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Antibody targeting studies in a transgenic murine model of spontaneous colorectal tumors
R W Wilkinson1, E L Ross, R Poulsom
1Applied Development Laboratory, Imperial Cancer Research Technology, Dominion House, 59 Bartholomew Close, London EC1A 7BE, United Kingdom.
Abstract:
Monoclonal antibodies (mAbs) have been used to treat malignancies in humans with varying degrees of success. Progress has been hindered by the lack of suitable animal models, which would ideally consist of immunocompetent animals that are tolerant to tumor-associated antigens. Suitable models would allow the study and optimization of anti-tumor immunotherapy. We describe a murine model for the study of immunotherapy in colorectal cancers. Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein that is expressed on normal human intestinal epithelium and that is overexpressed in intestinal tumors. Mice that are transgenic for the human CEA gene (CEA.Tg) were crossed with multiple intestinal neoplasia (MIN) mice. MIN mice carry a germline APC mutation and are prone to the development of intestinal adenomas. The offspring from the MIN x CEA.Tg cross developed intestinal adenomas that were shown by immunohistochemistry to overexpress CEA. Pharmacokinetic studies by using (125)I-labeled anti-CEA mAb PR1A3 showed rapid localization of antibody to tissues expressing CEA, especially the gastrointestinal tract. Macroscopic and microscopic radioautographic analysis of the gastrointestinal tracts from MIN/CEA.Tg mice indicated that PR1A3 targeted and was retained in tumors at levels higher than in areas of normal gut. These results demonstrate the utility of the MIN/CEA.Tg mouse as a model for the study of anti-CEA immunotherapy and, furthermore, demonstrate the efficiency of tumor localization by PR1A3.
Insights
A new mouse model combining human carcinoembryonic antigen (CEA) expression and intestinal tumors allows for the study of anti-CEA immunotherapy. This model demonstrates effective targeting and retention of anti-CEA monoclonal antibodies in colorectal tumors.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Monoclonal antibodies (mAbs) show variable success in treating human malignancies.
- Lack of suitable immunocompetent animal models tolerant to tumor-associated antigens hinders immunotherapy research.
- Carcinogenic embryonic antigen (CEA) is overexpressed in intestinal tumors, making it a target for immunotherapy.
Purpose of the Study:
- To develop and validate a murine model for studying anti-CEA immunotherapy in colorectal cancer.
- To assess the utility of the MIN/CEA.Tg mouse model for preclinical immunotherapy studies.
- To evaluate the tumor-targeting efficiency of the anti-CEA mAb PR1A3.
Main Methods:
- Generation of MIN/CEA.Tg mice by crossing multiple intestinal neoplasia (MIN) mice with human CEA transgenic (CEA.Tg) mice.
- Immunohistochemical analysis to confirm CEA overexpression in intestinal adenomas of MIN/CEA.Tg offspring.
- Pharmacokinetic and radioautographic studies using (125)I-labeled anti-CEA mAb PR1A3 to assess antibody localization and retention in tumors.
Main Results:
- MIN/CEA.Tg mice developed intestinal adenomas that overexpressed CEA.
- (125)I-labeled anti-CEA mAb PR1A3 rapidly localized to CEA-expressing tissues, particularly the gastrointestinal tract.
- Radioautographic analysis showed higher retention of PR1A3 in tumors compared to normal gut tissue.
Conclusions:
- The MIN/CEA.Tg mouse is a valuable model for studying anti-CEA immunotherapy in colorectal cancer.
- The anti-CEA mAb PR1A3 demonstrates efficient tumor localization and retention in this model.
- This model facilitates the optimization of anti-tumor immunotherapy strategies targeting CEA.
