cKIT antibody drug conjugates
The present invention relates to anti-cKIT antibodies, antibody fragments, antibody drug conjugates, and their uses for the treatment of cancer.
1. An antibody drug conjugate of the formula
Ab-(L-(D) m ) n
or a pharmaceutically acceptable salt thereof; wherein
Ab is an antibody or antigen binding fragment thereof that specifically binds to an epitope of human cKIT at SEQ ID NO. 161 and SEQ ID NO. 162;
L is a linker;
D is a drug moiety;
m is an integer from 1 to 8; and
n is an integer from 1 to 10.
2. The antibody drug conjugate of claim 1 , wherein said n is 3 or 4.
3. The antibody drug conjugate of claim 1 , wherein said antibody or antigen binding fragment thereof comprises:
(i) a heavy chain variable region that comprises (a) a HCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO: 76, (b) a HCDR2 of SEQ ID NO: 77, (c) a HCDR3 of SEQ ID NO: 78; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 85, (e) a LCDR2 of SEQ ID NO: 86, and (f) a LCDR3 of SEQ ID NO: 87;
(ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 22, (b) a HCDR2 of SEQ ID NO: 23, (c) a HCDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 31, (e) a LCDR2 of SEQ ID NO: 32, and (f) a LCDR3 of SEQ ID NO: 33;
(iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 130, (b) a HCDR2 of SEQ ID NO: 131, (c) a HCDR3 of SEQ ID NO: 132; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 139, (e) a LCDR2 of SEQ ID NO: 140, and (f) a LCDR3 of SEQ ID NO: 141;
(iv) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 58, (b) a HCDR2 of SEQ ID NO: 59, (c) a HCDR3 of SEQ ID NO: 60; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 67, (e) a LCDR2 of SEQ ID NO: 68, and (f) a LCDR3 of SEQ ID NO: 69;
(v) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 40, (b) a HCDR2 of SEQ ID NO: 41, (c) a HCDR3 of SEQ ID NO: 42; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 49, (e) a LCDR2 of SEQ ID NO: 50, and (f) a LCDR3 of SEQ ID NO: 51;
(vi) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 94, (b) a HCDR2 of SEQ ID NO: 95, (c) a HCDR3 of SEQ ID NO: 96; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 103, (d) a LCDR2 of SEQ ID NO: 104, and (f) a LCDR3 of SEQ ID NO: 105;
(vii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 112, (b) a HCDR2 of SEQ ID NO: 113, (c) a HCDR3 of SEQ ID NO: 114; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 121, (e) a LCDR2 of SEQ ID NO: 122, and (f) a LCDR3 of SEQ ID NO: 123; or
(viii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 3, (b) a HCDR2 of SEQ ID NO: 4, (c) a HCDR3 of SEQ ID NO: 5; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 12, (e) a LCDR2 of SEQ ID NO: 13, and (f) a LCDR3 of SEQ ID NO: 14.
4. The antibody drug conjugate of claim 3 , in which one or two amino acids within a CDR have been modified, deleted or substituted.
5. The antibody drug conjugate of claim 1 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, a single chain antibody(scFv) or a Fab antibody fragment.
6. The antibody drug conjugate of claim 1 , wherein said linker (L) is selected from the group consisting of a cleavable linker, a non-cleavable linker, a hydrophilic linker, a procharged linker and a dicarboxylic acid based linker.
7. The antibody drug conjugate of claim 6 , wherein the linker is a cross-linking reagent selected from the group consisting of N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl(4-iodoacetyl)aminobenzoate (SIAB), maleimide PEG NHS, N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC), N-sulfosuccinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (sulfo-SMCC) or 2,5-dioxopyrrolidin-1-yl 17-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-1-oate (CX1-1).
8. The antibody drug conjugate of claim 7 , wherein said linker is the cross-linking reagent N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC).
9. The antibody drug conjugate of claim 1 , wherein said drug moiety (D) is selected from the group consisting of a V-ATPase inhibitor, a pro-apoptotic agent, a Bcl2 inhibitor, an MCL1 inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a maytansinoid, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins, a DPPIV inhibitor, proteasome inhibitors, inhibitors of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a kinesin inhibitor, an HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder and a DHFR inhibitor.
10. The antibody drug conjugate of claim 9 , wherein the drug moiety is a maytansinoid.
11. The antibody drug conjugate of claim 10 , wherein the maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).
12. The antibody drug conjugate of claim 1 in combination with another therapeutic agent.
13. The antibody drug conjugate of claim 12 , wherein the therapeutic agent is selected from the group consisting of: Imatinib, Sunitinib, NVP-LCL161, NVP-BEZ235, NVP-BKM120, NVP-BYL719, NVP-CCG168, Everolimus, NVP-HSP990 and NVP-BVB808.
