Anti-cd39 antibodies, compositions comprising anti-cd39 antibodies and methods of using anti-cd39 antibodies

Abstract

Provided herein are antibodies that selectively bind to CD39 and its isoforms and homologs, and compositions comprising the antibodies. Also provided are methods of using the antibodies, such as therapeutic and diagnostic methods.

What is claimed is: 
     
         1 . An antigen binding protein that binds specifically to a human CD39 (hCD39) and is capable of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of the following:
 a) inhibiting binding of CD39 to ATP;   b) inhibiting conversion by CD39 of ATP to ADP and/or ADP to AMP;   c) decreasing affinity of CD39 for ATP or ADP;   d) inhibiting or impeding release of ADP or AMP from CD39;   e) impeding or inhibiting CD39 processivity;   f) inhibiting platelet aggregation;   g) decreasing levels of phosphate, ADP, AMP, and/or adenosine and/or increasing levels of ATP;   h) increasing T effector cell function;   i) decreasing the number of regulatory T cells in tissues or in circulation;   j) suppressing regulatory T cells or regulatory T cell activity;   k) increasing B cell function;   l) increasing antigen presenting cell function;   m) inhibiting CD39 function on tumor cells;   n) inhibiting processing of at least one of phospho-antigen from phosphorylated isoprenoid, phosphorylated vitamin B metabolite, and/or phosphorylated riboflavin;   o) decreasing or preventing activation of phospho antigen specific T cells selected from MAIT cells and γδ T cells;   p) inhibiting angiogenesis;   q) increasing proliferation of stimulated CD4 +  and CD8 +  T cells;   r) increasing stimulated PBMC Secretion of INF-γ, TNF-α, IL-2 and/or IL-1β.   
     
     
         2 . The antigen binding protein of  claim 1 , wherein the antigen binding protein has 1, 2, 3, 4, 5, 6, or 7 of the following characteristics:
 a) is a monoclonal antibody;   b) is a human antibody, a humanized antibody, or a chimeric antibody;   c) is a bispecific antibody, a multi-specific antibody, a diabody, or a multivalent antibody;   d) is of the IgG1, IgG2, IgG3, IgG4, or IgM type;   e) is an antigen-binding antibody fragment;   f) is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, or an Fv fragment; and/or   g) is a single chain antibody, a single domain antibody, or a nanobody.   
     
     
         3 . A pharmaceutical composition comprising an effective amount of an antibody which binds to hCD39 and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of the following of characteristics:
 a) blocks or decreases hydrolysis of ATP to ADP and/or ADP to AMP as determined by at least one of: (i) a decreased phosphate release (Pi), (ii) an increase in ATP levels, and (iii) a decrease of ADP, AMP, and/or adenosine levels,   b) increases T effector cell activity;   c) suppresses regulatory T cell or decreases a regulatory T cell activity;   d) decreases number of regulatory T cells in tissues or in circulation;   e) increases B cell function;   f) increases antigen presenting cell function;   g) inhibits CD39 function on tumor cells;   h) blocks or inhibits processing of at least one of phospho-antigen from a phosphorylated isoprenoid, phosphorylated vitamin B metabolite, and phosphorylated riboflavin;   i) decreases or prevents activation of phospho antigen specific T cells selected from MAIT cells and γβ T cells;   k) inhibits angiogenesis;   l) decreases affinity for ATP and/or ADP;   m) inhibits release of ADP or AMP from CD39;   n) impedes or inhibits CD39 processivity;   o) inhibits platelet aggregation;   p) increases proliferation of stimulated CD4 +  and CD8 +  T cells;   r) increases stimulated PBMC Secretion of INF-γ, TNF-α, IL-2, and/or IL-1β.   
     
     
         4 . A pharmaceutical composition comprising the antigen-binding protein of  claim 1  or  claim 2 . 
     
     
         5 . The pharmaceutical composition of  claim 4 , further comprising an effective amount of at least one of the following
 a) an anti-PD-1 antibody,   b) an anti-PD-L1 antibody,   c) an anti-CD73 antibody,   d) an anti-CD38 antibody,   e) an anti-A2A receptor antibody,   f) an anti-A2B receptor antibody,   g) an anti-A2A/A2B dual receptor antibody, or any combination thereof,   or   h) a small molecule inhibitor,   
       or a combination thereof. 
     
