Excellent effects and possible mechanisms of action of a new antibody–drug conjugate against EGFR-positive triple-negative breast cancer

作     者：Dan-Dan Zhou Wei-Qi Bai Xiao-Tian Zhai Li-Ping Sun Yong-Su Zhen Zhuo-Rong Li Qing-Fang Miao Dan?Dan Zhou;Wei?Qi Bai;Xiao?Tian Zhai;Li?Ping Sun;Yong?Su Zhen;Zhuo?Rong Li;Qing?Fang Miao

作者机构：NHC Key Laboratory of Biotechnology of AntibioticsInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeNo.1 Tiantan XilBeijing 100050China Department of Organic ChemistryInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeNo.1 Tiantan XiliBeijing 100050China 

出 版 物：《Military Medical Research》 (军事医学研究（英文版）)

年 卷 期：2022年第9卷第4期

页      面：419-431页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-1-I2M-026) the Beijing Natural Science Foundation(7202133) the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2021-RW350-002) 

主　　题：Triple-negative breast cancer Epidermal growth factor receptor Antibody–drug conjugate Targeted therapy Antitumor effect 

摘      要：Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast *** is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted *** growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in ***004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our *** study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor ***:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by *** gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western ***-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony *** migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion *** cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in ***,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 *** they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,*** sizes and the body weights of mice were measured every 4 *** effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed