Methods of treating a kit-associated cancer by administering anti-kit antibodies
Provided herein, in one aspect, are antibodies that immunospecifically bind to a human KIT antigen comprising the fourth and/or fifth extracellular Ig-like domains (that is, D4 and/or D5 domains), polynucleotides comprising nucleotide sequences encoding such antibodies, and expression vectors and host cells for producing such antibodies. The antibodies can inhibit KIT activity, such as ligand-induced receptor phosphorylation. Also provided herein are kits and pharmaceutical compositions comprising antibodies that specifically bind to a KIT antigen, as well as methods of treating or managing a KIT-associated disorder or disease and methods of diagnosing a KIT-associated disorder or disease using the antibodies described herein.
1. A method for treating or managing a KIT-associated-cancer that is accompanied by gain-of-function KIT activity, increase in KIT activity, or overexpression of KIT, comprising administering to a subject in need thereof a therapeutically effective amount of and isolated antibody, or an antigen-binding fragment thereof, which immunospecifically binds to hum KIT and comprises:
(i) a light chain variable region (“VL”) comprising the amino acid sequence:
DIVMTQSPSX K1 LSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKX K2 LIYSASYRYSGVPDRFX K3 GSGSGTDFTLTISSLQX K4 EDFAX K5 YX K6 CQQY NSYPRTFGGGTKVEIK (SEQ. ID NO.: 12), wherein X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, X K2 is an amino acid with an aliphatic hydroxyl side chain, X K4 is an amino acid with an aliphatic hydroxyl side chain or is P, X K5 is an amino acid with a charged or acidic side chain, and X K6 is an amino acid with an aromatic side chain; and
(ii) a heavy chain variable region (“VH”) comprising the amino acid sequence:
QVQLVQSGAEX H1 KKPGASVKX H2 SCKASGYTFTDYYINWVX H3 QAPGKG LEWIARIYPGSGNTYYNEKFKGRX H4 TX H5 TAX H6 KSTSTAYMX H7 LSSLRSE DX H8 AVYFCARGVYYFDYWGQGTTVTVSS (SEQ. ID NO.: 11), wherein X H1 is an amino acid with an aliphatic side chain, X H2 is an amino acid with an aliphatic side chain, X H3 is an amino acid with a polar or basic side chain, X H4 is an amino acid with an aliphatic side chain, X H5 is an amino acid with aliphatic side chain, X H6 is an amino acid with an acidic side chain, X H7 is an amino acid with an acidic or amide derivative side chain, and X H8 is an amino acid with and aliphatic hydroxyl side chain.
2. The method of claim 1 , wherein the KIT-associated cancer is refractory to treatment by a tyrosine kinase inhibitor.
3. The method of claim 1 , wherein the method further comprises administering a second therapeutic agent.
4. The method of claim 3 , wherein the second therapeutic agent is a chemotherapeutic agent, tyrosine kinase inhibitor, a histone deacetylase inhibitor, an antibody, or a cytokine.
5. The method of claim 4 , wherein the tyrosine kinase inhibitor is imatinib mesylate or SU11248.
6. A method for inhibiting KIT activity by at least about 10% in a cell expressing KIT comprising contacting the cell with an effective amount of an isolated antibody, or an antigen-binding fragment thereof, which immunospecifically binds to human KIT and comprises:
(i) a VL comprising the amino acid sequence:
DIVMTQSPSX K1 LSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKX K2 LIYSASYRYSGVPDRFX K3 GSGSGTDFTLTISSLQX K4 EDFAX K5 CQQY NSYPRTFGGGTKVEIK (SEQ. ID NO.: 12), wherein X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, X K2 is an amino acid with an aliphatic or aliphatic hydroxyl side chain, X K3 is an amino acid with an aliphatic hydroxyl side chain, X K4 is an amino acid with an aliphatic hydroxyl side chain or is P, X K5 is an amino acid with a charged or acidic side chain, and X K6 is an amino acid with an aromatic side chain; and
(ii) a VH comprising the amino acid sequence:
QVQLVQSGAEX H1 KKPGASVKX H2 SCKASGYTFTDYYINWVX H3 QAPGKG LEWIARIYPGSGNTYYNEKFKGRX H4 TX h5 TAX H6 KSTSTAYMX H7 LSSLRSE DX H8 AVYFCARGVYYFDYWGQGTTVTVSS (SEQ. ID NO.: 11), wherein X H1 is an amino acid with an aliphatic side chain, X H2 is an amino acid with an aliphatic side chain, X H3 is an amino acid with a polar or basic side chain, X H4 is an amino acid with an aliphatic side chain, X H5 is an amino acid with an aliphatic side chain, X H6 is an amino acid with an acidic side chain, X H7 is an amino acid with an acidic or amide derivative side chain, and X H8 is an amino acid with an aliphatic hydroxyl side chain.
7. The method of claim 1 , wherein X K1 is the amino acid F or S, X K2 is the amino acid A or S, X K3 is the amino acid T or S, X K4 is the amino acid S or P, X K5 is the amino acid D or T, X K6 is the amino acid F or Y.
8. The method of claim 1 , wherein X H1 is the amino acid L or V, X H2 is the amino acid L or V, X H3 is the amino acid K or R, X H4 is the amino acid V or A, X H5 is the amino acid L or I, X H6 is the amino acid E or D, X H7 is the amino acid Q or E, and X H8 is the amino acid S or T.
