Kol Arjan, Terwisscha van Scheltinga Anton, Pool Martin, Gerdes Christian, de Vries Elisabeth, de Jong Steven
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Oncotarget. 2017 Jul 11;8(28):45432-45446. doi: 10.18632/oncotarget.17139.
Imgatuzumab is a novel glycoengineered anti-epidermal growth factor receptor (EGFR) monoclonal antibody optimized to induce both antibody-dependent cellular cytotoxicity (ADCC) and EGFR signal transduction inhibition. We investigated anti-EGFR monoclonal antibodies imgatuzumab and cetuximab-induced internalization and membranous turnover of EGFR, and whether this affected imgatuzumab-mediated ADCC responses and growth inhibition of non-small cell lung cancer (NSCLC) cells.In a panel of wild-type EGFR expressing human NSCLC cell lines, membranous and total EGFR levels were downregulated more effectively by imgatuzumab when compared with cetuximab. Imgatuzumab plus cetuximab enhanced EGFR internalization and reduced membranous turnover of EGFR, resulting in an even stronger downregulation of EGFR. Immunofluorescent analysis showed that combined treatment increased clustering of receptor-antibody complexes and directed internalized EGFR to lysosomes. The antibody combination potently inhibited intracellular signaling and epidermal growth factor (EGF)-dependent cell proliferation. More importantly, robust EGFR downregulation after 72 hours with the antibody combination did not impair ADCC responses.In conclusion, imgatuzumab plus cetuximab leads to a strong downregulation of EGFR and superior cell growth inhibition in vitro without affecting antibody-induced ADCC responses. These findings support further clinical exploration of the antibody combination in EGFR wild-type NSCLC.
因加图单抗是一种新型的糖基工程化抗表皮生长因子受体（EGFR）单克隆抗体，经优化可诱导抗体依赖性细胞毒性（ADCC）和抑制EGFR信号转导。我们研究了抗EGFR单克隆抗体因加图单抗和西妥昔单抗诱导的EGFR内化和膜周转，以及这是否会影响因加图单抗介导的ADCC反应和非小细胞肺癌（NSCLC）细胞的生长抑制。在一组表达野生型EGFR的人NSCLC细胞系中，与西妥昔单抗相比，因加图单抗能更有效地下调膜和总EGFR水平。因加图单抗加西妥昔单抗可增强EGFR内化并减少EGFR的膜周转，从而导致EGFR更强的下调。免疫荧光分析表明，联合治疗增加了受体-抗体复合物的聚集，并将内化的EGFR导向溶酶体。抗体组合有效抑制细胞内信号传导和表皮生长因子（EGF）依赖性细胞增殖。更重要的是，抗体组合在72小时后对EGFR的强烈下调并未损害ADCC反应。总之，因加图单抗加西妥昔单抗可导致EGFR在体外强烈下调并具有卓越的细胞生长抑制作用，而不影响抗体诱导的ADCC反应。这些发现支持在EGFR野生型NSCLC中进一步对该抗体组合进行临床探索。
