Human monocarboxylate transporter 1 antibody and use thereof

Abstract

To provide antibodies that selectively and specifically bind to human monocarboxylate transporter 1 (MCT1), have desirable developability and patient-safety profiles, and can be used to treat MCT1 associated disorders, such as autoimmune diseases.SOLUTION: To provide antibodies having specific sequences and inhibiting MCT1 mediated responses (e.g., metabolic product transport, T-cell and B-cell proliferation) and / or driving regulatory T-cell differentiation, as well as compositions comprising such MCT1 antibodies, and methods of using such MCT1 antibodies and compositions.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of medicine. In particular, the present disclosure relates to antibodies that specifically bind to human monocarboxylate transporter 1 (MCT1) (anti-human MCT1 antibodies), compositions comprising such anti-human MCT1 antibodies, and methods of using such anti-human MCT1 antibodies. [Background technology]

[0002] Monocarboxylate transporter 1 (also known as MCT1, SLC16A1, HHF7, MCT, MCT1D, or "solute carrier family 16 member 1") is a multi-transmembrane protein involved in the facilitated transport of important metabolites, including the products of glycolysis. MCT1 is a member of one of the largest families of surface membrane proteins known as solute channel proteins (SLCs), whose function involves the transport of important cellular nutrients, metabolites, ions, hormones, and lipids across membranes. MCT1 belongs to the SLC16 family of transporters, five of which have been shown to transport monocarboxylic acids, such as pyruvate, lactate, and ketones (acetoacetate and β-hydroxybutyrate), in a facilitated, pH-dependent, and bidirectional manner. The SLC16 family transporters SLC16A1 (MCT1), SLC16A7 (MCT2), SLC16A8 (MCT3), and SLC16A3 (MCT4) have all been shown to transport monocarboxylic acids with Km values ​​ranging from 1 to 40 mM (Halestrap AP, IUBMB Life. 2012;64(1):1-9). MCT1, MCT3, and MCT4 are coexpressed with the Ig domain-containing surface protein CD147 (Basigin), which is important for proper cell surface expression in many cell types. MCT1 has been implicated in lactate transport, particularly in T and B cells (Fischer K, et al., Blood. 2007;109(9):3812-9).

[0003] Immune cells undergo changes in their metabolic requirements throughout development and require specific metabolic states to perform their effector functions. For example, both glycolysis and mitochondrial oxidative metabolism are altered in CD4 T cells of lupus-prone B6.Sle1.Sle2.Sle3(TC) mice compared with non-autoimmune controls. + It is elevated in T cells (Yin Y, et al., Sci Transl Med. 2015;7(274):274ra18). Treatment of TC mice with a combination of the mitochondrial metabolism inhibitor metformin and the glucose metabolism inhibitor 2-deoxy-D-glucose (2DG) normalized T cell metabolism and reversed disease biomarkers (Yin Y, et al., Sci Transl Med. 2015;7(274):274ra18). Both metformin and 2DG also reduced IFNγ production in vitro (Yin Y, et al., Sci Transl Med. 2015;7(274):274ra18). Blocking lactate export reduces flux through the glycolytic pathway and can redirect T cells away from effector function by altering Myc (Doherty JR, et al., Cancer Research. 2014;74(3):908-20, Wang R, et al., Immunity. 2011;35(6):871-82).

[0004] Individuals with homozygous MCT1 loss-of-function (LOF) mutations have been identified under stress (infection, starvation) due to altered ketone utilization and metabolism, yet MCT1-deficient adults remain healthy (van Hasselt PM, N Engl J Med. 2014, 371(20):1900-7; Balasubramaniam S, et al., JIMD Rep. 2016;29:33-8). Infants exhibited defective ketone utilization and sometimes exercise intolerance. These various symptoms disappeared with age, likely due to increased skeletal muscle mass during adolescence. Heterozygous family members of individuals with homozygous MCT1 mutations had no history of ketoacidosis, suggesting that LOF mutations cause ketoacidosis only in association with additional genetic and / or environmental factors (Balasubramaniam S, et al., JIMD Rep. 2016, 29:33-8). Outside of the immune system, MCT1, along with other MCTs, is expressed in multiple organs, including skeletal muscle, kidney, liver, testis, heart, and brain. The lack of widespread toxicity in individuals with MCT1 mutations is likely due to MCT redundancy. For example, MCT1, MCT2, and MCT4 are all expressed in the retina (Philp NJ, Investigative Ophthalmology & Visual Science. 2003, 44(3):1305-11), and no retinal defects are observed in individuals lacking MCT1, suggesting functional redundancy. To date, no overt immune deficiency has been observed in individuals lacking MCT1. Additionally, MCT1-deficient individuals do not exhibit erythrocyte dysfunction.

[0005] Given the widespread expression of MCTs across many tissues, small molecule MCT inhibitors have been developed. However, many of these small molecule approaches affect multiple MCTs, causing target toxicity, including tissue toxicity. Therefore, there remains a need for therapeutic agents that selectively and specifically target MCT1. Summary of the Invention

[0006] Antibodies targeting MCT1 have been disclosed, for example, as shown in WO19 / 136300. However, to date, no known antibodies that specifically bind to human MCT1 have been approved for therapeutic use or are in clinical development. Therefore, there is a need for antibodies that selectively and specifically bind to human MCT1, have desirable developability and patient safety profiles, and can be used to treat MCT1-related disorders, such as autoimmune diseases. [Brief explanation of the drawings]

[0007] [Figure 1] This shows that anti-human MCT1 antibody Ab1 binds to human MCT1 and promotes the differentiation of regulatory T cells in a concentration-dependent manner. [Figure 2A] These results show that anti-human MCT1 antibody Ab6 does not significantly induce ADCC (3A) or ADCP (3B) Fc-mediated effector function activity, or CDC (3C) activity. [Figure 2B] These results show that anti-human MCT1 antibody Ab6 does not significantly induce ADCC (3A) or ADCP (3B) Fc-mediated effector function activity, or CDC (3C) activity. [Figure 2C] These results show that anti-human MCT1 antibody Ab6 does not significantly induce ADCC (3A) or ADCP (3B) Fc-mediated effector function activity, or CDC (3C) activity. [Figure 3A] 1A shows preparative size exclusion chromatography (SEC) chromatograms of anti-human MCT1 antibody Ab1 (1A) and INX444 antibody (1B) after cell culture and affinity capture. [Figure 3B] 1A shows preparative size exclusion chromatography (SEC) chromatograms of anti-human MCT1 antibody Ab1 (1A) and INX444 antibody (1B) after cell culture and affinity capture. [Figure 4] An overlay of analytical SEC chromatograms comparing the retention times of anti-human MCT1 antibody Ab1 and INX444 IgG1EN is shown. [Figure 5]1 shows that mice treated with anti-human MCT1 antibody Ab1 exhibit protection from weight loss in a GvHD mouse model. [Figure 6] 1 shows that anti-human MCT1 antibody Ab6-treated mice exhibit protection from weight loss in a GvHD mouse model. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description The present disclosure provides antibodies that selectively and specifically bind to human MCT1, inhibit MCT1-mediated responses (e.g., metabolite transport, T cell and B cell proliferation), and / or drive regulatory T cell differentiation, as well as compositions comprising such MCT1 antibodies, and methods of using such MCT1 antibodies and compositions. In particular, the present disclosure provides anti-human MCT1 antibodies that specifically bind to human MCT1, have desirable binding affinity, inhibit MCT1-mediated responses, and have desirable developability and / or patient safety profiles, such as low immunogenicity risk. The desirable developability profile further reduces potentially complex and costly modifications in downstream analytical and manufacturing processes. The anti-human MCT1 antibodies disclosed herein can be used to treat MCT1-associated disorders such as autoimmune diseases (e.g., systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, psoriasis, or multiple sclerosis), allergic conditions, inflammatory conditions, metabolic disorders, transplant or cell therapy recipients, MCT1-positive cancers, exercise-induced hyperinsulinism (EIHI) conditions, and / or polycystic kidney disease (ADPKD). Therefore, the anti-human MCT1 antibodies provided herein have one or more of the following desirable properties: 1) specifically bind to human MCT1 with desirable binding affinity, 2) inhibit MCT1-mediated metabolite transport, 3) inhibit CD4 and CD8 T cell proliferation, 4) inhibit B cell proliferation, 5) drive differentiation of regulatory T cells (such as Foxp3+ regulatory T cells), 6) do not significantly induce effector function-mediated killing (such as ADCC, ADCP) or neutrophil activation in vitro, 7) do not significantly induce complement-mediated activity, 8) low risk of immunogenicity, 9) low culture oxidation and / or degradation, 10) low or no detectable binding to human serum proteins, 11) low hydrophobicity, and 12) desirable properties such as stability, solubility, and low nonspecific interactions, e.g., binding to analytical column resins, providing desirable developability and patient safety profiles for use in treating MCT1-associated disorders.

[0009] In some embodiments, the anti-human MCT1 antibodies disclosed herein are fully humanized antibodies. In some embodiments, the anti-human MCT1 antibodies disclosed herein specifically bind to human and / or cynomolgus monkey MCT1. In some embodiments, the anti-human MCT1 antibodies disclosed herein comprise a specific combination of framework amino acid sequences that support and enable optimal presentation of the specific CDR amino acid sequences disclosed herein. In some embodiments, such anti-human MCT1 antibodies have desirable binding affinities and functional activities, such as those described herein. In further embodiments, the anti-human MCT1 antibodies disclosed herein specifically bind to human MCT1 and inhibit metabolite transport (e.g., lactate, pyruvate, ketones) and T cell and / or B cell proliferation. In further embodiments, the anti-human MCT1 antibodies disclosed herein specifically bind to human MCT1 and drive the differentiation of regulatory T cells. In such embodiments, the expansion of regulatory T cells by the anti-human MCT1 antibodies disclosed herein results in the inhibition of autoimmune responses. In further embodiments, the anti-human MCT1 antibodies disclosed herein have desirable developability and / or patient safety profiles, such as acceptable immunogenicity risk, reduced or eliminated oxidation and culture degradation, nonspecific serum protein binding (e.g., serum IgG, apolipoproteins), and / or hydrophobicity, etc. These desirable developability profiles indicate reduced risk of aggregation and / or yield loss, reduced risk of faster clearance, desirable pharmacokinetic profile, solubility, stability, and / or reduced challenges in downstream purification and analytical processes.

[0010] In yet other embodiments, the anti-human MCT1 antibodies of the present disclosure do not significantly induce effector function-mediated killing and / or C1q complement activity.

[0011] Thus, in some embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity-determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity-determining regions LCDR1, LCDR2, and LCDR3, where HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 31, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 34 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 36 and a LC comprising SEQ ID NO: 37.

[0012] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 40, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 41 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 42 and a LC comprising SEQ ID NO: 37.

[0013] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 44, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 45 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 46 and a LC comprising SEQ ID NO: 37.

[0014] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises HCDR1 comprising SEQ ID NO: 48, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 49 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 50 and a LC comprising SEQ ID NO: 37.

[0015] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 52, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 53 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises an HC comprising SEQ ID NO: 54, and a light chain (LC) comprising SEQ ID NO: 37.

[0016] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 56, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 57 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises an (HC) comprising SEQ ID NO: 58, and a light chain (LC) comprising SEQ ID NO: 37.

[0017] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 60, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 61 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 62 and a LC comprising SEQ ID NO: 37.

[0018] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 64, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 65 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 66 and a LC comprising SEQ ID NO: 37.

[0019] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 68, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 69 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 70 and a LC comprising SEQ ID NO: 37.

[0020] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 72, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 73 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 74 and a LC comprising SEQ ID NO: 37.

[0021] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 76, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 77 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 78 and a LC comprising SEQ ID NO: 37.

[0022] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 80, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 81 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 82 and a LC comprising SEQ ID NO: 37.

[0023] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 84, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 85 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 86 and a LC comprising SEQ ID NO: 37.

[0024] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 88, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 89 and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 90 and a LC comprising SEQ ID NO: 37.

[0025] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 72, LCDR1 comprises SEQ ID NO: 4, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 73 and a VL comprising SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 74 and a LC comprising SEQ ID NO: 10.

[0026] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 68, LCDR1 comprises SEQ ID NO: 4, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 69 and a VL comprising SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 70 and a LC comprising SEQ ID NO: 10.

[0027] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity-determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity-determining regions LCDR1, LCDR2, and LCDR3, where HCDR1 comprises SEQ ID NO: 40, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 60, SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 84, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 41, 49, 53, 61, 77, 81, or 85, and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 42, 50, 54, 62, 78, 82, or 86, and a LC comprising SEQ ID NO: 37.

[0028] In some embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1, comprising a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 97, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, Xaa2 of SEQ ID NO: 97 is valine or arginine, Xaa7 of SEQ ID NO: 97 is arginine or leucine, Xaa9 of SEQ ID NO: 97 is asparagine or glycine, and Xaa 10 is tyrosine or isoleucine, and Xaa in SEQ ID NO: 97 12 is leucine or isoleucine, and Xaa in SEQ ID NO: 97 13is glutamine, valine, or glycine. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 41, 49, 53, 61, 77, 81, or 85, and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 42, 50, 54, 62, 78, 82, or 86, and a LC comprising SEQ ID NO: 37. In such embodiments, the anti-human MCT1 antibodies disclosed herein have desirable binding and functional activities.

[0029] In some embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity-determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity-determining regions LCDR1, LCDR2, and LCDR3, where HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 44 or SEQ ID NO: 88, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 45 or 89, and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 46 or 90, and a LC comprising SEQ ID NO: 37. In such embodiments, the disclosed anti-human MCT1 antibodies have desirable binding and functional activities.

