# US 11,028,145 B2 · ALK7:actriib heteromultimers and uses thereof

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- Number: US 11,028,145 B2
- Document ID: US11028145B2
- Status: Granted
- Kind: B2
- Application number: 16/251,935
- Filed: 2019-01-18
- Published: 2019-12-12
- Granted: 2021-06-08
- Earliest claimed: 2015-04-06
- Assignees: Acceleron Pharma Inc.
- Applicants: Acceleron Pharma Inc.
- Inventors: Ravindra Kumar; Asya Grinberg; Dianne Sako; Robert Scott Pearsall; Roselyne Castonguay; Gang Li; Yossi Dagon; John Knopf
- Web page: https://patentgrep.com/patent/US11028145B2

## CPC

- C07K 14/71: for growth factors; for growth regulators
- A61K 38/45: Transferases (2)
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- 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 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 9/12: transferring phosphorus containing groups, e.g. kinases (2.7)
- 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)
- 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)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

In certain aspects, the disclosure provides soluble heteromeric polypeptide complexes comprising an extracellular domain of an ALK7 receptor and an extracellular domain of ActRIIB In certain aspects, these ALK7:ActRIIB heteromultimers are can be used to improve metabolic parameters in a patient in need thereof. In certain aspects, these ALK7:ActRIIB heteromultimers are can be used to treat or prevent one or more kidney-associated disease or condition in a patient in need thereof.

## Claims

### Claim 1

A method of treating a kidney disorder in a subject in need thereof, comprising administering to the subject a soluble recombinant heteromultimer comprising:
(i) an ALK7 polypeptide comprising an amino acid sequence that is at least 90% identical to amino acids 28-92 of SEQ ID NO: 9, and
(ii) an ActRIIB polypeptide comprising an amino acid sequence that is at least 90% identical to amino acids 29-109 of SEQ ID NO: 1, and
wherein the heteromultimer binds to one or more of: activin B, activin C, and activin AC; and
wherein the kidney disorder is selected from a group consisting of kidney fibrosis and kidney inflammation.

### Claim 2 (depends on 1)

The method of claim 1, wherein the ALK7 polypeptide and/or ActRIIB polypeptide is a fusion protein that further comprises a heterologous domain.

### Claim 3 (depends on 2)

The method of claim 2, wherein the heterologous domain comprises an Fc immunoglobulin domain.

### Claim 4 (depends on 3)

The method of claim 3, wherein the Fc immunoglobulin domain comprises one or more amino acid modifications that promotes heterodimer formation.

### Claim 5 (depends on 3)

The method of claim 3, wherein the immunoglobulin Fc domain comprises one or more amino acid modifications that inhibit homodimer formation.

### Claim 6 (depends on 3)

The method of claim 3, wherein the heterologous domain comprises an Fc immunoglobulin domain from an IgG immunoglobulin.

### Claim 7 (depends on 2)

The method of claim 2, wherein the fusion protein further comprises a linker domain positioned between the ALK7 domain and the heterologous domain and/or a linker domain positioned between the ActRIIB domain and the heterologous domain.

### Claim 8 (depends on 1)

The method of claim 1, wherein the ALK7 polypeptide and/or ActRIIB polypeptide comprises one or more modified amino acid residues selected from the group consisting of: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, and an amino acid conjugated to a lipid moiety.

### Claim 9 (depends on 1)

The method of claim 1, wherein the ALK7 polypeptide and/or ActRIIB polypeptide is glycosylated.

### Claim 10 (depends on 1)

The method of claim 1, wherein the heteromultimer is an ALK7:ActRIIB heterodimer.

### Claim 11 (depends on 2)

The method of claim 2, wherein the ALK7 polypeptide comprises an amino acid sequence that is at least 95% identical to amino acids 28-92 of SEQ ID NO: 9, and wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 95% identical to amino acids 29-109 of SEQ ID NO: 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the ALK7 polypeptide comprises the amino acid sequence corresponding to amino acids 28-92 of SEQ ID NO: 9, and wherein the ActRIIB polypeptide comprises the amino acid sequence corresponding to amino acids 29-109 of SEQ ID NO: 1.

### Claim 13 (depends on 2)

The method of claim 2, wherein the ALK7 polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 46, and wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 2.

### Claim 14 (depends on 13)

The method of claim 13, wherein the ALK7 polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 46, and wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2.

### Claim 15 (depends on 14)

The method of claim 14, wherein the ALK7 polypeptide comprises the amino acid sequence of SEQ ID NO: 46, and wherein the ActRIIB polypeptide comprises the amino acid sequence of SEQ ID NO: 2.

### Claim 16 (depends on 2)

The method of claim 2, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 17 (depends on 12)

The method of claim 12, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 18 (depends on 14)

The method of claim 14, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 19 (depends on 15)

The method of claim 15, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 20 (depends on 11)

The method of claim 11, wherein the fusion protein further comprises a linker domain positioned between the ALK7 domain and the heterologous domain and/or a linker domain positioned between the ActRIIB domain and the heterologous domain.

### Claim 21 (depends on 12)

The method of claim 12, wherein the fusion protein further comprises a linker domain positioned between the ALK7 domain and the heterologous domain and/or a linker domain positioned between the ActRIIB domain and the heterologous domain.

### Claim 22 (depends on 15)

The method of claim 15, wherein the fusion protein further comprises a linker domain positioned between the ALK7 domain and the heterologous domain and/or a linker domain positioned between the ActRIIB domain and the heterologous domain.

### Claim 23 (depends on 14)

The method of claim 14, wherein the fusion protein further comprises a linker domain positioned between the ALK7 domain and the heterologous domain and/or a linker domain positioned between the ActRIIB domain and the heterologous domain.