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

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 ‐ TCK 11A9 and MA ‐ TCK 26D6) 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 ( TAFI a). 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 TAFI a activity assay, both mAbs inhibited TAFI a, whereas other mAbs targeting thrombin– TM ‐mediated TAFI activation did not. The inhibition of TAFI a activity, however, was substrate‐specific, because neither mAb inhibited the cleavage of thrombin‐activated osteopontin and C 5a by TAFI a, thus sparing the anti‐inflammatory activity of TAFI a. Conclusions Our anti‐ TAFI mAbs, by selectively inhibiting TAFI a activity on fibrin, may represent the prototype of a new class of TAFI inhibitors with improved pharmacologic activity.