Characterization and evaluation of monoclonal antibodies exhibiting differential effects on the activation of thrombin activatable fibrinolysis inhibitor and characterization and evaluation of nanobodies stimulating its zymogen activity.

The active form of 'Thrombin Activatable Fibrinolysis Inhibitor' (TAFIa) is generated through activation of the pro-enzyme TAFI (also known as procarboxypeptidase U (proCPU) by serine proteases such as thrombin (T), plasmin (Pli) and the thrombine/thrombomodulin (T/TM) complex. Many studies have demonstrated an association between TAFI levels or the extent of TAFI ectivation and various disease states. The current project intends to characterize in detail monoclonal antibodies that interfere with the activation of TAFIa trough different pathways. The planned experiments will allow us to determine the relative contribution of the various activators (T-, T/TM- en Pli). Epitope and paratope analysis will reveal the molecular mechanism of action and may contribute to rational drug design. Two unique nanobodies that stimulate the zymogen activity significantly will be used as tools to study the role of the zymogen activity and to evaluated whether agents that increase the intrinsic activity are able to modulate (i.e. increase) the bleeding time in particular conditions (e.g. hemphilia).

Keywords:Monoclonal antibody, Nanobody, Rational drug design, ProCPU, TAFI

Disciplines:Biochemistry and metabolism, Medical biochemistry and metabolism, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences, Cardiac and vascular medicine