Methods for inhibiting myostatin activation by administering anti-pro/latent myostatin antibodies

1. A method for inhibiting myostatin activation in a subject, the method comprising a step of:

administering to the subject a composition comprising an antibody, or antigen binding fragment thereof, that specifically binds pro-myostatin and latent myostatin and blocks release of mature myostatin, in an amount effective to cause two or more of the following in the subject:

(a) an increase in mass and/or function of a muscle tissue in the subject;

(b) a decrease in ratio of adipose-to-muscle tissue in the subject;

(c) a decrease in intramuscular fat infiltration in the subject; and

(d) prevention of muscle loss or atrophy in the subject;

wherein the subject is a human subject that benefits from reduced myostatin signaling;

wherein the amount is an amount that causes an increase in a level of circulating latent myostatin in a serum sample, as compared to a control; and,

wherein the antibody, or antigen binding fragment thereof, comprises any one of the following:

i) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 24 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 30;

ii) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to SEQ ID NO:1, a CDRH2 sequence that is at least 90% identical to SEQ ID NO:4, and a CDRH3 sequence that is at least 90% identical to SEQ ID NO:10, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to SEQ ID NO:12, a CDRL2 sequence that is at least 90% identical to SEQ ID NO:18, and a CDRL3 sequence that is at least 90% identical to SEQ ID NO:22;

iii) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 25 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 31;

iv) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 26 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 32;

v) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to SEQ ID NO:1, a CDRH2 sequence that is at least 90% identical to SEQ ID NO:6, and a CDRH3 sequence that is at least 90% identical to SEQ ID NO:11, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to SEQ ID NO:14, a CDRL2 sequence that is at least 90% identical to SEQ ID NO:20, and a CDRL3 sequence that is at least 90% identical to SEQ ID NO:23;

vi) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 27 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 33;

vii) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 28 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 34;

viii) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to SEQ ID NO:1, a CDRH2 sequence that is at least 90% identical to SEQ ID NO:8, and a CDRH3 sequence that is at least 90% identical to SEQ ID NO:11, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to SEQ ID NO:16, a CDRL2 sequence that is at least 90% identical to SEQ ID NO:20, and a CDRL3 sequence that is at least 90% identical to SEQ ID NO:23;

ix) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 29 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 35;

x) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO:29, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO:29, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO:29, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO:35, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO:35, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO:35;

xi) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 73 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 74;

xii) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO:73, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO:73, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO:73, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO:74, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO:74, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO:74;

xiii) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 78 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 79;

xiv) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO:78, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO:78, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO:78, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO:79, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO:79, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO:79;

xv) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO: 83 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO: 84; or

xvi) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO:83, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO:83, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO:83, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO:84, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO:84, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO:84.

2. The method of claim 1 , further comprising a step of:

selecting the subject who is (i) suffering from a muscle condition or disorder; (ii) suffering from, or at risk of developing, a metabolic disorder; or both (i) and (ii).

3. The method of claim 1 , wherein the subject has a muscle condition selected from the group consisting of: myopathy, muscular atrophy, muscular dystrophy, and nerve injury.

4. The method of claim 3 , wherein the muscular atrophy is associated with spinal muscular atrophy (SMA).

5. The method of claim 3 , wherein the nerve injury comprises partial denervation of neurons that innervate muscle, or impaired signaling between a motor neuron and a target muscle.

6. The method of claim 3 , wherein the muscular atrophy is associated with myotrophic lateral sclerosis (ALS).

7. The method of claim 3 , wherein the muscular atrophy is associated with myasthenia gravis.

8. The method of claim 1 , wherein the subject has a metabolic disease selected from the group consisting of type I diabetes, type II diabetes, obesity, metabolic syndrome/pre-diabetes, cardiovascular disease, non-alcoholic steatohepatitis (NASH), a hypo-metabolic state, double diabetes, Cushings disease, metabolic myopathies, androgen deficiency and an obesity syndrome.

9. The method of claim 8 , wherein the metabolic myopathy is a glycogen storage diseases or a lipid storage disorder.

10. The method of claim 1 , wherein the subject is treated with a second therapy.

11. The method of claim 10 , wherein the second therapy comprises neuroprotective therapy or a stem cell therapy.