Variant activin receptor polypeptides
The present invention provides variant activin IIB soluble receptor polypeptides and proteins capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11. The present invention also provides polynucleotides, vectors and host cells capable of producing the variant polypeptides and proteins. Compositions and methods for treating muscle-wasting and other diseases and disorders are also provided.
1. An isolated protein comprising a variant activin IIB receptor polypeptide (vActRIIB) wherein said polypeptide is selected from the group consisting of:
(a) a polypeptide having the sequence set forth in SEQ ID NO: 18, except for a single amino acid substitution at position 28 wherein the substitution is W for E;
(b) a polypeptide having the sequence set forth in amino acids 19 through 134 of SEQ ID NO: 18, except for a single amino acid substitution at position 28, wherein the substitution is W for E;
(c) a polypeptide having the sequence set forth in amino acids 23 through 134 of SEQ ID NO: 18, except for a single amino acid substitution at position 28, wherein the substitution is W for E; and
(d) a polypeptide consisting of the sequence set forth in amino acids 25 through 134 of SEQ ID NO: 18, except for a single amino acid substitution at position 28, wherein the substitution is W for E.
2. The protein of claim 1 wherein the vActRIIB polypeptide is fused to at least one heterologous polypeptide.
3. The protein of claim 2 , wherein heterologous polypeptide is an Fc domain.
4. The protein of claim 3 , wherein the protein further comprises a linker or a hinge linker between the vActRIIB polypeptide and the Fc domain.
5. A pharmaceutical composition comprising an effective amount of the protein of claim 1 in admixture with a pharmaceutically acceptable carrier.
6. The protein of claim 1 , wherein the vActIIB polypeptide further comprises the substitution A for R at position 64.
7. The protein of claim 6 , wherein the vActRIIB polypeptide is fused to at least one heterologous polypeptide.
8. The protein of claim 7 , wherein the heterologous polypeptide is an Fc domain.
9. The protein of claim 8 , wherein the protein further comprises a linker or a hinge linker between the vActRIIB polypeptide and the Fc domain.
10. The protein of claim 1 , wherein the vActRIIB polypeptide consists of a sequence having at least 95% identity to the sequence set forth in amino acids 19 through 134 of SEQ ID NO: 18, wherein W is substituted for E at position 28.
11. The protein of claim 10 , wherein the vActRIIB polypeptide is fused to at least one heterologous polypeptide.
12. The protein of claim 11 , wherein the heterologous polypeptide is an Fc domain.
13. The protein of claim 12 , wherein the protein further comprises a linker or a hinge linker between the vActRIIB polypeptide and the Fc domain.
14. The protein of claim 13 , wherein the polypeptide has the sequence set forth in SEQ ID NO: 62.
15. The protein of claim 1 , wherein the vActRIIB polypeptide consists of a sequence having at least 95% identity to the sequence set forth in amino acids 23 through 134 of SEQ ID NO: 18, wherein W is substituted for E at position 28.
16. The protein of claim 15 , wherein the vActRIIB polypeptide is fused to at least one heterologous polypeptide.
17. The protein of claim 16 , wherein the heterologous polypeptide is a Fc domain.
18. The protein of claim 17 , wherein the protein further comprises a linker or a hinge linker between the vActRIIB polypeptide and the Fc domain.
19. The protein of claim 1 , wherein the vActRIIB polypeptide consists of a sequence having at least 95% identity to the sequence set forth in amino acids 25 through 134 of SEQ ID NO: 18, wherein W is substituted for E at position 28.
20. The protein of claim 19 , wherein the polypeptide has the sequence set forth in SEQ ID NO: 87.
21. The protein of claim 19 , wherein the vActRIIB polypeptide is fused to at least one heterologous polypeptide.
22. The protein of claim 21 , wherein the heterologous polypeptide is an Fc domain.
23. The protein of claim 22 , wherein the protein further comprises a linker or a hinge linker between the vActRIIB polypeptide and the Fc domain.
24. The protein of claim 23 , wherein the polypeptide has the sequence set forth in SEQ ID NO: 91.