Recombinant Staphylokinase Variants With Altered Immunoreactivity

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Abstract
Background The thrombolytic potency and antibody induction of selected variants of recombinant staphylokinase (SakSTAR), including SakSTAR(K 74 ) with Lys74, SakSTAR(E 75 ) with Glu75, SakSTAR(EER) with Glu38, Glu75, and Arg77, and SakSTAR(K 74 ER) with Lys74, Glu75, and Arg77 replaced by Ala, were studied. Methods and Results In rabbits, SakSTAR(K 74 ) and SakSTAR(EER) elicited significantly less circulating neutralizing activity than SakSTAR and SakSTAR(E 75 ) ( P =.005 and P =.0002 versus SakSTAR, respectively). In baboons, SakSTAR(K 74 ) induced significantly fewer antibodies than wild-type SakSTAR ( P <.05). Intra-arterial administration in patients with peripheral arterial occlusion of SakSTAR(K 74 ) (n=11) or SakSTAR(K 74 ER) (n=6) induced significantly fewer circulating neutralizing antibodies [median values and interquartile ranges, 20 (3.8 to 26) and 2.4 (0.2 to 59) μg compound neutralized/mL plasma after 3 to 4 weeks ( P =.01 and P =.035 versus SakSTAR, respectively)] than SakSTAR (n=9) [median value and interquartile range, 93 (24 to 110) μg compound neutralized/mL plasma]. Overt neutralizing antibody induction (>10 μg compound neutralized/mL plasma) occurred in all 9 patients given wild-type SakSTAR, in 6 of the 11 SakSTAR(K 74 ) patients ( P =.038 versus SakSTAR), and in 2 of the 6 SakSTAR(K 74 ER) patients ( P =.011 versus SakSTAR). Conclusions SakSTAR(K 74 ), a variant of recombinant staphylokinase with a single substitution of Lys74 with Ala, and SakSTAR(K 74 ER), with Lys74, Glu75, and Arg77 substituted with Ala, have intact thrombolytic potencies but induce significantly less antibody formation in patients.

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