Method for improving the stability of purified Factor VIII after reconstitution
AssigneeCSL Limited
InventorsCarsten Horn, Sabine Zollner, Hubert Metzner, Stefan Schulte
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Abstract
The present disclosure relates to a method for increasing the stability of a Factor VIII molecule after purification, lyophilization and reconstitution, comprising preventing proteolytic cleavage of the Factor VIII molecule into a first fragment comprising essentially the A1 domain and the A2 domain and a second fragment comprising essentially the A3 domain, the C1 domain and the C2 domain throughout manufacturing the Factor VIII molecule. The disclosure further pertains to a method for improving the bioavailability of Factor VIII after intravenous and non-intravenous injection.
Claims24
A method of treatment or prophylaxis for a bleeding disorder, comprising administering a modified Factor VIII molecule to a subject,
- wherein the modified Factor VIII molecule comprises a Factor VIII molecule and a peptidic linker, wherein the Factor VIII molecule is modified by inactivating the proteolytic cleavage site between Arg1648 and Glu1649, and, if present in the Factor VIII molecule, the proteolytic cleavage site between Arg1313 and Ala1314, and
- wherein the modified Factor VIII molecule is administered at a dosage of 20 IU/kg to 50 IU/kg, provides an equal or higher mean residence time of the modified Factor VIII molecule as compared to mean residence time of a higher dosage of an administered human wild-type Factor VIII molecule and/or an administered B-domain deleted human Factor VIII molecule in which Asn745 is fused to Pro1640.
A method of treatment or prophylaxis for a bleeding disorder, comprising administering a modified Factor VIII molecule to a subject,
- wherein the modified Factor VIII molecule comprises a Factor VIII molecule and a peptidic linker, wherein the Factor VIII molecule is modified by inactivating the proteolytic cleavage site between Arg1648 and Glu1649, and, if present in the Factor VIII molecule, the proteolytic cleavage site between Arg1313 and Ala1314, and
- wherein the modified Factor VIII molecule is administered at a dosage of 20 IU/kg to 50 IU/kg, and while maintaining or reducing the clearance rate of the modified Factor VIII molecule as compared to the clearance rate of a higher dosage of an administered human wild-type Factor VIII molecule and/or an administered B-domain deleted human Factor VIII molecule in which Asn745 is fused to Pro1640.
A method of treatment or prophylaxis for a bleeding disorder, comprising administering a modified Factor VIII molecule to a subject,
- wherein the modified Factor VIII molecule comprises a Factor VIII molecule and a peptidic linker, wherein the Factor VIII molecule is modified by inactivating the proteolytic cleavage site between Arg1648 and Glu1649, and, if present in the Factor VIII molecule, the proteolytic cleavage site between Arg1313 and Ala1314, and
- wherein the modified Factor VIII molecule is administered at a dosage of 20 IU/kg to 50 IU/kg, while maintaining or increasing the area under the plasma concentration-time curve (AUC) of the modified Factor VIII molecule as compared to the AUC of a higher dosage of an administered human wild-type Factor VIII molecule and/or an administered B-domain deleted human Factor VIII molecule in which Asn745 is fused to Pro1640.
A method of treatment or prophylaxis for a bleeding disorder, comprising administering a modified Factor VIII molecule to a subject,
- wherein the modified Factor VIII molecule comprises a Factor VIII molecule and a peptidic linker, wherein the Factor VIII molecule is modified by inactivating the proteolytic cleavage site between Arg1648 and Glu1649, and, if present in the Factor VIII molecule, the proteolytic cleavage site between Arg1313 and Ala1314, and
- wherein the modified Factor VIII molecule is administered at a dosage of 20 IU/kg to 50 IU/kg, while maintaining or increasing the plasma half-life of the modified Factor VIII molecule as compared to the plasma half-life of a higher dosage of an administered human wild-type Factor VIII molecule and/or an administered B-domain deleted human Factor VIII molecule in which Asn745 is fused to Pro1640.
Dependencies are inferred from the claim text.