BACKGROUND: Pulmonary embolism occurs frequently in hospitalized patients. Thrombolytic therapy, currently used as the major treatment, has often been associated with severe bleeding complications and has thereby been life-threatening. We have developed a novel therapeutic method based on our newly created pulmonary endothelium-specific antibody. METHODS AND RESULTS: We isolated membrane proteins of rat pulmonary vascular luminal endothelium and obtained a monoclonal antibody, RE8F5, which antigen was uniquely expressed by the pulmonary capillary endothelium. In vivo biodistribution showed that RE8F5 and its urokinase conjugate were rapidly and specifically accumulated in lung. Urokinase and the conjugate were compared in rats with pulmonary, hepatic, and lower-limb embolus. In a pulmonary embolus model, the conjugate exhibited 12-fold enhanced thrombolytic potency over urokinase, whereas plasma fibrinogen and bleeding time were unaffected. In 2 other models, no significant thrombolysis was induced by the conjugate. In contrast, thrombolysis by urokinase was found to be comparable to the pulmonary embolus model. In addition, urokinase caused significant consumption of fibrinogen in all experiments. CONCLUSIONS: These data show that urokinase equipped with lung endothelium-specific antibody is an ideal treatment for pulmonary embolism, with a high efficacy of thrombolysis and low risk of bleeding.
BACKGROUND:Pulmonary embolism occurs frequently in hospitalized patients. Thrombolytic therapy, currently used as the major treatment, has often been associated with severe bleeding complications and has thereby been life-threatening. We have developed a novel therapeutic method based on our newly created pulmonary endothelium-specific antibody. METHODS AND RESULTS: We isolated membrane proteins of rat pulmonary vascular luminal endothelium and obtained a monoclonal antibody, RE8F5, which antigen was uniquely expressed by the pulmonary capillary endothelium. In vivo biodistribution showed that RE8F5 and its urokinase conjugate were rapidly and specifically accumulated in lung. Urokinase and the conjugate were compared in rats with pulmonary, hepatic, and lower-limb embolus. In a pulmonary embolus model, the conjugate exhibited 12-fold enhanced thrombolytic potency over urokinase, whereas plasma fibrinogen and bleeding time were unaffected. In 2 other models, no significant thrombolysis was induced by the conjugate. In contrast, thrombolysis by urokinase was found to be comparable to the pulmonary embolus model. In addition, urokinase caused significant consumption of fibrinogen in all experiments. CONCLUSIONS: These data show that urokinase equipped with lung endothelium-specific antibody is an ideal treatment for pulmonary embolism, with a high efficacy of thrombolysis and low risk of bleeding.
Authors: Bi-Sen Ding; Claudia Gottstein; Andrea Grunow; Alice Kuo; Kumkum Ganguly; Steven M Albelda; Douglas B Cines; Vladimir R Muzykantov Journal: Blood Date: 2005-09-06 Impact factor: 22.113
Authors: Raisa Yu Kiseleva; Patrick M Glassman; Colin F Greineder; Elizabeth D Hood; Vladimir V Shuvaev; Vladimir R Muzykantov Journal: Drug Deliv Transl Res Date: 2018-08 Impact factor: 4.617
Authors: Bi-Sen Ding; Daniel J Nolan; Peipei Guo; Alexander O Babazadeh; Zhongwei Cao; Zev Rosenwaks; Ronald G Crystal; Michael Simons; Thomas N Sato; Stefan Worgall; Koji Shido; Sina Y Rabbany; Shahin Rafii Journal: Cell Date: 2011-10-28 Impact factor: 41.582