Activin-actriia antagonists for inhibiting germ cell maturation
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 inhibiting follicle-stimulating hormone (FSH) production in a subject desiring to delay or inhibit his or her germ cell maturation, the method comprising administering to the 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 the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:3.
3. The method of claim 1 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:2.
4. The method of claim 1 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:7.
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.
6. The method of claim 5 , wherein each polypeptide of the dimer comprises the amino acid sequence of SEQ ID NO:2.
7. The method of claim 6 , wherein the ActRIIa-Fc fusion protein comprises three or more sialic acid moieties.
8. The method of claim 7 , wherein the ActRIIa-Fc fusion protein is produced by expression in CHO cells.
9. The method of claim 7 , wherein the ActRIIa-Fc fusion protein comprises between three and five sialic acid moieties.
10. The method of claim 6 , 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.
11. The method of claim 10 , wherein the ActRIIa-Fc fusion protein has four sialic acid moieties per dimer.
12. 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:2.
13. 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.
14. 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:12.
15. The method of claim 1 , wherein the ActRIIa-Fc fusion protein comprises the amino acid sequence of SEQ ID NO:12.
16. The method of claim 1 , wherein the subject has elevated FSH levels.
17. 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.
18. 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.
19. The method of claim 1 , wherein at least 0.3 mg/kg of the ActRIIa-Fc fusion protein is administered to the subject.