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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1895-1902. Prepublished online as a Blood First Edition Paper on May 30, 2006; DOI 10.1182/blood-2005-11-012336.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Human complement receptor type 1–directed loading of tissue plasminogen activator on circulating erythrocytes for prophylactic fibrinolysisFrom the Institute for Environmental Medicine, the Department of Pathology and Laboratory Medicine, and the Department of Pharmacology and Targeted Therapeutics Program of the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia; the Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville; Elusys Therapeutics, Pine Brook, NC; and Centro Nacional De Investigationes Cardiovasculares (CNIC), Madrid, Spain.
Plasminogen activators (PAs) are not used for thromboprophylaxis due to rapid clearance, bleeding, and extravascular toxicity. We describe a novel strategy that overcomes these limitations. We conjugated tissue-type PA (tPA) to a monoclonal antibody (mAb) against complement receptor type 1 (CR1) expressed primarily on human RBCs. Anti-CR1/tPA conjugate, but not control conjugate (mIgG/tPA), bound to human RBCs (1.2 x 103 tPA molecules/cell at saturation), endowing them with fibrinolytic activity. In vitro, RBC-bound anti-CR1/tPA caused 90% clot lysis versus 20% by naive RBCs. In vivo, more than 40% of anti-CR1/125I-tPA remained within the circulation (
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
90% bound to RBCs) 3 hours after injection in transgenic mice expressing human CR1 (TgN-hCR1) versus less than 10% in wild-type (WT) mice, without RBC damage; approximately 90% of mIgG/125I-tPA was cleared from the circulation within 30 minutes in both WT and TgN-hCR1 mice. Anti-CR1/tPA accelerated lysis of pulmonary emboli and prevented stable occlusive carotid arterial thrombi from forming after injection in TgN-hCR1 mice, but not in WT mice, whereas soluble tPA and mIgG/tPA were ineffective. Anti-CR1/tPA caused 20-fold less rebleeding in TgN-hCR1 mice than the same dose of tPA. CR1-directed immunotargeting of PAs to circulating RBCs provides a safe and practical means to deliver fibrinolytics for thromboprophylaxis in settings characterized by a high imminent risk of thrombosis. 
