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

Patent metadata

Field	Value
Publication number	US-9353356-B2
Application number	US-201313754234-A
Country	US
Kind code	B2
Filing date	Jan 30, 2013
Priority date	Sep 18, 2007
Publication date	May 31, 2016
Grant date	May 31, 2016

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.

First claim

We claim:

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 −7 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 prot

Assignees

• Acceleron Pharma Inc
• Acceleron Pharma Inc

Inventors

• Knopf John
• Seehra Jasbir
• Sherman Matthew L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/08

  for decreasing, blocking or antagonising the activity of the anterior pituitary hormones · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P15/18

  Feminine contraceptives · CPC title