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The Epithelial Glycoprotein 2 (EGP-2) Promoter-driven Epithelial-specific Expression of EGP-2 in Transgenic Mice

A New Model to Study Carcinoma-directed Immunotherapy¹

Department of Pathology and Laboratory Medicine, section of Medical Biology [P. M. J. M., M. C. H., W. H. A. D., B-J. K., H. v. d. M., M. G. L. B., M. H. J. R., L. F. M. H. d. L.] and Pathology [H. H.], University Hospital Groningen, 9713 GZ Groningen; Department of Medical Genetics, University of Groningen, 9713AW Groningen [C. H. C. M. B.]; and Groningen University Institute for Drug Exploration, 9713 EZ Groningen [P. M. J. M., M. C. H., B-J. K., L. F. M. H. d. L.], the Netherlands.

The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), a M_r 38,000 transmembrane antigen also known as 17–1A or Ep-CAM, is commonly used for targeted immunotherapy of carcinomas because it is strongly expressed by most carcinomas. EGP-2 is, however, also expressed in most normal epithelia. To evaluate anti-EGP-2-directed treatment-associated effects on tumors and on EGP-2-positive normal tissue, we generated EGP-2-expressing transgenic mice. A 55-kb DNA fragment consisting of the 14-kb genomic coding sequence of the human EGP-2 gene with 10-kb-upstream and 31-kb-downstream sequences was isolated and used to direct EGP-2 expression in an epithelium-specific manner. In the EGP-2 transgenic mice, EGP-2 appeared to be specifically expressed in all of those epithelial tissues that also express EGP-2 in humans, whereas all of the other tissues were negative. The specific in vivo localization of the i.v. administered anti-EGP-2 monoclonal antibody MOC31 was studied in EGP-2-positive and -negative tumors induced s.c. in this EGP-2 transgenic mouse model. Immunohistochemical analysis showed specific localization of MOC31 in the EGP-2-positive tumors but not in the EGP-2-negative tumors. No anti-EGP-2 monoclonal antibody localization was observed in any of the EGP-2-positive normal mouse tissues, which indicated a limited in vivo accessibility. In conclusion, an EGP-2 transgenic mouse model has been generated that expresses the EGP-2 antigen as in humans and, therefore, can serve as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities in both tumors and normal tissue.

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