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.
AIMS Trial Study Group ( 1988 ). Effect of intravenous APSAC on mortality after acute myocardial infarction: Preliminary report of a placebo-controlled clinical trial. Lanceti: 545—549.
2.
Artus JA, Cockburn A., Fuller J., McMurdo AS, White DJ (1987). The pre-clinical Toxicology of Anisoylated Plasminogen Streptokinase Activator Complex. Drugs33 (Suppl 3): 97—101.
3.
Assessment of the Safety and Efficacy of a New Thrombolytic (Assent-2) Investigators (1999). Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double blind randomised trial. Lancet354: 716—722.
4.
Coan MJ, Giddens W., Ellis W., Reichenbach DD (1983). Selective myocardial cell necrosis in non-human primates. Arch Pathol Lab Med107: 34—39.
5.
Collen D., Sinnaeve P., Demarsin E., Moreau H., De Maeyer M., Jespers L., Laroche Y., Van de Werf F. (2000). Polyethylene glycol-derivatized cysteine-substitution variants of recombinant staphylokinase for single bolus treatment of acute myocardial infarction. Circulation102: 1766—1772.
6.
Collen D., Van de Werf F. (1993). Coronary thrombolysi s with recombinant staphylokinas e in patients with evolving myocardial infarction. Circulation87: 1850—1853.
7.
Collen D., Van Hoef B., Schlott B., Hartmann M., Guehrs KH, Lijnen HR (1993). Mechanisms of activation of mammalian plasma fibrinolytic systems with streptokinase and with recombinant staphylokinase. Eur J Biochem216: 307—314.
8.
Collen D. (1996). Fibrin-selective thrombolytic therapy for acute myocardial infarction. Circulation93: 857—865.
9.
Collen D., Moreau H., Stockx L., Vanderschueren S. (1996). Recombinant staphylokinase variants with altered immunoreactivity II: Thrombolytic properties and antibody induction. Circulation94: 207—216.
10.
Collen D. (1998). Staphylokinase: a potent, uniquely fibrin-selective thrombolytic agent. Nature Med4: 279—284.
11.
Collen D. (1999). The plasminogen (fibrinolytic) system. Thromb Haemost82: 259—270.
12.
Declerck PJ , Vanderschueren S., Billiet J., Moreau H., Collen D. (1994). Prevelance and induction of circulating antibodies against recombinant staphylokinase . Thromb Haemost71: 129—133.
13.
Di Muzio A. (1997). Inflammatory myopathy after intravenous Streptokinase. Muscle Nerve20: 619—621.
14.
Gruppo Italiano per lo Studio della Sterptochinasi nell' Infarto Miocardico (GISSI) (1987). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancetii: 871— 874.
15.
Gulba DC, Praus M., Dechend R., Hauck S., Mahler M., Zitvz R., Baldus B., Mueller W., Dietz R. (1997). Update on the toxicology and pharmacology of rDSPA alpha 1 (bat-PA) in animals and humans. Fibrinol Proteol11(Suppl 2): 55—62.
16.
ISIS-2 (Second International Study of Infarct Survival) Collaborative group (1988). Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancetii: 349—360.
17.
Kellner A., Robertson T. (1954). Selective necrosis of cardiac and skeletal muscle induced experimentally by means of proteolytic enzyme solutions given intravenously . J Exp Med99: 387—403.
18.
Laroche Y., Heymans S., Capaert S., De Cock F., Demarsin E., Collen D. (2000). Recombinant Staphylokinas e variants with reduced antigenicity due to elimination of B-lymphocyte epitopes. Blood96: 1425—1432.
19.
Lijnen HR, De Cock F., Matsuo O., Collen D. (1992). Comparative fibrinolytic and fibrinogenolytic properties of staphylokinase and streptokinase in plasma of different species in vitro. Fibrinolysis6: 33—37.
20.
Mattheussen M., Mubagwa K., Rusy BF, Van Aken H., Flameng D. (1993). Potentiated state contractions in isolated hearts: Effects of ischemia and reperfusion. Am J Physiol264: H1663—H1673.
21.
Reichenbach DD, Benditt EP (1970). Catecholamine s and cardiomyopathy. The pathogenesi s and potential importance of myofibrillar degeneration. Human Pathol1: 125—150.
22.
Schlott B., Guehrs KH, Hartmann M., Roecker A., Collen D. (1997). Staphylokinase requires NH2-terminal proteolysis for plasminogen activation. J Biol Chem272: 6067—6072.
23.
Schlott B., Hartmann M., Gührs KH, Birch-Hirschfeld E., Pohl HD, Vanderschueren S., Van de Werf F., Michoel A., Collen D., Behnke D. (1994). High yield production and purification of recombinant staphylokinase for thrombolytic therapy. BioTechnology12: 185—189.
24.
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators (1997). A comparison of reteplase with alteplase for acute myocardial infarction . N Engl J Med337: 1118—1123.
25.
Vanderschueren S., Barrios L., Kerdsinchai P., Van den Heuvel P., Hermans L., Vrolix M., De Man F., Benit E., Muyldermans L., Collen D., Van de Werf F. (1995). A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction. The STAR Trial Group. Circulation92: 2044—2049.
26.
Vanderschueren S., Dens J., Kerdsinchai P., Desmet W., Vrolix M., De Man F., Van den Heuvel P., Hermans L., Collen D., Van de Werf F. (1997). A pilot randomized coronary patency trial of double-bolus recombinant staphylokinase versus front-loaded alteplase in acute myocardial infarction . Am Heart J134: 213—219.
27.
Vanwetswinkel S., Plaisance S., Zhang Z., Valinhout I., Brepoels K., Lasters I., Collen D., Jespers L. (2000). Pharmacokinetic and thrombolytic properties of cystein-linked polyethylene glycol derivatives of staphylokinase . Blood95: 936—942.
