Methods of using activin receptor type iia variants
AssigneeKeros Therapeutics, Inc.
InventorsJasbir S. SEEHRA, Jennifer LACHEY, Elissa FURUTANI
Life of this patent
Estimating the term…
Abstract
The invention features polypeptides that include an extracellular ActRIIA variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIA variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions containing said polypeptides and methods of using the polypeptides to treat diseases and conditions including neuromuscular diseases, osteogenesis imperfecta, myelofibrosis, thrombocytopenia, neutropenia, and age-related and treatment-related metabolic disease.
Claims18
1-6. (canceled)
A method of treating a subject having or at risk of developing thrombocytopenia, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant, the variant having a sequence of
- (SEQ ID NO:
- 1)
- GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11
- X12X13X14HCX15ATWX16NISGSIEIVX17X18GCX19X20X21DX22
- NCYDRTDCVEX23X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVT
- QPTS,
- wherein X1 is F or Y;
- X2 is F or Y;
- X3 is E or A;
- X4 is K or L;
- X5 is D or E;
- X6 is R or A;
- X7 is P or R;
- X8 is Y or E;
- X9 is D or E;
- X10 is K or Q;
- X11 is D or A;
- X12 is K or A;
- X13 is R or A;
- X14 is R or L;
- X15 is F or Y;
- X16 is K, R, or A;
- X17 is K, A, Y, F, or I;
- X18 is Q or K;
- X19 is W or A;
- X20 is L or A;
- X21 is D, K, R, A, F, G, M, N, or I;
- X22 is I, F, or A;
- X23 is K or T;
- X24 is K or E;
- X25 is D or E;
- X26 is S or N;
- and X27 is E or Q, and
- wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIa having the sequence of SEQ ID NO:
- 73 or an extracellular ActRIIa having any one of the sequences of SEQ ID NOs:
- 76-96.
8-10. (canceled)
12-26. (canceled)
A method of treating a subject having or at risk of developing neutropenia, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant, the variant having a sequence of
- (SEQ ID NO:
- 1)
- GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11
- X12X13X14HCX15ATWX16NISGSIEIVX17X18GCX19X20X21DX22
- NCYDRTDCVEX23X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVT
- QPTS,
- wherein X1 is F or Y;
- X2 is F or Y;
- X3 is E or A;
- X4 is K or L;
- X5 is D or E;
- X6 is R or A;
- X7 is P or R;
- X8 is Y or E;
- X9 is D or E;
- X10 is K or Q;
- X11 is D or A;
- X12 is K or A;
- X13 is R or A;
- X14 is R or L;
- X15 is F or Y;
- X16 is K, R, or A;
- X17 is K, A, Y, F, or I;
- X18 is Q or K;
- X19 is W or A;
- X20 is L or A;
- X21 is D, K, R, A, F, G, M, N, or I;
- X22 is I, F, or A;
- X23 is K or T;
- X24 is K or E;
- X25 is D or E;
- X26 is S or N;
- and X27 is E or Q, and
- wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIa having the sequence of SEQ ID NO:
- 73 or an extracellular ActRIIa having any one of the sequences of SEQ ID NOs:
- 76-96.
29-50. (canceled)
A method of treating a subject having congenital dyserythropoietic anemia, congenital sideroblastic anemia, anemia associated with myelofibrosis treatment, anemia associated with Pearson syndrome, or anemia associated with dyskeratosis congenita, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant, the variant having a sequence of
- (SEQ ID NO:
- 1)
- GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11
- X12X13X14HCX15ATWX16NISGSIEIVX17X18GCX19X20X21DX22
- NCYDRTDCVEX23X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVT
- QPTS,
- wherein X1 is F or Y;
- X2 is F or Y;
- X3 is E or A;
- X4 is K or L;
- X5 is D or E;
- X6 is R or A;
- X7 is P or R;
- X8 is Y or E;
- X9 is D or E;
- X10 is K or Q;
- X11 is D or A;
- X12 is K or A;
- X13 is R or A;
- X14 is R or L;
- X15 is F or Y;
- X16 is K, R, or A;
- X17 is K, A, Y, F, or I;
- X18 is Q or K;
- X19 is W or A;
- X20 is L or A;
- X21 is D, K, R, A, F, G, M, N, or I;
- X22 is I, F, or A;
- X23 is K or T;
- X24 is K or E;
- X25 is D or E;
- X26 is S or N;
- and X27 is E or Q, and
- wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIa having the sequence of SEQ ID NO:
- 73 or an extracellular ActRIIa having any one of the sequences of SEQ ID NOs:
- 76-96.
