Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse

Abstract

Recently, the first series of small molecule inhibitors of PD-1/PD-L1 were reported by Bristol-Myers Squibb (BMS), which were developed using a homogeneous time-resolved fluorescence (HTRF)-based screening investigation of the PD-1/PD-L1 interaction. Additional crystallographic and biophysical studies showed that these compounds inhibited the interaction of PD-1/PD-L1 by inducing the dimerization of PD-L1, in which each dimer binds one molecule of the stabilizer at its interface. However, the immunological mechanism of the antitumor effect of these compounds remains to be elucidated. In the present study, we focused on BMS-202 (a representative of the BMS compounds) and investigated its antitumor activity using in vitro and in vivo experiments. BMS-202 inhibited the proliferation of strongly PD-L1-positive SCC-3 cells (IC 50 15 μM) and anti-CD3 antibody-activated Jurkat cells (IC 50 10 μM) in vitro. Additionally, BMS-202 had no regulatory effect on the PD-1 or PD-L1 expression level on the cell surface of these cells. In an in vivo study using humanized MHC-double knockout (dKO) NOG mice, BMS-202 showed a clear antitumor effect compared with the controls; however, a direct cytotoxic effect was revealed to be involved in the antitumor mechanism, as there was no lymphocyte accumulation in the tumor site. These results suggest that the antitumor effect of BMS-202 might be partly mediated by a direct off-target cytotoxic effect in addition to the immune response-based mechanism. Also, the humanized dKO NOG mouse model used in this study was shown to be a useful tool for the screening of small molecule inhibitors of PD-1/PD-L1 binding that can inhibit tumor growth via an immune-response-mediated mechanism.

Systematic insight into the active constituents and mechanism of Guiqi Baizhu for the treatment of gastric cancer

“…The results showed that HER2 and PD-L1 are highly expressed in MKN-45 cells (Figure5A,B). We used confocal microscopy to verify this result, which is consistent with western blot analysis (Figure5C,D).As we had confirmed that HER2 and PD-L1 were overexpressed in MKN-45 cells, the cytotoxic activities of compounds targeting HER2 and PD-L155 were determined by CCK-8 assay; the IC 50 values of quercetin, daidzein, and isorhamnetin were 19.27 μmol/L, 21.48 μmol/L, and 10.84 μmol/L, respectively. Formononetin could not inhibit proliferation of tumor cells, as shown in Figure6.…”

“…As we had confirmed that HER2 and PD‐L1 were overexpressed in MKN‐45 cells, the cytotoxic activities of compounds targeting HER2 and PD‐L1 55 were determined by CCK‐8 assay; the IC 50 values of quercetin, daidzein, and isorhamnetin were 19.27 μmol/L, 21.48 μmol/L, and 10.84 μmol/L, respectively. Formononetin could not inhibit proliferation of tumor cells, as shown in Figure 6.…”

The PD‐1/PD‐L1 binding inhibitor BMS‐202 suppresses the synthesis and secretion of gonadotropins and enhances apoptosis via p38 MAPK signaling pathway

“…Compared with monoclonal antibodies, small‐molecule inhibitors have the advantage of high oral utilization, low cost, and a high targeting rate. Accumulated evidence has shown that BMS‐202 regulates tumor growth based on a specific immunological mechanism, which has not been confirmed in clinic (Ashizawa et al, 2019; Zhang et al, 2019). Recent studies have reported an increasing trend regarding the prevalence of anti‐PD‐1/PD‐L1‐induced hypophysitis with different clinical characteristics (Lupi et al, 2019).…”

Synergy of nanodiamond-doxorubicin conjugates and PD-L1 blockade effectively turns tumor associated macrophages against tumor cells

“…All concentrations and dosages of Nano-DOX were normalized to DOX. BMS-1 is one of a series of small molecule agents that are able to induce PD-L1 dimerization and thereby blocks its interaction with PD-1 [23][24][25]…”

“…To test this postulate, we subjected human and murine TAM models (hM2 and mM2) in mixed culture with NSCLC cells to Nano-DOX alone or a combination of Nano-DOX and BMS-1. BMS-1 is a small molecule agent that induces PD-L1 dimerization and thereby blocks its interaction with PD-1 [23][24][25] . Indeed, both hM2 and mM2 displayed enhanced M1-like activation by the Nano-DOX/BMS-1 combination over Nano-DOX alone, as revealed by the analysis of M1 surface markers (CD80, CD86 and MHC-II), M2 surface marker (CD206) and phagocytic function (Fig.…”