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

Autor:	Zhao XY; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA. xiao-yan.zhao@bayer.com., Wilmen A; Biological Research, Bayer AG, 42113, Wuppertal, Germany., Wang D; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China., Wang X; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China., Bauzon M; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Kim JY; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Linden L; Biological Research, Bayer AG, 42113, Wuppertal, Germany., Li L; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China., Egner U; Structural Biology, Bayer AG, 13342, Berlin, Germany., Marquardt T; Structural Biology, Bayer AG, 13342, Berlin, Germany., Moosmayer D; Structural Biology, Bayer AG, 13342, Berlin, Germany., Tebbe J; Biological Research, Bayer AG, 42113, Wuppertal, Germany., Glück JM; Biological Research, Bayer AG, 42113, Wuppertal, Germany., Ellinger P; Biological Research, Bayer AG, 42113, Wuppertal, Germany., McLean K; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Yuan S; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Yegneswaran S; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Jiang X; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Evans V; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Gu JM; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Schneider D; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Zhu Y; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Xu Y; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Mallari C; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Hesslein A; Biological Development, Bayer, Berkeley, CA, 94710, USA., Wang Y; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Schmidt N; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Gutberlet K; Pathology/Toxicology, Bayer AG, 42096, Wuppertal, Germany., Ruehl-Fehlert C; Pathology/Toxicology, Bayer AG, 42096, Wuppertal, Germany., Freyberger A; Pathology/Toxicology, Bayer AG, 42096, Wuppertal, Germany., Hermiston T; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Patel C; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Sim D; US Innovation Center, Bayer, 455 Mission Bay Blvd. South, San Francisco, CA, 94158, USA., Mosnier LO; The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA, 92037, USA. lmosnier@scripps.edu., Laux V; TRG-Cardiology/Hematology, Bayer AG, Aprather Weg 18a, 42113, Wuppertal, Germany. volker.laux@ime.fraunhofer.de.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Jun 12; Vol. 11 (1), pp. 2992. Date of Electronic Publication: 2020 Jun 12.
DOI:	10.1038/s41467-020-16720-9
Abstrakt:	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.
Databáze:	MEDLINE
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