Tgf-beta receptor type ii variants and uses thereof

Patent metadata

Field	Value
Publication number	US-2016376341-A1
Application number	US-201615044883-A
Country	US
Kind code	A1
Filing date	Feb 16, 2016
Priority date	Aug 22, 2013
Publication date	Dec 29, 2016
Grant date	—

Abstract

In certain aspects, the present disclosure relates to polypeptides comprising a truncated, ligand-binding portion of the extracellular domain of TβRII polypeptide useful to selectively antagonize a TβRII ligand. The disclosure further provides compositions and methods for use in treating or preventing TGFβ associated disorders.

First claim

1 . A TβRII fusion polypeptide comprising a first amino acid sequence from the extracellular domain of TβRII and a heterologous amino acid sequence, wherein the first amino acid sequence consists of an amino acid sequence at least 80% identical to:
a) a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 5 and ending at any of positions 153 to 159 of SEQ ID NO: 5 or
b) a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 6 and ending at any of positions 178 to 184 of SEQ ID NO: 6.

2 - 12 . (canceled)

13 . The TβRII fusion polypeptide of claim 1 , wherein the first amino acid sequence is at least 80% identical to the sequence of SEQ ID NO: 7 or SEQ ID NO: 13, or active fragment thereof, and wherein the first amino acid sequence has a D at the position corresponding to position 36 of SEQ ID NO: 47 and/or a K at the position corresponding to position 76 of SEQ ID NO: 47.

14 . The TβRII fusion polypeptide of claim 13 wherein the first amino acid sequence comprises an N-terminal truncation of 1-12 amino acids corresponding to amino acids 1-12 of SEQ ID NO: 7 or 1-37 amino acids corresponding to amino acids 1-37 of SEQ ID NO: 13.

15 - 16 . (canceled)

17 . The TβRII fusion polypeptide of claim 13 , wherein the first amino acid sequence comprises a C-terminal truncation of 1-6 amino acids corresponding to amino acids 137-132 of SEQ ID NO: 7 or amino acids 162-157 of SEQ ID NO: 13.

18 . (canceled)

19 . The TβRII fusion polypeptide of claim 1 , wherein the first amino acid sequence comprises an insertion corresponding to SEQ ID NO: 18 between the residues corresponding to positions 117 and 118 of SEQ ID NO: 47.

20 . (canceled)

21 . The TβRII fusion polypeptide of claim 1 , wherein the heterologous amino acid sequence is joined to the TβRII polypeptide by a linker, and wherein the heterologous amino acid sequence comprises a polypeptide portion selected from: an immunoglobulin Fc domain and a serum albumin.

22 - 24 . (canceled)

25 . The TβRII fusion polypeptide of claim 1 , wherein the first amino acid sequence comprises an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 7-17 and 47-49.

26 - 29 . (canceled)

30 . The TβRII fusion polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 53, 54, 55, 56, 57, 58, 59, 60, 61, and 62.

31 - 38 . (canceled)

39 . An isolated polynucleotide that hybridizes under stringent conditions to a complement of a nucleotide sequence selected from SEQ ID NOs: 26, 28, 30, 32, 34, 36, 38, 40, 42 and 44.

40 . A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim 39 .

41 . A cell transformed with an isolated polynucleotide of claim 39 .

42 . (canceled)

43 . The cell of claim 41 , wherein the cell is a CHO cell or a human cell.

44 . A pharmaceutical preparation comprising the polypeptide of claim 1 and a pharmaceutically acceptable excipient.

45 . (canceled)

46 . A method of treating a disease or condition associated with a TGFβ superfamily member in a patient in need thereof, the method comprising administering to the patient an effective amount of a TβRII fusion polypeptide, wherein the polypeptide comprises a first amino acid sequence from the extracellular domain of TβRII and a heterologous amino acid sequence, wherein the first amino acid sequence consists of an amino acid sequence at least 80% identical to:
a) a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 5 and ending at any of positions 153 to 159 of SEQ ID NO: 5 or
b) a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 6 and ending at any of positions 178 to 184 of SEQ ID NO: 6.

47 . (canceled)

48 . The method of claim 46 , wherein the disease or condition is a cancer, a fibrotic or sclerotic disease or disorder, or heart disease.

49 . The method of claim 46 , wherein the disease or condition is selected from stomach cancer, intestinal cancer, skin cancer, breast cancer, melanoma, bone cancer, thyroid cancer, scleroderma, atherosclerosis, liver fibrosis, diffuse systemic sclerosis, glomerulonephritis, neural scarring, dermal scarring, radiation-induced fibrosis, hepatic fibrosis, myelofibrosis, hereditary hemorrhagic telangiectasia (HHT), Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm syndrome, arterial tortuosity syndrome, pre-eclampsia, atherosclerosis, restenosis, and hypertrophic cardiomyopathy/congestive heart failure.

50 - 53 . (canceled)

54 . An antibody, or antigen binding fragment thereof, that binds to GDF15 and blocks the interaction between GDF15 and TβRII.

55 . A GDF15 polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or a fragment thereof that binds TβRII, wherein the GDF15 polypeptide is at least 95% pure, with respect to protein contaminants.

56 . The GDF15 polypeptide of claim 55 , wherein the GDF15 polypeptide binds to the TβRII polypeptide of claim 1 .

57 . The GDF15 polypeptide of claim 55 , wherein the GDF15 polypeptide binds TβRII with an equilibrium dissociation constant (K D ) of no greater than 10 −8 M.

58 - 69 . (canceled)

Assignees

• Acceleron Pharma Inc

Inventors

• Kumar Ravindra
• Grinberg Asya
• Sako Dianne S
• Castonguay Roselyne
• Steeves Rita

Classifications

• 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/04

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