Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia
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Published:2020-06-12
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhao Xiao-Yan, Wilmen Andreas, Wang Dongli, Wang XinquanORCID, Bauzon Maxine, Kim Ji-Yun, Linden Lars, Li Liang, Egner Ursula, Marquardt Tobias, Moosmayer Dieter, Tebbe Jan, Glück Julian Marius, Ellinger Philipp, McLean Kirk, Yuan Shujun, Yegneswaran Subramanian, Jiang Xiaoqiao, Evans Vince, Gu Jian-Ming, Schneider Doug, Zhu Ying, Xu Yifan, Mallari Cornell, Hesslein Ashley, Wang Yan, Schmidt Nicole, Gutberlet Katrin, Ruehl-Fehlert Christine, Freyberger Alexius, Hermiston Terry, Patel Chandra, Sim Derek, Mosnier Laurent O.ORCID, Laux Volker
Abstract
AbstractActivated 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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