Myostatin binding agents

Abstract

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 wherein said agent has the structure:
 (X1)a-F1-(X2)b, or multimers thereof;   wherein F1 is a vehicle; and X1 and X2 are each independently selected from   -(L1)c-P1;   -(L1)c-P1-(L2)d-P2;   -(L1)c-P1-(L2)d-P2-(L3)e-P3;   and -(L1)c-P1-(L2)d-P2-(L3)e-P3-(L4)f-P4;   wherein P1, P2, P3, and P4 are peptides capable of binding myostatin, and are independently selected from SEQ ID NO: 305 through 351 and SEQ ID NO: 357 through 454;   wherein L1, L2, L3, and L4 are each linkers;   and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a and b is 1, and physiologically acceptable salts thereof.   
     
     
         2 . The binding agent of  claim 1 , wherein the binding agent has the structure F1-(L1)c-P1 or F1-(L1)c-P1-(L2)d-P2. 
     
     
         3 . The binding agent of  claim 2 , wherein the peptide is selected from any one of SEQ ID NO: 305-308, 310-313, 315-331, 333, 335-346, wherein F1 is an Fc domain. 
     
     
         4 . The binding agent of  claim 1  comprising the structure F1-(L1)-P1, wherein F1 is a human IgG Fc, wherein L1 is (Gly)5 (SEQ ID NO: 635), wherein the binding agent further comprises AQ and wherein P1 is selected from SEQ ID NO: 311, SEQ ID NO: 325, SEQ ID NO: 326, SEQ ID NO: 336, SEQ ID NO: 337, and SEQ ID NO: 345. 
     
     
         5 . A pharmaceutical composition comprising a therapeutically effective amount of the binding agent of  claim 1  in admixture with a pharmaceutically acceptable carrier thereof. 
     
     
         6 . An isolated polynucleotide encoding the binding agent of  claim 1 . 
     
     
         7 . The isolated polynucleotide of  claim 6 , wherein the polynucleotide is selected from any one of SEQ ID NO: 573 through 614, and 616, 618, 620, 622, 624, 626, 628, 630, 632. 
     
     
         8 . An expression vector comprising the polynucleotide of  claim 6 . 
     
     
         9 . A host cell comprising the expression vector of  claim 8 . 
     
     
         10 . The host cell of  claim 9 , wherein the host cell is an  E. coli  cell. 
     
     
         11 . A method of making a myostatin binding agent comprising culturing the host cell of  claim 9  under conditions suitable for expressing the binding agent, and purifying the binding agent. 
     
     
         12 . A method of inhibiting myostatin activity in a subject comprising administering an effective amount of the pharmaceutical composition of  claim 5  to the subject. 
     
     
         13 . A method of increasing lean muscle mass in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 5  to the subject. 
     
     
         14 . A method of increasing the ratio of lean muscle mass to fat in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 5  to the subject. 
     
     
         15 . A method of treating a muscle-wasting disease in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 5  to the subject. 
     
     
         16 . The method of  claim 15 , 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. 
     
     
         17 . A method of treating a myostatin-related metabolic disorder in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 5  to the subject. 
     
     
         18 . The method of  claim 17 , wherein the metabolic disorder is selected from diabetes, obesity, hyperglycemia, and bone loss. 
     
     
         19 . 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. 
     
     
         20 . A kit comprising the binding agent of  claim 1  and instructions for use.