     
         6 . The pharmaceutical composition of  claim 4  or  claim 5 , further comprising one or both of
 a) an antibody to an inhibitory receptor or ligand and/or 
 b) an antibody to a costimulatory receptor or ligand, 
 
       or a combination thereof. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein
 (i) the inhibitory receptor or ligand is at least one of CTLA-4, PD-L2, LAG-3, Tim3, neuritin, BTLA, CECAM-1, CECAM-5, VISTA, LAIR1, CD160, 2B4, TGF-R, HHLA2, ILT2, ILT3, ILT4, HLA-G, HLA-C, and/or a Killer-cell immunoglobulin-like receptor (KIR) and/or   (ii) the costimulatory receptor or ligand is at least one of OX40, CD2, CD27, CDS, ICAM-1, LFA-1, ICOS (CD278), 4-1BB (CD137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and/or CD83.   
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the costimulatory receptor or ligand LFA-1 further comprises an LFA-1 β-chain CD18 and/or an LFA-1 α-chain CD11a. 
     
     
         9 . The antigen binding protein of  claim 1 , wherein the antigen binding protein has one or more of the following characteristics:
 a) binds to a human CD39 polypeptide or a variant thereof with a KD of less than about 20 nM;   b) binds to a cyno CD39 polypeptide or a variant thereof with a KD of less than about 200 nM;   c) binds to a murine CD39 polypeptide or a variant thereof with a KD of less than about 200 nM; or   d) a combination of at least 2 of a), b), and c).   
     
     
         10 . An antigen binding protein that competes or is capable of competing for binding to human CD39 with a reference antigen binding protein, wherein the reference antigen binding protein is the antigen binding protein of  claim 1 . 
     
     
         11 . An antigen binding protein that binds to or is capable of competing for binding to human CD39 with a reference antigen binding protein, wherein the reference antigen binding protein binds to an epitope at positions 143-158 or 274-277 of SEQ ID NO: 249 on a human CD39 polypeptide, including, but not limited to, D150, E153, R154 or N99 alone or in combination with D150, E153, R154 or any combination thereof. 
     
     
         12 . The antigen binding protein of  claim 10  or  claim 11 , wherein the antigen binding protein and the reference antibody cross-compete or are capable of cross-competing for binding to a human CD39. 
     
     
         13 . The antigen binding protein of  claim 1 , comprising a human heavy chain constant region or fragment or a variant thereof, wherein the constant region variant comprises up to 20 conservatively modified amino acid substitutions from any sequence set forth SEQ ID NOs: 179-218. 
     
     
         14 . An isolated antibody molecule capable of binding to human CD39 (hCD39), comprising a heavy chain variable region (VH) and a light chain variable region (VL), VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of:
 a) a VHCDR1 having the sequence set forth in SEQ ID NOs: 1-45,   b) a VHCDR2 having the sequence set forth in SEQ ID NOs: 46-81,   c) a VHCDR3 having the sequence set forth in SEQ ID NOs: 82-109,   d) a VLCDR1 having the sequence set forth in SEQ ID NOs: 110-124,   e) a VLCDR2 having the sequence set forth in SEQ ID NOs: 125-140, and   f) a VLCDR3 having the sequence set forth in SEQ ID NOs: 141-166.   
     
     
         15 . An isolated antibody molecule capable of binding to human CD39 (hCD39), comprising a heavy chain variable region (VH) and a light chain variable region (VL),
 the VH comprising,   a) a VHCDR1 having a sequence set forth in SEQ ID NOs: 1-45,   b) a VHCDR2 having a sequence set forth in SEQ ID NOs: 46-81, and   c) a VHCDR3 having a sequence set forth in SEQ ID NOs: 82-109; and   the VL comprising,   a) a VLCDR1 having a sequence set forth in SEQ ID NO: 110-124,   b) a VLCDR2 having a sequence set forth in SEQ ID NO: 125-140, and   c) a VLCDR3 having a sequence set forth in SEQ ID NO: 141-166.   
     
     
         16 . An isolated nucleic acid encoding an antigen binding protein according to  claim 1 ,  claim 14 , or  claim 15 . 
     
     
         17 . An expression vector comprising the nucleic acid according to  claim 16 . 
     
     
         18 . A prokaryotic or eukaryotic host cell comprising the vector of  claim 17 . 
     
