Abstract 345: Trop2 and B7H4 bi-specific ADC with improved efficacy and safety for gynecologic cancers

Abstract The effectiveness of Antibody-Drug Conjugates (ADCs) is closely associated with the level of tumor antigen expression and the administered drug dose, as observed in both preclinical and clinical settings. Trop2-targeted ADCs represent a promising therapeutic approach for various solid tumors; however, their efficacy is constrained by the expression levels of Trop2 and the off-tumor, on-target toxicity. To address these limitations, we have developed a bi-specific ADC that targets both Trop2 and B7H4, aiming to increase the overall tumor antigen expression level, and reduce the off-tumor toxicity associated with Trop2 by incorporating a single-arm Trop2 antibody and employing a less toxic Topoi NT3 linker payload in the ADC. Our research has confirmed the co-expression of Trop2 and B7H4 on tumor cells in Triple Negative Breast Cancer, ovarian cancer, and endometrial cancer, while not on normal mucosal epithelial cells. This co-expression profile supports the use of our bi-specific approach to improve cancer targeting efficiency while minimizing toxicity to normal tissues. In vitro studies demonstrate that our bi-specific Trop2/B7H4 ADC (IBI3022) exhibits superior cytotoxicity in HT29 cells overexpressing Trop2 and B7H4 compared to mono-specific ADC benchmarks targeting Trop2 or B7H4. Additionally, IBI3022 shows comparable efficacy to B7H4 ADC in B7H4-positive HCC1569 cells and to Trop2 ADC IBI130 in Trop2-positive BxPC3 and HCC1954 cells. In vivo, IBI3022 demonstrates enhanced tumor suppression compared to mono-specific ADC benchmarks in various tumor models with differing levels of Trop2 and B7H4 expression, including MDA-MB-468, HT29-Trop2-B7H4, HCC1806, JIMT1, and NUGC4. The half-life of IBI3022 in mice is 113 hours, supporting its sustained in vivo efficacy. The developability profile of IBI3022 is favorable, and notably, it is well-tolerated in cynomolgus macaques at doses up to 50 mg/kg. Overall, IBI3022 represents a promising bi-specific ADC for the treatment of gynecologic cancers, offering improved efficacy and safety profiles. Citation Format: Jing Chen, Chenjuan Zhu, Chenchen Zhu, Zhongmin Liu, Min Wu, Weiwei Wu, Junjie Deng, Yi Wang, Xiguang Zhang, Yiming Li. Trop2 and B7H4 bi-specific ADC with improved efficacy and safety for gynecologic cancers [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 345.