[0030] In some embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1, comprising a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 98, HCDR3 comprises SEQ ID NO: 32, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, Xaa4 of SEQ ID NO: 98 is arginine or serine, Xaa9 of SEQ ID NO: 98 is isoleucine or glutamic acid, and Xaa 13 is glutamic acid or arginine. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 45 or 89, and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 46 or 90, and a LC comprising SEQ ID NO: 37. In such embodiments, the anti-human MCT1 antibodies disclosed herein have desirable binding and functional activities.

[0031] In some embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1 and comprises a VH and a VL, wherein the VH comprises heavy chain complementarity-determining regions HCDR1, HCDR2, and HCDR3; and the VL comprises light chain complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, and HCDR3 comprises SEQ ID NO: 56, SEQ ID NO: 64, SEQ ID NO: 68, or SEQ ID NO: 72, and wherein LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 57, 65, 69, or 73, and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises an HC comprising SEQ ID NO: 58, 66, 70, or 74, and an LC comprising SEQ ID NO: 37. In such embodiments, the anti-human MCT1 antibodies disclosed herein have desirable binding and functional activities.

[0032] In some embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human MCT1, comprising a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 30, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 99, LCDR1 comprises SEQ ID NO: 33, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6. In some embodiments, Xaa4 of SEQ ID NO: 99 is arginine or leucine, Xaa6 of SEQ ID NO: 99 is histidine, arginine, or tyrosine, and Xaa of SEQ ID NO: 99 is arginine or leucine. 20 is alanine or proline. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 57, 65, 69, or 73, and a VL comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising SEQ ID NO: 58, 66, 70, or 74, and a LC comprising SEQ ID NO: 37. In such embodiments, the anti-human MCT1 antibodies disclosed herein have desirable binding and functional activities.

[0033] In some embodiments, the disclosure provides an antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC and LC comprise the following amino acid sequences: a. HC comprises SEQ ID NO: 9 and LC comprises SEQ ID NO: 10; b. HC comprises SEQ ID NO: 9 and LC comprises SEQ ID NO: 15; c. HC comprises SEQ ID NO: 19 and LC comprises SEQ ID NO: 15; d. HC comprises SEQ ID NO: 23 and LC comprises SEQ ID NO: 24, or e. HC comprises SEQ ID NO:28 and LC comprises SEQ ID NO:24.

[0034] In some embodiments, the present disclosure provides an antibody comprising a heavy chain (HC) comprising SEQ ID NO: 9, 19, 23, 28 and a light chain (LC) comprising SEQ ID NO: 10, 15, 24. In some embodiments, the present disclosure provides an antibody comprising a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In some embodiments, the present disclosure provides an antibody comprising a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 15. In some embodiments, the present disclosure provides an antibody comprising a heavy chain comprising SEQ ID NO: 19 and a light chain comprising SEQ ID NO: 15. In some embodiments, the present disclosure provides an antibody comprising a heavy chain comprising SEQ ID NO: 23 and a light chain comprising SEQ ID NO: 24. In some embodiments, the present disclosure provides an antibody comprising a heavy chain comprising SEQ ID NO: 28 and a light chain comprising SEQ ID NO: 24.

[0035] In some embodiments, the disclosure provides an antibody comprising a heavy chain variable region (VH) comprising SEQ ID NO: 7, 18, 21, or 27, and a light chain variable region (VL) comprising SEQ ID NO: 8, 13, or 22. In some embodiments, the VH comprises SEQ ID NO: 7 and the VL comprises SEQ ID NO: 8. In some embodiments, the VH comprises SEQ ID NO: 7 and the VL comprises SEQ ID NO: 13. In some embodiments, the VH comprises SEQ ID NO: 18 and the VL comprises SEQ ID NO: 13. In some embodiments, the VH comprises SEQ ID NO: 21 and the VL comprises SEQ ID NO: 22. In some embodiments, the VH comprises SEQ ID NO: 27 and the VL comprises SEQ ID NO: 22.

[0036] In some embodiments, the anti-human MCT1 antibodies disclosed herein have altered variable regions. In some embodiments, the modifications are in the VH. In some embodiments, the modifications are in the VL. In some embodiments, the modifications are in both the VH and the VL. In some embodiments, the anti-human MCT1 antibodies disclosed herein have different human framework regions. In some embodiments, the VH and VL of the anti-human MCT1 antibodies disclosed herein comprise specific combinations of framework amino acid sequences that support the specific CDR amino acid sequences disclosed herein. In some embodiments, the VH and VL of the anti-human MCT1 antibodies disclosed herein have specific combinations of framework amino acid sequences that allow optimal presentation of the CDR amino acid sequences disclosed herein. In some embodiments, the specific combinations of framework amino acid sequences provided herein support the specific CDR amino acid sequences provided herein, allowing optimal presentation of the CDR amino acid sequences, and providing the desired binding affinity and functional activity of the antibody (e.g., inhibiting metabolite transport and B and / or T cell proliferation, and driving regulatory T cell differentiation) and / or improved development characteristics and / or patient safety. Thus, in some embodiments, the anti-human MCT1 antibodies disclosed herein have improved developability and / or safety profiles compared to MCT1 antibodies known in the art, such as INX444 described in WO 19 / 136300. In such embodiments, the anti-human MCT1 antibodies disclosed herein have a reduced risk of immunogenicity compared to INX444. In yet other embodiments, the anti-human MCT1 antibodies disclosed herein have reduced oxidation and culture degradation compared to INX444. In yet other embodiments, the anti-human MCT1 antibodies disclosed herein have eliminated or reduced non-specific human serum protein binding compared to INX444. In yet other embodiments, the anti-human MCT1 antibodies disclosed herein have reduced non-specific interactions, such as binding to purification column resins, compared to INX444.In further embodiments, the anti-human MCT1 antibodies disclosed herein have reduced hydrophobicity compared to INX444. As such, the anti-human MCT1 antibodies disclosed herein have reduced problems in downstream purification and analytical processes and / or improved pharmacokinetic profiles when compared to INX444.

[0037] In some embodiments, the anti-human MCT1 antibodies disclosed herein have modified human IgG1 or human IgG4 constant regions.

[0038] In some embodiments, the anti-human MCT1 antibodies disclosed herein have a modified Fc region (e.g., a modified IgG1, IgG2, IgG3, or IgG4 Fc region) with reduced or eliminated Fc effector function. Compared with antibodies comprising a wild-type IgG Fc region, such anti-human MCT1 antibodies described herein exhibit reduced or eliminated binding to FcγR receptors and thus reduced cytotoxicity. Sufficiently reducing or eliminating the effector function of anti-human MCT1 antibodies comprising such modified Fc regions can improve patient safety.

[0039] In some embodiments, the anti-human MCT1 antibody has a human IgG1 isotype. In such embodiments, the anti-human MCT1 antibody described herein has a modified IgG1 Fc region that eliminates Fc effector function, i.e., is IgG1 Fc effector null. For example, such an anti-human MCT1 antibody comprises an IgG1 Fc region containing the amino acid substitutions L234A, L235E, G237A, A330S, and P331S (all amino acid residues are numbered according to the EU index numbering system), and exhibits reduced binding to FcγR and C1q receptors. In some embodiments, the anti-human MCT1 antibody described herein has a modified human IgG1 Fc region (also referred to as an IgG1EN Fc region) containing an alanine at residue 234, a glutamic acid at residue 235, an alanine at residue 237, a serine at residue 330, and a serine at residue 331 (all residues are numbered according to the EU index numbering system). In other embodiments, the anti-human MCT1 antibodies described herein have a modified human IgG1 Fc region (also referred to as an INX LALA Fc region) comprising an alanine at residue 234, an alanine at residue 235, an arginine at residue 269, and an alanine at residue 322 (all residues numbered according to the EU index numbering system).

[0040] Different allotypes (polymorphisms) of human IgG1, such as the G1m3, G1m17, G1m1, and G1m2 allotypes, have been previously described (Jefferis R., et al., mAbs 1(4):1-7, 2009; Webster C., et al., mAbs 2016, 8(2):253-263). The heavy chain of human IgG1 protein may be expressed as the G1m3, G1m17,1, or G1m17,1,2 allotype. The allotype of IgG4 has not been defined (Jefferis R., et al., mAbs 1(4):1-7, 2009). In some embodiments, the anti-human MCT1 antibody described herein comprises a heavy chain of the IgG1 G1m3 allotype, which contains an arginine at position 214, a glutamic acid at position 356, and a methionine at position 358 (all residues numbered according to the EU index). In some embodiments, the anti-human MCT1 antibodies described herein comprise a heavy chain of the IgG1 G1m17,1 allotype containing a lysine at position 214, an aspartic acid at position 356, and a leucine at position 358 (all residues numbered according to the EU index).

[0041] Human MCT1 is expressed in activated T cells and B cells. When the anti-human MCT1 antibodies described herein bind to MCT1, they reduce, suppress, decrease, or inhibit MCT1 function in MCT1-expressing cells, such as activated T cells and B cells. In such embodiments, the anti-human MCT1 antibodies or antigen-binding fragments thereof bind to human MCT1 and inhibit MCT1-mediated transport, CD4 and CD8 T cell proliferation, and / or B cell proliferation. In some embodiments, the anti-human MCT1 antibodies or antigen-binding fragments thereof inhibit MCT1-mediated transport in T cells, resulting in altered T cell differentiation. Such altered T cell differentiation may further promote the differentiation of regulatory T cells (Tregs). Regulation of regulatory T cells involves the use of FoxP3 + and Foxp3 -These include, but are not limited to, Tregs. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 and inhibits MCT1-mediated transport by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 and inhibits MCT1-mediated metabolite transport by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 and inhibits MCT1-mediated pyruvate transport by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 and inhibits MCT1-mediated lactate transport by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 on T cells and inhibits MCT1-mediated CD4 T cell proliferation by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 on T cells and inhibits MCT1-mediated CD8 T cell proliferation by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 on T cells and inhibits MCT1-mediated CD4 and CD8 T cell proliferation by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure binds to human MCT1 on B cells and inhibits MCT1-mediated B cell proliferation by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0042] In some embodiments, the anti-human MCT1 antibodies of the present disclosure bind to human MCT1 and inhibit human MCT1-mediated transport in a conformation-dependent manner.

[0043] In some embodiments, the present disclosure provides nucleic acids encoding the heavy or light chain, i.e., VH or VL, of novel anti-human MCT1 antibodies, and vectors comprising such nucleic acids.

[0044] In some embodiments, the disclosure provides a nucleic acid comprising the sequence of SEQ ID NO: 11, 20, 25, 29, 38, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 12, 17, 26, or 39.

[0045] In some embodiments, nucleic acids encoding the heavy or light chain of an antibody that specifically binds to human MCT1 are provided. In some embodiments, nucleic acids comprising a sequence encoding SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 10, 15, 24, or 37 are provided. In some embodiments, nucleic acids comprising a sequence encoding an antibody heavy chain comprising SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90 are provided. For example, the nucleic acid can comprise a sequence selected from SEQ ID NO: 11, 20, 25, 29, 38, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, or 91. In some embodiments, provided herein is a nucleic acid comprising a sequence encoding an antibody light chain comprising SEQ ID NO: 10, 15, 24, or 37. For example, the nucleic acid can comprise a sequence selected from SEQ ID NO: 12, 17, 26, or 39.

[0046] In some embodiments of the present disclosure, nucleic acids encoding the VH or VL of an antibody that specifically binds to human MCT1 are provided. In some embodiments, nucleic acids are provided that comprise a sequence encoding SEQ ID NO: 7, 18, 21, 27, 34, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 8, 13, 22, or 35. In some embodiments, nucleic acids are provided that comprise a sequence encoding an antibody VH comprising SEQ ID NO: 7, 18, 21, 27, 34, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, or 89. In some embodiments, nucleic acids are provided that comprise a sequence encoding an antibody VL comprising SEQ ID NO: 8, 13, 22, or 35.

[0047] In some embodiments of the present disclosure, a vector is provided that contains a nucleic acid sequence encoding an antibody heavy or light chain. For example, such a vector can contain a nucleic acid sequence encoding SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90. In some embodiments, the vector contains a nucleic acid sequence encoding SEQ ID NO: 10, 15, 24, or 37.

[0048] Also provided herein are vectors comprising a nucleic acid sequence encoding an antibody VH or VL. For example, such vectors can comprise a nucleic acid sequence encoding SEQ ID NO: 7, 18, 21, 27, 34, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, or 89. In some embodiments, the vector comprises a nucleic acid sequence encoding SEQ ID NO: 8, 13, 22, or 35.

[0049] Also provided herein are vectors comprising a first nucleic acid sequence encoding an antibody heavy chain and a second nucleic acid sequence encoding an antibody light chain. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90, and a second nucleic acid sequence encoding SEQ ID NO: 10, 15, 24, or 37.

[0050] In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:9 and a second nucleic acid sequence encoding SEQ ID NO:10. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:9 and a second nucleic acid sequence encoding SEQ ID NO:15. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:19 and a second nucleic acid sequence encoding SEQ ID NO:15. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:23 and a second nucleic acid sequence encoding SEQ ID NO:24. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:28 and a second nucleic acid sequence encoding SEQ ID NO:24. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:36 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:42 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:46 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:50 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:54 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:58 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:62 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:66 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:70 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:74 and a second nucleic acid sequence encoding SEQ ID NO:37.In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:78 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:82 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:86 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:90 and a second nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:74 and a second nucleic acid sequence encoding SEQ ID NO:10. In some embodiments, the vector comprises a first nucleic acid sequence encoding SEQ ID NO:70 and a second nucleic acid sequence encoding SEQ ID NO:10.

