232 INCB090244, a potent small molecule that inhibits the PD-L1/PD-1 axis and functions similarly to PD-L1 antibodies

• DOI: 10.1136/jitc-2021-sitc2021.232
• Publication Date: 2021-11-09T15:06:59Z
• Authors: Jonathan Rios-Doria; Alla Volgina; Prafulla Gokhale; Hao Liu; Christina Stevens; Nina Zolotarjova; Darlise DiMatteo; Kanishk Kapilashrami; Elham Behshad; Pramod Thekkat; Gengjie Yang; Leslie Hall; Chrysi Kanellopoulou; Mark Rupar; Christopher Maddage; April Horsey; Krista Burke; Yan-ou Yang; Maryanne Covington; Steve Wang; Phillip Liu; Richard Wynn; David Reardon; Holly Koblish
• Keywords: Internalization; Blocking antibody

Background Blocking the PD-L1 immune checkpoint axis with therapeutic antibodies against either ligand or PD-1 has proven to be an effective treatment modality for multiple cancer histologies. Small molecules targeting PD-L1/PD-1 represent alternate of blocking this pathway. INCB090244 is a small molecule that blocks interaction and restores T cell function similar clinical stage inhibitor INCB086550. Methods MDA-MB-231 CHO cells overexpressing were used investigate effects on dimerization, intracellular trafficking. In vivo, CD34+ humanized mice harboring tumors C57Bl/6 bearing GL261 subcutaneous orthotopic efficacy, biodistribution, pharmacodynamic INCB090244. Human specific gene expression changes in from analyzed by RNA sequencing. Results vitro, potently disrupted PD-L1:PD-1 interaction, induced inhibited PD-1-mediated negative signaling, resulting enhanced IFN gamma IL-2 production primary human cells. Following internalization co-localization Golgi apparatus partial localization nucleus. After washing, full restoration at surface was observed after 5 days culture vitro. reduced tumor growth tumors, levels as atezolizumab. Antitumor activity completely abrogated immunodeficient mice, confirming pharmacologic dependency competent system. sequencing analysis these demonstrated activation signatures blockade antibodies. Biodistribution studies both orthotopically implanted glioma higher accumulation tissue compared Conclusions effectively dimerization PD-L1, restored immunity vitro vivo models, suitable surrogate candidate those patients receiving brain penetration antibodies, suggesting potential advantage inhibitors accessing intratumoral regions. These data further support evaluation alternative approach therapy.