MONOCLONAL ANTIBODY-TOXIN CONJUGATES FOR TUMOR THERAPY IN VIVO

单克隆抗体选择性结合肿瘤细胞分化抗原 在体外和体内。 由于自然效应器机制通常不 介导单克隆抗体结合细胞的杀伤，我们已经设计了方法 将毒性极强的蛋白质与抗体连接起来， 肿瘤细胞 我们已经成功地开发了几种新的方法来应用 体内免疫毒素。 1)克隆毒素，然后改变它们的结构， 基因水平降低非靶细胞毒性; 2）鞘内注射 施用免疫毒素治疗脑肿瘤， 动物模型中肿瘤细胞的对数; 3）制备基因表达载体， 用于人脑肿瘤临床试验的工程免疫毒素 患者; 4）预防针对免疫毒素的免疫应答， 抗-CD 4抗体; 5）大鼠中浦肯野细胞的特异性缺失， 豚鼠和恒河猴; 6）使用人细胞毒性蛋白， 作为与抗体连接以选择性靶向细胞的RNA酶;以及7） 了解人类核糖核酸酶神经毒素的机制。

Monoclonal antibodies selectively bind tumor cell differentiation antigens in vitro and in vivo. Since natural effector mechanisms often do not mediate killing of monoclonal antibody bound cells we have devised methods of linking extremely toxic proteins to the antibodies to selectively kill tumor cells. We have succeeded in developing several new approaches to apply immunotoxins in vivo. 1) Cloning toxins, then altering their structure at the gene level to decrease non target cell toxicity; 2) intrathecal administration of immunotoxins for therapy of brain tumors that kill 2-5 logs of tumor cells in animal models; 3) preparation of genetically engineered immunotoxins for clinical trials of human brain tumor patients; 4) prevention of an immune response against immunotoxin with anti-CD4 antibodies; 5) specific deletion of Purkinje cells in rats, guinea pigs, and rhesus monkeys; 6) use of human cytotoxic proteins such as RNase linked to antibodies to selectively target cells; and 7) understanding the mechanism of human RNase neurotoxins.