Actriib binding agents and uses thereof

Abstract

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

1 . An anti-ActRIIB antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO:1. 
     
     
         2 . The anti-ActRIIB antibody or functional fragment thereof according to  claim 1 , wherein the anti-ActRIIB antibody or functional fragment thereof binds to ActRIIB with a K D  of 1 nM or less. 
     
     
         3 . The anti-ActRIIB antibody or functional fragment thereof according to  claim 1 , wherein the anti-ActRIIB antibody or functional fragment thereof inhibits myostatin binding to ActRIIB. 
     
     
         4 . The anti-ActRIIB antibody or functional fragment thereof according to  claim 1 , wherein the anti-ActRIIB antibody or functional fragment thereof inhibits myostatin induced signaling as measured by a Smad dependent reporter gene assay. 
     
     
         5 . The anti-ActRIIB antibody or functional fragment thereof according to  claim 1 , wherein the anti-ActRIIB antibody or functional fragment thereof binds to ActRIIB with a 10-fold or greater affinity that it binds to ActRIIA. 
     
     
         6 . The anti-ActRIIB antibody or functional fragment thereof according to  claim 1 , wherein the anti-ActRIIB antibody or functional fragment thereof binds to an epitope selected from the group consisting of: amino acids 77-83 of SEQ ID NO:1, amino acids 60-64 of SEQ ID NO:1, 73-74 of SEQ ID NO:1, amino acids 73-83 of SEQ ID NO:1, amino acids 98-101 of SEQ ID NO:1; amino acids 35-39 of SEQ ID NO:1 and amino acids 52-55 of SEQ ID NO:1. 
     
     
         7 . The anti-ActRIIB antibody or functional fragment thereof according to  claim 1 , wherein the anti-ActRIIB antibody or functional fragment thereof is of the IgG1 isotype. 
     
     
         8 . The anti-ActRIIB antibody or functional fragment thereof according to  claim 1 , wherein the anti-ActRIIB antibody or functional fragment thereof is characterized by an altered effector function through mutation of the Fc region. 
     
     
         9 . An isolated polynucleotide sequence encoding the antibody or functional fragment thereof according to  claim 1 . 
     
     
         10 . A cloning or expression vector comprising the isolated polynucleotide sequence according to  claim 9 . 
     
     
         11 . An isolated host cell comprising the vector according to  claim 10 . 
     
     
         12 . A process for the production of an antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO:1, comprising culturing the host cell of  claim 11  and isolating the antibody or functional fragment thereof. 
     
     
         13 . A pharmaceutical composition comprising the anti-ActRIIB antibody or functional fragment thereof according to  claim 1 . 
     
     
         14 . The pharmaceutical composition of  claim 13 , where the composition further comprises a pharmaceutically acceptable diluent or carrier. 
     
     
         15 . The antibody or fragment thereof of  claim 2  that comprises at least one, at least two, at least three, at least four, at least five or at least six CDR sequences having at least 80% identity to a CDR selected from the group consisting of SEQ ID NOs: 37-42. 
     
     
         16 . The antibody or fragment thereof according to  claim 15  wherein said percent identity is at least 85%. 
     
     
         17 . The antibody or fragment thereof according to  claim 15  wherein said percent identity is at least 90%. 
     
     
         18 . The antibody or fragment thereof according to  claim 15  wherein said percent identity is at least 95%. 
     
     
         19 . The antibody or fragment thereof according to  claim 15  wherein said percent identity is 100%. 
     
     
         20 . An isolated antibody or functional fragment thereof capable of binding to the following epitopes of ActRIIB: (a) amino acids 77-83 of SEQ ID NO: 1 (CWLDDFN); (b) amino acids 52-55 (EQDK); (c) 60-64 amino acids (YASWR) of SEQ ID NO: 1; and (d) amino acids 73-83 of SEQ ID NO: 1 (VKKGCWLDDFN). 
     
     
         21 . The antibody or functional fragment thereof according to  claim 20 , wherein said antibody or functional fragment thereof is of the IgG1 isotype. 
     
     
         22 . The antibody or functional fragment thereof according to  claim 20 , which has altered effector function through mutation of the Fc region. 
     
     
         23 . An isolated polynucleotide encoding an antibody or functional fragment thereof capable of binding to the following epitopes of ActRIIB: (a) amino acids 77-83 of SEQ ID NO: 1 (CWLDDFN); (b) amino acids 52-55 (EQDK); (c) amino acids 60-64 (YASWR) of SEQ ID NO: 1; and (d) amino acids 73-83 of SEQ ID NO: 1 (VKKGCWLDDFN). 
     
     
         24 . A cloning or expression vector comprising an isolated polynucleotide according to  claim 23 . 
     
