BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice
| Autor: | Joe Salas, Tongyao Liu, Randy Mauldin, Jiayun Liu, Terrence M. Dobrowsky, Jurg M. Sommer, Volker Schellenberger, Susannah Patarroyo-White, Mark Tie, Ayman Ismail, Buyue Yang, Haiyan Jiang, Arjan van der Flier, Qi Lu, Chris Furcht, Nancy Moore, Tyler Carlage, John Kulman, Baisong Mei, Amy M Holthaus, Allison Goodman, Zhan Liu, Lily Zhu, Robert T. Peters, Deana Rabinovich, Glenn F. Pierce, Ekta Seth Chhabra, Douglas Drager, Oblaise Mercury, Zhiqian Liu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
Primates 0301 basic medicine congenital hereditary and neonatal diseases and abnormalities Recombinant Fusion Proteins Immunology Hemorrhage Endogeny 030204 cardiovascular system & hematology Pharmacology Hemophilia A Biochemistry Thrombosis and Hemostasis law.invention Mice 03 medical and health sciences 0302 clinical medicine Von Willebrand factor Pharmacokinetics law hemic and lymphatic diseases von Willebrand Factor Animals Humans Medicine Hemostatic function Hemostasis Factor VIII biology business.industry Cell Biology Hematology Protein engineering Fusion protein Mice Inbred C57BL 030104 developmental biology Recombinant DNA biology.protein business |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2019001292 |
| Popis: | 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-DʹD3 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|