BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice

被引：81

作者：

Chhabra, Ekta Seth ^{[1
]}

Liu, Tongyao ^{[1
]}

Kulman, John ^{[2
]}

Patarroyo-White, Susannah ^{[1
]}

Yang, Buyue ^{[1
]}

Lu, Qi ^{[1
]}

Drager, Douglas ^{[1
]}

Moore, Nancy ^{[1
]}

Liu, Jiayun ^{[1
]}

Holthaus, Amy M. ^{[1
]}

Sommer, Jurg M. ^{[1
]}

Ismail, Ayman ^{[1
]}

Rabinovich, Deana ^{[1
]}

Liu, Zhan ^{[1
]}

van der Flier, Arjan ^{[1
]}

Goodman, Allison ^{[1
]}

Furcht, Chris ^{[2
]}

Tie, Mark ^{[2
]}

Carlage, Tyler ^{[2
]}

Mauldin, Randy ^{[2
]}

Dobrowsky, Terrence M. ^{[2
]}

Liu, Zhiqian ^{[2
]}

Mercury, Oblaise ^{[1
]}

Zhu, Lily ^{[2
]}

Mei, Baisong ^{[3
]}

Schellenberger, Volker ^{[4
]}

Jiang, Haiyan ^{[2
]}

Pierce, Glenn F. ^{[2
]}

Salas, Joe ^{[1
]}

Peters, Robert ^{[1
]}

机构：

[1] Sanofi, 225 Second Ave, Waltham, MA 02451 USA

[2] Biogen Inc, 14 Cambridge Ctr, Cambridge, MA 02142 USA

[3] Sanofi, Cambridge, MA USA

[4] Amunix Pharmaceut Inc, Mountain View, CA USA

来源：

BLOOD | 2020年 / 135卷 / 17期

关键词：

RECOMBINANT FACTOR-VIII; FC FUSION PROTEIN; PROLONGED ACTIVITY; FUNCTIONAL-CHARACTERIZATION; FULL-LENGTH; HALF-LIFE; FACTOR-IX; SAFETY; RFVIIIFC; EFFICACY;

D O I：

10.1182/blood.2019001292

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 similar to 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 immunoglobulinG1 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.

引用

页码：1484 / 1496

页数：13

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