ML-T7 is a potent T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) inhibitor, which targets the FG-CC’ loop and binds to Tim-3 to disrupt the interaction between Tim-3 and phosphatidylserine/carcinoembryonic antigen–related cell adhesion molecule 1 (PtdSer/CEACAM1). The Kd values of ML-T7 binds to hTim-3 and mTim-3 are 6.98 and 7.40μM, respectively. Tim-3 is highly expressed on exhausted T cells in tumors and mediates T-cell terminal differentiation and exhaustion during chronic viral infection and tumor progression. ML-T7 promoted T cell survival and suppressed T cell exhaustion to enhance the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells in vitro and in vivo[1].
In vitro, ML-T7 (1-20μM; 4h) dose-dependently promoted cell proliferation, cytokine production, and cytotoxicity of C57BL/6-Tg(TcraTcrb)1100Mjb/J (OT-I) mice CD8+ CTLs[1]. ML-T7 (10μM; 48h) significantly enhanced the production of IFN-γ, TNF-α, CD107a, and granzyme B in the human NK92 and increased its cytotoxic activity against K562-Fluc cells at different effector-to-target (E:T) ratios[1]. ML-T7 (10μM; 24h) enhanced maturation marker expression and antigen-presenting capacity in LPS (1μg/mL)-stimulated dendritic cells (DC)[1].
In vivo, ML-T7 (20 and 50mg/kg; i.p.; every 2 days for 20 days) enhanced dendritic cell maturation, increased the infiltration and multifunctionality of CD8⁺ T cells, and reduced PD-1 expression and T-cell exhaustion, thereby significantly inhibiting tumor growth and prolonging survival in Akt/c-Myc-induced HCC C57BL/6 mice models[1]. ML-T7 (50mg/kg; i.p.; every 2 days for 20 days) increased the number and activity of CD8⁺ T cells in tumors and spleens, alleviated T-cell exhaustion, enhanced NK-cell function and dendritic cell maturation, and significantly suppressed tumor progression and prolonged survival in Akt/N-Ras-induced HCC mouse model[1].
References:
[1] Ma, Shuaiya et al. “Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models.” Science translational medicine vol. 15,722 (2023): eadg6752.