ACVR2A-SPECIFIC ANTIBODY AND METHOD OF USE THEREOF
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, wherein the antibody comprises:
(a) a variable domain comprising:
i. heavy chain CDR1, CDR2 and CDR3 regions that are identical the heavy chain CDR1, CDR2 and CDR3 regions of an antibody selected from any of Tables 2A-2F; and
ii. light chain CDR1, CDR2 and CDR3 regions that are identical the light chain CDR1, CDR2 and CDR3 regions of the antibody selected from any of Tables 2A-2F; or
(b) a variant of said variable domain of (a) that is otherwise identical to said antibody variable domain except for up to 15 amino acid substitutions in said CDR regions.
2 . An antibody that specifically binds to ACVR2A, wherein the antibody comprises:
a heavy chain variable domain comprising: a heavy chain framework, a CDR1 region, a CDR2 region, and a CDR3 region of sequence AxxAxWHDTxLD (SEQ ID NO: 6618); and
a light chain variable domain comprising: a light chain framework, a CDR1 region, a CDR2 region, and a CDR3 region.
3 . The antibody of claim 1 , wherein the heavy chain variable domain comprises a CDR3 region of sequence ARSATWHDTxLD (SEQ ID NO: 6549), 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).
4 . The antibody of claim 1 , wherein the antibody comprises:
a heavy chain variable domain comprising:
i. a CDR1 region that has a sequence of D/SS/DYG/SMH/N (SEQ ID NO: 6550),
ii. a CDR2 region that has a sequence of WVA/SS/G/NINYNG/SGYT/KS/G (SEQ ID NO: 6619), and
iii. a CDR3 region that has a sequence of ARAANWHDTA/HLD (SEQ ID NO: 6620); and
a light chain variable domain comprising:
i. a CDR1 region that has a sequence of L/V/I/SS/T/RYL/VNWY (SEQ ID NO: 6554),
ii. a CDR2 region that has a sequence of LV/LIYA/YNA/V/TT/S/NS/NR/LA/H/Q/P (SEQ ID NO: 6621), and
iii. a CDR3 region that has a sequence of QQ/HSY/DD/E/S/NL/N/S/TPL (SEQ ID NO: 6593).
5 . The antibody of claim 1 , wherein the antibody comprises:
a heavy chain variable domain comprising:
i. a CDR1 region that has a sequence of D/SS/DYG/SMH/N (SEQ ID NO: 6550),
ii. a CDR2 region that has a sequence of WVA/SS/G/NINYNG/SGYT/KS/G (SEQ ID NO: 6551), and
iii. a CDR3 region that has a sequence of ARAATWHDTH/ALD (SEQ ID NO: 6559); and
a light chain variable domain comprising:
i. a CDR1 region that has a sequence of L/V/I/SS/TYL/VNWY (SEQ ID NO: 6561),
ii. a CDR2 region that has a sequence of LL/VIYA/YA/T/VT/S/NS/NR/LA/P/Q (SEQ ID NO: 6563), and
iii. a CDR3 region that has a sequence of QQSY/D/ND/E/S/NL/S/T/NPL (SEQ ID NO: 6565).
6 . The antibody of claim 1 , wherein the antibody comprises:
a heavy chain variable domain comprising:
i. a CDR1 region that has a sequence of S/DS/DYS/GMN/H (SEQ ID NO: 6566),
ii. a CDR2 region that has a sequence of WVS/AG/S/NINYNG/SGYT/KS/G (SEQ ID NO: 6567), and
iii. a CDR3 region that has a sequence of ARGANWHDTA/HLD (SEQ ID NO: 6543); and
a light chain variable domain comprising:
i. a CDR1 region that has a sequence of L/V/S/IS/TYL/VNWY (SEQ ID NO: 6569),
ii. a CDR2 region that has a sequence of LL/VIYAA/V/TT/SSR/LA/H/Q (SEQ ID NO: 6571), and
iii. a CDR3 region that has a sequence of QQSY/DD/E/S/NS/T/N/LPL (SEQ ID NO: 6573).
