IMMUNOTOXINS RECOGNIZING A NEW EPITOPE ON THE NEURAL CELL-ADHESION MOLECULE HAVE POTENT CYTOTOXIC EFFECTS AGAINST SMALL-CELL LUNG-CANCER

The present study describes a comparison of two potent immunotoxins wh ich utilise an identical targeting component, a monoclonal antibody (S EN7) specific for small cell lung cancer (SCLC), conjugated to two dif ferent effector components, blocked ricin (bR) and Pseudomonas exotoxi n A (PE). SEN7 recognises a novel epitope on the neural cell adhesion molecule (NCAM) which is highly associated with SCLC. The immunotoxins SEN7-PE and SEN7-bR were selectively and potently active against a nu mber of SCLC cell lines, of both classic and variant morphologies, inh ibiting the incorporation of [H-3]leucine with IC50 values ranging bet ween 22 pM and 85 pM and between 7 pM and 62 pM for SEN7-PE and SEN7-b R respectively. Intoxication by both immunotoxins proceeded rapidly fo llowing short 2 h lag phases; the initial rates of protein synthesis i nhibition occurred with t(50) values of 6.5 h for SEN7-PE and 5.5 h fo r SEN7-bR. Monensin drastically enhanced the cytotoxic activity of the weakly active SEN7-ricin A-chain by 2,100-fold and of SEN7-bR by 80-f old but had no effect on SEN7-PE. In limiting dilution assays, four an d more than 4.5 logs of clonogenic SW2 tumour cells were selectively e liminated from the cultures during continuous exposure to the immunoto xins SEN7-PE and SEN7-bR respectively, while antigen-negative cells re quired up to 1,000-fold more drug for a similar cell kill. SW2 cells s urviving SEN7-bR treatment in the cultures did not express NCAM and co nsequently were not selectively killed by SEN7 immunotoxins. SW2 cells surviving continuous exposure to SEN7-PE showed no alteration in NCAM expression but were more resistant to intoxication mediated by PE. Th ese cells were still sensitive to SEN7-bR.