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It is ideal for the target antigen of a cytotoxic therapeutic antibody against cancer to be cancer-specific, but such antigens are rare. Thus an alternative strategy for target selection is necessary. Desmoglein 3 (DSG3) is highly expressed in lung squamous cell carcinoma, while it is well-known that anti-DSG3 antibodies cause pemphigus vulgaris, an autoimmune disease. We evaluated DSG3 as a novel target by selecting an epitope that exerts efficacy against cancer with no pathogenic effects in normal tissues. Pathogenic anti-DSG3 antibodies induce skin blisters by inhibiting the cell-cell interaction in a Ca2+-dependent manner. We screened anti-DSG3 antibodies that bind DGS3 independent of Ca2+ and have high antibody-dependent cell cytotoxicity (ADCC) activity against DSG3-expressing cells. These selected antibodies did not inhibit cell-cell interaction and showed ADCC activity against squamous cell carcinoma cell lines. Furthermore, one of the DSG3 antibodies showed anti-tumour activity in tumour mouse models but did not induce adverse effects such as blister formation in the skin. Thus it was possible to generate an antibody against DSG3 by using an appropriate epitope that retained efficacy with no pathogenicity. This approach of epitope selection may expand the variety of druggable target molecules.

Generation of an anti-desmoglein 3 antibody without pathogenic activity of pemphigus vulgaris for therapeutic application to squamous cell carcinoma