Activin-actriia antagonists and uses for treating or preventing breast cancer

• US 9,526,759 B2
• Filed: 02/01/2008
• Issued: 12/27/2016
• Est. Priority Date: 02/01/2007
• Status: Active Grant

• Current Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Original Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Inventors: Knopf, John, Seehra, Jasbir, Kumar, Ravindra
• Primary Examiner(s): Dent, Alana Harris
• Application Number:
  US12/012,510
• Publication Number:
  US 20090074768A1
• Time in Patent Office: 3,252 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/1796 for hormones for neuromediators A61K38/1787
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• 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
• CPC Class Codes: C07K 2319/32 fusions with soluble part of a cell surface receptor, "decoy receptors"
• CPC Class Codes: C12N 9/12 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/1103 Receptor protein serine/threonine kinase (2.7.11.30)
• CPC Class Codes: G01N 2333/91205 Phosphotransferases in general
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes
• CPC Class Codes: G01N 33/57415 of breast

Abstract

In certain aspects, the present invention provides compositions and methods for treating or preventing breast cancer in humans.

Claims

1. A method for treating or preventing estrogen receptor-negative breast cancer in a human patient, the method comprising administering to a patient in need thereof an effective amount of an ActRIIa-Fc fusion protein, wherein the ActRIIa-Fc fusion protein comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:

2, and wherein the ActRIIa-Fc fusion protein binds to activin A.

2. The method of claim 1, wherein the ActRIIa-Fc fusion protein has one or more of the following characteristics:

a. binds to activin A with a K_D of at least 10<sup>−

7</sup> M; and

b. inhibits ActRIIa signaling in a cell.

3. The method of claim 2, wherein said ActRIIa-Fc fusion protein comprises one or more modified amino acid residues selected from:

a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, and an amino acid conjugated to a lipid moiety.

4. The method of claim 1, wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:

2.

5. The method of claim 1, wherein the ActRIIa-Fc fusion protein is a dimer formed of two polypeptides that each comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

2, and wherein the ActRIIa-Fc fusion protein comprises three or more sialic acid moieties.

6. The method of claim 5, wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:

2.

7. The method of claim 6, wherein the ActRIIa-Fc fusion protein comprises from three to five sialic acid moieties.

8. The method of claim 7, wherein the method causes less than a 10% increase in the patient'"'"'s skeletal muscle mass.

9. The method of claim 7, wherein the ActRIIa-Fc fusion protein is administered so as to reach a serum concentration of the fusion protein in the patient of at least 0.2 mg/kg.

10. The method of claim 7, wherein the ActRIIa-Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:

7.

11. The method of claim 7, wherein the ActRIIa-Fc fusion protein has a serum half-life of between 15 and 40 days in normal, healthy humans.

12. The method of claim 7, wherein the ActRIIa-Fc fusion protein is administered to the patient no more frequently than once per week.

13. The method of claim 7, wherein the ActRIIa-Fc fusion protein is administered to the patient no more frequently than once per month.

14. The method of claim 7, wherein the ActRIIa-Fc fusion protein is administered to the patient no more frequently than once per three months.

15. The method of claim 1, further comprising administering a radiation therapy, endocrine therapy or cytotoxic agent to the human patient.

16. The method of claim 1, wherein the human patient is a female with one or more risk factors for breast cancer.

17. The method of claim 1, wherein the ActRIIa-Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:

7.

18. The method of claim 17, wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:

7.

19. The method of claim 10, wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:

7.

20. The method of claim 1, wherein the patient is at risk for developing metastatic cancer.

21. The method of claim 1, wherein the patient has a primary breast cancer tumor or proliferative lesion of the breast, and wherein the ActRIIa-Fc fusion protein is administered to the patient prior to the development of metastatic lesions.

22. The method of claim 1, wherein the patient has a primary breast cancer tumor or proliferative lesion of the breast, and wherein the ActRIIa-Fc fusion protein is administered to the patient prior to metastatic spread of cancer cells to the bone.

23. The method of claim 1, wherein the method is for treating estrogen receptor-negative breast cancer in a human patient.

24. The method of claim 23, wherein the ActRIIa-Fc fusion protein comprises a polypeptide comprising the amino acid sequence of SEQ ID NO:

2.

25. The method of claim 23, wherein the ActRIIa-Fc fusion protein comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:

7.

26. The method of claim 23, wherein the ActRIIa-Fc fusion protein comprises a polypeptide comprising the amino acid sequence of SEQ ID NO:

7.

27. The method of claim 23, wherein the ActRIIa-Fc fusion protein is a dimer comprising two polypeptides that each comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

7.

28. The method of claim 23, wherein the ActRIIa-Fc fusion protein is a dimer comprising two polypeptides that each comprise the amino acid sequence of SEQ ID NO:

7.

29. The method of claim 1, wherein the method is for preventing estrogen receptor-negative breast cancer in a human patient.

30. The method of claim 29, wherein the ActRIIa-Fc fusion protein comprises a polypeptide comprising the amino acid sequence of SEQ ID NO:

2.

31. The method of claim 29, wherein the ActRIIa-Fc fusion protein comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:

7.

32. The method of claim 29, wherein the ActRIIa-Fc fusion protein comprises a polypeptide comprising the amino acid sequence of SEQ ID NO:

7.

33. The method of claim 29, wherein the ActRIIa-Fc fusion protein is a dimer comprising two polypeptides that each comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

7.

34. The method of claim 29, wherein the ActRIIa-Fc fusion protein is a dimer comprising two polypeptides that each comprise the amino acid sequence of SEQ ID NO:

7.