Safety and efficacy of an oral <scp>CCR</scp>3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo‐controlled clinical trial

Neighbour, Helen; Boulet, Louis Philippe; Lemière, Catherine; Sehmi, Roma; Leigh, Richard; Sousa, Ana R.; Martin, James G.; Dallow, Nigel; Gilbert, Jane; Allen, Ann; Hall, David A.; Nair, Parameswaran

doi:10.1111/cea.12244

Cited by 83 publications

(55 citation statements)

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“…CCR3 was previously shown to be a target in allergic disease, and various oral CCR3 antagonists have been developed [30][31][32][33] . Some of these antagonists have already been tested in clinical studies, and their safety has been confirmed in humans [32,33] . Although their targets are allergy-related diseases, based on the results of our present study, these oral CCR3 antagonists may have potential as a new therapeutic approach for retinal neovascularization, such as for diabetic retinopathy in the future.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Retinal Neovascularization by Anti-CCR3 Treatment in an Oxygen-Induced Retinopathy Model in Mice

et al. 2017

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Purpose: To investigate the association between retinal neovascularization and the CC chemokine receptor-3 (CCR3) in a mouse model of oxygen-induced retinopathy (OIR). Methods: An OIR model in C57BL/6J mice was used as a retinal neovascularization model. An enzyme-linked immunosorbent assay was performed to evaluate the chronological change in vascular endothelial growth factor A (VEGF-A) and eotaxin expressions. CCR3 and VEGF subtype expression in the retina was examined using real-time RT-PCR, and CCR3, eotaxin, VEGF-A, and CD31 expression was examined immunohistochemically. A CCR3 neutralizing antibody (Ab) was injected into the vitreous humor on both postnatal days 12 (P12) and 14 (P14). Retinal neovascularizations were quantified by measurement of the percentages of neovascular area. Results: The mean eotaxin and VEGF-A protein level was significantly downregulated at P10 and P12 and was significantly upregulated at P14 and P17 (p < 0.05). CCR3 mRNA expression was significantly upregulated at P12 (p < 0.05). VEGF164 mRNA expression was significantly upregulated at P14 (p < 0.05). The areas of vaso-obliteration and neovascularization were significantly suppressed in anti-CCR3 Ab-treated eyes (p < 0.05). Anti-CCR3 Ab treatment suppressed VEGF and eotaxin but not monocyte chemoattractant protein-1. And VEGF 164 mRNA but not VEGF120 mRNA was suppressed by anti-CCR3 Ab treatment. Conclusions: The present data suggest that anti-CCR3 treatment can suppress retinal neovascularization. Anti-CCR3 treatment may have potential as a new therapy for retinopathies with retinal neovascularization such as diabetic retinopathy and retinopathy of prematurity.

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Section: Discussionmentioning

confidence: 99%

Suppression of Retinal Neovascularization by Anti-CCR3 Treatment in an Oxygen-Induced Retinopathy Model in Mice

et al. 2017

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“…Therefore, interfering with CCR3 ligation has been proposed as a therapeutic strategy for the treatment of allergic asthma with eosinophilia. However, a recent double-blind parallel-group study of 60 asthma patients with 94.9 % sputum eosinophils did not show a significant reduction in sputum or blood eosinophil counts or improvement of lung function [57]. These observations challenge the role of CCR3 in airway eosinophilia in asthma.…”

