Methods of treating hemophilia in patients having developed inhibitory antibodies

Abstract

This invention relates to Factor VIII muteins that are covalently bound, at a predefined site that is not an N-terminal amine, to one or more biocompatible polymers such as polyethylene glycol. The mutein conjugates retain FVIII procoagulant activity and have improved pharmacokinetic properties.

1 .- 35 . (canceled) 
     
     
         36 . A method for the treatment of hemophilia in a patient who has already developed factor VIII inhibitory antibodies comprising administering a therapeutically effective amount of a pharmaceutical composition of a conjugate having factor VIII procoagulant activity comprising a functional factor VIII polypeptide covalently attached to one or more biocompatible polymers. 
     
     
         37 . The method of  claim 36 , wherein the biocompatible polymer comprises polyalkylene oxide. 
     
     
         38 . The method of  claim 36 , wherein the biocompatible polymer comprises polyethylene glycol. 
     
     
         39 . The method of  claim 38 , wherein the polyethylene glycol comprises methoxypolyethylene glycol. 
     
     
         40 . The method of  claim 39 , wherein the methoxypolyethylene glycol has a size range of from 3 kD to 100 kD. 
     
     
         41 . The method of  claim 40 , wherein the methoxypolyethylene glycol has a size range of from 5 kD to 64 kD. 
     
     
         42 . The method of  claim 41 , wherein the methoxypolyethylene glycol has a size range of from 5 kD to 43 kD. 
     
     
         43 . The method of  claim 36 , wherein the biocompatible polymer is covalently attached to the functional factor VIII polypeptide at a site that is or is within 20 angstrom of a binding site for factor VIII inhibitory antibodies. 
     
     
         44 . The method of  claim 36 , wherein the binding of factor VIII inhibitory antibodies to the conjugate is less than binding of the antibodies to the polypeptide when it is not conjugated. 
     
     
         45 . The method of  claim 36 , wherein the conjugate comprises a functional factor VIII polypeptide comprising the amino acid sequence of SEQ ID NO: 3 or 4. 
     
     
         46 . The method of  claim 38 , wherein the conjugate is monopegylated or dipegylated. 
     
     
         47 . The method of  claim 38 , wherein the conjugate comprises a functional factor VIII polypeptide comprising the amino acid sequence of SEQ ID NO: 4 or an allelic variant thereof.