Waldmann T A, Grant A, Tendler C, Greenberg S, Goldman C, Bamford R, Junghans R P, Nelson D
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Immunol. 1990 Nov;10(6 Suppl):19S-28S; discussion 28S-29S. doi: 10.1007/BF00918688.
We have proposed a multichain model for the high-affinity interleukin-2 (IL-2) receptor involving two IL-2-binding peptides, a 70/75 kilodalton (kD) and a 55 kD, reactive with the anti-Tac monoclonal antibody, which are associated in a receptor complex. With the use of coprecipitation analysis, radiolabeled interleukin-2 cross-linking procedures, and flow cytometric resonance energy transfer measurements, a series of additional peptides of molecular weight 22,000, 35,000, 40,000, 75,000 (non-IL-2 binding), 95,000-105,000, and 180,000 has been associated with the two interleukin-2-binding peptides. In contrast to resting T cells, the abnormal T cells of patients with human T-cell lymphotropic virus I-associated adult T-cell leukemia, patients with select autoimmune disorders, and individuals rejecting allografts express the Tac peptide (p55) of the IL-2 receptor. To exploit this difference in Tac antigen expression, we have initiated therapeutic trials using unmodified anti-Tac, conjugates of anti-Tac with truncated Pseudomonas exotoxin PE-40, interleukin-2-truncated toxin fusion proteins, and alpha- and beta-emitting isotopic chelates of anti-Tac. Furthermore, by genetic engineering humanized hyperchimeric anti-Tac molecules have been prepared in which the molecule is entirely human IgG1, except for the small complementarity-determining regions that are retained from the mouse antibody. This "humanized" antibody manifested the ability to perform antibody-dependent cellular cytotoxicity absent in the original mouse monoclonal. The clinical application of anti-interleukin-2 receptor-directed therapy represents a new perspective for the treatment of certain neoplastic diseases and autoimmune disorders and for the prevention of allograft rejection.
我们提出了一种高亲和力白细胞介素-2（IL-2）受体的多链模型，该模型涉及两条与抗Tac单克隆抗体反应的IL-2结合肽，一条70/75千道尔顿（kD）和一条55 kD，它们存在于受体复合物中。通过共沉淀分析、放射性标记的白细胞介素-2交联程序以及流式细胞术共振能量转移测量，一系列分子量为22,000、35,000、40,000、75,000（非IL-2结合）、95,000 - 105,000和180,000的额外肽与这两条IL-2结合肽相关联。与静息T细胞不同，人类嗜T细胞病毒I相关的成人T细胞白血病患者、某些自身免疫性疾病患者以及同种异体移植排斥个体的异常T细胞表达IL-2受体的Tac肽（p55）。为利用Tac抗原表达的这种差异，我们已开始使用未修饰的抗Tac、抗Tac与截短的铜绿假单胞菌外毒素PE-40的缀合物、白细胞介素-2 - 截短毒素融合蛋白以及抗Tac的α和β发射同位素螯合物进行治疗试验。此外，通过基因工程制备了人源化超嵌合抗Tac分子，其中除了从小鼠抗体保留的小互补决定区外，该分子完全是人IgG1。这种“人源化”抗体表现出在原始小鼠单克隆抗体中不存在的进行抗体依赖性细胞毒性的能力。抗白细胞介素-2受体导向治疗的临床应用为某些肿瘤疾病和自身免疫性疾病的治疗以及同种异体移植排斥的预防提供了新的视角。
