BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice
Author:
Seth Chhabra Ekta1ORCID, Liu Tongyao1, Kulman John2, Patarroyo-White Susannah1, Yang Buyue1, Lu Qi1ORCID, Drager Douglas1, Moore Nancy1, Liu Jiayun1, Holthaus Amy M.1, Sommer Jurg M.1, Ismail Ayman1, Rabinovich Deana1, Liu Zhan1, van der Flier Arjan1, Goodman Allison1, Furcht Chris2, Tie Mark2, Carlage Tyler2, Mauldin Randy2, Dobrowsky Terrence M.2, Liu Zhiqian2, Mercury Oblaise1ORCID, Zhu Lily2, Mei Baisong3, Schellenberger Volker4, Jiang Haiyan2, Pierce Glenn F.2, Salas Joe1, Peters Robert1ORCID
Affiliation:
1. Sanofi, Waltham, MA; 2. Biogen, Inc, Cambridge, MA; 3. Sanofi, Cambridge, MA; and 4. Amunix Pharmaceuticals, Inc, Mountain View, CA
Abstract
AbstractFactor 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.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Reference61 articles.
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