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Targetted immunotherapy with enzyme-labeled antibodies

酶标抗体靶向免疫治疗

基本信息

批准号：
60480156
负责人：
NAKANE Kazuo
金额：
$ 4.16万
依托单位：
Tokai University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1985
资助国家：
日本
起止时间：
1985 至 1987
项目状态：
已结题

项目摘要

Carcinoembryonic antigen (CEA) is found only at the brush border of normal colonic columnar epithelial cells,but is found all around the surface of colonic cancer cells. By taking an advantage of the change on the distribution of antigens on the surface of transformed epithelial cells, we undertook to develop a method to eliminate such neoplastic cells from the body. As a preliminary experiment, nude mice bearing human CEA producing tumor were injected with rabbit anti-human CEA IgG labeled with glucose oxidase. The injection of antibody was following by an i.v. in jection of NaI. The rational for this approach was that the injected enzyme-labeled antibody will be deposited on the surface of CEA producing tumor cells and produces hydrogen peroxide, the hydrogen peroxide will oxidize the plasma membrane and become permeable to iodine ion and the iodine will kill the cells. It was found that the size of tumor was reduced significantly, but the mice underwent an insulin shock like hepoglycemia and CEA-enzyme labeled antibody immune complex were deposited on the glomerular basement membrance. To circumvent the problems, with this investigation, galactose oxidase was used in place of glucose oxidase and another cell surface antigen of which distribution will change as the CEA when the cell are transformed, but is insoluble in the plasma were sought. To obtain the antigen, a new isolation method for the brush border from colonic epithelial cells was developed, and from the isolated brush border, several brush border specific antigens with molecular weight of several thousand were identified. The utilization of cell surface antigens which are inaccessible to the circulation on normal epithelial cells, but become accessible upon transformation as the targets of immuno-targeted therpy does not require tumor specific antigens and the use of hydrogen peroxide labeled antibodies should avoid the systemic side effect of toxin labeled antibodies.

癌胚抗原（CEA）仅在正常结肠柱状上皮细胞的刷状缘发现，但在结肠癌细胞的表面周围发现。通过利用转化上皮细胞表面抗原分布的变化，我们着手开发一种从体内消除这种肿瘤细胞的方法。作为初步实验，用葡萄糖氧化酶标记的兔抗人CEA IgG注射荷人产生CEA的肿瘤的裸鼠。注射抗体后静脉注射NaI。这种方法的原理是注射的酶标记抗体将沉积在产生CEA的肿瘤细胞的表面上并产生过氧化氢，过氧化氢将氧化质膜并变得可渗透碘离子，碘将杀死细胞。结果发现，肿瘤体积明显缩小，但小鼠经历了胰岛素休克样肝炎，CEA-酶标抗体免疫复合物沉积在肾小球基底膜上。为了避免这些问题，在本研究中，使用半乳糖氧化酶代替葡萄糖氧化酶，并寻找另一种细胞表面抗原，当细胞转化时，其分布将改变为CEA，但不溶于血浆。为获得刷状缘抗原，我们建立了一种新的从结肠上皮细胞中分离刷状缘的方法，并从分离的刷状缘中鉴定出了几种分子量为几千的刷状缘特异性抗原。利用正常上皮细胞上的循环不可接近但在转化后变得可接近的细胞表面抗原作为免疫靶向治疗的靶标不需要肿瘤特异性抗原，并且使用过氧化氢标记的抗体应避免毒素标记的抗体的全身副作用。