Batra J K, FitzGerald D, Gately M, Chaudhary V K, Pastan I
Division of Cancer Biology and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
J Biol Chem. 1990 Sep 5;265(25):15198-202.
Anti-Tac(Fv)-PE40 is a chimeric single chain immunotoxin in which anti-Tac variable heavy and light chains held together by a peptide linker are attached to PE40, a truncated form of Pseudomonas exotoxin. This molecule was shown to be extremely cytotoxic for interleukin 2 (IL2) receptor bearing cells in tissue culture (Chaudhary, V. K., Queen, C., Junghans, R. P., Waldmann, T. A., FitzGerald, D. J., and Pastan, I. (1989) Nature 339, 394-397). Here we describe various forms of anti-Tac(Fv)-PE40 protein in which the order of the variable domains of anti-Tac has been switched and also three different types of peptide linkers have been used. All these proteins were purified to near homogeneity and were found to have similar cytotoxic activities against various human cells expressing the p55 subunit of the IL2 receptor. Anti-Tac(Fv)-PE40 was also found to have a very potent suppressive activity against phytohemagglutinin-activated human lymphoblasts and in a human mixed lymphocyte reaction. Anti-Tac(Fv)-PE40 appeared in the blood rapidly in mice after intraperitoneal administration and could be detected in the blood for up to 8 h. Anti-Tac(Fv)-PE40 warrants evaluation as an anti-tumor and immunosuppressive agent in humans.
抗 Tac(Fv)-PE40 是一种嵌合单链免疫毒素，其中由肽接头连接在一起的抗 Tac 重链和轻链可变区与 PE40（铜绿假单胞菌外毒素的截短形式）相连。在组织培养中，该分子对表达白细胞介素 2（IL-2）受体的细胞具有极强的细胞毒性（Chaudhary, V. K., Queen, C., Junghans, R. P., Waldmann, T. A., FitzGerald, D. J., and Pastan, I. (1989) Nature 339, 394 - 397）。在此，我们描述了抗 Tac(Fv)-PE40 蛋白的多种形式，其中抗 Tac 可变区的顺序已被调换，并且使用了三种不同类型的肽接头。所有这些蛋白均被纯化至近乎同质，并且发现它们对表达 IL-2 受体 p55 亚基的各种人类细胞具有相似的细胞毒性活性。抗 Tac(Fv)-PE40 还被发现对植物血凝素激活的人类淋巴母细胞以及人类混合淋巴细胞反应具有非常强的抑制活性。腹腔注射后，抗 Tac(Fv)-PE40 在小鼠血液中迅速出现，并且在血液中可检测长达 8 小时。抗 Tac(Fv)-PE40 值得作为一种抗肿瘤和免疫抑制剂在人类中进行评估。