     
         19 . An oncolytic virus encoding the nucleic acid of either of  claim 16  or  17 . 
     
     
         20 . A method for the production of a recombinant protein comprising the steps of expressing a nucleic acid according to  claim 16  in a prokaryotic or eukaryotic host cell and recovering the protein from the cell or the cell culture supernatant. 
     
     
         21 . A method for treatment of a subject suffering from cancer, a chronic infection, or from an inflammatory disease, comprising the step of administering to the subject a pharmaceutical composition comprising an effective amount of the antigen binding protein of  claim 1  or the pharmaceutical composition of  claim 3 . 
     
     
         22 . The method of  claim 21 , wherein the cancer is a solid cancer. 
     
     
         23 . The method of  claim 21 , wherein the cancer is a hematological cancer. 
     
     
         24 . A method for modulating immune system function in a subject in need thereof, comprising the step of contacting a population of immune cells of the subject with a pharmaceutical composition comprising an effective amount of the antigen binding protein of  claim 1 , under conditions such that the immune system is modulated. 
     
     
         25 . A method for inducing or enhancing an immune response in a subject in need thereof, comprising the step of administering to the subject a pharmaceutical composition comprising an antigen binding protein, wherein the immune response is generated against a tumor antigen. 
     
     
         26 . The method of  claim 24  or  claim 25 , wherein the subject is a human subject. 
     
     
         27 . The method of  claim 25 , wherein the antigen binding protein comprises a bispecific antibody or a complexing antigen binding protein. 
     
     
         28 . The method of  claim 27 , wherein the antigen binding protein, the bispecific antibody, or the complexing antigen binding protein is administered in an amount sufficient to achieve 1, 2, 3, 4, 5, 6, or 7 of the following in the subject:
 a) reduction of CD39 ATPase activity in a target cell population;   b) reduction of regulatory T cells suppression of activity of effector T cells;   c) reduction of levels of regulatory T cells;   d) activation of effector T cells;   e) induction or enhancement of effector T cell proliferation;   f) inhibition of tumor growth; and/or   g) induction of tumor regression.   
     
     
         29 . The method of  claim 28 , wherein the target cell population comprises T cells, B cells, monocytes, macrophages, dendritic cells, myeloid-derived suppressor cells, and/or tumor cells. 
     
     
         30 . The method of  claim 25 , wherein the method further comprises one or more of the following
 a) administering chemotherapy;   b) administering radiation therapy; and/or   c) administering one or more additional therapeutic agents.   
     
     
         31 . The method of  claim 30 , wherein the one or more additional therapeutic agents comprise one or more immunostimulatory agents. 
     
     
         32 . The method of  claim 31 , wherein the one or more immunostimulatory agents comprise an antagonist to an inhibitory receptor of an immune cell. 
     
     
         33 . The method of  claim 32 , wherein the inhibitory receptor is at least one of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, Tim3, neuritin, BTLA, CECAM-1, CECAM-5, VISTA, LAIR1, CD160, 2B4, TGF-R, and/or a Killer-cell immunoglobulin-like receptor (KIR). 
     
     
         34 . The method of  claim 31 , wherein the one or more immunostimulatory agents comprise an agonist of a co-stimulatory receptor of an immune cell. 
     
     
         35 . The method of  claim 34 , wherein the co-stimulatory receptor is OX40, CD2, CD27, CDS, ICAM-1, LFA-1, ICOS (CD278), 4-1BB (CD137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or a CD83 ligand. 
     
     
         36 . The method of  claim 35 , wherein the costimulatory receptor or ligand LFA-1 further comprises an LFA-1 β-chains CD18 and/or an LFA-1 α-chain CD11a. 
     
     
         37 . The method of  claim 31 , wherein the one or more immunostimulatory agents comprise a cytokine. 
     
     
         38 . The method of  claim 37 , wherein the cytokine is at least one of IL-2, IL-5, IL-7, IL-12, IL-15, and/or IL-21. 
     
     
         39 . The method of  claim 31 , wherein the one or more immunostimulatory agents comprise an oncolytic virus. 
     
     
         40 . The method of  claim 39 , wherein the oncolytic virus is a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, or a maraba virus. 
     
     
         41 . The method of  claim 31 , wherein the one or more immunostimulatory agents comprise a chimeric antigen engineered T cell. 
     
