INSERM, UMR-S 945, AP-HP, Hôpital Pitié-Salpêtrière, Service d'Hématologie Biologique, Paris, France.
Leukemia. 2011 Jan;25(1):101-9. doi: 10.1038/leu.2010.240. Epub 2010 Oct 26.
Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FcγRIIIA) is well preserved in CD16(+)CD56(dim) cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FcγRIIIA-optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti-CD20 mAbs optimized for FcγR engagement in CLL patients.
尽管抗 CD20 单克隆抗体（mAb）在治疗慢性淋巴细胞白血病（CLL）方面显示出良好的前景，但抗 CD20 mAb 利妥昔单抗在 CLL 治疗中的成功是有限的。最近，人们设计了具有更强细胞毒性的新型抗 CD20 mAb，但到目前为止，这些 mAb 大多仅在来自健康供体的自然杀伤（NK）细胞的体外进行了测试。由于尚不清楚这些优化的细胞毒性 mAb 是否会改善 CLL 患者 NK 细胞对肿瘤细胞的杀伤作用，我们详细地描述了 CLL 患者 NK 细胞的相关表型和功能特征。这些患者的 CD16(+)CD56(dim)细胞毒性 NK 细胞中，抑制性和激活性 NK 细胞受体以及 Fc 受体 IIIA（FcγRIIIA）的表达得到了很好的保留，这与疾病进展无关。这些细胞在细胞因子刺激后具有完全的功能。此外，与利妥昔单抗相比，FcγRIIIA 优化的 LFB-R603 抗 CD20 mAb 介导的来自 CLL 患者和健康供体的 NK 细胞的抗体依赖性细胞介导的细胞毒性作用要强 100 倍。与利妥昔单抗相比，LFB-R603 在较低浓度下就观察到对自体 B-CLL 细胞的脱颗粒增强，而与 CLL 的预后因素无关。这些发现有力地证明了在 CLL 患者中进一步开发针对 FcγR 结合的抗 CD20 mAb 的合理性。
