首创CHK1抑制剂抗体药物偶联物克服现有ADC载荷的局限性，为HER2阳性及TOP1抑制剂耐药肿瘤提供新选择

Background: Current ADCs rely almost exclusively on two payload classes -TOP1 poisons and microtubule inhibitors- leading to significant toxicity, frequent dose interruptions and reductions, and limited options once resistance develops. To address these limitations, we developed a first-in-class ADC incorporating a novel payload class: a CHK1 inhibitor (CHK1i). The novel payload exploits the presence of DNA replication stress in cancer, leading to greater selectivity. Methods: Trastuzumab variants containing engineered cysteines were generated to enable site-specific conjugation. A proprietary cleavable linker was synthesized and conjugated to the CHK1i payload. The resulting ADC was evaluated for HER2-dependent activity in vitro and tested in vivo in a HER2-positive breast cancer xenograft model (HCC1569). Results: As a small molecule, the CHK1i was about 50-fold less toxic to normal cells than a TOP1 poison (deruxtecan) while maintaining comparable potency in cancer cell lines. When bound to the ADC linker, the CHK1i was not toxic to cells, in contrast to the deruxtecan-linker, which retains toxicity. Trastuzumab with five engineered cysteines, combined with a novel cleavable linker and a CHK1i as payload, enabled enhanced ADC potency and selective killing of HER2-positive cancer cells. In vivo testing of the ADC, administered intravenously once per week for five consecutive weeks, demonstrated antitumor efficacy at 10 mg/kg in the HCC1569 xenograft model. Mice were monitored for three weeks after treatment completion, and tumor growth inhibition was still observed. No body weight loss or obvious signs of toxicity were detected. Conclusions: This first-in-class CHK1i ADC expands payload diversity, aims to address resistance to existing ADCs and reduce nonspecific toxicity, offering the potential for a wider therapeutic window.