Press O W, Hansen J A, Farr A, Martin P J
Department of Medicine (Division of Oncology), University of Washington, Seattle 98195.
Cancer Res. 1988 Apr 15;48(8):2249-57.
Treatment of lymphoid malignancies with monoclonal antibodies (mAbs) and immunoconjugates is a promising new immunotherapeutic approach. However, few published studies have examined in detail the subcellular fate of antibodies following binding to lymphocyte cell surface antigens. In this study, we have investigated the disposition of monoclonal anti-CD3 antibody 64.1 following binding to normal and malignant T-lymphocytes by using cellular radioimmunoassays and immunoperoxidase and immunogold electron microscopy. Anti-CD3 mAbs were predominantly cleared from the cell membrane at 37 degrees C by receptor-mediated endocytosis, although passive shedding of antibody was also observed. Internalized antibody was sequentially transferred from coated pits to receptosomes and eventually to lysosomes. Intralysosomal degradation appeared to be the ultimate fate of internalized radiolabeled mAbs and was followed by exocytosis of free 125I to the culture medium. Ammonium chloride and monensin were potent inhibitors of lysosomal degradation of 125I-anti-CD3 mAbs and caused intracellular trapping of radiolabeled antibodies. The rapid endocytosis, degradation, and exocytosis of antibody observed in these studies elucidate the mechanism of the improved efficacy of anti-CD3 immunoconjugates when used in conjunction with inhibitors of lysosomal action.
用单克隆抗体（mAb）和免疫缀合物治疗淋巴样恶性肿瘤是一种很有前景的新型免疫治疗方法。然而，很少有已发表的研究详细考察抗体与淋巴细胞表面抗原结合后的亚细胞命运。在本研究中，我们通过细胞放射免疫分析以及免疫过氧化物酶和免疫金电子显微镜技术，研究了单克隆抗CD3抗体64.1与正常和恶性T淋巴细胞结合后的处置情况。抗CD3单克隆抗体在37℃时主要通过受体介导的内吞作用从细胞膜清除，不过也观察到了抗体的被动脱落。内化的抗体依次从有被小窝转移至受体小体，最终进入溶酶体。溶酶体内的降解似乎是内化的放射性标记单克隆抗体的最终归宿，随后游离的125I会通过胞吐作用释放到培养基中。氯化铵和莫能菌素是125I - 抗CD3单克隆抗体溶酶体降解的有效抑制剂，并导致放射性标记抗体在细胞内滞留。这些研究中观察到的抗体快速内吞、降解和胞吐作用，阐明了抗CD3免疫缀合物与溶酶体作用抑制剂联合使用时疗效提高的机制。
