Harjunpää A, Junnikkala S, Meri S
Department of Bacteriology and Immunology, University and University Central Hospital of Helsinki, Finland.
Scand J Immunol. 2000 Jun;51(6):634-41. doi: 10.1046/j.1365-3083.2000.00745.x.
Rituximab (IDEC-C2B8, Mabthera(R)) is a chimeric (human-mouse) monoclonal antibody (MoAb) against the B-cell specific CD20-antigen. It has been used for the clinical treatment of non-Hodgkin's lymphomas, but variable clinical results suggest that some lymphoma cells remain resistant. In the present study we have evaluated the relative efficiencies of humoral and cell-mediated effector mechanisms complement-dependent cytotoxicity (CDC), antibody-(ADCC), complement-(CDCC) dependent cellular cytotoxicity and apoptosis on lymphoma cell killing by rituximab. Rituximab activated the cytolytic complement (C) cascade and induced a strong CDC, but the rituximab-triggered ADCC and CDCC were relatively ineffective. The CDC was strongly enhanced by antibodies against the C inhibitor CD59 (protectin). Neutralization of CD55 (DAF) and CD46 (MCP) had a similar but weaker effect. Rituximab also induced apoptosis but in a cell line-dependent fashion. The results strongly emphasize the role of direct CDC as the major, fast and efficient effector mechanism of rituximab. In the immunotherapeutic treatment of B-cell lymphomas, it is important to consider the role of C-regulatory proteins as an escape mechanism of the malignant cells. Our results suggest that the effect of rituximab therapy could be enhanced by combining it with neutralization of CD59.
利妥昔单抗（IDEC-C2B8，美罗华®）是一种针对B细胞特异性CD20抗原的嵌合（人-鼠）单克隆抗体（MoAb）。它已被用于非霍奇金淋巴瘤的临床治疗，但不同的临床结果表明，一些淋巴瘤细胞仍然具有抗性。在本研究中，我们评估了体液和细胞介导的效应机制——补体依赖的细胞毒性（CDC）、抗体依赖的细胞毒性（ADCC）、补体依赖的细胞毒性（CDCC）以及凋亡在利妥昔单抗杀伤淋巴瘤细胞方面的相对效率。利妥昔单抗激活了溶细胞补体（C）级联反应并诱导了强烈的CDC，但利妥昔单抗引发的ADCC和CDCC相对无效。抗C抑制剂CD59（保护素）的抗体强烈增强了CDC。对CD55（衰变加速因子，DAF）和CD46（膜辅蛋白，MCP）的中和作用具有类似但较弱的效果。利妥昔单抗还以细胞系依赖的方式诱导凋亡。结果强烈强调了直接CDC作为利妥昔单抗主要、快速且有效的效应机制的作用。在B细胞淋巴瘤的免疫治疗中，重要的是要考虑C调节蛋白作为恶性细胞逃逸机制的作用。我们的结果表明，将利妥昔单抗与CD59的中和作用相结合可增强其治疗效果。
