Unlocking the Potential of PD-L1 Small-Molecule Antagonists: Preclinical Insights and Therapeutic Promise

Monoclonal antibodies targeting PD-L1 or PD-1 have demonstrated efficacy in various cancer types by reactivating T cell responses. However, small molecule inhibitors of the PD-(L)1 pathway could offer advantages such as better tissue penetration and the potential for oral administration. A new class of small molecule PD-L1 antagonists has been discovered that induces internalization of PD-L1, thereby blocking the PD-1 interaction and enhancing T cell activity.

These small molecules have shown high affinity for human PD-L1, effectively disrupting the PD-L1:PD-1 bond and inhibiting SHP2 recruitment to PD-1. This leads to a reduction in PD-1's suppressive effect on T cell activation and a restoration of IFNγ production. The antagonists also decrease PD-L1 expression on tumor cells and monocytes with potent IC50 values, providing a pharmacodynamic biomarker.

In a humanized mouse model with MDA-MB-231 tumors, oral dosing of these small molecule antagonists for 28 days resulted in a dose-dependent decrease in tumor growth and an increase in tumor-infiltrating T cells. Similar results were observed in a murine MC38 xenograft model overexpressing human PD-L1, with dose-dependent tumor growth inhibition and T cell infiltration. No activity was seen in immunocompromised mice, underlining the importance of an intact immune system.

Comparative preclinical studies showed that the small molecule antagonists had equivalent anti-tumor effects to approved PD-(L)1 monoclonal antibodies. This suggests that oral small molecule PD-L1 antagonists can effectively block the PD-(L)1 axis and stimulate immune responses, warranting further clinical exploration as a new immunotherapy strategy.