9. The method of claim 1 , wherein the antibody is a human IgG1 or IgG4 antibody.
10. The method claim 1 , wherein the antibody is a monoclonal antibody.
11. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is an antigen-binding fragment of a Fab fragment.
12. The method of claim 1 , wherein the antibody is a bispecific antibody.
13. The method of claim 1 , wherein the antibody is fused to a heterologous polypeptide.
14. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is a conjugate linked to an agent.
15. The method of claim 6 , wherein X K1 is the amino acid F or S, X K2 is the amino acid A or S, X K3 is the amino acid T or S, X K4 is the amino acid S or P, X K5 is the amino acid D or T, X K6 is the amino acid F or Y.
16. The method of claim 6 , wherein X H1 is the amino acid L or V, X H2 is the amino acid L or V, X H3 is the amino acid K or R, X H4 is the amino acid V or A, X H5 is the amino acid L or I, X H6 is the amino acid E or D, X H7 is the amino acid Q or E, and X H8 is the amino acid S or T.
17. A method or treating or managing a KIT-associated-cancer that is accompanied by gain-of-function KIT activity, increase in KIT activity, or overexpression of KIT, comprising administering to a subject in need thereof a therapeutically effective amount of an isolated antibody, or an antigen-binding fragment thereof, which immunospecifically binds to human KIT and comprises a VL and VH, wherein:
(i) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(ii) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(iii) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6;
(iv) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(v) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(vi) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(vii) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(viii) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6;
(ix) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(x) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(xi) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 5;
(xii) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(xiii) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(xiv) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(xv) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 5;
(xvi) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6;
(xvii) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(xviii) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(xix) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 5;
(xx) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6.
18. A method for inhibiting KIT activity by at least about 10% in a cell expressing KIT comprising contacting the cell with an effective amount of an isolated antibody, or an antigen-binding fragment thereof, which immunspecifically binds to human KIT and comprises a VL and a VH, wherein:
(i) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(ii) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(iii) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6;
(iv) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 5;
(v) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(vi) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(vii) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(viii) the VL comprises the amino acid sequence of SEQ. ID NO.: 7 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6;
(ix) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(x) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(xi) the VL comprises the amino acid sequence of SEQ. ID NO.: 8 and the VH comprises the amino acid sequence of SEQ. ID NO.: 5;
(xii) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(xiii) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 3;
(xiv) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(xv) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 5;
(xvi) the VL comprises the amino acid sequence of SEQ. ID NO.: 9 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6;
(xvii) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 2;
(xviii) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 4;
(xix) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 5;
(xx) the VL comprises the amino acid sequence of SEQ. ID NO.: 10 and the VH comprises the amino acid sequence of SEQ. ID NO.: 6.
19. A method for treating or managing a KIT-associated-cancer that is accompanied by gain-of-function KIT activity, increase in KIT activity, or overexpression of KIT, comprising administering to a subject in need thereof a therapeutically effective amount of an isolated antibody, or an antigen-binding fragment thereof, which immunospecifically binds to human KIT, wherein said antibody or antigen-binding fragment thereof comprises:
(i) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 2;
(ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 3;
(iii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 4;
(iv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 5;
(v) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 6;
(vi) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 2;
(vii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 3;
(viii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 4;
(ix) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 5;
(x) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 6;
(xi) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 2;
(xii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 3;
(xiii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 4;
(xiv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 5;
(xv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 6;
(xvi) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xvii) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xviii) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xix) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xx) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxi) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxii) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxiii) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxiv) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 62, and 63, respectively;
(xxv) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 62, and 63, respectively;
(xxvi) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 62, and 63, respectively;
(xxvii) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 62, and 63, respectively;
(xxviii) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxix) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxx) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxxi) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxii) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 70, 71, and 72, respectively;
(xxiii) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 70, 71, and 72, respectively; or
(xxxiv) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 70, 71, and 72, respectively.
20. A method for inhibiting KIT activity by at least about 10% in a cell expressing KIT comprising contacting the cell with an effective amount of an isolated antibody, or an antigen-binding fragment thereof, which immunospecifically binds to human KIT, wheren said antibody or antigen-binding fragment thereof comprises:
(i) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 2;
(ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 3;
(iii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 4;
(iv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 5;
(v) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 19, 20, and 21, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 6;
(vi) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 2;
(vii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 3;
(viii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 4;
(ix) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 5;
(x) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 59, 60, and 61, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 6;
(xi) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 2;
(xii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 3;
(xiii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 4;
(xiv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 5;
(xv) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequence of SEQ. ID NOs.: 66, 67, and 68, respectively; and a VH comprising the amino acid sequence of SEQ. ID NO.: 6;
(xvi) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xvii) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xviii) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xix) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 16, 17, and 18, respectively;
(xx) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxi) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxii) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxiii) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 57, and 58, respectively;
(xxiv) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid
(xxv) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 62, and 63, respectively;
(xxvi) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 62, and 63, respectively;
(xxvii) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 56, 62, and 63, respectively;
(xxviii) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxix) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxx) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxxi) a VL comprising the amino acid sequence of SEQ. ID NO.: 10, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 64, 65, and 58, respectively;
(xxxii) a VL comprising the amino acid sequence of SEQ. ID NO.: 7, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 70, 71, and 72, respectively;
(xxxiii) a VL comprising the amino acid sequence of SEQ. ID NO.: 8, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 70, 71, and 72, respectively; or
(xxxiv) a VL comprising the amino acid sequence of SEQ. ID NO.: 9, and a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ. ID NOs.: 70, 71, and 72, respectively.