METHODS FOR TREATING METABOLIC DISEASES BY INHIBITING MYOSTATIN ACTIVATION
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 reducing the frequency of bone fracture in a subject having a muscle condition or disorder who has experienced at least one previous bone fracture, comprising administering to the subject an antibody or antigen-binding fragment thereof,
wherein the antibody or antigen-binding fragment thereof comprises six complementarity determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein:
a) CDRH1 comprises the amino acid sequence of SEQ ID NO: 1, CDRH2 comprises the amino acid sequence of SEQ ID NO: 4, CDRH3 comprises the amino acid sequence of SEQ ID NO: 10, CDRL1 comprises the amino acid sequence of SEQ ID NO: 12, CDRL2 comprises the amino acid sequence of SEQ ID NO: 18, and CDRL3 comprises the amino acid sequence of SEQ ID NO: 22, wherein the CDR sequences are numbered according to Kabat numbering system; or
b) CDRH1 comprises the amino acid sequence of SEQ ID NO: 2, CDRH2 comprises the amino acid sequence of SEQ ID NO: 5, CDRH3 comprises the amino acid sequence of SEQ ID NO: 10, CDRL1 comprises the amino acid sequence of SEQ ID NO: 13, CDRL2 comprises the amino acid sequence of SEQ ID NO: 19, and CDRL3 comprises the amino acid sequence of SEQ ID NO: 22, wherein the CDR sequences are numbered according to IMGT numbering system.
22 . The method of claim 21 , wherein the muscle condition or disorder is a myopathy or a muscular dystrophy.
23 . The method of claim 21 , wherein the muscle condition or disorder is a disease with an impaired neurological signaling.
24 . The method of claim 23 , wherein the disease with an impaired neurological signaling is spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), or myasthenia gravis.
25 . The method of claim 23 , wherein the disease with an impaired neurological signaling is spinal muscular atrophy (SMA).
26 . The method of claim 22 , wherein the muscular dystrophy is Duchenne's muscular dystrophy (DMD).
27 . The method of claim 21 , wherein the antibody or antigen-binding fragment thereof is administered to the subject in an amount effective to cause one or more of the following in the subject:
a) an increase in bone mineral density in a weight bearing or a non-weight-bearing bone;
b) an increase in volume in a weight bearing or a non-weight-bearing bone;
c) prevention or retardation of bone loss;
d) a reduction in the degree of bone fracture;
e) an increase in the rate of bone repair; or
f) enhancement of bone homeostasis.
28 . The method of claim 27 , wherein the enhancement of bone homeostasis comprises improving one or more of: relative bone volume; trabecular bone volume; trabecular number; trabecular thickness; trabecular spacing/separation; bone cross section; cortical bone area; cortical endosteal perimeter; cortical periosteal perimeter; cortical porosity; and cortical cross section thickness in a subject.
29 . The method of claim 21 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25, a light chain variable region comprising the amino acid sequence of SEQ ID NO: 31, or a combination thereof.
30 . The method of claim 21 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 31.
31 . The method of claim 30 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain comprising the amino acid sequence of SEQ ID NO: 51.
32 . The method of claim 31 , wherein the N-terminal glutamine (Q) of the heavy chain is a pyroglutamic acid residue and the N-terminal glutamine (Q) of the light chain is a pyroglutamic acid residue.
33 . The method of claim 21 , wherein the myostatin inhibitor blocks activation of mature myostatin and/or blocks release of mature myostatin.
34 . The method of claim 21 , wherein the myostatin inhibitor specifically binds to pro/latent myostatin.
35 . The method of claim 21 , wherein the antibody does not bind mature myostatin.
36 . The method of claim 21 , wherein the subject has ambulatory Type 3 SMA.
37 . The method of claim 21 , wherein the subject has Type 2 SMA or non-ambulatory Type 3 SMA.
38 . The method of claim 21 , wherein the subject is on a neuronal corrector therapy.
39 . The method of claim 21 , wherein the subject has not received a neuronal corrector therapy or is not a candidate for a neuronal corrector therapy.
40 . The method of claim 39 , wherein the subject is not a candidate for a neuronal corrector therapy and has undergone a spinal fusion procedure.