Jill Reckless, Val Piercy, Kate Langley, Ian Purvis, David Fox & David Grainger (2009) FX125L, a novel small molecule chemokine inhibitor, attenuates neutrophil accumulation in a model of allergic asthma and exhibits a superior efficacy profile to dexamethasone or monteleukast.Late Breaking oral presentation (abstract 1418) at the XXVIII Congress of the European Academy of Allergy and Clinical Immunology, EAACI 2009, held in Warsaw, Poland on 6-10 June 2009.
ABSTRACT: Mild allergic asthma, characterized by an eosinophilic lung infiltrate is generally well controlled by existing therapeutic strategies, combining beta agonists for symptomatic relief with anti-inflammatory agents such as corticosteroids and leukotriene receptor antagonists. In contrast, severe steroid resistant asthma and COPD are characterized by a significant neutrophil component. Here we compared the effect of a broad-spectrum chemokine inhibitor (FX125L) with a corticosteroid (dexamethasone; DEX) and a leukotriene antagonist (montelukast) on multiple end-points, in a rodent model of allergic asthma. Adult BN rats were sensitized with endotoxin-free ovalbumin (ETF-OVA; 1mg in saline ip) on day 0, and challenged with an intratracheal administration of 0.01mg ETF-OVA + 1µg LPS on day 8, 15 and 22. Groups (n=6) were then sacrificed at 3, 24 and 72hrs following the last challenge. In this model, there is a substantial neutrophil response by 3 hrs, maximal at 24hrs, with a later macrophage and eosinophil response. FX125L (10mg/kg/day from day 8 onwards) abolished eosinophil and macrophage recruitment, and inhibited neutrophil accumulation by 44%.
DEX (0.3mg/kg on day 7, 14 and 21) also abolished eosinophil and macrophage recruitment, but significantly increased neutrophil numbers (+21%). In contrast, montelukast (10mg/kg twice daily from day 8) had only a modest suppressive effect on eosinophil numbers and no effect on neutrophil accumulation. Similar results were obtained measuring MPO antigen levels in BAL, with FX125L suppressing both total antigen (-38%; p<0.05) and the fraction released, while DEX increased total MPO antigen (+28%) but suppressed MPO release. Surprisingly, montelukast dramatically increased total MPO antigen, by more than 5-fold. FX125L and DEX had similar effects on other end-points (including suppression of mast cell chymase in BAL and inhibition of TNF-a release), while montelukast had no effect on these parameters. We conclude that FX125L, an aminolactam chemokine inhibitor currently in Phase I clinical trials, has a similar profile to corticosteroids in a rodent model of allergic asthma, with the additional benefit of reducing neutrophil accumulation, and was considerably superior to montelukast. Broad spectrum chemokine inhibitors such as FX125L represent a promising new class of therapeutics for the treatment of allergic asthma, with the possibility of efficacy in neutrophil-dominated steroid-resistant asthma and COPD.