Methods of treating cancer using antibodies that immunospecifically bind to TRAIL receptors

• US 7,348,003 B2
• Filed: 11/12/2004
• Issued: 03/25/2008
• Est. Priority Date: 05/25/2001
• Status: Expired due to Term

• Current Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Original Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Inventors: Vaughan, Tristan, Rosen, Craig A., Ruben, Steven M., Albert, Vivian R., Dobson, Claire, Salcedo, Theodora W.
• Primary Examiner(s): Blanchard; David J.
• Application Number:
  US10/986,047
• Publication Number:
  US 20050129699A1
• Time in Patent Office: 1,229 Days
• Field of Search: 424/130.1, 424/133.1, 424/135.1, 424/142.1, 424/143.1, 424/155.1, 424/181.1, 435/69.6, 435/70.2
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)

Abstract

The present invention relates to antibodies and related molecules that immunospecifically bind to TRAIL receptor, TR4. Such antibodies have uses, for example, in the prevention and treatment of cancers and other proliferative disorders. The invention also relates to nucleic acid molecules encoding anti-TR4 antibodies, vectors and host cells containing these nucleic acids, and methods for producing the same. The present invention relates to methods and compositions for preventing, detecting, diagnosing, treating or ameliorating a disease or disorder, especially cancer and other hyperproliferative disorders, comprising administering to an animal, preferably a human, an effective amount of one or more antibodies or fragments or variants thereof, or related molecules, that immunospecifically bind to TRAIL receptor TR4.

Claims

1. A method of treating a TR4 expressing cancer comprising administering to an animal an isolated antibody or fragment thereof comprising the amino acid sequence selected from the group consisting of:

(a) an amino acid sequence that is at least 95% identical to the VH and VL domains of SEQ ID NO;

42;

(b) an amino acid sequence that is at least 95% identical to the VH and VL domains of SEQ ID NO;

43; and

(c) an amino acid sequence that is at least 95% identical to the VH and VL domains of SEQ ID NO;

47;

wherein said antibody or fragment thereof immunospecifically binds a TR4 protein selected from the group consisting of;

(i) a polypeptide having the amino acid sequence of any one of amino acid residues 1 to 468 of SEQ ID NO;

1, amino acid residues 24 to 468 of SEQ ID NO;

1, amino acid residues 24 to 238 of SEQ ID NO;

1, and amino acid residues 109 to 240 of SEQ ID NO;

1;

(ii) a multimer of the polypeptide of (i);

(iii) the polypeptide of (i) expressed on the surface of a cell; and

(iv) the multimer of (ii) expressed on the surface of a cell;

or a composition containing said antibody or fragment thereof.

2. The method of claim 1 wherein the animal is a human.

3. The method of claim 1 wherein the cancer is colon cancer.

4. The method of claim 1 wherein the cancer is breast cancer.

5. The method of claim 1 wherein the cancer is uterine cancer.

6. The method of claim 1 wherein the cancer is pancreatic cancer.

7. The method of claim 1 wherein the cancer is lung cancer.

8. The method of claim 1 wherein the cancer is gastrointestinal cancer.

9. The method of claim 1 wherein the cancer is Kaposi'"'"'s sarcoma.

10. The method of claim 1 wherein the cancer is a cancer of the central nervous system.

11. The method of claim 10 wherein the cancer of the central nervous system is a neuroblastoma.

12. The method of claim 10 wherein the cancer of the central nervous system is a glioblastoma.

13. The method of claim 1, wherein the antibody or fragment thereof is administered in combination with a chemotherapeutic agent.

14. The method of claim 13, wherein chemotherapeutic agent is selected from the group consisting of:

(a) irinotecan;

(b) paclitaxel; and

(c) gemcitabine.

35. The method of claim 1, wherein said antibody or fragment thereof comprises a VH domain having the amino acid sequence of the VH domain of SEQ ID NO:

42 and a VL domain having the amino acid sequence of the VL domain of SEQ ID NO;

42.

37. The method of claim 1, wherein said antibody is expressed by the cell line of ATCC Deposit PTA-3570.

38. The method of claim 1, wherein said antibody is expressed by the cell line of ATCC Deposit PTA-3571.

39. The method of claim 1, wherein said antibody or fragment thereof is selected from the group consisting of:

(a) a whole immunoglobulin molecule;

(b) an scFv;

(c) a monoclonal antibody;

(d) a human antibody;

(e) a chimeric antibody;

(f) a Fab fragment;

(g) an Fab′

fragment;

(h) an F(ab′

)2;

(i) an Fv; and

(j) a disulfide linked Fv.

40. The method of claim 1, wherein said antibody or fragment thereof comprises a VH domain having the amino acid sequence of the VH domain of SEQ ID NO:

47 and a VL domain having the amino acid sequence of the VL domain of SEQ ID NO;

47.

15. A method of inhibiting the growth of or killing TR4 expressing cells, comprising administering to an animal in which such inhibition of growth or killing of TR4 receptor expressing cells is desired, an isolated antibody or fragment thereof comprising the amino acid sequence selected from the group consisting of:

(a) an amino acid sequence that is at least 95% identical to the VH and VL domains of SEQ ID NO;

42;

(b) an amino acid sequence that is at least 95% identical to the VH and VL domains of SEQ ID NO;

43; and

(c) an amino acid sequence that is at least 95% identical to the VH and VL domains of SEQ ID NO;

47;

wherein said antibody or fragment thereof immunospecifically binds a TR4 protein selected from the group consisting of;

(i) a polypeptide having the amino acid sequence of any one of amino acid residues 1 to 468 of SEQ ID NO;

1, amino acid residues 24 to 468of SEQ ID NO;

1, amino acid residues 24 to 238 of SEQ ID NO;

1, and amino acid residues 109 to 240 of SEQ ID NO;

1;

(ii) a multimer of the polypeptide of (i);

(iii) the polypeptide of (i) expressed on the surface of a cell; and

(iv) the multimer of (ii)expressed on the surface of a cell;

or a composition containing said antibody or fragment thereof in an amount effective to inhibit the growth of or kill TR4 expressing cells.

