表皮生长因子受体抑制剂
癌症研究
体内
医学
西妥昔单抗
克拉斯
癌症
表皮生长因子受体
药理学
信号转导
埃罗替尼
单克隆抗体
抗体
免疫学
生物
内科学
结直肠癌
生物技术
生物化学
作者
Kaijie He,Jianyan Xu,Jindong Liang,Jiahua Jiang,Mi Tang,Xin Ye,Lianshan Zhang,Lianshan Zhang,Beibei Fu,Yan Li,Chang Bai,Lianshan Zhang,Weikang Tao
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2019-04-08
卷期号:18 (6): 1104-1114
被引量:15
标识
DOI:10.1158/1535-7163.mct-18-0854
摘要
Abstract Although inhibiting EGFR-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the EGFR signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the EGFR functionality. Given the fact that overexpression of EGFR is commonly seen in many cancers, an EGFR-targeting antibody–drug conjugate (ADC) can selectively kill cancer cells independently of blocking EGFR-mediated signaling. Herein, we describe SHR-A1307, a novel anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged half-life, and conjugated with a proprietary toxin payload that has increased index of EGFR targeting–dependent versus EGFR targeting–independent cytotoxicity. SHR-A1307 demonstrated strong and sustained antitumor activities in EGFR-positive tumors harboring different oncogenic mutations on EGFR, KRAS, or PIK3CA. Antitumor efficacy of SHR-A1307 correlated with EGFR expression levels in vitro and in vivo, regardless of the mutation status of EGFR signaling mediators and a resultant resistance to EGFR signaling inhibitors. Cynomolgus monkey toxicology study showed that SHR-A1307 is well tolerated with a wide therapeutic index. SHR-A1307 is a promising therapeutic option for EGFR-expressing cancers, including those resistant or refractory to the EGFR pathway inhibitors.
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