Activin-ActRIIa antagonists and uses for decreasing or inhibiting FSH secretion
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.
1. A method for decreasing follicle-stimulating hormone (FSH) levels in a human subject, the method comprising administering to a subject in need thereof an amount of an activin receptor type IIa-immunoglobulin Fc domain (ActRIIa-Fc) fusion protein effective to reduce FSH levels in the subject, 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:3, wherein the amount administered results in an ActRIIa-Fc serum concentration of at least 1000 ng/mL, and wherein the ActRIIa-Fc fusion protein binds to activin.
2. The method of claim 1 , wherein administration of the ActRIIa-Fc fusion protein alleviates or reduces at least one symptom of an FSH related disorder.
3. The method of claim 2 , wherein the FSH related disorder is prostate cancer and administration of the ActRIIa-Fc fusion protein inhibits the progression of prostate cancer, delays the onset of metastasis, or decreases tumor size.
4. The method of claim 3 , wherein the prostate cancer is hormone-refractory prostate cancer.
5. The method of claim 4 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 7.
6. The method of claim 3 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
7. The method of claim 3 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 7.
8. The method of claim 2 , wherein the FSH related disorder is FSH-secreting pituitary tumor.
9. The method of claim 8 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
10. The method of claim 8 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 7.
11. The method of claim 2 , wherein the subject is a female afflicted with one or more ovarian cysts and administration of the ActRIIa-Fc fusion protein reduces the size of the cysts, inhibits growth of the cysts, or inhibits formation of new cysts.
12. The method of claim 11 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
13. The method of claim 11 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 7.
14. The method of claim 1 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:3.
15. The method of claim 1 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:2.
16. 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.
17. The method of claim 16 , wherein the ActRIIa-Fc fusion protein comprises three or more sialic acid moieties.
18. The method of claim 16 , wherein the ActRIIa-Fc fusion protein is produced by expression in CHO cells.
19. The method of claim 16 , wherein the ActRIIa-Fc fusion protein comprises between three and five sialic acid moieties.
20. The method of claim 16 , wherein the ActRIIa-Fc fusion protein has a serum half-life of 25 to 32 days on average in normal, healthy humans and equivalent bioavailability when administered intravenously or subcutaneously.
21. The method of claim 20 , wherein the ActRIIa-Fc fusion protein has four sialic acid moieties per dimer.
22. The method of claim 1 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:7.
23. The method of claim 22 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
24. The method of claim 1 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
25. The method of claim 1 , wherein the ActRIIa-Fc fusion protein has a serum half-life of between 15 and 30 days.
26. The method of claim 25 , wherein the ActRIIa-Fc fusion protein is administered to the subject no more frequently than once per week.
27. The method of claim 26 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
28. The method of claim 25 , wherein the ActRIIa-Fc fusion protein is administered to the subject no more frequently than once per month.
29. The method of claim 28 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
30. The method of claim 1 , wherein the ActRIIa-Fc fusion protein is administered subcutaneously.
31. The method of claim 30 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
32. The method of any of claim 1 , wherein the method causes less than 10% increase in the subject's skeletal muscle mass.
33. The method of claim 1 , further comprising administering a radiation therapy, endocrine therapy or cytotoxic agent to the human subject.
34. The method of claim 33 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the patient.
35. 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:2.
36. 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.
37. 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.
38. The method of claim 1 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:12.
39. The method of claim 1 , wherein the ActRIIa-Fc fusion protein has one or more of the following characteristics:
i. binds to activin with a K D of at least 10 −7 M; and
ii. inhibits ActRIIa signaling in a cell.
40. 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.