7 . The antibody of claim 1 , wherein the antibody comprises:
a heavy chain variable domain comprising:
i. a CDR1 region that has a sequence of S/DS/DYS/GMN/H (SEQ ID NO: 6574),
ii. a CDR2 region that has a sequence of WVA/SG/N/SINYNG/SGYT/KS/G (SEQ ID NO: 6575), and
iii. a CDR3 region that has a sequence of ARGATWHDTH/ALD (SEQ ID NO: 6595); and
a light chain variable domain comprising:
i. a CDR1 region that has a sequence of L/I/V/SS/TYL/VNWY (SEQ ID NO: 6596),
ii. a CDR2 region that has a sequence of LL/VIYAA/V/TT/SSR/LA/H/Q (SEQ ID NO: 6571), and
iii. a CDR3 region that has a sequence of QQSY/DD/E/S/NT/S/N/LPL (SEQ ID NO: 6577).
8 . The antibody of claim 1 , wherein the antibody comprises:
a heavy chain variable domain comprising:
i. a CDR1 region that has a sequence of S/DS/DYG/SMN/H (SEQ ID NO: 6578),
ii. a CDR2 region that has a sequence of WVS/AG/N/SINYNG/SGYT/KS/G (SEQ ID NO: 6579), and
iii. a CDR3 region that has a sequence of AR/KSANWHDTA/HLD (SEQ ID NO: 6580); and
a light chain variable domain comprising:
i. a CDR1 region that has a sequence of L/V/I/SS/TYL/VNWY (SEQ ID NO: 6561),
ii. a CDR2 region that has a sequence of LL/VIYA/YAN/TT/SS/NR/LA/H/Q (SEQ ID NO: 6582), and
iii. a CDR3 region that has a sequence of QQSY/DD/E/N/SS/T/L/NPL (SEQ ID NO: 6598).
9 . The antibody of claim 1 , wherein the antibody comprises:
a heavy chain variable domain comprising:
i. a CDR1 region that has a sequence of D/SS/DYS/GMN/H (SEQ ID NO: 6584),
ii. a CDR2 region that has a sequence of WVA/SG/N/SINYNG/SGYT/KS/G (SEQ ID NO: 6585), and
iii. a CDR3 region that has a sequence of ARSATWHDTH/ALD (SEQ ID NO: 6586); and
a light chain variable domain comprising:
i. a CDR1 region that has a sequence of L/V/I/SS/T/RYL/VNWY (SEQ ID NO: 6588),
ii. a CDR2 region that has a sequence of LL/VIYA/YAN/TT/SS/NR/LA/H/Q (SEQ ID NO: 6590), and
iii. a CDR3 region that has a sequence of QQSY/DD/E/S/NL/N/T/SPL (SEQ ID NO: 6591).
10 . The antibody of claim 1 , wherein the antibody comprises:
a heavy chain variable domain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of the heavy chain variable domain of an antibody selected from any of Tables 2A-2F; and
a light chain variable domain comprising an amino acid sequence that is at least 80% identical to the light chain variable domain of the antibody selected from any of Tables 2A-2F.
11 . The antibody of claim 1 , wherein the heavy chain variable domain and the light chain variable domain are present in separate polypeptides.
12 . The antibody of claim 1 , wherein the heavy chain variable domain and the light chain variable domain are present in a single polypeptide.
13 . 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 .
14 . The antibody of claim 1 , wherein the antibody comprises a covalently linked non-peptide synthetic polymer.
15 . The antibody of claim 14 , wherein the synthetic polymer is poly(ethylene glycol) polymer.
16 . The antibody of claim 1 , wherein the antibody comprises a covalently linked lipid or fatty acid moiety.
17 . The antibody of claim 1 , wherein the antibody comprises a covalently linked polysaccharide or carbohydrate moiety.
18 . The antibody of claim 1 , wherein the antibody is a single chain Fv (scFv) antibody.
19 . The antibody of claim 18 , wherein the scFv is multimerized.
20 - 22 . (canceled)
23 . A method of treating a condition in a patient comprising administering to a patient in need thereof an effective amount of the antibody of claim 1 .
24 . The method according to claim 23 , wherein the condition is associated with muscle atrophy.
25 . The method according to claim 23 , wherein the condition is characterized by a decrease in muscle mass or muscle function, or insufficient lean body mass.
26 . The method according to claim 23 , wherein the condition is cachexia or sarcopenia.