Zhang Ting, Xu Jianyan, Yin Junzhao, Gao Yun, Zheng Hanwen, Fu Beibei, Sun Jiakang, Xu Zhibin, Tu Shiwei, Mao Yuchang, Wen Weiyun, Qu Bolei, You Lingfeng, Xue Zhendong, Sun Xing, Cao Dan, Feng Jun, Hu Min, He Feng
Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China.
Shanghai Shengdi Pharmaceutical Co., Ltd., Shanghai, China.
PLoS One. 2025 Jun 26;20(6):e0326691. doi: 10.1371/journal.pone.0326691. eCollection 2025.
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 and it is necessary to discover a HER2-directed ADC with better safety profiles. SHR-A1811 is composed of trastuzumab, a cleavable linker and a novel topoisomerase I inhibitor, SHR169265. The results indicated that SHR169265 shows better permeability, strong cytotoxicity and faster systemic clearance than DXd analog (SHR197971). 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 synthesized T-DXd) and anti-HER2-SHR169265 (DAR 8) in multiple mouse xenograft models with a range of HER2 expression levels. SHR-A1811 exhibited a good pharmacokinetics profile, outstanding stability in plasma across different species and a favorable preclinical safety profile. The highest non-severely toxic dose (HNSTD) in cynomolgus monkeys was 40 mg/kg with thymus as the main target organ. The above results suggested that SHR-A1811 is a potential best-in-class anti-HER2 ADC with a highly permeable payload, optimized DAR, great potency and better safety profiles. Currently SHR-A1811 has entered phase II and phase III clinical studies for breast cancer, gastric cancer, colorectal cancer, and NSCLC.
靶向HER2的抗体药物偶联物（ADC），尤其是曲妥珠单抗德曲妥珠单抗（T-DXd），已经彻底改变了HER2表达或突变癌症的治疗格局。然而，不良事件仍然不可避免，因此有必要发现一种安全性更好的HER2导向ADC。SHR-A1811由曲妥珠单抗、可裂解连接子和新型拓扑异构酶I抑制剂SHR169265组成。结果表明，与DXd类似物（SHR197971）相比，SHR169265具有更好的渗透性、更强的细胞毒性和更快的全身清除率。通过平衡疗效和毒性，将SHR-A1811的药物与抗体比率（DAR）优化为6。SHR-A1811对多种细胞系表现出HER2依赖性生长抑制，并具有理想的旁观者杀伤能力。在多个具有不同HER2表达水平的小鼠异种移植模型中，SHR-A1811以剂量依赖性方式导致肿瘤生长抑制甚至消退，至少与HRA18-C015（一种合成的T-DXd）和抗HER2-SHR169265（DAR 8）相当。SHR-A1811表现出良好的药代动力学特征，在不同物种的血浆中具有出色的稳定性和良好的临床前安全性。食蟹猴的最高非严重毒性剂量（HNSTD）为40mg/kg，主要靶器官为胸腺。上述结果表明，SHR-A1811是一种潜在的同类最佳抗HER2 ADC，具有高渗透性的有效载荷、优化的DAR、强大的效力和更好的安全性。目前，SHR-A1811已进入针对乳腺癌、胃癌、结直肠癌和非小细胞肺癌的II期和III期临床研究。
