Anti-CDH6 antibody drug conjugates

Patent metadata

Field	Value
Publication number	US-9982045-B2
Application number	US-201514820897-A
Country	US
Kind code	B2
Filing date	Aug 7, 2015
Priority date	Aug 12, 2014
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention relates to anti-CDH6 antibodies, antibody fragments, antibody drug conjugates, and their uses for the treatment of cancer.

First claim

What is claimed is:

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 comprising: a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:224, (b) a LCDR2 of SEQ ID NO:225, (c) a LCDR3 of SEQ ID NO:226; and a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO: 227, (e) a HCDR2 of SEQ ID NO: 228, and (f) a HCDR3 of SEQ ID NO:229 that specifically binds to an epitope of human CDH6;
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: a heavy chain variable region (vH) that comprises SEQ ID NO: 230, and a light chain variable region (vL) that comprises SEQ ID NO:231.

4. The antibody drug conjugate of claim 1 , wherein said antibody or antigen binding fragment thereof comprises: a heavy chain that comprises SEQ ID NO: 234, and a light chain that comprises SEQ ID NO:235.

5. The antibody drug conjugate of claim 3 , that retains at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identity over either the variable light or variable heavy region.

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 derived from a cross-linking reagent selected from the group consisting of: N-succinimidyl-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (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 derived from N-succinimidyl-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB).

9. The antibody drug conjugate of claim 1 , wherein said drug moiety (D) is selected from a group consisting of: a maytansinoid, 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 MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1, 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-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) or N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1).

12. The antibody drug conjugate of claim 1 in combination with another therapeutic agent.

13. The antibody drug conjugate of claim 1 in combination with a therapeutic agent listed in Table 18.

14. The antibody drug conjugate of claim 13 in combination with a BCL2 inhibitor, a BCL-XL inhibitor, a BCL2/BCL-XL inhibitor, an IAP inhibitor or a MEK inhibitor.

15. The antibody drug conjugate of claim 1 in combination with an immune modulatory molecule.

16. An antibody drug conjugate of the formula:

or a pharmaceutically acceptable salt thereof; wherein;
Ab is an antibody or antigen binding fragment comprising a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:224, (b) a LCDR2 of SEQ ID NO:225, (c) a LCDR3 of SEQ ID NO:226; and a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO: 227, (e) a HCDR2 of SEQ ID NO: 228, and (f) a HCDR3 of SEQ ID NO:229 thereof that specifically binds to human CDH6, and n is an integer from 1 to 10.

17. The antibody drug conjugate of claim 16 in combination with a BCL2 inhibitor, a BCL-XL inhibitor, a BCL2/BCL-XL inhibitor, an IAP inhibitor or a MEK inhibitor.

18. The antibody drug conjugate of claim 16 in combination with an immune modulatory molecule.

19. A pharmaceutical composition comprising the antibody drug conjugate of claim 1 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 wherein said composition is prepared as a lyophilisate.

Assignees

• Bialucha Carl Uli
• Collins Scott
• Duerr Clemens
• Hu Tiancen
• Janatpour Mary Jo
• Meyer Matthew John
• Novartis Ag

Inventors

• Bialucha Carl Uli
• Collins Scott
• Dürr Clemens
• Hu Tiancen
• Janatpour Mary Jo
• Meyer Matthew John

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• A61K47/6861

  the tumour determinant being from kidney or bladder cancer cell · CPC title