Tgf-beta receptor type ii variants and uses thereof

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.

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 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 23 of SEQ ID NO: 5 and ending at position 159 of SEQ ID NO: 5. 
     
     
         3 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 29 of SEQ ID NO: 5 and ending at position 159 of SEQ ID NO: 5. 
     
     
         4 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 35 of SEQ ID NO: 5 and ending at position 159 of SEQ ID NO: 5. 
     
     
         5 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 23 of SEQ ID NO: 5 and ending at position 153 of SEQ ID NO: 5. 
     
     
         6 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 29 of SEQ ID NO: 5 and ending at position 153 of SEQ ID NO: 5. 
     
     
         7 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 35 of SEQ ID NO: 5 and ending at position 153 of SEQ ID NO: 5. 
     
     
         8 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 23 of SEQ ID NO: 6 and ending at positions 184 of SEQ ID NO: 6. 
     
     
         9 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 29 of SEQ ID NO: 6 and ending at position 184 of SEQ ID NO: 6. 
     
     
         10 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 23 of SEQ ID NO: 6 and ending at position 178 of SEQ ID NO: 6. 
     
     
         11 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of the sequence beginning at position 29 of SEQ ID NO: 6 and ending at position 178 of SEQ ID NO: 6. 
     
     
         12 . The TβRII fusion polypeptide of  claim 1 , wherein the first amino acid sequence consists of a sequence that 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. 
     
     
         13 . A TβRII fusion polypeptide comprising a first amino acid sequence at least 80% identical to the sequence of SEQ ID NO: 7 or SEQ ID NO: 13, or active fragment thereof, and a second heterologous portion, 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 . The TβRII fusion polypeptide of  claim 13 , wherein the first amino acid sequence comprises an N-terminal truncation of 6 amino acids corresponding to amino acids 1-6 of SEQ ID NO: 7 or SEQ ID NO: 13. 
     
     
         16 . The TβRII fusion polypeptide of  claim 13 , wherein the first amino acid sequence comprises an N-terminal truncation of 12 amino acids corresponding to amino acids 1-12 of SEQ ID NO: 7 or 37 amino acids corresponding to amino acids 1-37 of SEQ ID NO: 13. 
     
     
         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 . The TβRII fusion polypeptide of  claim 13 , wherein the first amino acid sequence comprises a C-terminal truncation of 6 amino acids corresponding to amino acids 132-137 of SEQ ID NO: 7 or amino acids 157-162 of SEQ ID NO: 13. 
     
     
         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 . The TβRII fusion polypeptide of  claim 1 , wherein the heterologous portion comprises one or more polypeptide portions that enhance one or more of: in vivo stability, in vivo half life, uptake/administration, tissue localization or distribution, formation of protein complexes, and/or purification. 
     
     
         21 . The TβRII fusion polypeptide of  claim 1 , wherein the heterologous portion comprises a polypeptide portion selected from: an immunoglobulin Fc domain and a serum albumin. 
     
     
         22 . The TβRII fusion polypeptide of  claim 21 , wherein the immunoglobulin Fc domain is joined to the TβRII polypeptide by a linker. 
     
     
         23 . The TβRII fusion polypeptide of  claim 1 , wherein the polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent. 
     
     
         24 . The TβRII fusion polypeptide of  claim 23 , wherein the polypeptide is glycosylated. 
     
     
         25 . A TβRII fusion polypeptide comprising a first amino acid sequence consisting of a portion of the extracellular domain of TβRII that 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, and a second heterologous portion. 
     
     
         26 - 35 . (canceled) 
     
     
         36 . The polypeptide of  claim 1 , wherein the polypeptide binds human GDF15 with an equilibrium dissociation constant (K D ) less than 1×10 −8  M. 
     
     
         37 . The polypeptide of  claim 1 , wherein the polypeptide has a glycosylation pattern characteristic of expression of the polypeptide in CHO cells. 
     
     
         38 . A homodimer comprising two polypeptides as defined in  claim 1 . 
     
     
         39 . An isolated polynucleotide comprising a coding sequence for the polypeptide of  claim 1 . 
     
     
         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  35 . 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . A pharmaceutical preparation comprising the polypeptide of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         45 . A method of modulating the response of a cell to a TGFβ superfamily member, the method comprising exposing the cell to a polypeptide of  claim 1 . 
     
     
         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 polypeptide of  claim 1 . 
     
     
         47 - 69 . (canceled)