[0051] Also provided are compositions comprising a first vector comprising a nucleic acid sequence encoding an antibody heavy chain and a second vector comprising a nucleic acid sequence encoding an antibody light chain. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90, and a second nucleic acid sequence encoding SEQ ID NO: 10, 15, 24, or 37.

[0052] In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:10. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:15. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:19 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:15. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:23 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:24. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:28 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:24. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:36 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:42 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:46 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:50 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:54 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:58 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:62 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37.In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:66 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:70 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:74 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:78 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:82 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:86 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:90 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 74 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO: 10. In some embodiments, the composition comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 70 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO: 10.

[0053] The nucleic acids of the present disclosure can be expressed in host cells, for example, after the nucleic acid is operably linked to an expression control sequence. Expression control sequences capable of expressing an operably linked nucleic acid are well known in the art. The expression vector may include a sequence encoding one or more signal peptides that facilitate secretion of the polypeptide from the host cell. An expression vector containing a nucleic acid of interest (e.g., a nucleic acid encoding an antibody heavy or light chain) can be introduced into host cells by well-known methods, such as stable or transient transfection, transformation, transduction, or infection. Additionally, the expression vector may include one or more selectable markers, such as tetracycline, neomycin, and dihydrofolate reductase, to facilitate detection of host cells transformed with the desired nucleic acid sequence.

[0054] In another aspect, provided herein are cells, e.g., host cells, comprising a nucleic acid, vector, or nucleic acid composition described herein. Host cells can be stably or transiently transfected, transformed, transduced, or infected with one or more expression vectors expressing all or a portion of an antibody described herein. In some embodiments, host cells can be stably or transiently transfected, transformed, transduced, or infected with expression vectors expressing the HC and LC polypeptides of an antibody of the present disclosure. In some embodiments, host cells can be stably or transiently transfected, transformed, transduced, or infected with a first vector expressing the HC polypeptide and a second vector expressing the LC polypeptide of an antibody described herein. Such host cells, e.g., mammalian host cells, can express the antibodies that specifically bind to human MCT1 described herein. Mammalian host cells known to be capable of expressing antibodies include CHO cells, HEK293 cells, COS cells, and NS0 cells.

[0055] In some embodiments, a cell, e.g., a host cell, comprises a vector comprising a first nucleic acid sequence encoding SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90 and a second nucleic acid sequence encoding SEQ ID NO: 10, 15, 24, or 37.

[0056] In some embodiments, a cell, e.g., a host cell, comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90, and a second vector comprising a nucleic acid sequence encoding SEQ ID NO: 10, 15, 24, or 37.

[0057] In some embodiments, the cell comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9, 70, or 74 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:10. In some embodiments, the cell comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9 or 19 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:15. In some embodiments, the cell comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:23 or 28 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:24. In some embodiments, the cell comprises a first vector comprising a nucleic acid sequence encoding SEQ ID NO:36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:37.

[0058] The present disclosure further provides a process for producing an antibody or antigen-binding portion thereof that specifically binds to human MCT1 described herein by culturing the above-described host cells, e.g., mammalian host cells, under conditions such that the antibody is expressed and recovering the expressed antibody from the culture medium. The medium into which the antibody is secreted can be purified by conventional techniques. Various methods of protein purification may be used, and such methods are known in the art and are described, for example, in Deutscher, Methods in Enzymology 182:83-89 (1990) and Scopes, Protein Purification: Principles and Practice, 3rd Edition, Springer, NY (1994).

[0059] The present disclosure further provides an antibody or antigen-binding fragment thereof produced by any of the processes described herein.

[0060] In another aspect, the present invention provides pharmaceutical compositions comprising the antibody, nucleic acid, or vector described herein. Such pharmaceutical compositions may also comprise one or more pharmaceutically acceptable excipients, diluents, or carriers. Pharmaceutical compositions can be prepared by methods well known in the art (e.g., Remington: The Science and Practice of Pharmacy, 22nd ed. (2012), A. Loyd et al., Pharmaceutical Press).

[0061] In some embodiments, the anti-human MCT1 antibodies, nucleic acids, vectors, or pharmaceutical compositions described herein can be used to inhibit activated T cells and / or B cells and treat conditions associated with overactive T cells and B cells, such as autoimmune, allergic, or inflammatory conditions. In some embodiments, the anti-human MCT1 antibodies, nucleic acids, vectors, or pharmaceutical compositions described herein can be used to increase the activity or number of regulatory T cells and treat conditions associated with overactive T cells and B cells, such as autoimmune, allergic, or inflammatory conditions. Such autoimmune, inflammatory, and allergic conditions include, for example, rheumatoid arthritis (RA), psoriatic arthritis, psoriasis, scleroderma, multiple sclerosis, lupus, inflammatory bowel disease (IBD), immune thrombocytopenia (ITP), diabetes, graft-versus-host disease (GvHD), sarcoidosis, allergic asthma, and hepatitis-related hepatotoxicity. These anti-human MCT1 antibodies can also be used to treat transplant or cell therapy recipients by inhibiting unwanted T cell immune responses against transplanted cells, tissues, or organs, such as tissue grafts, CAR-T cell therapy or gene therapy constructs, or cells containing the constructs.

[0062] In some embodiments, the present disclosure provides a method for treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-human MCT1 antibody, a nucleic acid encoding such an antibody, a vector encoding such a nucleic acid, or such an antibody as provided herein, or a pharmaceutical composition comprising such an antibody. Examples of autoimmune diseases include systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, psoriasis, or multiple sclerosis. In further embodiments, the present disclosure provides a method for treating an allergic condition, an inflammatory condition, a metabolic disorder, a transplant or cell therapy recipient, an MCT1-positive cancer, an exercise-induced hyperinsulinism (EIHI) condition, or polycystic kidney disease (ADPKD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody, a nucleic acid encoding such an antibody, a vector comprising such a nucleic acid, or a pharmaceutical composition comprising an antibody as provided herein. The antibodies, nucleic acids, vectors, or pharmaceutical compositions described herein can be administered parenterally (e.g., subcutaneously and intravenously).

[0063] In some embodiments, the present disclosure provides an anti-human MCT1 antibody, nucleic acid, vector, or pharmaceutical composition described herein for use in therapy. The present disclosure also provides an anti-human MCT1 antibody, nucleic acid, vector, cell, or pharmaceutical composition described herein for use in treating an autoimmune disease, an allergic condition, an inflammatory condition, a metabolic disorder, a transplant or cell therapy recipient, an MCT1-positive cancer, an EIHI condition, or ADPKD. The present disclosure also provides an anti-human MCT1 antibody, nucleic acid, vector, cell, or pharmaceutical composition described herein for use in treating an autoimmune disease, such as systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, psoriasis, or multiple sclerosis.

[0064] The present disclosure further provides the use of an anti-human MCT1 antibody, nucleic acid, vector, cell, or pharmaceutical composition described herein for use in the manufacture of a medicament for the treatment of an autoimmune disease, an allergic condition, an inflammatory condition, a metabolic disorder, a transplant or cell therapy recipient, an MCT1-positive cancer, an EIHI condition, or ADPKD.

[0065] One potential advantage of the methods and therapeutic uses disclosed herein is the potential to provide significant and / or long-lasting relief in patients suffering from autoimmune diseases, allergic diseases, inflammatory conditions, metabolic disorders, transplant or cell therapy recipients, MCT1-positive cancers, EIHI conditions, or ADPKD, with an acceptable developability and / or safety profile, including acceptable immunogenicity, tolerability, toxicity, and / or adverse events, so that the patient holistically benefits from the therapy.

[0066] The term "MCT1," as used herein, unless otherwise specified, refers to any naturally occurring mature MCT1 resulting from intracellular processing of an MCT1 precursor protein. The term includes MCT1 from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus or rhesus monkeys) and rodents (e.g., mice and rats), unless otherwise indicated. The term also includes naturally occurring variants of MCT1, such as splice variants or allelic variants. The amino acid sequence of an example of human MCT1 is known in the art, e.g., NCBI reference sequence number NP_003042.3 (SEQ ID NO: 95). The amino acid sequence of an example of cynomolgus monkey MCT1 is also known in the art, e.g., UniProt accession number A0A2K5VB69 (SEQ ID NO: 96). The term "human MCT1" is used herein to collectively refer to all known human MCT1 isoforms and polymorphic forms.

[0067] As used herein, the term "antibody" refers to an immunoglobulin molecule that binds to an antigen. Antibody embodiments include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, bispecific or multispecific antibodies, or conjugated antibodies. The antibody may be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0068] An exemplary antibody is an immunoglobulin G (IgG) antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC) cross-linked via interchain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains contains a variable region of approximately 100 to 125 amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region refers to the region of an antibody that contains the Fc region and CH1 domain of the antibody heavy chain. Each light chain is composed of a light chain variable region (VL) and a light chain constant region. IgG isotypes can be further divided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4). The numbering of amino acid residues in the constant region is based on the EU index by Kabat. Kabat et al, Sequences of Proteins of Immunological Interest, 5th edition, Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health (1991). The terms EU index numbering or EU numbering are used interchangeably herein.

[0069] The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). The CDRs are exposed on the surface of the protein and are critical regions of the antibody for antigen-binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Herein, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." The CDRs contain most of the residues that form specific interactions with the antigen. The assignment of amino acid residues to CDRs has been described by Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).The CDR regions of the anti-human MCT1 antibodies described herein are defined by a combination of the above definitions.

[0070] Embodiments of the present disclosure also include antibody fragments or antigen-binding fragments that comprise at least a portion of an antibody that retains the ability to specifically interact with an antigen, such as, for example, Fab, Fab', F(ab')2, Fv fragments, scFv, scFab, disulfide-linked Fv (sdFv), Fd fragments, and linear antibodies, which may be fused to an Fc region or an IgG heavy chain constant region.

[0071] As used herein, the term "Fc region" refers to the region of an antibody comprising the CH2 and CH3 domains of the antibody heavy chain. Optionally, the Fc region may include a portion of the hinge region or the entire hinge region of the antibody heavy chain. Biological activities, such as effector functions, are attributed to the Fc region, which vary depending on the antibody isotype. Examples of antibody effector functions include Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), C1q binding, complement-dependent cytotoxicity (CDC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0072] The terms "Fc receptor" and "FcR" refer to a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR is a native sequence human FcR. "Fc gamma receptors" or "FcγR" are FcRs that bind IgG antibodies and include receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. FcRs are reviewed in Ravetch and Kinet, Ann. Rev. Immunol., 9:457-92 (1991), Capel et al., Immunomethods, 4:25-34 (1994), and de Haas et al., J. Lab. Clin. Med., 126:330-41 (1995).

[0073] The term "bind," as used herein, unless otherwise specified, is intended to mean the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, resulting in proximity of the two proteins or molecules as determined by common methods known in the art.

[0074] The term "nucleic acid," as used interchangeably herein, refers to a polymer of nucleotides, including single- and / or double-stranded nucleotide-containing molecules, such as DNA, cDNA, and RNA molecules, that incorporate naturally occurring nucleotides, modified nucleotides, and / or nucleotide analogs. Polynucleotides of the present disclosure can also include substrates incorporated therein, for example, by DNA or RNA polymerase or a synthetic reaction.

[0075] As used herein, the term "subject" refers to a mammal, including, but not limited to, humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, etc. Preferably, the subject is a human.

[0076] As used herein, the term "therapeutically effective amount" refers to an amount of a protein, nucleic acid, vector, or composition that induces a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or that improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to the necessary amount (dosage and duration and means of administration) of a protein, nucleic acid, vector, or composition that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent, and / or ameliorate a condition, disorder, or disease to achieve a desired therapeutic result. A therapeutically effective amount of a protein, antibody, vector, or composition may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the protein, antibody, vector, or composition to induce a desired response in an individual. A therapeutically effective amount is also an amount in which any toxic or detrimental effects of the protein, antibody, vector, or composition of the invention are outweighed by the therapeutically beneficial effects.

[0077] The term "inhibit" as used herein refers to, for example, decreasing, reducing, slowing, diminishing, stopping, disrupting, eliminating, antagonizing, or blocking a biological response or activity, but does not necessarily indicate complete elimination of the biological response.

[0078] As used herein, "treatment" or "treating" refers to any process that may slow, control, retard, or halt the progression of a disorder or disease symptom disclosed herein, but does not necessarily indicate the complete disappearance of all disorder or disease symptoms. Treatment includes the administration of a protein or nucleic acid or vector or composition for the treatment of a disease or condition in a patient, particularly a human.

[0079] As used herein, the term "about" means within 5%.

[0080] As used herein, the terms "a," "an," "the," and similar terms as used in the context of this disclosure (particularly in the context of the claims) should be construed to encompass both the singular and the plural, unless otherwise specified herein or clearly contradicted by context.

[0081] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows that anti-human MCT1 antibody Ab1 binds to human MCT1 and promotes the differentiation of regulatory T cells in a concentration-dependent manner. 2A, 2B, and 2C show that anti-human MCT1 antibody Ab6 does not significantly induce ADCC (3A) or ADCP (3B) Fc-mediated effector function activity, or CDC (3C) activity. 3A and 3B show preparative size exclusion chromatography (SEC) chromatograms of anti-human MCT1 antibody Ab1 (1A) and INX444 antibody (1B) after cell culture and affinity capture. Figure 4 shows an overlay of analytical SEC chromatograms comparing the retention times of anti-human MCT1 antibody Ab1 and INX444 IgG1EN. FIG. 5 shows that mice treated with anti-human MCT1 antibody Ab1 exhibit protection from weight loss in a GvHD mouse model. FIG. 6 shows that in a GvHD mouse model, mice treated with anti-human MCT1 antibody Ab6 exhibit protection from weight loss. [Example]

[0082] The following examples are offered to illustrate, but not to limit, the claimed invention.

