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Evaluation of a transgenic mouse model for anti-human CEA radioimmunotherapeutics
Robert W Wilkinson1, Elizabeth L Ross, David Ellison
1Applied Development Laboratory, Imperial Cancer Research Technology, St. Bartholomew's Hospital, London, United Kingdom.
Unlabelled:
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.
Insights
A human carcinoembryonic antigen (CEA) transgenic mouse model effectively mimics human CEA expression for preclinical testing of anti-CEA antibodies. The PR1A3 antibody demonstrated specific targeting of CEA-expressing tissues and tumors in this model.
Area of Science:
- Oncology
- Immunology
- Transgenic Animal Models
Background:
- Carcinoembryonic antigen (CEA) is a tumor marker often overexpressed in various cancers.
- Preclinical models are crucial for evaluating the efficacy of targeted cancer therapies.
Purpose of the Study:
- To assess a human CEA transgenic (CEA.Tg) mouse model for preclinical evaluation of anti-CEA agents.
- To validate the targeting potential of the anti-CEA antibody, PR1A3, in vivo.
Main Methods:
- CEA expression was analyzed in CEA.Tg mice and wild-type controls.
- Biodistribution studies were conducted using 125I-labeled anti-CEA (PR1A3) and isotype control (IC) monoclonal antibodies (mAbs) in wild-type and CEA.Tg mice.
- Studies included tumor-bearing CEA.Tg and nude mice.
Main Results:
- CEA.Tg mice exhibited low serum CEA levels and primary CEA expression in the gastrointestinal tract, similar to humans.
- The PR1A3 antibody specifically localized to CEA-expressing tissues in CEA.Tg mice, with higher retention in the gastrointestinal tract compared to IC mAb.
- In tumor-bearing mice, PR1A3 effectively targeted CEA-expressing tumors and showed high retention at the tumor site.
Conclusions:
- The CEA.Tg mouse model accurately reflects human CEA expression patterns.
- The anti-CEA antibody PR1A3 demonstrates significant targeting potential in a relevant preclinical model.
- Transgenic models are valuable tools for preclinical assessment of targeted therapeutic agents.