An EGP-2/Ep-CAM-expressing transgenic rat model to evaluate antibody-mediated immunotherapy

The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), also k nown as 17-1A or EpCAM, is a 38-kDa transmembrane antigen, commonly used fo r targeted immunotherapy of carcinomas. Although strongly expressed by most carcinomas, EGP-2 is also expressed in most simple epithelia. To evaluate treatment-associated effects and side-effects on tumor and normal tissue re spectively, we generated an EGP-2-expressing transgenic Wistar rat. To expr ess the cDNA of the EGP-2 in an epithelium-specific manner, the 5' and 3' d istal flanking regions of the human keratin 18 (K18) gene were used. EGP-2 protein expression was observed in the liver and pancreas, whereas EGP-2 mR NA could also be detected in lung, intestine, stomach and kidney tissues. I n this rat, EGP-2-positive tumors can be induced by injecting a rat-derived carcinoma cell line transfected with the GA733-2 cDNA encoding EGP-2. Tran sgenic rats were used to study specific in vivo localization of an i.v. ant i-EGP-2 monoclonal antibody, MOC31, applied i.v. Immunohistochemical analys es showed the specific localization of MOC31 in s.c. induced EGP-2-positive tumors, as well as in the liver. In contrast, in EGP-2-transgenic rats, MO C31 did not bind to EGP-2-negative tumors, the pancreas, or other normal ti ssues in vivo. In conclusion, an EGP-2-transgenic rat model has been genera ted that serves as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities.