Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia

Xiao-Yan Zhao (), Andreas Wilmen, Dongli Wang, Xinquan Wang, Maxine Bauzon, Ji-Yun Kim, Lars Linden, Liang Li, Ursula Egner, Tobias Marquardt, Dieter Moosmayer, Jan Tebbe, Julian Marius Glück, Philipp Ellinger, Kirk McLean, Shujun Yuan, Subramanian Yegneswaran, Xiaoqiao Jiang, Vince Evans, Jian-Ming Gu, Doug Schneider, Ying Zhu, Yifan Xu, Cornell Mallari, Ashley Hesslein, Yan Wang, Nicole Schmidt, Katrin Gutberlet, Christine Ruehl-Fehlert, Alexius Freyberger, Terry Hermiston, Chandra Patel, Derek Sim, Laurent O. Mosnier () and Volker Laux ()
Additional contact information
Xiao-Yan Zhao: US Innovation Center, Bayer
Andreas Wilmen: Biological Research, Bayer AG
Dongli Wang: Tsinghua University
Xinquan Wang: Tsinghua University
Maxine Bauzon: US Innovation Center, Bayer
Ji-Yun Kim: US Innovation Center, Bayer
Lars Linden: Biological Research, Bayer AG
Liang Li: Tsinghua University
Ursula Egner: Structural Biology, Bayer AG
Tobias Marquardt: Structural Biology, Bayer AG
Dieter Moosmayer: Structural Biology, Bayer AG
Jan Tebbe: Biological Research, Bayer AG
Julian Marius Glück: Biological Research, Bayer AG
Philipp Ellinger: Biological Research, Bayer AG
Kirk McLean: US Innovation Center, Bayer
Shujun Yuan: US Innovation Center, Bayer
Subramanian Yegneswaran: US Innovation Center, Bayer
Xiaoqiao Jiang: US Innovation Center, Bayer
Vince Evans: US Innovation Center, Bayer
Jian-Ming Gu: US Innovation Center, Bayer
Doug Schneider: US Innovation Center, Bayer
Ying Zhu: US Innovation Center, Bayer
Yifan Xu: US Innovation Center, Bayer
Cornell Mallari: US Innovation Center, Bayer
Ashley Hesslein: Biological Development, Bayer
Yan Wang: US Innovation Center, Bayer
Nicole Schmidt: US Innovation Center, Bayer
Katrin Gutberlet: Pathology/Toxicology, Bayer AG
Christine Ruehl-Fehlert: Pathology/Toxicology, Bayer AG
Alexius Freyberger: Pathology/Toxicology, Bayer AG
Terry Hermiston: US Innovation Center, Bayer
Chandra Patel: US Innovation Center, Bayer
Derek Sim: US Innovation Center, Bayer
Laurent O. Mosnier: The Scripps Research Institute
Volker Laux: TRG-Cardiology/Hematology, Bayer AG

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Based on the hypothesis that specific inhibition of APC’s anticoagulant but not its cytoprotective activity can be beneficial for hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are tested: A type I active-site binding mAb and a type II mAb binding to an exosite on APC (required for anticoagulant activity) as shown by X-ray crystallography. Both mAbs increase thrombin generation and promote plasma clotting. Type I blocks all APC activities, whereas type II preserves APC’s cytoprotective function. In normal monkeys, type I causes many adverse effects including animal death. In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data show that the type II mAb can specifically inhibit APC’s anticoagulant function without compromising its cytoprotective function and offers superior therapeutic opportunities for hemophilia.

Date: 2020
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DOI: 10.1038/s41467-020-16720-9

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