[0083] Example 1: Antibody generation and engineering of humanized MCT1 antibodies (anti-human MCT1 antibodies). Antibody Engineering and Production: A humanized MCT1 antibody was generated by engineering and empirical testing of the parent anti-MCT1 rat monoclonal antibody M1056 (described in WO 19 / 136300) through humanization and CDR engineering. The previously described monoclonal antibody INX444 [described in WO 19 / 136300] was derived from the parent rat antibody M1056 through humanization, CDR engineering, and light chain shuffling. However, analysis of INX444 identified several development challenges and risk factors. Significant oxidation and clipping were observed in cell culture, resulting in oxidative instability. Nonspecific interactions of INX444 with column resins and serum proteins were observed, creating challenges in downstream analytical and manufacturing processes and impacting the potential clinical development and commercial viability of this antibody. Furthermore, rapid clearance and a high immunogenicity risk of INX444 were observed. The VH and VL sequences of INX444 each contain at least five non-human framework residues, as well as CDR mutations introduced into the VH parent rat antibody sequence and non-parent VL CDR segments introduced by light chain shuffling. To overcome the developability challenges and immunogenicity shortcomings of INX444, an extensive humanization and engineering approach was taken to de novo humanize and engineer the parent rat M1056 antibody. Following framework replacement, the CDRs and IgG constant regions of the newly humanized antibody (anti-human MCT1 antibody) were engineered to further improve desired properties.

[0084] The anti-human MCT1 antibodies described herein can be synthesized and purified by well-known methods. Suitable host cells, such as Chinese hamster ovary cells (CHO), can be transiently or stably transfected with an expression system for antibody secretion using a predetermined HC:LC vector ratio when two vectors are used, or with a single vector system encoding both the heavy and light chains. Clarified medium into which the antibody is secreted can be purified using commonly used techniques.

[0085] Antibody framework engineering: To overcome the impact of framework and CDR amino acid residues on the immunogenic properties observed with INX444, a different humanization and engineering approach was chosen. Briefly, the parent rat antibody M1056 was humanized using a framework library approach. For the framework library, 12 human VH framework germline genes (1-24, 1-46, 1-69, 2-5, 3-15, 3-23, 3-53, 3-72, 4-04, 4-39, 5-51, and 6-01) containing the CDRs of M1056 according to two different CDR definitions and eight human VL framework genes (A-19, A-26, A-27, B-2, B-3, L-2, L-12, and O-2) (generating two 96HC / LC combinatorial libraries) were synthesized and cloned into heavy and light chain human IgG1 expression vectors. A total of 192 combinations were generated and transiently transfected into Chinese hamster ovary (CHO) cells. Supernatants from transfected CHO cells were evaluated for functional activity, including inhibition of MCT1 transporter activity, and in some cases for MCT1 cell binding, T cell inhibition, stability, and immunogenicity.

[0086] Screening of the human framework library revealed that 21 of 192 fully human framework antibodies displaying CDRs derived from the parent rat antibody (M1056) exhibited significant functional activity as determined by a bromopyruvate transport assay. The remaining antibodies showed no significant activity. After preliminary assessment of stability and immunogenicity risk, 12 framework antibody combinations were further characterized experimentally, assessing properties such as cell-based MCT1 binding, functional activity by inhibition of T cell proliferation, biophysical properties, and human serum binding. From these analyses, five antibodies (i.e., Ab1, Ab2, Ab3, Ab4, and Ab5) were selected for further detailed characterization, with a particular focus on immunogenicity assessment, as shown in Tables 1 and 2. These five framework antibodies demonstrated significant improvements in developability, purification suitability on standard platforms, and key readouts for assessing clinical immunogenicity risk. All five framework antibodies were confirmed to bind specifically and selectively to MCT1. The described framework engineering (i.e., humanization) process was a key step in improving antibody developability through the interrogation of a comprehensive combinatorial library of a representative subset of fully human VH and VL germline sequences bearing / displaying parent rodent antibody CDRs to identify productive solutions (or framework permutations). The five framework antibodies ultimately selected, each with a specific VH / VL combination of fully human germline frameworks displaying M1056-derived CDRs, demonstrated significantly improved properties relevant to process development and clinical development, including immunogenicity.

[0087] Furthermore, the tryptophan mutation introduced into HCDR3 of INX444 was removed during the humanization process, which restored all six CDRs to the parental CDR sequences, significantly improving oxidation.

[0088] Antibody CDR Engineering: The humanized framework antibody Ab1 was selected for further engineering. Using a site-saturation mutagenesis approach, a comprehensive library containing all possible natural amino acid substitutions (excluding cysteine) for each VH and VL CDR amino acid residue of the humanized framework antibody Ab1 was generated. The resulting 1,444 Ab1 CDR antibody variants were screened for MCT1 cell binding using a high-throughput flow cytometry assay, and putative hits were scaled up and confirmed for binding and functional activity. This initial mutagenesis effort revealed inconsistencies in the readouts of binding and functional activity in some cases (e.g., certain mutations that caused apparent improvements in binding did not translate to improved inhibitory activity and, in some cases, reduced functional activity), suggesting a decoupling of mechanistic structure-activity requirements for transporter binding and functional transport inhibition of antibodies. Selected mutations showed modest improvements in binding and potency, and a second round of site-saturation mutagenesis was performed. A key amino acid change (HC CDR1 F27R) discovered in the initial CDR library screen was determined to improve binding affinity and functional activity (e.g., inhibition of metabolite transport and CD4 / CD8 T cell proliferation) and was embedded in a new saturation mutagenesis library. To address the observed differences in the structural requirements for binding and inhibition, the screening strategy was modified to incorporate parallel high-throughput analysis of all 1,444 new antibody variants for cell-based binding and inhibition of MCT-mediated transport using a high-throughput bromopyruvate (BP) in vitro transport assay. CDR mutations that significantly improved binding and / or functional activity were identified in assays such as BP transport and T cell inhibition (some are shown in Table 3). The best single amino acid changes were combined in a rationally designed combinatorial library, and the resulting antibodies were screened for functional activity (BP transport and T cell inhibition).A panel of 16 hits, designated Ab6 through Ab21, from the combinatorial library showing the most improved potency (shown in Tables 1, 2, and 3) were evaluated for developability and immunogenicity to determine highly potent therapeutic antibodies with developability and immunogenicity properties that would enable clinical development.

[0089] Engineering the antibody constant region: A human IgG1 effector-null backbone with amino acid substitutions at L234A, L235E, G237A, A330S, and P331S (all amino acid residues are numbered according to the EU index) exhibited reduced binding to FcγR and C1q receptors, and one designated IgG1EN was selected for the exemplary anti-human MCT1 antibody. INX444, described in WO 19 / 136300, has an Fc region with alanine at residue 234, alanine at residue 235, arginine at residue 269, and alanine at residue 322, designated INX444 LALA herein, which was converted to an IgG1EN backbone (designated INX444 IgG1EN). No significant differences in effector function activity, developmental profile, or immunogenicity profile were observed between the two different backbones on INX444, INX444 LALA and INX444 IgG1EN. [Table 1] [Table 2] [Table 3]

[0090] Example 2: Binding affinity of anti-human MCT1 antibodies Binding affinity of antibody screening at 25°C: Exemplary anti-human MCT1 antibodies were screened for binding to human MCT1 using a competitive Meso Scale Discovery (MSD) binding assay. Briefly, four fixed concentrations of each antibody were incubated with a 2- or 3-fold dilution series on HEK WT cells (MCT1 1.09 x 106 The antibodies were mixed with 100 μg of goat anti-human FC (validated to express the receptor / cells) to obtain final concentrations of 250, 125, 62.5, and 31.25 pM (n=1) for each antibody, resulting in a cell gradient of 60 to 58,500 cells per mL. The mixtures were incubated at 37°C for 1-2 days. After incubation, the incubated samples were spun down at 500 x g for 5 minutes to remove the cells. A 96-well multi-array plate (Meso Scale Diagnostics, catalog no. L15XA-3) was coated overnight at 4°C with 1 μg / mL of goat anti-human FC in phosphate-buffered saline (PBS). After coating, the plate was washed three times with 150 μL of PBST (PBS containing 0.05% Tween® 20) and blocked with 150 μL / well of PBS 3% Blocker A buffer (catalog no. R93BA-1) for 1 hour at 25°C. The plate was then washed three times with PBST. 50 μL of the pre-incubated antibody:cell dilution series was transferred to wells and incubated for 1 hour at 25°C with shaking at 700 rpm. The plate was washed three times with PBST. Next, 100 μL of 1 μg / mL anti-human kappa biotin antibody (Cat. #2060-08) was added, and the plate was incubated for 1 hour at 25°C with shaking at 700 rpm. After washing the plate three times with PBST, 100 μL of 1 μg / mL MSD sulfo-tag streptavidin antibody (Meso Scale Diagnostics Cat. #R32 AD1) was added, and the plate was incubated for 1 hour at 25°C with shaking at 700 rpm. The plate was washed three times with PBST, and 150 μL / well of 1X Read Buffer T was added to the wells. 15 minutes after buffer addition, the plate was analyzed on a SECTOR® Imager 6000 (Meso Scale Diagnostics). The apparent KD is determined by fitting a sigmoidal curve to the ECL response versus log(MCT1 receptor concentration) using the assay development toolkit graphed with normalized electrochemiluminescence (ECL) values.

[0091] Representative results shown in Table 4a indicate that the anti-human MCT1 antibodies had desirable binding affinities for human MCT1.

[0092] Binding Affinity of Ab1 and Ab6 at 37°C: The binding affinity of the exemplary anti-human MCT1 antibodies Ab1 and Ab6 to human MCT1 was measured using a competitive mesoscale discovery (MSD) binding assay. Briefly, two fixed concentrations of each antibody were inoculated into a dilution series of HEK WT cells (MCT1 1.09 x 10 6The antibodies were mixed with goat anti-human FC (validated to express the receptor / cells) in triplicate to obtain final concentrations of 50 pM and 5 pM for each antibody and a 3-fold cell gradient of 29–4400 cells per mL. The mixture was incubated at 37°C for 36–48 hours with shaking at 300 rpm. After incubation, the incubated samples were spun down at 500 × g for 8 minutes to remove the cells. A 96-well multi-array plate (Meso Scale Diagnostics, catalog no. L15XA-3) was coated overnight at 4°C with 3 μg / mL goat anti-human FC in phosphate-buffered saline (PBS). After coating, the plate was washed three times with 150 μL of PBST (PBS containing 0.05% Tween® 20) and blocked with 150 μL / well of PBS 3% Blocker A buffer (Meso Scale Diagnostics, catalog no. R93BA-1) for 30 minutes at 37°C. The plate was then washed three times with PBST. 50 μL of the pre-incubated antibody:cell dilution series was transferred to wells and incubated for 1 hour at 37°C with shaking at 1000 rpm. The plate was washed three times with PBST. 100 μL of 1 μg / mL anti-human kappa biotin antibody (Southern Biotech, catalog number 2060-08) was then added, and the plate was incubated for 30 minutes at 37°C with shaking at 1000 rpm. After washing the plate three times with PBST, 100 μL of 1 μg / mL MSD sulfotag streptavidin antibody (Meso Scale Diagnostics, catalog number R32AD-1) was added, and the plate was incubated for 15 minutes at 37°C with shaking at 1000 rpm. Plates were washed three times with PBST, and 150 μL / well of 1X Read Buffer T (Meso Scale Diagnostics, catalog number R92TC-1) was added to the wells and analyzed on a SECTOR® Imager 6000 (Meso Scale Diagnostics) 15 minutes after buffer addition. Apparent K values ​​were calculated by fitting a sigmoidal curve to the ECL response versus log(MCT1 receptor concentration) using the Assay Development Toolkit graphed with normalized electrochemiluminescence (ECL) values. DEach experiment was performed in triplicate on separate independent dilution series and plates. Data reported are the mean K D It was.

[0093] The results shown in Table 4b indicate that anti-human MCT1 Ab1 and Ab6 have desirable binding affinities for human MCT1. [Table 4] [Table 5]

[0094] Example 3: Functional characterization of anti-human MCT1 antibodies Inhibition of MCT1-mediated transport: An in vitro bromopyruvate functional transport assay was used to evaluate the ability of the exemplary anti-human MCT1 antibodies to inhibit MCT1-mediated transport activity. HEK293T cells expressing MCT1 were pretreated with the exemplary anti-human MCT1 antibodies or small molecule MCT1 inhibitors for 1 hour at 37°C. The cells were then incubated with the cytotoxic reagent 3-bromopyruvate (3-BrPy) at concentrations ranging from 25 to 500 mM for 2 to 6 hours. ATP production from dying cells was quantified in a 96-well plate using a commercially available viability kit (ATPlite, PerkinElmer), and viability was measured using luminescence. Reduction in ATP production indicates functional activity of the antibody. Pre-humanized mouse or chimeric antibodies were used as positive control antibodies. MCT1 / CD147 double knockout 293T cells were used as a negative control cell line.