     
         25 . An isolated host cell comprising a vector according to  claim 24 . 
     
     
         26 . A composition comprising an isolated polynucleotide of  claim 23 . 
     
     
         27 . An isolated antibody or functional fragment thereof which is: (a) capable of binding to the epitope of amino acids 77-83 of SEQ ID NO: 1 (CWLDDFN); (b) capable of binding to the epitope of amino acids 52-55 (EQDK); and (c) amino acids 60-64 (YASWR) of SEQ ID NO: 1. 
     
     
         28 . The antibody or functional fragment thereof according to  claim 27 , wherein said antibody or functional fragment thereof is of the IgG1 isotype. 
     
     
         29 . The antibody of functional fragment thereof according to  claim 27 , which has altered effector function through mutation of the Fc region. 
     
     
         30 . A composition comprising the antibody or functional fragment thereof of  claim 27 . 
     
     
         31 . The composition according to  claim 30 , further comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         32 . An isolated human antibody or functional fragment thereof which is: (a) capable of binding to the epitope of amino acids 77-83 of SEQ ID NO: 1 (CWLDDFN); (b) capable of binding to the epitope of amino acids 52-55 (EQDK); and (c) amino acids 60-64 (YASWR) of SEQ ID NO: 1. 
     
     
         33 . The antibody or functional fragment thereof according to  claim 32 , wherein said antibody or functional fragment thereof is of the IgG1 isotype. 
     
     
         34 . The antibody of functional fragment thereof according to  claim 32 , which has altered effector function through mutation of the Fc region. 
     
     
         35 . A composition comprising the antibody or functional fragment thereof of  claim 32 . 
     
     
         36 . The composition according to  claim 35 , further comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         37 . An isolated antibody or functional fragment thereof capable of binding to each of the following epitopes of ActRIIB: (a) amino acids 78-83 of SEQ ID NO: 1 (WLDDFN); (b) amino acids 49-63 of SEQ ID NO: 1 (CEGEQDKRLHCYASW); and (c) amino acids 76-84 of SEQ ID NO: 1 (GCWLDDFNC). 
     
     
         38 . The antibody or functional fragment thereof according to  claim 37 , wherein said antibody or functional fragment thereof is of the IgG1 isotype. 
     
     
         39 . The antibody or functional fragment thereof according to  claim 37 , which has altered effector function through mutation of the Fc region. 
     
     
         40 . An isolated polynucleotide encoding an antibody or functional fragment thereof capable of binding to each of the following epitopes of ActRIIB: (a) amino acids 78-83 of SEQ ID NO: 1 (WLDDFN); (b) amino acids 49-63 of SEQ ID NO: 1 (CEGEQDKRLHCYASW); and (c) amino acids 76-84 of SEQ ID NO: 1 (GCWLDDFNC). 
     
     
         41 . A cloning or expression vector comprising one or more copies of an isolated polynucleotide according to  claim 40 . 
     
     
         42 . An isolated host cell comprising one or more copies of a vector according to  claim 41 . 
     
     
         43 . A composition comprising an isolated polynucleotide of  claim 40 . 
     
     
         44 . An isolated antibody or functional fragment thereof which is: (a) capable of binding to an epitope consisting of amino acids 78-83 of SEQ ID NO: 1 (WLDDFN); and (b) capable of binding to an epitope consisting of amino acids 49-63 of SEQ ID NO: 1 (CEGEQDKRLHCYASW). 
     
     
         45 . The antibody or functional fragment thereof according to  claim 44 , wherein said antibody or functional fragment thereof is of the IgG1 isotype. 
     
     
         46 . The antibody or functional fragment thereof according to  claim 44 , which has altered effector function through mutation of the Fc region. 
     
     
         47 . A composition comprising an antibody or functional fragment thereof of  claim 44 . 
     
     
         48 . The composition according to  claim 47 , further comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         49 . An isolated human antibody or functional fragment thereof which is: (a) capable of binding to an epitope consisting of amino acids 78-83 of SEQ ID NO: 1 (WLDDFN); and (b) capable of binding to an epitope consisting of amino acids 49-63 of SEQ ID NO: 1 (CEGEQDKRLHCYASW). 
     
     
         50 . The antibody or functional fragment thereof according to  claim 49 , wherein said antibody or functional fragment thereof is of the IgG1 isotype. 
     
     
         51 . The antibody or functional fragment thereof according to  claim 49 , which has altered effector function through mutation of the Fc region. 
     
     
         52 . A composition comprising an antibody or functional fragment thereof of  claim 49 . 
     
     
         53 . The composition according to  claim 52 , further comprising a pharmaceutically acceptable diluent or carrier.