Moons L, Vanlinthout I, Roelants I, Moreadith R, Collen D, Rapold H J
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium.
Toxicol Pathol. 2001 May-Jun;29(3):285-91. doi: 10.1080/019262301316905237.
SY 161-P5, a polyethylene glycol derivatized (PEGylated) mutant of the recombinant Staphylokinase (rSak) variant SakSTAR, exhibiting reduced antigenicity is in clinical development for treatment of acute myocardial infarction as a single bolus injection. A series of safety studies were performed in vivo as a routine toxicology program with SY 161-P5 (PEG-rSakSTAR) and with the recombinant Staphylokinase variant Sak42D (rSak42D). For both compounds, intravenous single bolus injections of up to 100-fold therapeutic equivalent, as well as repeated injections during 7 to 28 days revealed no significant pathological findings in mice, rats or hamsters. However, New Zealand white rabbits developed clinically silent, multifocal myocarditis following single or repeat doses of SY 161-P5 or of Sak42D. These findings were dose-independent and reversible. A similar species-specific cardiotoxic effect has previously been described for other proteolytic proteins, including the approved drugs Streptokinase and Acetylated Plasminogen Streptokinase Complex (APSAC). The large experience with these drugs, as well as the clinical data accumulated both with PEGylated and non-PEGylated rSak variants to date, do not indicate cardiotoxic hazards associated with the use of these drugs in humans.
SY 161-P5是重组葡萄球菌激酶（rSak）变体SakSTAR的聚乙二醇衍生化（聚乙二醇化）突变体，抗原性降低，正作为单次推注用于治疗急性心肌梗死的临床开发。作为常规毒理学项目，对SY 161-P5（聚乙二醇化rSakSTAR）和重组葡萄球菌激酶变体Sak42D（rSak42D）进行了一系列体内安全性研究。对于这两种化合物，静脉内单次推注高达100倍治疗等效剂量，以及在7至28天内重复注射，在小鼠、大鼠或仓鼠中均未发现明显的病理结果。然而，新西兰白兔在单次或重复剂量的SY 161-P5或Sak42D后出现了临床无症状的多灶性心肌炎。这些发现与剂量无关且可逆转。先前已描述了其他蛋白水解蛋白（包括已批准的药物链激酶和乙酰化纤溶酶原链激酶复合物（APSAC））具有类似的物种特异性心脏毒性作用。这些药物的大量经验以及迄今为止聚乙二醇化和非聚乙二醇化rSak变体积累的临床数据均未表明使用这些药物对人类有心脏毒性危害。
