期刊
CIRCULATION RESEARCH
卷 114, 期 7, 页码 1083-1093出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.114.302514
关键词
blood platelets; thrombolytic therapy; thrombosis; urokinase-type plasminogen activator
资金
- National Health and Medical Research Council (NHMRC) [1028145, 1045756]
- National Heart Foundation [G05M2134, CR11M6066]
- Australian Research Council Future Fellowship [FT0992210]
- NHMRC Principle Research Fellowship
- Monash University
- Baker IDI Heart and Diabetes Institute
- German Research Foundation
- Victorian Government's Operational Infrastructure Support Program
- Australian Research Council [FT0992210] Funding Source: Australian Research Council
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 (scFv(SCE5)), 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 scFv(SCE5)-scuPA (75 U/g body weight) prevented carotid artery occlusion after ferric chloride injury in a plasminogen-dependent process compared with saline (P<0.001), and blood flow recovery was similar to high-dose nontargeted urokinase (500 U/g body weight). Tail bleeding time was significantly prolonged with this high dose of nontargeted urokinase, but not with equally effective targeted scFv(SCE5)-scuPA at 75 U/g body weight. Real-time in vivo molecular ultrasound imaging demonstrates significant therapeutic reduction of thrombus size after administration of 75 U/g body weight scFv(SCE5)-scuPA as compared with the same dose of a mutated, nontargeting scFv-scuPA or vehicle. The ability of scFv(SCE5)-scuPA to lyse thrombi was lost in plasminogen-deficient mice, but could be restored by intravenous injection of plasminogen. Conclusions: Targeting of scuPA to activated glycoprotein IIb/IIIa allows effective thrombolysis and the potential novel use as a fibrinolytic agent for thromboprophylaxis without bleeding complications.
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