Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain.
Mol Cancer. 2010 Jun 7;9:139. doi: 10.1186/1476-4598-9-139.
Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), increases survival in patients with advanced EGFR-positive non-small cell lung cancer when administrated in combination with chemotherapy. In this study, we investigated the role of complement activation in the antitumor mechanism of this therapeutic drug.
EGFR-expressing lung cancer cell lines were able to bind cetuximab and initiate complement activation by the classical pathway, irrespective of the mutational status of EGFR. This activation led to deposition of complement components and increase in complement-mediated cell death. The influence of complement activation on the activity of cetuximab in vivo was evaluated in xenografts of A549 lung cancer cells on nude mice. A549 cells express wild-type EGFR and have a KRAS mutation. Cetuximab activity against A549 xenografts was highly dependent on complement activation, since complement depletion completely abrogated the antitumor efficacy of cetuximab. Moreover, cetuximab activity was significantly higher on A549 cells in which a complement inhibitor, factor H, was genetically downregulated.
We demonstrate for the first time that the in vivo antitumor activity of cetuximab can be associated with a complement-mediated immune response. These results may have important implications for the development of new cetuximab-based therapeutic strategies and for the identification of markers that predict clinical response.
西妥昔单抗是一种针对表皮生长因子受体（EGFR）的抗体，当与化疗联合用于治疗 EGFR 阳性的晚期非小细胞肺癌患者时，可提高患者的生存率。在这项研究中，我们研究了补体激活在这种治疗药物的抗肿瘤机制中的作用。
表达 EGFR 的肺癌细胞系能够结合西妥昔单抗并通过经典途径启动补体激活，而与 EGFR 的突变状态无关。这种激活导致补体成分的沉积和补体介导的细胞死亡增加。在裸鼠的 A549 肺癌细胞异种移植模型中评估了补体激活对西妥昔单抗体内活性的影响。A549 细胞表达野生型 EGFR 并具有 KRAS 突变。西妥昔单抗对 A549 异种移植物的活性高度依赖于补体激活，因为补体耗竭完全阻断了西妥昔单抗的抗肿瘤疗效。此外，在遗传下调补体抑制剂因子 H 的 A549 细胞中，西妥昔单抗的活性显著更高。
我们首次证明，西妥昔单抗的体内抗肿瘤活性可能与补体介导的免疫反应有关。这些结果可能对开发新的西妥昔单抗治疗策略和识别预测临床反应的标志物具有重要意义。
