US 11,857,599 B2
Compositions and methods for treating spinal muscular atrophy
Ravindra Kumar, Acton, MA (US); Rajasekhar Naga Venkata Sai Suragani, Wrentham, MA (US); and Jia Li, Danvers, MA (US)
Assigned to Acceleron Pharma Inc., Rahway, NJ (US)
Appl. No. 16/499,098
Filed by Acceleron Pharma Inc., Cambridge, MA (US)
PCT Filed Apr. 2, 2018, PCT No. PCT/US2018/025689
§ 371(c)(1), (2) Date Sep. 27, 2019,
PCT Pub. No. WO2018/187209, PCT Pub. Date Oct. 11, 2018.
Claims priority of provisional application 62/480,835, filed on Apr. 3, 2017.
Prior Publication US 2022/0088142 A1, Mar. 24, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 38/18 (2006.01); A61K 38/17 (2006.01); A61P 21/00 (2006.01); A61K 31/7125 (2006.01); A61K 45/06 (2006.01); C07K 14/71 (2006.01); C12N 15/113 (2010.01)
CPC A61K 38/1841 (2013.01) [A61K 31/7125 (2013.01); A61K 38/18 (2013.01); A61K 45/06 (2013.01); A61P 21/00 (2018.01); C07K 14/71 (2013.01); C12N 15/113 (2013.01); A61K 38/179 (2013.01); C07K 2319/30 (2013.01); C07K 2319/32 (2013.01); C12N 2310/11 (2013.01); C12N 2320/31 (2013.01)] 30 Claims
 
1. A method of treating spinal muscular atrophy (SMA) in a patient in need thereof, comprising administering to the patient an effective amount of a recombinant ALK4:ActRIIB heteromultimer comprising at least one ALK4-Fc fusion protein and at least one ActRIIB-Fc fusion protein, wherein
(A) the at least one ALK4-Fc fusion protein comprises an ALK4 polypeptide and an IgG1 Fc domain polypeptide, wherein the ALK4 polypeptide comprises an amino acid sequence selected from
(i) an amino acid sequence at least 90% identical to amino acid residues 34-101 of SEQ ID NO: 9; and
(ii) an amino acid sequence at least 90% identical to SEQ ID NO: 10; and
(B) the at least one ActRIIB-Fc fusion protein comprises an ActRIIB polypeptide and an IgG1 Fc domain polypeptide, wherein the ActRIIB polypeptide comprises an amino acid sequence selected from
(i) an amino acid sequence at least 90% identical to amino acid residues 29-109 of SEQ ID NO: 1;
(ii) an amino acid sequence at least 90% identical to SEQ ID NO: 2;
(iii) an amino acid sequence least sequence 90% identical to SEQ ID NO: 3;
(iv) an amino acid sequence as set forth in SEQ ID NO: 5;
(v) an amino acid as set forth in SEQ ID NO: 6;
wherein the Fc domain polypeptide of
(a) one of the ALK4-Fc and the ActRIIB-Fc fusion proteins has an amino acid sequence of SEQ ID NO: 23 and the other has an amino acid sequence of SEQ ID NO: 24;
(b) one of the ALK4-Fc and the ActRIIB-Fc fusion proteins has an amino acid sequence of SEQ ID NO: 25 and the other has an amino acid sequence of SEQ ID NO: 26;
(c) one of the ALK4-Fc and the ActRIIB-Fc fusion proteins has an amino acid sequence of SEQ ID NO: 27 and the other has an amino acid sequence of SEQ ID NO: 28;
wherein the Fc domain polypeptide of one of the ALK4-Fc and the ActRIIB-Fc fusion proteins is optionally substituted at position H213 by an arginine (H213R); or
(d) one of the ALK4-Fc and the ActRIIB-Fc fusion proteins has an amino acid sequence of SEQ ID NO: 66 and the other has an amino acid sequence of SEQ ID NO: 67;
wherein in (a)-(d), the Fc domain polypeptide may optionally be provided with the lysine (K) residue removed from the C-terminus.