Isolated protein comprising an activin type IIB5 receptor polypeptide and uses thereof
The present invention provides novel activin IIB5 receptor polypeptides 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 receptor polypeptides. Compositions and methods for treating muscle-wasting, metabolic and other disorders are also provided.
1. An isolated protein comprising an activin type IIB5 receptor polypeptide, wherein the polypeptide is selected from the group consisting of:
(a) a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 2; and
(b) the polypeptide of (a), wherein the C terminal of the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 3; and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11.
2. The protein of claim 1 , wherein the polypeptide is fused to at least one heterologous polypeptide.
3. The protein of claim 2 , wherein the heterologous protein is an Fc polypeptide.
4. The protein of claim 3 , wherein the Fe polypeptide is attached via a linker sequence.
5. A pharmaceutical composition comprising the activin type IIB5 receptor protein of claim 1 in admixture with a pharmaceutically acceptable carrier.
6. A method of inhibiting myostatin activity in a subject in need thereof comprising administering a therapeutically effective amount of the composition of claim 5 to the subject.
7. A method of increasing lean muscle mass in a subject in need thereof comprising administering a therapeutically effective amount of the composition of claim 5 to the subject.
8. The method of claim 7 , wherein the subject is a food animal.
9. A method of increasing the ratio of lean muscle mass to fat in a subject in need thereof comprising administering a therapeutically effective amount of the composition of claim 5 to the subject.
10. A method of treating a muscle-wasting disease in a subject suffering from such as disease comprising administering a therapeutically effective amount of the composition of claim 5 to the subject.
11. The method of claim 10 , wherein the disease is cancer cachexia.
12. The method of claim 10 , wherein the disease selected from muscular dystrophy, amyotrophic lateral sclerosis, congestive obstructive pulmonary disease, chronic heart failure, cancer caehexia, AIDS, renal failure, uremia, rheumatoid arthritis, age-related sarcopenia, organ atrophy, carpal tunnel syndrome, androgen deprivation, and muscle-wasting due to prolonged bed rest, spinal chord injury, stroke, bone fracture, and aging.
13. A method of treating bone loss or obesity comprising administering a therapeutically effective amount of the composition of claim 5 to the subject.
14. An isolated protein comprising an activin type IIB5 receptor polypeptide, wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 2.
15. The protein of claim 14 , wherein amino acid residue 64 in SEQ ID NO: 2 is alanine.
16. An isolated protein comprising a polypeptide encoded by the polynucleotide set forth in SEQ ID NO: 1.