Junghans R P, Waldmann T A, Landolfi N F, Avdalovic N M, Schneider W P, Queen C
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cancer Res. 1990 Mar 1;50(5):1495-502.
The Mr 55,000 interleukin 2 receptor peptide (Tac; CD25) is not expressed by normal resting T-cells but is markedly up-regulated in adult T-cell leukemia and other malignancies, as well as on T-cells activated in normal immune, autoimmune, allograft, and graft-versus-host settings. Anti-Tac is a mouse monoclonal antibody directed against the Tac peptide. Our prior attempts to use this antibody in humans for antitumor therapy and immune regulation have been limited by weak recruitment of effector functions and neutralization by antibodies to mouse immunoglobulins. To circumvent these difficulties, we prepared several chimeric "humanized" anti-Tac antibodies by genetic engineering, including one "hyperchimeric" antibody (anti-Tac-II) in which the molecule is human except for the small hypervariable segments of the complementarity-determining regions retained from the mouse antibody. These constructs maintain high affinities for antigen and abilities to block T-cell activation and demonstrate new capabilities to perform antibody-dependent cell-mediated cytotoxicity, absent in the mouse anti-Tac. Hence, humanized antibodies have been developed to a tumor-associated antigen and activated T-cell marker with significant features that offer new therapeutic possibilities for select neoplastic and immune disorders.
分子量为55,000的白细胞介素2受体肽（Tac；CD25）在正常静止T细胞中不表达，但在成人T细胞白血病和其他恶性肿瘤中显著上调，在正常免疫、自身免疫、同种异体移植和移植物抗宿主环境中被激活的T细胞上也显著上调。抗Tac是一种针对Tac肽的小鼠单克隆抗体。我们之前尝试在人体中使用这种抗体进行抗肿瘤治疗和免疫调节时，受到效应功能募集不足以及被抗小鼠免疫球蛋白抗体中和的限制。为了克服这些困难，我们通过基因工程制备了几种嵌合“人源化”抗Tac抗体，包括一种“超嵌合”抗体（抗Tac-II），其中除了从小鼠抗体保留的互补决定区的小超可变片段外，分子其余部分均为人类来源。这些构建体保持了对抗原的高亲和力以及阻断T细胞活化的能力，并展现出小鼠抗Tac所不具备的新能力，即执行抗体依赖性细胞介导的细胞毒性。因此，已经开发出针对肿瘤相关抗原和活化T细胞标志物的人源化抗体，其显著特性为某些肿瘤和免疫疾病提供了新的治疗可能性。
