Monoclonal antibodies targeting the antifibrinolytic activity of activated thrombin-activatable fibrinolysis inhibitor but not the anti-inflammatory activity on osteopontin and C5a

Abstract

Summary: Background: Recently, anti-thrombin-activatable fibrinolysis inhibitor (TAFI) mAbs selectively inhibiting plasmin-mediated TAFI activation were shown to stimulate fibrinolysis in vitro and in vivo, suggesting, in contrast to other findings, that plasmin-mediated TAFI activation plays an important role in fibrinolysis regulation. Objective: To further characterize the effects of two plasmin-specific anti-TAFI mAbs (MA-TCK11A9 and MA-TCK26D6) on TAFI-dependent inhibition of fibrinolysis. Methods and Results: Both mAbs inhibited plasmin-mediated but not thrombin/thrombomodulin-mediated TAFI activation, whereas neither inhibited the cleavage of hippuryl-arginine by activated TAFI (TAFIa). They stimulated tissue-type plasminogen activator-induced fibrinolysis in different clot lysis models through a TAFI-dependent mechanism, especially in the presence of thrombomodulin (TM), a condition in which TAFI is largely activated by the thrombin-TM complex. In a fibrinolysis-based TAFIa activity assay, both mAbs inhibited TAFIa, whereas other mAbs targeting thrombin-TM-mediated TAFI activation did not. The inhibition of TAFIa activity, however, was substrate-specific, because neither mAb inhibited the cleavage of thrombin-activated osteopontin and C5a by TAFIa, thus sparing the anti-inflammatory activity of TAFIa. Conclusions: Our anti-TAFI mAbs, by selectively inhibiting TAFIa activity on fibrin, may represent the prototype of a new class of TAFI inhibitors with improved pharmacologic activity. © 2013 International Society on Thrombosis and Haemostasis.