Vascular immunotargeting to endothelial surface in a specific macrodomain in alveolar capillaries.
A novel 85 kD glycoprotein (gp85) is a marker of the avesicular zone, a thin part of pulmonary endothelial cells separating alveolar and vascular compartments and lacking vesicles. This report presents the first evaluation whether mAb 30B3, a monoclonal antibody to gp85, can be used for targeting of drugs to the surface of lung endothelium. 125I-mAb 30B3 accumulated in isolated perfused lungs (IPL) (22.8 +/- 1.1 versus 0.5 +/- 0.1 %ID/g for 125I-IgG) and accumulated preferentially in the lungs after intravenous or intraarterial injection (10.9 +/- 0.7 and 11.0 +/- 1.5 versus 0.9 +/- 0.2 %ID/g for 125I-IgG). 125I-mAb 30B3 uptake in IPL was rapid (T1/2 15 min), saturable (Bmax appr. 10(5) molecules/cell), specific (inhibited by nonlabeled mAb 30B3) and temperature independent (26.3 +/- 2.1 versus 22.8 +/- 1.1 %ID/g at 6 degrees C versus 37 degrees C). Biotinylated mAb 30B3 permitted subsequent accumulation of perfused avidin derivative in IPL. Because these data indicated that mAb 30B3 binds to an accessible, poorly internalizable antigen in the lung, we conjugated mAb 30B3 with a plasminogen activator, 125I-tPA. After intravenous injection in rats, lung-to-blood ratio was 8.4 +/- 0.9 for mAb 30B3/125I-tPA versus 0.4 +/- 0.1 for IgG/125I-tPA, indicating that mAb 30B3 may deliver drugs, which was supposed to exert therapeutic action in the vascular lumen (e.g., antithrombotic proteins), to the surface of pulmonary endothelium.
Murciano
J C
JC
Institute for Environmental Medicine and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Harshaw
D W
DW
Ghitescu
L
L
Danilov
S M
SM
Muzykantov
V R
VR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002196:Capillaries / Q000000981:diagnostic imaging / Q000276:immunology*; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000000981:diagnostic imaging / Q000276:immunology*; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; C444759:gp85 protein, rat