CA-170 – A Potent Small-Molecule PD-L1 Inhibitor or Not?

Abstract

<b>CA-170</b> is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins - important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented. Using well-known in vitro methods: NMR binding assay, HTRF and cell-based activation assays, we clearly show that there is no direct binding between <b>CA-170</b> and PD-L1. To strengthen our reasoning, we performed control experiments on <b>AUNP-12</b> - a 29-mer peptide, which is a precursor of <b>CA-170</b>. Positive controls consisted of the well-documented small-molecule PD-L1 inhibitors: <b>BMS-1166</b> and <b>peptide-57</b>.