# US 2023/0265162 A1 · Methods of using activin receptor type iia variants

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- Number: US 2023/0265162 A1
- Document ID: US20230265162A1
- Status: Published application
- Kind: A1
- Application number: 17/945,324
- Filed: 2022-09-15
- Published: 2023-08-24
- Earliest claimed: 2020-03-20
- Assignees: Keros Therapeutics, Inc.
- Applicants: Keros Therapeutics, Inc.
- Inventors: Jasbir S. SEEHRA; Jennifer LACHEY; Elissa FURUTANI
- Web page: https://patentgrep.com/patent/US20230265162A1

## CPC

- C07K 14/71: for growth factors; for growth regulators
- C12Y 207/1103: Receptor protein serine/threonine kinase (2.7.11.30)
- A61K 38/1796: {for hormones (for neuromediators A61K38/1787)}
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/31: fusions, other than Fc, for prolonged plasma life, e.g. albumin
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12Y: ENZYMES
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim at position 1

1-6. (canceled)

### Claim 7

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.

### Claim at position 3

8-10. (canceled)

### Claim 11 (depends on 7)

The method of claim 7, wherein:
(a) the thrombocytopenia is associated with a bone marrow defect, a myelodysplastic syndrome, bone marrow transplantation, myelofibrosis, myelofibrosis treatment, ineffective hematopoiesis, Gaucher disease, aplastic anemia, Fanconi anemia, Diamond Blackfan anemia, Shwachman Diamond syndrome, heavy alcohol consumption, cirrhosis of the liver, cancer, an autoimmune disease, a viral infection, a bacterial infection, an enlarged spleen, a vitamin deficiency, cancer treatment, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, disseminated intravascular coagulation, hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, a reduction of platelets caused by medication, a dilution of platelets caused by a blood transfusion, hematopoietic stem cell transplantation, acquired amegakaryocytic thrombocytopenia, Pearson syndrome, dyskeratosis congenita, or contraindication to transfusion;
(b) the thrombocytopenia is familial thrombocytopenia; or
(c) the thrombocytopenia is immune thrombocytopenia.

### Claim at position 5

12-26. (canceled)

### Claim 27

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.

### Claim 28 (depends on 27)

The method of claim 27, wherein:
(a) the neutropenia is associated with a bone marrow defect, a myelodysplastic syndrome, bone marrow transplantation, myelofibrosis, ineffective hematopoiesis, aplastic anemia, Fanconi anemia, Diamond Blackfan anemia, Shwachman Diamond syndrome, paroxysmal nocturnal hemoglobinuria, cancer, a vitamin deficiency, an enlarged spleen, an autoimmune disease, a viral infection, a bacterial infection, cancer treatment, a reduction in neutrophils caused by medication, inflammation, hematopoietic stem cell transplantation, Pearson syndrome, dyskeratosis congenita, or contraindication to transfusion;
(b) the neutropenia is chronic idiopathic neutropenia; or
(c) the neutropenia is familial neutropenia.

### Claim at position 8

29-50. (canceled)

### Claim 51

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.

### Claim at position 10

52-54. (canceled)

### Claim 55

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.

### Claim at position 12

56-72. (canceled)

### Claim 73

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.

### Claim at position 14

74-97. (canceled)

### Claim 98

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.

### Claim at position 16

99-117. (canceled)

### Claim 118

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.

### Claim at position 18

119-145. (canceled)