1-(Chloromethyl)-2,3-dihydro-1H-benzo[e]indole dimer antibody-drug conjugate compounds, and methods of use and treatment

• US 10,544,215 B2
• Filed: 06/14/2016
• Issued: 01/28/2020
• Est. Priority Date: 12/16/2013
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Flygare, John A., Pillow, Thomas H., Safina, Brian, Verma, Vishal, Wei, BinQing, Denny, William, Giddens, Anna, Lee, Ho, Lu, Guo-Liang, Miller, Christian, Rewcastle, Gordon, Tercel, Moana, Bonnet, Muriel
• Primary Examiner(s): Halvorson, Mark
• Assistant Examiner(s): Akhoon, Kauser M
• Application Number:
  US15/182,444
• Publication Number:
  US 20160354485A1
• Time in Patent Office: 1,323 Days
• Field of Search: None
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6869 the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 209/60 Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL

Abstract

The invention provides antibody-drug conjugates comprising an antibody conjugated to a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) dimer drug moiety via a linker, and methods of using the antibody-drug conjugates.

Claims

1. An antibody-drug conjugate compound having the formula:

Ab-(L-D)_p

wherein;

Ab is an anti-Napi2b antibody;

L is a linker having the formula;

-Str-(Pep)_m-(Sp)_n-

where Str is a stretcher unit covalently attached to the anti-Napi2b antibody;

Pep is an optional peptide unit of two to twelve amino acid residues, Sp is an optional spacer unit covalently attached to a dimer drug moiety, and m and n are independently selected from 0 and 1;

p is an integer from 1 to 8;

D is the dimer drug moiety having the formula;

2. The antibody-drug conjugate compound of claim 1 wherein Str has the formula:

3. The antibody-drug conjugate compound of claim 2 wherein R⁶ is (CH₂)₅.

4. The antibody-drug conjugate compound of claim 1 wherein m is 0 and n is 0.

5. The antibody-drug conjugate compound of claim 1 wherein m is 0 and n is 1.

6. The antibody-drug conjugate compound of claim 1 wherein Str has the formula:

7. The antibody-drug conjugate compound of claim 1 wherein Str has the formula:

8. The antibody-drug conjugate compound of claim 7 wherein L forms a disulfide bond with a cysteine amino acid of the antibody, and R⁹ is C₂-C₆ alkylene-O where alkylene is optionally substituted with F, OH, O(C₁-C₆ alkyl), NH₂, NHCH₃, N(CH₃)₂, OP(O)₃H₂, and C₁-C₆ alkyl, where alkyl is optionally substituted with one or more F.

9. The antibody-drug conjugate compound of claim 1 wherein m is 1 and n is 1.

10. The antibody-drug conjugate compound of claim 1 wherein m is 1 and Pep comprises two to twelve amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline.

11. The antibody-drug conjugate compound of claim 10 wherein Pep is valine-citrulline.

12. The antibody-drug conjugate compound of claim 1 wherein n is 1 and Sp comprises para-aminobenzyl or para-aminobenzyloxycarbonyl.

13. The antibody-drug conjugate compound of claim 9 having the formula:

14. The antibody-drug conjugate compound of claim 13 wherein the amino acid side chain is independently selected from H, —

CH₃, —

CH₂(C₆H₅), —

CH₂CH₂CH₂CH₂NH₂, —

CH₂CH₂CH₂NHC(NH)NH₂, —

CHCH(CH₃)CH₃, and —

CH₂CH₂CH₂NHC(O)NH₂.

15. The antibody-drug conjugate compound of claim 13 having the formula:

16. The antibody-drug conjugate compound of claim 13 having the formula:

17. The antibody-drug conjugate compound of claim 15 having the formula:

18. The antibody-drug conjugate compound of claim 16 having the formula:

19. The antibody-drug conjugate compound of claim 18 having the formula:

20. The antibody-drug conjugate compound of claim 16 having the formula:

21. The antibody-drug conjugate compound of claim 20 having the formula:

22. The antibody-drug conjugate compound of claim 16 having the formula:

23. The antibody-drug conjugate compound of claim 1 where R^a and R^b form a five or six membered heterocyclyl group selected from N-methylpiperazinyl, morpholinyl, piperidyl, and pyrrolidinyl.

24. The antibody-drug conjugate compound of claim 1 where T is C₃-C₅ alkylene.

25. The antibody-drug conjugate compound of claim 24 where T is selected from (CH₂)₃, (CH₂)₄ and (CH₂)₅.

26. The antibody-drug conjugate compound of claim 1 where T is (C₁-C₆ alkylene)-Y-(C₁-C₆ alkylene), where Y is phenyl substituted with a bond to L.

27. The antibody-drug conjugate compound of claim 1 where T is (C₂-C₆ alkenylene)-Y-(C₂-C₆ alkenylene), where Y is phenyl substituted with a bond to L.

28. The antibody-drug conjugate compound of claim 1 where Y is selected from phenyl, pyridyl, 1-methyl-1H-benzo[d]imidazole, and [1,2,4]triazolo[1,5-a]pyridine.

29. A pharmaceutical composition comprising the antibody-drug conjugate compound of claim 1, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.