Factor VIII Molecules with Reduced VWF Binding

Abstract

The present invention relates to a recombinant Factor VIII molecule, wherein said molecule has reduced vWF binding capacity, and wherein said molecule is covalently conjugated with at least one side group.

1 . A recombinant Factor VIII molecule, wherein said molecule has reduced vWF binding capacity, and wherein said molecule is covalently conjugated with at least one side group. 
     
     
         2 . The recombinant FVIII molecule according to  claim 1 , wherein the side group is selected from one or more of the group consisting of: a hydrophilic polymer, an albumin binder, an antibody or a fragment thereof, and albumin. 
     
     
         3 . The recombinant FVIII molecule according to  claim 1 , wherein the Factor VIII molecule is a B-domain truncated variant. 
     
     
         4 . The recombinant FVIII molecule according to  claim 3 , wherein the side group is covalently conjugated to the truncated B-domain, and wherein Factor VIII activation results in removal of the covalently conjugated side group. 
     
     
         5 . The recombinant FVIII molecule according to  claim 4 , wherein said molecule is covalently conjugated with a hydrophilic polymer via an O-linked oligosaccharide in the truncated B domain, and wherein Factor VIII activation results in removal of the covalently conjugated hydrophilic polymer. 
     
     
         6 . The recombinant FVIII molecule according to  claim 5 , wherein the O-linked oligosaccharide is attached to an O-glycosylation site that is made by truncation of the B-domain. 
     
     
         7 . The recombinant FVIII molecule according to  claim 1 , wherein said molecule comprises a point mutation in residue 1680. 
     
     
         8 . The recombinant FVIII molecule according to  claim 1 , wherein the Factor molecule comprises a deletion of one or more amino acids in the region spanning residue 1670-1684. 
     
     
         9 . The recombinant FVIII molecule according to  claim 1 , wherein the side group is PEG. 
     
     
         10 . A method of making the recombinant FVIII molecule according to  claim 1 , wherein said method comprises attaching a side group to a Factor VIII molecule having reduced capacity to bind vWF. 
     
     
         11 . The recombinant FVIII molecule obtainable by a method according to  claim 10 . 
     
     
         12 . A method of treating a haemophilic disease comprising administering to a patient in need thereof a therapeutically effective amount of the recombinant FVIII molecule according to  claim 1 . 
     
     
         13 . A pharmaceutical composition comprising a molecule according to  claim 1 .