Identification of a small molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical models

T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed
in dysfunctional and exhausted T cells, has been widely acknowledged as a
promising immune checkpoint target for tumor immunotherapy. Here, using a
strategy combining virtual and functional screening, we identified a
compound named ML-T7 that targets the FG-CC’ cleft of Tim-3, a highly
conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic
antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the
survival and antitumor activity of primary CD8+ cytotoxic T lymphocytes
(CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their
exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells’
killing activity and DC antigen-presenting capacity, consistent with the
reported activity of Tim-3. Notably, ML-T7 strengthened DCs’ functions
through both Tim-3 and Tim-4, consistent with the hypothesis that Tim-4
contains a similar FG-CC’ loop. Intraperitoneal dosing of ML-T7 showed
comparable tumor inhibitory effects to Tim-3 blocking antibody. ML-T7
reduced syngeneic tumor progression in both wildtype and Tim-3 humanized
mice and alleviated the immunosuppressive microenvironment. Furthermore,
combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than
monotherapy in mice, supporting further development of ML-T7 for tumor
immunotherapy. Our study demonstrates a potential small molecule for
selectively blocking Tim-3 and warrants further study.