Key Laboratory of Biomedical Engineering of Fujian Province, Department of Biomaterials, College of Materials, Xiamen University, Xiamen, 361005, China.
Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China.
ACS Chem Biol. 2021 Apr 16;16(4):724-730. doi: 10.1021/acschembio.1c00022. Epub 2021 Apr 8.
While Cetuximab can be used to treat KRAS wild-type colon cancer cells by targeting EGFR and inhibiting the activation of downstream signaling pathways, it exhibits little therapeutic effect on KRAS mutant colon cancer cells. Natural killer (NK) cells are a class of powerful immune cells with anticancer activities. However, NK cells typically lack inherent tumor targeting abilities. Here, a new method is established to bestow NK-92 cells with tumor targeting abilities by installing cetuximab on the cell surface. Through metabolic glycoengineering, azide groups were introduced onto the surface of NK-92 cells. Bioorthogonal strain promoted the azide-alkyne cycloaddition click reaction of engineered NK-92 cells with alkyne modified cetuximab functionalized NK cells with the antibody. The resulting NK-92 cells were significantly more effective than the parent NK-92 cells in protecting against tumor development in a KRAS mutant mouse tumor model resistant to cetuximab treatment. Thus, NK cell functionalization with antibodies enabled by metabolic glycoengineering is a promising strategy to enhance anticancer immune therapy.
西妥昔单抗可以通过靶向 EGFR 并抑制下游信号通路的激活来治疗 KRAS 野生型结肠癌细胞，但对 KRAS 突变型结肠癌细胞几乎没有治疗作用。自然杀伤 (NK) 细胞是一类具有抗癌活性的强大免疫细胞。然而，NK 细胞通常缺乏内在的肿瘤靶向能力。在这里，通过在细胞表面安装西妥昔单抗，建立了一种赋予 NK-92 细胞肿瘤靶向能力的新方法。通过代谢糖基工程，在 NK-92 细胞表面引入叠氮基团。生物正交应变促进了工程化的 NK-92 细胞与炔基修饰的西妥昔单抗的点击反应，将抗体功能化的 NK 细胞与西妥昔单抗功能化的 NK 细胞结合。与亲本 NK-92 细胞相比，在对西妥昔单抗治疗耐药的 KRAS 突变型小鼠肿瘤模型中，这种 NK-92 细胞在抵抗肿瘤发展方面的效果显著增强。因此，通过代谢糖基工程实现的 NK 细胞抗体功能化是增强抗癌免疫治疗的一种很有前途的策略。
