Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease

• US 7,829,531 B2
• Filed: 03/20/2009
• Issued: 11/09/2010
• Est. Priority Date: 07/31/2002
• Status: Expired due to Term

• Current Assignee: Seagen Inc. (Pfizer Inc.)
• Original Assignee: Seattle Genetics Incorporated (Pfizer Inc.)
• Inventors: Doronina, Svetlana O., Senter, Peter D., Toki, Brian E.
• Primary Examiner(s): Bradley; Christina
• Application Number:
  US12/408,646
• Publication Number:
  US 20090324621A1
• Time in Patent Office: 599 Days
• Field of Search: None
• US Class Current: 424/178.1
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/642 the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6867 the tumour determinant being from a cell of a blood cancer
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof

Abstract

Drug-Linker-Ligand Conjugates are disclosed in which a Drug is linked to a Ligand via a peptide-based Linker unit. In one embodiment, the Ligand is an Antibody. Drug-Linker compounds and Drug compounds are also disclosed. Methods for treating cancer, an autoimmune disease or an infectious disease using the compounds and compositions of the invention are also disclosed.

Claims

1. A drug-linker-antibody conjugate of Formula Ia:

LA_a-W_w—

Y_y-D)_p 

 

Ia

or a pharmaceutically acceptable salt thereof,

wherein,

L- is an antibody that immunospecifically binds to a cancer cell antigen which is on the surface of a cancer cell;

-A_a-W_w—

Y_y—

is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein;

-A- is a Stretcher unit;

a is 1;

each —

W—

is independently an Amino Acid unit;

—

Y—

is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12,

y is 1 or 2;

p ranges from 1 to about 20; and

-D is a Drug unit of the formula

3. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein R¹⁰ is

5. The drug-linker-antibody conjugate of claim 3 or a pharmaceutically acceptable salt thereof wherein R² is —

C₁-C₈ alkyl.

7. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof where -D is a Drug unit having the structure

8. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein the antibody is a monoclonal antibody.

9. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein the antibody is a full length immunoglobulin molecule.

10. The drug-linker-antibody conjugate of claim 9 or a pharmaceutically acceptable salt thereof wherein the antibody is bound to the Stretcher unit via an interchain thiol of the antibody.

11. The drug-linker-antibody conjugate of claim 8 or a pharmaceutically acceptable salt thereof wherein the antibody is a chimeric antibody.

12. The drug-linker-antibody conjugate of claim 11 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.

13. The drug-linker-antibody conjugate of claim 12 or a pharmaceutically acceptable salt thereof wherein the antibody immunospecifically binds human CD30 antigen.

15. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof where —

W_w—

is represented by Formula VII;

16. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof where —

W_w—

is -valine-citrulline-, the amino terminus of —

W_w—

forming a bond with a Stretcher unit, and the C-terminus of —

W_w—

forming a bond with a Spacer unit.

17. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to about 5.

18. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to 10.

19. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein the linker unit is cleavable by cathepsin B.

21. The drug-linker-antibody conjugate of claim 1 having the formula below:

22. The drug-linker-antibody conjugate of claim 21 or a pharmaceutically acceptable salt thereof wherein the antibody is a monoclonal antibody.

23. The drug-linker-antibody conjugate of claim 21 or a pharmaceutically acceptable salt thereof wherein the antibody is a full length immunoglobulin molecule.

24. The drug-linker-antibody conjugate of claim 23 or a pharmaceutically acceptable salt thereof wherein the antibody is bound to the Stretcher unit via an interchain thiol of the antibody.

25. The drug-linker-antibody conjugate of claim 22 or a pharmaceutically acceptable salt thereof wherein the antibody is a chimeric antibody.

26. The drug-linker-antibody conjugate of claim 25 or a pharmaceutically acceptable salt thereof wherein the chimeric antibody comprises a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.

27. The drug-linker-antibody conjugate of claim 21 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to about 5.

28. The drug-linker-antibody conjugate of claim 21 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to 10.

29. The drug-linker-antibody conjugate of claim 1 having the formula below:

30. The drug-linker-antibody conjugate of claim 29 or a pharmaceutically acceptable salt thereof wherein the antibody is a monoclonal antibody.

31. The drug-linker-antibody conjugate of claim 30 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.

65. The drug-linker-antibody conjugate of claim 26 or a pharmaceutically acceptable salt thereof wherein the antibody immunospecifically binds human CD30 antigen.

