Selective rat lung endothelial targeting with a new set of monoclonal antibodies to angiotensin I-converting enzyme.
We demonstrated previously that monoclonal antibody (mAb) 9B9 to angiotensin-converting enzyme (ACE) accumulates selectively in the rat lung after systemic injection and thus is a powerful tool for immunotargeting therapeutic agents/genes to the lung microvasculature. Bearing in mind the tremendous research and therapeutic potential of lung immunotargeting via ACE, we generated a novel set of mAbs to rat ACE in order to enhance the repertoire of mAbs suitable for targeting drugs/genes to the rat lung. Five new mAbs recognizing different epitopes on rat ACE were examined for their efficacy to bind rat ACE both in vitro and in vivo. Gene delivery into cultured rat lung endothelial cells increased 30-50-fold after coating modified adenoviruses (containing Ig-binding domain) with mAbs to rat ACE. Radiolabeled mAbs specifically accumulated in the lung after systemic injection. mAb 1A2, 4H3 and 2E1 demonstrated the highest efficacy of lung uptake-around 50% of injected dose per gram of tissue; for mAb 1A2, the selectivity of lung uptake (ratio of lung to blood radioactivity) was 205. The effect of the mAbs on ACE shedding was epitope-specific: injection of mAb 1A2 and 4H3 did not change lung ACE activity, whereas injection of mAb 2E1 and 9B9 decreased rat lung ACE activity by 20%. None of the tested mAbs inhibited ACE activity in vitro. A new set of mAbs to rat ACE demonstrated highly efficient and selective lung accumulation and thus have the potential for targeting drugs/genes to the pulmonary vasculature in different rat models of lung diseases.
Balyasnikova
Irina V
IV
Anesthesiology Research Center, Department of Anesthesiology, University of Illinois at Chicago, 1819 W. Polk St. (M/C 519), Chicago, IL 60612, USA.
Metzger
Roman
R
Visintine
David J
DJ
Dimasius
Vidas
V
Sun
Zhu-Li
ZL
Berestetskaya
Yuliya V
YV
McDonald
Timothy D
TD
Curiel
David T
DT
Minshall
Richard D
RD
Danilov
Sergei M
SM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D000918:Antibody Specificity / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006825:Hybridomas / Q000276:immunology; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D051381:Rats; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007703:Peptidyl-Dipeptidase A