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

• US 10,442,836 B2
• Filed: 06/16/2014
• Issued: 10/15/2019
• Est. Priority Date: 08/12/2013
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Flygare, John, Pillow, Thomas, 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): Huynh, Phuong
• Application Number:
  US14/305,643
• Publication Number:
  US 20150165063A1
• Time in Patent Office: 1,947 Days
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/68035 the drug being a pyrrolobenzodiazepine
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 207/40 2,5-Pyrrolidine-diones
• CPC Class Codes: C07D 209/60 Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
• CPC Class Codes: C07D 209/62 Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/572 Five-membered rings
• 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: C07H 15/24 Condensed ring systems having three or more rings
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/3061 : Blood cells
• CPC Class Codes: C07K 16/3069 : Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• CPC Class Codes: C07K 5/06052 : Val-amino acid

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 antibody;

wherein the antibody is a cysteine engineered, anti-CD22 antibody, wherein a cysteine group at the A118C site (EU numbering) of the heavy chain, also numbered as 121 by Sequential numbering or 114 by Kabat numbering, of the cysteine engineered antibody is attached to the linker L, and that comprises three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) wherein;

HVR-L1 comprises the amino acid sequence of SEQ ID NO;

1;

HVR-L2 comprises the amino acid sequence of SEQ ID NO;

2;

HVR-L3 comprises the amino acid sequence of SEQ ID NO;

3;

HVR-H1 comprises the amino acid sequence of SEQ ID NO;

4;

HVR-H2 comprises the amino acid sequence of SEQ ID NO;

5; and

HVR-H3 comprises the amino acid sequence of SEQ ID NO;

6;

L is a linker having the formula;

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

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

wherein Str has a formula selected from the group consisting of;

2. The antibody-drug conjugate compound of claim 1 wherein R⁶ is (CH₂)₅.

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

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

5. The antibody-drug conjugate compound of claim 1 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.

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

7. The antibody-drug conjugate compound of claim 1 wherein Pep is valine-citrulline.

8. The antibody-drug conjugate compound of claim 6 having the formula:

9. The antibody-drug conjugate compound of claim 8 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.

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

11. The antibody-drug conjugate compound of claim 8 having the formula:

12. The antibody-drug conjugate compound of claim 11 having the formula:

13. The antibody-drug conjugate compound of claim 6 having the formula:

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

15. The antibody-drug conjugate compound of claim 6 having the formula:

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

17. The antibody-drug conjugate compound of claim 8 having the formula:

18. 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.

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

20. The antibody-drug conjugate compound of claim 19 where T is selected from (CH₂)₃, (CH₂)₄ and (CH₂)₅.

21. 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.

22. 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.

23. 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.

24. A pharmaceutical composition comprising the antibody-drug conjugate compound of claim 1, and a pharmaceutically acceptable excipient.

25. A kit for treating cancer, comprising:

a) the pharmaceutical composition of claim 24; and

b) instructions for use.

29. The conjugate according to claim 1, wherein p is 1, 2, 3 or 4.

30. The conjugate according claim 1, wherein p is 1 or 2.

34. The antibody-drug conjugate compound from claim 1 wherein the antibody-drug conjugate compound is prepared by conjugating the cysteine engineered, anti-CD22antibody with a linker-drug intermediate selected from the group consisting of:

26. A linker-drug intermediate having the formula:

X-L-D

wherein;

X is a reactive functional group selected from maleimide and pyridyl disulfide;

L is a linker having the formula;

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

where Str is a stretcher unit covalently attached to X;

Pep is an optional peptide unit of two to twelve amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline, Sp is an optional spacer unit covalently attached to a dimer drug moiety comprising para-aminobenzyl or para-aminobenzyloxycarbonyl, and m and n are independently selected from 0 and 1;

D is the dimer drug moiety having the formula;

27. The linker-drug intermediate of claim 26 wherein X is

28. A linker-drug intermediate selected from the group consisting of:

31. A linker-drug intermediate having the formula

32. An antibody-drug conjugate having the formula

33. A pharmaceutical composition comprising an antibody drug conjugate of claim 32 and a pharmaceutically acceptable excipient.