Fevipiprant antagonises prostaglandin D2-induced activation of type-2 CD8 T cells (Tc2)

Introduction and Aims: Fevipiprant is a potent and selective prostaglandin D₂ (PGD₂) receptor 2 (DP₂) antagonist showing clinical benefit in uncontrolled asthma in clinical trials. CD8⁺DP₂⁺ Tc₂ cells are elevated in patients with severe eosinophilic asthma. The aim of this study is to investigate the effect of Fevipiprant on PGD₂/DP₂-mediated Tc₂ activities. Methods: CD3⁺CD8⁺DP₂⁺ Tc₂ cells were isolated from human blood and cultured. The cell migration, cytokine production, apoptosis in response to PGD₂ in the presence of various concentrations of Fevipiprant were examined in vitro with chemotaxis, ELISA, qPCR and apoptosis assays. DP₁ agonist (BW245C), DP₁ antagonist (BW868A) and DP₂ antagonist (TM30089) were used as controls to justify the DP₂ specificity of Fevipiprant. Intracellular staining (ICS) for type-2 cytokines was used to measure the effect of Fevipiprant on activation of Tc₂ cells ex vivo induced by PGD₂ in the blood from severe eosinophilic asthma. (Ethical approval: Leicestershire, Northamptonshire Research Ethics Committee 08/H0406/189) Results: Fevipiprant potently and specifically inhibited PGD₂-induced Tc₂ migration (IC₅₀ = 9.9 nM), cytokines production (IC₅₀ for IL-4, IL-5 and IL-13 = 3.5-17.8 nM) and apoptosis suppression in vitro. Fevipiprant also inhibited type-2 cytokine production from Tc₂ cells ex vivo in the blood from severe eosinophilic asthma. Conclusions: Fevipiprant is a potent inhibitor of DP₂-mediated Tc₂ activation. Given the role of Tc₂ in severe eosinophilic asthma, these data support further development of Fevipiprant as a novel therapy for uncontrolled asthma, targeting Tc₂ cells in addition to other established type-2 immune cells including Th₂, ILC₂ and eosinophils.