# US 2019/0375820 A1 · Alk7:actriib heteromultimers and uses thereof

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- Number: US 2019/0375820 A1
- Document ID: US20190375820A1
- Status: Published application
- Kind: A1
- Application number: 16/251,935
- Filed: 2019-01-18
- Published: 2019-12-12
- 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/US20190375820A1

## 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 recombinant heteromultimer comprising an ALK7 polypeptide and an ActRIIB polypeptide; wherein the heteromultimer binds to one or more ligands selected from the group consisting of: activin A, activin B, activin C, activin E, activin AB, activin AE, activin BC, activin BE, GDF8, GDF11, nodal, BMP5, GDF3, and BMP10.

### Claim 2 (depends on 1)

The method of claim 1, wherein the ALK7 polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that:
a) begins at any one of amino acids 21, 22, 23, 24, 25, 26, 27, or 28 SEQ ID NO: 9, and
b) ends at any one of amino acids 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, or 113 of SEQ ID NO: 9.

### Claim at position 3

3-7. (canceled)

### Claim 8 (depends on 1)

The method of claim 1, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that:
a) begins at any one of amino acids 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 SEQ ID NO: 1, and
b) ends at any one of amino acids 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134 of SEQ ID NO: 1.

### Claim at position 5

9-15. (canceled)

### Claim 16 (depends on 1)

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

### Claim at position 7

17-19. (canceled)

### Claim 20 (depends on 16)

The method of claim 16, wherein the heterologous domain comprises an Fc immunoglobulin domain.

### Claim 21 (depends on 20)

The method of claim 20, wherein the Fc immunoglobulin domain comprises one or more amino acid modifications that promotes heterodimer formation.

### Claim 22 (depends on 20)

The method of claim 20, wherein the immunoglobulin Fc domain comprises one or more amino acid modifications that inhibit homodimer formation.

### Claim 23 (depends on 20)

The method of claim 20, wherein the heterologous domain comprises an Fc immunoglobulin domain from an IgG immunoglobulin.

### Claim at position 12

24-71. (canceled)

### Claim 72 (depends on 1)

The method of claim 1, 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 at position 14

73-84. (canceled)

### Claim 85 (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 at position 16

86-88. (canceled)

### Claim 89 (depends on 1)

The method of claim 1, wherein the ALK7 polypeptide and/or ActRIIB polypeptide is glycosylated and has a glycosylation pattern obtainable from a Chinese hamster ovary cell line.

### Claim at position 18

90-134. (canceled)

### Claim 135 (depends on 1)

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

### Claim at position 20

136-160. (canceled)

### Claim 161 (depends on 1)

The method of claim 1, wherein the ALK7 polypeptide comprises an amino acid sequence that is at least 90% 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 90% identical to amino acids 29-109 of SEQ ID NO: 1.

### Claim 162 (depends on 1)

The method of claim 1, 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 163 (depends on 1)

The method of claim 1, 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 164 (depends on 1)

The method of claim 1, 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 165 (depends on 1)

The method of claim 1, 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 166 (depends on 161)

The method of claim 161, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 167 (depends on 162)

The method of claim 162, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 168 (depends on 164)

The method of claim 164, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 169 (depends on 165)

The method of claim 165, wherein the heterologous domain comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain.

### Claim 170 (depends on 161)

The method of claim 161, 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 171 (depends on 162)

The method of claim 162, 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 172 (depends on 165)

The method of claim 165, 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 173 (depends on 164)

The method of claim 164, 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 174 (depends on 1)

The method of claim 1, wherein the kidney disease or disorder is associated with kidney fibrosis.

### Claim 175 (depends on 1)

The method of claim 1, wherein the kidney disease or disorder is chronic kidney disease.

### Claim 176

A method of treating obesity in a subject in need thereof, comprising administering to the subject a recombinant heteromultimer comprising an ALK7 polypeptide and an ActRIIB polypeptide; wherein the heteromultimer binds to one or more ligands selected from the group consisting of: activin A, activin B, activin C, activin E, activin AB, activin AE, activin BC, activin BE, GDF8, GDF11, nodal, BMP5, GDF3, and BMP10.