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

• US 7,659,241 B2
• Filed: 07/31/2003
• Issued: 02/09/2010
• Est. Priority Date: 07/31/2002
• Status: Active Grant

• Current Assignee: Seagen Inc.
• Original Assignee: Seattle Genetics Incorporated
• Inventors: Doronina, Svetlana O., Senter, Peter D., Toki, Brian E.
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): Bradley; Christina
• Application Number:
  US10/522,911
• Publication Number:
  US 20060074008A1
• Time in Patent Office: 2,385 Days
• Field of Search: None
• US Class Current: 514/1.1
• 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

Compounds and compositions are disclosed in which a Drug unit (D) is linked to a Ligand unit (L). In an exemplary embodiment, the compound is of the formula
LAa-Ww-Yy-D)_p  Ia
or a pharmaceutically acceptable salt thereof, where A is a stretcher unit, W is an amino acid unit, Y is a spacer unit, D is of the formula

and a, w, y, p and R²-R¹⁰ are as disclosed in the specification. Methods for treating cancer, autoimmune disease, and infectious disease using the compounds and compositions of the invention are also disclosed.

Claims

1. A compound of the Formula Ia:

LAa-Ww-Yy-D)_p 

 

Ia;

or a pharmaceutically acceptable salt thereof,

wherein,

L—

is a Ligand unit;

—

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 compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

D is a Drug unit having the structure;

4. The compound or a pharmaceutically acceptable salt of the compound of claim 1 or claim 2 wherein the Ligand unit is an antibody.

5. The compound or a pharmaceutically acceptable salt of the compound of claim 4 wherein the antibody is a monoclonal antibody.

6. The compound or a pharmaceutically acceptable salt of the compound of claim 5 wherein the monoclonal antibody specifically binds the CD30 antigen, the CD20 antigen, the Lewis X or Y antigen, the CD33 antigen, the CD38 antigen, the CEA antigen, CD19 antigen, the CA15-3 antigen or the epidermal growth factor antigen.

7. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

Yy- is;

8. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

A—

is;

9. The compound or a pharmaceutically acceptable salt at the compound of claim 1 wherein —

A—

is;

10. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

A—

is;

11. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

A—

is;

12. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

A—

is;

13. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

A—

is;

14. The compound or a pharmaceutically acceptable salt of the compound of claim 8 wherein —

A—

is;

15. The compound or a pharmaceutically acceptable salt of the compound of claim 9 wherein —

A—

is;

16. The compound or a pharmaceutically acceptable salt of the compound of claim 11 wherein —

A—

is;

17. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

W_w—

is -Phenylalanine-Lysine-, the amino terminus of —

W_w—

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

W_w—

forming a bond with the Spacer unit.

19. The compound of claim 8 having the structure:

23. The compound of claim 1 having the structure:

24. The compound of claim 1 having the structure:

25. The compound of claim 1 having the formula:

26. The compound or pharmaceutically acceptable salt thereof of claim 25 wherein L specifically binds the CD20 antigen.

27. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 1 or claim 2, and a pharmaceutically acceptable carrier or vehicle.

28. The compound or a pharmaceutically acceptable salt thereof of claim 1 in an isolated or a purified form.

29. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

W_w—

is valine-citrulline, the amino terminus of —

W_w—

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

W_w—

forming a bond with a the Spacer unit.

31. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 29 and a pharmaceutically acceptable carrier or vehicle.

32. The compound or a pharmaceutically acceptable salt thereof of claim 29 in an isolated or a purified form.

33. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein

—

Aa-Ww-Yy- has the formula;

35. The compound or a pharmaceutically acceptable salt of the compound of claim 33 or 34 wherein the ligand unit is a monoclonal antibody.

36. The compound or pharmaceutically acceptable salt thereof of claim 1 wherein R¹⁰ is

38. The compound or a pharmaceutically acceptable salt of the compound of claim 6 wherein the monoclonal antibody specifically binds the CD30 antigen.

39. The compound or a pharmaceutically acceptable salt of the compound at claim 6 wherein the monoclonal antibody specifically binds the CD19 antigen.

40. The compound or a pharmaceutically acceptable salt of the compound of claim 6 wherein the monoclonal antibody specifically binds the CD33 antigen.

41. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein —

A_a—

is;

42. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein p ranges from 1 to about 5.

43. The compound of claim 33 having the structure:

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein L is a monoclonal antibody.

45. The compound or pharmaceutically acceptable salt thereof of claim 25 wherein L specifically binds the CD20 antigen.

46. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 44 and a pharmaceutically acceptable carrier or vehicle.

