Abstract LB031: SHR-A1811, a novel anti-HER2 ADC with superior bystander effect, optimal DAR and favorable safety profiles

作者：Ting Zhang, Lingfeng You, Jianyan Xu, Junzhao Yin, Bolei Qu, Yuchang Mao, Beibei Fu, Dan Cao, Linda Zhao, Jun Feng, Min Hu, Feng He · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/1538-7445.am2023-lb031 · 被引用次数：25 · 研究领域：HER2/EGFR in Cancer Research、Monoclonal and Polyclonal Antibodies Research、Radiopharmaceutical Chemistry and Applications

Abstract Current clinical HER2-targeting ADCs, especially T-DXd, have shown strong efficacy in HER2-expressing/mutant cancers, however, with adverse events such as hematologic toxicities and interstitial lung disease (ILD)/pneumonitis. Here we presented a potential best-in-class HER2-directed ADC, SHR-A1811, which was composed of trastuzumab, a stable and cleavable linker, and a novel topoisomerase I inhibitor payload (SHR9265). SHR9265 was a delicately selected exatecan derivative with a better liposolubility and cellular permeability: SHR9265 had a higher AlogP value than SHR7971, synthesized using published DXd structure (3.67 vs. 2.72). Consistently, SHR9265 showed ~5 times higher membrane permeability (PAMPA model) at pH5 and pH7.4. Cell killing activity of SHR9265 was ~3 times more potent than SHR7971. SHR-A1811 had a drug-to-antibody ratio (DAR) of 5.7, and showed HER2-dependent growth inhibition against various breast cancer and gastric cancer cell lines. In the bystander killing system, SHR-A1811 was able to kill both SK-BR-3 (HER2+) and MDA-MB-468 (HER2-) cells when co-cultured, with the IC50 on MDA-MB-468 of 0.28 nM. The in vitro efficacy of SHR-A1811 was comparable with anti-Her2-SHR9265 (DAR 7.5) and ADC1 (synthesized using T-DXd structure), and stronger than anti-Her2-SHR9265 (DAR 3.5). In SK-BR-3 (HER2 high), JIMT-1 (HER2 moderate) and capan-1 (HER2 low) xenograft models, SHR-A1811 treatment resulted in a dramatic and sustained inhibition of tumor growth. A sig...