[0095] The results shown in Table 5 demonstrate that the exemplified anti-human MCT1 antibodies inhibit MCT1 receptor-mediated transport in the bromopyruvate assay and can therefore also be identified as antagonistic anti-human MCT1 antibodies. [Table 6]

[0096] Inhibition of CD4 / CD8 T cell proliferation: Inhibition of T cell proliferation by the exemplified anti-human MCT1 antibodies was evaluated in primary T cells isolated from human PBMCs. Human PBMCs were isolated from human blood samples by standard Ficoll-Paque™ plus (GE HEALTHCARE) density gradient centrifugation, and primary T cells were isolated from the PBMC suspension by negative selection using the EasySep™ Human T Cell Enrichment Kit (STEMCELL™ T Technology) according to the manufacturer's protocol. Isolated human primary B cells were labeled with Cell Trace Violet dye (Thermo Fisher) and cultured at 1 x 10 6 Cells were resuspended at 300 μg / mL and plated in complete medium (RPMI-1640 containing 10% fetal bovine serum, 1× MEM-non-essential amino acids, 1 mM sodium pyruvate, 1× penicillin-streptomycin solution (all from Corning®), and 1× GlutaMAX™ (Gibco™), 0.1% β-mercaptoethanol (LIFE TECHNOLOGIES) into polystyrene 96-well U-bottom plates. Anti-human MCT1 antibody or isotype-referenced antibody was added at 300 μg / mL in a 4-fold diluted, 11-point titration. Cells were stimulated with human CD3 / CD28 Dynabeads (GIBCO) for 3 days at 37°C and 5% CO2. T cell proliferation was analyzed by FACS as dilutions of cell trace violet dye.

[0097] The results showed that the exemplified anti-human MCT1 antibodies inhibited CD4 and CD8 T cell proliferation in a dose-dependent manner. Table 6 shows the IC values ​​of the exemplified anti-human MCT1 antibodies for inhibition of CD4 and CD8 T cell proliferation. 50 Indicates the value. [Table 7]

[0098] In vitro regulatory T cell differentiation: Enhancement of regulatory T (Treg) cell proliferation induced by the exemplified anti-human MCT1 antibody was evaluated in primary naive CD4 T cells isolated from PBMCs. Human PBMCs were isolated from human blood samples by standard Ficoll-Paque™ plus (GE HEALTHCARE) density gradient centrifugation, and primary naive CD4 T cells were isolated from the PBMC suspension by negative selection according to the manufacturer's protocol (StemCell). 1 × 10 isolated human primary CD4 T cells were cultured at 1 × 10 6 The cells were resuspended at 0.05% erythrocytes / mL and seeded into polystyrene 96-well U-bottom plates in complete medium (RPMI-1640 containing 10% fetal bovine serum, 1x MEM-non-essential amino acids, 1 mM sodium pyruvate, 1x penicillin-streptomycin solution (all from Corning®), and 1x GlutaMAX™ (Gibco™), 0.1% β-mercaptoethanol (LIFE TECHNOLOGIES). Exemplary anti-human MCT1 antibodies or isotype control antibodies were added at different concentrations. Cells were stimulated with anti-CD3 / CD28 Diman beads (Gibco) and hrTGFb (R&D) and hrIL-2 (R&D) for 3 days at 37°C and 5% CO2. Treg differentiation was analyzed by FACS as the % of FoxP3+ / CD25+ cells.

[0099] The results shown in Figure 1 and Tables 7 and 8 demonstrate that the anti-human MCT1 antibodies Ab1 and Ab6 increased regulatory T cell differentiation in a concentration-dependent manner compared to the isotype control. These results demonstrate an unexpected benefit of the anti-human MCT1 antibodies and suggest that treatment with Ab1 or Ab6 may promote the differentiation of regulatory T cells that subsequently inhibit autoimmune responses. [Table 8] [Table 9]

[0100] B cell proliferation: Inhibition of B cell proliferation by the exemplified anti-human MCT1 antibodies was evaluated in primary B cells isolated from human PBMCs. Human PBMCs were isolated from human blood samples by standard Ficoll-Paque™ plus (GE HEALTHCARE) density gradient centrifugation, and primary B cells were isolated from the PBMC suspension by positive selection with CD19 microbeads according to the manufacturer's protocol (Miltenyi Biotec). Human primary B cells were labeled with Cell Trace Violet dye (Thermo Fisher) and cultured at 1 × 10 6 Cells were resuspended at 300 μg / mL and plated in complete medium (RPMI-1640 with 10% fetal bovine serum, 1× MEM-non-essential amino acids, 1 mM sodium pyruvate, 1× penicillin-streptomycin solution (all from Corning®), and 1× GlutaMAX™ (Gibco™), 0.1% β-mercaptoethanol (LIFE TECHNOLOGIES) into polystyrene 96-well U-bottom plates. Exemplary anti-human MCT1 antibodies or isotype control antibodies were added at 300 μg / mL in 4-fold diluted, 11-point titrations. Cells were stimulated with human MEGACD40L protein (ENZO) and rhIL-4 (R&D) for 5 days at 37°C and 5% CO2. B cell proliferation was analyzed by FACS as dilutions of cell trace violet dye.

[0101] The results, as shown in Table 9, demonstrate that the exemplified anti-human MCT1 antibody Ab6 inhibits B cell proliferation in a dose-dependent manner, with an average IC from three donors. 50 was shown to be 2.95 nM. [Table 10]

[0102] Example 4: Fcy receptor binding and effector function activities of anti-human MCT1 antibodies In vitro human FcyR binding and effector function activities were performed to confirm that the anti-human MCT1 antibody lacked detectable FcyR binding, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) activities.

[0103] Human Fcγ receptor binding. Biacore T100 (Cytiva), Biacore reagents, and Scrubber2 Biacore Evaluation Software (Biologics 2008) were used for SPR binding analysis of the MCT1 antibody. Additionally, IgGEN and LALA IgG backbones were also compared for Fcγ receptor binding. Series S CM5 chips (Cytiva P / N BR100530) were prepared using the manufacturer's EDC / NHS amine coupling method (Cytiva P / N BR100050). Briefly, the surfaces of all four flow cells (FCs) were activated by injecting a 1:1 mixture of EDC / NHS at 10 μL / min for 7 minutes. Protein A (Calbiochem P / N 539202) was diluted to 100 μg / mL in 10 mM acetate buffer, pH 4.5, and immobilized to approximately 400 RU on all four FCs by a 7-minute injection at a flow rate of 10 μL / min. Unreacted sites were blocked by a 7-minute injection of ethanolamine at 10 μL / min. Non-covalently bound protein was removed using 2×10 μL injections of glycine, pH 1.5. The running buffer was 1×HBS-EP+ (TEKNOVA, P / N H8022). FcγR extracellular domains (ECDs)—FcγRI (CD64), FcγRIIA_131R, and FcγRIIA_131H (CD32a), FcγRIIIA_158V, FcγRIIIA_158F (CD16a), and FcγRIIb (CD32b)—were generated from stable CHO cell expression. All FcγR ECDs were purified using IgG Sepharose and size-exclusion chromatography (SEC). For FcγRI binding, antibodies were diluted to 2.5 μg / mL in running buffer, and approximately 150 RU of each antibody was captured in FCs 2–4 (RU capture). FC1 was the reference FC, so no antibody was captured in FC1. FcγRI ECDs were diluted to 200 nM in running buffer and then serially diluted 2-fold in running buffer to 0.78 nM. At least two injections of each concentration were injected into all FCs at 40 μL / min for 120 s, followed by a 1200 s dissociation phase.Regeneration was performed by injecting 15 μL of 10 mM glycine, pH 1.5, at 30 μL / min into all FCs. Reference-subtracted data were collected for FC2FC1, FC3-FC1, and FC4-FC1. Measurements were taken at 25°C. Affinity (K D ) were calculated using either steady-state equilibrium analysis or a "1:1 (Langmuir) binding" model for BIA analysis using Scrubber2 Biacore software. For FcγRIIa, FcγRIIb, and FcγRIIIa binding, antibodies were diluted to 5 μg / mL in running buffer, and approximately 500 RU of each antibody was captured by FCs 2–4 (RU capture). FC1 again served as the reference FC. Fcγ receptor ECDs were diluted to 10 μM in running buffer and then serially diluted 2-fold to 39 nM in running buffer. Duplicate injections of each concentration were injected into all FCs at 40 μL / min for 60 s, followed by a 120 s dissociation phase. Regeneration was performed by injecting 15 μL of 10 mM glycine, pH 1.5, into all FCs at 30 μL / min. Reference-subtracted data were collected as FC2-FC1, FC3-FC1, and FC4-FC1. Measurements were taken at 25°C. Affinity (K D ) was calculated using steady-state equilibrium analysis with Scrubber2 Biacore® evaluation software.

[0104] The results demonstrated in Table 10 indicate that the IgG1EN Fc and LALA Fc backbones do not bind to Fcγ receptors. [Table 11]

[0105] C1q binding. 96-well microplates were coated with 100 μL / well of each antibody diluted in DPBS (Dulbecco's HyClone) at concentrations ranging from 10 μg / mL to 0.19 μg / mL. Tests were performed in duplicate wells. The plates were sealed and incubated overnight at 4°C. The coating reagent was removed, and 200 μL / well of casein blocking reagent (Thermo) was added. The plates were sealed and incubated for 2 hours at room temperature (RT). The plates were washed three times with wash buffer (1x TBE containing 0.05% Tween 20), and 100 μL / well of 10 μg / mL human C1q (MS Biomedical) diluted in casein blocking reagent was added and incubated for 3 hours at room temperature. The plate was then washed three times with wash buffer, after which 100 μL / well of a 1:800 dilution of sheep anti-human C1q-HRP (Abcam #ab46191) in casein blocker was added and incubated for 1 hour at room temperature. The plate was washed six times with wash buffer, and 100 μL / well of TMB substrate (Pierce) was added to each well and incubated for 7 minutes. The reaction was stopped by adding 100 μL of 1N HCl to each well. Optical density was immediately measured using a colorimetric microplate reader set at 450 nm. Data were analyzed using SoftMax Pro 7.1 data acquisition and analysis software.

[0106] Results (not shown) showed that the exemplified anti-human MCT1 antibody Ab6 and the IgG1EN control did not bind to complement component C1q when compared to the human IgG1 positive control antibody, which bound in a dose-dependent manner.

[0107] In vitro ADCC, ADCP, and CDC activity. Raji cells expressing MCT1 and CD20 were used as target cells for three assays. For ADCC assays, the Jurkat FcγRIIIa (V158)-NFAT-Luc cell line (Eli Lilly and Company), which stably co-expresses human FcγRIIIa (V158), human FcεRγ chain, and an NFAT luciferase reporter gene, was used as the effector cell line. For ADCP assays, the Jurkat FcγRIIa-NFAT-Luc cell line, which stably co-expresses human FcγRIIa (H131) and an NFAT luciferase reporter gene (G988A, Promega), was used as the effector cell line. Briefly, test samples were serially diluted 4-fold in duplicate, and 50 μL / well of diluted test compound or assay buffer was added to a 96-well plate (Costar 3917). Raji cells were cultured in assay medium to a final cell density of 1.0x10 6 The cells were diluted to 3x10 cells / mL and a volume of 50 μL cells / well was added to ADCC, ADCP, and CDC assay plates containing 50 μL / well of serially diluted test samples. The ADCC, ADCP, and CDC assay plates were gently agitated at 200 rpm on a plate shaker for 30 seconds and then incubated at 37°C for 1 hour. 3x10 stably transfected Jurkat V158 or Jurkat H131 cells were added to the plates. 6The test samples were diluted to a concentration of 1000 cells / mL, and 50 μL / well was added to each ADCC and ADCP assay plate containing serially diluted test samples and Raji cells. The plates were mixed by gentle agitation at 200 rpm for 30 seconds on a plate shaker and then incubated at 37°C for 4 hours. Prediluted complement from human serum (Quidel A113) was added to the CDC plates containing serially diluted test samples and Raji cells (50 μL / well). The plates were mixed by gentle agitation at 200 rpm for 30 seconds on a plate shaker and then incubated at 37°C for 2 hours. After incubation, the ADCC, ADCP, and CDC plates were returned to room temperature for 10 minutes, after which 100 μL of One-glo Ex (E8130, Promega) was added to the ADCC and ADCP assay plates and Cell-Titer Glo (G7571, Promega) was added to the CDC assay plate. Luminescence was read using an Envision 11 multimode plate reader using 0.2 cps integration. Results were analyzed using Prism v8.2 (Graph pad).

[0108] In vitro neutrophil activation. Heparinized human whole blood obtained from three independent healthy donors was used. Blood was diluted 1:1 with assay medium and plated at 100 μL / well in a 96-well plate. Test antibodies were titrated into the diluted whole blood starting at 300 μg / mL, followed by a 1:5 serial dilution. R848 (TLR7 agonist) was used as a positive control at a final concentration of 1 μg / mL. All conditions were performed in triplicate. Samples were incubated for 1 hour or overnight, after which red blood cells were lysed using ACK buffer, and the cells were washed and stained with the following antibody cocktail: anti-CD3-BV785 (Cat. No. 317330, Biolegend), anti-CD45-BV421 (Cat. No. 563879, BD Bioscience), CD66b-FITC (Cat. No. 555724, BD Bioscience), and CD11b-PE-Cy7 (Cat. No. 552850, BD Bioscience). Cells were stained for 30 minutes at room temperature, washed, and acquired using a FortessaX-20. Data were analyzed using FlowJo and plotted in Prism GraphPad. Neutrophils were identified based on their size and granularity and expression of the following markers: CD45+ / CD3- / CD66b+ / CD11b+. CD66b and CD11b expression was analyzed as gMFI (geometric mean fluorescence intensity) of CD45+ / CD3- / CD66b+ / CD11b+ cells.

