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

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.