Endoglin peptides to treat fibrotic diseases

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 treat fibrotic disorders.

1 . A method of treating or preventing a fibrotic disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of an endoglin polypeptide comprising an amino acid sequence at least 95% identical to amino acids 42-333 of SEQ ID NO: 1. 
     
     
         2 . The method of  claim 1 , wherein the fibrotic disorder is liver fibrosis. 
     
     
         3 . The method of  claim 2 , wherein the liver fibrosis is liver cirrhosis, alcohol-induced liver fibrosis, biliary duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, congenital hepatic fibrosis or autoimmune hepatitis. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the endoglin polypeptide does not include a sequence consisting of amino acids 379-430 of SEQ ID NO: 1. 
     
     
         6 . The method of  claim 1 , wherein the endoglin polypeptide comprises an amino acid sequence at least 95% identical to a sequence beginning at an amino acid corresponding to any of positions 26-42 of SEQ ID NO: 1 and ending at an amino acid corresponding to any of positions 333-378 of SEQ ID NO: 1. 
     
     
         7 . The method of  claim 1 , wherein the endoglin polypeptide comprises an amino acid sequence at least 95% identical to a sequence selected from a group consisting of:
 a. amino acids 26-346 of SEQ ID NO: 1,   b. amino acids 26-359 of SEQ ID NO: 1, and   c. amino acids 26-378 of SEQ ID NO: 1.   
     
     
         8 . The method of  claim 1 , wherein the endoglin polypeptide consists of a first portion consisting of an amino acid sequence at least 95% identical to a sequence selected from a group consisting of:
 a. amino acids 26-346 of SEQ ID NO: 1,   b. amino acids 26-359 of SEQ ID NO: 1, and   c. amino acids 26-378 of SEQ ID NO: 1   and a second portion that is heterologous to SEQ ID NO: 1.   
     
     
         9 . The method of  claim 8 , wherein the second portion of the endoglin polypeptide comprises an Fc portion of an IgG. 
     
     
         10 . The method of  claim 1 , wherein the endoglin polypeptide is a dimer. 
     
     
         11 . The method of  claim 1 , wherein the endoglin polypeptide is a homodimer. 
     
     
         12 . The method of  claim 1 , wherein the endoglin polypeptide does not include more than 50 consecutive amino acids from a sequence consisting of amino acids 379-586 of SEQ ID NO: 1. 
     
     
         13 . The method of  claim 1 , wherein the endoglin polypeptide binds human BMP-9 with an equilibrium dissociation constant (KD) less than 1×10 −9  M or a dissociation rate constant (kd) less than 1×10 −3  s −1 . 
     
     
         14 . The method of  claim 1 , wherein the endoglin polypeptide binds human BMP-9 with an equilibrium dissociation constant (KD) less than 1×10 −9  M or a dissociation rate constant (kd) less than 5×10 −4  s −1 . 
     
     
         15 . The method of  claim 1 , wherein the endoglin polypeptide binds human BMP-10 with an equilibrium dissociation constant (KD) less than 1×10 −9  M or a dissociation rate constant (kd) less than 5×10 −3  s −1 . 
     
     
         16 . The method of  claim 1 , wherein the endoglin polypeptide binds human BMP-10 with an equilibrium dissociation constant (KD) less than 1×10 −9  M or a dissociation rate constant (kd) less than 2.5×10 −3  s −1 . 
     
     
         17 . The method of  claim 1 , wherein the endoglin polypeptide does not bind human TGF-β1, human TGF-β3, human VEGF, or human basic fibroblast growth factor (FGF-2). 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the endoglin polypeptide includes a portion selected from the group consisting of: a constant domain of an immunoglobulin and a serum albumin. 
     
     
         20 . The method of  claim 1 , wherein the endoglin polypeptide comprises an immunoglobulin Fc domain. 
     
     
         21 . The method of  claim 20 , wherein the immunoglobulin Fc domain is joined to the ENG polypeptide portion by a linker. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the endoglin 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 . (canceled)