Cadherin-17 (CDH17) is highly expressed in
gastric cancer and is thus considered to be a good target for antibody
therapy. CDH17 is classified as a nonclassical
cadherin, in that it is composed of seven extracellular
cadherin domains. We generated anti-CDH17
monoclonal antibodies (mAbs) which recognize the extracellular domain of CDH17. Competitive assay using AGS, a
gastric cancer cell line, cells revealed that five selected anti-CDH17 mAbs recognize different
epitopes on CDH17. As AGS cells were shown to exhibit broad expression pattern of CDH17 by flow cytometry, we separated three clones with a low (10,000/cell), medium (50,000/cell), and high (200,000/cell) expression level, designating them as AGSlow, AGSmed, and AGShigh, respectively. The mAbs, coupled with
saporin, exhibited effective cytotoxicity to AGShigh, but poor cytotoxicity to AGSlow. By contrast, the
immunotoxin cocktail using the three clones D2101, D2005, and D2008, which recognize different
epitopes, exhibited efficient cytotoxicity, even to the AGSlow group. The effect of the
immunotoxin cocktail is synergistic, as the combination index was demonstrated to be below 1.0, as calculated by the method of Chou and Talalay using CalcuSyn software. These results suggest that the
immunotoxin cocktail targeted to multiple
epitopes has synergistic effects on low expression level cells, which expand the applicable range of
immunotoxin therapy for
cancer.