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US 2003/0148953 A1Published application
Inactivation resistant factor VIII
AssigneeUniversity of Michigan
InventorsRandal J. Kaufman, Steven W. Pipe
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AssigneeUniversity of Michigan
InventorsRandal J. Kaufman, Steven W. Pipe
Estimating the term…
The present invention provides novel purified and isolated nucleic acid sequences encoding procoagulant-active FVIII proteins. The nucleic acid sequences of the present invention encode amino acid sequences corresponding to known human FVIII sequences, wherein residue Phe309 is mutated. The nucleic acid sequences of the present invention also encode amino acid sequences corresponding to known human FVIII sequences, wherein the APC cleavage sites, Arg336 and Ile562, are mutated. The nucleic acid sequences of the present invention further encode amino acid sequences corresponding to known human FVIII sequences, wherein the B-domain is deleted, the von Willebrand factor binding site is deleted, a thrombin cleavage site is mutated, an amino acid sequence spacer is inserted between the A2- and A3-domains. Methods of producing the FVIII proteins of the invention, nucleotide sequences encoding such proteins, pharmaceutical compositions containing the nucleotide sequences or proteins, as well as methods of treating patients suffering from hemophilia, are also provided.
A procoagulant-active FVIII protein comprising a human FVIII polypeptide that is modified, wherein the modification comprises a deletion of the B domain, a deletion of the von Willebrand factor binding site, a mutation at Arg740 and an addition of an amino acid sequence spacer between the A2- and A3-domains, wherein the amino acid sequence spacer is of a sufficient length so that upon activation, the procoagulant-active FVIII protein becomes a heterodimer.
A procoagulant-active FVIII protein comprising the A1-, A2-, A3-, C1- and C2- domains of human Factor VIII, characterized in that upon thrombin activation, the protein becomes a heterodimer comprising an A1-domain fragment and an A2-A3-C1-C2 chain.
A procoagulant-active FVIII protein comprising a human FVIII polypeptide that is modified, wherein the modification consists of a deletion of the B domain, a deletion of the von Willebrand factor binding site, a mutation at Arg740 and an addition of an amino acid sequence spacer between the A2- and A3-domains, wherein the amino acid sequence spacer is of a sufficient length so that upon activation, the procoagulant-active FVIII protein becomes a heterodimer.
A method for treating hemophilia comprising the steps of administering a procoagulant-active FVIII protein comprising a human FVIII polypeptide that is modified, wherein the modification comprises a deletion of the B domain, a deletion of the von Willebrand factor binding site, a mutation at Arg740 and an addition of an amino acid sequence spacer between the A2- and A3-domains.
A method for treating hemophilia comprising the step of administering a procoagulant-active FVIII protein comprising a human FVIII polypeptide that is modified, wherein the modification consists of a deletion of the B domain, a deletion of the von Willebrand factor binding site, a mutation at Arg740 and an addition of an amino acid sequence spacer between the A2- and A3-domains.
Dependencies are inferred from the claim text.