     
         42 . The method of  claim 31 , wherein the one or more immunostimulatory agents comprise a bi- or multispecific T cell directed antibody. 
     
     
         43 . The method of  claim 25 , wherein the one or more additional therapeutic agents comprise at least one trap for an immune suppressive agent. 
     
     
         44 . The method of  claim 43 , wherein the at least one trap for an immune suppressive agent comprises at least one of an anti-TGF-beta antibody, a TGFb receptor trap, an anti-IL-10 antibody and/or anti-IL-10 receptor trap, and/or an anti-IL-35 antibody trap and/or an anti-IL-35 receptor trap. 
     
     
         45 . The method of any one of any of  claims 3 - 44 , wherein administration of the pharmaceutical composition results in induction or enhancement of proliferation of a T-effector cell, or modulation of I-kappaB and/or NF-κB in the T cell, or modulation of CD39 activity in the T cell, or T cell receptor induced signaling in a T-effector cell, or a combination thereof. 
     
     
         46 . A method of screening for a test compound comprising an antigen binding protein of  claim 1  capable of inhibiting an activity of CD39, comprising the steps of:
 contacting a test sample containing CD39 with a test compound; 
 comparing the activity of the test sample to a control sample; 
 whereby a decrease in the activity of CD39 in the test sample compared to the control sample identifies the compound as one that inhibits the activity of CD39. 
 
     
     
         47 . The method of  claim 46 , wherein the control sample comprises a sample not contacted with a test compound. 
     
     
         48 . An isolated antibody molecule capable of binding to human CD39 (hCD39), comprising a heavy chain variable region (VH) and a light chain variable region (VL),
 VH comprising at least one of:   a) a VHCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 1-45,   b) a VHCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 46-81, and   c) a VHCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 82-109; and   VL comprising at least one of:   a) a VLCDR1 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 110-124,   b) a VLCDR2 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs: 125-140, and   c) a VLCDR3 having an amino acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NOs 141-166.   
     
     
         49 . An isolated antibody molecule capable of binding to human CD39 (hCD39), comprising a heavy chain variable region (VH) and a light chain variable region (VL),
 VH comprising at least one of:   a) a VHCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOs: 1-45,   b) a VHCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOs: 46-81, and   c) a VHCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOs: 82-109; and   VL comprising at least one of:   a) a VLCDR1 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOs: 110-124,   b) a VLCDR2 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOs: 125-140, and   c) a VLCDR3 having an amino acid sequence that is homologous to the sequence set forth in SEQ ID NOs: 141-166.   
     
     
         50 . An isolated antibody molecule capable of binding to human CD39 (hCD39), comprising a heavy chain and a light chain, the heavy chain comprising one or more molecules having a sequence consisting of one of SEQ ID NO: 255, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 263, SEQ ID NO: 265, SEQ ID NO: 267, SEQ ID NO: 269, SEQ ID NO: 271, SEQ ID NO: 273, SEQ ID NO: 275, SEQ ID NO: 277, SEQ ID NO: 279, SEQ ID NO: 281, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295 and the light chain comprising one or more molecules having a sequence consisting of one of SEQ ID NO: 256, SEQ ID NO: 258, SEQ ID NO: 260, SEQ ID NO: 262, SEQ ID NO: 264, SEQ ID NO: 266, SEQ ID NO: 268, SEQ ID NO: 270, SEQ ID NO: 272, SEQ ID NO: 274, SEQ ID NO: 276, SEQ ID NO: 278, SEQ ID NO: 280, SEQ ID NO: 282, SEQ ID NO: 284, SEQ ID NO: 286, SEQ ID NO: 288, SEQ ID NO: 290, SEQ ID NO: 292, SEQ ID NO: 294, or SEQ ID NO: 296. 
     
     
         51 . An isolated antibody molecule capable of binding to human CD39 (hCD39), comprising a heavy chain and a light chain,
 a) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 255 and the light chain comprising one or more, each molecule having a sequence consisting of SEQ ID NO: 256;   b) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 257 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 258;   c) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 259 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 260;   d) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 261 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 262;   e) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 263 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 264;   f) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 265 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 266;   g) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 267 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 268;   h) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 269 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 270;   i) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 271 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 272;   j) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 273 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 274;   k) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 275 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 276;   l) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 277 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 278   m) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 279 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 280;   n) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 281 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 282;   o) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 283 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 284;   p) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 285 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 286;   q) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 287 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 288;   r) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 289 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 290;   s) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 291 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 292;   t) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 293 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 294; or   u) the heavy chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 295 and the light chain comprising one or more molecules, each molecule having a sequence consisting of SEQ ID NO: 296.   
     
