CRTH2 antagonists in asthma: current perspectives

Abstract

Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) binds to prostaglandin D2. CRTH2 is expressed on various cell types including eosinophils, mast cells, and basophils. CRTH2 and prostaglandin D2 are involved in allergic inflammation and eosinophil activation. Orally administered CRTH2 antagonists are in clinical development for the treatment of asthma. The biology and clinical trial data indicate that CRTH2 antagonists should be targeted toward eosinophilic asthma. This article reviews the clinical evidence for CRTH2 involvement in asthma pathophysiology and clinical trials of CRTH2 antagonists in asthma. CRTH2 antagonists could provide a practical alternative to biological treatments for patients with severe asthma. Future perspectives for this class of drug are considered, including the selection of the subgroup of patients most likely to show a meaningful treatment response.

A phase 2 study to evaluate the safety, efficacy and pharmacokinetics of DP2 antagonist GB001 and to explore biomarkers of airway inflammation in mild‐to‐moderate asthma

“…DP2 is expressed by Th2 cells, ILC2, epithelial cells, basophils and eosinophils . Antagonism of DP2 inhibits activation of eosinophils as measured by CD11b expression and inhibits ESC induced by PGD2 ex vivo.…”

“…The main source of PGD2 in the airway tissue is the mast cell. DP2 signalling promotes the recruitment and activation of basophils and eosinophils and stimulates Th2 and ILC2 cells to release type 2 cytokines [IL‐4 and IL‐13 (primarily produced by basophils), and IL‐5 (primarily produced by eosinophils)], leading to the development, amplification and persistence of type 2 inflammation . Hence, it is hypothesized that DP2 antagonists will inhibit recruitment and activation of Th2 and ILC2 cells, basophils and eosinophils, with a consequent reduction in airway inflammation and improvement in lung function.…”

Pleiotropic Role and Bidirectional Immunomodulation of Innate Lymphoid Cells in Cancer

“…Antibodies against IL-5 and anti-IL-4 receptor α subunit that block ILC2 function have provided encouraging results in patients with chronic rhinosinusitis (169). Similarly, inhibition of ILC2 function by chemoattractant receptor-homologous molecule expressed on Th2 cells (CTTH2) antagonists restores lung function in patients with asthma (170).…”

Lipid‐Embedded Molecular Dynamics Simulation Model for Exploring the Reverse Prostaglandin D2 Agonism of CT‐133 towards CRTH2 in the Treatment of Type‐2 Inflammation Dependent Diseases

“…This underscores the role that CRTH2 directly plays in the recruitment and release of inflammatory cells and pro‐inflammatory cytokines such as interleukin‐4 (IL‐4), IL‐5 and IL‐13 in response to its native agonist, prostaglandin D2 (PGD2) . CRTH2 activation has therefore been implicated in the pathogenesis of type 2 inflammation diseases involving allergies such as asthma, rhinitis and cigarette smoke (CS) induced inflammation . Recent studies has also established the activities of CRTH2 beyond allergy and asthma to involve pro‐fibrotic and antifibrotic effects in the respiratory tract, abetting renal fibrosis and inflammation through repression of interleukin 4 and 13 as well as inflammation induced cancer .…”

“…[15] CRTH2 activation has therefore been implicated in the pathogenesis of type 2 inflammation diseases involving allergies such as asthma, rhinitis and cigarette smoke (CS) induced inflammation. [16][17][18][19] Recent studies has also established the activities of CRTH2 beyond allergy and asthma to involve pro-fibrotic and antifibrotic effects in the respiratory tract, [20,21] abetting renal fibrosis and inflammation through repression of interleukin 4 and 13 [22] as well as inflammation induced cancer. [23,24] These activities of CRTH2 is in response to its activation by prostaglandin d2 (PGD2) and its metabolites.…”