In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. In normal monkeys, type I causes many adverse effects including animal death. Type I blocks all APC activities, whereas type II preserves APC’s cytoprotective function.
Both mAbs increase thrombin generation and promote plasma clotting. 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.
Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions.
