SYNERGISTIC FIBRINOLYSIS - COMBINED EFFECTS OF PLASMINOGEN ACTIVATORS AND AN ANTIBODY THAT INHIBITS ALPHA-2-ANTIPLASMIN

To improve the efficacy of plasminogen activators, we produced a monoclonal antibody (RWR) that inhibits human α2-antiplasmin (α2AP). In addition to inhibiting α2AP in plasma, RWR binds to and inhibits fibrin cross-linked α2AP and reproduces the "spontaneous" clot lysis that is the hallmark of human α2AP deficiency. By inhibiting the inactivation of plasmin by α2AP, RWR interacts synergistically with plasminogen activators to increase the potency (for 50% clot lysis) of urokinase by 80-fold, tissue plasminogen activator by 27-fold, and streptokinase by 20-fold. Yet, for a given amount of fibrinolysis, the combination of RWR and lower doses of plasminogen activator leads to less fibrinogen consumption than is obtained with higher, equipotent doses of plasminogen activator alone. These results suggest a strategy for increasing the efficacy of plasminogen activators. More generally, this approach to amplifying enzymatic activity by immunoneutralizing an inhibitor may be useful in other biologic processes that are rigidly governed by inhibitors.