抗体-药物偶联物
药品
癌症研究
人口
抗药性
抗体
肿瘤科
药理学
医学
免疫学
癌症
乳腺癌
内科学
生物
单克隆抗体
环境卫生
微生物学
作者
Chisato M. Yamazaki,A Yamaguchi,Yasuaki Anami,Wei Xiong,Yoshihiro Otani,Jangsoon Lee,Naoto T. Ueno,Ningyan Zhang,Zhiqiang An,Kyoji Tsuchikama
标识
DOI:10.1101/2020.12.18.423326
摘要
ABSTRACT Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal immunogenicity, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in a xenograft mouse model representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.
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