[0109] The results in Figure 2A show that, compared with the positive control wild-type IgG1 anti-human MCT1 antibody and a CD20 antibody that induced ADCC activity in a dose-dependent manner, the exemplary anti-human MCT1 antibody Ab6 did not induce ADCC activity at any tested concentration. The results in Figure 2B show that, compared with the positive control wild-type IgG1 anti-human MCT1 antibody and a CD20 antibody that induced ADCP activity in a dose-dependent manner, the exemplary anti-human MCT1 antibody Ab6 did not significantly induce ADCP activity at any tested concentration. Neutrophil activation assay results (not shown) confirmed the lack of FcγRIIa activation by the anti-human MCT1 antibody Ab6 at all time points and concentrations tested. These results collectively indicated that Ab6 is unlikely to induce Fc-mediated effector function activity in vivo.

[0110] The results in Figure 2C showed that neither the exemplified anti-human MCT1 antibody Ab6 nor the wild-type IgG1 control antibody induced CDC activity, compared to the anti-CD20 positive control, which induced CDC activity in a dose-dependent manner.

[0111] Example 5: Developmental characteristics of anti-human MCT1 antibodies The biophysical and chemical properties of the anti-human MCT1 antibody were evaluated to determine the developability profile of the antibody.

[0112] Oxidation and Degradation During Cultivation: The oxidation and degradation of the exemplified anti-human MCT1 antibody during cultivation was evaluated. The exemplified anti-human MCT1 antibody was expressed in CHO cells and subjected to the following Protein A capture method. The capture column (MabSelect™ SuRe™ Protein A) was neutralized by washing with two column volumes of 50 mM Tris pH 8.0 and then equilibrated with 20 mM Tris pH 7.0. The harvest from the cell-free bioreactor containing the antibody was then loaded onto the column. Following sample loading, the column was washed with 20 mM Tris pH 7.0, then with two column volumes of 20 mM Tris pH 7.0 + 1 M NaCl, and then with 20 mM Tris pH 7.0. The MCT1 antibody was then eluted from the column using 20 mM acetate + 5 mM citrate buffer (pH 2.9). Elution fractions were collected by UV absorbance (>200 mAu) and pooled together. The pool was then adjusted to pH 5 with 1 M Tris pH 8.0 and incubated for 15 minutes with agitation at room temperature. The eluate was then allowed to stand at room temperature for a total of 1 hour. The sample pool was spun down at 3000 x g for 5 minutes at 20°C to remove host cell protein (HCP) precipitates. The sample supernatant was then filtered through a 0.22 micron steri-flip PDVF filter (Millipore) and subjected to preparative SEC (see Figures 3A and 3B).

[0113] The results demonstrated in Figures 3A and 3B demonstrate that the illustrated anti-human MCT1 antibody possesses a desirable oxidation and degradation profile for development. Specifically, the SEC profile of Ab1 (Figure 3A) showed a narrow, single peak without a shoulder peak. This indicates reduced antibody degradation (e.g., clipping during incubation) or oxidation compared to INX444, providing desirable development characteristics and reducing potential complications and costly modifications in downstream analysis and manufacturing processes (e.g., allowing for the collection of high-purity material via standard purification procedures). The SEC profile of the INX444 antibody (Figure 3B) showed a front-shoulder peak in the elution profile. Further analysis of the INX444 antibody by LC / MS / MS identified a front-shoulder peak due to antibody clipping during incubation (multiple CH1 clipping sites) and oxidation (mostly observed at amino acid residue W105). Application of standard platform purification procedures was not suitable for removing these impurities from the INX444 antibody, posing challenges to downstream purification processes and development.

[0114] Interaction with analytical size-exclusion column: 3 μg of the indicated anti-human MCT1 antibody (≥96% purity) was injected onto an analytical size-exclusion column (TOSOH TSKgel-UP-SW3000, Fisher Scientific, Cat. 50-104-9800) on an Agilent HPLC system at a mobile phase flow rate of 0.35 mL / min. The UV signal was detected at 214 nm.

[0115] The results demonstrated in Table 11 and Figure 4 indicate that the retention time of the exemplary anti-human MCT1 antibodies on the analytical size-exclusion column was significantly reduced (range: 3.78-4.04 min) compared to INX444 (5.18 min). Specifically, these results indicated a reduced interaction between the exemplary anti-human MCT1 antibodies and the column resin compared to the INX444 antibody (as demonstrated by the peak widths of Ab1 and INX444 in Figure 4). The strong interaction between the antibody and the column resin poses challenges for developing analytical methods to detect soluble high molecular weight species and requires modifications to downstream analytical processes. [Table 12]

[0116] Hydrophobic interaction chromatography (HIC): 20 µg of IgG sample (1 mg / mL) was diluted 1:1 with 2x Buffer A concentrate (2 M ammonium sulfate, 0.1 M sodium phosphate, pH 6.8) to a final ammonium sulfate concentration of 1 M before analysis. A TSKgel Butyl-NPR (4.6 mm ID x 10 cm, 2.5 µm, Tosoh #42168) column was used, with a 2 min hold in mobile phase A (1 M ammonium sulfate, 50 mM sodium phosphate, pH 6.8), followed by a 23 min linear gradient (0 to 100% B) of mobile phase A and mobile phase B (50 mM sodium phosphate, pH 6.8) at a flow rate of 1 mL / min. A 5 min final hold at 100% mobile phase B was used to remove residual protein while monitoring UV absorbance at 280 nm and 215 nm.

[0117] The results shown in Table 12 indicate that the exemplified anti-human MCT1 antibodies Ab6-Ab21 have lower retention times on the hydrophobic interaction column (ranging from 6.53 to 8.46 minutes), indicating lower hydrophobicity when compared to INX444, which has a retention time of 12 minutes. Antibody hydrophobicity can lead to downstream manufacturing issues, such as reduced expression and protein aggregation. [Table 13]

[0118] Cross-Interaction Chromatography: For cross-interaction chromatography (CIC) IgG columns, approximately 30 mg of human serum polyclonal antibody (I4506, Sigma) was bound to a 1 mL HiTrap NHS-activated column (17-0716-01, GE Healthcare) followed by quenching with ethanolamine and Tris. A blank column (control column without IgG) was prepared by deactivating with ethanolamine and Tris. Using 10 mM sodium phosphate, 10 mM NaCl, pH 6.5 as the mobile phase on an Agilent 1260 Series HPLC system, 20 μg of each antibody was injected onto each column (IgG and blank) at a constant flow rate of 0.2 mL / min. The retention times (RT) obtained on both the IgG and blank columns were used to calculate K' (IgG K' = [IgG column RT - blank column RT] / blank column RT). Additionally, because peak tailing occurred in some samples, the peak width at 50% height was also acquired to monitor the "stickiness" of the test antibody.

[0119] The results demonstrated in Table 13 indicate that the exemplified anti-human MCT1 antibodies did not exhibit significant nonspecific binding to serum IgG or the blank column, as indicated by the IgG column retention times (5.07-5.41 min) and blank peak widths (ranging from 4.81 to 5.01 min) compared to INX444 (IgG RT of 11 min, blank peak width of 6.81 min). Furthermore, the IgG peak widths of the exemplified antibodies were 1.36-1.94 min and 0.88-1.2 min, respectively, indicating lower IgG interaction with the column resin compared to INX444 (IgG peak width of 8 min, blank peak width of 2 min). The shorter IgG retention time on the CIC column indicates potential improved antibody solubility. [Table 14]

[0120] Solubility: Solubility was assessed by concentrating 100 mg of the exemplified anti-human MCT1 antibody to a volume of approximately 0.5 mL using a 30 kDa molecular weight cutoff centrifugal filter (e.g., Amicon UC filter, Millipore, catalog number UFC903024). The final concentration of the sample was measured using a Solo VPE spectrophotometer (C Technologies, Inc.). The results showed that the exemplified anti-human MCT1 antibody was highly soluble.

[0121] Thermal stability: Differential scanning calorimetry (DSC) was used to evaluate the stability of the exemplified anti-human MCT1 antibodies against thermal denaturation. DSC was performed using a Malvern MicroCal VP-DSC instrument. Samples were heated from 20°C to 110°C at a constant rate of 60°C / h. The analytical method was performed using a MicroCal VP-Capillary DSC automated analysis program. Baseline correction was performed, and T onset and T were determined. The results showed that the exemplified anti-human MCT1 antibodies have comparable Tm and acceptable thermal stability for development.

[0122] Chemical Stability: The stability of the exemplary MCT1 antibody is assessed at high concentrations (approximately 100 mg / mL) in an acceptable buffer. Concentrated samples are incubated at 5°C and 35°C for a period of 4 weeks. After incubation, samples are analyzed for the percentage loss of the main peak (Δ% main peak) by size exclusion chromatography (SEC), for fragmentation by capillary electrophoresis (CE-SDS), and for chemical modifications (e.g., deamidation, isomerization, or oxidation) by LCMS peptide mapping.

[0123] Freeze / Thaw Stability: Freeze / thaw stability is assessed using three slow, repeated, controlled temperature cycles that mimic the freeze / thaw conditions of a large volume of bulk drug substance placed at -70°C at a high concentration (approximately 100 mg / mL).

[0124] Example 6: Immunogenicity risk profiling of exemplified anti-human MCT1 antibodies Immunogenicity T cell proliferation assay: The ability of the exemplified anti-human MCT1 antibody or test candidate MAPPS peptide to activate CD4+ T cells by inducing cell proliferation was assessed. CD8+ T cell-depleted PBMCs were prepared and labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). Each sample was tested with a medium control, keyhole limpet hemocyanin (KLH, positive control), the respective treatment control (positive clinical benchmark antibody or peptide immunogenicity control), the exemplified antibody, or the test candidate MAPPS peptide. Cells were cultured and incubated for 7 days. On day 7, samples were analyzed by flow cytometry for CD4+ T cell proliferation responses. The median mitotic index (CDI) was calculated. Nine donors were evaluated. Donors with a CDI of 2.5 or greater were considered positive responders. Donor frequency across all donors was assessed.

[0125] The results demonstrated in Table 14 indicate that the exemplified anti-human MCT1 antibodies tested significantly reduced T cell proliferation (range of 0% to 22% positive donor responses) from the nine donors tested, indicating a low immunogenicity risk compared to the positive control anti-CXCR4 antibody, which demonstrated a 78% positive donor response. These results demonstrate the low immunogenicity risk profile of the exemplified anti-human MCT1 antibodies. INX444 demonstrated an 89% positive donor response in the T cell proliferation assay, indicating a high immunogenicity risk profile. [Table 15]

[0126] Serum protein binding: To further evaluate the immunogenicity risk profile of the exemplified anti-human MCT1 antibodies, serum protein binding was determined using mass spectrometry (MS). Antibodies diluted in PBS were coated onto Nunc MaxiSorp (or Immulon 4 HBX) microplates at 3 μg / well overnight at 4°C. The following day, the plates were washed three times with 200 μL of cold PBS and blocked with 100 μL of PBS / 1% BSA for 3 hours at room temperature. The blocking solution was removed, and the plates were washed three times again. 100 μL of human serum samples (pooled serum from eight donors, diluted 1:1 with PBS / protease inhibitors) were added to the wells, and the plates were incubated overnight at 4°C. The following day, the samples were removed, and the plates were washed 10 times with 200 μL of cold PBS. Bound proteins were eluted with 1% acid, reduced, alkylated, and digested with trypsin. Tryptic peptides were analyzed by nanoLC / MS using a Thermo QE-HFX (or LUMOS) mass spectrometer. Peptide and protein identifications were generated by an internal proteomics pipeline using a trypsin enzyme search algorithm and a human database supplemented with test antibody sequences. Ions were quantified using internal proteomics tools (Chrom-Alignment, Meta-consense, Quant) and analyzed in JMP using a one-way analysis / each pair, Student's t-test (or all pairs, Tukey HSD) platform. Ions with p<0.05 and a difference of >1 were considered enriched.

[0127] MS analysis results showed that the exemplified anti-human MCT1 antibody had no detectable binding to serum proteins. This lack of binding indicates a reduced risk of immunogenicity and a reduced risk of faster clearance, thus providing a potentially desirable safety, immunogenicity, and PK profile for the exemplified anti-human MCT1 antibody. Results further demonstrated that INX444 bound to multiple apolipoproteins in serum, potentially indicating a high risk of immunogenicity and rapid clearance.

[0128] Example 7: In vivo characterization of anti-human MCT1 antibodies Graft-versus-host disease (GvHD) assay: Female NSG™ mice (NOD.Cg-Prkdc scid Il2rg tm1Wjl / SzJ, JAX Labs, Stock#05557) were housed three per cage at 72°C under a 12-hour light / dark cycle with food and water available ad libitum (n=33). Human PBMCs were isolated from LRS tubes obtained from the San Diego Blood Bank (San Diego, CA) using SepMate50 Ficol preparation tubes according to the manufacturer's instructions (StemCell Technologies, Vancouver, BC). Freshly isolated PBMCs were diluted to 1.2 × 10 in PBS. 8 The PBMCs were suspended at 100 μL / mL and transplanted intravenously into mice on day 0 with 100 μL of the PBMC suspension (1.2 × 10 7 PBMCs were administered to 100 mice (n = 29 / cell / mouse). Four mice were not transplanted as non-transplant controls. On day 1, mice were divided into weight-matched groups and subcutaneously administered a human IgG1EN isotype control antibody, or Ab1 or Ab6. Treatment continued once a week for the remainder of the experiment. Physical examinations and body weight measurements were performed regularly. Spleen cells from Ab6-treated mice at the end of the study were further evaluated for regulatory T cell proliferation.

[0129] The results demonstrated in Figures 5 and 6 indicated that treatment with Ab1 or Ab6, respectively, at a specific dose, could achieve complete protection from weight loss, similar to the non-transplanted control group. Surprisingly, as shown in Table 15, treatment with the anti-human MCT1 antibody Ab6 significantly reduced FoxP3 expression in splenocytes at the end of the study when compared to the control. + These results suggest that Ab6-induced regulatory T cell proliferation may also contribute to protection from weight loss. [Table 16]

[0130] array Ab1 SEQ ID NO: 1 HCDR1 for Ab1, Ab2, Ab3, Ab4, and Ab5 TVSGFSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 3 HCDR3 for Ab1, Ab2, Ab3, Ab4, and Ab5 ARNSWYHGTYYSPGYYVMDA SEQ ID NO: 4 LCDR1 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab20, and Ab21 KGSQNINNYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 7 VH for Ab1 and Ab2 QVQLVQSGAEVKKPGASVKVSCTVSGFSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNSWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 8 VL for Ab1, Ab20, and Ab21 EIVLTQSPGTLSLSPGERATLSCKGSQNINNYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 9 HC for Ab1 and Ab2 QVQLVQSGAEVKKPGASVKVSCTVSGFSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNSWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 10 LC for Ab1, Ab20, and Ab21 EIVLTQSPGTLSLSPGERATLSCKGSQNINNYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 11 HC DNA for Ab1 and Ab2 SEQ ID NO: 12 LC DNA for Ab1, Ab20, and Ab21 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCAATAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab2 SEQ ID NO: 1 HCDR1 for Ab1, Ab2, Ab3, Ab4, and Ab5 TVSGFSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 3 HCDR3 for Ab1, Ab2, Ab3, Ab4, and Ab5 ARNSWYHGTYYSPGYYVMDA SEQ ID NO: 4 LCDR1 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab20, and Ab21 KGSQNINNYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 7 VH for Ab1 and Ab2 QVQLVQSGAEVKKPGASVKVSCTVSGFSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNSWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 13 VL for Ab2 and Ab3 DIQMTQSPSTLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 9 HC for Ab1 and Ab2 QVQLVQSGAEVKKPGASVKVSCTVSGFSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNSWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 15 LC for Ab2 and Ab3 DIQMTQSPSTLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 11 HC DNA for Ab1 and Ab2 SEQ ID NO: 17 LC DNA for Ab2 and Ab3 GATATTCAGATGACACAGAGCCCTTCCACCCTGAGCGCCATGTAGGCGACCGGGTAACTATAACATGTAAAGGCTCACAAAACATCAATAACTATTTGGCCTGGTATCAGCAAAAGCCAGGAAAAGCTCCTAAACTCTTGATATACAACAGACATAAC TTGCAAACTGGGGTGCCAAGTCGCTTCAGCGGGAGTGGCTCAGGTACAGAGTTTACTCTTACCATTTCCTCCCTGCAACCTGACGATTTTGCCACCTACTATTGCTACCAATATTCCGATGGATACACTTTCGGGGGTGGTACTAAAGTTGAGATTAAGC GAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab3 SEQ ID NO: 1 HCDR1 for Ab1, Ab2, Ab3, Ab4, and Ab5 TVSGFSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 3 HCDR3 for Ab1, Ab2, Ab3, Ab4, and Ab5 ARNSWYHGTYYSPGYYVMDA SEQ ID NO: 4 LCDR1 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab20, and Ab21 KGSQNINNYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 18 VH for Ab3 EVQLVESGGGLVQPGGSRLSCTVSGFSLTNYHLQWVRQAPGKGLEWVGFIRSSGNTEYNSEFKSRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARNSWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 13 VL for Ab2 and Ab3 DIQMTQSPSTLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 19 HC for Ab3 EVQLVESGGGLVQPGGSLRLSTVSGFSLTNYHLQWVRQAPGKGLEWVGFIRSSGNTEYNSEFKSRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARNSWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 15 LC for Ab2 and Ab3 DIQMTQSPSTLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 20 HC DNA for Ab3 SEQ ID NO: 17 LC DNA for Ab2 and Ab3 GATATTCAGATGACACAGAGCCCTTCCACCCTGAGCGCCATGTAGGCGACCGGGTAACTATAACATGTAAAGGCTCACAAAACATCAATAACTATTTGGCCTGGTATCAGCAAAAGCCAGGAAAAGCTCCTAAACTCTTGATATACAACAGACATAAC TTGCAAACTGGGGTGCCAAGTCGCTTCAGCGGGAGTGGCTCAGGTACAGAGTTTACTCTTACCATTTCCTCCCTGCAACCTGACGATTTTGCCACCTACTATTGCTACCAATATTCCGATGGATACACTTTCGGGGGTGGTACTAAAGTTGAGATTAAGC GAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab4 SEQ ID NO: 1 HCDR1 for Ab1, Ab2, Ab3, Ab4, and Ab5 TVSGFSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 3 HCDR3 for Ab1, Ab2, Ab3, Ab4, and Ab5 ARNSWYHGTYYSPGYYVMDA SEQ ID NO: 4 LCDR1 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab20, and Ab21 KGSQNINNYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 21 VH for Ab4 EVQLVESGGGLVKPGGSLRLSCTVSGFSLTNYHLQWVRQAPGKGLEWVGFIRSSGNTEYNSEFKSRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARNSWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 22 VL for Ab4 and Ab5 DIQMTQSPSSLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 23 HC for Ab4 EVQLVESGGGLVKPGGSLRLSCTVSGFSLTNYHLQWVRQAPGKGLEWVGFIRSSGNTEYNSEFKSRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARNSWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 24 LC for Ab4 and Ab5 DIQMTQSPSSLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 25 HC DNA for Ab4 SEQ ID NO: 26 LC DNA for Ab4 and Ab5 GATATTCAAATGACACAATCTCCCTCCAGCCTGTCAGCCTCTGTTGGAGACAGGGTAACTATAACATGCAAAGGCTCCCAAAACATAAATAATTACTTGGCCTGGTATCAAACAGAAACCTGGTAAGGCACCTAAGCTGCTCATCTACAATAGGCATAAC CTTCAGACTGGCGTTCCTTCTAGGTTTAGCGGGTCAGGGTCCGGTACCGATTTTACCCTCACAATATCCAGTCTTCAACCCGAGGACTTCGCAACATATTATTGTTATCAGTATTCTGATGGTTACACCTTCGGAGGGGGAACTAAGGTGGAGATCAAGC GAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab5 SEQ ID NO: 1 HCDR1 for Ab1, Ab2, Ab3, Ab4, and Ab5 TVSGFSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 3 HCDR3 for Ab1, Ab2, Ab3, Ab4, and Ab5 ARNSWYHGTYYSPGYYVMDA SEQ ID NO: 4 LCDR1 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab20, and Ab21 KGSQNINNYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 27 VH for Ab5 EVQLVQSGAEVKKPGESLKISCTVSGFSLTNYHLQWVRQMPGKGLEWMGFIRSSGNTEYNSEFKSQVTISADKSISTAYLQWSSLKASDTAMYYCARNSWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 22 VL for Ab4 and Ab5 DIQMTQSPSSLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 28 HC against Ab5 EVQLVQSGAEVKKPGESLKISCTVSGFSLTNYHLQWVRQMPGKGLEWMGFIRSSGNTEYNSEFKSQVTISADKSISTAYLQWSSLKASDTAMYYCARNSWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 24 LC for Ab4 and Ab5 DIQMTQSPSSLSASVGDRVTITCKGSQNINNYLAWYQQKPGKAPKLLIYNRHNLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 29 HC DNA for Ab5 SEQ ID NO: 26 LC DNA for Ab4 and Ab5 GATATTCAAATGACACAATCTCCCTCCAGCCTGTCAGCCTCTGTTGGAGACAGGGTAACTATAACATGCAAAGGCTCCCAAAACATAAATAATTACTTGGCCTGGTATCAAACAGAAACCTGGTAAGGCACCTAAGCTGCTCATCTACAATAGGCATAAC CTTCAGACTGGCGTTCCTTCTAGGTTTAGCGGGTCAGGGTCCGGTACCGATTTTACCCTCACAATATCCAGTCTTCAACCCGAGGACTTCGCAACATATTATTGTTATCAGTATTCTGATGGTTACACCTTCGGAGGGGGAACTAAGGTGGAGATCAAGC GAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab6 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 31 HCDR2 for Ab6 FIRSSGNTEYNSRFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 34 VH for Ab6 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSRFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 36 HC for Ab6 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSRFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 38 HC DNA for Ab6 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab7 SEQ ID NO: 40 HCDR1 for Ab7 TVSGRSRTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 41 VH for Ab7 QVQLVQSGAEVKKPGASVKVSCTVSGRSRTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 42 HC for Ab7 QVQLVQSGAEVKKPGASVKVSCTVSGRSRTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 43 HC DNA for Ab7 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab8 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 44 HCDR2 for Ab8 FIRSSGNTIYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 45 VH for Ab8 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTIYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 46 HC for Ab8 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTIYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 47 HC DNA for Ab8 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab9 SEQ ID NO: 48 HCDR1 for Ab9 TVSGRSLTNYHIQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 49 VH for Ab9 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHIQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 50 HC for Ab9 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHIQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 51 HC DNA for Ab9 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab10 SEQ ID NO: 52 HCDR1 for Ab10 TVSGRSLTGYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 53 VH for Ab10 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTGYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 54 HC for Ab10 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTGYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 55 HC DNA for Ab10 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab11 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 56 HCDR3 for Ab11 ARNRWHHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 57 VH for Ab11 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWHHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 58 HC for Ab11 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWHHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 59 HC DNA for Ab11 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab12 SEQ ID NO: 60 HCDR1 for Ab12 TVSGRSLTNYHLV SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 61 VH for Ab12 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLVWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 62 HC for Ab12 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLVWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 63 HC DNA for Ab12 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab13 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 64 HCDR3 for Ab13 ARNRWRHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 65 VH for Ab13 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWRHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 66 HC for Ab13 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWRHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 67 HC DNA for Ab13 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab14 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 68 HCDR3 for Ab14 and Ab21 ARNRWYHGTYYSPGYYVMDP SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 69 VH for Ab14 and Ab21 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDPWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 70 HC for Ab14 and Ab21 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD PWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 71 HC DNA for Ab14 and Ab21 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab15 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 72 HCDR3 for Ab15 and Ab20 ARNLWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 73 VH for Ab15 and Ab20 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNLWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 74 HC against Ab15 and Ab20 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNLWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 75 HC DNA for Ab15 and Ab20 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab16 SEQ ID NO: 76 HCDR1 for Ab16 TRSGRSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 77 VH for Ab16 QVQLVQSGAEVKKPGASVKVSCTRSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 78 HC for Ab16 QVQLVQSGAEVKKPGASVKVSCTRSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 79 HC DNA for Ab16 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab17 SEQ ID NO: 80 HCDR1 for Ab17 TVSGRSLTNIHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 81 VH for Ab17 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNIHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 82 HC for Ab17 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNIHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 83 HC DNA for Ab17 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab18 SEQ ID NO: 84 HCDR1 for Ab18 TVSGRSLTNYHLG SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 85 VH for Ab18 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLGWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 86 HC for Ab18 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLGWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 87 HC DNA for Ab18 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab19 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 88 HCDR2 for Ab19 FIRRSGNTEYNSEFKS SEQ ID NO: 32 HCDR3 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab12, Ab16, Ab17, Ab18, and Ab19 ARNRWYHGTYYSPGYYVMDA SEQ ID NO: 33 LCDR1 for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 KGSQNIENYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 89 VH for Ab19 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRRSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 35 VL for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 90 HC for Ab19 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRRSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37 LC for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 EIVLTQSPGTLSLSPGERATLSCKGSQNIENYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 91 HC DNA for Ab19 SEQ ID NO: 39 LC DNA for Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCGAGAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab20 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 72 HCDR3 for Ab15 and Ab20 ARNLWYHGTYYSPGYYVMDA SEQ ID NO: 4 LCDR1 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab20, and Ab21 KGSQNINNYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 73 VH for Ab15 and Ab20 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNLWYHGTYYSPGYYVMDAWGQGTLVTVSS SEQ ID NO: 8 VL for Ab1, Ab20, and Ab21 EIVLTQSPGTLSLSPGERATLSCKGSQNINNYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 74 HC against Ab15 and Ab20 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNLWYHGTYYSPGYYVMD AWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 10 LC for Ab1, Ab20, and Ab21 EIVLTQSPGTLSLSPGERATLSCKGSQNINNYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 75 HC DNA for Ab15 and Ab20 SEQ ID NO: 12 LC DNA for Ab1, Ab20, and Ab21 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCAATAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC Ab21 SEQ ID NO: 30 HCDR1 for Ab6, Ab8, Ab11, Ab13, Ab14, Ab15, Ab19, Ab20, and Ab21 TVSGRSLTNYHLQ SEQ ID NO: 2 HCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab7, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab20, and Ab21 FIRSSGNTEYNSEFKS SEQ ID NO: 68 HCDR3 for Ab14 and Ab21 ARNRWYHGTYYSPGYYVMDP SEQ ID NO: 4 LCDR1 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab20, and Ab21 KGSQNINNYLA SEQ ID NO: 5 LCDR2 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YNRHNLQT SEQ ID NO: 6 LCDR3 for Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, and Ab21 YQYSDGYT SEQ ID NO: 69 VH for Ab14 and Ab21 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMDPWGQGTLVTVSS SEQ ID NO: 8 VL for Ab1, Ab20, and Ab21 EIVLTQSPGTLSLSPGERATLSCKGSQNINNYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK SEQ ID NO: 70 HC for Ab14 and Ab21 QVQLVQSGAEVKKPGASVKVSCTVSGRSLTNYHLQWVRQAPGQGLEWMGFIRSSGNTEYNSEFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARNRWYHGTYYSPGYYVMD PWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPEEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 10 LC for Ab1, Ab20, and Ab21 EIVLTQSPGTLSLSPGERATLSCKGSQNINNYLAWYQQKPGQAPRLLIYNRHNLQTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCYQYSDGYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 71 HC DNA for Ab14 and Ab21 SEQ ID NO: 12 LC DNA for Ab1, Ab20, and Ab21 GAGATCGTCCTCACCCAGTCTCCCGGCACATTGAGTTTGAGTCCAGGTGAAAGAGCAACACTGAGCTGCAAAGGTAGCCAGAACATCAATAATTATCTTGCATGGTACCAGCAGAAACCTGGGCAGGCACCCAGGCTCTTGATCTACAATAGGCATAAC CTGCAGACAGGCATTCCTGATAGATTTTCTGGATCAGGTAGTGGTACCGACTTTACCCTTACCATCTCACGACTGGAGCCTGAAGATTTTGCCGTCTATTACTGTTATCAATACAGCGATGGTTACACTTTCGGGGGAGGGACAAAAGTGGAAATAAAGC GAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGA GAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC INX444 LALA SEQ ID NO: 92 INX444 HC to LALA (CDRs in bold and underlined) [Table 17] SEQ ID NO: 93 LC for INX444 LALA and INX444 IgG1EN (CDRs in bold and underlined) [Table 18] INX444 IgG1EN SEQ ID NO: 94 INX444 HC to IgG1EN (CDRs in bold and underlined) [Table 19] SEQ ID NO: 93 LC for INX444 LALA and INX444 IgG1EN (CDRs in bold and underlined) [Table 20] SEQ ID NO: 95 Human MCT1 protein MPPAVGGPVGYTPPDGGWGWAVVIGAFISIGFSYAFPKSITVFFKEIEGIFHATTSEVSWISSIMLAVMYGGGPISSILVNKYGSRIVMIVGGCLSGCGLIAASFCNTVQQLYVCIGVIGGLGLA FNLNPALTMIGKYFYKRRPLANGLAMAGSPVFLCTLAPLNQVFFGIFGWRGSFLILGGLLLNCVAGALMRPIGPKPTKAGKDKSKASLEKAGKSGVKKDLHDANTDLIGRHPKQEKRSVFQTIN QFLDLTLFTHRGFLLYLSGNVIMFFGLFAPLVFLSSYGKSQHYSSEKSAFLLSILAFVDMVARPSMGLVANTKPIRPRIQYFFAASVVANGVCHMLAPLSTTYVGFCVYAGFFGFAFGWLSSVLF ETLMDLVGPQRFSSAVGLVTIVECCPVLLGPPLLGRLNDMYGDYKYTYWACGVVLIISGIYLFIGMGINYRLLAKEQKANEQKKESKEEETSIDVAGKPNEVTKAAESPDQKDTDGPKEEESPV SEQ ID NO: 96 Cynomolgus monkey MCT1 protein MPPAVGGPVGYTPPDGGWGWAVVIGAFISIGFSYAFPKSITVFFKEIESIFHATTSEVSWISSIMLAVMYGGGPISSILVNKYGSRIVMIIGGCLSGCGLIAASFCNTVQELYFCIGFVGGLGLA FNLNPALTMIGKYFYKRRPLANGLAMAGSPVFLCTLAPLNQVFFDIFGWRGSFLILGGLLLNCVAGALMRPIGPKPTKAGKDKSKASLQKAGKSGVKKGRHDANTDLIGRHPKREKRSVFQTIN QFLDLTLFTHRGFLLYLSGNVIMFFGLFAPLVFLSSYGKSQHYSSEKSAFLLSILAFVDMVARPSMGLVANTKPIRPRIQYFFAASIVANGVCHMLAPLSTTYVGFCVYAGFFGFAFGWLSSVLF ETLMDLVGPQRFSSAVGLVTIVECCPVLLGPPLLGRLSDMYGDYKYTYWACGVVLIISGIYLFIGMGINYRLLAKEQKANEQKKESKEEETSIDVAGKPKEVTKAAESPDQKDTEEGPKEEDSPV SEQ ID NO: 97 HCDR1 [Table 21] Xaa2 is valine or arginine, Xaa7 is leucine or arginine, Xaa9 is asparagine or glycine, and Xaa 10 is tyrosine or isoleucine, and Xaa 12 is leucine or isoleucine, and Xaa 13 is glutamine, valine, or glycine SEQ ID NO: 98 HCDR2 [Table 22] Xaa4 is arginine or serine, Xaa9 is isoleucine or glutamic acid, and Xaa 13 is glutamic acid or arginine SEQ ID NO: 99 HCDR3 [Table 23] Xaa4 is arginine or leucine, Xaa6 is histidine, arginine, or tyrosine, and Xaa 20 is proline or alanine

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 30; said HCDR2 comprising SEQ ID NO: 31; the HCDR3 comprises SEQ ID NO: 32; the LCDR1 comprises SEQ ID NO: 33; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

2. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises SEQ ID NO: 34 and the VL comprises SEQ ID NO:

35.

3. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 36 and the LC comprises SEQ ID NO:

37.

4. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 30; said HCDR2 comprising SEQ ID NO:2; the HCDR3 comprises SEQ ID NO:56, SEQ ID NO:64, SEQ ID NO:68, or SEQ ID NO:72; the LCDR1 comprises SEQ ID NO: 33; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

5. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 30; said HCDR2 comprising SEQ ID NO:2; the HCDR3 comprises SEQ ID NO: 99; the LCDR1 comprises SEQ ID NO: 33; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

6. The antibody or antigen-binding fragment thereof of claim 4 or 5, wherein the VH comprises SEQ ID NO: 57, 65, 69, or 73, and the VL comprises SEQ ID NO:

35.

7. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 58, 66, 70, or 74, and the LC comprises SEQ ID NO:

37.

8. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 30; said HCDR2 comprising SEQ ID NO:2; the HCDR3 comprises SEQ ID NO: 72; the LCDR1 comprises SEQ ID NO: 4; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

9. The antibody or antigen-binding fragment thereof of claim 8, wherein the VH comprises SEQ ID NO: 73 and the VL comprises SEQ ID NO:

8.

10. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 74 and the LC comprises SEQ ID NO:

10.

11. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 30; said HCDR2 comprising SEQ ID NO:2; the HCDR3 comprises SEQ ID NO: 68; the LCDR1 comprises SEQ ID NO: 4; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

12. The antibody or antigen-binding fragment thereof of claim 11, wherein the VH comprises SEQ ID NO: 69 and the VL comprises SEQ ID NO:

8.

13. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 70 and the LC comprises SEQ ID NO:

10.

14. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; the HCDR1 comprises SEQ ID NO:40, SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:76, SEQ ID NO:80, or SEQ ID NO:84; said HCDR2 comprising SEQ ID NO:2; the HCDR3 comprises SEQ ID NO: 32; the LCDR1 comprises SEQ ID NO: 33; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

15. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 97; said HCDR2 comprising SEQ ID NO:2; the HCDR3 comprises SEQ ID NO: 32; the LCDR1 comprises SEQ ID NO: 33; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

16. The antibody or antigen-binding fragment thereof of claim 14 or 15, wherein the VH comprises SEQ ID NO: 41, 49, 53, 61, 77, 81, or 85, and the VL comprises SEQ ID NO:

35.

17. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 42, 50, 54, 62, 78, 82, or 86, and the LC comprises SEQ ID NO:

37.

18. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 30; the HCDR2 comprises SEQ ID NO:44 or SEQ ID NO:88; the HCDR3 comprises SEQ ID NO: 32; the LCDR1 comprises SEQ ID NO: 33; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

19. An antibody or antigen-binding fragment thereof that specifically binds to human MCT1, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 30; said HCDR2 comprising SEQ ID NO: 98; the HCDR3 comprises SEQ ID NO: 32; the LCDR1 comprises SEQ ID NO: 33; the LCDR2 comprises SEQ ID NO:5, and An antibody or antigen-binding fragment thereof, wherein the LCDR3 comprises SEQ ID NO:

6.

20. 20. The antibody or antigen-binding fragment thereof of claim 18 or 19, wherein the VH comprises SEQ ID NO: 45 or 89 and the VL comprises SEQ ID NO:

35.

21. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 46 or 90, and the LC comprises SEQ ID NO:

37.

22. An antibody or antibody-binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 7, 18, 21, or 27, and the VL comprises SEQ ID NO: 8, 13, or 22.

23. comprising a heavy chain variable region (VH) and a light chain variable region (VL), a. the VH comprises SEQ ID NO: 7 and the VL comprises SEQ ID NO: 8; or b. the VH comprises SEQ ID NO:7 and the VL comprises SEQ ID NO:13; c. the VH comprises SEQ ID NO: 18 and the VL comprises SEQ ID NO: 13; d. the VH comprises SEQ ID NO: 21 and the VL comprises SEQ ID NO: 22; or e. The antibody or antigen-binding fragment thereof of claim 22, wherein the VH comprises SEQ ID NO: 27 and the VL comprises SEQ ID NO:

22.

24. 1. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC and the LC comprise the following amino acid sequences: a. the HC comprises SEQ ID NO:9 and the LC comprises SEQ ID NO:10; b. the HC comprises SEQ ID NO:9 and the LC comprises SEQ ID NO:15; c. the HC comprises SEQ ID NO: 19 and the LC comprises SEQ ID NO: 15; d. the HC comprises SEQ ID NO:23 and the LC comprises SEQ ID NO:24, or e. The HC comprises SEQ ID NO:28 and the LC comprises SEQ ID NO:

24.

25. 24. The antibody or antigen-binding fragment thereof of any one of claims 1, 2, 4-6, 8, 9, 11, 12, 14-16, 18-20, or 22, 23, wherein the antibody comprises a human IgG1 isotype.

26. The antibody or antigen-binding fragment thereof of claim 25, wherein the human IgG1 is effector null.

27. A nucleic acid comprising a sequence encoding SEQ ID NO: 9, 19, 23, 28, 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 10, 15, 24, or 37.

28. A vector comprising the nucleic acid of claim 27.

29. 29. The vector of claim 28, wherein the vector comprises a first nucleic acid sequence encoding SEQ ID NO: 9, 70, or 74 and a second nucleic acid sequence encoding SEQ ID NO:

10.

30. 29. The vector of claim 28, wherein the vector comprises a first nucleic acid sequence encoding SEQ ID NO: 9 or 19 and a second nucleic acid sequence encoding SEQ ID NO:

15.

31. 29. The vector of claim 28, wherein the vector comprises a first nucleic acid sequence encoding SEQ ID NO: 23 or 28 and a second nucleic acid sequence encoding SEQ ID NO:

24.

32. 29. The vector of claim 28, wherein the vector comprises a first nucleic acid sequence encoding SEQ ID NO: 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90 and a second nucleic acid sequence encoding SEQ ID NO:

37.

33. A composition comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9, 70, or 74, and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

10.

34. A composition comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9 or 19 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

15.

35. A composition comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO:23 or 28 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

24.

36. A composition comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90, and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

37.

37. A cell comprising the vector according to any one of claims 28 to 36.

38. A cell comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9, 70, or 74, and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

10.

39. A cell comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO:9 or 19 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

15.

40. A cell comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO:23 or 28 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

24.

41. A cell comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 36, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, or 90, and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

37.

42. The cell according to any one of claims 37 to 41, wherein the cell is a mammalian cell.

43. 42. A method of producing an antibody, comprising culturing a cell of any one of claims 38 to 41 under conditions such that the antibody is expressed, and then recovering the expressed antibody from the culture medium.

44. 44. An antibody produced by the method of claim 43.

45. A pharmaceutical composition comprising the antibody of any one of claims 1 to 26 or 44 and a pharmaceutically acceptable excipient, diluent, or carrier.

46. 46. ​​A method of inhibiting the activity or number of T effector cells or B cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of claims 1 to 26 or 44 or the pharmaceutical composition of claim 45.

47. 46. ​​A method for increasing the activity or number of regulatory T cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of claims 1 to 26 or 44 or the pharmaceutical composition of claim 45.

48. 46. ​​A method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of claims 1 to 26 or 44 or the pharmaceutical composition of claim 45.

49. 49. The method of claim 48, wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, psoriasis, or multiple sclerosis.

50. 46. ​​A method of treating an allergic condition, an inflammatory condition, a metabolic disorder, a transplant or cell therapy recipient, an MCT1 positive cancer, an exercise-induced hyperinsulinism (EIHI) condition, or polycystic kidney disease (ADPKD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of claims 1-26 or 44, or the pharmaceutical composition of claim 45.

51. 45. The antibody of any one of claims 1 to 26 or 44 for use in therapy.

52. An antibody according to any one of claims 1 to 26 or 44 or a pharmaceutical composition according to claim 45 for use in the treatment of an autoimmune disease.

53. 53. The antibody or pharmaceutical composition for use according to claim 52, wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, psoriasis, or multiple sclerosis.

54. 46. ​​The antibody of any one of claims 1 to 26 or 44 or the pharmaceutical composition of claim 45 for use in treating an allergic condition, an inflammatory condition, a metabolic disorder, a transplant or cell therapy recipient, an MCT1 positive cancer, an EIHI condition, or polycystic kidney disease (ADPKD).

55. 13. Use of an antibody according to any one of claims 1 to 26 or 44 in the manufacture of a medicament for the treatment of an autoimmune disease.

56. 56. The use of claim 55, wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, psoriasis, or multiple sclerosis.

57. 130. Use of the antibody of any one of claims 1 to 26 or 44 in the manufacture of a medicament for use in treating an allergic condition, an inflammatory condition, a metabolic disorder, a transplant or cell therapy recipient, an MCT1 positive cancer, an EIHI condition, or polycystic kidney disease (ADPKD).

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