Actriia binding agents and uses thereof

Abstract

The disclosure provides, among other aspects, neutralizing antibodies and portions thereof that bind to ActRIIA and uses for same.

1 . A method for treating a patient having a condition characterized by muscle loss or damage, the method comprising administering an isolated antibody or fragment thereof that binds to human ActRIIa and cross-blocks the binding of Ab-14E1 to human ActRIIA, and wherein the antibody Ab-14E1 comprises: a) the heavy chain variable region CDR1 of SEQ ID NO: 4, b) the heavy chain variable region CDR2 of SEQ ID NO: 5, c) the heavy chain variable region CDR3 of SEQ ID NO: 6, d) the light chain variable region CDR1 of SEQ ID NO: 7, e) the light chain variable region CDR2 of SEQ ID NO: 8, and f) the light chain variable region CDR3 of SEQ ID NO: 9. 
     
     
         2 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the antibody or fragment thereof contacts one or more amino acids in the extracellular domain of human ActRIIA, selected from a group consisting of:
 a. a phenylalanine at position 13 of SEQ ID NO: 16,   b. a phenylalanine at position 14 of SEQ ID NO: 16,   c. an asparagine at position 15 of SEQ ID NO: 16,   d. an asparagine at position 17 of SEQ ID NO: 16,   e. an aspartate at position 21 of SEQ ID NO: 16,   f. an arginine at position 22 of SEQ ID NO: 16,   g. a threonine at position 23 of SEQ ID NO: 16,   h. a glutamate at position 29 of SEQ ID NO: 16,   i. a proline at position 30 of SEQ ID NO: 16,   j. a cysteine at position 31 of SEQ ID NO: 16,   k. a tyrosine at position 32 of SEQ ID NO: 16,   l. a glycine at position 33 of SEQ ID NO: 16,   m. an aspartate at position 34 of SEQ ID NO: 16,   n. an aspartate at position 36 of SEQ ID NO: 16,   o. a lysine at position 37 of SEQ ID NO: 16,   p. an arginine at position 39 of SEQ ID NO: 16,   q. a histidine at position 40 of SEQ ID NO: 16,   r. a phenylalanine at position 42 of SEQ ID NO: 16,   s. a threonine at position 44 of SEQ ID NO: 16,   t. a lysine at position 46 of SEQ ID NO: 16,   u. a valine at position 55 of SEQ ID NO: 16,   v. a lysine at position 56 of SEQ ID NO: 16,   w. a glutamine at position 57 of SEQ ID NO: 16,   x. a glycine at position 58 of SEQ ID NO: 16,   y. a cysteine at position 59 of SEQ ID NO: 16,   z. a tryptophan at position 60 of SEQ ID NO: 16,   aa. a leucine at position 61 of SEQ ID NO: 16,   bb. an aspartate at position 62 of SEQ ID NO: 16,   cc. an aspartate at position 63 of SEQ ID NO: 16,   dd. an isoleucine at position 64 of SEQ ID NO: 16,   ee. an asparagine at position 65 of SEQ ID NO: 16,   ff. a cysteine at position 66 of SEQ ID NO: 16,   gg. a lysine at position 76 of SEQ ID NO: 16,   hh. a glutamate at position 80 of SEQ ID NO: 16,   ii. a valine at position 81 of SEQ ID NO: 16,   jj. a phenylalanine at position 83 of SEQ ID NO: 16, and   kk. a cysteine at position 85 of SEQ ID NO: 16.   
     
     
         7 - 16 . (canceled) 
     
     
         17 . The method according to  claim 1 , in which the condition is characterized by insufficient lean body mass. 
     
     
         18 . The method according to  claim 1 , in which the condition is characterized by a decrease in muscle mass or muscle function. 
     
     
         19 . The method according to  claim 1 , in which the condition is cancer cachexia or sarcopenia. 
     
     
         20 . The method according to  claim 1 , in which the patient has undesirably high levels of follicle-stimulating hormone. 
     
     
         21 . The method according to  claim 1 , wherein the antibody or fragment thereof is formulated as part of a pharmaceutical composition. 
     
     
         22 . The method to  claim 24 , wherein the antibody or fragment thereof is formulated in combination with one or more of a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         23 . The method according to  claim 1  wherein the antibody or fragment is conjugated to at least one of Fc, polyethylene glycol, albumin, and transferrin. 
     
     
         24 . The method according to  claim 1 , wherein the antibody or fragment is selected from: an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, an IgG4 antibody, an IgG2/G4 hybrid antibody, an IgE antibody, an IgM antibody, an IgD antibody, or an IgA antibody. 
     
     
         25 . The method according to  claim 1 , wherein the antibody or fragment, wherein the antibody is a fragment selected from: an F(ab′) 2  fragment, an Fab fragment, an Fab′ fragment, an Fv fragment, or an Fd fragment. 
     
     
         26 . The method according to  claim 1 , wherein the antibody or fragment thereof is a monoclonal antibody. 
     
     
         27 . The method according to  claim 1 , wherein the antibody or fragment thereof is a chimeric antibody. 
     
     
         28 . The method according to  claim 1 , wherein the antibody or fragment thereof is humanized. 
     
     
         29 . The method according to  claim 1 , wherein the antibody or fragment thereof is a human antibody. 
     
     
         30 . The method of  claim 1 , wherein the condition is selected from the group consisting of: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), fascioscapulohumeral muscular dystrophy (FSH or FSHD) (also known as Landouzy-Dejerine), myotonic muscular dystrophy (MMD), oculopharyngeal muscular dystrophy (OPMD), distal muscular dystrophy (DD), congenital muscular dystrophy (CMD), and scapulohumeral muscular dystrophy (SMD).