Christiaansen J E, Burnside S S, Sears D W
J Immunol. 1987 Apr 1;138(7):2236-43.
Although monoclonal antibodies (mAb) can elicit potent ADCC by human K lymphocytes, different mAb, even of the same antibody subclass or even of the same target antigen specificity, vary considerably as to their efficiency in eliciting ADCC. The extensive variability in ADCC efficiencies of murine IgG2a mAb is analyzed here. In cold-target inhibition experiments it was found that only cells coated with "ADCC-efficient" IgG2a mAb, and not "ADCC-inefficient" IgG2a mAb, inhibit K effector cell lysis of radiolabeled target cells by ADCC. This result indicates that the spatial orientation of the antibodies on the target cell membrane influences the net efficiency of ADCC reactions by affecting the efficiency of interaction between antibody and the Fc receptors (FcR) of K cells. It is proposed that a "favorable" orientation of antibodies on the target cell membrane is required for efficient ADCC reactions. This proposal is directly supported by the observation that one IgG2a mAb (20.8.4), which cross-reacts with several different H-2 alloantigens, was found to elicit efficient ADCC only when bound to certain of its possible target cell antigens. It was also observed in these studies that the organization of antibodies on a target cell membrane influences the net efficiency of ADCC reactions. It is proposed that a "favorable" antibody organization on the target cell membrane is also required for efficient ADCC reactions. This proposal is supported by the observation that certain antihuman beta 2m (anti-Hu beta 2m) IgG2a mAb, which elicit efficient ADCC lysis of human target cells, fail to elicit the lysis of murine cells having Hu beta 2m molecules coupled randomly to their external membrane surfaces. The differences in the way the Hu beta 2m was organized on the surfaces of the human cells and the murine-Hu beta 2m cell conjugates presumably caused differences in the way the bound antibodies were organized on the cell surfaces, which in turn resulted in the ADCC efficiency differences observed for the same mAb with the different target cell types. Because ADCC reactions appear to be sensitive to both the orientation and the organization of cell surface-bound antibodies, certain types of structural alterations or variations in the membrane molecules (relative to other neighboring structures on the target cell membrane) are potentially detectable by quantitative differences or variations in ADCC reactions.
尽管单克隆抗体（mAb）可通过人K淋巴细胞引发强效的抗体依赖的细胞介导的细胞毒性作用（ADCC），但不同的单克隆抗体，即使属于同一抗体亚类，甚至针对相同的靶抗原具有特异性，其引发ADCC的效率也存在很大差异。本文分析了鼠源IgG2a单克隆抗体在ADCC效率方面的广泛变异性。在冷靶抑制实验中发现，只有被“ADCC高效”的IgG2a单克隆抗体包被的细胞，而非“ADCC低效”的IgG2a单克隆抗体包被的细胞，才能通过ADCC抑制K效应细胞对放射性标记靶细胞的裂解。这一结果表明，靶细胞膜上抗体的空间取向通过影响抗体与K细胞的Fc受体（FcR）之间的相互作用效率，进而影响ADCC反应的净效率。有人提出，靶细胞膜上抗体的“有利”取向是高效ADCC反应所必需的。这一观点直接得到以下观察结果的支持：一种与几种不同的H-2同种异体抗原发生交叉反应的IgG2a单克隆抗体（20.8.4），只有在与某些可能的靶细胞抗原结合时才能引发高效的ADCC。在这些研究中还观察到，靶细胞膜上抗体的组织方式会影响ADCC反应的净效率。有人提出，靶细胞膜上“有利”的抗体组织方式也是高效ADCC反应所必需的。这一观点得到以下观察结果的支持：某些抗人β2微球蛋白（抗Huβ2m）IgG2a单克隆抗体，可引发对人靶细胞的高效ADCC裂解，但却无法引发对其外膜表面随机偶联有Huβ2m分子的鼠细胞的裂解。人细胞表面和鼠-Huβ2m细胞偶联物表面上Huβ2m组织方式的差异，可能导致结合抗体在细胞表面的组织方式不同，进而导致同一单克隆抗体对不同靶细胞类型观察到的ADCC效率差异。由于ADCC反应似乎对细胞表面结合抗体的取向和组织方式都很敏感，因此膜分子的某些类型的结构改变或变化（相对于靶细胞膜上的其他相邻结构）可能通过ADCC反应中的定量差异或变化而被检测到。
