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

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 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. Conclusions 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.