NOVEL FACTOR VIII:C POLYPEPTIDE ANALOGS WITH ALTERED PROTEASE SITES

摘要

Factor VIII:C polypeptide analogs are provided that are native Factor VIII:C polypeptides that contain amino acid modifications at one or more amino acid residues adjacent an Arg residue, provided that the Arg residue is not at a Factor VIII:C activation site. Such modifications create one or more Arg-Pro or Pro-Arg linkages. Nucleic acid molecules encoding Factor VIII:C polypeptide analogs, vectors and host cells containing such nucleic acid molecules are also provided. Additional modifications include the creation of a tripeptide having the formula P3-P2-P1, wherein P3 is a residue selected from the group consisting of Phe, Glu, and Pro; P2 is any amino acid residue except Ser and P2 is not Leu335 and is not Asn1720; and P1 is Arg. Other modifications include substitutions at the non-activating Arg residues occurring at positions Arg336, Arg1719 and/or Arg1721. Further provided are analog complexes that contain at least two such analogs. Methods of producing the analogs, the analog complexes, nucleic acids encoding the same, vectors, and host cells are also provided as well as methods of using such compositions for prevention or treatment of active Factor VIII:C polypeptide deficiencies.