# US 2014/0194355 A1 · Isolated Nucleic Acid Molecules Encoding Variant Activin Receptor Polypeptides

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- Number: US 2014/0194355 A1
- Document ID: US20140194355A1
- Status: Published application
- Kind: A1
- Application number: 14/204,460
- Filed: 2014-03-11
- Published: 2014-07-10
- Earliest claimed: 2007-03-06
- Assignees: Amgen Inc.
- Applicants: Amgen Inc.
- Inventors: Jeonghoon Sun; Lei-Ting Tony Tam; Hui-Quan Han; Keith Soo-Nyung Kwak; Xiaolan Zhou
- Web page: https://patentgrep.com/patent/US20140194355A1

## CPC

- C07K 14/71: for growth factors; for growth regulators
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)
- C07K 2319/00: Fusion polypeptide
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention provides variant activin IIB soluble receptor polypeptides and proteins capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11. The present invention also provides polynucleotides, vectors and host cells capable of producing the variant polypeptides and proteins. Compositions and methods for treating muscle-wasting and other diseases and disorders are also provided.

## Claims

### Claim 1

An isolated protein comprising a variant activin IIB receptor polypeptide (vActRIIB) wherein said polypeptide is selected from the group consisting of:
(a) a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 18, except for an amino acid substitution at position 28;
(b) a polypeptide comprising the amino acid sequence set forth in amino acids 19 through 134 of SEQ ID NO: 18, except for an amino acid substitution at position 28;
(c) a polypeptide comprising the amino acid sequence set forth in amino acids 23 through 134 of SEQ ID NO: 18, except for an amino acid substitution at position 28;
(d) a polypeptide comprising the amino acid sequence set forth in amino acids 25 through 134 of SEQ ID NO: 18, except for an amino acid substitution at position 28;
(e) a polypeptide having at least 95% identity to any one of (a) through (d), wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11.

### Claim 2 (depends on 1)

The protein of claim 1, wherein the substitution at position 28 of the vActRIIB polypeptide is selected from the group consisting of A, F, Q, V, I, L, M, K, H, W, and Y for E.

### Claim 3 (depends on 1)

The protein of claim 1, wherein the substitution at position 28 of the vActRIIB polypeptide is selected from the group of amino acids consisting of A, W and Y for E.

### Claim 4 (depends on 1)

The protein of claim 1, wherein the substitution at position 28 of the vActRIIB polypeptide is W for E.

### Claim 5 (depends on 1)

The protein of claim 1, wherein the isolated protein further comprises SEQ ID NO:79.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the isolated protein further comprises SEQ ID NO:80.

### Claim 7 (depends on 1)

The protein of claim 1, wherein the polypeptide sequence has at least 95% identity to the amino acid sequence set forth at amino acids 25 through 134 of SEQ ID NO: 18, and wherein the polypeptide comprises an amino acid substitution at position 28.

### Claim 8 (depends on 1)

The protein of claim 1, wherein the polypeptide sequence has at least 95% identity to the amino acid sequence set forth at amino acids 25 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is W for E, and wherein the isolated protein further comprises an Fc domain linked to vActRIIB via a linker.

### Claim 9 (depends on 1)

The protein of claim 1, wherein the polypeptide sequence has at least 99% identity to the amino acid sequence set forth at amino acids 25 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is W for E, and wherein the isolated protein further comprises a human Fc domain (SEQ ID NO:80) linked to vActRIIB via a peptide linker (SEQ ID NO:79).

### Claim 10 (depends on 1)

The isolated protein of claim 1, wherein the polypeptide is fused to at least one heterologous polypeptide.

### Claim 11 (depends on 1)

A dimer comprising the protein of claim 1.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising the protein of claim 1 and an excipient.

### Claim 13 (depends on 1)

An isolated nucleic acid molecule comprised a polynucleotide encoding the protein of claim 1, or its full length complement.

### Claim 14 (depends on 13)

A recombinant expression vector comprising the nucleic acid molecule of claim 13.

### Claim 15 (depends on 14)

A host cell comprising the recombinant vector of claim 14.

### Claim 16 (depends on 15)

A method of producing a protein, comprising culturing the host cell of claim 15, thereby producing the protein.

### Claim 17 (depends on 1)

A method for inhibiting myostatin in a subject, comprising administering the protein of claim 1 to the subject.

### Claim 18 (depends on 1)

A method for increasing lean muscle mass or increasing the ratio of lean muscle mass to fat mass in a subject, comprising administering the protein of claim 1 to the subject.

### Claim 19 (depends on 1)

A method for treating a muscle-wasting disease or a metabolic disorder in a subject, comprising administering the protein of claim 1 to the subject.

### Claim 20 (depends on 1)

A method for treating a disease in which activin is over-expressed in a subject, comprising administering the protein of claim 1 to the subject, optionally wherein the disease is cancer.