Novel Thrombolytic Drug Based on Thrombin Cleavable Microplasminogen Coupled to a Single-Chain Antibody Specific for Activated GPIIb/IIIa

Thomas Bonnard, Zachary Tennant, BeEri Niego, Ruchi Kanojia, Karen Alt, Shweta Jagdale, Lok Soon Law, Sheena Rigby, Robert Lindsay Medcalf, Karlheinz Peter, Christoph Eugen Hagemeyer

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Background Thrombolytic therapy for acute thrombosis is limited by life-threatening side effects such as major bleeding and neurotoxicity. New treatment options with enhanced fibrinolytic potential are therefore required. Here, we report the development of a new thrombolytic molecule that exploits key features of thrombosis. We designed a recombinant microplasminogen modified to be activated by the prothrombotic serine-protease thrombin (HtPlg), fused to an activation-specific antitextendashglycoprotein IIb/IIIa single-chain antibody (SCE5), thereby hijacking the coagulation system to initiate thrombolysis.Methods and Results The resulting fusion protein named SCE5-HtPlg shows in~vitro targeting towards the highly abundant activated form of the fibrinogen receptor glycoprotein IIb/IIIa expressed on activated human platelets. Following thrombin formation, SCE5-HtPlg is activated to contain active microplasmin. We evaluate the effectiveness of our targeted thrombolytic construct in two models of thromboembolic disease. Administration of SCE5-HtPlg (4~μg/g body weight) resulted in effective thrombolysis 20~minutes after injection in a ferric chloridetextendashinduced model of mesenteric thrombosis (48textpm3% versus 92textpm5% for saline control, Plt;0.01) and also reduced emboli formation in a model of pulmonary embolism (Plt;0.01 versus saline). Furthermore, at these effective therapeutic doses, the SCE5-HtPlg did not prolong bleeding time compared with saline (P=0.99).Conclusions Our novel fusion molecule is a potent and effective treatment for thrombosis that enables in~vivo thrombolysis without bleeding time prolongation. The activation of this construct by thrombin generated within the clot itself rather than by a plasminogen activator, which needs to be delivered systemically, provides a novel targeted approach to improve thrombolysis.
Original languageEnglish
Article numbere004535
JournalJournal of the American Heart Association
Issue number2
Publication statusPublished - 3 Feb 2017

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