The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma
The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma
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DOI：
10.1038/sj.leu.2404415
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发表时间：
2006-12-01
期刊：
影响因子：
11.4
通讯作者：
Ueda, R.
中科院分区：
文献类型：
--
作者：
Ishida, T.;Ishii, T.;Ueda, R.
在这里，我们报告一些霍奇金淋巴瘤 (HL) 患者 (23.8%) 的肿瘤细胞呈 CC 趋化因子受体 4 (CCR4) 阳性。因此，我们测试了嵌合抗 CCR4 单克隆抗体 (mAb) KM2760，其 Fc 区被去岩藻糖基化以增强抗体依赖性细胞毒性 (ADCC)，作为难治性 HL 的新型免疫疗法。 KM2760 在治疗环境中的 CCR4 阳性 HL 小鼠模型中表现出有希望的抗肿瘤活性。尽管 KM2760 不会诱导小鼠自然杀伤 (NK) 细胞介导的任何 ADCC，但它在体外显着增强小鼠单核细胞/巨噬细胞介导的针对 CCR4 阳性 HL 细胞系的吞噬作用。连同 KM2760 在体外没有表现出任何补体依赖性细胞毒性或直接抗增殖活性的发现一起，这些数据表明 KM2760 通过小鼠中的单核细胞/巨噬细胞发挥其强大的体内抗肿瘤活性。在人体系统中，KM2760 增强单核细胞/巨噬细胞介导的吞噬活性。此外，它在体外诱导了由 NK 细胞介导的针对 CCR4 阳性 HL 细胞系的强大 ADCC。因此，可以想象，KM2760 在人类中比在小鼠中具有更有效的抗肿瘤活性。总的来说，这项研究强烈表明抗 CCR4 mAb 可能成为 CCR4 阳性 HL 患者的一种新型治疗方式。
Here, we report that tumor cells from some patients (23.8%) with Hodgkin lymphoma (HL) are positive for CC chemokine receptor 4 (CCR4). We therefore tested the chimeric anti-CCR4 monoclonal antibody (mAb), KM2760, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity (ADCC), as a novel immunotherapy for refractory HL. KM2760 demonstrated a promising antitumor activity in the CCR4-positive HL-bearing mouse model in the therapeutic setting. Although KM2760 did not induce any ADCC mediated by mouse natural killer (NK) cells, it significantly enhanced phagocytosis mediated by mouse monocytes/macrophages against the CCR4-positive HL cell line in vitro. Together with the findings that KM2760 did not exhibit any complement-dependent cytotoxicity or direct antiproliferation activity in vitro, these data indicated that KM2760 exerted its robust in vivo antitumor activity via monocytes/macrophages in mice. In the human system, KM2760 enhanced phagocytic activity mediated by monocytes/macrophages. Furthermore, it induced robust ADCC mediated by NK cells against the CCR4-positive HL cell line in vitro. Thus, it is conceivable that KM2760 would have much more potent antitumor activity in humans than in mice. Collectively, this study strongly indicates that anti-CCR4 mAb could be a novel treatment modality for patients with CCR4-positive HL.