Mongini P K, Liu Q, Vilensky M A, Highet P F, Inman J K
Department of Rheumatology, Hospital for Joint Diseases, New York, NY; the Department of Pathology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, NY, USA.
Blood. 1998 Nov 15;92(10):3756-71.
The influence of ligand:receptor affinity on B-cell antigen receptor (BCR)-induced apoptosis in the IgM+ Burkitt lymphoma line, Ramos, was evaluated with a group of affinity-diverse murine monoclonal antibodies (MoAbs) specific for human B-cell IgM. The studies showed not only a minimal affinity threshold for the induction of apoptosis, but, interestingly, also a maximal affinity threshold above which increases in affinity were associated with diminished apoptosis. The lesser capacity of high-affinity MoAb to induce apoptosis was paralleled by a lesser capacity to induce receptor cross-linking. At high ligand concentration, high MoAb affinity was also associated with a diminished capacity to induce early protein tyrosine phosphorylation. The compromised capacity of two high-affinity MoAbs to trigger apoptosis may be, at least in part, explained by two separate phenomena that can impair the formation of mIgM cross-links: (1) more stable univalent binding and (2) a tendency for monogamous binding of both MoAb Fab to two Fab epitopes on mIgM. These in vitro studies suggest that the use of the highest affinity MoAbs for antireceptor immunotherapies that depend on receptor cross-linking might, on occasion, be contraindicated.
利用一组对人B细胞IgM具有不同亲和力的鼠单克隆抗体（MoAb），评估了配体与受体亲和力对IgM⁺伯基特淋巴瘤细胞系Ramos中B细胞抗原受体（BCR）诱导的细胞凋亡的影响。研究不仅显示了诱导细胞凋亡的最小亲和力阈值，而且有趣的是，还显示了最大亲和力阈值，超过该阈值，亲和力增加与细胞凋亡减少相关。高亲和力MoAb诱导细胞凋亡的能力较弱，同时诱导受体交联的能力也较弱。在高配体浓度下，高MoAb亲和力还与诱导早期蛋白酪氨酸磷酸化的能力降低有关。两种高亲和力MoAb触发细胞凋亡的能力受损，至少部分可以由两种单独的现象来解释，这两种现象会损害mIgM交联的形成：（1）更稳定的单价结合和（2）MoAb的两个Fab片段与mIgM上的两个Fab表位进行一夫一妻制结合的倾向。这些体外研究表明，对于依赖受体交联的抗受体免疫疗法，使用最高亲和力的MoAb有时可能是禁忌的。
