On the lmmunogenicity of Recombinant Staphylokinase

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 !gO-related neutralizing activity in plasma with a lag phase of 10 to 12 days, from a baseline of 0.2 ± 0.06 j..lg STAR neutralized per ml plasma (mean ± SEM) to a maximum of 30 ± 6.2 fLg/ml after 3 to 9 weeks, which persisted at a level of 14 ± 5.8 j.Lg/ml after 18 months (n = 4). In 4 baboons with a 1251-fibrin labeled clot in an extracorporeal arteriovenous loop, i. v. administration of 63 fLg/kg STAR over 1 h, repeated at weekly intervals, induced a progressive increase of STAR-neutralizing activity (from 0.05 ± 0.1 j.Lg/ml at baseline to 4.8 ± 1.5 fLg/ml at week 6), which was paralleled by a reduction of in vivo clot lysis (from 60 ± 7% to 8 ± 3% ). After temporary discontinuation of STARadministration, 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 f.lg/kg STAR over 1 h, repeated at weekly intervals, also induced a progressive increase of STAR-neutralizing activity (from 0.5 ± 0.2 j.Lg/ml at baseline to 6.4 ± 1.1 j.Lg/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-administration 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.