Section: Small Molecules Chemokine Receptor Antagonistsmentioning

confidence: 92%

New Targets for Immune Modulation in Asthma

Veen

Akdiş

2014

Curr Treat Options Allergy

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Opinion statementCurative treatment for asthma poses a challenge. Standard asthma therapy is primarily based on immunosuppressive and bronchodilator drugs, which confer shortterm symptom relief but do not cure the disease. Approximately 5-10 % of asthma patients do not respond to conventional therapy. Currently, allergen-specific immunotherapy (SIT) is the only available curative treatment for allergic asthma patients, and is most effective in monosensitized individuals. Toll-like receptor (TLR) 4 and TLR9 agonists can be used as an adjuvant to improve the efficacy of allergen-SIT. Anti-IgE therapy is currently used with varying success rates for the treatment of allergic asthma. Appropriate diagnosis and recognition of the etiology of underlying disease symptoms is essential for the success of novel immunomodulatory treatments. Disease classification based on endotypes will facilitate the appropriate choice for therapy, as endotypes describe subtypes of asthma, which are defined by distinct pathological mechanisms. Novel immunomodulatory therapies are targeting specific cytokines or cell-surface receptors and interfere with these pathological mechanisms, thereby altering the course of the disease. A range of novel immunomodulatory drugs is currently under development for the treatment of asthma. These drugs specifically target key molecules that play a role in the pathways involved in the pathogenesis of asthma, and include biologicals that primarily target cytokines and cytokine receptors, as well as small molecules that target chemokine receptors and TLRs. The safety and efficacy of many of these novel drugs still remain to be determined.

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“…The CC chemokine receptors CC chemokine receptor type 3 (CCR3) and CCR4 are G-protein-coupled receptors that are highly expressed in eosinophils and basophils, T H 1 and T H 2 cells, and airway epithelia. CCR3 and CCR4 act as receptors for a variety of chemokines including the eotaxins CCL5, CCL17, and CCL22, which play a role in asthma pathophysiology [23]. There is evidence that CCR3 inhibition may decrease inflammation, and CCR4 is believed to be able to recruit T H 2 cells to inflammatory sites [24].…”

Section: The Pathophysiology Of Asthmamentioning

confidence: 99%

“…GW 766994 is a selective, competitively binding CCR3 antagonist that has already completed phase I trials in patients with mild to moderate asthma and high sputum eosinophilia [23]. Mogamulizumab (AMG 761) is a humanized monoclonal afucosylated anti-CCR4 IgG1 antibody [82].…”

Section: Drugs Targeting Ccr3 and Ccr4mentioning

confidence: 99%

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

Heck¹,

Nguyen

Le³

et al. 2015

Int Arch Allergy Immunol

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Bronchial asthma is a heterogeneous, complex, chronic inflammatory and obstructive pulmonary disease driven by various pathways to present with different phenotypes. A small proportion of asthmatics (5-10%) suffer from severe asthma with symptoms that cannot be controlled by guideline therapy with high doses of inhaled steroids plus a second controller, such as long-acting β₂ agonists (LABA) or leukotriene receptor antagonists, or even systemic steroids. The discovery and characterization of the pathways that drive different asthma phenotypes have opened up new therapeutic avenues for asthma treatment. The approval of the humanized anti-IgE antibody omalizumab for the treatment of severe allergic asthma has paved the way for other cytokine-targeting therapies, particularly those targeting interleukin (IL)-4, IL-5, IL-9, IL-13, IL-17, and IL-23 and the epithelium-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Knowledge of the molecular basis of asthma phenotypes has helped, and continues to help, the development of novel biologicals that target a diverse array of phenotype-specific molecular targets in patients suffering from severe asthma. This review summarizes potential therapeutic approaches that are likely to show clinical efficacy in the near future, focusing on biologicals as promising novel therapies for severe asthma.

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Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo‐controlled clinical trial

Abstract: In conclusion, this study calls into question the role of CCR3 in airway eosinophilia in asthma and suggests that other cellular mechanisms mediated by the CCR3 receptor may contribute to airway hyperresponsiveness.

Cited by 83 publications

References 40 publications

Suppression of Retinal Neovascularization by Anti-CCR3 Treatment in an Oxygen-Induced Retinopathy Model in Mice

Suppression of Retinal Neovascularization by Anti-CCR3 Treatment in an Oxygen-Induced Retinopathy Model in Mice

New Targets for Immune Modulation in Asthma

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

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