Abstract 5582: Trispecific TCE with second signal boosts bolid tumor response efficacy, durability and safety

Abstract T-cell engager(TCE) drugs have demonstrated substantial clinical benefits in hematological malignancies, yet their application to solid tumor therapy remains challenging. Key hurdles include on-target off-tumor toxicity, inadequate immune cell infiltration into the tumor microenvironment, and T-cell exhaustion. Moreover, sustained stimulation of the first signal can induce T-cell anergy or apoptosis, underscoring an urgent need for safer and more effective next-generation TCEs. Herein, we have developed FPE021, a triple-specific TCE targeting CD3, CD28, and CDH17. Through optimized affinities for the first and second signals combined with rational structural screening, FPE021 does not induce T-cell fratricide or non-specific activation, indicating a favorable safety profile. Notably, compared with bispecific TCEs, FPE021 exhibits stronger cytotoxicity in vitro and more potent tumor suppression in vivo. Furthermore, the integration of the second signal effectively enhances T-cell proliferation and mitigates T-cell apoptosis. Collectively, FPE021 represents a promising therapeutic strategy to overcome the current barriers limiting TCE efficacy in solid tumor treatment. Citation Format: Yuanyuan Wang, Huijuan Lu, Hanmian Cai, Chun Liu, Liang Xiao, Peipei Hu, Chang Zhou, Yongting Huo, Di Lu. Trispecific TCE with second signal boosts bolid tumor response efficacy, durability and safety abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5582.