Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy
Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy
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DOI：
10.4049/jimmunol.173.7.4699
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Parren, PWHI
中科院分区：
文献类型：
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作者：
Bleeker, WK;van Bueren, JJL;Parren, PWHI
表皮生长因子受体（EGF-R）过表达在大量实体瘤中很常见，是一种不良预后指标。EGF-R的过度表达与肿瘤密切相关，这种酪氨酸激酶型受体被认为是Ab治疗的一个有吸引力的靶点。在这项研究中，我们描述了mAb 2F8的评估，mAb 2F8是一种针对EGF-R的高亲和力人单抗（IgG1kappa），使用人Ig转基因小鼠开发。mAb 2F8有效阻断EGF和tgf - α与EGF- r的结合。在饱和浓度下，2F8完全阻断EGF-R信号通路，抑制过表达EGF-R的A431细胞的体外增殖。在低受体占用的低浓度下，2F8在体外诱导了高效的抗体依赖性细胞介导的细胞毒性（ADCC）。体内研究表明，A431异种肿瘤移植模型在胸腺小鼠体内具有较强的抗肿瘤作用。体外分析2f8治疗小鼠肿瘤异种移植物中EGF-R的状态，发现有两种治疗机制。首先，阻断EGF-R信号，这在受体完全饱和时最有效，因此需要相对较高的Ab剂量。其次，在2F8受体占用率非常低的情况下，我们在小鼠中观察到有效的抗肿瘤作用，这可能是基于免疫效应机制的参与，特别是ADCC。综上所述，我们的研究结果表明，ADCC是这种抗体的重要效应机制，在相对低的剂量下有效。
Epidermal growth factor receptor (EGF-R) overexpression is common in a large number of solid tumors and represents a negative prognostic, indicator. Overexpression of EGF-R is strongly tumor associated, and this tyrosine kinase type receptor is considered an attractive target for Ab therapy. In this study, we describe the evaluation of mAb 2F8, a high avidity human mAb (IgG1kappa) directed against EGF-R, developed using human Ig transgenic mice. mAb 2F8 effectively blocked binding of EGF and TGF-alpha to the EGF-R. At saturating concentrations, 2F8 completely blocked EGF-R signaling and inhibited the in vitro proliferation of EGF-R-overexpressing A431 cells. At much lower concentrations, associated with low receptor occupancy, 2F8 induced efficient Ab-dependent cell-mediated cytotoxicity (ADCC) in vitro. In vivo studies showed potent antitumor effects in models with A431 tumor xenografts in athymic mice. Ex vivo analysis of the EGF-R status in tumor xenografts in 2F8-treated mice revealed that there are two therapeutic mechanisms. First, blocking of EGF-R signaling, which is most effective at complete receptor saturation and therefore requires a relatively high Ab dose. Second, at very low 2F8 receptor occupancy, we observed potent antitumor effects in mice, which are likely based on the engagement of immune effector mechanisms, in particular ADCC. Taken together, our findings indicate that ADCC represents an important effector mechanism of this Ab, which is effective at relatively low dose.