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(Circulation. 1996;94:207-216.)
© 1996 American Heart Association, Inc.

Articles

Recombinant Staphylokinase Variants With Altered Immunoreactivity

II: Thrombolytic Properties and Antibody Induction

Desire Collen, MD, PhD; Huberte Moreau; Luc Stockx, MD; Steven Vanderschueren, MD

the Center for Molecular and Vascular Biology (D.C., H.M., S.V.), and the Department of Radiology, University Hospitals Gasthuisberg (L.S.), University of Leuven, Belgium.

Correspondence to D. Collen, MD, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg O & N, Herestr 49, B-3000 Leuven, Belgium. E-mail desire.collen@med.kuleuven.ac.be.

Background The substitution variants K35A,E38A,K74A,E75A,R77A (SakSTAR.M38) and K74A,E75A,R77A,E80A,D82A (SakSTAR.M89) of recombinant staphylokinase (SakSTAR) with reduced antibody reactivity were assayed for thrombolytic potency and antibody induction in animal models and in patients.

Methods and Results In a ¹²⁵I-fibrin–labeled pulmonary embolism model in the hamster, the doses giving 50% clot lysis in 90 minutes were 25 µg/kg for SakSTAR, 85 µg/kg for SakSTAR.M38, and 90 µg/kg for SakSTAR.M89. In rabbits with ¹²⁵I-fibrin–labeled plasma clots incorporated into extracorporeal arteriovenous loops, lysis within 2 hours was 76±18% (mean±SD, n=28) with 400 µg/kg SakSTAR, 53±13% (n=8) with 1000 µg/kg SakSTAR.M38, and 39±13% (n=6) with 800 µg/kg SakSTAR.M89. When groups of eight rabbits were immunized by intravenous administration of 0.2 to 1.0 mg/kg compound followed by subcutaneous injection of 0.4 mg in Freund's adjuvant at 2, 3, and 5 weeks, SakSTAR.M38 and SakSTAR.M89 elicited markedly less circulating neutralizing activity, compared with SakSTAR, when determined at 6 weeks (neutralizing 6.1±3.0 and 4.9±1.3 µg compound/mL plasma, respectively, versus 20±17 µg/mL; P=.02 and P=.01, respectively) and induced significantly less resistance to thrombolysis (residual thrombolytic potency producing 59±25% and 39±12% lysis, respectively, versus 8.5±5.7%; P=.008 and P=.006, respectively). In patients with peripheral arterial occlusion, intra-arterial administration of SakSTAR.M38 (n=4) or SakSTAR.M89 (n=4) induced significantly fewer circulating neutralizing antibodies (P=.03) and specific IgG (P=.01) at 2 to 3 weeks than SakSTAR (n=8).

Conclusions SakSTAR.M38 and SakSTAR.M89 induce less antibody formation and might constitute preferred agents for thrombolytic therapy in humans.

Key Words: staphylokinase • immunology • antibodies

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