Abstract 4249: IBI3019, a first-in-class EGFR/CDH17/CD16A tri-specific antibody, demonstrated potent efficacy against CRC and an excellent safety profile in preclinical studies

Abstract Inhibition of EGFR signaling is clinically effective in colorectal cancer (CRC) as evidenced by the approval for Cetuximab in combination with chemotherapy or Encorafenib, a BRAF inhibitor, and the promising clinical results when combined with KRAS inhibitors, such as Adagrasib or Sotorasib. This underscores the clinical versatility of EGFR antibodies. However, these strategies are inevitably associated with high target-related toxicities, which limit the maximal potential of the drugs. Here, we designed IBI3019, a next-generation EGFR blocker that targets EGFR, CDH17 and CD16A. By targeting CDH17, an adhesion molecule overexpressed in CRC, we enhanced EGFR inhibition capabilities of the tri-specific antibody on the tumor while sparing normal tissues, particularly skin tissues, which are commonly associated with severe toxicities from EGFR blockers. Additionally, IBI3019 incorporates a high affinity CD16A single domain antibody that mediates stronger antibody-dependent cell cytotoxicity (ADCC) than IgG1 used in Cetuximab or the low fucosylated Fc of Amivantamab, a bispecific antibody targeting c-MET and EGFR, both in vitro and in vivo. IBI3019 demonstrated more potent in vitro efficacy than Cetuximab and Amivantamab in CRC cell lines, regardless of KRAS mutation status or the expression of CDH17, c-MET and EGFR. It exhibited strong synergy with Fulzerasib, a KRAS G12C inhibitor and MRTX1133, a KRAS-G12D inhibitor. In NCI-H508 and CCK81 CRC cell line-derived xenograft (CDX) models, IBI3019 suppressed tumor growth more effectively than Cetuximab and Amivantamab. Importantly, in a CRC patient-derived xenograft (PDX) model that is insensitive to Cetuximab, IBI3019 achieved near complete eradication of tumors in all mice. In pre-toxicity studies, cynomolgus monkeys were administrated 4 weekly doses of 50 mg/kg or 150 mg/kg of IBI3019 intravenously, and no mortality or serious toxicity was observed in either group. The highest non-severely toxic dose (HNSTD) of IBI3019 is 150 mg/kg and the calculated therapeutic index is 66. In contrast, previous reports indicated that 5 out of 10 monkeys treated with 75 mg/kg/week of Cetuximab exhibited early mortalities associated with excessive dermatologic toxicities. These results underscore the high safety profile of IBI3019. IBI3019 is a highly optimized FIC molecule with enhanced EGFR blocking capability and ADCC, maximizing tumor inhibition while minimizing toxicity. Its superior efficacy and safety profile support further clinical evaluation. Citation Format: Tiongsun Chia, Weiwei Wu, Li Li, Shuaixiang Zhou, Jia Lu, Shuming Lin, Ming Wu, Jia Liu, Feifei Wang, Ya Liu, Chenjuan Zhu, Ying Zhang, Yayao Yan, Huisi Liu, Jian Guan, Junjie Deng, Ninghuan Li, Zhihai Wu, Bin Li, Enhong Zhong, Bingliang Chen, Kaijie He. IBI3019, a first-in-class EGFR/CDH17/CD16A tri-specific antibody, demonstrated potent efficacy against CRC and an excellent safety profile in preclinical studies [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 4249.