Defucosylated anti-CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: A novel immunotherapy for aggressive/refractory mycosis fungoides and Sezary syndrome
Defucosylated anti-CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: A novel immunotherapy for aggressive/refractory mycosis fungoides and Sezary syndrome
复制标题
DOI：
10.1158/1078-0432.ccr-07-1324
复制
发表时间：
2007-11-01
影响因子：
11.5
通讯作者：
Ueda, Ryuzo
中科院分区：
文献类型：
--
作者：
Yano, Hiroki;Ishida, Takashi;Ueda, Ryuzo
目的：晚期塞扎里综合征 (SS) 和蕈样肉芽肿 (MF) 预后不佳。由于 CC 趋化因子受体 4 (CCR4) 在 MF/SS 细胞的皮肤归巢能力中具有重要作用，因此我们推测抗 CCR4 单克隆抗体 (mAb) 可能代表一种针对侵袭性/难治性 MF/SS 的新型治疗剂。 实验设计：去岩藻糖基化的下一代治疗性 mAb KM2760 诱导增强的抗体依赖性细胞毒性 (ADCC)。在此，我们在体外和体内动物模型中评估了该抗体针对侵袭性 MF/SS 肿瘤细胞的治疗潜力。结果：KM2760 通过健康对照的外周血单核细胞 (PBMC) 诱导针对 MF/SS 细胞系以及侵袭性 MF/SS 患者的原发性肿瘤细胞的强大 ADCC。 KM2760 在播散性和非播散性 MF/SS 小鼠模型中也显示出显着的抗肿瘤活性。此外，在 KM2760 诱导的由患者 PBMC 介导的 ADCC 体外检测中，仅 4 小时后就有大约 30% 的自体 MF/SS 肿瘤细胞被杀死，尽管这些 PBMC 中存在的自然杀伤细胞数量很少。还表明，去岩藻糖基化治疗性单克隆抗体诱导的 ADCC 可以通过免疫调节细胞因子白细胞介素 12、IFN-α-2b 和 IFN-γ 大大增强。 结论：本研究鼓励我们在 CCR 4 阳性 T 细胞淋巴瘤（包括侵袭性 MF/SS）患者中进行完全去岩藻糖基化抗 CCR4 mAb 的 I 期临床试验 (ClinicalTrials.gov)标识符：NCT00355472）。在不久的将来，针对侵袭性/难治性 MF/SS 的去岩藻糖基化抗 CCR4 mAb 单药治疗以及与免疫调节细胞因子联合治疗的疗效都将在临床上得到证实。
Purpose: Sezary syndrome (SS) and Mycosis fungoides (MF) in the advanced stage have dismal prognoses. Because CC chemokine receptor 4 (CCR4) has an important role in the skin-homing capacity of MF/SS cells, we postulated that anti-CCR4 monoclonal antibody (mAb) could represent a novel therapeutic agent against aggressive/refractory MF/SS.Experimental Design: The defucosylated next-generation therapeutic mAb KM2760 induces enhanced antibody-dependent cellular cytotoxicity (ADCC). Here, we assessed the therapeutic potential of this antibody against aggressive MF/SS tumor cells in vitro and in animal models in vivo.Results: KM2760 induced robust ADCC by peripheral blood mononuclear cell (PBMC) from healthy controls against a MF/SS cell line as well as against primary tumor cells from patients with aggressive MF/SS. KM2760 also showed significant antitumor activity in disseminated and nondisseminated MF/SS mouse models. In addition, similar to 30% of autologous MF/SS tumor cells were killed in in vitro assays of KM2760-induced ADCC mediated by patients' PBMC after only 4 h, despite the low numbers of natural killer cells present in these PBMCs. It is also shown that ADCC induced by defucosylated therapeutic mAb can be greatly augmented by the immunomodulatory cytokines interleukin-12, IFN-alpha-2b, and IFN-gamma.Conclusions: The present study has encouraged us in the conducting of a phase I clinical trial of a completely defucosylated anti-CCR4 mAb in patients with CCR 4-positive T-cell lymphomas, including aggressive MF/SS (ClinicalTrials.gov identifier: NCT00355472). In the near future, the efficacy not only of defucosylated anti-CCR4 mAb single-agent treatment but also of combination therapy with immunomodulatory cytokines will be clinically established to target aggressive/refractory MF/SS.