Abstract 12419: Preclinical Safety and Efficacy of a Novel Thrombolytic Agent Administered by Rapid Bolus Injection: Clot Specific Streptokinase (CSSK/SMRX-11)
Introduction: Clot specific Streptokinase (CSSK), also known as SMRX-11, is a novel recombinant protein, produced and purified from a yeast system (Pichia pastoris). Novel fibrin binding domains attached to each end of streptokinase mask the ability of the streptokinase component of SMRX-11 to interact with blood plasminogen. As a result, SMRX-11 remains inactive in the blood circulation and does not convert blood plasminogen into plasmin until the fibrin binding domains are cleaved by clot-bound plasmin. This is in contrast to native Streptokinase (SK), which indiscriminately converts plasminogen into plasmin. The molecular weight of the glycosylated SMRX-11 protein is approximately 80kD, with a specific activity of 80,000 Units/mg of protein. Results. In vitro experiments comparing SMRX-11 to other fibrinolytics (SK and tPA), demonstrated that SMRX-11 lyses experimentally-preformed human blood clots without reducing residual plasma fibrinogen levels. Initial in vitro studies compared the activity of SMRX-11 to lyse human whole blood clots to native Streptokinase (SK) and tissue Plasminogen Activator (tPA). SMRX-11 had comparable clot lysis activity to SK, with tPA eliciting a slightly greater percent clot lysis. Additional in vitro studies determined the relative fibrinogenolytic effects of SMRX-11 versus tPA. SMRX-11 demonstrated superior fibrinogen sparing compared to tPA with minimal consumption of alpha-2 antiplasmin relative to native SK. In vivo, SMRX-11 (0.7-1.4 mg/kg as an iv bolus), lysed experimentally-induced femoral arterial thrombi in cynomolgus monkeys with relatively minor fluctuation in plasma fibrinogen, forearm bleeding time or hemodynamics. In GLP safety studies, treatment with SMRX-11 at doses of 1, 3 and 10 mg/kg/day for 5 consecutive days was generally well-tolerated in male and female cynomolgus monkeys. Thus, the low dose of 1 mg/kg was considered the No-Observed Adverse Effect Level (NOAEL) for daily repeat-dose administration of SMRX-11 administered via bolus i.v. injection in cynomolgus monkeys. Conclusion. SMRX-11 represents a novel pharmacophore with the appropriate preclinical safety and efficacy profile to warrant clinical investigation for acute treatment of myocardial infarction and stroke.
Author Disclosures: R.J. Shebuski: Employment; Significant; Symmetrix Biotech, Inc. K. Joshi: Employment; Significant; CSIR-Institute of Microbial Technology. A. Pande: Employment; Significant; CSIR-Institute of Microbial Technology. R. Sharma: Employment; Significant; Symmetrix Biotech, Inc. Y. Prashar: Employment; Significant; Symmetrix Biotech, Inc. J. Kapeghian: Consultant/Advisory Board; Modest; Symmetrix Biotech, Inc. G. Sahni: Employment; Significant; CSIR-Institute of Microbial Technology.
- © 2015 by American Heart Association, Inc.