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.
Highlights
Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions
Type I antiAPC monoclonal antibodies (mAbs) was identified by panning the n-CoDeR® phage-display library of human antibody fragment antigen-binding (Fab) fragments (BioInvent International AB)
Blocking the natural anticoagulants is emerging as a promising strategy for hemophilia therapy, which is supported by initial results of clinical trials[23,24]
Summary
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. We identify two types of anti-APC mAbs: a type I active-site binder and a type II non-active-site binder Both mAbs effectively increase thrombin generation in vitro by blocking the anticoagulant activity of APC, but only type II retains APC’s cytoprotective function, and is safe to normalize hemostasis in monkeys with hemophilia. Type II anti-APC mAb has therapeutic potential for prophylactic treatment of PWH with inhibitors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
