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 comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 76, (b) a VH CDR2 of SEQ ID NO: 77, (c) a VH CDR3 of SEQ ID NO: 78; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 85, (e) a VL CDR2 of SEQ ID NO: 86, and (f) a VL CDR3 of SEQ ID NO: 87 and specifically binds to an epitope of human cKIT at domains 1-3 (SEQ ID NO. 155);
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 linker 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.
4. The antibody drug conjugate of claim 3 , wherein the linker is derived from 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).
5. The antibody drug conjugate of claim 4 , wherein said linker is derived from the cross-linking reagent N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC).
6. The antibody drug conjugate of claim 5 , wherein the drug moiety is a maytansinoid.
7. The antibody drug conjugate of claim 6 , 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).
8. An antibody drug conjugate of the formula
or a pharmaceutically acceptable salt thereof; wherein
Ab is an antibody or antigen binding fragment thereof that comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 76, (b) a VH CDR2 of SEQ ID NO: 77, (c) a VH CDR3 of SEQ ID NO: 78; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 85, (e) a VL CDR2 of SEQ ID NO: 86, and (f) a VL CDR3 of SEQ ID NO: 87, specifically binds to human cKIT, and comprises at least n number of primary amines; and
n is an integer from 1 to 10.
9. The antibody drug conjugate of claim 8 , wherein said n is 3 or 4.
10. The antibody drug conjugate of claim 8 , wherein said antibody is a human or humanized antibody.
11. The antibody drug conjugate of claim 8 , wherein said antibody is a monoclonal antibody.
12. A pharmaceutical composition comprising the antibody drug conjugate of claim 1 and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition of claim 12 wherein said composition is prepared as a lyophilisate.
14. The pharmaceutical composition of claim 13 , wherein said lyophilisate comprises the antibody drug conjugate of claim 1 , sodium succinate, and polysorbate 20.
15. The antibody or antigen binding fragment of claim 1 , wherein said antibody or antigen binding fragment is a single chain antibody (scFv).