Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia.
Xiao-Yan ZhaoAndreas WilmenDongli WangXinquan WangMaxine BauzonJi-Yun KimLars LindenLiang LiUrsula EgnerTobias MarquardtDieter MoosmayerJan TebbeJulian Marius GlückPhilipp EllingerKirk McLeanShujun YuanSubramanian YegneswaranXiaoqiao JiangVince EvansJian-Ming GuDoug SchneiderYing ZhuYifan XuCornell MallariAshley HessleinYan WangNicole SchmidtKatrin GutberletChristine Ruehl-FehlertAlexius FreybergerTerry HermistonChandra PatelDerek SimLaurent O MosnierVolker LauxPublished in: Nature communications (2020)
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.
Keyphrases
- atrial fibrillation
- venous thromboembolism
- monoclonal antibody
- magnetic resonance
- liver failure
- high resolution
- magnetic resonance imaging
- binding protein
- protein protein
- amino acid
- mesenchymal stem cells
- cancer therapy
- bone marrow
- small molecule
- big data
- drug induced
- data analysis
- aortic dissection
- dna binding
- hepatitis b virus
- mechanical ventilation
- acute respiratory distress syndrome