DR5 LIGAND DRUG CONJUGATES

• US 20110070248A1
• Filed: 09/23/2010
• Published: 03/24/2011
• Est. Priority Date: 09/24/2009
• Status: Abandoned Application

• Current Assignee: Seattle Genetics Incorporated
• Original Assignee: Daiichi Sankyo Company Limited, Seattle Genetics Incorporated
• Inventors: Ichikawa, Kimihisa, Yoshida, Hiroko, Yada, Ayumi, Fujiwara, Kosaku
• Application Number:
  US12/889,306
• Publication Number:
  US 20110070248A1
• Time in Patent Office: Days
• US Class Current: 424/178.1
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Ligand Drug Conjugates are provided having a DR5 binding moiety attached via linking groups and/or spacers to a therapeutic agent and are effective in treatment of various cancers.

Claims

1. A ligand drug conjugate comprising a DR5 binding agent covalently attached to a cytotoxic agent.

31. A pharmaceutical composition comprising the ligand drug conjugate of claim 1, in admixture with a pharmaceutically acceptable excipient.

32. An anti-tumor agent comprising the ligand drug conjugate of claim 1, as an effective ingredient.

33. A method of treating cancer comprising administering to a subject in need thereof an effective amount of a ligand drug conjugate of claim 1.

34. A method in accordance with claim 33, wherein said cancer is selected from the group consisting of melanoma, colorectal cancer, non-small cell lung carcinoma, uterine cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, and hematological cancer.

35. A method in accordance with claim 33, wherein said cancer is pancreatic cancer.

36. A method in accordance with claim 33, wherein said cancer is melanoma.

37. A method in accordance with claim 33, wherein said cancer is breast cancer.

2. A ligand drug conjugate having Formula (I):

L-(LU-D)_p 

 

(I)

or a pharmaceutically acceptable salt thereof, having specificity for target cells expressing DR5, wherein

L is a ligand unit which is a DR⁵ binding agent; and

(LU-D) is a Linker unit-Drug unit moiety, wherein

LU is a Linker unit, and

D is a Drug unit having cytostatic or cytotoxic activity against said target cells; and

the subscript p is an integer of from 1 to 20.

3. The ligand-drug conjugate of claim 2, wherein the Drug unit has formula D_E or D_F:

4. The ligand drug conjugate of claim 3, wherein the Drug unit has formula D_E or a pharmaceutically acceptable salt form thereof.

5. The ligand drug conjugate of claim 3, wherein the Drug unit has the formula:

6. The ligand drug conjugate of claim 3, wherein the Drug unit has the formula:

7. The ligand drug conjugate of claim 3, wherein the Drug unit has the formula:

8. The ligand drug conjugate of claim 2, wherein LU has the formula:

-A_a-W_w—

Y_y—

or a pharmaceutically acceptable salt form thereof, wherein,

-A- is a Stretcher unit;

the subscript a is 0 or 1;

each W is independently an amino acid unit;

the subscript w is an integer of from 0 to 12;

—

Y—

is a Spacer unit; and

the subscript y is 0, 1 or 2.

9. The ligand drug conjugate of claim 8, having the formula:

10. The ligand drug conjugate of claim 8, having the formula:

11. The ligand drug conjugate of claim 8, having the formula:

12. The ligand drug conjugate of claim 8, having the formula:

13. The ligand drug conjugate of claim 8, having the formula:

14. The ligand drug conjugate of claim 8, having the formula:

15. The ligand drug conjugate of claim 8, wherein w is an integer ranging from 2 to 12, and y is 1 or 2.

16. The ligand drug conjugate of claim 8, wherein w is 2 and y is 1 or 2.

17. The ligand drug conjugate of claim 8, wherein W_w is -valine-citrulline- and y is 1 or 2.

21. The ligand drug conjugate of claim 3, wherein D is D_E.

22. The ligand drug conjugate of claim 3, wherein D is D_F.

23. The ligand drug conjugate of claim 3, wherein L is an anti-DR5 antibody.

18. A ligand drug conjugate having the formula:

24. The ligand drug conjugate of any of claim 18, 19, or 20, wherein the anti-DR5 antibody comprises (a) a heavy chain immunoglobulin having the CDR1 consisting of amino residues 1-5 of SEQ ID NO:

3, the CDR2 consisting of amino acid residues 1-17 of SEQ ID NO;

4, and the CDR3 consisting of amino acid residues 1-10 of SEQ ID NO;

5; and

(b) a light chain immunoglobulin having the CDR1 consisting of amino residues 1-11 of SEQ ID NO;

6, the CDR2 consisting of amino acid residues 1-7 of SEQ ID NO;

7, and the CDR3 consisting of amino acid residues 1-8 of SEQ ID NO;

8.

25. The ligand drug conjugate of any of claim 18, 19, or 20, wherein the anti-DR5 antibody comprises the heavy chain variable region comprising amino acid residues 1-118 of SEQ ID NO:

1 and the light chain variable region comprising amino acid residues 1-107 of SEQ ID NO;

2.

26. The ligand drug conjugate of any of claim 18, 19, or 20, wherein the anti-DR5 antibody comprises the heavy chain consisting of amino residues 1-449 of SEQ ID NO:

1 and the light chain consisting of amino acid residues 1-213 of SEQ ID NO;

2.

27. The ligand drug conjugate of claim 18, wherein p is from 3 to 5.

19. A ligand drug conjugate having the formula:

28. The ligand drug conjugate of claim 19, wherein p is from 1 to 3.

29. The ligand drug conjugate of claim 19, wherein p is from 3 to 5.

20. A ligand drug conjugate having the formula:

30. The ligand drug conjugate of claim 20, wherein p is from 3 to 5.