Activin Type 2 Receptor Binding Proteins and Methods of Making Them
This disclosure provides ActRII-binding proteins such as anti-ActRIIA and anti-ActRIIB antibodies, and compositions and methods for making the ActRII-binding proteins. In certain aspects the ActRII-binding proteins inhibit, or antagonize, ActRII activity. In addition, the disclosure provides compositions and methods for diagnosing and treating diseases and conditions associated muscle wasting; a fibrotic condition; an inflammatory, cardiovascular, pulmonary, musculoskeletal, neurologic, ocular, skeletal, autoimmune, or metabolic disease or condition; wound healing; and cancer, and other ActRII-mediated diseases and conditions.
1 . An activin receptor type II (ActRII)-binding antibody comprising a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VLCDR3, wherein VH-CDR1, VH-CDR2, and VH-CDR3 are VH-CDR1, VH-CDR2, and VH-CDR3 in SEQ ID NO:125, respectively, and VL-CDR1, VL-CDR2, and VL-CDR3 are VL-CDR1, VL-CDR2, and VL-CDR3 in SEQ ID NO:132, respectively, wherein the antibody binds activin receptor type IIA (ActRIIA).
2 . An ActRII-binding antibody comprising a set of CDRs in which:
(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:126;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:127;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:128;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:133;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:134; and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:135,
wherein the antibody binds ActRIIA.
3 . The ActRII-binding antibody of claim 2 , which comprises a VH sequence having at least 90% identity to SEQ ID NO:125 and a VL sequence having at least 90% identity to SEQ ID NO:132.
4 . The ActRII-binding antibody of claim 2 , which comprises a VH sequence of SEQ ID NO:125 and a VL sequence of SEQ ID NO:132.
5 . The ActRII-binding antibody of claim 2 , wherein the antibody has at least one characteristic selected from:
(a) competing with activin A, activin B, BMP7, BMP9, BMP10, GDF8 (myostatin), GDF11, or Nodal, for binding to ActRIIA;
(b) decreasing the phosphorylation of one or more Smads in cells expressing ActRIIA in the presence of an ActRIIA ligand;
(c) decreasing the phosphorylation of ALK4 and/or ALK7 in cells expressing ActRIIB and/or ActRIIA and ALK4 and/or ALK7 in the presence of an ActRIIA ligand; and
(d) binding to ActRIIA with a K D of ≤1 nM and ≥1 pM as determined by BIACORE® analysis.
6 . The ActRII-binding antibody of claim 2 , wherein the antibody is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a bi-specific antibody, a multi-specific antibody, or an ActRII-binding antibody fragment.
7 . The ActRII-binding antibody of claim 6 , wherein the ActRII-binding antibody fragment is selected from a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule.
8 . The ActRII-binding antibody of claim 2 , wherein the antibody further comprises a heavy chain immunoglobulin constant domain selected from:
(a) a human IgA constant domain;
(b) a human IgD constant domain;
(c) a human IgE constant domain;
(d) a human IgG 1 constant domain;
(e) a human IgG2 constant domain;
(f) a human IgG3 constant domain;
(g) a human IgG4 constant domain; and
(h) a human IgM constant domain.
9 . The ActRII-binding antibody of claim 2 , wherein the antibody further comprises a light chain immunoglobulin constant domain selected from:
(a) a human lg kappa constant domain; and
(b) a human lg lambda constant domain.
10 . The ActRII-binding antibody of claim 2 , wherein the antibody further comprises a human IgG1 heavy chain constant domain and a human lambda light chain constant domain.
11 . A nucleic acid molecule or a set of nucleic acid molecules encoding the ActRII-binding antibody according to claim 2 .
12 . A vector comprising the nucleic acid molecule or the set of nucleic acid molecules according to claim 11 .
13 . A host cell comprising the nucleic acid molecule or the set of nucleic acid molecules of claim 10 .
14 . A method of making an ActRII-binding antibody, said method comprising culturing the host cell according to claim 13 under suitable conditions for producing the ActRII-binding antibody.
15 . An ActRII-binding antibody produced using the method of claim 14 .
16 . A pharmaceutical composition comprising an ActRII-binding antibody according to claim 2 and a pharmaceutically acceptable carrier.