Methods of increasing muscle mass by administration of activin type 2 receptor antibodies
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. A method for increasing muscle mass in a subject, comprising administering to a subject in need thereof an ActRII-binding antibody comprising a set of CDRs in which:
(i) VH-CDR1 has the amino acid sequence of SEQ ID NO:166;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:167;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:168;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:173;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:174; and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:175;
and wherein the antibody binds ActRIIB.
2. The method of claim 1 , wherein the subject has a disease or condition selected from a degenerative muscle disease, muscular dystrophy, muscle atrophy, and muscle wasting.
3. The method of claim 1 , wherein the ActRII-binding antibody is administered alone or as part of a combination therapy.
4. The method of claim 1 , wherein the ActRII-binding antibody comprises a VH sequence of SEQ ID NO:165 and a VL sequence of SEQ ID NO:172.
5. The method of claim 1 , wherein the ActRII-binding 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 ActRIIB or ActRIIA;
(b) decreasing the phosphorylation of one or more Smads in cells expressing ActRIIB and/or ActRIIA in the presence of an ActRIIB or ActRIIA ligand;
(c) decreasing the phosphorylation of ALK4 or ALK7 in cells expressing ActRIIB or ActRIIA and ALK4 or ALK7 in the presence of an ActRIIB or ActRIIA ligand; and
(d) binding to ActRIIB or ActRIIA with a KD of ≤1 nM and ≥1 pM, as determined by BIACORE® analysis.
6. The method of claim 1 , wherein the ActRII-binding 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 method of claim 6 , wherein the ActRII-binding antibody fragment is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, an Fv fragment, a diabody, or a single chain antibody molecule.
8. The method of claim 6 , wherein the ActRII-binding 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 IgG1 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 method of claim 6 , wherein the ActRII-binding antibody further comprises a light chain immunoglobulin constant domain selected from:
(a) a human Ig kappa constant domain; and
(b) a human Ig lambda constant domain.
10. The method of claim 6 , wherein the ActRII-binding antibody further comprises a human IgG1 heavy chain constant domain and a human lambda light chain constant domain.