Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
复制标题
DOI：
10.1038/s41587-019-0073-7
复制
发表时间：
2019-05-01
影响因子：
46.9
通讯作者：
Ward, E. Sally
中科院分区：
文献类型：
--
作者：
Kang, Jeffrey C.;Sun, Wei;Ward, E. Sally
我们通过相对于近中性pH在酸性内体pH下大幅降低其对HER 2的亲和力来提高含有人表皮生长因子受体2（HER 2）特异性抗体帕妥珠单抗的抗体-药物缀合物（ADC）的效力。这些工程化帕妥珠单抗变体显示出增加的溶酶体递送和对表达中间HER 2水平的肿瘤细胞的细胞毒性。在小鼠的HER 2（int）异种移植肿瘤模型中，变体显示出比母体ADC和临床批准的HER 2特异性ADC更高的治疗功效。
We improve the potency of antibody-drug conjugates (ADCs) containing the human epidermal growth factor receptor 2 (HER2)-specific antibody pertuzumab by substantially reducing their affinity for HER2 at acidic endosomal pH relative to near neutral pH. These engineered pertuzumab variants show increased lysosomal delivery and cytotoxicity towards tumor cells expressing intermediate HER2 levels. In HER2(int) xenograft tumor models in mice, the variants show higher therapeutic efficacy than the parent ADC and a clinically approved HER2-specific ADC.