SHR-A1811, a novel anti-HER2 antibody–drug conjugate with optimal drug-to-antibody ratio, superior bystander killing effect and favorable safety profiles

作者：Ting Zhang, Jianyan Xu, Junzhao Yin, Yun Gao, Han–Wen Zheng, Beibei Fu, Jiakang Sun, Zhibing Xu, Shiwei Tu, Yuchang Mao, Weiyun Wen, Bolei Qu, Lingfeng You, Zhendong Xue, Xing Sun, Dan Cao, Jun Feng, Min Hu, Feng He · 发表于：Research Square · 年份：2023 · DOI：10.21203/rs.3.rs-3770094/v1 · 被引用次数：2 · 研究领域：HER2/EGFR in Cancer Research、Monoclonal and Polyclonal Antibodies Research、Nanofabrication and Lithography Techniques

Abstract Background HER2-targeting antibody–drug conjugates (ADCs), especially trastuzumab deruxtecan (T-DXd), have revolutionized the treatment landscape of HER2-expressing or mutant cancers. However, undesired adverse events are still inevitable. It is necessary to discover a novel HER2-directed ADC with better safety profiles. Methods SHR-A1811 is composed of trastuzumab, a cleavable linker and a novel topoisomerase I inhibitor, SHR169265. The permeability and pharmacokinetics of SHR169265 were detected by PAMPA assay and LC-MS/MS System. CellTiter-Glo cell viability assay was used to determine the cytotoxicity and bystander killing effect of SHR169265 and SHR-A1811. The antitumor efficacy of SHR-A1811 was evaluated in mouse xenograft models with different HER2 expression levels. The toxicity of SHR-A1811 were evaluated in cynomolgus monkeys. Results SHR169265 showed better permeability, stronger cytotoxicity and faster systemic clearance than SHR197971 (a DXd analog). The drug-to-antibody ratio (DAR) of SHR-A1811 was optimized as 6 via balancing efficacy and toxicity. SHR-A1811 showed HER2-dependent growth inhibition against various cell lines and desirable bystander killing capability. SHR-A1811 led to tumor growth inhibition or even regression in a dose-dependent manner, at least comparable as HRA18-C015 (a biosimilar of T-DXd) and anti-HER2-SHR169265 (DAR 8) in multiple xenograft models with a range of HER2 expression levels. SHR-A1811 exhibited a good pharmacokinetic...