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Mice Transgenic for Human Carcinoembryonic Antigen as a Model for Immunotherapy¹

Divisions of Immunology [P. C., K. R-D., F. J. P.] and Biology [J. M.], Beckman Research Institute of the City of Hope, and Division of Pathology [J. F. S.], City of Hope National Medical Center, Duarte, California 91010

Mice transgenic for the human carcinoembryonic antigen (CEA) gene were prepared for use as a preclinical model for immunotherapy. A 32.6-kb fragment containing the complete human CEA gene and flanking sequences was isolated from a genomic cosmid clone and used to produce transgenic C57BL/6 mice. A homozygous line was established that was designated C57BL/6J-TgN(CEAGe)18FJP. Southern blot analysis showed that this line contained intact copies of the cosmid clone, with approximately 19 integrated copies at one chromosomal location. A mouse-human chimeric anti-CEA monoclonal antibody was used to examine CEA expression by immunohistochemical staining of frozen tissue sections. In the cecum and colon, approximately 20% of the luminal epithelial cells had strong cytoplasmic staining, whereas occasional glands showed intense staining. CEA was also expressed in gastric foveolar cells, whereas small intestine villi had only a few (<1%) positive cells. CEA was not found by immunohistochemistry in other tissues of the digestive tract, nor was it found in a wide range of other tissues or organs. Concordance in results was obtained between immunohistochemistry and analysis of tissue extracts by enzyme immunoassay. The lone exception was the testis, which was positive only by enzyme immunoassay. Expression of human CEA was not observed in tissues derived from nontransgenic mice. The fecal content of CEA in transgenic mice was approximately 100-fold less than that observed for humans. Circulating CEA was not detected. A CEA-transfected syngeneic murine colon carcinoma cell line, MC-38, was prepared that had stable expression of CEA in vitro and in vivo. The molecular size of CEA produced by CEA-transfected MC-38 cells and by the colon of transgenic mice was similar to that obtained with CEA purified from human colon tumors. Anti-CEA antibody appeared in nontransgenic but not transgenic mice bearing transfected MC-38 tumors. These findings demonstrate that CEA distribution and its properties in tissues of mice transgenic for the human CEA gene are similar to that observed in human tissues. As in humans, immune responsiveness to CEA, as reflected by antibody formation, was not detectable in transgenic mice bearing CEA-positive tumors. Thus, CEA transgenic mice may serve as a useful model for studying the efficacy and safety of various immunotherapy strategies directed at this tumor self-antigen.

¹ This work was supported by NIH Grants CA58327 and CA70320. Additional support was provided by NIH Cancer Core Grant CA33572 to the City of Hope.

² To whom requests for reprints should be addressed, at Vanderbilt University Medical Center, Department of Pathology, C-3321 MCN, Nashville, TN 37232.

Received 8/19/97. Accepted 2/ 2/98.

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