisting of SEQ ID NOS: 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22; and a CDR3 selected from the group consisting of SEQ ID NOS: 23, 24, 25, 26, 96, 27,

28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 and 102; and wherein the light chain comprises: a CDR1 selected from the group consisting of SEQ ID NOS: 39, 40, 41, 42, 43, 44, 45, and 46; a CDR2 selected from the group consisting of SEQ ID NOS: 47, 48, 49, and 50; and a CDR3 selected from the group consisting of SEQ ID NOS: 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, and 62.

[0006] The heavy chain variable region may have at least 70% sequence identity to an amino acid sequence as set forth in SEQ ID NOS: 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, or 81. The light chain variable region may have at least 70% sequence identity to an amino acid sequence as set forth in SEQ ID NOS: 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,

93, or 94.

[0007] The human immunoglobulin or antigen binding fragment may comprise heavy chain variable region and light chain variable region pairs, such as: SEQ ID NO:63 and SEQ ID NO: 82; SEQ ID NO: 64 and SEQ ID NO: 83; SEQ ID NO: 65 and SEQ ID NO: 83; SEQ ID NO: 66 and SEQ ID NO: 83; SEQ ID NO: 67 and SEQ ID NO: 83; SEQ ID NO: 68 and SEQ ID NO: 84; SEQ ID NO: 69 and SEQ ID NO: 85; SEQ ID NO: 70 and SEQ ID NO: 86; SEQ ID NO: 71 and SEQ ID NO: 87; SEQ ID NO: 72 and SEQ ID NO: 88; SEQ ID NO: 73 and SEQ ID NO: 89; SEQ ID NO: 74 and SEQ ID NO: 89; SEQ ID NO: 75 and SEQ ID NO: 89; SEQ ID NO: 76 and SEQ ID NO: 89; SEQ ID NO: 77 and SEQ ID NO: 90; SEQ ID NO: 78 and SEQ ID NO: 91; SEQ ID NO: 79 and SEQ ID NO: 92; SEQ ID NO: 80 and SEQ ID NO: 92; SEQ ID NO: 81 and SEQ ID NO: 92; SEQ ID NO: 79 and SEQ ID NO: 93; SEQ ID NO: 80 and SEQ ID NO: 93; SEQ ID NO: 81 and SEQ ID NO: 93; SEQ ID NO: 79 and SEQ ID NO: 94; SEQ ID NO: 80 and SEQ ID NO: 94; or SEQ ID NO: 81 and SEQ ID NO: 94.

[0008] The antigen binding fragment may be a ScFv (single chain fragment variable) antibody, Fab fragment, F(ab')2 fragment, or Fv fragment. The immunoglobulin or antigen binding fragment thereof may bind a transmembrane glycoprotein NMB (GPNMB) with a KD < 10-4.

[0009] The human immunoglobulin or antigen binding fragment thereof may be produced by Alloy mice.

[00010] The human immunoglobulin or antigen binding fragment may bind to GPNMB at one or more regions of the extracellular domain (ECD). The human immunoglobulin or antigen binding fragment thereof may competitively bind to GPNMB.

[00011] The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 1), CDR-H2 (SEQ ID NO: 12), and CDR-H3 (SEQ ID NO: 23) and CDR-L1 (SEQ ID NO: 39), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO: 51). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 13), and CDR-H3 (SEQ ID NO: 24) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 52). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 14), and CDR-H3 (SEQ ID NO: 25) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 52). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 14), and CDR-H3 (SEQ ID NO: 26) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 52). The human immunoglobulin or antigen binding fragment may comprise CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 15), and CDR-H3 (SEQ ID NO: 25) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 52). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 3), CDR-H2 (SEQ ID NO: 12), and CDR-H3 (SEQ ID NO: 96) and CDR-L1 (SEQ ID NO: 39), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO: 53). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 4), CDR-H2 (SEQ ID NO: 16), and CDR-H3 (SEQ ID NO: 27) and CDR-L1 (SEQ ID NO: 41), CDR-L2 (SEQ ID NO:

49), and CDR-L3 (SEQ ID NO: 54). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 5), CDR-H2 (SEQ ID NO: 17), and CDR-H3 (SEQ ID NO: 28) and CDR-L1 (SEQ ID NO: 42), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 55). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 6), CDR-H2 (SEQ ID NO: 18), and CDR-H3 (SEQ ID NO: 29) and CDR-L1 (SEQ ID NO: 39), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO: 56).

The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 7), CDR-H2 (SEQ ID NO: 19), and CDR-H3 (SEQ ID NO: 30) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 57). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 31) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 58). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 32) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO:

50), and CDR-L3 (SEQ ID NO: 58). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 33) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 58). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 34) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 58).

The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 9), CDR-H2 (SEQ ID NO: 12), and CDR-H3 (SEQ ID NO: 102) and CDR-L1 (SEQ ID NO: 45), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO: 53). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 10), CDR-H2 (SEQ ID NO: 21), and CDR-H3 (SEQ ID NO: 35) and CDR-L1 (SEQ ID NO: 41), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 36) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 37) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 38) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 36) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 61). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 37) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 61). The human immunoglobulin or antigen binding fragment may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 38) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 61). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 36) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 62). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 37) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 62). The human immunoglobulin or antigen binding fragment thereof may comprise CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 38) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 62).

[00012] The disclosure also relates to an isolated nucleic acid encoding a human anti- GPNMB antibody or antigen binding fragment thereof, a vector comprising the nucleic acid, and a host cell comprising the nucleic acid.

[00013] The disclosure further relates to methods of treating a disease or a disorder.

[00014] In embodiments, the disease or disorder is cancer and the method comprises administering a therapeutically effective amount of the human immunoglobulin or antigen binding fragments disclosed herein to a subject in need thereof. The subject may have or may be suspected of having myeloid-derived suppressor cell (MDSC)-driven tumor expansion, GPNMB-positive MDSCs, pro-inflammatory tumor microenvironment (TME), tumor-associated macrophages (TAMs), metastasis, or a solid tumor.

[00015] In embodiments, the disease or disorder is a neurodegenerative disease (such as Alzheimer’s disease and Parkinson’s disease), obesity, diabetes, or osteopetrosis.

[00016] The disclosure also relates to a method, comprising obtaining a sample from a subject; and using a human immunoglobulin or antigen binding fragment thereof disclosed herein to measure a GPNMB protein level of the sample obtained from the subject; or measure a GPNMB expression level on myeloid-derived suppressor cells (MDSCs) or immunosuppressive macrophages in the sample; or measure a number of GNPMB-positive MDSCs or immunosuppressive macrophages in the sample; and then administering, as a function of the measures, a specific therapeutic drug. The sample may be blood, serum, or a cancer biopsy. The measuring step may comprise at least one of immunofluorescence assay, fluorescence-activated cell sorting (FACS), T-cell suppression assay, or surface plasmon resonance (SPR). Administering a specific therapeutic drug may further comprise comparing a measured GPNMB protein level, GPNMB expression level, or number of GPNMB-positive MDSCs to a threshold value.

[00017] The disclosure also relates to a method, comprising administering to a subject a human immunoglobulin or antigen binding fragment thereof having binding specificity for GPNMB, whereby macrophages of the subject increase secretion of IL12p40, TNFa, and/or IL10.

[00018] The disclosure also relates to pharmaceutical compositions comprising a human immunoglobulin or antigen binding fragment thereof disclosed herein and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient may be any and all solvents, dispersion media, coatings, antibacterial agents and antifungal agents, isotonic agents, and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The pharmaceutical compositions may also be included in a container, pack, or dispenser together with instructions for administration. BRIEF DESCRIPTION OF THE DRAWINGS

[00019] This disclosure will be more fully understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

[00020] FIGs. lA-10 are graphs showing FACS binding of human anti-GPNMB monoclonal antibodies to human GPNMB on ExpiCHO cells.

[00021] FIG. 2A is a graph showing FACS binding of human anti-GPNMB monoclonal antibodies to human GPNMB on ExpiCHO cells and FIG. 2B is a table describing the EC50 values corresponding to each of the human anti-GPNMB monoclonal antibodies shown in the curves of FIG. 2 A.

[00022] FIGs. 3A-3I are graphs showing FACS binding of optimized human anti-GPNMB monoclonal antibody L16 and B01 clones to human GPNMB on ExpiCHO cells.

[00023] FIGs. 4 A and 4B are graphs showing FACS binding of optimized human anti- GPNMB monoclonal antibody L16 and B01 clones to human GPNMB on ExpiCHO cells, and FIG. 4C is a table describing the EC50 values of the curves of FIGS. 4A and 4B.

[00024] FIGs. 5A-50 are graphs showing FACS binding cross-reactivity of human anti- GPNMB antibodies to cynomolgus GPNMB on ExpiCHO cells.

[00025] FIG. 6A is a graph showing FACS binding cross-reactivity of human anti- GPNMB antibodies to cynomolgus GPNMB on ExpiCHO cells, and FIG. 6B is a table describing the EC50 value of the curves shows in FIG. 6A.

[00026] FIGs. 7A-7I are graphs showing FACS binding cross-reactivity of optimized clones L16 and B01 human anti-GPNMB antibodies to cynomolgus GPNMB on ExpiCHO cells.

[00027] FIGs. 8 A and 8B are graphs showing FACS binding of optimized human anti- GPNMB monoclonal antibody L16 and B01 clones to cynomolgus GPNMB on ExpiCHO cells, and FIG. 8C is a table describing EC50 values of the curves shown in FIG. 8A and FIG. 8B. [00028] FIGs. 9A and 9B are graphs showing macrophage assay results measuring RNA levels of IL10 (FIG.9A) and TGFpi (FIG. 9B) 48 hours after human anti-GPNMB antibody treatment.

[00029] FIGs. 10A and 10B are graphs showing macrophage assay results measuring RNA levels of IL12b (FIG. 10A) and IL6 (FIG. 10B) 48 hours after human anti-GPNMB antibody treatment.

[00030] FIGs. 11 A, 1 IB, and 11C are graphs showing macrophage assay results measuring secreted protein of IL10 (FIG. 11 A), IL12p40 (FIG. 1 IB), and TNFa (FIG. 11C) 48 hours after human anti-GPNMB antibody treatment.

[00031] FIGs. 12A-12D are graphs showing macrophage donor assay results measuring RNA levels of IL10 (FIG. 12A and 12B) and IL12b (FIG. 12C and FIG. 12D) 48 hours after human anti-GPNMB antibody treatment.

[00032] FIGs. 13A and 13B are graphs showing macrophage IL10 RNA (FIG. 13A) and IL10 secreted protein (FIG. 13B) expression levels 48 hours after human anti-GPNMB antibody treatment at 10 pg/ml, 3D5-2 at 5 pg/ml and B01 DVHC at 20 pg/ml.

[00033] FIG. 14 is a graph showing macrophage TNFa secreted protein expression 24 hours after human anti-GPNMB antibody treatment at 10 pg/ml, 3D5-2 at 5 pg/ml and B01 DVHC at 20 pg/ml.

[00034] FIG. 15 is a graph showing macrophage TNFa secreted protein expression 48 hours after human anti-GPNMB antibody treatment at 10 pg/ml, 3D5-2 at 5 pg/ml and B01 DVHC at 20 pg/ml.

[00035] FIGs. 16A and 16B are graphs showing macrophage IL12b RNA (FIG. 16 A) and IL12p40 secreted protein (FIG. 16B) expression levels 48 hours after human anti-GPNMB antibody treatment at 10 pg/ml, 3D5-2 at 5 pg/ml and B01 DVHC at 20 pg/ml.

[00036] FIGs. 17A-17F are graphs showing secretion by macrophages of TNFa (FIGs. 17A and 17D), IL-12p40 (FIGs. 17B and 17E), and IL-10 (FIGs. 17C and 17F) 48 hours after human anti-GPNMB serial dilution antibody treatment. Donor 1, FIGs. 17A-17C; Donor 2, FIGs. 17D-17F.

DETAILED DESCRIPTION

[00037] Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein receptor, which can function as an immune checkpoint that inhibits T-cell activation. GPNMB may also be referred to as dendritic cell-associated transmembrane protein (DC-HIL), osteoactivin (OA), or hematopoietic growth factor inducible neurokinin- 1 type (HGFIN).

[00038] GPNMB contains a single pass transmembrane domain, an extracellular domain (ECD), and a short cytoplasmic tail. The cytoplasmic tail of GPNMB comprises a half immunoreceptor tyrosine-based inhibitory motif (hemITIM) motif responsible for co-inhibition of T cell receptor (TCR) mediated signaling. The extracellular domain of GPNMB contains an RGD motif and a polycystic kidney disease (PKD) domain, which together mediate cell-cell adhesion. GPNMB ECD ligands may include a multitude of extracellular matrix and plasma proteins and may be involved in binding via the RGD motif, such as the extracellular domain of NKA al, syndecan 4, cd44, atplal, integrins, heparan sulfate proteins, VEGFR, and the a5b1 fibronectin receptor.

[00039] In humans, GPNMB is expressed on a variety of cells, including osteoclasts, dendritic cells, macrophages, and breast epithelia and has been associated with regulating a variety of physiological processes, including suppression of T-cell activation. For example in breast cancer, GPNMB overexpression induces an invasive phenotype, enhances primary tumor growth, promotes endothelial cell recruitment, and drives lung and bone metastasis. It is thought that expression of GPNMB may function to interact directly with T-cells and impair activation to down-modulate anti-tumor immune responses, thereby allowing cancer cells to evade immunologic recognition and destruction.

[00040] As antigen-specific T cells differentiate, they may acquire increased expression of cytotoxic molecules, and therefore may acquire increased cytotoxic potential. The biological function of GPNMB is to inhibit activation and proliferation of these T cells; although, in contrast to this immunosuppressive role, phosphorylation of GPNMB’s hemITAM tyrosine residue in dendritic cells induces increased cytokine secretion, particularly tumor necrosis factor alpha (TNFa) and interleukin- 1b (IL-Ib), augmenting the activation of nearby naive T-cells. In cancer and infectious disease, it has been shown beneficial to restore T-cell activity, prompting interest in targeting GPNMB.

[00041] Certain exemplary embodiments are described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the antibodies, fragments thereof, compositions of matter, kits, and related methods and therapies disclosed herein.

DEFINITIONS

[00042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this present disclosure belongs. The terminology used in the description of the present disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present disclosure and any invention(s) described or otherwise provided for herein.

[00043] Amino acids are represented herein by either the one-letter code, or the three- letter code, both in accordance with established usage.

[00044] All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and/or paragraph in which the reference is presented.

[00045] As used in the description of the present disclosure and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[00046] As used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or"). [00047] The terms "about" and "approximately" as used herein when referring to a measurable value such as an amount of polypeptide, dose, time, temperature, enzymatic activity or other biological activity and the like, is meant to encompass variations of ± 20%, ± 10%, ±

5%, ± 1%, + 0.5%, or even ± 0.1% of the specified amount.

[00048] The transitional phrase "consisting essentially of means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim, "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. See In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in the original); see also MPEP § 2111.03.

[00049] The term "consists essentially of (and grammatical variants), as applied to a polynucleotide or polypeptide sequence of this present disclosure, means a polynucleotide or polypeptide that consists of both the recited sequence (e.g., SEQ ID NO) and a total of ten or less (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) additional amino acids on the N-terminal and/or C-terminal ends of the recited sequence such that the function of polypeptide is not materially altered. The total of ten or less additional amino acids can include the total number of additional amino acids on both ends added together.

[00050] An "effective amount" as used herein is an amount that provides a desired effect. The term “effective amount” refers to a dosage or amount that is sufficient to reduce the activity of GPNMB to result in amelioration of symptoms in a patient or to achieve a desired biological outcome, e.g., reduced activity of GPNMB, modulation of lymphocyte co-inhibition response, increased or decreased activation of cytotoxic T and NK cells, or increased or decreased release oflFNy by cytotoxic T cells or NK cells.

[00051] A "therapeutically effective" amount as used herein is an amount that provides some improvement or benefit to the subject. Alternatively stated, a "therapeutically effective" amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. [00052] By the terms "treat," "treating," or "treatment of," it is intended that the severity of the condition of the subject is reduced, or at least partially improved or modified, and that some alleviation, mitigation, or decrease in at least one clinical symptom is achieved.

[00053] The term "cancer" as used herein refers to any benign or malignant abnormal growth of cells. Examples include, without limitation, breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft- tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma. In some embodiments, the cancer is selected from the group of tumor-forming cancers. A person skilled in the art will recognize which cancers fall within the purview of that group.

[00054] The term "isolated" can refer to a polypeptide that is substantially free of cellular material, viral material, and/or culture medium (when produced by recombinant DNA techniques), or chemical precursors or other chemicals (when chemically synthesized).

Moreover, an "isolated fragment" is a fragment of a polypeptide that is not naturally occurring as a fragment and would not be found in the natural state. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to provide the polypeptide or nucleic acid in a form in which it can be used for the intended purpose. Thus, the term "isolated" refers to a molecule that is substantially free of its natural environment. For instance, an isolated protein is substantially free of cellular material or other proteins from the cell or tissue source from which it is derived. The term "isolated" also refers to preparations where the isolated protein is sufficiently pure to be administered as a pharmaceutical composition, or approximately at least 70-80% (w/w) pure, more preferably, approximately at least 80-90% (w/w) pure, even more preferably, approximately 90-95% pure; and, most preferably, approximately at least 95%, approximately at least 96%, approximately at least 97%, approximately at least 98%, approximately at least 99%, or approximately 100% (w/w) pure.

[00055] The term "fragment" as applied to a polypeptide, will be understood to mean an amino acid sequence of reduced length relative to a reference polypeptide or amino acid sequence and comprising, consisting essentially of, and/or consisting of an amino acid sequence of contiguous amino acids identical or almost identical (e.g., approximately 90%, approximately 92%, approximately 95%, approximately 98%, approximately 99% identical) to the reference polypeptide or amino acid sequence. Such a polypeptide fragment according to the present disclosure may be, where appropriate, included in a larger polypeptide of which it is a constituent. In some embodiments, such fragments can comprise, consist essentially of, and/or consist of peptides having a length of at least about 4, about 6, about 8, about 10, about 12, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, 7 about 5, about 100, about 150, about 200, or more consecutive amino acids of a polypeptide or amino acid sequence according to the present disclosure.

[00056] As used herein, the terms "protein" and "polypeptide" are used interchangeably and encompass both peptides and proteins, unless indicated otherwise.

[00057] A "fusion protein" is a polypeptide produced when two heterologous nucleotide sequences or fragments thereof coding for two (or more) different polypeptides not found fused together in nature are fused together in the correct translational reading frame. Illustrative fusion polypeptides include fusions of a polypeptide of the present disclosure (or a fragment thereof) to all or a portion of glutathione s-transferase, maltose-binding protein, or a reporter protein (e.g., Green Fluorescent Protein, b -glucuronidase, b-galactosidase, luciferase, etc.), hemagglutinin, c- myc, FLAG epitope, etc.

[00058] As used herein, a "functional polypeptide” or "functional fragment" is one that substantially retains at least one biological activity normally associated with that polypeptide (e.g., target protein binding). In particular embodiments, the "functional" polypeptide or "functional fragment" substantially retains all of the activities possessed by the unmodified peptide. By "substantially retains" biological activity, it is meant that the polypeptide retains at least about 20%, about 30%, about 40%, about 50%, about 60%, about 75%, about 85%, about 90%, about 95%, about 97%, about 98%, about 99%, or more, of the biological activity of the native polypeptide (and can even have a higher level of activity than the native polypeptide). A "non-functional" polypeptide is one that exhibits little or essentially no detectable biological activity normally associated with the polypeptide (e.g., at most, only an insignificant amount, e.g., less than about 10% or even less than about 5%). Biological activities such as protein binding can be measured using assays that are well known in the art and as described herein.

[00059] The term “immunoglobulin”, commonly referred to as an "antibody" or "antibodies", as used herein refers to all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE. The antibody can be monoclonal or polyclonal and can be of any species of origin, including, for example, mouse, rat, rabbit, horse, goat, sheep, camel, or human, or can be a chimeric antibody. The antibodies can be recombinant monoclonal antibodies produced according to the methods disclosed, for example, in U.S. Patent No. 4,474,893 or U.S. Patent No. 4,816,567. The antibodies can also be chemically constructed, for example, according to the methods disclosed in U.S. Patent No. 4,676,980.

[00060] The terms "antigen-binding domain," "antigen-binding fragment," and "binding fragment" refer to a part of an antibody molecule that comprises amino acids responsible for the specific binding between the antibody and the antigen. In instances where an antigen is large, the antigen-binding domain may only bind to a part of the antigen. A portion of the antigen molecule that is responsible for specific interactions with the antigen-binding domain is referred to as "epitope" or "antigenic determinant". The fragment may include the constant region (Fc), as is present in antibodies, or include any singular fragment of an antibody, such as the Fab domain, the light chain variable domain, heavy chain variable domain, and the like.

[00061] The term "repertoire" refers to a genetically diverse collection of nucleotides derived wholly or partially from sequences that encode expressed immunoglobulins. The sequences can be generated by in vivo rearrangement of, e.g., V, D, and J segments for H chains and, e.g., V and J segment for L chains. Alternatively, the sequences may be generated from a cell line by in vitro stimulation, in response to which the rearrangement occurs. Alternatively, part or all of the sequences may be obtained by combining, e.g., unrearranged V segments with D and J segments, by nucleotide synthesis, randomized mutagenesis, and other methods, for example as disclosed in U.S. Patent No. 5,565,332.

[00062] The terms "specific interaction" and "specific binding" refer to two molecules forming a complex that is relatively stable under physiologic conditions. Specific binding can be characterized by a high affinity and a low to moderate capacity, as distinguished from non specific binding, which usually has a low affinity with a moderate to high capacity. Typically, binding is considered specific when the affinity constant KA is higher than approximately 106 M-l, or more preferably higher than approximately 108 M-l. If necessary, non-specific binding can be reduced without substantially affecting specific binding, for example, by varying the binding conditions. The appropriate binding conditions such as concentration of antibodies, ionic strength of the solution, temperature, time allowed for binding, concentration of a blocking agent (e.g., serum albumin, milk casein), etc., may be optimized by a skilled artisan using routine techniques.

[00063] The terms “competitive binding” and “competitive inhibition” as referred to herein to interruption of a chemical or biological pathway, owing to one substance inhibiting the effect of another by competing with it for binding or bonding. Typically, competitive inhibition prevents binding of the target molecule as known as the ‘substrate’, to an enzyme’s ‘active site’. Competitive binding by antibodies may be characterized as an antibody binding the surface of the antigen in a location that is required for the antigen to elicit its effect. Antibodies may be used for competitive binding immunoassays where the antibody may serve as a diagnostic tool for detecting the presence of an antigen from a sample. For example, the antigen of interest and a labeled analog may be incubated with a fixed concentration of the antibody, and the signal produced is based on competition between the analyte and corresponding labeled analog for antibody binding sites.

[00064] The phrase "substantially as set out" means that the relevant CDR, VH, or VL domain of the disclosure will be either identical to, or have only insubstantial differences in the specified regions (e.g., a CDR) from the sequence of which is set out. Insubstantial differences include minor amino acid changes, such as substitutions of one (1) or two (2) out of any five (5) amino acids in the sequence of a specified region.

[00065] The term "GPNMB activity" refers to one or more lymphocyte co-inhibitory activities associated with GPNMB. For example, GPNMB activity may mean modulation of cytotoxic T and NK cell activation.

[00066] The term "modulate," and its cognates, refer to a reduction or an increase in the activity of GPNMB associated with activation of T cells and NK cells due to its interaction with an anti-GPNMB antibody, wherein the reduction or increase is relative to the activity of GPNMB in the absence of the same antibody. A reduction or an increase in activity is preferably at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more. When GPNMB activity is reduced, the terms "modulatory" and "modulate" are interchangeable with the terms "inhibitory" and "inhibit." When GPNMB activity is increased, the terms "modulatory" and "modulate" are interchangeable with the terms "activating" and "activate."

ANTIBODIES AND COMPOSITIONS

[00067] The present disclosure allows for the identification and characterization of antibodies that specifically bind to the extracellular domain of GPNMB, either of cells or the proteolytically-cleaved ECD product, by interfering with the binding of integrins to the extracellular domain of GPNMB. By interfering with binding of an integrin ligand to GPNMB, such antibodies modulate (e.g., neutralize) the interaction between GPNMB and its ligands. The antibodies described herein can be used as effective therapeutic agents for treatment of cancer either as monotherapy, or in combination with other immunotherapy agents (such as checkpoint inhibitors, including anti -PD- 1 antibodies, anti-PD-Ll antibodies, or anti-CTLA4 antibodies), or in combination with chemotherapy agents, radiotherapy (XRT), or cancer vaccines. Such antibodies, or fragments thereof, can be used as an adjunct therapy for cancer treatment, regardless if the cancer cells express GPNMB. [00068] Similarly, the antibodies described herein can be used as effective therapeutic agents for the treatment of diseases or disorders, such as neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), obesity, diabetes, and osteopetrosis, either as monotherapy, or in combination with other agents or treatment modalities.

[00069] Intact antibodies, also known as immunoglobulins, are typically tetrameric glycosylated proteins composed of two light (L) chains of approximately 25 kDa each and two heavy (H) chains of approximately 50 kDa each. Two types of light chain, designated as the l chain and the k chain, are found in antibodies. Depending on the amino acid sequence of the constant domain of heavy chains, immunoglobulins can be assigned to five major classes: A, D, E, G, and M, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[00070] The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known in the art. Briefly, each light chain can be composed of an N- terminal variable domain (VL) and a constant domain (CL). Each heavy chain can be composed of an N-terminal variable domain (VH), three or four constant domains (CH), and a hinge region. The CH domain most proximal to VH is designated as CHI . The VH and VL domains consist or comprise of four regions of relatively conserved sequence called framework regions (FR1, FR2, FR3, and FR4), which form a scaffold for three regions of hypervariable sequence called complementarity determining regions (CDRs). The CDRs can contain most of the residues responsible for specific interactions with the antigen. The three CDRs are referred to as CDR1, CDR2, and CDR3. CDR constituents on the heavy chain are referred to as HI, H2, and H3, while CDR constituents on the light chain are referred to as LI, L2, and L3, accordingly. CDR3 and particularly H3, are the greatest source of molecular diversity within the antigen-binding domain. H3, for example, can be as short as two amino acid residues of greater than 26.

