IP Library › Granted Patent US 9,353,356
Granted Patent B2
US 9,353,356 · App. 13/754,234 · Granted May 31, 2016

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

Inventors: John Knopf (Carlisle, MA); Jasbir Seehra (Lexington, MA); Matthew L. Sherman (Newton, MA)
Assignee: Acceleron Pharma Inc.
C12N9/12A61K38/179
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Quick Facts
Patent No.
US 9,353,356
App. No.
13/754,234
Granted
May 31, 2016
Kind
B2
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 (47)

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 protein binds to activin A.

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

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 5, 2013
From: KNOPF, JOHN; SEEHRA, JASBIR; SHERMAN, MATTHEW L.
To: ACCELERON PHARMA INC.
Reel/Frame 029925/0385 →
Continuity (4)
Continuation 13111393 · May 19, 2011
Division 12284112 · Sep 17, 2008
Provisional Application 60994399 · Sep 18, 2007
Related Publication 20130195862A1 · Aug 1, 2013