     
         52 . An isolated nucleic acid encoding an antigen binding protein according to any one of  claims 48 - 51 . 
     
     
         53 . An isolated antibody molecule capable of binding to human CD39 (hCD39), comprising a heavy chain variable region (VH) and a light chain variable region (VL), VH and/or VL comprising 1, 2, 3, 4, 5, or 6 of:
 a) a VHCDR1 sequence comprising:
 (i) a Kabat CDRH1 sequence defined by the consensus sequence S-Y-Δ 3 -M-Δ 5  (SEQ ID NOS: 25-29 and 44-45), where Δ 3  is E, F, Q, or Y and Δ 5  is H or Y; 
 (ii) a Kabat CDR-H1 sequence defined by the consensus sequence θ 1 -θ 2 -θ 3 -I-S (SEQ ID NOS: 30-37), where θ 1  is A, H, K, L, S, or W; θ 2  is L, M, N, or T; and θ 3  is A or P; 
 (iii) a Kabat CDR-H1 sequence defined by the consensus sequence η 1 -Y-η 3 -I-S SEQ ID NOS: 38-41), where η 1  is S, K, N, or R and η 3  is A or G; 
 (iv) a Chothia CDR-H1 sequence defined by the consensus sequence G-Y-T-F-Ω 5 -S-Y (SEQ ID NOS: 1-2 and 4-6), where Ω 5  is T, K, Q, F, or V; 
 (v) a Chothia CDR-H1 sequence defined by the consensus sequence G-G-T-F-ν 5 -ν 6 -Y (SEQ ID NOS: 17-22 and 24), where ν 5  is S, G, or E and ν 6  is S, K, R, or S; or 
 (vi) a Chothia CDR-H1 consensus sequence defined by the consensus sequence G-G-T-F-κ 5 -κ 6 -κ 7  (SEQ ID NOS: 7-16), where κ 5  is S, Q, P, or A; κ 6  is S, K, H, L, A, or W; and κ 7  is Y, L, T, N, or M, 
   b) a VHCDR2 sequence comprising:
 (i) a Kabat CDR-H2 sequence defined by the consensus sequence ε 1 -I-N-P-ε 5 -ε 6 -G-S-T-ε 10 -Y-A-Q-K-F-Q-G (SEQ ID NOS: 63-66 and 68), where ε 1  is K, S, R, or V; as is L, R, or S; ε 6  is G or V; and ε 10  is S or W; 
 (ii) a Kabat CDR-H2 sequence defined by the consensus sequence G-I-α 3 -α 4 -α 5 -α 6 -G-T-A-N-Y-A-Q-K-F-Q-G (SEQ ID NOS: 69-72), where α 3  is I or L or is absent; α 4  is P or is absent; and as is I, G, or R; and α 6  is A, F, or G; 
 (iii) a Kabat CDR-H2 sequence defined by the consensus sequence β 1 -I-I-P-β 5 -β 6 -G-β 8 -A-N-Y-A-Q-K-F-G-Q (SEQ ID NOS: 74 and 76-79), where β 1  is S or G; β 5  is I, E, S, or T; β 6  is F, I, or S; and β 8  is I or T; 
 (iv) a Chothia CDR-H2 sequence defined by the consensus sequence N-P-ε 5 -ε 6 -G-S-T (SEQ ID NOS: 46-48), where ε 5  is L, R, or S and ε 6  is G or V; 
 (v) a Chothia CDR-H2 sequence defined by the consensus sequence α 3 -α 4 -α 5 -α 6 -G-T-A (SEQ ID NOS: 51-54), where α 3  is I or L or is absent; α 4  is P or is absent; and as is I, G, or R; and α 6  is A, F, or G; or 
 (vi) a Chothia CDR-H2 sequence defined by the consensus sequence I-P-β 5 -β 6 -G-β 8 -A (SEQ ID NOS: 56-60), where β 5  is I, E, S, or T; β 6  is F, I, or S; and β 8  is I or T, 