47. The compound or a pharmaceutically acceptable salt thereof of claim 44 in an isolated or a purified form.

48. The compound or a pharmaceutically acceptable salt of the compound of claim 44 wherein p ranges from 1 to about 5.

49. The compound or a pharmaceutically acceptable salt of the compound of claim 43 wherein L is a monoclonal antibody that specifically binds the CD30 antigen, the CD20 antigen, the Lewis X or Y antigen, the CD33 antigen, the CD19 antigen, the CD38 antigen, the CEA antigen, the CA15-3 antigen or the epidermal growth factor antigen.

50. The compound or a pharmaceutically acceptable salt of the compound of claim 49 wherein the monoclonal antibody specifically binds the CD30 antigen.

75. The compound or a pharmaceutically acceptable salt of the compound of claim 1 wherein R² is —

C₁-C₈ alkyl.

2. A compound of the formula Ia:

LA_a—

W_w—

Y_y—

D)_p 

 

Ia;

or a pharmaceutically acceptable salt thereof,

wherein,

L—

is a Ligand unit;

—

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;

34. The compound or a pharmaceutically acceptable salt of the compound of claim 2 wherein

—

Aa-Ww-Yy- has the formula;

37. The compound or pharmaceutically acceptable salt thereof of claim 2 wherein R¹⁰ is:

77. The compound or a pharmaceutically acceptable salt of the compound of claim 2 wherein R² is -methyl.

18. A compound of the formula:

20. The compound of claim 18 having the structure:

21. The compound of claim 18 having the structure:

22. The compound of claim 18 having the structure:

30. The Compound of claim 18 or a pharmaceutically acceptable salt of the Compound of claim 18, wherein

—

A′

is selected from the group consisting of;

74. The compound of claim 30 or a pharmaceutically acceptable salt of the compound of claim 20, wherein

A_a—

is;

51. A composition comprising drug-linker-ligand conjugates having Formula Ia:

LA_a—

W_w—

Y_y—

D)_p 

 

Ia

or a pharmaceutically acceptable sail thereof;

wherein,

L—

is a Ligand unit;

—

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 5 and is the average number of —

A_a—

W_w—

Y_y—

D units per ligand in the composition; and

—

D is a Drug unit of the formula;

53. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, R¹⁰ is

55. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, —

D is a Drug unit having the structure;

56. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, —

Aa-Ww-Yy- has the formula;

58. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the ligand unit is a monoclonal anti body.

59. The composition of claim 58 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen, the CD20 antigen, the CD19 antigen, the Lewis X or Y antigen, the CD33 antigen, the CD38 antigen, the CEA antigen, the CA15-3 antigen or the epidermal growth factor antigen.

61. The composition of claim 59 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen.

62. The composition of claim 59 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD33 antigen.

76. The composition of claim 51 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, R² is —

C₁-C₈ alkyl.

52. A composition comprising drug-linker-ligand conjugates having Formula Ia:

LA_a—

W_w—

Y_y—

D)_p 

 

Ia;

or a pharmaceutically acceptable salt thereof

wherein,

L—

is a Ligand unit;

—

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 5 and is the average number of —

A_a—

W_w—

Y_y—

D units per ligand in the composition; and

—

D is a Drug unit having the structure;

54. The composition of claim 52 wherein in the drug-linker-ligand conjugates pharmaceutically acceptable salt thereof, R¹⁰ is

57. The composition of claim 52 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, —

Aa-Ww-Yy- has the formula;

63. The composition of claim 57 wherein the drug-linker-ligand conjugates have the formula:

64. The composition of claim 63 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, L is a monoclonal antibody.

65. The composition of claim 64 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD20 antigen, the CD30 antigen, the CD33 antigen, the CD19 antigen, the CD38 antigen, the CA15-3 antigen, the CEA antigen, or the epidermal growth factor antigen.

66. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen.

67. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD19 antigen.

68. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD20 antigen.

69. The composition of claim 65 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD33 antigen.

70. The composition of claim 52 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, L is a monoclonal antibody.

71. The composition of claim 70 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD20 antigen, the CD30 antigen, the CD33 antigen, the CD19 antigen, the CD38 antigen, the CA15-3 antigen, the CEA antigen, or the epidermal growth factor antigen.

72. The composition of claim 71 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD30 antigen.

73. The composition of claim 64 wherein the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the antibody is attached to the drug moiety through a cysteine residue of the antibody.

78. The composition of claim 52 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, R² is -methyl.

60. The composition of 59 wherein in the drug-linker-ligand conjugates or pharmaceutically acceptable salt thereof, the monoclonal antibody specifically binds the CD19 antigen.