Methods of treating a kit-associated cancer by administering anti-kit antibodies

Patent metadata

Field	Value
Publication number	US-10184007-B2
Application number	US-201715433482-A
Country	US
Kind code	B2
Filing date	Feb 15, 2017
Priority date	Jul 25, 2012
Publication date	Jan 22, 2019
Grant date	Jan 22, 2019

Abstract

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.

First claim

What is claimed:

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

Assignees

• Celldex Therapeutics Inc

Inventors

• Hadari Yaron
• Mandel-Bausch Elizabeth M
• Carr Francis Joseph
• Jones Timothy David
• Perry Laura Clare Alexandra

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/04

  for non-specific disorders of the connective tissue · CPC title