ACTRIIB BINDING AGENTS AND USES THEREOF
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.