[00071] The Fab fragment (Fragment antigen-binding), or Fab, consists or comprises of the VH-CHl and VL-CL domains covalently linked by a disulfide bond between the constant regions. Known to those skilled in the art, a Fab (50,000 daltons) is a monovalent fragment that is produced from IgG and IgM, consisting or comprising of the VH, CHI and VL, CL regions, linked by an intramolecular disulfide bond. To overcome the tendency of non-covalently linked VH and VL domains in the Fv to dissociate when co-expressed in a host cell, a so-called single chain (sc) Fv fragment (scFv) can be constructed. In a scFv, a flexible and adequately long polypeptide links either the C-terminus of the VH to the N-terminus of the VL, or the C-terminus of the VL to the N-terminus of the VH. Most commonly, a 15-residue (Gly4Ser)3 peptide (SEQ ID NO: 103) can be used as a linker, but other linkers are also known in the art.

[00072] Antibody diversity is a result of combinatorial assembly of multiple germline genes encoding variable regions and a variety of somatic events. The somatic events can include recombination of variable gene segments with diversity (D) and joining (J) gene segments to make a complete VH region and the recombination of variable and joining gene segments to make a complete VL region. The recombination process itself is imprecise, resulting in the loss or addition of amino acids at the V(D)J junctions. These mechanisms of diversity occur in the developing B cell prior to antigen exposure. After antigenic stimulation, the expressed antibody genes in B cells can undergo somatic mutation.

[00073] Based on the estimated number of germline gene segments, the random recombination of these segments, and random VH-VL pairing, up to approximately 1.6x107 different antibodies can be produced according to Fundamental Immunology, 3rd ed., ed. Paul, Raven Press, New York, N.Y., 1993. When other processes which contribute to antibody diversity (such as somatic mutation) are taken into account, it is thought that upwards of approximately 1x1010 different antibodies could be potentially generated, as supported by Immunoglobulin Genes, 2nd ed., eds. Jonio et ak, Academic Press, San Diego, Calif., 1995. Because of the many processes involved in antibody diversity, it is highly unlikely that independently generated antibodies will have identical amino acid sequences in the CDRs.

[00074] The present disclosure provides novel antibody variable heavy and light chain regions (VH and VL) and antibody heavy and light chains derived from human immunoglobulin gene libraries, which are effective in blocking GPNMB signaling in cells expressing cell surface GPNMB. These heavy and light chains and their variable regions provide a scaffold structure for carrying CDRs. A CDR can generally be, though is not limited to, an antibody heavy or light chain, or a portion thereof, in which the CDR is located at a location corresponding to the CDR of naturally occurring VH and VL. The structures and locations of immunoglobulin variable domains may be determined, for example, as described in Kabat et al., Sequences of Proteins of Immunological Interest, No. 91-3242, National Institutes of Health Publications, Bethesda, Md., 1991.

[00075] The antibodies of the present disclosure, such as those described herein, exhibit at least two functions in the immune system. Firstly, they bind GPNMB, and by virtue of their binding ability they may block interacting partners from binding to GPNMB. Secondly, they may prevent bidirectional GPNMB signaling - both through GPNMB and interaction partner pathways, thereby allowing T-cell activation. Such antibodies, or antigen-binding fragments, are useful for therapeutic and diagnostic purposes, including treatment of cancer.

[00076] Antibodies as described herein can be conjugated to other moieties, such as toxins, enzymes, inorganic compounds, or receptors. Antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) are three well known antibody mediated mechanisms for killing, and thus depleting, target cells.

[00077] Binding of the antibody to the target cell through the antigen binding region (variable domain) of the antibody can provide a linkage of the target cell to immune effectors through the Fc region(s) of the constant region of the antibody. In ADCC, typically the Fc region of the antibody binds to FcyRIIIa receptor on the immune effector cell, e.g., an NK cell, which can then kill the target cell. In ADCP, typically the Fc region of the antibody binds to FcyRIIa receptor on the immune effector cell, e.g., a macrophage cell, which can then engulf and kill the target cell. CDC is induced when the immune complex Clq binds to the Fc region of the antibody bound to the target cell, triggering the formation of a membrane attack complex that punches holes into the surface of the target cell.

[00078] Thus, the constant region of the antibody mediates effector functions, including the activation of complement and interaction with Fc receptors, enabling effects such as ADCC, ADCP, or CDC. Neither CHI nor CK or Ck domains mediate effector functions, which is the reason why Fabs do not show ADCC, ADCP, or CDC. [00079] There are three classes of Fc gamma receptors, FcyRI (CD64), FcyRII (CD 32), and FcyRIII (CD 16). Only FcyRI is able to bind IgG in a monomeric form, and the affinity of FcyRI receptors compared to the immunoglobulin receptors FcyRII and FcyRIII is high. The high affinity receptor FcyRI is constitutively expressed on monocytes, macrophages, and dendritic cells, and expression can be induced on neutrophils and eosinophils. Thus, these cells can be recruited to a target cell through antibody or antibody fragment thereof comprising Fc region, bound to the target cell.

[00080] The FcyRI la receptor is found on macrophages, monocytes, and neutrophils, and the FcyRIIb receptor is found on B-cells, macrophages, mast cells, and eosinophils. The FcyRIIIa receptor is found on NK cells, macrophages, eosinophils, monocytes, and T cells, and the FcyRIIIb receptor is highly expressed on neutrophils. Again, these various cell types can be recruited to a target cell by an antibody bound to the target cell through an antibody or antibody fragment thereof comprising the Fc region, bound to the target cell.

[00081] Thus, the GPNMB binding molecules, including antibodies and antigen binding fragments thereof, and methods thereof, including those pertaining to GPNMB inhibition in a subject or in vitro, in some aspects comprise a GPNMB antigen binding site together with an antibody constant domain or fragment thereof. This can function to mediate an effector function, including but not limited to ADCC, ADCP, or CDC. In some aspects the GPNMB binding molecule consists of or comprises the antigen binding site of an antibody and a peptide binding Fc-effector molecule, as described in International Patent Application Publication No. WO 02/44215.

[00082] In some aspects, the antibodies and/or antigen binding fragments thereof provided for by the instant disclosure are conjugated to a toxic agent, and thus do not necessarily rely on endogenous effector cells in ADCC, ADCP, or CDC to deplete the target cells, e.g., pathogenic cells and/or cancer cells expressing cell surface GPNMB.

[00083] Immunoconjugates which include one or more cytotoxins are referred to as "immunotoxins." Antibodies conjugated to a cytotoxic agent, drug, or the like are also known as antibody-drug conjugates (ADC). An immunoconjugate may have a half-life of sufficient periods of time for the antibody-drug conjugate to be internalized, degraded, and induce cell killing by the released toxin. For example, GPNMB includes a dileucine motif in the cytoplasmic tail with a D/ExxxLL sequence, which is commonly associated with functions such as rapid receptor internalization and subsequent lysosomal/endosomal targeting. Antibody binding to GPNMB on cancer cells overexpressing GNPMB may trigger internalization mechanisms such as clathrin-mediated endocytosis (CME), clathrin-independent endocytosis (CIE), caveolin-dependent pathways, micropinocytosis, clathrin-independent carriers (CLICs), circular dorsal ruffling (CDR), among other mechanisms, whereby the antibody-drug conjugate immunocomplex may be trafficked into GPNMB-upregulated cancer cells allowing action by the drug.

[00084] A cytotoxin or cytotoxic agent can include any agent that is detrimental to (e.g., kills) cells. Suitable cytotoxic agents for forming immunoconjugates of the present disclosure include taxol, tubulysins, duostatins, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, maytansine or an analog or derivative thereof, mitoxantrone, mithramycin, actinomycin D, 1 -dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin; calicheamicin or analogs or derivatives thereof, antimetabolites (such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabin, 5-fluorouracil, decarbazine, hydroxyurea, asparaginase, gemcitabine, cladribine), alkylating agents (such as mechlorethamine, thioepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin and other platinum derivatives, such as carboplatin; as well as duocarmycin A, duocarmycin SA, CC-1065 (a.k.a. rachelmycin), or analogs or derivatives of CC-1065), dolastatin, auristatin, pyrrolo[2,l-c][l,4]benzodiazepins (PDBs), indolinobenzodiazepine (IGNs) or analogues thereof, antibiotics (such as dactinomycin (formerly actinomycin), bleomycin, daunorubicin (formerly daunomycin), doxorubicin, idarubicin, mithramycin, mitomycin, mitoxantrone, plicamycin, anthramycin (AMC)), anti mitotic agents (e.g., tubulin-targeting agents), such as diphtheria toxin and related molecules (such as diphtheria A chain and active fragments thereof and hybrid molecules); ricin toxin (such as ricin A or a deglycosylated ricin A chain toxin), cholera toxin, a Shiga-like toxin (SLT-I, SLT-II, SLT-IIV), LT toxin, C3 toxin, Shiga toxin, pertussis toxin, tetanus toxin, soybean Bowman-Birk protease inhibitor, Pseudomonas exotoxin, alorin, saporin, modeccin, gelanin, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, and enomycin toxins. Other suitable conjugated molecules include antimicrobial/lytic peptides such as CLIP, Magainin 2, mellitin, Cecropin, and PI 8; ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, diphtheria toxin, and Pseudomonas endotoxin.

SUPPLEMENTAL THERAPEUTIC AGENTS

[00085] The antibodies of the present disclosure, including fragments thereof and conjugates thereof, can optionally be delivered to a patient in conjunction with other therapeutic agents. The additional therapeutic agents can be delivered concurrently with the antibodies of the present disclosure. As used herein, the word "concurrently" means sufficiently close in time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other).

[00086] In some embodiments the antibodies of the present disclosure can be administered in conjunction with anti-cancer agents, such as: 1) vinca alkaloids (e.g., vinblastine, vincristine); 2) epipodophyllotoxins (e.g., etoposide and teniposide); 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)); 4) enzymes (e.g., L-asparaginase); 5) biological response modifiers (e.g., interferon-alfa); 6) platinum coordinating complexes (e.g., cisplatin and carboplatin); 7) anthracenediones (e.g., mitoxantrone); 8) substituted ureas (e.g., hydroxyurea);

9) methylhydrazine derivatives (e.g., procarbazine (N-methylhydrazine; MIH)); 10) adrenocortical suppressants (e.g., mitotane (o,r'-DDD) and aminoglutethimide); 11) adrenocorticosteroids (e.g., prednisone); 12) progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate); 13) estrogens (e.g., diethylstilbestrol and ethinyl estradiol); 14) antiestrogens (e.g., tamoxifen); 15) androgens (e.g., testosterone propionate and fluoxymesterone); 16) antiandrogens (e.g., flutamide): and 17) gonadotropin releasing hormone analogs (e.g., leuprolide). In some embodiments the antibodies of the present disclosure can be administered in conjunction with anti -angiogenesis agents, such as antibodies to VEGF (e.g., bevacizumab (AVASTIN), ranibizumab (LUCENTIS)) and other promoters of angiogenesis (e.g., bFGF, angiopoietin-1), antibodies to alpha-v/beta-3 vascular integrin (e.g., VITAXIN), angiostatin, endostatin, dalteparin, ABT-510, CNGRC peptide TNF alpha conjugate ("CNGRC" disclosed as SEQ ID NO: 97), cyclophosphamide, combretastatin A4 phosphate, dimethylxanthenone acetic acid, docetaxel, lenalidomide, enzastaurin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation (Abraxane), soy isoflavone (Genistein), tamoxifen citrate, thalidomide, ADH-1 (EXHERIN), AG-013736, AMG-706, AZD2171, sorafenib tosylate, BMS-582664, CHIR-265, pazopanib, PI-88, vatalanib, everolimus, suramin, sunitinib malate,

XL 184, ZD6474, ATN-161, cilengitide, and celecoxib.

[00087] In some embodiments, the antibodies of the present disclosure can be administered in conjunction with immunosuppressive agents including, for example, cyclosporine A, rapamycin, glucocorticoids, azathioprine, mizoribine, aspirin derivatives, hydroxychloroquine, methotrexate, cyclophosphamide and FK506 (tacrolimus).

[00088] Though an antigen-binding domain typically comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH), however, it does not necessarily have to comprise both. For example, a so-called Fd antibody fragment consists only of a VH domain, but still retains some antigen-binding function of the intact antibody.

[00089] Anti-GPNMB antibodies may optionally comprise antibody constant regions or parts thereof. For example, a VL domain may have attached, at its C terminus, antibody light chain constant domains including human CK or Ck chains. Similarly, a specific antigen-binding domain based on a VH domain may have attached all or part of an immunoglobulin heavy chain derived from any antibody isotope, e.g., IgG, IgA, IgE, and IgM and any of the isotope sub classes, which include but are not limited to, IgGl and IgG4. The DNA and amino acid sequences for the C-terminal fragment of are well known in the art.

[00090] In certain embodiments, the antibodies can specifically bind an epitope within the extracellular domain (ECD) of human GPNMB, with an affinity, as expressed in KD, of at least about 1 mM (1000 nM), about 1 nM (1000 pM), about 100 pM, about 10 pM, or about 5 pM.

