RECOMBINANT STAPHYLOKINASE FOR THROMBOLYTIC THERAPY

Staphylokinase, a 136 amino acid bacterial protein with profibrinolyti c properties which is produced in high amounts by routine recombinant DNA technology, has a unique structure, mechanism of action and fibrin -specificity. Preclinical investigations revealed attractive propertie s for thrombolytic therapy, including high thrombolytic potency, also towards platelet-rich thrombi, fibrin-specificity in human plasma and high sensitivity to antifibrinolytic agents. A pilot recanalization st udy in 10 patients with evolving transmural myocardial infarction conf irmed the fibrin-specificity of recombinant staphylokinase (Sak). In p atients with peripheral arterial occlusion, the recanalization rate an d speed of Sak compare favorably with figures reported for established thrombolytic agents. A disadvantage of Sak is its antigenicity. Neutr alizing antibody titers were low at baseline and during the first week after administration, but increased steeply and remained elevated the reafter, precluding repeated use. Surprisingly however, the antigenici ty of Sak in laboratory animals and patients could be significantly at tenuated while preserving thrombolytic potential, by replacing selecte d clustered charged amino acids by alanine. The clinical experience to date is encouraging yet limited and will need to be expanded to deter mine the optimal dose and mode of administration, the optimal conjunct ive therapy, the value in the treatment of other thromboembolic disord ers and, ultimately, the merits in terms of safety and survival relati ve to established and new thrombolytics. It remains to be seen whether the immunogenicity of Sak can be reduced to the extent that repeated therapy may be feasible without jeopardizing thrombolytic efficacy and safety.