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Evaluation of a Transgenic Mouse Model for Anti-Human CEA Radioimmunotherapeutics

¹ Applied Development Laboratory, Imperial Cancer Research Technology, St. Bartholomew’s Hospital, London, United Kingdom
² Nuclear Medicine Group, Cancer Research U.K., St. Bartholomew’s Hospital, London, United Kingdom
³ Tumor Immunology Group, Department of Urology, Ludwig-Maximilians-University, Muenchen, Germany

In this study, a human carcinoembryonic antigen (CEA) transgenic (CEA.Tg) mouse model was evaluated for the preclinical assessment of agents directed against CEA. Methods: Cell-type and organ-specific expression of CEA was studied in CEA.Tg mice derived from a colony that carries the complete human CEA gene together with flanking regulatory sequences and also in wild-type controls. Biodistribution studies were performed on wild-type and CEA.Tg mice by intravenous injection of ¹²⁵I-labeled anti-CEA (PR1A3) or isotype control (IC) murine monoclonal antibodies (mAbs). Studies were also performed on tumor-bearing CEA.Tg and nude mice. Results: As with humans, the CEA.Tg mice had low serum levels of CEA (mean, 8.8 ± 5.52 ng/mL), and cell-surface CEA expression was primarily localized in the gastrointestinal tract. Both mAbs showed similar biodistribution patterns in the wild-type mice, whereas in the CEA.Tg mice, PR1A3 specifically localized to the CEA-expressing tissues. In the gastrointestinal tract, the percentage injected dose for PR1A3 was significantly higher than that for IC mAb at all the time points sampled. In CEA.Tg mice bearing a murine tumor transfected with human CEA, PR1A3 targeted tissues with constitutive CEA expression and was retained at the tumor site at high levels, whereas in nude mice, PR1A3 localized only to the site of the transplanted tumor. Conclusion: These results demonstrate the targeting potential of the anti-CEA antibody, PR1A3, and emphasize the value of using a transgenic model in preclinical studies.

Key Words: carcinoembryonic antigen • transgenic mice • radiolabeled antibody

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