ACVR2A-specific antibody and method of treatment of muscle atrophy
The present disclosure provides antibodies that specifically bind to and block signaling by ACVR2A, i.e., ACVR2A but not ACVR2B, as well as methods for using the same. The antibodies may be used for the treatment of a number of conditions associated with muscle atrophy, as well as other conditions.
1. An antibody that specifically binds to ACVR2A (Activin Receptor Type IIA), wherein the antibody comprises:
(a) a variable domain comprising:
i. a HC CDR(heavy chain complementarity determining region)1 of sequence SSYGMN (SEQ ID NO: 4453), a HC CDR2 of sequence WVAGINYNGGYTS (SEQ ID NO: 4622), and a HC CDR3 of sequence ARSATWHDTALD (SEQ ID NO: 4791); and
ii. a LC CDR(light chain complementarity determining region) of sequence LSYLNWY (SEQ ID NO: 4960), a LC CDR2 of sequence LVIYAATSRA (SEQ ID NO: 5129) and a LC CDR3 of sequence QQSYDSPL (SEQ ID NO: 5298);
(b) a variable domain comprising:
i. a HC CDR1 of sequence SSYGMN (SEQ ID NO: 4453), a HC CDR2 of sequence WVAGINYNGGYTS (SEQ ID NO: 4622), and a HC CDR3 of sequence AxxAxWHDTxLD (SEQ ID NO: 6618), where x is any amino acid;
ii. a LC CDR of sequence LSYLNWY (SEQ ID NO: 4960), a LC CDR2 of sequence LVIYAATSRA (SEQ ID NO: 5129) and a LC CDR3 of sequence QQSYDSPL (SEQ ID NO: 5298); or
(c) a variant of said variable domain of (b) that is otherwise identical to said variable domain of (b) except for up to one amino acid substitution in each of the HC CDR1, HC CDR2, LC CDR1, LC CDR2 and LC CDR3 regions.
2. The antibody of claim 1 , wherein the antibody comprises an HC CDR3 of sequence ARSATWHDTH/ALD (SEQ ID NO: 6586), ARAATWHDTxLD (SEQ ID NO: 6540), ARGANWHDTxLD (SEQ ID NO: 6542), ARGATWHDTxLD (SEQ ID NO: 6544), ARSANWHDTxLD (SEQ ID NO: 6546) or ARSATWHDTxLD (SEQ ID NO: 6548).
3. The antibody of claim 1 , wherein the antibody comprises:
a HC CDR3 of sequence ARSATWHDTH/ALD (SEQ ID NO: 6586).
4. The antibody of 1 , wherein the antibody comprises:
a heavy chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 4115; and
a light chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 4284.
5. The antibody of claim 1 , wherein the heavy chain CDRs and the light chain CDRs are present in separate polypeptides.
6. The antibody of claim 1 , wherein the heavy chain CDRs and the light chain CDRs are present in a single polypeptide.
7. The antibody of claim 1 , wherein the antibody binds ACVR2A with an affinity in the range of 10 7 M −1 to 10 12 M −1 .
8. The antibody of claim 1 , wherein the antibody comprises a covalently linked non-peptide synthetic polymer.
9. The antibody of claim 8 , wherein the synthetic polymer is poly(ethylene glycol) polymer.
10. The antibody of claim 1 , wherein the antibody comprises a covalently linked lipid or fatty acid moiety.
11. The antibody of claim 1 , wherein the antibody comprises a covalently linked polysaccharide or carbohydrate moiety.
12. The antibody of claim 1 , wherein the antibody is a single chain Fv (scFv) antibody.
13. The antibody of claim 12 , wherein the scFv is multimerized.
14. A method of treating a condition associated with muscle atrophy, decrease in muscle mass or insufficient lean body mass in a patient comprising administering to the patient an effective amount of the antibody of claim 1 .
15. The method according to claim 14 , wherein the condition is associated with muscle atrophy.
16. The method according to claim 14 , wherein the condition is characterized by a decrease in muscle mass or muscle function, or insufficient lean body mass.
17. The method according to claim 14 , wherein the condition is cachexia or sarcopenia.