Wilkinson R W, Ross E L, Poulsom R, Ilyas M, Straub J, Snary D, Bodmer W F, Mather S J
Applied Development Laboratory, Imperial Cancer Research Technology, Dominion House, 59 Bartholomew Close, London EC1A 7BE, United Kingdom.
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10256-60. doi: 10.1073/pnas.181353498. Epub 2001 Aug 21.
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.
单克隆抗体（mAb）已被用于治疗人类恶性肿瘤，取得了不同程度的成功。由于缺乏合适的动物模型，进展受到了阻碍，理想的动物模型应由对肿瘤相关抗原耐受的免疫活性动物组成。合适的模型将有助于抗肿瘤免疫疗法的研究和优化。我们描述了一种用于研究结直肠癌免疫疗法的小鼠模型。癌胚抗原（CEA）是一种细胞表面糖蛋白，在正常人类肠上皮细胞上表达，在肠道肿瘤中过表达。将人类CEA基因转基因小鼠（CEA.Tg）与多重肠道肿瘤（MIN）小鼠杂交。MIN小鼠携带种系APC突变，易于发生肠道腺瘤。MIN×CEA.Tg杂交后代发生了肠道腺瘤，免疫组织化学显示其CEA过表达。使用（125）I标记的抗CEA单克隆抗体PR1A3进行的药代动力学研究表明，抗体能快速定位到表达CEA的组织，尤其是胃肠道。对MIN/CEA.Tg小鼠胃肠道进行的宏观和微观放射自显影分析表明，PR1A3靶向肿瘤并在肿瘤中保留的水平高于正常肠道区域。这些结果证明了MIN/CEA.Tg小鼠作为抗CEA免疫疗法研究模型的实用性，此外，还证明了PR1A3对肿瘤定位的有效性。
