Enhancement of thrombolytic therapy with deglycosylated forms of

Abstract

This invention provides an improved method for enhancing the activity of thrombolytic agents, including t-PA, scu-PA, tcu-PA, streptokinase, acylated plasminogen-streptokinase activator complex (APSAC), mixtures of these, and other activators of plasminogen. The enhancement method comprises supplementation of plasma plasminogen levels with deglycosylated forms of glu- and lys-plasminogen. Deglycosylated plasminogen refers herein to glu- or lys-plasminogen 2 having a single oligosaccharide chain at Thr.sub.345, plasminogens having a single oligosaccharide chain at Asn.sub.288, and unglycosylated forms of plasminogen. The work described herein shows that a less glycosylated form of plasminogen (glu-plasminogen 2) has a higher affinity for fibrin clots than a more glycosylated plasminogen (glu-plasminogen 1). Based on this work, it is believed that glycosylation of plasminogen inhibits binding of plasminogen to fibrin clots, perhaps due to steric hindrance, and further, that deglycosylated forms of plasminogen may be more effective enhancers of scu-PA in thrombolytic therapy than fully glycosylated forms of plasminogen. Improved enhancement of the activity of thrombolytic agents allows the use of lower therapeutic doses and thus, is expected to relieve some of the bleeding and other side effects of thrombolytic therapy.