Inhibition of antigen-induced airway inflammation and hyperresponsiveness in guinea pigs by a selective antagonist of “chemoattractant receptor homologous molecule expressed on Th2 cells” (CRTH2)

Tasaki, Mamoru; Kobayashi, Miki; Tenda, Yoshiyuki; Tsujimoto, Susumu; Nakazato, Shoko; Numazaki, Mako; Hirano, Yasuno; Matsuda, Hiroshi; Terasaka, Tadashi; Miyao, Yasuhiro; Shimizu, Yoshiyuki; Hirayama, Yoshitaka

doi:10.1016/j.ejps.2013.04.017

Cited by 8 publications

(3 citation statements)

References 26 publications

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“…The research interest in CRTh2 receptor antagonists is based on their ability to prevent the PGD 2 ‐mediated inflammatory response in allergic diseases, as demonstrated in various preclinical models and clinical reports . Allergic conditions are characterized by PGD2‐mediated recruitment of Th2 cells and eosinophils that express CRTh2 receptors.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

Erpenbeck

Vets²,

Gheyle³

et al. 2016

Clinical Pharm in Drug Dev

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We evaluated the pharmacokinetics (PK), safety, and tolerability of a novel oral CRTh2 antagonist, fevipiprant (QAW039), in healthy subjects. Peak concentrations of fevipiprant in plasma were observed 1‒3 hours postdosing. Concentrations declined in a multiexponential manner, followed by an apparent terminal phase (t1/2, ∼20 hours). Steady state was achieved in 4 days with <2‐fold accumulation. Elimination was partly by renal excretion (≤30% of the dose) and glucuronidation. Food had minimal impact on the PK of fevipiprant, and it was well tolerated at single and multiple oral doses up to 500 mg/day. No dose‐dependent adverse events were observed, and all the events were mild or moderate in severity. Systemic concentrations were sufficiently high to achieve relevant target occupancy, considering in vitro pharmacology data. In summary, the data support further development as a once‐daily oral therapy for allergic diseases.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

Erpenbeck

Vets²,

Gheyle³

et al. 2016

Clinical Pharm in Drug Dev

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“…Chemoattractant receptor‐homologous molecule expressed on Th2 cells (CRTH2) is a cell surface molecule, which binds to prostaglandin D2. In recent studies, it has been demonstrated that prostaglandin D2 can have potent proinflammatory effects in allergic pathological conditions such as AD and asthma . A CRTH2 antagonist can attenuate late‐phase inflammation in transgenic mice model with allergic dermatitis through inhibiting neutrophil activation .…”

Section: Targeting Cytokines and Cytokine Signalingmentioning

confidence: 99%

New insights into T cells and their signature cytokines in atopic dermatitis

Wang

Landén

2015

IUBMB Life

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An imbalance of the adaptive immune system mediated by various T cells plays a pivotal role in the pathogenesis of atopic dermatitis (AD). Traditionally, sustained exposure of pathogens tailors immune responses and drives the development of specialized T helper (Th) 2-bias cytokine environment. The increasing understanding of T cell biology has refreshed the roles of classical Th2 responses and regulatory T cells in the development of AD. In particular, the identification of novel CD41 T cell subsets such as Th9, Th17, and Th22 cells provide further interpretation of immunological mechanisms underlying AD. In this report, we reviewed the functional roles of CD4 1 T cell subsets and their derived signature cytokines in AD. We focused on important discoveries of the contribution of CD4 1 T cell cytokines to immunomodulation in AD, and particularly, highlighted the multiple consequences of immune dysregulation on the barrier defect of the skin. We subsequently discussed the flexibility and plasticity of these T cells in vivo in terms of cytokine production. T cells involved in innate immunity were also mentioned. Taking

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“…A genetic polymorphism in CRTH2 has been identified in patients with asthma and is suspected of contributing to the development of asthma [15]. Studies exploring the effects of CRTH2 antagonists including TM30089, TASP0412098, ASP5642, MK7246, and certain other molecules in asthma models of mice [16][17][18], guinea pigs [19,20], or sheep [21,22] reported improvements in eosinophilic inflammation, respiratory function, and/or AHR. In addition, several clinical trials in asthmatic patients treated with certain CRTH2 antagonists, such as GB001 [23], AZD1981 [24], QAW039 [25,26], OC000459 [27][28][29], and ACT-129968 [30], reported limited improvements in lung function and asthma symptoms, although such effects were not observed in some trials, including a trial that evaluated AMG 853 [31].…”

Section: Introductionmentioning

confidence: 99%

The Prostaglandin D2 Receptor CRTH2 Contributes to Airway Hyperresponsiveness during Airway Inflammation Induced by Sensitization without an Adjuvant in Mice

Hanzawa,

Sugiura,

Nakae

et al. 2024

Int Arch Allergy Immunol

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Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells.

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Inhibition of antigen-induced airway inflammation and hyperresponsiveness in guinea pigs by a selective antagonist of “chemoattractant receptor homologous molecule expressed on Th2 cells” (CRTH2)

Cited by 8 publications

References 26 publications

Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

New insights into T cells and their signature cytokines in atopic dermatitis

The Prostaglandin D2 Receptor CRTH2 Contributes to Airway Hyperresponsiveness during Airway Inflammation Induced by Sensitization without an Adjuvant in Mice

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