Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia
| Autor: | Chandra Patel, Julian Marius Glück, Derek Sim, Shujun Yuan, Ying Zhu, Yan Wang, Terry Hermiston, Liang Li, Cornell Mallari, Dieter Moosmayer, Christine Ruehl-Fehlert, Xiaoqiao Jiang, Xiao-Yan Zhao, Katrin Gutberlet, Xinquan Wang, Dongli Wang, Laurent O. Mosnier, Jan Tebbe, Ashley Hesslein, Vince Evans, Yifan Xu, Subramanian Yegneswaran, Nicole Schmidt, Lars Linden, Andreas Wilmen, Kirk Mclean, Jian-Ming Gu, Tobias Marquardt, Doug Schneider, Ursula Egner, Philipp Ellinger, Volker Laux, Ji-Yun Kim, Alexius Freyberger, Maxine Bauzon |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Bleeding Time Cell Membrane Permeability medicine.drug_class Science General Physics and Astronomy Hemorrhage Pharmacology Monoclonal antibody Inhibitory postsynaptic potential Crystallography X-Ray Hemophilia A General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Immunoglobulin Fab Fragments 0302 clinical medicine Antithrombotic medicine Human Umbilical Vein Endothelial Cells Animals Humans lcsh:Science Cells Cultured Protein C Inhibitor Serine protease Multidisciplinary biology Chemistry Anticoagulant Antibodies Monoclonal General Chemistry Macaca fascicularis 030104 developmental biology biology.protein lcsh:Q Antibody therapy Antibody Function (biology) Protein C Haematological diseases 030215 immunology medicine.drug |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) |
| ISSN: | 2041-1723 |
| Popis: | 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. Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Here, the authors develop a monoclonal antibody that specifically inhibits APC’s anticoagulant function without compromising its cytoprotective function, and shows efficacy in animal models. |
| Databáze: | OpenAIRE |
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