Abstract 340: GenSci139, a highly differentiated EGFR×HER2 bispecific ADC, for the treatment of multiple solid tumors

Abstract Background: Enhertu®/DS-8201, a HER2-directed ADC, has been used for the treatment of multiple tumor types, including HER2-positive and HER2-low breast cancer, HER2-mutant NSCLC, HER2-positive gastric cancer, etc. Despite Enhertu’s success as a breakthrough therapy, significant unmet need remains in the HER2-low settings and in the occurrence of secondary resistance. Dual targeting of EGFR and HER2 represents a promising approach to the treatment of HER2-low patients and to overcoming drug resistance, as they are both oncogenic drivers and widely co-expressed. We developed GenSci139, an EGFR×HER2 bispecific ADC with a highly stable but cleavable linker and a potent topoisomerase 1 inhibitor payload, using our proprietary platform technologies. Preclinical studies are underway to evaluate the potential of GenSci139 as a novel targeted therapy across multiple solid tumor types. Methods: GenSci139’s plasma stability, in vitro cellular binding, internalization, cytotoxicity, and bystander effect, and blocking activity of GenSci139 or its parental bispecific antibody on EGFR/HER2 signaling in a number of human cancer cell lines were characterized. In vivo anti-tumor activity of GenSci139 was evaluated in a number of human cancer CDX models in mice. In addition, the ability of GenSci139 to induce immunogenic cell death (ICD) in tumor cell cultures was assessed. Results: GenSci139 showed much better in vitro plasma stability than DS-8201, suggesting a favorable PK and safety profile. GenSci139 exhibited stronger in vitro tumor cell binding and internalization activities than DS-8201 and potent direct cytotoxicity and bystander killing effect in tumor cell lines. The parental bispecific antibody of GenSci139 inhibited EGF-induced signaling and cell proliferation in tumor cell culture. GenSci139 demonstrated superior in vivo anti-tumor efficacy versus DS-8201 in a number of CDX models in mice. In addition, GenSci139 was shown to induce hallmarks of ICD in tumor cells, providing a complementary anti-tumor mechanism when in a combination therapy regimen with immune checkpoint inhibitors. Conclusion: These data suggest the potential of GenSci139 as a novel and effective therapy across a variety of tumor types, including urothelial cancer, lung cancer, gastric cancer, colorectal cancer, ovarian cancer, breast cancer, etc., and support its further evaluation in IND-enabling studies. Citation Format: Xiaojuan Chai, Fu Li, Hongmei Xie, Yuting Lu, Nan Li, Hanxi Yu, Li Tong, Weiming He, Wenqiang Zhai, Fanglong Yang, John L. Xu. GenSci139, a highly differentiated EGFR×HER2 bispecific ADC, for the treatment of multiple 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 340.