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BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice.
- Source :
-
Blood [Blood] 2020 Apr 23; Vol. 135 (17), pp. 1484-1496. - Publication Year :
- 2020
-
Abstract
- Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-D'D3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.<br /> (© 2020 by The American Society of Hematology.)
- Subjects :
- Animals
Factor VIII genetics
Hemophilia A metabolism
Hemophilia A pathology
Hemostasis
Humans
Male
Mice
Mice, Inbred C57BL
Primates
von Willebrand Factor genetics
Factor VIII metabolism
Hemophilia A therapy
Hemorrhage prevention & control
Recombinant Fusion Proteins administration & dosage
von Willebrand Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 135
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 32078672
- Full Text :
- https://doi.org/10.1182/blood.2019001292