Hemostatic properties of a TFPI antibody

Abstract

Bleeds in hemophilia are treated either on demand or prophylactically by intravenous replacement therapy with FVIII or FIX. However, there is a call for subcutaneous and less frequent drug administration, and this need may be met by administration of a suitable antibody. Pioneering studies in vitro] and in a rabbit hemophilia model suggest that blockage of tissue factor pathway inhibitor (TFPI) provides a potential alternative approach to current therapy of hemophilia patients. TFPI down-regulates the initiation of coagulation by inhibition of FVIIa/TF/FXa and blockage of TFPI enhances FXa and thrombin generation. In line with these discoveries, TFPI targeting reagents with different potential benefits are currently evaluated as possible novel therapeutic agents. The development and testing of these agents in in vitro and in vivo hemophilia models provide new information about the mode of action of TFPI and its role in hemostasis. Blockage of TFPI with various antagonists has been shown to effectively enhance FX activation by TF/FVIIa and improve clot formation in hemophilia blood and plasma. The monoclonal antibody, mAb 2021, is one such antagonist directed towards the Kunitz-type protease inhibitor (KPI) 2 domain of TFPI which is now being tested in preclinical and clinical trials. Using mAb 2021, we have confirmed the original findings, and further characterized the pro-haemostatic effect of this specific anti-KPI-2 mAb in preclinical studies.