Toxicologic Pathology

 

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Toxicologic Pathology, Vol. 29, No. 3, 285-291 (2001)
DOI: 10.1080/019262301316905237

Toxicology Studies with Recombinant Staphylokinase and with SY 161-P5, a Polyethylene Glycol-Derivatized Cysteine-Substitution Mutant

Lieve Moons

Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium

Ingrid Vanlinthout

Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium

Ivo Roelants

Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium

Randall Moreadith

ThromboGenics Ltd, Dublin, Ireland

Desire Collen

Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium, desire.collen{at}med.kuleuven.ac.be, ThromboGenics Ltd, Dublin, Ireland

Hans J. Rapold

ThromboGenics Ltd, Dublin, Ireland

SY161-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 speciesspecific 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.

Key Words: Myocardial infarction • myocarditis • thrombolysis • rabbit • rat • hamster


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