14. An antibody drug conjugate of the formula
or a pharmaceutically acceptable salt thereof; wherein;
Ab is an antibody or antigen binding fragment thereof that specifically binds to human cKIT at SEQ ID NO. 161 and SEQ ID NO. 162, and wherein n is an integer from 1 to 10.
15. The antibody drug conjugate of claim 14 , wherein said Ab is an antibody or antigen binding fragment thereof comprises:
(i) a heavy chain variable region that comprises (a) a HCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO: 76, (b) a HCDR2 of SEQ ID NO: 77, (c) a HCDR3 of SEQ ID NO: 78; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 85, (e) a LCDR2 of SEQ ID NO: 86, and (f) a LCDR3 of SEQ ID NO: 87;
(ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 22, (b) a HCDR2 of SEQ ID NO: 23, (c) a HCDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 31, (e) a LCDR2 of SEQ ID NO: 32, and (f) a LCDR3 of SEQ ID NO: 33;
(iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 130, (b) a HCDR2 of SEQ ID NO: 131, (c) a HCDR3 of SEQ ID NO: 132; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 139, (e) a LCDR2 of SEQ ID NO: 140, and (f) a LCDR3 of SEQ ID NO: 141;
(iv) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 58, (b) a HCDR2 of SEQ ID NO: 59, (c) a HCDR3 of SEQ ID NO: 60; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 67, (e) a LCDR2 of SEQ ID NO: 68, and (f) a LCDR3 of SEQ ID NO: 69;
(v) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 40, (b) a HCDR2 of SEQ ID NO: 41, (c) a HCDR3 of SEQ ID NO: 42; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 49, (e) a LCDR2 of SEQ ID NO: 50, and (f) a LCDR3 of SEQ ID NO: 51;
(vi) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 94, (b) a HCDR2 of SEQ ID NO: 95, (c) a HCDR3 of SEQ ID NO: 96; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 103, (d) a LCDR2 of SEQ ID NO: 104, and (f) a LCDR3 of SEQ ID NO: 105;
(vii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 112, (b) a HCDR2 of SEQ ID NO: 113, (c) a HCDR3 of SEQ ID NO: 114; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 121, (e) a LCDR2 of SEQ ID NO: 122, and (f) a LCDR3 of SEQ ID NO: 123; or
(viii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 3, (b) a HCDR2 of SEQ ID NO: 4, (c) a HCDR3 of SEQ ID NO: 5; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 12, (e) a LCDR2 of SEQ ID NO: 13, and (f) a LCDR3 of SEQ ID NO: 14.
16. The antibody drug conjugate of claim 14 in which one or two amino acids within a CDR have been modified, deleted or substituted.
17. The antibody drug conjugate of claim 14 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, a single chain antibody(scFv) or a Fab antibody fragment.
18. The antibody drug conjugate of claim 14 , wherein said n is an integer from 2 to 8.
19. The antibody drug conjugate of claim 14 , wherein said n is an integer from 3 to 4.
20. The antibody drug conjugate of claim 14 in combination with another therapeutic agent.
21. The antibody drug conjugate of claim 20 , wherein the therapeutic agent is selected from the group consisting of: Imatinib, Sunitinib, NVP-LCL161, NVP-BEZ235, NVP-BKM120, NVP-BYL719, NVP-CCG168, Everolimus, NVP-HSP990 and NVP-BVB808.
22. A pharmaceutical composition comprising the antibody drug conjugate of claim 14 and a pharmaceutically acceptable carrier.
23. The pharmaceutical composition of claim 22 wherein said composition is prepared as a lyophilisate.
24. The pharmaceutical composition of claim 23 , wherein said lyophilisate comprises the antibody drug conjugate of claim 14 , sodium succinate, and polysorbate 20.
25. A method of treating an cKIT positive cancer in a patient in need thereof, comprising administering to said patient the antibody drug conjugate of claim 14 .
26. The method of claim 25 , wherein said cancer is selected from the group consisting of gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), acute myeloid leukemia (AML), melanoma, mast cell leukemia (MCL), mastocytosis, neurofibromatosis, breast cancer, non-small cell lung cancer (NSCLC) and pancreatic cancer.
27. The method of claim 26 , wherein the antibody drug conjugate or the pharmaceutical composition is administered in combination with another therapeutic agent.
28. The method of claim 27 , wherein the antibody drug conjugate or the pharmaceutical composition is administered in combination with a therapeutic agent selected from the group consisting of: Imatinib, Sunitinib, NVP-LCL161, NVP-BEZ235, NVP-BKM120, NVP-BYL719, NVP-CCG168, Everolimus, NVP-HSP990 and NVP-BVB808.
29. A vector comprising a nucleic acid that encodes the antibody or antigen binding fragment of claim 1 .
30. An isolated host cell comprising the vector according to claim 29 .
31. A process for producing an antibody or antigen binding fragment comprising cultivating the host cell of claim 30 and recovering the antibody from the culture.