Abstract T-cell engagers (TCEs) have emerged as a research hotspot in recent years, owing to their ability to precisely mediate T cell killing of target cells. However, their clinical translation is frequently hindered by core challenges: insufficient target specificity, inadequate preclinical safety risk assessment, and poor developability. Thus, an advanced technological platform is urgently needed to break through these barriers and facilitate the efficient translation of TCEs from basic research to clinical applications. Here, we established a TCE platform with distinctive technological advantages. Its core highlight lies in the integration of nanobodies targeting the first and second signals of T-cell activation, which possess cross-reactive binding activity between human and cynomolgus monkey, a feature provides crucial support for the preclinical safety assessment. Verification data demonstrates that the TCEs armed with our CD3 nanobody not only exhibit excellent cytotoxicity but also demonstrate favorable safety profiles and robust developability. Nanobodies not only meet the requirements of diverse structural design but also, due to their relatively small molecular weight, are best suited for in vivo TCE development. Currently, relying on the core components of this platform, we have initiated the development of three types of differentiated TCE projects:secondary signal enhanced TCEs, biased activation TCEs and dual-target TCEs. These core components and TCE projects will provide crucial support for achieving excellent therapeutic efficacy in oncology and autoimmune diseases. Citation Format: Yuanyuan Wang, Ce Gu, Liang Xiao, Huijuan Lu, Ruhan Lin, Tingchu Wu, Peipei Hu, Chang Zhou, Fan Wu, Jian Guo, Yongting Huo, Di Lu, . Human-cynomolgus cross-reactive CD3 nanobody-centric TCE platform enhances clinical translation 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 1637.
Wang et al. (Fri,) studied this question.