Abstract 3417: Preclinical studies of BR-2302: A HER3xEGFR bi-specific Exd-containing ADC

Abstract HER3 has emerged as a critical player in the resistance mechanisms against therapies targeting the epidermal growth factor receptor (EGFR). Its upregulation can activate alternative signaling pathways, enabling cancer cells to bypass the effects of EGFR inhibitors, which often results in treatment failure. To combat this issue, novel HER3-targeting therapies are under investigation, including antibody-drug conjugates (ADCs) such as Patritumab Deruxtecan (U3-1402), which have shown encouraging results in clinical trials, underscoring the potential of HER3 targeting to overcome resistance. The development of bispecific ADCs that target both HER3 and EGFR represents a pioneering approach that may enhance therapeutic efficacy through dual targeting. Izalonatamab brengitecan (BL-B01D1), an ADC designed for simultaneous targeting of EGFR and HER3, has demonstrated substantial clinical benefits in heavily pretreated patients with EGFR-mutant non-small cell lung cancer (NSCLC). Building on this strategy, we are advancing a novel bispecific ADC, BR-2302, which employs a human IgG1 format bi-specific antibody with high affinity for HER3 and moderate affinity for EGFR. This innovative design aims to maximize therapeutic effectiveness while minimizing on-target/off-tumor toxicity associated with the widespread expression of EGFR in normal tissues. Our comprehensive studies on BR-2302 have focused on its in vitro cytotoxicity and in vivo tumor inhibitory effects across various cancer cell lines and xenograft models expressing the target antigens. BR-2302 exhibited significant anti-tumor activity in vitro, achieving subnanomolar IC50 values against HER3-expressing cell lines regardless of their EGFR expression levels. in vivo experiments demonstrated remarkable tumor growth inhibition and sustained regression in human lung and colon cancer xenograft models, surpassing the tumor inhibitory effects of established benchmark ADCs. Collectively, our findings indicate that BR-2302 possesses promising anti-tumor properties. This innovative therapeutic approach has the potential to improve treatment outcomes for patients with solid tumors expressing both HER3 and EGFR, warranting further clinical exploration. Citation Format: Yang Wang, Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Qi Zhang, Ziping Wei, Yuhong Zhou. Preclinical studies of BR-2302: A HER3xEGFR bi-specific Exd-containing ADC [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 3417.