{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["18(6)"],"submitter":["Sullivan KMC"],"pubmed_abstract":["The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies that block this pathway have been approved in multiple tumor indications. As a next generation therapy, small molecule inhibitors of PD-L1 have inherent drug properties that may be advantageous for certain patient populations compared to antibody therapies. In this report we present the pharmacology of the orally-available, small molecule PD-L1 inhibitor CCX559 for cancer immunotherapy. CCX559 potently and selectively inhibited PD-L1 binding to PD-1 and CD80 in vitro, and increased activation of primary human T cells in a T cell receptor-dependent fashion. Oral administration of CCX559 demonstrated anti-tumor activity similar to an anti-human PD-L1 antibody in two murine tumor models. Treatment of cells with CCX559 induced PD-L1 dimer formation and internalization, which prevented interaction with PD-1. Cell surface PD-L1 expression recovered in MC38 tumors upon CCX559 clearance post dosing. In a cynomolgus monkey pharmacodynamic study, CCX559 increased plasma levels of soluble PD-L1. These results support the clinical development of CCX559 for solid tumors; CCX559 is currently in a Phase 1, first in patient, multicenter, open-label, dose-escalation study (ACTRN12621001342808)."],"journal":["PloS one"],"pagination":["e0286724"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10246841"],"repository":["biostudies-literature"],"pubmed_title":["CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity."],"pmcid":["PMC10246841"],"pubmed_authors":["Zhao BN","Chhina V","Miao S","Mali V","Sullivan KMC","Liu S","Zhang P","Yau S","Vilalta M","Scamp R","Dang T","Wang Y","Dunlap C","Yang J","Lange C","Kumamoto A","Charo I","Ertl LS","Zeng Y","Fan P","McMurtrie D","Ebsworth K","Li S","Lui R","Easterday A","Schall TJ","Miao Z"],"additional_accession":[]},"is_claimable":false,"name":"CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity.","description":"The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies that block this pathway have been approved in multiple tumor indications. As a next generation therapy, small molecule inhibitors of PD-L1 have inherent drug properties that may be advantageous for certain patient populations compared to antibody therapies. In this report we present the pharmacology of the orally-available, small molecule PD-L1 inhibitor CCX559 for cancer immunotherapy. CCX559 potently and selectively inhibited PD-L1 binding to PD-1 and CD80 in vitro, and increased activation of primary human T cells in a T cell receptor-dependent fashion. Oral administration of CCX559 demonstrated anti-tumor activity similar to an anti-human PD-L1 antibody in two murine tumor models. Treatment of cells with CCX559 induced PD-L1 dimer formation and internalization, which prevented interaction with PD-1. Cell surface PD-L1 expression recovered in MC38 tumors upon CCX559 clearance post dosing. In a cynomolgus monkey pharmacodynamic study, CCX559 increased plasma levels of soluble PD-L1. These results support the clinical development of CCX559 for solid tumors; CCX559 is currently in a Phase 1, first in patient, multicenter, open-label, dose-escalation study (ACTRN12621001342808).","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023","modification":"2025-04-19T08:11:21.586Z","creation":"2025-04-19T08:11:21.586Z"},"accession":"S-EPMC10246841","cross_references":{"pubmed":["37285333"],"doi":["10.1371/journal.pone.0286724"]}}