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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

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title = "Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets",
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",
author = "Xiaowei Wang and Jathushan Palasubramaniam and Yannik Gkanatsas and Hohmann, {Jan David} and Erik Westein and Ruchi Kanojia and Karen Alt and Dexing Huang and Fu Jia and Ingo Ahrens and Medcalf, {Robert Lindsay} and Karlheinz Peter and Hagemeyer, {Christoph E}",
year = "2014",
doi = "10.1161/CIRCRESAHA.114.302514",
language = "English",
volume = "114",
pages = "1083 -- 1093",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams & Wilkins",
number = "7",

}

Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets. / Wang, Xiaowei; Palasubramaniam, Jathushan; Gkanatsas, Yannik; Hohmann, Jan David; Westein, Erik; Kanojia, Ruchi; Alt, Karen; Huang, Dexing; Jia, Fu; Ahrens, Ingo; Medcalf, Robert Lindsay; Peter, Karlheinz; Hagemeyer, Christoph E.

In: Circulation Research, Vol. 114, No. 7, 2014, p. 1083 - 1093.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets

AU - Wang, Xiaowei

AU - Palasubramaniam, Jathushan

AU - Gkanatsas, Yannik

AU - Hohmann, Jan David

AU - Westein, Erik

AU - Kanojia, Ruchi

AU - Alt, Karen

AU - Huang, Dexing

AU - Jia, Fu

AU - Ahrens, Ingo

AU - Medcalf, Robert Lindsay

AU - Peter, Karlheinz

AU - Hagemeyer, Christoph E

PY - 2014

Y1 - 2014

N2 - 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

AB - 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

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JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

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