The amino acid sequences of ECDs of human GPNMB is set out in SEQ ID NO: 95 (see Table

1)^. Table 1

ANTIBODY BINDING SPECIFICITY

[00091] It is contemplated that antibodies of the present disclosure may also bind with other proteins, including, for example, recombinant proteins comprising all or a portion of GPNMB.

[00092] One skilled in the art will recognize that the antibodies of this present disclosure may be used to detect, measure, and inhibit proteins that differ somewhat from GPNMB. The antibodies can be expected to retain the specificity of binding so long as the target protein comprises a sequence which is at least about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more identical to any sequence of at least about 130, about 100, about 80, about 60, about 40, or about 20 of contiguous amino acids in the sequence set forth SEQ ID NO:X or SEQ ID NO:Y. The percent identity is determined by standard alignment algorithms such as, for example, Basic Local Alignment Tool (BLAST) described in Altshul et al. (1990) J. Mol. Biol., 215: 403-410, the algorithm ofNeedleman et al. (1970) J. Mol. Biol., 48: 444-453, or the algorithm of Meyers et al. (1988) Comput. Appl. Biosci., 4: 11-17. [00093] In addition to the sequence homology analyses, epitope mapping (see, e.g., Epitope Mapping Protocols, ed. Morris, Humana Press, 1996) and secondary and tertiary structure analyses can be carried out to identify specific 3D structures assumed by the disclosed antibodies and their complexes with antigens. Such methods include, but are not limited to, X- ray crystallography (Engstom (1974) Biochem. Exp. Biol., 11:7-13), cryo-electron microscopy (Long et al. (2015) Proceedings of the National Academy of Sciences of the United States of America, 112(45): 13898-13903), and computer modeling of virtual representations of the presently disclosed antibodies (Fletterick et al. (1986) Computer Graphics and Molecular Modeling, in Current Communications in Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, N. Y.).

ANTIBODY VARIANTS

[00094] This disclosure also provides methods for obtaining an antibody specific for GPNMB. Complementarity-determining regions (CDRs) in such antibodies are not limited to the specific sequences of VH and VL identified in the Examples below, and may include variants of these sequences. Such variants may be derived from the sequences listed in the Examples by a skilled artisan using techniques well known in the art. For example, amino acid substitutions, deletions, or additions, can be made in the framework regions (FRs) and/or in CDRs. While changes in the FRs can usually be designed to improve stability and immunogenicity of the antibody, changes in the CDRs can typically be designed to increase affinity of the antibody for its target.

[00095] Changes to FRs include, but are not limited to, humanizing a non-human derived or engineering certain framework residues that are important for antigen contact or for stabilizing the binding site, e.g., changing the class or subclass of the constant region, changing specific amino acid residues which might alter the effector function such as Fc receptor binding, e.g., as described in U.S. Patent Nos. 5,624,821 and 5,648,260 and Lund et al. (1991) J. Immun. 147: 2657-2662 and Morgan et al. (1995) Immunology 86: 319-324, or changing the species from which the constant region is derived.

[00096] Variants of FRs also include naturally occurring immunoglobulin allotypes. Such affinity-increasing changes may be determined empirically by routine techniques that involve altering the CDR and testing the affinity antibody for its target. For example, conservative amino acid substitutions can be made within any one of the disclosed CDRs. Various alterations can be made according to the methods described, for example, in Antibody Engineering, 2nd ed., Oxford University Press, ed. Borrebaeck, 1995. These include but are not limited to nucleotide sequences that are altered by the substitution of different codons that encode a functionally equivalent amino acid residue within the sequence, thus producing a “silent” change. For example, the nonpolar amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine. The polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. The positively charged (basic) amino acids include arginine, lysine, and histidine. The negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Substitutes for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs.) Furthermore, any native residue in the polypeptide may also be substituted with alanine (see, e.g., MacLennan et al. (1998) Acta Physiol. Scand. Suppl. 643:55-67; Sasaki et al. (1998) Adv. Biophys. 35:1-24).

[00097] The term “percent (%) sequence identity” as used herein refers to the percentage of nucleotides or amino acids in a candidate sequence that are identical with the nucleotides or amino acids in a reference nucleic acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as ClustalW, Clustal Omega, BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software.

[00098] The % sequence identity of a given nucleotides or amino acids sequence X to, with, or against a given nucleic acid sequence Y (which can alternatively be phrased as a given sequence X that has or comprises a certain % sequence identity to, with, or against a given sequence Y) is calculated as follows: 100 times the fraction W/Z, where W is the number of nucleotides or amino acids scored as identical matches by the sequence alignment program in that program's alignment of X and Y, and where Z is the total number of nucleotides or amino acids in Y. It will be appreciated that where the length of sequence X is not equal to the length of sequence Y, the % sequence identity of X to Y will not equal the % sequence identity of Y to X. [00099] Antibody fragments included within the scope of the present disclosure include, for example: Fab, Fab', F(ab')2, and Fv fragments; domain antibodies, diabodies; vaccibodies, linear antibodies; single-chain antibody (ScFv) molecules; and multispecific antibodies formed from antibody fragments. Such fragments can be produced by known techniques. For example, F(ab')2 fragments can be produced by pepsin digestion of the antibody molecule, and Fab fragments can be generated by reducing the disulfide bridges of the F(ab')2 fragments. Alternatively, Fab expression libraries can be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (see Huse et al, Science 1989 Dec 8;246(4935): 1275-1281).

[000100] Monoclonal antibodies used to carry out the present disclosure can be produced in a hybridoma cell line according to the technique of Kohler and Milstein, Nature 265:495 (1975). For example, a solution containing the appropriate antigen can be injected into a mouse and, after a sufficient time, the mouse sacrificed, and spleen cells obtained. The spleen cells can then be immortalized by fusing them, for example with myeloma cells or with lymphoma cells, typically in the presence of polyethylene glycol, to produce hybridoma cells. The hybridoma cells can then be grown in a suitable medium and the supernatant screened for monoclonal antibodies having the desired specificity. Monoclonal Fab fragments can be produced in E. coli by recombinant techniques known to those skilled in the art. Antibodies specific to the target polypeptide can also be obtained by phage display techniques known in the art.

[000101] Various immunoassays can be used for screening to identify antibodies having the desired specificity for the extracellular domain of GPNMB. Numerous protocols for competitive binding or immunoradiometric assays using monoclonal antibodies with established specificity are well known in the art. Such immunoassays typically involve the measurement of complex formation between an antigen and its specific antibody (e.g., antigen/antibody complex formation). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non- interfering epitopes on the polypeptides or peptides of this disclosure can be used as well as a competitive binding assay.

[000102] In certain embodiments, anti-GPNMB antibodies, or antigen-binding fragments thereof, may be used in methods for diagnostic purposes of detecting GPNMB. Method may include obtaining a sample from a subject, wherein the sample may include a physical biological sample, preferably tumor biopsy, blood, or serum, although other samples containing epithelial cells, cancer cells, white blood cells (WBCs) may be considered. Sample may be subjected to an immunoglobulin or antigen binding fragment thereof to measure a GPNMB protein level of the sample obtained from the subject; measure a GPNMB expression level on myeloid-derived suppressor cells (MDSCs) or immunosuppressive macrophages in the sample; or measure a number of GNPMB-positive MDSCs or immunosuppressive macrophages in the sample. Measurements may be performed using, for instance, fluorescence-based immunoassays such as fluorescence-activated cell sorting (FACS), ELISA, among other assay. Antibody treatments of samples may include assays with WBC-specific samples such as macrophage assays for protein section and mRNA expression modulation, T-cell suppression assay. Measurements may be made using antibody-affinity techniques to measure GPNMB protein levels including, for example, using surface plasmon resonance (SPR), affinity capture probes, and the like. Measurements of GPNMB levels, or aberrant GPNMB expression may inform administration of a specific therapeutic drug, for example as described above. Administering a specific therapeutic drug may include comparing a measured GPNMB protein level, GPNMB expression level, or number of GPNMB-positive MDSCs to a threshold value, such as an expected normal threshold among samples from healthy cohorts of individuals.

[000103] Further to the conjugates described above, anti-GPNMB antibodies described herein can be conjugated to a solid support (e.g., beads, plates, slides, grids, sensors, or wells formed from materials such as latex or polystyrene) in accordance with known techniques. Anti- GPNMB antibodies described herein can likewise be conjugated to detectable groups such as radiolabels (e.g., 35S, 1251, 1311 or 99mTc, which may also be attached to antibodies using conventional chemistry), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), and fluorescence labels (e.g., fluorescein) in accordance with known techniques. Detectable labels may further include chemical moieties such as biotin, which may be detected via binding to a specific cognate detectable moiety, e.g., labeled avidin. Determination of the formation of an antibody/antigen complex in the methods of this disclosure can be by detection of, for example, precipitation, agglutination, flocculation, radioactivity, color development or change, fluorescence, luminescence, etc., and is well known in the art. [000104] As described above, anti-GPNMB antibodies described herein can be linked to another functional molecule, e.g., another peptide or protein (albumin, another antibody, etc.), toxin, radioisotope, cytotoxic or cytostatic agents. For example, the antibodies can be linked by chemical cross-linking or by recombinant methods. The antibodies may also be linked to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent No. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, and 4,179,337. The antibodies can be chemically modified by covalent conjugation to a polymer, for example, to increase their circulating half-life. Exemplary polymers and methods to attach them are also shown in U.S. Patent Nos. 4,766,106, 4,179,337, 4,495,285, and 4,609,546.

GPNMB COMPOSITIONS

[000105] In some embodiments, an anti-GPNMB antibody comprises one, two, three, four, five, and/or six CDRs of any one of the antibodies described herein. In some embodiments, an anti-GPNMB antibody comprises (i) one, two, and/or three heavy chain CDRs from Table 2, and/or (ii) one, two, and/or three light chain CDRs from Table 2 . In some embodiments, an anti-GPNMB antibody comprises (i) three heavy chain CDRs from Table 2 (i.e., a CDR-H1, a CDR-H2, and a CDR-H3), and (ii) three light chain CDRs from Table 2.

[000106] In some embodiments, a human anti-GPNMB antibody comprises (i) one, two, and/or three heavy chain CDRs, and/or (ii) one, two, and/or three light chain CDRs from Table 2.

Table 2

[000107] There are multiple antibody variable chain numbering schemes, including those proposed by Kabat (Wu and Kabat, 1970, J Exp Med. (1970) 132:211-50.); , Kabat EA, Te Wu T, Foeller C, Perry HM, Gottesman KS. Sequences of Proteins of Immunological Interest. Diane Publishing Company (1992).), Chothia (1987, Chothia C, Lesk a M. Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol. (1987) 196:901-17); Al-Lazikani et ak, (1997 Standard conformations for the canonical structures of immunoglobulins. J Mol Biol. (1997) 273:927-48), Lefranc (IMGT numbering; Lefranc, 1997 Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509; Lefranc et ak, 2005 IMGT- ONTOLOGY for immunogenetics and immunoinformatics. In Silico Biol. (2004) 4:17-29, and Honegger (Honegger and Pluckthun, 2001, Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis took J Mol Biol. (2001) 309:657-70), which makes it more complex.

[000108] Chothia and his colleagues defined CDRs based on structure, i.e. the location of the loops (Chothia and Lesk, 1987 supra; Al-Lazikani et ak, 1997, supra).

[000109] Kabat and Wu originally defined the CDRs in the early 1970s by amino acid sequence variability analysis (Wu and Kabat, 1970, supra; Kabat and Wu, 1971, supra). Since then, detailed genetic analyses and three-dimensional structural analyses have more clearly defined the structural basis of the antigen combining site in terms of the HVLs/CDRs, leading to definitions of contact residues (MacCallum et al., 1996, Antibody-antigen interactions: contact analysis and binding site topography. J Mol Biol. (1996) 262:732-745; Martin and Allen, 2007, Bioinformatics tools for antibody engineering. In: Diibel S, editor. Handbook of Therapeutic Antibodies. Weinheim: Wiley-VCH Verlag GmbH (2008). p. 95-117).

[000110] The AbM definition of CDRs, which was a compromise between the Rabat and Chothia definitions, was used in the AbM modeling software (Martin and Allen, 2007, supra). Martin and his colleagues also have formed a definition of CDRs based on the actual paratope, i.e. those residues that actually contact the antigen (Martin and Allen, 2007, supra), and have developed and tested an automated application called “Abnum” for variable chain numbering and CDR determination based on a correction of the Chothia approach (Abhinandan and Martin, 2008, Analysis and prediction of VH/VL packing in antibodies. Protein Eng Des Sel. (2010) 23:689-97,).

[000111] The Contact definition of CDRs is based on the observation that only 20 to 33 % of the amino acids within the CDRs make direct contact with the antigen (Padlan EA. Anatomy of the antibody molecule. Mol Immunol. (1994) 31:169- 217. These residues, named “Specificity Determining Residues (SDR)”, were first described by Padlan et al. (Padlan EA, Abergel C, Tipper JP. Identification of specificity-determining residues in antibodies. FASEB J OffPubl Fed Am Soc Exp Biol. (1995) 9:133-9). Their results show that these SDRs are involved in the interaction with the antigen and, in most cases, match with the most variable positions present in the CDRs. Using this SDR concept, MacCallum and co-workers suggested a new method to define the CDRs and re-named the SDRs “contact residues”. They also suggested that contact residues are more often located in the center of the paratope and, as Chothia mentioned before, non-contacting residues play a role in shaping the conformation of the CDR loops and therefore orientate the contact residues optimally for efficient and specific antigen binding.