   c) a VHCDR3 sequence comprising:
 (i) a CDR-H3 sequence defined by the consensus sequence G-K-R-E-G-G-T-E-Y-L-R-γ 12  (SEQ ID NOS: 82-86), where γ 12  is H, K, S, N, or V; 
 (ii) a CDR-H3 sequence defined by the consensus sequence E-S-G-Φ 4 -Y-R-D-H-R-L-Φ 11 -V (SEQ ID NOS: 94-96), where Φ 4  is G or T and Φ 11  is D or G; or 
 (iii) a CDR-H3 sequence defined by the consensus sequence G-G-A-K-Y-A-   7 -   8 -   9 -G-M-D-V (SEQ ID NOS: 87-93), where    7  is S, V, G, or R;    8  is T, Q, K, G, or R; and    9  is Y, H, L, or W, 
   d) a VLCDR1 sequence comprising:
 (i) a CDR-L1 sequence defined by the consensus sequence ϕ 1 -A-S-ϕ 4 -ϕ 5 -V-ϕ 7 -ϕ 8 -ϕ 9 -Y-L-A (SEQ ID NOS: 1101-114), where ϕ 1  is E, K, or R; ϕ 4  is Q or E; ϕ 5  is S or Y; ϕ 7  is S or A; ϕ 8  is S or Y; and ϕ 9  is D or S; 
 (ii) a CDR-L1 sequence defined by the consensus sequence ∂ 1 -A-S-Q-∂ 5 -∂ 6 -∂ 7 -∂ 8 -∂ 9 -L-∂ 11  (SEQ ID NOS: 118 and 120-123), where ∂ 1  is Q or R1; ∂ 5  is D or S; ∂ 6  is I or V; ∂ 7  is G or S; ∂ 8  is N, R, or S; ∂ 9  is N, Y, or W; and ∂ 11  is A or N; or 
 (iii) a CDR-L1 sequence defined by the consensus sequence K-S-S-Γ 4 -S-V-L-Γ 8 -S-Γ 10 -N-N-K-N-Y-L-A (SEQ ID NOS: 115-117), where Γ 4  is Q, R or K; Γ 8  is F or Y; and Γ 10  is S or N, 
   e) a VLCDR2 sequence comprising:
 (i) a CDR-L2 sequence defined by the consensus sequence ψ 1 -A-S-ψ 4 -R-ψ 6 -ψ 7  (SEQ ID NOS: 125-136), where ψ 1  is G or Y, ψ 4  is S or N; ψ 6  is A or H; and ψ 7  is T, Y, or N; 
 (ii) a CDR-L2 sequence defined by the consensus sequence D-A-S-χ 4 -R-A-T (SEQ ID NOS: 138 and 139), where £ 4  is N or K; or 
 (iii) a CDR-L2 sequence defined by the consensus sequence W-A-S-T-R-σ 6 -S (SEQ ID NOS: 131 and 133-134), where σ 6  is A, E, or Q, and 
   f) a VLCDR3 sequence comprising:
 (i) a CDR-L3 sequence defined by the consensus sequence Q-Q-Y-π 4 -π 5 -π 6 -π 7 -T (SEQ ID NOS: 141-147), where π 4  is G, H, or Y; π 5  is S, N, F, G, or R; π 6  is S, Y, A, G, or R; and its is P, I, or L; 
 (ii) a CDR-L3 sequence defined by consensus sequence Q-Q-λ 3 -λ 4 -λ 5 -λ 6 -P-T (SEQ ID NOS: 148-150), where λ 3  is R, F, H, S, L, D, Y, or V; λ 4  is S, V, T, G, L, Y, or N; λ 5  is N, L, F, K, or V; and λ 6  is W, F, Y, or L; 
 (iii) a CDR-L3 sequence defined by the consensus sequence Q-Q-Y-ρ 3 -ρ 4 -W-P-L-T (SEQ ID NOS: 151 and 152), where ρ 3  is N or L and ρ 4  is N or L; or 
 (iv) a CDR-L3 sequence defined by the consensus sequence Q-Q-ω 3 -ω 4 -ω 5 -ω 6 -P-ω 5 -T (SEQ ID NOS: 153-156), where ω 3  is Y or F; ω 4  is Y or W; ω 5  is S, L, T, or F; ω 6  is T, Y, or F; and ω 8  is L or P.