TY - JOUR
T1 - Selective rat lung endothelial targeting with a new set of monoclonal antibodies to angiotensin I-converting enzyme
AU - Balyasnikova, Irina V.
AU - Metzger, Roman
AU - Visintine, David J.
AU - Dimasius, Vidas
AU - Sun, Zhu Li
AU - Berestetskaya, Yuliya V.
AU - McDonald, Timothy D.
AU - Curiel, David T.
AU - Minshall, Richard D.
AU - Danilov, Sergei M.
N1 - Funding Information:
The authors thank Professor R.F. Albrecht, Head of the Department of Anesthesiology, University of Illinois at Chicago, for his continuous encouragement and support of this study. This study was supported in part by funds from POCARD, LTD, (Moscow, Russia), AHA Scientist Development Grant # 0330397Z and ALA of Metropolitan Chicago Research Grant (I.V.B.) and by RO1 HL 67962-01 (D.T.C.).
PY - 2005/8
Y1 - 2005/8
N2 - 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.
AB - 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.
KW - CD143
KW - Gene delivery
KW - Lung uptake
KW - Rat endothelial cells
UR - https://www.scopus.com/pages/publications/20144365995
U2 - 10.1016/j.pupt.2004.12.008
DO - 10.1016/j.pupt.2004.12.008
M3 - Article
C2 - 15777608
AN - SCOPUS:20144365995
SN - 1094-5539
VL - 18
SP - 251
EP - 267
JO - Pulmonary Pharmacology and Therapeutics
JF - Pulmonary Pharmacology and Therapeutics
IS - 4
ER -