Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets

Xiaowei Wang, Jathushan Palasubramaniam, Yannik Gkanatsas, Jan David Hohmann, Erik Westein, Ruchi Kanojia, Karen Alt, Dexing Huang, Fu Jia, Ingo Ahrens, Robert Lindsay Medcalf, Karlheinz Peter, Christoph E Hagemeyer

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50 Citations (Scopus)

Abstract

RATIONALE:: Fibrinolysis is a valuable alternative for the treatment of myocardial infarction when percutaneous coronary intervention is not available in a timely fashion. For acute ischemic stroke, fibrinolysis is the only treatment option with a very narrow therapeutic window. Clinically approved thrombolytics have significant drawbacks, including bleeding complications. Thus their use is highly restricted, leaving many patients untreated. OBJECTIVE:: We developed a novel targeted fibrinolytic drug that is directed against activated platelets. METHODS AND RESULTS:: We fused single-chain urokinase plasminogen activator (scuPA) to a small recombinant antibody (scFvSCE5), which targets the activated form of the platelet-integrin glycoprotein IIb/IIIa. Antibody binding and scuPA activity of this recombinant fusion protein were on par with the parent molecules. Prophylactic in vivo administration of scFvSCE5-scuPA (75 U/g body weight) prevented carotid artery occlusion after ferric chloride injury in a plasminogen-dependent process compared with saline (P
Original languageEnglish
Pages (from-to)1083 - 1093
Number of pages11
JournalCirculation Research
Volume114
Issue number7
DOIs
Publication statusPublished - 2014

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