Modified recombinant factor viii and von willebrand factor and methods of use

Abstract

The present invention provides novel methods of increasing the survival of a coagulation protein by inhibiting the interaction with a clearance receptor. The invention also provides methods of preparing compositions that inhibit coagulation protein clearance receptors. Conjugated coagulation proteins, including compositions and formulations thereof, are also provided by the present invention.

1 . A method of increasing the survival of a coagulation protein by inhibiting the interaction with a clearance receptor, the method comprising the steps of:
 (a) modifying a coagulation protein with a water soluble polymer, and   (b) administering to a mammal in need thereof a therapeutically effective amount of a composition comprising the modified coagulation factor;   wherein the modification increases the survival of the protein in the blood circulation of a mammal.   
     
     
         2 . The method of  claim 1 , wherein the coagulation protein is Factor VIII or von Willebrand Factor. 
     
     
         3 . The method of  claim 1 , wherein the clearance receptor is from the class of LFP receptors, vLDL receptors, LDL receptor related protein, megalin receptors, and macrophage mannose receptors. 
     
     
         4 . The method of  claim 3 , wherein the clearance receptor is LRP1 
     
     
         5 . The method of  claim 1 , wherein the water soluble polymer is selected from the group consisting of polysialic acid and polyethylene glycol. 
     
     
         6 . The method of  claim 1 , wherein the water soluble polymer is releasable from the coagulation protein. 
     
     
         7 . The method of  claim 1 , wherein the water soluble polymer is stably linked to the protein. 
     
     
         8 . The method of  claim 1 , wherein the water soluble polymer is linked to the protein via a linker. 
     
     
         9 . A method of increasing the survival of Factor VIII by inhibiting the interaction with a clearance receptor, the method comprising the steps of:
 (a) modifying a binding protein of Factor VIII with a water soluble polymer, and   (b) administering to a mammal in need thereof a therapeutically effective amount of a composition comprising the modified binding protein,   wherein said binding protein is von Willebrand Factor.   
     
     
         10 . The method of  claim 9 , wherein said clearance receptor is LRP1. 
     
     
         11 . The method of  claim 9 , wherein the water soluble polymer is selected from the group consisting of polysialic acid and polyethylene glycol. 
     
     
         12 . The method of  claim 9 , wherein Factor VIII is administered with the modified von Willebrand Factor. 
     
     
         13 . The method of  claim 12 , wherein the Factor VIII being administered is also modified with a water soluble polymer. 
     
     
         14 - 33 . (canceled)