期刊
BLOOD
卷 115, 期 25, 页码 5241-5248出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-01-261610
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资金
- National Institutes of Health [RO1 HL090697, P01HL0764606, HL-077760, NS-053410-03, 1R21CA141228-01, R01 AI037618, R01 AI041592]
- University of Pennsylvania Institute for Translational Medicine and Therapeutics (ITMAT)
- American Heart Association [SDG 0535258N]
- Fondo de Investigaciones Sanitarias [PI081795]
Plasminogen activators (PAs) are used to treat life-threatening thrombosis, but not for thromboprophylaxis because of rapid clearance, risk of bleeding, and central nervous system (CNS) toxicity. We describe a novel strategy that may help to overcome these limitations by targeting a thrombin-activated PA pro-drug to circulating red blood cells (RBCs). We fused a single chain antibody (scFv Ter-119) that binds to mouse glycophorin A (GPA) with a variant human single-chain low molecular weight urokinase construct that can be activated selectively by thrombin (scFv/uPA-T). scFv/uPA-T bound specifically to mouse RBCs without altering their biocompatibility and retained its zymogenic properties until converted by thrombin into an active 2-chain molecule. As a result, RBC-bound scFv/uPA-T caused thrombin-induced fibrinolysis. One hour and 48 hours after intravenous (IV) injection in mice, approximately 70% and approximately 35% of scFv/ uPA-T was retained in the blood, respectively, and approximately 95% of the circulating scFv/uPA-T remained bound to RBCs. A single IV injection of scFv/uPA-T provided effective prophylaxis against arterial and venous thrombosis for up to 24 hours. Thus, prophylactic delivery of RBC-targeted PA pro-drugs activated selectively at the site of clot formation represents a new approach to prevent thrombosis in clinical settings where the risk of clotting is high. (Blood. 2010; 115(25):5241-5248)
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