# US 2021/0275637 A1 · Activin receptor type iia variants and methods of use thereof

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- Number: US 2021/0275637 A1
- Document ID: US20210275637A1
- Status: Published application
- Kind: A1
- Application number: 17/327,914
- Filed: 2021-05-24
- Published: 2021-09-09
- Earliest claimed: 2016-11-10
- Assignees: Keros Therapeutics, Inc.
- Applicants: Keros Therapeutics, Inc.
- Inventors: Jasbir S. SEEHRA; Jennifer LACHEY
- Web page: https://patentgrep.com/patent/US20210275637A1

## CPC

- A61K 38/18: Growth factors; Growth regulators
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/71: for growth factors; for growth regulators
- C07K 14/76: Albumins
- C12N 9/12: transferring phosphorus containing groups, e.g. kinases (2.7)
- C12N 15/85: for animal cells
- C12P 21/02: having a known sequence of two or more amino acids, e.g. glutathione
- C12Y 207/1103: Receptor protein serine/threonine kinase (2.7.11.30)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- 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
- 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
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C12Y: ENZYMES

## 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 and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, e.g., Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, inclusion body myositis, amyotrophic lateral sclerosis, sarcopenia; or cancer cachexia; or metabolic diseases, e.g., obesity, Type-1 diabetes, or Type-2 diabetes.

## Claims

### Claim 1

A nucleic acid molecule encoding a polypeptide comprising an extracellular activin receptor type Ila (ActRIIa) variant and an Fc domain, the variant having a sequence of
(SEQ ID NO: 1)
GAILGRSETQECLX1X2NANWX3X4X5X6TNQTGVEX7CX8GX9X10X11X12X13
X14HCX15ATWX16NISGSIEIVX17Xl8GCX19X20X21DX22NCYDRTDCVEX23
X24X25X26PX27VYFCCCEGNMCNEKFSYFPEMEVTQPTS,
wherein X1 is F or Y; X2 is Y; X3 is E; X4 is L; X5 is D or E; X6 is R; X7 is P or R; X8 is E; X9 is E; X10 is K or Q; X11 is D; X12 is K; X13 is R; X14 is L; X15 is F or Y; X16 is K or R; X17 is K; X18 is K; X19 is W; X20 is L; X21 is D; X22 is I or F; X23 is T; X24 is K or E; X25 is E; X26 is N; and X27 is Q.

### Claim 2 (depends on 1)

The nucleic acid molecule of claim 1, wherein X1 is F and X10 is K.

### Claim 3 (depends on 1)

The nucleic acid molecule of claim 1, wherein the variant has the sequence of any one of SEQ ID NOs: 6-72.

### Claim 4 (depends on 1)

The nucleic acid molecule of claim 1, wherein the polypeptide further comprises a C-terminal extension of one or more amino acids at the C-terminus of the ActRIIa variant.

### Claim 5 (depends on 4)

The nucleic acid molecule of claim 4, wherein the C-terminal extension is NP or NPVTPK (SEQ ID NO: 155).

### Claim 6 (depends on 1)

The nucleic acid molecule of claim 1, wherein the Fc domain is fused to the C-terminus of the ActRIIa variant by way of a linker.

### Claim 7 (depends on 1)

The nucleic acid molecule of claim 1, wherein the variant has the sequence of any one of SEQ ID NOs: 6, 38, 41, 44, 58, 69, 70, 71, and 72.

### Claim 8 (depends on 1)

The nucleic acid molecule of claim 1, wherein the variant has the sequence of SEQ ID NO: 69.

### Claim 9 (depends on 8)

The nucleic acid molecule of claim 8, wherein the Fc domain is fused to the C-terminus of the ActRIIa variant by way of a linker.

### Claim 10 (depends on 1)

A vector comprising the nucleic acid molecule of claim 1.

### Claim 11 (depends on 10)

The vector of claim 10, wherein the vector is a viral vector.

### Claim 12 (depends on 11)

The vector of claim 11, wherein the viral vector is a retroviral vector, an adenoviral vector, a poxviral vector, an adeno-associated viral vector, or an alphaviral vector.