Methods for treating metabolic diseases by inhibiting myostatin activation

Abstract

The present invention relates to antibodies, or antigen-binding fragments thereof, that specifically bind proMyostatin and/or latent Myostatin, and methods and uses thereof for treating metabolic diseases.

1 - 20 . (canceled) 
     
     
         21 . A method of treating a metabolic disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a myostatin-selective inhibitor, wherein the pharmaceutical composition has been prepared by a process comprising screening for an antibody or an antigen-binding fragment thereof that selectively binds to myostatin and/or a protein complex comprising myostatin and is capable of decreasing expression of pyruvate dehydrogenase kinase 4 (PDK4) and increasing expression of pyruvate dehydrogenase phosphatase 1 (PDP1) after administration. 
     
     
         22 . The method of  claim 21 , wherein the pharmaceutical composition is administered in conjunction with a calorie restricted diet. 
     
     
         23 . The method of  claim 21 , wherein the preparation of the pharmaceutical composition comprises culturing a host cell comprising one or more polynucleotides encoding the antibody or antigen-binding fragment under conditions that allow for expression of the antibody or antigen-binding fragment. 
     
     
         24 . The method of  claim 21 , wherein the preparation of the pharmaceutical composition comprises purifying the antibody or antigen-binding fragment from the culture. 
     
     
         25 . The method of  claim 21 , wherein the preparation of the pharmaceutical composition comprises formulating the antibody or antigen-binding fragment into a pharmaceutical composition suitable for administration to the subject, wherein the composition further comprises a pharmaceutically acceptable carrier or excipient. 
     
     
         26 . The method of  claim 21 , wherein the myostatin-selective inhibitor is administered in an amount effective to decrease expression of PDK4 and increase expression of PDP1 in the subject. 
     
     
         27 . The method of  claim 21 , wherein the metabolic disease is or comprises insulin resistance, inflammation, abnormal lipid metabolism, and/or an increase in intramuscular fat infiltration. 
     
     
         28 . The method of  claim 21 , wherein metabolic disease is obesity, metabolic syndrome, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and/or diabetes. 
     
     
         29 . The method of  claim 28 , wherein the obesity is diet-induced obesity, obesity associated with type II diabetes, or sarcopenic obesity. 
     
     
         30 . The method of  claim 28 , wherein the diabetes is type I diabetes or type II diabetes. 
     
     
         31 . The method of  claim 21 , wherein the myostatin-selective inhibitor is engineered to bind FcRn with greater affinity at pH 7.4 relative to a non-engineered counterpart. 
     
     
         32 . The method of  claim 21 , wherein the myostatin-selective inhibitor is administered subcutaneously. 
     
     
         33 . The method of  claim 21 , wherein the host cells are CHO cells, 293 cells, or NS0 cells. 
     
     
         34 . The method of  claim 21 , wherein the myostatin-selective inhibitor is an antibody or antigen-binding fragment that has been screened for the ability to bind to mature myostatin, GDF11, and/or Activin A, wherein the antibody or antigen-binding fragment does not bind to mature myostatin, GDF11, or Activin A. 
     
     
         35 . The method of  claim 21 , wherein the myostatin-selective inhibitor is an antibody or antigen-binding fragment that binds to pro/latent myostatin. 
     
     
         36 . The method of  claim 21 , further comprising administering to the subject an insulin secretion-promoting agent. 
     
     
         37 . The method of  claim 21 , wherein the subject is a human subject. 
     
     
         38 . The method of  claim 21 , wherein the subject is on an exercise regimen. 
     
     
         39 . The method of  claim 21 , wherein the subject is not on an exercise regimen and/or is physical activity-limited. 
     
     
         40 . The method of  claim 21 , wherein myostatin-selective inhibitor is administered in an amount effective to:
 (a) increase expression of SHARP1 in the subject;   (b) decrease expression of MYL2, MYL4, and/or TNNC1 in the subject; and/or,   (c) decrease expression of PGC1A, NOR1, UCP1, and/or NUR77 in the subject.   
     
     
         41 . The method of  claim 21 , wherein the administration is sufficient to cause at least one of the following in the subject:
 (a) increase in mass and/or function of a muscle tissue;   (b) increase in mass and/or function of a fast twitch muscle tissue;   (c) increase in mass and/or function of a slow twitch muscle tissue;   (d) increase in metabolic rate;   (e) increase in insulin sensitivity;   (f) increase in the level of brown adipose tissue;   (g) increase in the level of beige adipose tissue;   (h) decrease in the level of white adipose tissue;   (i) decrease in the level of visceral adipose tissue;   (j) decrease in the ratio of adipose-to-muscle tissue;   (k) increase in glucose uptake by a target tissue, wherein the target tissue is brown adipose tissue, beige adipose tissue, or muscle tissue;   (l) decrease in glucose uptake by a target tissue, wherein the target tissue is a white adipose tissue or a liver tissue;   (m) decrease in muscle catabolism of protein and/or muscle release of amino acids;   (n) increase in insulin dependent glycemic control;   (o) decrease in intramuscular fat infiltration;   (p) prevention of muscle loss or atrophy;   (q) increase in bone density or volume; and   (r) prevention or reduction of bone loss or fracture.