Thrombolytic and pharmacokinetic properties of an immunoconjugate of single-chain urokinase-type plasminogen activator (u-PA) and a bispecific monoclonal antibody against fibrin and against u-PA in baboons

Abstract

Targeting of plasminogen activators to the fibrin component of a thrombus with the use of monoclonal antibodies (MA) directed against human fibrin may enhance their thrombolytic potency and fibrin-specificity. The thrombolytic and pharmacokinetic properties of rscu-PA/MA-FU1-74, an immunoconjugate of recombinant single-chain urokinase-type plasminogen activator (rscu-PA) and a bispecific MA directed against u-PA and against the β-chain of human fibrin (MA-FU1-74), were investigated in baboons with a [125I]fibrin-labeled autologous blood clot in the femoral vein. Continuous intravenous infusion of rscu-PA/MA-FU1-74 (1:1.2 molar ratio) over 2 hours showed a fivefold increased thrombolytic potency (lysis per unit dose) over that of unconjugated rscu-PA, as evidenced both by a higher maximal rate of lysis (380% ± 68% v 78% ± 25% lysis per mg u-PA equivalent of compound administered per kg body weight, P < .001), and by a lower dose at which the maximal rate of lysis occurs (0.19 ± 0.03 v 0.82 ± 0.10 mg compound per kg body weight, P