52-54. (canceled)
A method of treating a subject having or at risk of developing a myelodysplastic syndrome, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant, the variant having a sequence of
- (SEQ ID NO:
- 1)
- GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11
- X12X13X14HCX15ATWX16NISGSIEIVX17X18GCX19X20X21DX22
- NCYDRTDCVEX23X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVT
- QPTS,
- wherein X1 is F or Y;
- X2 is F or Y;
- X3 is E or A;
- X4 is K or L;
- X5 is D or E;
- X6 is R or A;
- X7 is P or R;
- X8 is Y or E;
- X9 is D or E;
- X10 is K or Q;
- X11 is D or A;
- X12 is K or A;
- X13 is R or A;
- X14 is R or L;
- X15 is F or Y;
- X16 is K, R, or A;
- X17 is K, A, Y, F, or I;
- X18 is Q or K;
- X19 is W or A;
- X20 is L or A;
- X21 is D, K, R, A, F, G, M, N, or I;
- X22 is I, F, or A;
- X23 is K or T;
- X24 is K or E;
- X25 is D or E;
- X26 is S or N;
- and X27 is E or Q, and
- wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIa having the sequence of SEQ ID NO:
- 73 or an extracellular ActRIIa having any one of the sequences of SEQ ID NOs:
- 76-96.
56-72. (canceled)
A method of treating a subject having or at risk of developing a neuromuscular disease, disuse atrophy, treatment-related muscle loss or atrophy, hypotonia, muscle loss or atrophy associated with hypoxia, muscle loss or atrophy associated with a burn injury, HIV-related cachexia, cardiac cachexia, cachexia associated with chronic kidney disease, or pulmonary cachexia, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant, the variant having a sequence of
- (SEQ ID NO:
- 1)
- GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11
- X12X13X14HCX15ATWX16NISGSIEIVX17X18GCX19X20X21DX22
- NCYDRTDCVEX23X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVT
- QPTS,
- wherein X1 is F or Y;
- X2 is F or Y;
- X3 is E or A;
- X4 is K or L;
- X5 is D or E;
- X6 is R or A;
- X7 is P or R;
- X8 is Y or E;
- X9 is D or E;
- X10 is K or Q;
- X11 is D or A;
- X12 is K or A;
- X13 is R or A;
- X14 is R or L;
- X15 is F or Y;
- X16 is K, R, or A;
- X17 is K, A, Y, F, or I;
- X18 is Q or K;
- X19 is W or A;
- X20 is L or A;
- X21 is D, K, R, A, F, G, M, N, or I;
- X22 is I, F, or A;
- X23 is K or T;
- X24 is K or E;
- X25 is D or E;
- X26 is S or N;
- and X27 is E or Q, and
- wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIa having the sequence of SEQ ID NO:
- 73 or an extracellular ActRIIa having any one of the sequences of SEQ ID NOs:
- 76-96.
74-97. (canceled)
A method of treating a subject having or at risk of developing osteogenesis imperfecta, bone loss associated with bariatric surgery, bone loss associated with androgen or estrogen deprivation therapy, neuromuscular disease-related bone loss, burn-induced bone loss, or anorexia-related bone loss, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant, the variant having a sequence of
- (SEQ ID NO:
- 1)
- GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11
- X12X13X14HCX15ATWX16NISGSIEIVX17X18GCX19X20X21DX22
- NCYDRTDCVEX23X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVT
- QPTS,
- wherein X1 is F or Y;
- X2 is F or Y;
- X3 is E or A;
- X4 is K or L;
- X5 is D or E;
- X6 is R or A;
- X7 is P or R;
- X8 is Y or E;
- X9 is D or E;
- X10 is K or Q;
- X11 is D or A;
- X12 is K or A;
- X13 is R or A;
- X14 is R or L;
- X15 is F or Y;
- X16 is K, R, or A;
- X17 is K, A, Y, F, or I;
- X18 is Q or K;
- X19 is W or A;
- X20 is L or A;
- X21 is D, K, R, A, F, G, M, N, or I;
- X22 is I, F, or A;
- X23 is K or T;
- X24 is K or E;
- X25 is D or E;
- X26 is S or N;
- and X27 is E or Q, and
- wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIa having the sequence of SEQ ID NO:
- 73 or an extracellular ActRIIa having any one of the sequences of SEQ ID NOs:
- 76-96.
99-117. (canceled)
A method of treating and/or preventing treatment-related metabolic disease or age-related metabolic disease in a subject, comprising administering to said subject a therapeutically effective amount of a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant, the variant having a sequence of
- (SEQ ID NO:
- 1)
- GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11
- X12X13X14HCX15ATWX16NISGSIEIVX17X18GCX19X20X21DX22
- NCYDRTDCVEX23X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVT
- QPTS,
- wherein X1 is F or Y;
- X2 is F or Y;
- X3 is E or A;
- X4 is K or L;
- X5 is D or E;
- X6 is R or A;
- X7 is P or R;
- X8 is Y or E;
- X9 is D or E;
- X10 is K or Q;
- X11 is D or A;
- X12 is K or A;
- X13 is R or A;
- X14 is R or L;
- X15 is F or Y;
- X16 is K, R, or A;
- X17 is K, A, Y, F, or I;
- X18 is Q or K;
- X19 is W or A;
- X20 is L or A;
- X21 is D, K, R, A, F, G, M, N, or I;
- X22 is I, F, or A;
- X23 is K or T;
- X24 is K or E;
- X25 is D or E;
- X26 is S or N;
- and X27 is E or Q, and
- wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIa having the sequence of SEQ ID NO:
- 73 or an extracellular ActRIIa having any one of the sequences of SEQ ID NOs:
- 76-96.
119-145. (canceled)
Dependencies are inferred from the claim text.