[000112] The IMGT unique numbering for the V-REGION has allowed to redefine the limits of the Complementarity Determining Regions and Framework Regions, designated as CDR-IMGT and FR-IMGT, respectively in IMGT. The IMGT unique numbering for V- DOMAIN provides a standardized numbering for the CDR3-IMGT and FR4-IMGT of rearranged V-J-REGION and V-D-J-REGION.

[000113] A Complementarity Determining Region (CDR-IMGT) is a loop region of a V-

DOMAIN (Variable (V) Domain), delimited according to the IMGT unique numbering for V domain (Lefranc M. et al.(2003) IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev Comp Immunol 27:55-77). There are three CDR-IMGT in a V-DOMAIN: CDRl-IMGT (loop BC), CDR2-IMGT (loop C'C"), and CDR3-IMGT (loop FG).

[000114] In a V-DOMAIN (V domain of the immunoglobulins (IG) or antibodies and T cell receptors (TR)), the amino acids of the CDR-IMGT bind to an antigen (Epitope) and confer the specificity to the IG and TR (Paratope, IMGT-ONTOLOGY, SpecificityType). The first two CDR-IMGT are part of the V-REGION (encoded by a variable (V) gene), whereas the CDR3- IMGT corresponds to the junction and results from the rearrangement between a V gene and a joining (J) gene (V-J rearrangement) or between a V gene, a diversity (D) gene, and a J gene (V- D-J rearrangement) (Immunoglobulin Synthesis).

B04 Sequences

B04WT

[000115] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 82.

[000116] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 63. [000117] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 82 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 63.

[000118] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 82.

[000119] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 63.

[000120] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 82 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 63.

[000121] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 39, 47, and 51, respectively.

[000122] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 1, 12, and 23, respectively.

[000123] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 39, 47, 51, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 1, 12, and 23, respectively.

[000124] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 39, 47, and 51, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 1, 12, and 23, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 63 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 82.

[000125] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 1, 12, and 23, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 1, 12, and 23. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000126] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 39, 47, and 51, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 39, 47, and 51.

[000127] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 1, 12, and 23, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 1, 12, and 23 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs:39, 47, and 51, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 39, 47, and 51.

J06 Sequences

J06WT

[000128] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83. [000129] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 64.

[000130] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 64.

[000131] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 83.

[000132] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 64.

[000133] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 64. [000134] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 40, 48, and 52, respectively.

[000135] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 13, and 24, respectively.

[000136] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 40, 48, 52, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 13, and 24, respectively.

[000137] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 40, 48, and 52, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 13, and 24, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 64 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83.

[000138] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 13, and 24, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 2, 13, and 24. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000139] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 40, 48, and 52.

[000140] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 13, and 24, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 2, 13, and 24 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 40, 48, and 52.

J06_ HC G55V, G108R

[000141] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83. [000142] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 65.

[000143] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 65.

[000144] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 83.

[000145] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 65.

[000146] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 65. [000147] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 40, 48, and 52, respectively.

[000148] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 14, and 25, respectively.

[000149] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 40, 48, 52, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 14, and 25, respectively.

[000150] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 40, 48, and 52, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 14, and 25, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 65 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83.

[000151] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 14, and 25, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 2, 14, and 25. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000152] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%,

[000153] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 14, and 25, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 2, 14, and 25 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 40, 48, and 52.

J06_ HC G55V, G108V

[000154] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83. [000155] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 66.

[000156] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 66.

[000157] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 83.

[000158] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 66.

[000159] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 66. [000160] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 40, 48, and 52, respectively.

[000161] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 14, and 26, respectively.

[000162] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 40, 48, 52, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 14, and 26, respectively.

[000163] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 40, 48, and 52, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 14, and 26, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 66 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83.

[000164] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 14, and 26, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 2, 14, and 26. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000165] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%,

[000166] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 14, and 26, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 2, 14, and 26 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 40, 48, and 52.

J06_ HC G55V, G108R

[000167] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83. [000168] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 67.

[000169] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 67.

[000170] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 83.

[000171] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 67.

[000172] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 83 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 67. [000173] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 40, 48, and 52, respectively.

[000174] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 15, and 25, respectively.

[000175] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 39, 47, 51, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 15, and 25, respectively.

[000176] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 40, 48, and 52, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 2, 15, and 25, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 67 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 83.

[000177] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 15, and 25, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 2, 15, and 25. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000178] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%,

[000179] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 2, 15, and 25, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 2, 15, and 25 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 40, 48, and 52, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 40, 48, and 52.

L22 Sequences

L22WT

[000180] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 84.

[000181] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 68.

[000182] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 84 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 68.

[000183] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 84.

[000184] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 68.

[000185] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 84 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 68.

[000186] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 39, 47, and 53, respectively.

[000187] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 3, 12, and 96, respectively.

[000188] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 39, 47, 53, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 3, 12, and 96, respectively.

[000189] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 39, 47, and 53, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 3, 12, and 96, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 68 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 84.

[000190] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 3, 12, and 96, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 3, 12, and 96. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000191] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 39, 47, and 53, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 39, 47, and 53.

[000192] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 3, 12, and 96, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 3, 12, and 96 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 39, 47, and 53, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 39, 47, and 53.

J17 Sequences J17WT

[000193] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 85.

[000194] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 69.

[000195] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 85 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 69.

[000196] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 85.

[000197] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 69.

[000198] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 85 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 69.

[000199] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 41, 49, and 54, respectively.

[000200] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 4, 16, and 27, respectively.

[000201] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 41, 49, 54, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 4, 16, and 27, respectively.

[000202] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 41, 49, and 54, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 4, 16, and 27, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 69 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 85.

[000203] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 4, 16, and 27, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 4, 16, and 27. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000204] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 41, 49, and 54, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 41, 49, and 54.

[000205] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 4, 16, and 27, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 4, 16, and 27 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 41, 49, and 54, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 41, 49, and 54.

D24 Sequences

D24WT

[000206] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 86.

[000207] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 70.

[000208] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 86 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 70.

[000209] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 86.

[000210] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 70.

[000211] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 86 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 70.

[000212] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 42, 48, and 55, respectively.

[000213] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 5, 17, and 28, respectively.

[000214] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 42, 48, 55, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 5, 17, and 28, respectively.

[000215] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 42, 48, and 55, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 5, 17, and 28, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 70 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 86.

[000216] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 1, 12, and 23, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 5, 17, and 28. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000217] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 42, 48, and 55, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 42, 48, and 55.

[000218] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 5, 17, and 28, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 5, 17, and 28 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 42, 48, and 55, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 42, 48, and 55.

K10 Sequences

K10WT

[000219] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 87.

[000220] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 71.

[000221] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 87 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 71.

[000222] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 87. [000223] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 71.

[000224] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 87 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 71.

[000225] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 39, 47, and 56, respectively.

[000226] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 6, 18, and 29, respectively.

[000227] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 39, 47, 56, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 6, 18, and 29, respectively. [000228] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 39, 47, and 56, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 6, 18, and 29, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 71 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 87.

[000229] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 6, 18, and 29, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 6, 18, and 29. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000230] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 39, 47, and 56, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 39, 47, and 56.

[000231] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 6, 18, and 29, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 6, 18, and 29 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 39, 47, and 56, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 39, 47, and 56.

P19 Sequences

P19WT

[000232] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 88.

[000233] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 72.

[000234] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 88 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 72.

[000235] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 88.

[000236] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 72.

[000237] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 88 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 72.

[000238] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 43, 50, and 57, respectively.

[000239] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 7, 19, and 30, respectively.

[000240] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 43, 50, 57, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 7, 19, and 30, respectively.

[000241] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 43, 50, and 57, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 7, 19, and 30, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 72 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 88.

[000242] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 7, 19, and 30, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 7, 19, and 30. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000243] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 43, 50, and 57, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 43, 50, and 57.

[000244] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 7, 19, and 30, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 7, 19, and 30 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 43, 50, and 57, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 43, 50, and 57.

B01 Sequences

B01WT

[000245] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89.

[000246] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 73.

[000247] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 73. [000248] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 89.

[000249] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 73.

[000250] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 73.

[000251] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 44, 50, and 58, respectively.

[000252] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 31, respectively. [000253] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, 58, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 31, respectively.

[000254] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, and 58, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 31, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 73 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89.

[000255] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, and 31, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 8, 20, and 31. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs. [000256] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 44, 50, and 58.

[000257] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, and 31, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 8, 20, and 31 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 44, 50, and 58.

BOI HC PIIOV

[000258] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89.

[000259] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 74.

[000260] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 74.

[000261] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 89.

[000262] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 74.

[000263] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 74.

[000264] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 44, 50, and 58, respectively. [000265] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 32, respectively.

[000266] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, 58, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 32, respectively.

[000267] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, and 58, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 32, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 74 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89.

[000268] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, and 32, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 8, 20, and 32. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000269] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%,

[000270] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, and 32, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 8, 20, and 32 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 44, 50, and 58.

B01_ HC D109E

[000271] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89.

[000272] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 75. [000273] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 75.

[000274] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 89.

[000275] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 75.

[000276] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 75.

[000277] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 44, 50, and 58, respectively.

[000278] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 33, respectively.

[000279] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, 58, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 33, respectively.

[000280] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, and 58, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, and 33, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 75 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89.

[000281] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, and 33, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 8, 20, and 33. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000282] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%,

[000283] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, and 33, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 8, 20, and 33 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 44, 50, and 58.

B01_ HC D109N

[000284] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89.

[000285] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 76.

[000286] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 76.

[000287] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 89.

[000288] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 76.

[000289] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 89 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 76. [000290] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 44, 50, and 58, respectively.

[000291] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, 34 and 102, respectively.

[000292] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, 58, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, 34 and 102, respectively.

[000293] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 44, 50, and 58, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 8, 20, 34 and 102, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%vsequence identity to SEQ ID NO: 76 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 89. [000294] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, 34 and 102, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 8, 20, 34 and 102. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000295] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%,

[000296] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 8, 20, 34 and 102, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 8, 20, 34 and 102 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 44, 50, and 58, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 44, 50, and 58.

C22 Sequences

C22WT [000297] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 90.

[000298] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 77.

[000299] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 90 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 77.

[000300] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 90.

[000301] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 77.

[000302] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 90 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 77.

[000303] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 45, 47, and 53, respectively.

[000304] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 9, 12, 34 and 102, respectively.

[000305] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 45, 47, 53, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 9, 12, 34 and 102, respectively.

[000306] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 45, 47, and 53, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 9, 12, 34 and 102, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 77 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 90.

[000307] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 9, 12, 34 and 102, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 9, 12, 34 and 102. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000308] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 45, 47, and 53, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 45, 47, and 53.

[000309] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 9, 12, 34, and 102, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 9, 12, 34, and 102 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 45, 47, and 53, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 45, 47, and 53.

F18 Sequences

F18WT

[000310] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 91.

[000311] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 78.

[000312] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 91 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 78.

[000313] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 91.

[000314] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 78.

[000315] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 91 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 78.

[000316] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 41, 50, and 59, respectively.

[000317] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 10, 21, and 35, respectively.

[000318] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 41, 50, 59, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 10, 21, and 35, respectively.

[000319] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 41, 50, and 59, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 10, 21, and 35, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 78 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 91.

[000320] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 1, 12, and 23, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 10, 21, and 35. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000321] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 41, 50, and 59, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 41, 50, and 59.

[000322] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 10, 21, and 35, or a sequence having at least 50%,

60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 10, 21, and 35 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 41, 50, and 59, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 41, 50, and 59.

L16 Sequences

L16WT

[000323] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92.

[000324] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79.

[000325] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79.

[000326] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 92. [000327] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 79.

[000328] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 92 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 79.

[000329] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 60, respectively.

[000330] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively.

[000331] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 60, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively. [000332] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 60, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92.

[000333] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 36, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 36. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000334] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 60, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 60.

[000335] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 36, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 36 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 60, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 60.

L 16_WTLC_ HC_D 100E

[000336] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92.

[000337] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80.

[000338] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80.

[000339] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 92.

[000340] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 80.

[000341] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 92 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 80.

[000342] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 60, respectively.

[000343] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively.

[000344] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 60, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively.

[000345] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 60, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92.

[000346] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 37, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 37. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000347] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 60, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 60.

[000348] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 37, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 37 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 60, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 60.

L 16_WTLC_ HC Gl 01 V

[000349] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92.

[000350] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81.

[000351] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81. [000352] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 92.

[000353] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 81.

[000354] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 92 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 81.

[000355] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 60, respectively.

[000356] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively. [000357] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 60, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively.

[000358] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 60, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 92.

[000359] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 38, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 38. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs. [000360] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 60, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 60.

[000361] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 38, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 38 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 60, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 60.

L 16_ LC D94E WTHC

[000362] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93.

[000363] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79.

[000364] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79.

[000365] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 93.

[000366] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 79.

[000367] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 93 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 79.

[000368] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 61, respectively. [000369] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively.

[000370] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 61, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively.

[000371] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 61, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93.

[000372] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 36, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 36. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000373] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 61, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 61.

[000374] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 36, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 36 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 61, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 61.

L 16_ LC_D94E_ HC D 100E

[000375] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93.

