Anti-activin A antibodies and uses thereof
The disclosure provides compositions and methods relating to or derived from anti-activin A binding proteins, including antibodies. In particular embodiments, the disclosure provides fully human, humanized, and chimeric anti-activin A antibodies that bind human activin A, activin A-binding fragments and derivatives of such antibodies, and activin A-binding polypeptides comprising such fragments. Other embodiments provide nucleic acids encoding such antibodies, antibody fragments and derivatives and polypeptides, cells comprising such polynucleotides, methods of making such antibodies, antibody fragments and derivatives and polypeptides, and methods of using such antibodies, antibody fragments and derivatives and polypeptides, including methods of treating or diagnosing subjects having activin A-related disorders or conditions including cachexia related to gonadal cancer, other cancers, rheumatoid arthritis, and other diseases.
1. An isolated antibody or antigen binding fragment thereof, comprising:
a. a light chain variable domain (VL) comprising:
i. a light chain CDR1 sequence of SEQ ID NO:11;
ii. a light chain CDR2 sequence of SEQ ID NO:12; and
iii. a light chain CDR3 sequence of SEQ ID NO:13; and
b. a heavy chain variable domain (VH) comprising:
i. a heavy chain CDR1 sequence of SEQ ID NO:62;
ii. a heavy chain CDR2 sequence of SEQ ID NO:63; and
iii. a heavy chain CDR3 sequence of SEQ ID NO:64,
wherein said antibody or antigen binding fragment thereof binds specifically to human activin A.
2. The isolated antibody or antigen binding fragment thereof of claim 1 , comprising either:
a. a light chain variable domain sequence of SEQ ID NO:9;
b. a heavy chain variable domain sequence of SEQ ID NO:10; or
c. the light chain variable domain of (a) and the heavy chain variable domain of (b).
3. The isolated antibody or antigen binding fragment thereof of claim 1 that, when bound to activin A:
a. inhibits activin A;
b. cross-competes with a reference antibody for binding to activin A;
c. binds to the same epitope of activin A as said reference antibody;
d. binds to activin A with substantially the same Kd as said reference antibody; or
e. binds to activin A with substantially the smile off rate as said reference antibody;
wherein said reference antibody comprises a combination of light chain and heavy chain variable domain sequences of: SEQ ID NOS: 9 and 10.
4. The isolated antibody or antigen binding fragment thereof of claim 1 or 2 that, when bound to a human activin A, inhibits binding of activin A to human activin A receptor.
5. The isolated antibody or antigen binding fragment thereof of claim 1 or 2 , wherein said antigen binding protein possesses an in vivo biological activity of attenuating cachexia in colon tumor-bearing mice.
6. The isolated antibody or antigen binding fragment thereof of claim 1 or 2 , wherein the antibody is an isolated fully human antibody that specifically binds to the cysteine knot region, (amino acids C11-S33 and/or amino acids C81-E111), of activin A (SEQ ID NO:225).
7. The isolated antibody or antigen binding fragment thereof of claim 6 , wherein the antibody possesses an in vivo biological activity of attenuating cachexia in colon tumor-bearing mice.
8. The isolated antibody or antigen binding fragment thereof of claim 1 or 2 , wherein the antibody is an isolated fully human antibody that
a) specifically binds to the cysteine knot region, amino acids C11-S33 and/or amino acids C81-E111, of activin A (SEQ ID NO:225), wherein said fully human antibody inhibits the binding of activin A to activin A receptor in vitro, or
b) specifically binds to the cysteine knot region, amino acids C11-S33 and/or amino acids C81-E111, of activin A (SEQ ID NO:225), wherein said fully human antibody inhibits the binding of activin A to activin A receptor in vivo, or
c) specifically binds to amino acids K13-Y39 of activin A (SEQ ID NO:225), wherein said fully human antibody inhibits the binding of activin A to activin A receptor in vitro, or
d) specifically binds to amino acids V82-N107 of activin A (SEQ ID NO:225), wherein said fully human antibody inhibits the binding of activin A to activin A receptor in vitro, or
e) specifically binds to amino acids K13-Y39 of activin A (SEQ ID NO:225), wherein said fully human antibody inhibits the binding of activin A to activin A receptor in vivo, or
f) specifically binds to amino acids V82-N107 of activin A (SEQ ID NO:225), wherein said fully human antibody inhibits the binding of activin A to activin A receptor in vivo.