title: Immunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer.
abstract: The present study describes a comparison of two potent immunotoxins which utilise an identical targeting component, a monoclonal antibody (SEN7) specific for small cell lung cancer (SCLC), conjugated to two different effector components, blocked ricin (bR) and Pseudomonas exotoxin 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 number of SCLC cell lines, of both classic and variant morphologies, inhibiting the incorporation of [3H]leucine with IC50 values ranging between 22 pM and 85 pM and between 7 pM and 62 pM for SEN7-PE and SEN7-bR respectively. Intoxication by both immunotoxins proceeded rapidly following short 2 h lag phases; the initial rates of protein synthesis inhibition occurred with t50 values of 6.5 h for SEN7-PE and 5.5 h for 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-fold but had no effect on SEN7-PE. In limiting dilution assays, four and more than 4.5 logs of clonogenic SW2 tumour cells were selectively eliminated from the cultures during continuous exposure to the immunotoxins SEN7-PE and SEN7-bR respectively, while antigen-negative cells required up to 1,000-fold more drug for a similar cell kill. SW2 cells surviving SEN7-bR treatment in the cultures did not express NCAM and consequently 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. These cells were still sensitive to SEN7-bR.
authors.affiliation: Division of Oncology, University Hospital, Zürich, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Zangemeister-Wittke
authors.forename: A R
authors.initials: AR
authors.lastname: Collinson
authors.forename: B
authors.initials: B
authors.lastname: Frösch
authors.forename: R
authors.initials: R
authors.lastname: Waibel
authors.forename: T
authors.initials: T
authors.lastname: Schenker
authors.forename: R A
authors.initials: RA
authors.lastname: Stahel
mesh_terms: D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001427:Bacterial Toxins; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology*; D046508:Culture Techniques; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology*; D005098:Exotoxins / Q000633:toxicity*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology* / Q000378:metabolism / Q000633:toxicity*; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012276:Ricin / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D015816:Cell Adhesion Molecules, Neuronal; D000939:Epitopes; D005098:Exotoxins; D000922:Immunotoxins; D009363:Neoplasm Proteins; D012276:Ricin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A