Activin-actriia antagonists for treating a follicle-stimulating horomone-secreting pituitary tumor

• US 9,353,356 B2
• Filed: 01/30/2013
• Issued: 05/31/2016
• Est. Priority Date: 09/18/2007
• Status: Active Grant

• Current Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Original Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Inventors: Knopf, John, Seehra, Jasbir, Sherman, Matthew L.
• Primary Examiner(s): BORGEEST, CHRISTINA M
• Application Number:
  US13/754,234
• Publication Number:
  US 20130195862A1
• Time in Patent Office: 1,217 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• 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: A61P 5/08 for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• 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: 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)

Abstract

In certain aspects, the present invention provides compositions and methods for decreasing FSH levels in a patient. The patient may, for example, be diagnosed with an FSH-related disorder or desire to delay or inhibit germ cell maturation.

Claims

1. A method for decreasing follicle-stimulating hormone (FSH) levels in a human patient having a FSH-secreting pituitary tumor, the method comprising administering to a human patient in need thereof an activin receptor type IIa-immunoglobulin Fc domain (ActRIIa-Fc) fusion protein on a dosing schedule effective to reduce FSH levels in the patient, wherein the ActRIIa portion of the ActRIIa-Fc fusion protein comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

3, wherein the dosing schedule comprises administering the ActRIIa-Fc fusion in an amount that results in an ActRIIa-Fc serum concentration of at least 1000 ng/mL, and wherein the ActRIIa-Fc fusion protein binds to activin and/or GDF 11.

2. The method of claim 1, wherein the ActRIIa-Fc fusion protein has a serum half-life from 25 to 35 days on average in normal, healthy humans.

3. The method of claim 1, wherein the dosing schedule comprises administering at least 0.05 to 0.5 mg/kg of the ActRIIa-Fc fusion protein to the patient.

4. The method of claim 1, wherein the dosing schedule comprises administering at least 0.3 mg/kg of the ActRIIa-Fc fusion protein to the patient.

5. The method of claim 1, wherein the dosing schedule comprises administering the ActRIIa-Fc fusion protein to the patient on a weekly basis.

6. The method of claim 1, wherein the dosing schedule comprises administering the ActRIIa-Fc fusion protein to the patient on a biweekly basis.

7. The method of claim 1, wherein the dosing schedule comprises administering at least 0.1 to 3.0 mg/kg of the ActRIIa-Fc fusion protein to the patient.

8. The method of claim 7, wherein the dosing schedule comprises administering at least 0.1 mg/kg of the ActRIIa-Fc fusion protein to the patient.

9. The method of claim 7, wherein the dosing schedule comprises administering at least 0.3 mg/kg of the ActRIIa-Fc fusion protein to the patient.

10. The method of claim 7, wherein the dosing schedule comprises administering at least 0.5 mg/kg of the ActRIIa-Fc fusion protein to the patient.

11. The method of claim 7, wherein the dosing schedule comprises administering at least 0.7 mg/kg of the ActRIIa-Fc fusion protein to the patient.

12. The method of claim 7, wherein the dosing schedule comprises administering at least 1.0 mg/kg of the ActRIIa-Fc fusion protein to the patient.

13. The method of claim 7, wherein the dosing schedule comprises administering at least 2.0 mg/kg of the ActRIIa-Fc fusion protein to the patient.

14. The method of claim 7, wherein the dosing schedule comprises administering at least 3.0 mg/kg of the ActRIIa-Fc fusion protein to the patient.

15. The method of claim 1, wherein the dosing schedule comprises administering the ActRIIa-Fc fusion protein to the patient on a monthly basis.

16. The method of claim 1, wherein the dosing schedule comprises administering the ActRIIa-Fc fusion protein to the patient on a bimonthly basis.

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

3.

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

3.

19. The method of claim 1, wherein the ActRIIa portion of the ActRIIa-Fc fusion protein comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

2.

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

2.

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

2.

22. The method of claim 1, wherein the ActRIIa-Fc fusion protein comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

7.

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

7.

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

7.

25. The method of claim 1, wherein the ActRIIa-Fc fusion protein comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

12.

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

12.

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

12.

28. 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 90% identical to the amino acid sequence of SEQ ID NO:

7.

29. The method of claim 28, wherein the dimer comprises 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.

30. The method of claim 28, wherein the dimer comprises two polypeptides that each comprise the amino acid sequence of SEQ ID NO:

7.

31. The method of claim 28, wherein the ActRIIa-Fc fusion protein comprises three or more sialic acid moieties.

32. The method of claim 28, wherein the ActRIIa-Fc fusion protein comprises from three to five sialic acid moieties.

33. The method of claim 1, wherein the ActRIIa-Fc fusion protein is expressed in a CHO cell.

34. The method of claim 1, wherein the ActRIIa-Fc fusion protein is expressed using a Tissue Plasminogen Activator (TPA) leader sequence.

35. The method of claim 34, wherein the TPA leader sequence comprises the amino acid sequence of SEQ ID NO:

9.

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

i. binds to an ActRIIa ligand with a K_D of at least 10<sup>−

7</sup>M; and

ii. inhibits ActRIIa signaling in a cell.

37. The method of claim 1, wherein the ActRIIa-Fc fusion protein includes 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, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent.

38. The method of claim 1, wherein the ActRIIa-Fc fusion protein is administered subcutaneously.

39. The method of claim 1, wherein the ActRIIa-Fc fusion protein binds to activin.

40. The method of claim 39, wherein the ActRIIa-Fc fusion protein binds to activin A.

41. The method of claim 39, wherein the ActRIIa-Fc fusion protein binds to activin B.

42. The method of claim 1, wherein the ActRIIa-Fc fusion protein binds to GDF 11.

43. The method of claim 1, wherein the ActRIIa-Fc fusion protein binds to activin and GDF 11.

44. The method of claim 43, wherein the ActRIIa-Fc fusion protein binds to activin A.

45. The method of claim 43, wherein the ActRIIa-Fc fusion protein binds to activin B.