A Bispecific Antifibrin-antiplatelet Urokinase Conjugate (BAAUC) Induces Enhanced Clot Lysis and Inhibits Platelet Aggregation

Johannes Ruef; Thomas K. Nordt; Karlheinz Peter; Marschall S. Runge; Wolfgang Kübler; Christoph Bode

doi:10.1055/s-0037-1614638

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(01): 109-114
DOI: 10.1055/s-0037-1614638

Rapid Communication

Schattauer GmbH

A Bispecific Antifibrin-antiplatelet Urokinase Conjugate (BAAUC) Induces Enhanced Clot Lysis and Inhibits Platelet Aggregation

Johannes Ruef

²From the Medizinische Klinik III/Kardiologie, Universität Heidelberg, Heidelberg, Germany

,

Thomas K. Nordt

²From the Medizinische Klinik III/Kardiologie, Universität Heidelberg, Heidelberg, Germany

,

Karlheinz Peter

²From the Medizinische Klinik III/Kardiologie, Universität Heidelberg, Heidelberg, Germany

,

Marschall S. Runge

¹Division of Cardiology, University of Texas Medical Branch, Galveston, Texas, USA

,

Wolfgang Kübler

²From the Medizinische Klinik III/Kardiologie, Universität Heidelberg, Heidelberg, Germany

,

Christoph Bode

²From the Medizinische Klinik III/Kardiologie, Universität Heidelberg, Heidelberg, Germany

› Author Affiliations

Abstract

Summary

Thrombolysis is well established in the treatment of acute myocardial infarction. However, clinical application of thrombolytic agents has limitations with respect to efficacy and specificity. To achieve highly effective and at the same time clot-selective plasminogen activation urokinase was coupled to a bispecific antibody consisting of the mono-valent Fab’ from the antifibrin monoclonal antibody 59D8 and the monovalent Fab’ from the anti-glycoprotein GPIIb/IIIa monoclonal antibody 7E3. The bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) was synthesized and characterized. Assays with either immobilized platelets, GPIIb/IIIa or fibrin showed an increase in plasminogen activation compared to uncoupled urokinase by 10-fold, 58-fold and 13-fold, respectivley (p < 0.0001 each). In vitro clot lysis was performed on platelet-rich and fibrin-rich clots and revealed an up to 5-fold higher potency of BAAUC compared to uncoupled urokinase (p < 0.0001). In vitro platelet aggregation was effectively inhibited by the hybrid molecule, whereas urokinase had no effect. BAAUC and two monospecific urokinase-conjugates, UK-59D8-IgG and UK-7E3-(Fab’)₂ were compared with each other with regard to similar tests. In vitro clot assays with platelet-rich and platelet-poor clots were performed. BAAUC achieved a significantly higher plasminogen activation compared to each of the monospecific conjugates (p < 0.05, respectively). We conclude that BAAUC, a bispecific plasminogen activator with antifibrin and antiplatelet properties has the potency to lyse both fibrin-rich and platelet-rich thrombi with high efficacy and to effectively inhibit platelet aggregation.

Full Text

References

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