66. The drug-linker-antibody conjugate of claim 22 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a human immunoglobulin constant region.

67. The drug-linker-antibody conjugate of claim 66 or a pharmaceutically acceptable salt thereof wherein the antibody is an IgG1.

68. The drug-linker-antibody conjugate of claim 30 or a pharmaceutically acceptable salt thereof wherein the antibody immunospecifically binds human CD30 antigen.

75. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein p ranges from about 7 to about 9.

76. The drug-linker-antibody conjugate of claim 21 or a pharmaceutically acceptable salt thereof wherein p ranges from about 7 to about 9.

77. The drug-linker-antibody conjugate of claim 29 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to 10.

2. A drug-linker-antibody conjugate of the formula Ia:

LA_a-W_w—

Y_y-D)_p 

 

Ia

or a pharmaceutically acceptable salt thereof,

wherein,

L- is an antibody that immunospecifically binds to a cancer cell antigen which is on the surface of a cancer cell;

-A_a-W_w—

Y_y—

is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein;

-A- is a Stretcher unit;

a is 1;

each —

W—

is independently an Amino Acid unit;

—

Y—

is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to about 20; and

-D is a Drug unit having the structure

4. The drug-linker-antibody conjugate of claim 2 or a pharmaceutically acceptable salt thereof wherein R¹⁰ is

6. The drug-linker-antibody conjugate of claim 4 or a pharmaceutically acceptable salt thereof wherein R² is methyl.

14. The drug-linker-antibody conjugate of claim 2 or a pharmaceutically acceptable salt thereof wherein the antibody is a monoclonal antibody.

20. The drug-linker-antibody conjugate of claim 2 or a pharmaceutically acceptable salt thereof wherein the linker unit is cleavable by cathepsin B.

59. The drug-linker-antibody conjugate of claim 14 or a pharmaceutically acceptable salt thereof wherein the antibody is a chimeric antibody.

60. The drug-linker-antibody conjugate of claim 14 or a pharmaceutically acceptable salt thereof wherein the antibody is a humanized antibody.

61. The drug-linker-antibody conjugate of claim 14 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a human immunoglobulin constant region.

62. The drug-linker-antibody conjugate of claim 61 or a pharmaceutically acceptable salt thereof wherein the antibody is an IgG1.

63. The drug-linker-antibody conjugate of claim 59 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.

64. The drug-linker-antibody conjugate of claim 63 or a pharmaceutically acceptable salt thereof wherein the antibody immunospecifically binds human CD30 antigen.

32. A composition comprising drug-linker-antibody conjugates having Formula Ia:

LA_a-W_w—

Y_y-D)_p 

 

Ia

or a pharmaceutically acceptable salt thereof;

wherein,

L- is an antibody that immunospecifically binds to a cancer cell antigen which is on the surface of a cancer cell;

-A_a-W_w—

Y_y—

is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein;

-A- is a Stretcher unit;

a is 1;

each —

W—

is independently an Amino Acid unit;

—

Y—

is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to 10 and is the average number of -A_a-W_w—

Y_y-D units per antibody in the composition; and

-D is a Drug unit of the formula

34. The composition of claim 32 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, R² is —

C₁-C₈ alkyl.

36. The composition of claim 32 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, -D is a Drug unit having the structure

37. The composition of claim 32 wherein the drug-linker-antibody conjugates have the formula

38. The composition of claim 37 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a monoclonal antibody.

39. The composition of claim 37 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a full length immunoglobulin molecule.

40. The composition of claim 37 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is bound to the Stretcher unit via an interchain thiol of the antibody.

41. The composition of claim 38 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a chimeric antibody.

42. The composition of claim 41 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the chimeric antibody comprises a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.

43. The composition of claim 37 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, p ranges from 1 to about 5.

44. The composition of claim 32 wherein the drug-linker-antibody conjugates have the formula

45. The composition of claim 44 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a monoclonal antibody.

46. The composition of claim 45 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody comprises a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.

69. The composition of claim 38 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a humanized antibody.

70. The composition of claim 38 wherein in the drug-linker-antibody conjugates or a pharmaceutically acceptable salt thereof, the antibody comprises a human immunoglobulin constant region.