[000376] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80. [000377] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80.

[000378] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 93.

[000379] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 80.

[000380] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 93 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 80.

[000381] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 61, respectively.

[000382] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively.

[000383] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 61, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively.

[000384] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 61, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93.

[000385] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 37, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 37. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000386] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 61, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 61.

[000387] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 37, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 37 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 61, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 61.

L 16_ LC_D94E_ HC G 101 V

[000388] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93.

[000389] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81.

[000390] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81.

[000391] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 93.

[000392] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 81.

[000393] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 93 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 81. [000394] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 61, respectively.

[000395] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively.

[000396] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 61, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively.

[000397] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 61, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 93.

[000398] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 38, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 38. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000399] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 61, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 61.

[000400] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 38, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 38 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 61, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 61.

L 16_ LC P95 V_ WTHC

[000401] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94. [000402] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79.

[000403] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79.

[000404] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 94.

[000405] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 79.

[000406] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 94 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 79. [000407] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 62, respectively.

[000408] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively.

[000409] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 62, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively.

[000410] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 62, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 36, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 79 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94.

[000411] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 36, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 36. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000412] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 62, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 62.

[000413] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 36, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 36 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 62, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 62.

L 16_ LC P95 V_ HC D 100E

[000414] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94. [000415] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80.

[000416] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80.

[000417] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 94.

[000418] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 80.

[000419] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 94 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 80. [000420] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 62, respectively.

[000421] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively.

[000422] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 62, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively.

[000423] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 62, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 37, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94.

[000424] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 37, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 37. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000425] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 62, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 62.

[000426] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 37, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 37 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 62, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 62.

L 16_ LC P95 V_ HC Gl 01 V

[000427] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94. [000428] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81.

[000429] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81.

[000430] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the complementarity-determining region (CDR) regions such as including but not limited to framework (FR) regions, with the amino acid sequence of SEQ ID NO: 94.

[000431] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to FR regions, with the amino acid sequence of SEQ ID NO: 81.

[000432] One embodiment provides an antibody, preferably a monoclonal antibody, or an antigen binding fragment thereof having (i) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity in regions other than the CDR regions such as including, but not limited to, framework (FR) regions, with amino acid sequences of SEQ ID NO: 94 and (ii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity in regions other than the CDR regions such as including but not limited to FR regions, with amino acid sequences of SEQ ID NO: 81. [000433] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a light chain containing CDRs (CDR-L1, CDR-L2 and CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequences SEQ ID NOs: 46, 50, and 62, respectively.

[000434] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has a heavy chain containing CDRs (CDR-H1, CDR-H2 and CDR-H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively.

[000435] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, 62, respectively; and (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively.

[000436] One embodiment provides an antibody, preferably a monoclonal antibody, or antigen binding fragment thereof that has (i) a light chain variable region containing CDRs (CDR-L1, CDR-L2, CDR-L3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 46, 50, and 62, respectively; (ii) a heavy chain variable region containing CDRs (CDR-H1, CDR-H2, CDR- H3) having at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 11, 22, and 38, respectively; (iii) a heavy chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 81 and (iv) a light chain variable region with at least 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 94.

[000437] In some embodiments, the antibody, or a fragment thereof, comprises a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 38, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 11, 22, and 38. One of skill in the art understands that the CDRs play a role in binding specificity and that sequence substitutions are typically made outside of the CDRs, and that minimal changes are typically made within the CDRs. Thus, in some embodiments, sequences that are approximately at least 90% identical to the disclosed sequences comprise no changes, or only a minimal number of changes, to the CDRs.

[000438] In some embodiments, the antibody, or a fragment thereof, comprises a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 62, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 46, 50, and 62.

[000439] In some embodiments, the antibody, or a fragment thereof, comprises (i) a heavy chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 11, 22, and 38, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID Nos: 11, 22, and 38 and (ii) a light chain variable region that includes at least one CDR (e.g., 1, 2, or 3), or a portion thereof, from the amino acid sequence of SEQ ID NOs: 46, 50, and 62, or a sequence having at least 50%, 60%, 70%, 80%, 85%, 90%, at least 92%, at least 95%, about 96%, about 97%, about 98%, or about 99% identity with a sequence selected from the group consisting of SEQ ID NOs: 46, 50, and 62.

Table 3: EXEMPLARY SEQUENCES

Nucleic Acids, Cloning and Expression Systems

[000440] The present disclosure further provides isolated nucleic acids encoding the disclosed antibodies. The nucleic acids may comprise DNA or RNA and may be wholly or partially synthetic or recombinant. Reference to a nucleotide sequence as set out herein encompasses a DNA molecule with the specified sequence, and encompasses a RNA molecule with the specified sequence in which U is substituted for T, unless context requires otherwise.

[000441] The nucleic acids provided herein comprise a coding sequence for a CDR, a VH domain, and/or a VL domain disclosed herein. The present disclosure also provides constructs in the form of plasmids, vectors, phagemids, transcription or expression cassettes which comprise at least one nucleic acid encoding a CDR, a VH domain, and/or a VL domain disclosed here. The disclosure further provides a host cell which comprises one or more constructs as above.

[000442] Systems for cloning and expression of a polypeptide in a variety of different host cells are well known in the art. For cells suitable for producing antibodies, see Gene Expression Systems, Academic Press, eds. Fernandez et al., 1999. Briefly, suitable host cells include bacteria, plant cells, mammalian cells, and yeast and baculovirus systems. Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary cells (CHO), HeLa cells, baby hamster kidney cells, NSO mouse myeloma cells, and many others. Any protein expression system compatible with the invention may be used to produce the disclosed antibodies, such as use of the common bacterial host, E. coli. Differences between expression systems may require codon optimization, which may result in differences between DNA sequences for codons that are preferential to the expression system. Recombinant antibody production differences in glycosylation patterns - among other post-translation modifications - may occur between expression systems, potentially resulting in differing functionalities. Suitable expression systems include transgenic animals described in Gene Expression Systems, Academic Press, eds. Fernandez et al., 1999.

[000443] Suitable vectors can be chosen or constructed, so that they contain appropriate regulatory sequences, including promoter sequences, terminator sequences, polyadenylation sequences, enhancer sequences, marker genes and other sequences as appropriate. Vectors may be plasmids or viral, e.g., phage, or phagemid, as appropriate. For further details see, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, 1989. Many known techniques and protocols for manipulation of nucleic acid, for example, in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Current Protocols in Molecular Biology, 2nd Edition, eds. Ausubel et al., John Wiley & Sons, 1992.

[000444] A further aspect of the disclosure provides a host cell comprising a nucleic acid as disclosed here. A still further aspect provides a method comprising introducing such nucleic acid into a host cell. The introduction may employ any available technique. For eukaryotic cells, suitable techniques may include calcium phosphate transfection, DEAE-Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g., vaccinia or, for insect cells, baculovirus. For bacterial cells, suitable techniques may include calcium chloride transformation, electroporation and transfection using bacteriophage. The introduction of the nucleic acid into the cells may be followed by causing or allowing expression from the nucleic acid, e.g., by culturing host cells under conditions for expression of the gene. METHODS OF TREATMENT

[000445] The disclosed anti-GPNMB antibodies are capable of modulating the GPNMB- associated immune responses. In particular embodiments, the activation of cytotoxic T cells is mediated by modulation of GPNMB-interaction partner signaling axis. The disclosed antibodies can act as either agonists or antagonists of GPNMB, depending on the method of their use. The antibodies can be used to prevent, diagnose, or treat medical disorders in mammals, especially, in humans. Antibodies of the disclosure can also be used for isolating GPNMB or GPNMB- expressing cells, such as with use of antibody-based affinity capture techniques. Furthermore, the antibodies can be used to treat a subject at risk of or susceptible to a disorder or having a disorder associated with aberrant GPNMB expression or function.

[000446] Antibodies of the disclosure can be used in circumstances where modulation of cytotoxic T and NK cell activation may be desirable, for example, in certain types of cancers and infectious diseases. The antibodies of this disclosure may act as agonists, by binding GPNMB ECD and prompting intracellular signaling pathway via the cytoplasmic tail, mimicking GPNMB ligand binding. This may prove useful when diminished lymphocyte activation is desirable. The anti-GPNMB antibodies of the disclosure may be used as agonists against GPNMB in order to enhance the GPNMB -associated attenuation of cytotoxic (or CD8+) T cell activation.

[000447] Under certain circumstances, it may be desirable to elicit or enhance a patient's immune response in order to treat cancer or an infectious disease. The disorders being treated or prevented by the disclosed methods include but are not limited to infections with microbes (e.g. bacteria), viruses (e.g., systemic viral infections such as influenza, viral skin diseases such as herpes or shingles), or parasites; and cancer (e.g., melanoma and prostate cancers). Cytotoxic T and NK cell activation with anti-GPNMB antibodies enhances T and NK cell responses. In such cases, antibodies act as antagonists of GPNMB, blocking GPNMB-mediated intercellular signaling via an integrin receptor expressed on other cells.

[000448] GPNMB expressed on tumor-associated macrophages (TAMs) and MDSCs may drive immunosuppression in the tumor microenvironment through two distinct mechanisms: i) direct binding to T cells and inhibition of their function, and ii) immunosuppressive polarization of myeloid cells (TAMs and MDSCs). A solution in addressing such mechanisms may be found in generating an antibody that blocks the function of GPNMB, which may reinvigorate an immune response to drive clinical responses to solid tumors in patients who are refractory or resistant to checkpoint inhibitors due to an immunosuppressive myeloid cell compartment. Thus, in some embodiments, the antibodies can be used to inhibit or reduce the downregulatory activity associated with GPNMB, i.e., the activity associated with downregulation of cytotoxic T and NK cell activation.

[000449] As demonstrated in the Examples, a blockade of GPNMB/ interaction with antagonizing anti-GPNMB antibodies leads to enhanced macrophage responses and increased natural killer cell stimulatory factor 2, IL12b, mRNA levels and IL12p40 secretion, consistent with a downregulatory role for the GPNMB pathway in cytotoxic T and NK cell activation. At 48 hours post-treatment, mRNA levels for IL12 were observed at up to 40-fold+ increases, with up to about 100 pg/mL IL12p40. Such a robust increase in IL12 expression and secretion may function to assist in increasing IL23 protein levels, as IL12p40 serves as a subunit to fully functional IL23. NK cells express the IL-23 receptor and respond to IL-23 with increased IFN-g secretion and enhanced antibody-dependent cellular cytotoxicity. IL-23 may also induce proliferation of CD4 memory T cells (not naive cells). Functional effects have been seen with human anti-GPNMB antibodies; possible mechanisms include blocking cis interaction with self or unidentified ligand, blocking trans interaction with self or unidentified ligand, internalization , agonism or antagonism, and phagocytosing macrophages. Without wishing to be bound by theory, it is thought that treatment with anti-GPNMB antibodies may result in improved clinical responses to solid tumors in patients who are refractory or resistant to checkpoint inhibitors due to an immunosuppressive myeloid cell compartment.

[000450] Moreover, a concomitant decrease in IL10 mRNA levels was measured 48 hr. after anti-GPNMB treatment in macrophages. IL10 functions to downregulate the expression of Thl cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages, consistent with the downregulatory function of GPNMB. Treatment of macrophages with anti-GPNMB antibodies resulted in increased anti -turn or TNFa secretion at 24 hr. and 48 hour post treatment. In various embodiments, the antibodies inhibit binding of extracellular ligands, such as integrin, to GPNMB with an EC50 of less than about 50 nM, and more preferably less than about 40, 30, 20, 10, or 5 nM. Inhibition of GPNMB -interaction partner binding can be measured using techniques known in the art.

[000451] The antibodies or antibody compositions of the present disclosure are administered in therapeutically effective amounts. Generally, a therapeutically effective amount may vary with the subject's age, condition, and sex, as well as the severity of the medical condition of the subject. A therapeutically effective amount of antibody ranges from about 0.001 to about 30 mg/kg body weight, preferably from about 0.01 to about 25 mg/kg body weight, from about 0.1 to about 20 mg/kg body weight, or from about 1 to about 10 mg/kg. The dosage may be adjusted, as necessary, to suit observed effects of the treatment.

[000452] The appropriate dose is chosen based on clinical indications by a treating physician. The antibodies may be given as a bolus dose, to maximize the circulating levels of antibodies for the greatest length of time after the dose. Continuous infusion may also be used after the bolus dose.

[000453] Immune cells (e.g., T cells or NK cells) can also be isolated from a patient and incubated ex vivo with antibodies of the disclosure, or genetically engineered for chimeric antigen receptor (CAR) T-cell immunotherapy. In some embodiments, T cell and NK cell activation can be modulated by removing immune cells from a subject, contacting the immune cells in vitro with an anti-GPNMB antibody of the disclosure. Correspondingly, the production of CAR T-cells typically involves cell collection from a patient by leukapheresis, followed by elutriation to remove myeloid cells, T lymphocyte enrichment, transgene delivery, and ex vivo expansion. Transgene delivery may include, for example, providing a nucleic acid vector encoding for an anti-GPNMB single-chain variable fragment (scFv) comprising antibody variable heavy (VH) and variable light (VL) chains, fused by a peptide linker joined to an intracellular CD3z signaling domain. The resulting product may include a heterogenous population of patient-derived immune cells which express CARs for targeting GPNMB- expressing cancer cells. In such embodiments, the anti-GPNMB antibody may be used in a multivalent form such that GPNMB molecules on the surface of an immune cell become "crosslinked" upon binding to such antibodies. For example, the anti-GPNMB antibodies can be bound to solid support, such as beads, or crosslinked via a secondary antibody. The immune cells may be then isolated using methods known in the art and re-implanted into the patient with the newly engineered functionality as a therapy.

