Abstract 344: IBI3014, a TROP2xPD-L1 bi-specific ADC integrating ADC killing with checkpoint blockade within one molecule, exhibits promising efficacy and safety in preclinical models

Abstract Antibody-drug conjugates (ADCs) have emerged as a distinguished class of anticancer therapeutics. ADCs targeting Trophoblast Cell Surface Antigen 2 (TROP2) have shown efficacy in treating various epithelial tumors, such as non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Programmed Death Ligand 1 (PD-L1) serves as both an immune checkpoint and a tumor-associated antigen (TAA), commonly overexpressed in diverse tumor types. Growing evidence showed that ADCs can increase the efficacy of immunotherapeutic agents by multiple mechanisms, such as induction of immunogenic cell death, dendritic cell maturation, increase of T cell infiltration and expression of immune-regulatory proteins including PD-L1 and MHC. Both preclinical and early clinical studies suggest that ADCs and immunotherapy are promising combination options for tumor treatment. IBI3014 is an innovative TROP2 and PD-L1 dual-targeting ADC, comprising a humanized bispecific antibody linked to a novel DNA topoisomerase I inhibitor, NT1, via a cleavable linker. In vitro studies demonstrated the unconjugated bispecific antibody of IBI3014 has potent internalization activity potent immune checkpoint blocking activity. IBI3014 demonstrated superior cytotoxicity to benchmark and parental ADCs across several cell line-derived xenograft (CDX) models with different TROP2 and PD-L1 expression pattern, offering broader tumor type coverage. IBI3014 showed acceptable stability profile in mice and monkeys and can be well tolerated in monkeys with a highest non-severely toxic dose (HNSTD) of 50 mg/kg. Conclusion: IBI3014 represents a first-in-class bispecific ADC that integrates targeted cytotoxicity with checkpoint blockade within a single molecule. This dual mechanism of action not only enhances therapeutic efficacy but also maintains a favorable safety profile, which provides a promising approach for cancer therapy. Citation Format: Xiguang Zhang, Yanping Jin, Jinchang Lu, Ninghuan Li, Zhihai Wu, Min Wu, Yan Bian, Fenggen Fu, Weiwei Wu, Shuaixiang Zhou, Huizhong Xiong. IBI3014, a TROP2xPD-L1 bi-specific ADC integrating ADC killing with checkpoint blockade within one molecule, exhibits promising efficacy and safety in preclinical 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 344.