Expression and characterisation of finger protease (FP); a mutant tissue-type plasminogen activator (t-PA) with improved pharmacokinetics

Summary We have constructed, expressed and purified a novel thrombolytic, finger protease (FP), composed of only the finger and serine protease domains of t-PA. This molecule, when compared to t-PA, has improved pharmacokinetics (slower plasma clearance and a longer half-life) in both the rat and rabbit. It is half as potent as t-PA in a rabbit model of peripheral arterial thrombosis. At efficacious doses, FP produced larger changes in haemostatic parameters than those produced by t-PA. In vitro studies of the purified protein showed weak fibrin binding, and low specific activity of FP in both the S-2251 and human clot lysis assays. The behavior of this molecule suggests that novel fibrinolytics with improved pharmacokinetics and equivalent in vitro activity to t-PA will be more potent in vivo.