Trispecific TCE with second signal boosts solid tumor response efficacy, durability and safety

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.