On the Immunogenicity of Recombinant Staphylokinase in Patients and in Animal Models

Summary

Streptokinase and staphylokinase, the presently available thrombolytic agents of bacterial origin, are immunogenic in man; their use may cause allergic reactions and/or refractoriness to renewed administration. Infusion of 2 to 10 mg of recombinant staphylokinase (STAR) in 20 patients with acute myocardial infarction or peripheral arterial occlusion induced IgG-related neutralizing activity in plasma with a lag phase of 10 to 12 days, from a baseline of 0.2 ± 0.06 |ig STAR neutralized per ml plasma (mean ± SEM) to a maximum of 30 ± 6.2 µml after 3 to 9 weeks, which persisted at a level of 14 ± 5.8 µml after 18 months (n = 4).

In 4 baboons with a ¹²⁵I-fibrin labeled clot in an extracorporeal arteriovenous loop, i. v. administration of 63 fig/kg STAR over 1 h, repeated at weekly intervals, induced a progressive increase of STAR-neutralizing activity (from 0.05 ± 0.1 µml at baseline to 4.8 ± 1.5 µml at week 6), which was paralleled by a reduction of in vivo clot lysis (from 60 ± 7% to 8 ± 3%). After temporary discontinuation of STAR-administration, neutralizing activity reverted to baseline within 7 weeks, whereafter the sensitivity of in vivo clot lysis to STAR was restored. In rabbits, i. v. administration of 250 µkg STAR over 1 h, repeated at weekly intervals, also induced a progressive increase of STAR-neutralizing activity (from 0.5 ± 0.2 µml at baseline to 6.4 ± 1.1 [ig/ml at week 6), which was paralleled by a reduction of in vivo clot lysis (from 68 ± 3% to 31 ± 7%). Thus a single STAR-administra-tion elicits an immune response in patients with persistence of neutralizing antibodies for over 18 months. Although antibody induction in baboons and rabbits required repeated administrations and was more transient than in man, these animal models appear to be suitable for the evaluation of the thrombolytic and immunogenic properties of staphylokinase variants.

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