Lung endothelium targeting for pulmonary embolism thrombolysis.
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.


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.
Ding
Bi-Sen
BS
Institute of Molecular Medicine and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
Zhou
Ying-Jiang
YJ
Chen
Xin-Yuan
XY
Zhang
Jing
J
Zhang
Pei-Xiang
PX
Sun
Zi-Yong
ZY
Tan
Xiang-Yang
XY
Liu
Jian-Ning
JN
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000918:Antibody Specificity; D002196:Capillaries / Q000737:chemistry / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000737:chemistry / Q000276:immunology; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006470:Hemorrhage / Q000517:prevention & control; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008168:Lung / Q000098:blood supply*; D008565:Membrane Proteins / Q000276:immunology / Q000302:isolation & purification; D051379:Mice; D008807:Mice, Inbred BALB C; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D015912:Thrombolytic Therapy; D014018:Tissue Distribution; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D018796:Immunoconjugates; D008565:Membrane Proteins; D005340:Fibrinogen; D014568:Urokinase-Type Plasminogen Activator