Abstract 1587: A novel dual-payload HER3-directed antibody-drug conjugate, shows potent antitumor efficacy in HER3-low <i>in vivo</i> tumor models

Abstract HER3 (Receptor tyrosine-protein kinase erbB-3) is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers. Elevated HER3 expression is associated with poor patient outcomes and therapeutic resistance. Several HER3-ADCs have been developed for cancer therapy. To date, patritumab deruxtecan (U3-1402) is the only HER3-targeting therapy that has demonstrated clinical efficacy in both non-small cell lung cancer. But patritumab deruxtecan is ineffective in more challenging tumor type including low HER3 expression tumors.This study presents preclinical evaluation of a novel dual-payload HER3-targeting ADC, KHN922, composed of a humanised IgG1 antibody (patritumab) directed against HER3 which is conjugated to a topoisomerase I inhibitor (TopoIi) and an RNA polymerase II inhibitor (RNA POL IIi). KHN922 achieves an average drug-to-antibody ratio (DAR) of about 7.5 (3.9+3.6) using cystein and glycosite antibody coupling technologies with an appropriate DAR, high SEC purity, homogeneous particle size distribution, and favorable thermal stability.The dual mechanism of KHN922 enables the simultaneous inhibition of RNA synthesis and the induction of DNA double-strand breaks, resulting in a potent and synergistic anti-tumor effect both in vitro and in vivo xenograft mouse models in comparison to other TopoIi-TROP2-targeting ADCs. In low and ultra-low HER3 expression CDX models, the KHN922 demonstrated superior tumor suppression effects compared to single-TopoIi ADCs, patritumab deruxtecan and patritumab exatecan.Furthermore, KHN922 still showed strong activity to DXd-ADC treatment resistance CDX models. The non-GLP toxicity study in cynomolgus monkeys provided evidence of the favorable safety profile of KHN922, the highest non-severely toxic dose (HNSTD) is 50 mg/kg/dose. In summary, KHN922, an ADC with dual toxins and unique mechanisms of action, displayed superior anti-tumor effects, the ability to overcome treatment-resistance and tumour recurrences, and an acceptable safety profile in preclinical studies. These findings support the potential of KHN922 as a promising advanced therapeutic candidate for HER3 tumors. Citation Format: Yonghao Zhao, Pengfei Ren, Menglong Guan, Jiao Tang, Lu Qi, Xinzou Fan, Shijun Yin, Gang Lei, Xiao Ke. A novel dual-payload HER3-directed antibody-drug conjugate, shows potent antitumor efficacy in HER3-low in vivo tumor models [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 1587.