A NOVEL IMMUNOTOXIN RECOGNIZING THE EPITHELIAL GLYCOPROTEIN-2 HAS POTENT ANTITUMORAL ACTIVITY ON CHEMOTHERAPY-RESISTANT LUNG-CANCER

Resistance to chemotherapy is a major cause for failure in the treatme nt of lung cancer. Compared to conventional cytotoxic drugs, immunotox ins act by different mechanisms and thus might be promising for the tr eatment of chemoresistant cancer. The monoclonal antibody MOC31 recogn ises the epithelial glycoprotein-2 (EGP-2), a cell-surface antigen ass ociated with small-cell lung cancer (SCLC) and a major fraction of lun g adenocarcinomas. An immunotoxin composed of MOC31 and a recombinant form of Pseudomonas exotoxin A lacking the cell-binding domain (ETA(25 2-613)) was prepared, and its effect on lung cancer cell lines examine d. MOC31-ETA(252-613) was selectively cytotoxic to EGP-2-positive SCLC and adenocarcinoma cell lines inhibiting proliferation by 50% at conc entrations ranging from 0.01 nM to 0.3 nM. Moreover, the immunotoxin r educed the number of clonogenic tumour cells from cultures by factors of 10(4) and 10(5) during a 24-h and a 3-week exposure respectively. I n athymic mice, the immunotoxin, which revealed a serum half-life of a pproximately 4 h, caused substantial regression of small (40 mm(3)) ch emoresistant tumour xenografts and significantly delayed the growth of larger tumours (120 mm(3)). This finding indicates that MOC31-ETA(252 -613) may be useful for the treatment of lung cancer in the setting of chemoresistant minimal residual disease.