Endoglin polypeptides and uses thereof

Abstract

In certain aspects, the present disclosure relates to the insight that a polypeptide comprising a truncated, ligand-binding portion of the extracellular domain of endoglin (ENG) polypeptide may be used to inhibit angiogenesis in vivo, particularly in mammals suffering angiogenesis-related disorders.

1 .- 34 . (canceled) 
     
     
         35 . An endoglin fusion protein comprising:
 (a) a first portion that comprises amino acids 26-346 of SEQ ID NO: 1; and   (b) a second heterologous portion that comprises an immunoglobulin Fc domain.   
     
     
         36 . The endoglin fusion protein of  claim 35 , wherein the first portion does not include an amino acid sequence consisting of amino acids 379-430 of SEQ ID NO: 1. 
     
     
         37 . The endoglin fusion protein of claim  15 , wherein the endoglin polypeptide binds human BMP 9 with an equilibrium dissociation constant (K D ) less than 1×10 −9  M or a dissociation rate constant (kd) less than 1×10 −3  s −1 . 
     
     
         38 . The endoglin fusion protein of  claim 35 , wherein the endoglin polypeptide binds human BMP-9 with an equilibrium dissociation constant (K D ) less than 1×10 −9  M or a dissociation rate constant (kd) less than 5×10 4  s −1 . 
     
     
         39 . The endoglin fusion protein of  claim 35 , wherein the endoglin polypeptide binds human BMP-10 with an equilibrium dissociation constant (K D ) less than 1×10 −9  M or a dissociation rate constant (kd) less than 5×10 −3  s −1 . 
     
     
         40 . The endoglin fusion protein of  claim 35 , wherein the endoglin polypeptide binds human BMP-10 with an equilibrium dissociation constant (K D ) less than 1×10 −9  M or a dissociation rate constant (kd) less than or equal to 2.5×10 −3  s −1 . 
     
     
         41 . The endoglin fusion protein of  claim 35 , wherein the endoglin polypeptide does not bind human TGF-β1, human TGF-β3, human VEGF, or human basic fibroblast growth factor (FGF-2). 
     
     
         42 . The endoglin fusion protein of  claim 35 , wherein the second heterologous portion is joined to the first portion by a linker. 
     
     
         43 . The endoglin fusion protein of  claim 42 , wherein the linker consists of an amino acid sequence consisting of SEQ ID NO: 31 (TGGG) or SEQ ID NO: 32 (GGG). 
     
     
         44 . The endoglin fusion protein of  claim 35 , wherein the endoglin fusion protein 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. 
     
     
         45 . The endoglin fusion protein of  claim 42 , wherein the endoglin fusion protein comprises an amino acid sequence of SEQ ID NO: 36. 
     
     
         46 . The endoglin polypeptide of  claim 42 , wherein the endoglin fusion protein comprises an amino acid sequence of SEQ ID NO: 29. 
     
     
         47 . A dimer comprising the endoglin fusion protein of  claim 35 , wherein the dimer is a homodimer. 
     
     
         48 . A pharmaceutical preparation comprising the endoglin fusion protein of  claim 35  and a pharmaceutically acceptable excipient. 
     
     
         49 . An isolated polynucleotide comprising a coding sequence for the endoglin fusion protein of  claim 35 . 
     
     
         50 . The isolated polynucleotide of  claim 49 , wherein the polynucleotide comprises a nucleotide sequence of SEQ ID NO: 30. 
     
     
         51 . A cell transformed with the isolated polynucleotide of  claim 49 . 
     
     
         52 . The cell of  claim 51 , wherein the cell is a mammalian cell. 
     
     
         53 . The cell of  claim 52 , wherein the cell is a CHO cell or a human cell. 
     
     
         54 . A method for inhibiting a VEGF-inducible angiogenesis, the method comprising administering a subject in need thereof an effective amount of the endoglin fusion protein of  claim 35 .