Abstract 1756: Novel HER2 antibody drug conjugates with stable hydrophilic linkers

Abstract Background: The success of Trastuzumab deruxtecan (T-DXd) was previously attributed to its unique cleavable linker and membrane permeable payload. However, the robust efficacy in cancers with ultralow HER2 expression demands further understanding of its anti-tumor mechanisms. In addition, the occurrence of severe adverse events and the development of drug resistance in clinical settings highlights the importance of designing new ADCs with improved pharmacokinetics (PK) and alternative payloads. Here we present the mechanistic study of a novel HER2-directed ADC with an attempt to improve drug biodistribution, therapeutic window, and sustained efficacy. Methods: HER2-targeting ADC (FID-031) with a proprietary linker and a topoisomerase I inhibitor payload has been developed with an estimated drug to antibody ratio of 7 and evaluated by HPLC, SEC, HIC, ELISA, flow cytometry and cell viability assays in vitro. PK and tissue distribution of the ADC were evaluated in CD-1 mice and tumor bearing SCID mice. In vivo efficacy and anti-tumor mechanism were explored in CDX mouse models. Results: FID-031 showed both HER2-dependent cytotoxicity and a bystander killing effect comparable to the control ADC (T-DXd). In various CDX models, FID-031 demonstrated significantly improved and more sustained tumor growth inhibition than T-DXd at 1-3 mg/kg dose levels. In CD-1 mice, the levels of FID-031 and total antibody exhibited a prolonged half-life in circulation. In HER2-positive tumor-bearing mice, the free payload level from FID-031 was relatively low in plasma but significantly higher in tumor tissue compared to T-DXd, correlating with its superior efficacy in animal models. Immunohistochemistry of FID-031 revealed higher antibody distribution in the tumor microenvironment and deeper penetration in tumor parenchyma compared to T-DXd control. In both HER2 high- and low-expression CDX models, cancer-associated fibroblast and tumor-associated macrophage colocalized with ADC in the tumor microenvironment, suggesting critical roles of these cells in the ADC biological metabolism. Comparable levels of free payload accumulation were observed in normal tissues (i.e., lung, liver, kidney and spleen) for both FID-031 and T-DXd. Significantly lower level of free payload was observed in intestine tissue within the FID-031 treatment group compared to the T-DXd control group. In vivo toxicology studies in NHP are in progress. Conclusions: FID-031 is a novel HER2-targeting ADC with improved PK profile, tissue distribution, and efficacy. This study provides fresh insights on the design considerations for ADC development aimed towards improving safety and overcoming drug resistance. Citation Format: Zhiying Zou, Sichang Zhou, Jin Chu, Xueping Jiang, Zhongliang Jiang, Jing Ming Dong, Feng Bai, Jing Pan, Yuzhong Chen, Can Mao, Qun Sun, Lucas Pan, Greg Witham, Xiaoyu Wang, Gann Xu, Bingsen Zhou, Kai Qi, Lin Wang, Ray Yin. Novel HER2 antibody drug conjugates with stable hydrophilic linkers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1756.