16. The method of claim 15, wherein said antibody or fragment thereof comprises a VH domain having the amino acid sequence of the VH domain of SEQ ID NO:

42 and a VL domain having the amino acid sequence of the VL domain of SEQ ID NO;

42.

17. The method of claim 15, wherein said antibody or fragment thereof comprises a VH domain having the amino acid sequence of the VH domain of SEQ ID NO:

43 and a VL domain having the amino acid sequence of the VL domain of SEQ ID NO;

43.

18. The method of claim 15, wherein said antibody is expressed by the cell line of ATCC Deposit PTA-3570.

19. The method of claim 15, wherein said antibody is expressed by the cell line of ATCC Deposit PTA-3571.

20. The method of claim 15, wherein said antibody or fragment thereof is selected from the group consisting of:

(a) a whole immunoglobulin molecule;

(b) an scFv;

(c) a monoclonal antibody;

(d) a human antibody;

(e) a chimeric antibody;

(f) a Fab fragment;

(g) an Fab′

fragment;

(h) an F(ab′

)2;

(i) an Fv; and

(j) a disulfide linked Fv.

21. The method of claim 15, wherein the animal is a human.

22. The method of claim 15, wherein said TR4 expressing cells are cancer cells.

23. The method of claim 22 wherein the cancer cells are colon cancer cells.

24. The method of claim 22 wherein the cancer cells are breast cancer cells.

25. The method of claim 22 wherein the cancer cells are uterine cancer cells.

26. The method of claim 22 wherein the cancer cells are pancreatic cancer cells.

27. The method of claim 22 wherein the cancer cells are lung cancer cells.

28. The method of claim 22 wherein the cancer cells are gastrointestinal cancer cells.

29. The method of claim 22 wherein the cancer cells are Kaposi'"'"'s sarcoma cells.

30. The method of claim 22 wherein the cancer cells are central nervous system cancer cells.

31. The method of claim 30 wherein the central nervous system cancer cells are neuroblastoma cells.

32. The method of claim 30 wherein the central nervous system cancer cells are glioblastoma cells.

33. The method of claim 15, wherein the antibody or fragment thereof is administered in combination with a chemotherapetuic agent.

34. The method of claim 33, wherein the chemotherapeutic agent is selected from the group consisting of:

(a) irinotecan;

(b) paclitaxel; and

(c) gemcitabine.

36. The method of claim 15, wherein said antibody or fragment thereof comprises a VH domain having the amino acid sequence of the VH domain of SEQ ID NO:

43 and a VL domain having the amino acid sequence of the VL domain of SEQ ID NO;

43.

41. The method of claim 15, wherein said antibody or fragment thereof comprises a VH domain having the amino acid sequence of the VH domain of SEQ ID NO:

47 and a VL domain having the amino acid sequence of the VL domain of SEQ ID NO;

47.

42. A method of treating a TR4 expressing cancer comprising administering to an animal an isolated antibody or fragment thereof comprising amino acid residues 26-35, 50-66, 99-107, 157-170, 186-192, and 225-234 of the amino acid sequence selected from the group consisting of:

(a) SEQ ID NO;

42;

(b) SEQ ID NO;

43; and

(c) SEQ ID NO;

47;

wherein said antibody or fragment thereof immunospecifically binds a TR4 protein selected from the group consisting of;

(i) a polypeptide having the amino acid sequence of any one of amino acid residues 1 to 468 of SEQ ID NO;

1;

amino acid residues 24 to 468 of SEQ ID NO;

1;

amino acid residues 24 to 238 of SEQ ID NQ;

1; and

amino acid residues 109 to 240 of SEQ ID NO;

1;

(ii) a multimer of the polypeptide of (i);

(iii) the polypeptide of (i) expressed on the surface of a cell; and

(iv) the multimer of (ii) expressed on the surface of a cell.

43. A method of inhibiting the growth of or killing TR4 expressing cells, comprising administering to an animal in which such inhibition of growth or killing of TR4 receptor expressing cells is desired, an isolated antibody or fragment thereof comprising amino acid residues 26-35, 50-66, 99-107, 157-170, 186-192, and 225-234 of the amino acid sequence selected from the group consisting of:

(a) SEQ ID NO;

42;

(b) SEQ ID NO;

43; and

(c) SEQ ID NO;

47;

wherein said antibody or fragment thereof immunospecifically binds a TR4 protein selected from the group consisting of;

(i) a polypeptide having the amino acid sequence of any one of amino acid residues 1 to 468 of SEQ ID NO;

1;

amino acid residues 24 to 468 of SEQ ID NO;

1;

amino acid residues 24 to 238 of SEQ ID NO;

1; and

amino acid residues 109 to 240 of SEQ ID NO;

1;

(ii) a multimer of the polypeptide of (i);

(iii) the polypeptide of (i) expressed on the surface of a cell; and

(iv) the multimer of (ii) expressed on the surface of a cell.