[000454] In another aspect, the antibodies of the disclosure can be used as a targeting agent for delivery of another therapeutic or a cytotoxic agent (e.g., a toxin) to a cell expressing GPNMB. The method includes administering an anti-GPNMB antibody coupled to a therapeutic or a cytotoxic agent or under conditions that allow binding of the antibody to GPNMB.

[000455] The antibodies of the disclosure may also be used to detect the presence of GPNMB in biological samples. The amount of GPNMB detected may be correlated with the expression level of GPNMB, which, in turn, is correlated with the activation status of immune cells (e.g., activated T cells or NK cells) in the subject.

[000456] Detection methods that employ antibodies are well known in the art and include, for example, ELISA, radioimmunoassay, immunoblot, Western blot, immunofluorescence, immunoprecipitation. The antibodies may be provided in a diagnostic kit that incorporates one or more of these techniques to detect GPNMB. Such a kit may contain other components, packaging, instructions, or other material to aid the detection of the protein.

[000457] Where the antibodies are intended for diagnostic purposes, it may be desirable to modify them, for example, with a ligand group (such as biotin) or a detectable marker group (such as a fluorescent group, a radioisotope or an enzyme). If desired, the antibodies of the disclosure may be labeled using conventional techniques. Suitable detectable labels include, for example, fluorophores, chromophores, radioactive atoms, electron-dense reagents, enzymes, and ligands having specific binding partners. Enzymes are typically detected by their activity. For example, horseradish peroxidase can be detected by its ability to convert tetramethylbenzidine (TMB) to a blue pigment, quantifiable with a spectrophotometer. For detection, suitable binding partners include, but are not limited to, biotin and avidin or streptavidin, IgG and protein A, and the numerous receptor-ligand couples known in the art. Other permutations and possibilities will be readily apparent to those of ordinary skill in the art, and are considered as equivalents within the scope of the instant disclosure. [000458] Antibodies of the disclosure can be used in screening methods to identify inhibitors of the GPNMB pathway effective as therapeutics. In such a screening assay, a first binding mixture is formed by combining GPNMB and an antibody of the disclosure; and the amount of binding in the first binding mixture (MO) is measured. A second binding mixture is also formed by combining GPNMB, the antibody, and the compound or agent to be screened, and the amount of binding in the second binding mixture (Ml) is measured. A compound to be tested may be another anti-GPNMB antibody, as illustrated in the Examples. The amounts of binding in the first and second binding mixtures are then compared, for example, by calculating the M1/M0 ratio. The compound or agent is considered to be capable of modulating a GPNMB- associated downregulation of immune responses if a decrease in binding in the second binding mixture as compared to the first binding mixture is observed.

[000459] Human anti-GPNMB antibodies and antigen binding fragments thereof can be used to increase secretion of inflammatory cytokines (e.g., IL12p40, TNFa, and/or ILIO) by macrophages of a subject to whom an human anti-GPNMB antibody or antigen binding fragment thereof is administered. In embodiments, the human immunoglobulin or antigen binding fragment thereof comprises a heavy chain and a light chain, wherein said heavy chain comprises a CDR1 selected from the group consisting of SEQ ID NOs: 11, 1, 4, 6, and 8; a CDR2 selected from the group consisting of SEQ ID NOs: 22, 12, 16, 18, and 20; and a CDR3 selected from the group consisting of SEQ ID NOs: 36, 37, 23, 27, 29, 31, 32, 33, and 34; and wherein said light chain comprises a CDR1 selected from the group consisting of SEQ ID NOs: 46, 39, 41, and 44; a CDR2 selected from the group consisting of SEQ ID NOs: 50, 47, and 49; and a CDR3 selected from the group consisting of SEQ ID NOs: 60, 61, 62, 51, 54, 56, and 58. For example, the heavy chain can comprise a CDR1 having SEQ ID NO: 11; a CDR2 having SEQ ID NO: 22; and a CDR3 selected from the group consisting of SEQ ID NOs: 36 and 37; and the light chain can comprise a CDR1 having SEQ ID NO: 46; a CDR2 having SEQ ID NO: 50; and a CDR3 selected from the group consisting of SEQ ID NOs: 60, 61, and 62.

[000460] The formulation and optimization of binding mixtures is within the level of skill in the art, such binding mixtures may also contain buffers and salts necessary to enhance or to optimize binding, and additional control assays may be included in the screening assay of the disclosure. Compounds found to reduce the GPNMB-antibody binding by at least about 10% (i.e., M1/MCK0.9), preferably greater than about 30% may thus be identified and then, if desired, secondarily screened for the capacity to ameliorate a disorder in other assays or animal models as described below. The strength of the binding between GPNMB and an antibody can be measured using, for example, an enzyme-linked immunoadsorption assay (ELISA), radio-immunoassay (RIA), surface plasmon resonance-based technology (e.g., Biacore), all of which are techniques well known in the art.

[000461] The compound may then be tested in vitro as described in the Examples or in an animal model. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices. Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans.

[000462] Therapeutically effective dosages achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al. (1966) Cancer Chemother. Reports, 50(4): 219-244).

PHARMACEUTICAL COMPOSITIONS

[000463] The disclosure provides compositions comprising anti-GPNMB antibodies. Such compositions may be suitable for pharmaceutical use and administration to patients. The compositions typically comprise one or more antibodies, or fragments thereof, of the present disclosure and a pharmaceutically acceptable excipient. The phrase "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial agents and antifungal agents, isotonic agents, and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The pharmaceutical compositions may also be included in a container, pack, or dispenser together with instructions for administration. [000464] A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Methods to accomplish the administration are known to those of ordinary skill in the art. The administration may, for example, be intravenous, intraperitoneal, intramuscular, intracavity, intrathecal, intraarticular, intravitreal, subcutaneous, or transdermal. It may also be possible to obtain compositions which may be topically or orally administered, or which may be capable of transmission across mucous membranes.

[000465] Solutions or suspensions used for intradermal or subcutaneous application typically include one or more of the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Such preparations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[000466] Pharmaceutical compositions suitable for administration may include bulking agents, such as mannitol, lactose, sucrose, dextran, trehalose, or glycine, especially for subcutaneous, or transdermal injection. Pharmaceutical compositions may comprise one or more buffering agents or counterions, such as citrate, phosphate buffers, or acetate, amino acids such as histidine, aspartic acid, or glutamic acid, acids such as succinic acid, malic acid, or fumaric acid, cations such as aluminum, sodium, or zinc, anions such as nitrate, iodide, or chloride, among other suitable agents. Acceptable buffers may also include many of ‘Good’s Buffers’. Pharmaceutical compositions may include a variety of salts, such as sodium chloride or magnesium chloride, especially for purposes of controlling tonicity, aqueous solubility, or protein solubility. Depending on the handling and storage of antibodies disclosed herein, pharmaceutical compositions may include one or more cryoprotects such as glycerol, ethylene glycol, PEG, polymer, isopropanol, ethanol, sucrose, or DMSO, for the purposes of protecting solutions during freeze-thaw cycles. Pharmaceutical compositions may include one or more lyoprotectants such as sucrose, dextran, hydroxypropyl-beta-cyclodextrin, and the like, especially for the purposes of protecting protein products throughout the lyophilization process. [000467] Pharmaceutical compositions suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N. J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars; polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The 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 dispersion and/or by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate, and gelatin.

ADMINISTRATION AND DOSAGE

[000468] Methods to accomplish administration are known to those of ordinary skill in the art. The administration may, for example, be parental administration (e.g., intravenous, intraperitoneal, intramuscular, subcutaneous).

[000469] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration may be accomplished, for example, through the use of lozenges, nasal sprays, inhalers, or suppositories; For example, in case of antibodies that comprise the Fc portion, compositions may be capable of transmission across mucous membranes in intestine, mouth, or lungs (e.g., via the FcRn receptor- mediated pathway as described in U.S. Pat. No. 6,030,613). For transdermal administration, the active compounds may be formulated into ointments, salves, gels, or creams as generally known in the art. For administration by inhalation, the antibodies may be delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[000470] In certain embodiments, the presently disclosed antibodies are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, 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. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions containing the presently disclosed antibodies can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[000471] It may be advantageous to formulate parenteral compositions in a dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[000472] Toxicity and therapeutic efficacy of the composition of the disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.

[000473] Compositions that exhibit large therapeutic indices are preferred. For any composition used in the present disclosure, the therapeutically effective dose can be estimated initially from cell culture assays. Examples of suitable bioassays include DNA replication assays, cytokine release assays, transcription-based assays, GPNMB/integrin binding assays, immunological assays other assays as, for example, described in the Examples. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the antibody which achieves a half-maximal inhibition of symptoms). Circulating levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage lies preferably within a range of circulating concentrations with little or no toxicity. The dosage may vary depending upon the dosage form employed and the route of administration utilized..

[000474] The following Examples do not in any way limit the scope of the disclosure. One of ordinary skill in the art will recognize the numerous modifications and variations that may be performed without altering the spirit or scope of the present disclosure. Such modifications and variations are encompassed within the scope of the disclosure. The entire contents of all references, patents, and published patent applications cited throughout this application are herein incorporated by reference.

EXAMPLES

Example 1 : Antibody Generation and Optimization

[000475] Fab sequences of antibodies were grafted to IgG4 constant domains with mutation at hinge region S228P to stabilize the antibodies. DNA plasmids of heavy chain and light chain were transiently transfected in CHO cell line. Cell medium was harvested after transfected CHO cells incubated at 37 °C for about 9 days and then filtered with a 0.45 pm filter. Antibodies were purified from the media by Protein A resin using elution buffer at pH ~ 3.5. Final antibody product was buffer exchanged to PBS.

Example 2: Binding by Octet and FACS

[000476] Antibodies (lOug/ml in Octet buffer) were captured by AMC or AHC sensors. Affinity was determined with antigen GPNMB. Fc concentrations ranged from 0 to lOOnM. The binding curves were fitted with 1:2 bivalent analyte mode. The binding affinity of anti-GPNMB antibodies were analyzed by FACS by staining human GPNMB overexpressing-ExpiCHO cells with concentrations ranging from 0.306nM to 670nM. EC50 values were then calculated. [000477] KD and Koff rates displayed very low (undetectable) values in all antibodies corresponding to very high affinities. Fc-GPNMB exhibited high measures of affinity which may be due to avidity. Antibody binding suggests potentially 4 different epitopes present in the 6 tested samples (C22, K10, B04, J17, L16, and B01).

Table E2A. Anti -human GPNMB antibodies-Octet binding affinity to Recombinant Human GPNMB protein

Table E2B. Optimized Anti-human GPNMB antibodies-Octet binding affinity to Recombinant Human GPNMB protein

Example 3: Binding of anti-GPNMB mAbs on ExpiCHO cells overexpressing GPNMB

[000478] FIGs. 1 A-10 show FACS binding of human anti-GPNMB monoclonal antibodies

B04, J06, D24, P19, C22, B01, L22, J17, L16, F18, and K10, and comparative antibodies glembatumumab, 3D5, human IgG2, and human IgG4, to human GPNMB overexpressed by ExpiCHO cells, in comparison to parental ExpiCHO controls. FIG. 2A presents the data of FIGs. lA-10 on a single graph. FIG. 2B tabulates the EC50 values corresponding to each of the human anti-GPNMB monoclonal antibodies shown in the curves of FIG. 2 A.

[000479] FIGs. 3A-3I are graphs showing FACS binding of optimized human anti-GPNMB monoclonal antibody L16 and B01 clones to human GPNMB overexpressed on ExpiCHO cells, in comparison to parental ExpiCHO controls. FIG. 4A presents the L16 clone data of FIGs. 3A- 3D on a single graph, along with data for IgG4 control. FIG. 4B presents the B01 clone data of FIGs. 3E-3I on a single graph, also with data for IgG4 control. FIG. 4C tabulates the EC50 values of the curves of FIGS. 4 A and 4B.

[000480] FIGs. 5A-50 show FACS binding cross-reactivity of the same human anti- GPNMB antibodies and comparative antibodies of FIGs. lA-10 to cynomolgus GPNMB overexpressed on ExpiCHO cells, in comparison to parental ExpiCHO controls. FIG. 6 A presents the data of FIGs. 5A-50 in a single graph. FIG. 6B tabulates the EC50 value of the curves shows in FIG. 6A.

[000481] FIGs. 7A-7I are graphs showing FACS binding cross-reactivity of the optimized clones of L16 and B01 of FIGs. 3A-3I to cynomolgus GPNMB overexpressed on ExpiCHO cells, in comparison with parental ExpiCHO controls. FIGs. 8A and 8B present in single graphs the LI 6 clone data (FIG. 8 A) and the B01 clone data (FIG. 8B) from FIGs. 7A-7D and FIGs. 7E- 71, respectively. FIG. 8C tabulates the EC50 values of the curves shown in FIG. 8A and FIG. 8B.

