SELECTIVE AND POTENT INHIBITORY ANTIBODIES OF MYOSTATIN ACTIVATION
The present disclosure relates to antibodies and antigen-binding fragments that specifically bind to pro/latent myostatin and uses thereof.
1 - 113 . (canceled)
114 . A method of preserving lean mass in a subject, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to pro/latent myostatin, wherein the antibody or antigen-binding fragment comprises six complementarity determining regions (CDRs): H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2, and L-CDR3, wherein:
a) the H-CDR1 comprises the amino acid sequence of SEQ ID NO: 201, the H-CDR2 comprises the amino acid sequence of SEQ ID NO: 219, the H-CDR3 comprises the amino acid sequence of SEQ ID NO: 220, the L-CDR1 comprises the amino acid sequence of SEQ ID NO: 216, the L-CDR2 comprises the amino acid sequence of SEQ ID NO: 222, and the L-CDR3 comprises the amino acid sequence of SEQ ID NO: 223, wherein the CDR sequences are numbered according to Kabat numbering system;
b) the H-CDR1 comprises the amino acid sequence of SEQ ID NO: 234, the H-CDR2 2 comprises the amino acid sequence of SEQ ID NO: 235, the H-CDR3 comprises the amino acid sequence of SEQ ID NO: 236, the L-CDR1 comprises the amino acid sequence of SEQ ID NO: 237, the L-CDR2 comprises the amino acid sequence EVS, and the L-CDR3 comprises the amino acid sequence of SEQ ID NO: 239, wherein the CDR sequences are numbered according to Chothia numbering system; or
c) the H-CDR1 comprises the amino acid sequence of SEQ ID NO: 3, the H-CDR2 comprises the amino acid sequence of SEQ ID NO: 256, the H-CDR3 comprises the amino acid sequence of SEQ ID NO: 257, the L-CDR1 comprises the amino acid sequence of SEQ ID NO: 258, the L-CDR2 comprises the amino acid sequence EVS, and the L-CDR3 comprises the amino acid sequence of SEQ ID NO: 260, wherein the CDR sequences are numbered according to IMGT numbering system.
115 . A method of increasing motor function in a subject, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to pro/latent myostatin, wherein the antibody or antigen-binding fragment comprises six complementarity determining regions (CDRs): H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2, and L-CDR3, wherein:
a) the H-CDR1 comprises the amino acid sequence of SEQ ID NO: 201, the H-CDR2 comprises the amino acid sequence of SEQ ID NO: 219, the H-CDR3 comprises the amino acid sequence of SEQ ID NO: 220, the L-CDR1 comprises the amino acid sequence of SEQ ID NO: 216, the L-CDR2 comprises the amino acid sequence of SEQ ID NO: 222, and the L-CDR3 comprises the amino acid sequence of SEQ ID NO: 223, wherein the CDR sequences are numbered according to Kabat numbering system;
b) the H-CDR1 comprises the amino acid sequence of SEQ ID NO: 234, the H-CDR2 2 comprises the amino acid sequence of SEQ ID NO: 235, the H-CDR3 comprises the amino acid sequence of SEQ ID NO: 236, the L-CDR1 comprises the amino acid sequence of SEQ ID NO: 237, the L-CDR2 comprises the amino acid sequence EVS, and the L-CDR3 comprises the amino acid sequence of SEQ ID NO: 239, wherein the CDR sequences are numbered according to Chothia numbering system; or
c) the H-CDR1 comprises the amino acid sequence of SEQ ID NO: 3, the H-CDR2 comprises the amino acid sequence of SEQ ID NO: 256, the H-CDR3 comprises the amino acid sequence of SEQ ID NO: 257, the L-CDR1 comprises the amino acid sequence of SEQ ID NO: 258, the L-CDR2 comprises the amino acid sequence EVS, and the L-CDR3 comprises the amino acid sequence of SEQ ID NO: 260, wherein the CDR sequences are numbered according to IMGT numbering system.
116 . The method of claim 114 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 402, a light chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 412, or a combination thereof.
117 . The method of claim 114 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 402 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 412.
118 . The method of claim 114 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 503, a light chain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 504, or a combination thereof.
119 . The method of claim 114 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 503 and a light chain comprising the amino acid sequence of SEQ ID NO: 504.
120 . The method of claim 114 , wherein the antibody or antigen-binding fragment thereof is formulated in a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
121 . The method of claim 114 , wherein the subject has a muscle condition or disorder.
122 . The method of claim 121 , wherein the muscle condition or disorder is a neuromuscular disorder.
123 . The method of claim 121 , wherein the muscle condition or disorder is a myopathy or a muscular dystrophy.
124 . The method of claim 123 , wherein the muscular dystrophy is Duchenne's muscular dystrophy, Becker's muscular dystrophy, facioscapulohumeral muscular dystrophy, or Limb-Girdle muscular dystrophy.
125 . The method of claim 123 , wherein the muscular dystrophy is Duchenne's muscular dystrophy.
126 . The method of claim 123 , wherein the muscular dystrophy is facioscapulohumeral muscular dystrophy.
127 . The method of claim 121 , wherein the muscle condition or disorder is spinal muscular atrophy (SMA).
128 . The method of claim 121 , wherein the muscle condition or disorder is amyotrophic lateral sclerosis (ALS).
129 . The method of claim 114 , wherein administration of the antibody or antigen-binding fragment thereof decreases muscle loss or atrophy.
130 . The method of claim 114 , wherein of the antibody or antigen-binding fragment thereof is administered subcutaneously.
131 . A method of preserving lean mass in a subject who has spinal muscular atrophy (SMA), comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to pro/latent myostatin wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 402 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 412.
132 . The method of claim 131 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 503 and a light chain comprising the amino acid sequence of SEQ ID NO: 504.
133 , method of claim 131 , wherein of the antibody or antigen-binding fragment thereof is administered subcutaneously.