Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse
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- ASHIZAWA Tadashi
- Immunotherapy Division, Shizuoka Cancer Center Research Institute
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- IIZUKA Akira
- Immunotherapy Division, Shizuoka Cancer Center Research Institute
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- TANAKA Emiko
- Immunotherapy Division, Shizuoka Cancer Center Research Institute
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- KONDOU Ryota
- Immunotherapy Division, Shizuoka Cancer Center Research Institute
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- MIYATA Haruo
- Immunotherapy Division, Shizuoka Cancer Center Research Institute
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- MAEDA Chie
- Immunotherapy Division, Shizuoka Cancer Center Research Institute
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- SUGINO Takashi
- Division of Pathology, Shizuoka Cancer Center Hospital
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- YAMAGUCHI Ken
- Office of the president, Shizuoka Cancer Center Hospital
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- ANDO Takayuki
- Shizuoka Institute of the Environment and Hygiene
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- ISHIKAWA Yoshinobu
- School of Pharmaceutical Sciences, University of Shizuoka
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- ITO Mamoru
- Central Institute for Experimental Animals
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- AKIYAMA Yasuto
- Immunotherapy Division, Shizuoka Cancer Center Research Institute
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Abstract
<p>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 (IC50 15 μM) and anti-CD3 antibody-activated Jurkat cells (IC50 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.</p>
Journal
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- Biomedical Research
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Biomedical Research 40 (6), 243-250, 2019-12-01
Biomedical Research Press