C-ERBB-2 P185 - DIRECTED THERAPY IN HUMAN LUNG ADENOCARCINOMA/

Background. These experiments were conducted to determine whether p185 can be therapeutically targeted in adenocarcinoma of the lung using a n anti-p185-gelonin conjugate. c-erbB-2/p185 is overexpressed in up to one third of non-small cell lung cancers. CALU-3 is a human lung aden ocarcinoma cell line that overexpresses p185. muMoAb-4D5 is a murine a nti-p185 monoclonal immunoglobulin G(1). Gelonin is a potent type 1 ri bosomal inhibitory protein. Methods. 4D5 and gelonin were covalently m odified and linked. Purification was confirmed by SDS-polyacrylamide g el electrophoresis. Dose-dependent cytotoxicity was quantified using H -3-thymidine uptake by CALU-3 cells after incubation with 4D5-gelonin conjugate or with control substances (4D5, gelonin, unconjugated 4D5 gelonin, or control antibody MOPC-21). Results. The 4D5-gelonin conju gate showed a 50% inhibitory concentration of 3.5 x 10(-10) mol/L, but 4D5 alone demonstrated no cytotoxic effect. Gelonin and the unconjuga ted 4D5-gelonin mixture had one tenth the cytotoxicity of the 4D5-gelo nin conjugate (inhibitory concentration = 6.5 x 10(-9) mol/L and 8.5 x 10(-9) mol/L, respectively). The conjugate exhibited minimal toxicity against a p185-negative cell line (NIH3T3). Conclusions. Selective an d efficient killing of human lung adenocarcinoma cells can be achieved in vitro using c-erbB-2/p185-directed therapy.