Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Sci Rep. 2022 Jul 7;12(1):11561. doi: 10.1038/s41598-022-15838-8.
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), including cetuximab and panitumumab, have been used in clinic settings to treat cancer. They have also recently been applied to antibody-drug conjugates (ADCs); however, their clinical efficacy is limited by several issues, including lower internalization efficiency. The binding of cetuximab to the extracellular domain of EGFR suppresses ligand-induced events; therefore, we focus on ligand-independent non-canonical EGFR endocytosis for the delivery of ADCs into cells. Tumor necrosis factor-α (TNF-α) strongly induces the endocytosis of the cetuximab-EGFR complex within 15 min via the p38 phosphorylation of EGFR in a tyrosine kinase-independent manner. A secondary antibody conjugated with saporin, a ribosome-inactivating protein, also undergoes internalization with the complex and enhances its anti-proliferative activity. Anti-cancer agents, including cisplatin and temozolomide, also induce the p38-mediated internalization. The results of the present study demonstrate that synchronous non-canonical EGFR endocytosis may be a feasible strategy for promoting the therapeutic efficacy of EGFR-targeting ADCs in clinical settings.
针对表皮生长因子受体（EGFR）的单克隆抗体，包括西妥昔单抗和帕尼单抗，已在临床环境中用于治疗癌症。它们最近也被应用于抗体药物偶联物（ADC）；然而，它们的临床疗效受到几个问题的限制，包括内化效率较低。西妥昔单抗与 EGFR 的细胞外结构域结合，抑制配体诱导的事件；因此，我们专注于配体非依赖性非典型 EGFR 内吞作用，以将 ADC 递送到细胞内。肿瘤坏死因子-α（TNF-α）通过 EGFR 的 p38 磷酸化，以非酪氨酸激酶依赖性方式在 15 分钟内强烈诱导西妥昔单抗-EGFR 复合物的内吞作用。与复合物一起内化的、与次级抗体偶联的丝裂原蛋白，也增强了其抗增殖活性。包括顺铂和替莫唑胺在内的抗癌药物也诱导 p38 介导的内化。本研究的结果表明，同步的非典型 EGFR 内吞作用可能是一种可行的策略，可促进临床环境中针对 EGFR 的 ADC 的治疗效果。
