Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody selected for improved engagement of FcγRIIIA/CD16
Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody selected for improved engagement of FcγRIIIA/CD16
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DOI：
10.1111/j.1365-2141.2007.06974.x
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发表时间：
2008-03-01
影响因子：
6.5
通讯作者：
Merle-Beral, Helene
中科院分区：
文献类型：
--
作者：
de Romeuf, Christophe;Dutertre, Charles-Antoine;Merle-Beral, Helene
氟达拉滨、环磷酰胺和利妥昔单抗联合治疗慢性淋巴细胞白血病(CLL)的有效率很高。然而，在利妥昔单抗治疗后只观察到很差的反应。化学免疫疗法的使用通常与血液学和感染性并发症有关。因此，具有更强的杀伤CLL细胞能力的抗体可以导致对抗体单一治疗的更好的临床反应，以及在化学免疫治疗期间降低药物剂量的可能性。我们制备了一株低岩藻糖含量的嵌合抗CD20单抗EMAb-6。EMAb-6的细胞凋亡和补体活性与利妥昔单抗相似。相反，EMAb-6单抗表现出更好的Fcγ受体IIIA(Fc Gamma RIIIA)/CD16结合和Fc Gamma RIIIA依赖的效应功能。在低和最高饱和浓度的CLL细胞存在的情况下，它在体外诱导了更高的抗体依赖的细胞对CLL细胞的杀伤作用，并诱导Fc-Gamma RIIIA(+)Jurkat细胞产生更高的Fc-Gamma RIIIA(+)IL-2。CLL与包被EMAb-6或利妥昔单抗的淋巴瘤细胞的比较研究表明，低剂量和靶细胞表达较少CD20分子时，疗效差异更为明显。因此，EMAb-6单抗对低表达CD20的肿瘤细胞具有很强的细胞毒作用，有望成为治疗慢性淋巴细胞性白血病的候选药物。
Patients with chronic lymphocytic leukaemia (CLL) treated with a combination of fludarabine, cyclophosphamide and rituximab show a high response rate. However, only a poor response is observed following rituximab monotherapy. The use of chemo-immunotherapy is often associated with haematological and infectious complications. Thus, an antibody with an enhanced ability to kill CLL cells could lead to better clinical responses to antibody monotherapy and the possibility of lowering drug doses during chemo-immunotherapy. We generated a chimeric anti-CD20 monoclonal antibody (mAb), EMAB-6, which has a low fucose content. Apoptosis and complement activities for EMAB-6 were similar to those seen for rituximab. By contrast, EMAB-6 mAb showed improved Fc gamma receptor IIIA (Fc gamma RIIIA)/CD16 binding and Fc gamma RIIIA-dependent effector functions. It induced a higher in vitro antibody-dependent cellular cytotoxicity against CLL cells and a higher Fc gamma RIIIA-mediated interleukin-2 production by Fc gamma RIIIA(+) Jurkat cells in the presence of CLL cells at both low and maximally saturating concentrations. Comparative studies between CLL and lymphoma cells coated with EMAB-6 or rituximab indicated that the difference of efficacy was more pronounced at low doses and when target cells expressed fewer CD20 molecules. Thus, EMAB-6 mAb represents a promising drug candidate for the treatment of CLL by inducing a strong cytotoxicity against tumour cells that express low CD20 levels.