Abstract 291: The Fibrin-Specific Streptokinase SKΔ59 Is A Potent Fibrinolytic Agent in vivo
The ability of streptokinase (SK) to activate plasminogen (Pg) in plasma at sites distant from thrombi appears to limit its therapeutic efficiency. We examined the relative potency and specificity of recombinant SKΔ59 whose activity was engineered to be restricted to the fibrin thrombus. In standard assays of the fibrinolytic activity of Pg activators (fibrin-plate and turbidometric assays) we found that SKΔ59 displayed unique properties when compared to SK and t-PA. In vitro doses of SKΔ59 that were equivalent to t-PA and SK in fibrin plate assays were markedly more potent than t-PA and SK in plasma clot lysis assays. At doses where SKΔ59 gave equivalent fibrinolysis to t-PA and SK, SKΔ59 showed less plasma Pg degradation than t-PA (5±5% versus 20±10%) or SK (96±2%). Thrombolysis of human clots in vivo was studied in a humanized mouse model of thromboembolism where Pg−/ − mice were supplemented by physiologic levels (2 μM) of human Pg. In vivo dose response studies demonstrated that 0.19 mg/kg of SKΔ59 (n=4) was slightly better than 0.3 mg/kg of t-PA (n=4) (92±6% lysis versus 64±19%) and caused less degradation of Pg in plasma (8±14% versus 24±37%). SKΔ59 also showed markedly less Pg consumption than equivalent doses of SK (97±2%, n=3). We conclude that the engineering of fibrin-dependency into the SK molecule creates a Pg activator with unique properties of specificity and potency that are comparable to or better than t-PA.