71. The composition of claim 70 wherein in the drug-linker-antibody conjugates or a pharmaceutically acceptable salt thereof, the antibody is an IgG1.

72. The composition of claim 42 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody immunospecifically binds human CD30 antigen.

73. The composition of claim 45 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a humanized antibody.

74. The composition of claim 46 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody immunospecifically binds human CD30 antigen.

78. The composition of claim 37 wherein in the drug-linker antibody conjugates or pharmaceutically acceptable salt thereof, p ranges from about 7 to about 9.

79. The composition of claim 44 wherein in the drug-linker antibody conjugates or pharmaceutically acceptable salt thereof, p ranges from 1 to about 5.

33. A composition comprising drug-linker-antibody conjugates having Formula Ia:

LA_a-W_w—

Y_y-D)_p 

 

Ia

or a pharmaceutically acceptable salt thereof, wherein,

L- is an antibody that immunospecifically binds to a cancer cell antigen which is on the surface of a cancer cell;

-A_a-W_w—

Y_y—

is an enzymatically cleavable linker unit that links the Drug unit and the antibody , wherein;

-A- is a Stretcher unit;

a is 1;

each —

W—

is independently an Amino Acid unit;

—

Y—

is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to 10 and is the average number of -A_a-W_w—

Y_y-D units per antibody in the composition; and

-D is a Drug unit having the structure

35. The composition of claim 33 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, R² is methyl.

47. A method for the treatment of Hodgkin'"'"'s Disease or Anaplastic Large Cell Lymphoma in a human, the method comprising administering to the human an effective amount of a drug-linker-antibody conjugate wherein the drug-linker-antibody conjugate is taken up inside the cancer cell and, once inside the cancer cell, the linker unit is cleaved, resulting in release of drug;

the drug-linker-antibody conjugate having formula Ia;

LA_a-W_w—

Y_y-D)_p 

 

Ia

or a pharmaceutically acceptable salt thereof

wherein,

L- is an antibody that immunospecifically binds to human CD30 antigen;

-A_a-W_w—

Y_y—

is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein;

-A- is a Stretcher unit;

a is 1;

each —

W—

is independently an Amino Acid unit;

—

Y—

is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to about 20; and

-D is a Drug unit having the structure

48. The method of claim 47 wherein the method is for treating Hodgkin'"'"'s Disease.

49. The method of claim 47 wherein the drug-linker-antibody conjugate has the structure

50. The method of claim 49 wherein the antibody is a monoclonal antibody.

51. The method of claim 49 wherein the antibody is a chimeric antibody.

52. The method of claim 49 wherein the antibody is a humanized antibody.

53. A method for the treatment of Hodgkin'"'"'s Disease or Anaplastic Large Cell Lymphoma in a human, the method comprising administering to the human an effective amount of a composition comprising drug-linker-antibody conjugates and a pharmaceutically acceptable carrier wherein the drug-linker-antibody conjugates are taken up inside the cancer cell and, once inside the cancer cell, the linker units of the drug-linker-antibody conjugates are cleaved, resulting in release of drug;

the drug-linker-antibody conjugates having Formula Ia;

LA_a-W_w—

Y_y-D)_p 

 

Ia

or a pharmaceutically acceptable salt thereof;

wherein,

L- is an antibody that immunospecifically binds to human CD30 antigen;

-A_a-W_w—

Y_y—

is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein;

-A- is a Stretcher unit;

a is 1;

each —

W—

is independently an Amino Acid unit;

—

Y—

is a self-immolative Spacer unit;

w is an integer ranging from 2 to 12;

y is 1 or 2;

p ranges from 1 to 10 and is the average number of -A_a-W_w—

Y_y-D units per antibody in the composition; and

-D is a Drug unit of the formula

54. The method of claim 53 wherein the drug-linker-antibody conjugates have the structure

55. The method of claim 54 wherein the antibody is a monoclonal antibody.

56. The method of claim 55 wherein the antibody comprises a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.

57. The method of claim 54 wherein the antibody is a full length immunoglobulin molecule.

58. The method of claim 55 wherein the antibody is a humanized antibody.

80. The method of claim 53 wherein in the drug-linker antibody conjugates or pharmaceutically acceptable salt thereof, p ranges from 1 to about 5.

81. The method of claim 54 wherein in the drug-linker antibody conjugates or pharmaceutically acceptable salt thereof, p ranges from 1 to about 5.