PLoS ONE (Jan 2023)

CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity.

  • Kathleen M C Sullivan,
  • Marta Vilalta,
  • Linda S Ertl,
  • Yu Wang,
  • Carolyn Dunlap,
  • Karen Ebsworth,
  • Bin N Zhao,
  • Shijie Li,
  • Yibin Zeng,
  • Zhenhua Miao,
  • Pingchen Fan,
  • Venkat Mali,
  • Christopher Lange,
  • Darren McMurtrie,
  • Ju Yang,
  • Rebecca Lui,
  • Ryan Scamp,
  • Vicky Chhina,
  • Alice Kumamoto,
  • Simon Yau,
  • Ton Dang,
  • Ashton Easterday,
  • Shirley Liu,
  • Shichang Miao,
  • Israel Charo,
  • Thomas J Schall,
  • Penglie Zhang

DOI
https://doi.org/10.1371/journal.pone.0286724
Journal volume & issue
Vol. 18, no. 6
p. e0286724

Abstract

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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).