Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer
Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer
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DOI：
10.3892/ol.2017.7556
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发表时间：
2018-02-01
期刊：
影响因子：
2.9
通讯作者：
Kono, Koji
中科院分区：
文献类型：
--
作者：
Nakajima, Takahiro;Okayama, Hirokazu;Kono, Koji
用某些方法增强抗体依赖的细胞毒性(ADCC)可能是提高治疗性单抗(MAbs)疗效的一种有前途的方法。以前已经证明，从抗体寡糖(脱糖基)中去除岩藻糖会导致ADCC活性增强。为了建立这一程序的临床相关证据，本研究通过使用外周血单核细胞(PBMC)比较脱糖单抗和常规单抗来评价曲妥珠单抗和西妥昔单抗介导的ADCC。从20例胃肠道肿瘤患者和10例健康志愿者中分离出PBMCs。以PBMCs为效应细胞，两株胃癌细胞为靶细胞，测定ADCC。与使用来自健康供者和癌症患者的PBMC的常规单抗相比，脱糖单抗显著增强了ADCC。结果证实，与早期疾病或健康人相比，晚期疾病患者西妥昔单抗和曲妥珠单抗介导的ADCCs受损。而当用脱糖单抗代替常规单抗时，晚期患者的ADCC活性几乎与早期疾病或健康人相当。此外，在体外用丝裂原活化蛋白激酶抑制剂将ADCC相关分子的表达修饰为免疫抑制状态，传统的西妥昔单抗和曲妥珠单抗介导的ADCC表达下调，脱糖单抗克服了ADCC的下调。综上所述，脱糖治疗性单抗可以增强癌症患者的ADCC活性，从而可能导致更有效的抗癌治疗。
Enhancement of antibody-dependent cellular cytotoxicity (ADCC) with some modalities may be a promising approach to enhance the efficacy of therapeutic monoclonal antibodies (mAbs). It has previously been demonstrated that the removal of fucose from antibody oligosaccharides (defucosylation) leads to augmentation of ADCC activity. To establish clinically relevant evidence of this procedure, the present study evaluated trastuzumab- and cetuximab-mediated ADCC by comparing defucosylated mAbs with conventional mAbs using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 20 patients with gastrointestinal tract cancer and 10 healthy volunteers. ADCCs were measured using PBMCs as effector cells and two gastric cancer cell lines as target cells. ADCCs were significantly enhanced with defucosylated mAbs compared with conventional mAbs using PBMC from the healthy donors and patients with cancer. The results confirmed that the cetuximab- and trastuzumab-mediated ADCCs in advanced disease were impaired in comparison to those in early disease or healthy individuals. However, when the defucosylated mAbs were used instead of the conventional mAbs, the ADCC activities in the advanced cases were almost comparable with those in early disease or healthy individuals. Furthermore, the expression of ADCC associated molecules were modified toward immunosuppressive status with a mitogen-activated protein kinase inhibitor in vitro, the conventional cetuximab- and trastuzumab-mediated ADCC was downregulated, and the defucosylated mAbs overcome the downregulation of ADCC. In conclusion, defucosylated therapeutic mAbs may enhance ADCC activities in patients with cancer, which may lead to more effective anti-cancer treatments.