Myostatin binding agents, nucleic acids encoding the same, and methods of treatment
The present invention provides binding agents comprising peptides capable of binding myostatin and inhibiting its activity. In one embodiment the binding agent comprises at least one myostatin-binding peptide attached directly or indirectly to at least one vehicle such as a polymer or an Fc domain. The binding agents of the present invention produced increased lean muscle mass when administered to animals and decreased fat to muscle ratios. Therapeutic compositions containing the binding agents of the present invention are useful for treating muscle-wasting disorders and metabolic disorders including diabetes and obesity.
1. A binding agent capable of binding myostatin comprising the structure F 1 -(L 1 )-P 1 or multimers thereof, wherein F 1 is a human IgG Fc, wherein L 1 is (Gly) 5 , wherein the binding agent further comprises AQ and wherein P 1 is SEQ ID NO: 311.
2. A pharmaceutical composition comprising a therapeutically effective amount of the binding agent of claim 1 in admixture with a pharmaceutically acceptable carrier thereof.
3. An isolated nucleic acid molecule comprising a polynucleotide encoding a monomer of the binding agent of claim 1 .
4. The nucleic acid molecule of claim 3 , wherein the polynucleotide is SEQ ID NO:579.
5. An expression vector comprising the polynucleotide of claim 3 .
6. A host cell comprising the expression vector of claim 5 .
7. A method of making a myostatin binding agent comprising culturing the host cell of claim 6 under conditions suitable for expressing the binding agent, and purifying the binding agent.
8. A method of inhibiting myostatin activity in a subject comprising administering an effective amount of the composition of claim 2 to the subject.
9. A method of increasing lean muscle mass in a subject comprising administering the composition of claim 2 to the subject.
10. A method of increasing the ratio of lean muscle mass to fat in a subject comprising administering a therapeutically effective amount of the composition of claim 2 to the subject.
11. A method of treating a muscle-wasting disease in a subject comprising administering a therapeutically effective amount of the composition of claim 2 to the subject.
12. The method of claim 11 , wherein the disease is selected from muscular dystrophy, amyotrophic lateral sclerosis, congestive obstructive pulmonary disease, chronic heart failure, cancer, AIDs, renal failure, uremia, rheumatoid arthritis, age-related sarcopenia, and muscle-wasting due to prolonged bedrest, spinal chord injury, stroke, bone fracture, and aging.
13. A method of detecting or measuring myostatin in a sample comprising contacting the sample with the binding agent of claim 1 and detecting or measuring the bound complex.
14. The binding agent of claim 1 , wherein F 1 comprises the sequence of SEQ ID NO:296.
15. The binding agent of claim 1 , wherein (L 1 )-P 1 comprises the sequence SEQ ID NO:617.
16. A binding agent capable of binding myostatin comprising a dimer of a polypeptide with the structure F 1 -(L 1 )-P 1 , wherein F 1 a human IgG Fc comprising the sequence of SEQ ID NO:296 and L 1 is (Gly) 5 , wherein the binding agent further comprises AQ and P 1 is SEQ ID NO: 311.
17. A pharmaceutical composition comprising a therapeutically effective amount of the binding agent of claim 16 in admixture with a pharmaceutically acceptable carrier thereof.
18. An isolated nucleic acid molecule comprising a polynucleotide encoding a monomer of the binding agent of claim 16 .
19. An expression vector comprising the polynucleotide of claim 18 .
20. A host cell comprising the expression vector of claim 19 .
21. A host cell comprising the expression vector of claim 19 , wherein the host cell is an E. coli cell.
22. A method of making a myostatin binding agent comprising culturing the host cell of claim 21 under conditions suitable for expressing the binding agent, and purifying the binding agent.
23. A method of inhibiting myostatin activity in a subject comprising administering an effective amount of the composition of claim 17 to the subject.
24. A method of increasing lean muscle mass in a subject comprising administering the composition of claim 17 to the subject.
25. A method of increasing the ratio of lean muscle mass to fat in a subject comprising administering a therapeutically effective amount of the composition of claim 17 to the subject.
26. A method of treating a muscle-wasting disease in a subject comprising administering a therapeutically effective amount of the composition of claim 17 to the subject.
27. The method of claim 26 , wherein the disease is selected from muscular dystrophy, amyotrophic lateral sclerosis, congestive obstructive pulmonary disease, chronic heart failure, cancer, AIDs, renal failure, uremia, rheumatoid arthritis, age-related sarcopenia, and muscle-wasting due to prolonged bedrest, spinal chord injury, stroke, bone fracture, and aging.
28. A method of detecting or measuring myostatin in a sample comprising contacting the sample with a binding agent of claim 16 and detecting or measuring the bound complex.