Activin-ActRIIa antagonists and uses for treating multiple myeloma

1. A method for reducing myeloma tumor cell burden in a human patient, the method comprising administering to a patient afflicted with multiple myeloma an effective amount of an activin type IIa receptor-immunoglobulin Fc domain (ActRIIa-Fc) fusion protein to reduce myeloma tumor cell burden in the patient, wherein the ActRIIA-Fc fusion protein is selected from the group consisting of:

a) a dimer formed of two polypeptides that each comprise an amino acid sequence at least 95% identical to SEQ ID NO:2 joined by disulfide bonding;

b) a dimer formed of two polypeptides that each comprise an amino acid sequence at least 95% identical to SEQ ID NO:3 joined by disulfide bonding;

c) a dimer formed of two polypeptides that each comprise an amino acid sequence at least 95% identical to SEQ ID NO:7 joined by disulfide bonding; and

d) a dimer formed of two polypeptides that each comprise an amino acid sequence at least 95% identical to SEQ ID NO:12 joined by disulfide bonding,

wherein the ActRIIa-Fc fusion protein comprises three or more sialic acid moieties, and wherein the ActRIIa-Fc fusion protein binds to activin A.

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

i. binds to activin A with a K D of at least 10 −7 M; and

ii. inhibits ActRIIa signaling in a cell.

3. The method of claim 1 , wherein said 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.

4. 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.

5. The method of claim 4 , wherein the ActRIIa-Fc fusion protein is a dimer formed of two polypeptides that each comprise the amino acid sequence of SEQ ID NO:2 joined by disulfide bonding.

6. The method of claim 5 , wherein the ActRIIa-Fc fusion protein comprises between three and five sialic acid moieties.

7. 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:3.

8. The method of claim 7 , wherein the ActRIIa-Fc fusion protein is a dimer formed of two polypeptides that each comprise the amino acid sequence of SEQ ID NO:3 joined by disulfide bonding.

9. 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:12.

10. The method of claim 9 , wherein the ActRIIa-Fc fusion protein is a dimer formed of two polypeptides that each comprise the amino acid sequence of SEQ ID NO:12 joined by disulfide bonding.

11. 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:7.

12. The method of claim 11 , wherein the ActRIIa-Fc fusion protein is a dimer formed of two polypeptides that each comprise the amino acid sequence of SEQ ID NO:7 joined by disulfide bonding.

13. The method of claim 12 , wherein the ActRIIa-Fc fusion protein is administered to the patient no more frequently than once per week.

14. The method of claim 12 , wherein the ActRIIa-Fc fusion protein is administered to the patient no more frequently than once per month.

15. The method of claim 12 , wherein the ActRIIa-Fc fusion protein is administered to the patient no more frequently that once per three months.

16. The method of claim 1 , wherein the method causes less than 10% increase in the patient's skeletal muscle mass.

17. The method of claim 1 , wherein the ActRIIa-Fc fusion protein is administered so as to reach a serum concentration in the patient of at least 1000 ng/mL.

18. The method of claim 1 , wherein the ActRIIa-Fc fusion protein has a serum half-life of between 15 and 40 days in normal, healthy humans.

19. The method of claim 1 , where the ActRIIa-Fc fusion protein is a dimer formed of two polypeptides that each comprise an amino acid sequence at least 95% identical to SEQ ID NO: 7 joined by disulfide bonding, wherein one or both of the polypeptides have one fewer amino acids at the amino- or carboxy-termini than are shown in SEQ ID NO:7.

20. The method of claim 1 , wherein the ActRIIa-Fc fusion protein has 4 sialic acid moieties.

21. The method of claim 1 , wherein the ActRIIa-Fc fusion protein is recombinantly expressed in CHO cells using a TPA leader sequence.