1-(CHLOROMETHYL)-2,3-DIHYDRO-1H-BENZO[E]INDOLE DIMER ANTIBODY-DRUG CONJUGATE COMPOUNDS, AND METHODS OF USE AND TREATMENT

• US 20150165063A1
• Filed: 06/16/2014
• Published: 06/18/2015
• 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, Denny, William, Lu, Guo-Liang, Tercel, Moana, Bonnet, Muriel, Pillow, Thomas, Safina, Brian, Verma, Vishal, Wei, Binqing, Giddens, Anna, Lee, Ho, Miller, Christian, Rewcastle, Gordon
• Granted Patent: US 10,442,836 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 47/6849 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;

L is a linker having the formula;

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

where Str is a stretcher unit covalently attached to the 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 14 having the formula:

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

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

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

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

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

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

22. The antibody-drug conjugate compound of claim 20 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. The antibody-drug conjugate compound of claim 1 where D′

is;

30. The antibody-drug conjugate compound of claim 1 where D′

is;

31. The antibody-drug conjugate compound of claim 1 where D′

is;

33. The antibody-drug conjugate compound of claim 1 wherein the antibody is an anti-CD22 antibody.

34. The antibody-drug conjugate compound of claim 33 wherein the anti-CD22 antibody 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.

35. The antibody-drug conjugate compound of claim 1 wherein the antibody is an anti-MUC 16 antibody.

36. The antibody-drug conjugate compound of claim 35 wherein the anti-MUC16 antibody 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;

7;

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

8;

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

9;

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

10;

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

11; and

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

12.

37. The antibody-drug conjugate compound of claim 35 wherein the anti-MUC 16 antibody is a cysteine-engineered antibody comprising one or more free cysteine amino acid residues located in a light chain sequence selected from SEQ ID NOs:

15-32, or in a heavy chain sequence selected from SEQ ID NOs;

33-46.

38. The antibody-drug conjugate compound of claim 1 wherein the antibody is an anti-HER2 antibody.

39. The antibody-drug conjugate compound of claim 1 wherein the anti-HER2 antibody is trastuzumab.

40. The antibody-drug conjugate compound of claim 1 wherein the antibody is an anti-CD33 antibody.

41. The antibody-drug conjugate compound of claim 40 wherein the anti-CD33 antibody 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;

51;

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

52;

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

53;

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

54;

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

55; and

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

56.

42. The antibody-drug conjugate compound of claim 40 wherein the anti-CD33 antibody comprises a light chain hypervariable region of SEQ ID NO:

57 or a heavy chain variable region of SEQ ID NO;

58.

43. The antibody-drug conjugate compound of claim 40 wherein the anti-CD33 antibody 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;

59;

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

60;

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

61;

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

62;

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

63; and

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

64.

44. The antibody-drug conjugate compound of claim 40 wherein the anti-CD33 antibody comprises a light chain hypervariable region selected from SEQ ID NO:

65, SEQ ID NO;

67, SEQ ID NO;

69, and SEQ ID NO;

71;

or a heavy chain variable region selected from of SEQ ID NO;

66, SEQ ID NO;

68, SEQ ID NO;

70, and SEQ ID NO;

72.

45. A pharmaceutical composition comprising the antibody-drug conjugate compound of any one of claims 1 to 44, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

46. A method of treating cancer comprising administering to a patient a therapeutically-effective amount of the pharmaceutical composition of claim 45.

47. A kit for treating cancer, comprising:

a) the pharmaceutical composition of claim 45; and

b) instructions for use.

54. The CBI dimer drug moiety compound of claim 41 selected from:

55. A conjugate according to any one of claims 1, wherein p is 1,2,3 or 4.

56. A conjugate according to any one of claims 1, wherein p is 1 or 2.

57. A conjugate of claim 1, which is

58. A conjugate of claim 1, which is

59. A conjugate of claim 1, which is

60. A conjugate of any one of claims 57, wherein Ab is an anti-HER2 antibody.

61. A conjugate of any one of claims 57, wherein Ab is an anti-CLL-1 antibody.

62. A conjugate of any one of claims 57, wherein Ab is an anti-CD22 antibody.

63. A conjugate of any one of claims 57, wherein Ab is an anti-CD79b antibody.

32. (canceled)

48. A linker-drug intermediate having the formula:

X-L-D

wherein;

X is a reactive functional group selected from maleimide, thiol, amino, bromide, bromoacetamido, iodoacetamido, p-toluenesulfonate, iodide, hydroxyl, carboxyl, pyridyl disulfide, and N-hydroxysuccinimide;

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, Sp is an optional spacer unit covalently attached to a dimer drug moiety, and m and n are independently selected from 0 and 1;

D is the dimer drug moiety having the formula;

49. The linker-drug intermediate of claim 48 wherein X is

50. The linker-drug intermediate of claim 48 selected from:

51-52. -52. (canceled)

53. A CBI dimer drug moiety compound having the formula: