Abstract 2872: DXC018: A novel HER2 dual-payload bispecific ADC with promising potential for gastrointestinal cancers and other solid tumors

Abstract HER2 (human epidermal growth factor receptor 2) is a transmembrane tyrosine kinase receptor critical for cell growth and differentiation. As a pivotal therapeutic target, HER2 has been extensively investigated in ADC drug development, resulting in numerous innovative designs along with approval in recent years. Among these, dual-payload ADCs, particularly those utilizing small molecules with distinct mechanisms of action, represent a promising yet still evolving area of research. DXC018 is a novel HER2-targeting bispecific antibody-drug conjugate (ADC) featuring dual epitope binding and dual payload delivery. The bispecific feature of DXC018 to bind HER2 domains II and IV with high affinity, enables its target specificity and therapeutic efficacy. Its payload, comprising an antimetabolite inhibitor and a topoisomerase I inhibitor, effectively induces DNA damage and cytotoxic effects. Pharmacokinetic studies in mice revealed favorable properties, with overlapping pharmacokinetic profiles for the ADC and total antibody, indicating excellent linker stability. Toxicological evaluations confirmed its tolerability at doses up to 300 mg/kg. In xenograft models of human cancer cells, including NCI-N87, JIMT-1, and CFPAC-1 cells, DXC018 exhibited superior or comparable antitumor activity to Dxd conjugate at equivalent doses. These findings suggest that DXC018, by leveraging dual HER2 binding and the complementary mechanisms of the antimetabolite and the topoisomerase I inhibition, offers significant therapeutic potential for the treatment of gastrointestinal malignancies and the other solid tumors. This innovative dual-action design establishes DXC018 as a promising next-generation ADC to address unmet needs in gastrointestinal cancers. Citation Format: Huihui Guo, Yong Du, Yuanyuan Huang, Juan Wang, Qingliang Yang, Junxiang Jia, Jun Zheng, Hangbo Ye, Fang Du, Meng Dai, Hui Xia, Xiaoxiao Chen, Xingyan Jiang, Ziyu Zhao, Wei Liu, Robert Yongxin Zhao. DXC018: A novel HER2 dual-payload bispecific ADC with promising potential for gastrointestinal cancers and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2872.