Kreitman R J, Pastan I
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Leuk Lymphoma. 1994 Mar;13(1-2):1-10.
Interleukin 2 (IL2) receptors (IL2R's) are found on malignant cells in many human leukemias and lymphomas and are expressed by activated T cells in many autoimmune disorders. Anti-Tac(Fv), a single-chain protein composed of the variable heavy and light domains of the anti-IL2R monoclonal antibody anti-Tac, can be genetically fused to derivatives of Pseudomonas exotoxin (PE) or diphtheria toxin (DT) to form potent immunotoxins. We have shown that anti-Tac(Fv) binds to low affinity IL2R's on fresh chronic lymphocytic leukemia (CLL) and adult T-cell leukemia (ATL) cells and can target either toxin to kill those cells. Anti-Tac(Fv)-PE40, containing the truncated form of PE without its binding domain, was cytotoxic to malignant cells from 8 of 8 ATL patients tested, with IC50's ranging from 0.11 to 5.5 ng/ml. Anti-Tac(Fv)-PE40KDEL, a derivative of anti-Tac(Fv)-PE40 which contains the KDEL carboxyl terminus, was more cytotoxic toward cells from all ATL patients and also killed CLL cells from 8 of 16 patients. DT388-anti-Tac(Fv), containing amino acids 1-388 of DT fused to the amino terminus of anti-Tac(Fv), was less cytotoxic than anti-Tac(Fv)-PE40 on ATL cells from 4 of 5 patients, but was cytotoxic toward CLL cells from 12 of 16 patients. DT388-IL2, where IL2 is substituted for anti-Tac(Fv), is similar to DAB389IL2, an IL2-toxin currently in clinical trials. DT388-IL2 and DAB389IL2 differ by only a few amino acids and have equal cytotoxic activity. DT388-IL2 was cytotoxic toward ATL cells from all patients tested, but usually required much higher concentrations than anti-Tac(Fv)-PE40 and was poorly active against CLL cells. Thus, recombinant toxins containing anti-Tac(Fv) are cytotoxic toward freshly isolated CLL and ATL cells and will be studied further as potential therapy for IL2R-related disorders.
白细胞介素2（IL2）受体（IL2R）存在于许多人类白血病和淋巴瘤的恶性细胞上，在许多自身免疫性疾病中，活化的T细胞也会表达。抗Tac（Fv）是一种单链蛋白，由抗IL2R单克隆抗体抗Tac的可变重链和轻链结构域组成，可与铜绿假单胞菌外毒素（PE）或白喉毒素（DT）的衍生物进行基因融合，形成强效免疫毒素。我们已经表明，抗Tac（Fv）可与新鲜慢性淋巴细胞白血病（CLL）和成人T细胞白血病（ATL）细胞上的低亲和力IL2R结合，并能将两种毒素靶向作用于这些细胞以将其杀死。抗Tac（Fv）-PE40含有不含结合结构域的截短形式的PE，对8例接受检测的ATL患者中的8例的恶性细胞具有细胞毒性，IC50范围为0.11至5.5 ng/ml。抗Tac（Fv）-PE40KDEL是抗Tac（Fv）-PE40的衍生物，含有KDEL羧基末端，对所有ATL患者的细胞具有更强的细胞毒性，并且还杀死了16例患者中8例的CLL细胞。DT388-抗Tac（Fv）含有与抗Tac（Fv）氨基末端融合的DT的1至388个氨基酸，对5例患者中4例的ATL细胞的细胞毒性低于抗Tac（Fv）-PE40，但对16例患者中12例的CLL细胞具有细胞毒性。DT388-IL2用IL2替代了抗Tac（Fv），类似于目前正在进行临床试验的IL2毒素DAB389IL2。DT388-IL2和DAB389IL2仅相差几个氨基酸，并且具有相同的细胞毒性活性。DT388-IL2对所有接受检测的患者的ATL细胞具有细胞毒性，但通常需要比抗Tac（Fv）-PE40高得多的浓度，并且对CLL细胞的活性较差。因此，含有抗Tac（Fv）的重组毒素对新鲜分离的CLL和ATL细胞具有细胞毒性，并将作为IL2R相关疾病的潜在治疗方法进行进一步研究。
