Alk4:actriib heteromultimers and uses thereof

Patent metadata

Field	Value
Publication number	US-2016289292-A1
Application number	US-201615092573-A
Country	US
Kind code	A1
Filing date	Apr 6, 2016
Priority date	Apr 6, 2015
Publication date	Oct 6, 2016
Grant date	—

Abstract

In certain aspects, the disclosure provides soluble heteromeric polypeptide complexes comprising an extracellular domain of an ALK4 receptor and an extracellular domain of ActRIIB. In certain aspects, such soluble ALK4:ActRIIB complexes may be used to regulate (promote or inhibit) growth of tissues or cells including, for example, muscle, bone, cartilage, fat, neural tissue, tumors, and/or cancerous cells. In certain aspects, such ALK4:ActRIIB complexes are can be used to improve muscle formation, bone formation, metabolic parameters, and disorders associated with these tissues, cellular networks, kidney, and endocrine systems.

First claim

1 . A recombinant heteromultimer comprising an ALK4 polypeptide and an ActRIIB polypeptide.

2 . The heteromultimer of claim 1 , wherein the ALK4 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 of 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34 SEQ ID NO: 9, and b) ends at any one of amino acids 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, or 126 of SEQ ID NO: 9.

3 - 6 . (canceled)

7 . The heteromultimer 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 of 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.

8 - 14 . (canceled)

15 . The heteromultimer of claim 1 , wherein the ALK4 and/or ActRIIB polypeptide is a fusion protein further comprising a heterologous domain.

16 - 18 . (canceled)

19 . The heteromultimer of claim 1 , wherein the heterologous domain comprises an Fc immunoglobulin domain.

20 . The heteromultimer of claim 19 , wherein the Fc immunoglobulin domain comprises one or more amino acid modifications that promotes heterodimer formation.

21 . The heteromultimer of claim 19 , wherein the immunoglobulin Fc domain comprises one or more amino acid modifications that inhibit homodimer formation.

22 . The heteromultimer of claim 19 , wherein the heterologous domain comprises an Fc immunoglobulin domain from an IgG immunoglobulin.

23 - 70 . (canceled)

71 . The heteromultimer of claim 15 , wherein the fusion protein further comprises a linker domain positioned between the ALK4 domain and the heterologous domain and/or a linker domain positioned between the ActRIIB domain and the heterologous domain.

72 - 83 . (canceled)

84 . The heteromultimer of claim 1 , wherein the ALK4 polypeptide and/or ActRIIB polypeptide comprises one or 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.

85 - 87 . (canceled)

88 . The heteromultimer of claim 1 , wherein the ALK4 polypeptide and/or ActRIIB polypeptide is glycosylated and has a glycosylation pattern obtainable from a Chinese hamster ovary cell line.

89 . (canceled)

90 . The heteromultimer of claim 1 , wherein the heteromultimer binds to one or more ligands selected from the group consisting of: activin A, activin B, GDF8, GDF11, BMP6, BMP10, and GDF3.

91 - 102 . (canceled)

103 . The heteromultimer of claim 1 , wherein the heteromultimer inhibits ligand signaling in a cell-based assay, and wherein the ligand is selected from the group consisting of: activin A, activin B, GDF8, GDF11, BMP6, BMP10, and GDF3.

104 - 113 . (canceled)

114 . The heteromultimer of claim 1 , wherein the heteromultimer is an ALK4:ActRIIB heterodimer.

115 . A pharmaceutical preparation comprising the heteromultimer of claim 1 and a pharmaceutically acceptable carrier.

116 . The pharmaceutical preparation of claim 115 , wherein the pharmaceutical preparation is substantially pyrogen-free.

117 . The pharmaceutical preparation of claim 115 , wherein the pharmaceutical preparation further comprises an additional active agent.

118 . The pharmaceutical preparation of claim 11 , wherein the pharmaceutical preparation comprises less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or less than about 1% ALK4 homomultimers.

119 . The pharmaceutical preparation of claim 115 , wherein the pharmaceutical preparation comprises less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or less than about 1% ActRIIB homomultimers.

120 - 139 . (canceled)

140 . A method for treating a patient having a disorder associated with muscle loss or insufficient muscle growth, comprising administering to a patient in need thereof an effective amount of a heteromultimer comprising an ALK4 polypeptide and an ActRIIB polypeptide.

141 . The method of claim 140 , wherein the patient has a disorder selected from the group consisting of: muscle atrophy, muscular dystrophy, Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, amyotrophic lateral sclerosis, cachexia associated with cancer or cancer therapy.

142 - 148 . (canceled)

149 . A method for treating a patient having a disorder associated with neurodegeneration, comprising administering to the patient in need thereof an effective amount of a heteromultimer comprising an ALK4 polypeptide and an ActRIIB polypeptide.

150 . The method of claim 149 , wherein the disorder is amyotrophic lateral sclerosis.

151 - 214 . (canceled)

Assignees

• Acceleron Pharma Inc

Inventors

• Kumar Ravindra
• Grinberg Asya
• Sako Dianne
• Pearsall Robert Scott
• Castonguay Roselyne

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title