uPAR-Targeting T Cell Engager Exerts Senolytic Effects in Mice and Non-Human Primates With Serum Aminotransferase Activity as a Safety Monitor.

Jian Deng, Xiaozhu Zeng, Jing Guo, Lihong Li, Shirui Zou, Nan Liu, Shuai He, Lanzhen Yan, Qiong Wang, Yongjie Zhu, Ben Wang, Dong Yang, Longbao Lv, Xudong Zhao

Department of Targeting Therapy & Immunology and Laboratory of Cell Engineering & Immunotherapy, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.Department of Targeting Therapy & Immunology and Laboratory of Cell Engineering & Immunotherapy, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China. · pubmed

Paper

Abstract

Senolytic CAR-T cells targeting uPAR induce dose-dependent toxicities. Although dosage adjustment mitigates these toxicities in laboratory mice, clinical translation remains challenging owing to the unpredictability of CAR-T cell proliferation across heterogeneous patient populations. In contrast, bispecific T-cell engagers (BiTEs) offer a safer alternative with superior dose-titratability. Here, we have developed a GFD-CD3 BiTE by employing the growth factor-like domain (GFD) of the natural ligand uPA as the targeting moiety to target uPAR-positive senescent cells. Dose-range finding studies revealed that high-dose GFD-CD3 predominantly induced hepatotoxicity through T cell-mediated attack on hepatic endothelial cells. Crucially, under transaminase-guided monitoring, low-dose GFD-CD3 effectively eliminated senescent cells and alleviated age-related pathologies in aged mice and non-human primates without adverse effects. These findings establish GFD-CD3 as a clinically translatable senolytic agent and provide the compelling preclinical evidence for BiTE as a senolytic strategy.

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Research summary

The paper demonstrates that a uPAR-targeting bispecific T-cell engager (GFD-CD3) can effectively eliminate senescent cells and alleviate age-related pathologies in mice and non-human primates with a manageable safety profile. This is relevant because it addresses the "inflammaging" and cellular senescence hallmarks of aging by providing a clinically translatable mechanism to remove senescent cells, which is a core strategy for extending healthspan and potentially lifespan.

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