Example 4: Macrophage assays (cytokine expression and secretion)

[000482] Numerous macrophage assays were run to measure cytokine expression and secretion after human anti-GPNMB antibody treatment. Results are shown in FIGs. 9A-9B, 10A-10B, 11 A- llC, 12A-12D, 13A-13B, 14, 15, 16A-16B, 17A-17F.

[000483] In one experiment IL-10 (FIG. 9 A), TGF-b (FIG. 9B), IL12b (FIG. 10 A), and IL6 (FIG. 10B) mRNA expression was measured (n=2-3 donors per condition).

[000484] Secreted protein was measured 48 hours post-polarization for IL10 combined donors (FIG. 11 A), IL-12p40 combined donors (FIG. 1 IB), and TNFa combined donors (FIG.

11C). n=3 donors per conditions.

[000485] Individual donor mRNA expression of IL10 (FIGs. 12A and 12B) and IL12b (FIGs. 12C and 12D) was also measured after 48 hours - LPS 0.02ng in all conditions.

[000486] RNA and protein expression levels in a single donor were measured after 48 hours for IL10 (FIG. 13A and FIG. 13B). [000487] TNFa secreted protein expression from a single donor was measured after 24 hours (FIG. 14), and 48 hours (FIG. 15).

[000488] IL12b RNA expression (FIG. 16 A) and IL12p40 protein expression (FIG. 16B) was measured after 48 hours, from a single donor.

[000489] The secretion of cytokines TNFa (FIGs. 17A and 17D), IL-12p40 (FIGs. 17B and 17E), and IL-10 (FIGs. 17C and 17F) by primary human macrophages upon exposure to IgG4, IgG2, 3D5, glembatumumab, or anti-GPNMB antibody clones B04, J06, L22, J17, D24, L16, L16 EPLC EGHC, LI 6 DVLC EGHC, PI 9, FI 8, C22, B01, and K10 was determined for macrophages from two donors. Donor 1, FIGs. 17A-17C; Donor 2, FIGs. 17D-17F.

INCORPORATION BY REFERENCE

[000490] The disclosure of each and every U.S. and foreign patent and pending patent application and publication referred to herein is specifically incorporated herein by reference in its entirety, as are the contents of Sequence Listing and Figures.

EQUIVALENTS

[000491] Those skilled in the art will understand that the disclosures described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope of the present disclosure is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present disclosure. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents of the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims. Any combination of the embodiments disclosed in the any plurality of the dependent claims or Examples is contemplated to be within the scope of the disclosure.

OTHER EMBODIMENTS

[000492] From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various usages and conditions, including the use of different signal sequences and nucleic acid sequences to express the antibodies of the invention having the same or similar protein sequence are considered to be within the scope of the invention. Other embodiments according to the invention are within the following claims.

[000493] Recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or sub combination) of listed elements. Recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[000494] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[000495] Other embodiments are within the following claims.

Claims

1. A human immunoglobulin or antigen binding fragment thereof having binding specificity for glycoprotein nonmetastatic melanoma protein B (GPNMB) comprising a heavy chain and a light chain: a) wherein said heavy chain comprises: i. a CDR1 selected from the group consisting of SEQ ID NOs: 11, 1, 2, 3, 4, 5,

6, 7, 8, 9, and 10; ii. a CDR2 selected from the group consisting of SEQ ID NOs: 22, 12, 13, 14,

15, 16, 17, 18, 19, 20, and 21; and iii. a CDR3 selected from the group consisting of SEQ ID NOs: 36, 37, 38, 23,

24, 25, 26, 96, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 102; and b) wherein said light chain comprises: i. a CDR1 selected from the group consisting of SEQ ID NOs: 46, 39, 40, 41,

42, 43, 44, and 45; ii. a CDR2 selected from the group consisting of SEQ ID NOs: 50, 47, 48, and 49; and iii. a CDR3 selected from the group consisting of SEQ ID NOs: 60, 61, 62, 51,

52, 53, 54, 55, 56, 57, 58, and 59.

2. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising a heavy chain variable region having at least 70% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 79, 80, 81, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, or 78.

3. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising a light chain variable region having at least 70% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 92, 93, 94, 82, 83, 84, 85, 86, 87, 88, 89, 90, or 91.

4. The human immunoglobulin or antigen binding fragment thereof of claim 1, wherein said heavy chain variable region and light chain variable region comprises: a. SEQ ID NO: 79 and SEQ ID NO: 92; b. SEQ ID NO: 80 and SEQ ID NO: 92; c. SEQ ID NO: 81 and SEQ ID NO: 92; d. SEQ ID NO: 79 and SEQ ID NO: 93; e. SEQ ID NO: 80 and SEQ ID NO: 93; f SEQ ID NO: 81 and SEQ ID NO: 93; g. SEQ ID NO: 79 and SEQ ID NO: 94; h. SEQ ID NO: 80 and SEQ ID NO: 94; i. SEQ ID NO: 81 and SEQ ID NO: 94; j. SEQ ID NO: 63 and SEQ ID NO: 82; k. SEQ ID NO: 64 and SEQ ID NO: 83; l. SEQ ID NO: 65 and SEQ ID NO: 83; m. SEQ ID NO: 66 and SEQ ID NO: 83; n. SEQ ID NO: 67 and SEQ ID NO: 83; o. SEQ ID NO: 68 and SEQ ID NO: 84; p. SEQ ID NO: 69 and SEQ ID NO: 85; q. SEQ ID NO: 70 and SEQ ID NO: 86; r. SEQ ID NO: 71 and SEQ ID NO: 87; s. SEQ ID NO: 72 and SEQ ID NO: 88; t. SEQ ID NO: 73 and SEQ ID NO: 89; u. SEQ ID NO: 74 and SEQ ID NO: 89; v. SEQ ID NO: 75 and SEQ ID NO: 89; w. SEQ ID NO: 76 and SEQ ID NO: 89; x. SEQ ID NO: 77 and SEQ ID NO: 90; or y. SEQ ID NO: 78 and SEQ ID NO: 91.

5. The human immunoglobulin or antigen binding fragment thereof of any one of the preceding claims, wherein the antigen binding fragment is selected from a ScFv (single chain fragment variable) antibody, Fab fragment, F(ab’)2 fragment, or Fv fragment.

6. The human immunoglobulin or antigen binding fragment thereof of any one of the preceding claims, wherein the immunoglobulin or antigen binding fragment thereof binds a transmembrane glycoprotein NMB (GPNMB) with a KD < 10⁴.

7. The human immunoglobulin or antigen binding fragment thereof of any one of the preceding claims produced by Alloy mice.

8. The human immunoglobulin or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment binds to GPNMB at one or more regions of the extracellular domain (ECD).

9. The human immunoglobulin or antigen binding fragment thereof of any one of the preceding claims that competitively binds to GPNMB.

10. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 36) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60).

11. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 37) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60).

12. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 38) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60).

13. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 36) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO:

61).

14. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 37) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO:

61).

15. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 38) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 61).

16. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 36) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO:

62).

17. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 37) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 62).

18. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 11), CDR-H2 (SEQ ID NO: 22), and CDR-H3 (SEQ ID NO: 38) and CDR-L1 (SEQ ID NO: 46), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO:

62).

19. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 1), CDR-H2 (SEQ ID NO: 12), and CDR-H3 (SEQ ID NO: 23) and CDR-L1 (SEQ ID NO: 39), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO:

51).

20. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 13), and CDR-H3 (SEQ ID NO: 24) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO:

52).

21. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 14), and CDR-H3 (SEQ ID NO: 25) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 52).

22. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 14), and CDR-H3 (SEQ ID NO: 26) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 52).

23. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 2), CDR-H2 (SEQ ID NO: 15), and CDR-H3 (SEQ ID NO: 25) and CDR-L1 (SEQ ID NO: 40), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 52).

24. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 3), CDR-H2 (SEQ ID NO: 12), and CDR-H3 (SEQ ID NO: 96) and CDR-L1 (SEQ ID NO: 39), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO: 53).

25. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 4), CDR-H2 (SEQ ID NO: 16), and CDR-H3 (SEQ ID NO: 27) and CDR-L1 (SEQ ID NO: 41), CDR-L2 (SEQ ID NO: 49), and CDR-L3 (SEQ ID NO:

54).

26. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 5), CDR-H2 (SEQ ID NO: 17), and CDR-H3 (SEQ ID NO: 28) and CDR-L1 (SEQ ID NO: 42), CDR-L2 (SEQ ID NO: 48), and CDR-L3 (SEQ ID NO: 55).

27. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 6), CDR-H2 (SEQ ID NO: 18), and CDR-H3 (SEQ ID NO: 29) and CDR-L1 (SEQ ID NO: 39), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO:

56).

28. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 7), CDR-H2 (SEQ ID NO: 19), and CDR-H3 (SEQ ID NO: 30) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 57).

29. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 31) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 58).

30. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 32) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO:

58).

31. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 33) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 58).

32. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising

CDR-H1 (SEQ ID NO: 8), CDR-H2 (SEQ ID NO: 20), and CDR-H3 (SEQ ID NO: 34 or 102) and CDR-L1 (SEQ ID NO: 44), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID

NO: 58).

33. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 9), CDR-H2 (SEQ ID NO: 12), and CDR-H3 (SEQ ID NO: 34 or 102) and CDR-L1 (SEQ ID NO: 45), CDR-L2 (SEQ ID NO: 47), and CDR-L3 (SEQ ID NO: 53).

34. The human immunoglobulin or antigen binding fragment thereof of claim 1 comprising CDR-H1 (SEQ ID NO: 10), CDR-H2 (SEQ ID NO: 21), and CDR-H3 (SEQ ID NO: 35) and CDR-L1 (SEQ ID NO: 41), CDR-L2 (SEQ ID NO: 50), and CDR-L3 (SEQ ID NO: 60).

35. An isolated nucleic acid encoding a human anti-GPNMB antibody or antigen binding fragment thereof of any one of the preceding claims.

36. A method of treating a disease or disorder, comprising: a) administering a therapeutically effective amount of the human immunoglobulin or antigen binding fragment thereof of any one of claims 1 to 33 to a subject in need thereof.

37. The method of claim 36, wherein the disease or disorder is cancer.

38. The method of claim 37, wherein the subject has or is suspected of having myeloid- derived suppressor cell (MDSC)-driven tumor expansion, GPNMB-positive MDSCs, pro- inflammatory tumor microenvironment (TME), tumor-associated macrophages (TAMs), metastasis, or a solid tumor.

39. The method of claim 36, wherein the disease or disorder is selected from the group consisting of neurodegenerative diseases, obesity, diabetes, and osteopetrosis.

40. A method, comprising: a) obtaining a sample from a subject; and b) using a human immunoglobulin or antigen binding fragment thereof of any one of claims 1-33 to: i. measure a GPNMB protein level of the sample obtained from the subject; or ii. measure a GPNMB expression level on myeloid-derived suppressor cells (MDSCs) or immunosuppressive macrophages in the sample; or iii. measure a number of GNPMB -positive MDSCs or immunosuppressive macrophages in the sample; c) administering, as a function of the measure of step (b) a specific therapeutic drug.

41. The method of claim 40, wherein step (b) comprises at least one of immunofluorescence assay, fluorescence-activated cell sorting (FACS), T-cell suppression assay, or surface plasmon resonance (SPR).

42. The method of claim 40, wherein administering a specific therapeutic drug further comprises comparing a measured GPNMB protein level, GPNMB expression level, or number of GPNMB-positive MDSCs to a threshold value.

43. A pharmaceutical composition comprising a human immunoglobulin or antigen binding fragment thereof of any one of claims 1-33 and one or more pharmaceutically acceptable excipients.

44. A method, comprising: administering to a subject a human immunoglobulin or antigen binding fragment thereof having binding specificity for glycoprotein nonmetastatic melanoma protein B (GPNMB), whereby macrophages of the subject increase secretion of an inflammatory cytokine, wherein the human immunoglobulin or antigen binding fragment thereof comprises a heavy chain and a light chain: wherein said heavy chain comprises: i. a CDR1 selected from the group consisting of SEQ ID NOs: 11, 1, 4, 6, and 8; ii. a CDR2 selected from the group consisting of SEQ ID NOs: 22, 12, 16, 18, and 20; and iii. a CDR3 selected from the group consisting of SEQ ID NOs: 36, 37, 23, 27,

29, 31, 32, 33, and 34; and wherein said light chain comprises: i. a CDR1 selected from the group consisting of SEQ ID NOs: 46, 39, 41, and 44; ii. a CDR2 selected from the group consisting of SEQ ID NOs: 50, 47, and 49; and iii. a CDR3 selected from the group consisting of SEQ ID NOs: 60, 61, 62, 51,

54, 56, and 58.

45. The method of claim 44, wherein said heavy chain comprises: i . a CDR1 having SEQ ID NO : 11 ; ii. a CDR2 having SEQ ID NO: 22; and iii. a CDR3 selected from the group consisting of SEQ ID NOs: 36 and 37; and wherein said light chain comprises: i. a CDR1 having SEQ ID NO: 46; ii. a CDR2 having SEQ ID NO: 50; and iii. a CDR3 selected from the group consisting of SEQ ID NOs: 60, 61, and 62.

46. The method of claim 43 or 44, wherein the inflammatory cytokine is IL12p40, TNFa, and/or IL10.