The trials and tribulations of anti–IL-5 …

Abstract

We read with considerable interest the October 2001 Rostrum article by Paul O'Byrne and colleagues,1O'Byrne PM Inman MD Paramesawaran K. The trials and tribulations of IL-5, eosinophils, and allergic asthma.J Allergy Clin Immunol. 2001; 108: 503-508Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar in which they provide a critical analysis of our study on the effects of an IL-5–blocking mAb.2Leckie MJ ten Brinke A Khan J Diamant Z O'Connor BJ Walls CM et al.Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response.Lancet. 2000; 356: 2144-2148Abstract Full Text Full Text PDF PubMed Scopus (1665) Google Scholar After a single intravenous infusion of a humanized mAb directed against IL-5 (SB240563), there was pronounced suppression of peripheral blood eosinophil numbers as well as considerably reduced numbers of sputum eosinophils 24 hours after inhaled allergen challenge. However, despite these clear effects, anti–IL-5 did not protect against the late asthmatic reaction (LAR) to inhaled allergen and did not have apparent significant effects on baseline or allergen-induced airway reactivity to histamine. The primary aim of our study with anti–IL-5 was to assess the tolerability of this agent in patients with mild asthma, and this is the reason that our parallel design study was restricted to groups of 8 patients assigned to receive anti–IL-5 at low or high dose or placebo. We would agree with O'Byrne et al that there was not enough power in our preliminary study to exclude a minor effect of anti–IL-5 on the LAR.3Inman MD Watson R Cockroft DW Wong BJO Hargreave FE O'Byrne PM. Reproducibility of allergen-induced early and late asthmatic responses.J Allergy Clin Immunol. 1995; 95: 1191-1195Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar However, we disagree with the criticism that our article lacks a measure of variance, inasmuch as 95% CIs were used extensively in our presentation of the effects of anti–IL-5 (see our Table II). In particular, with regard to the LAR difference between placebo and high-dose anti–IL-5 on day 29, there is a mean of –0.3, the LAR being considered to be the maximum percent fall in FEV1, with a 95% CI ranging from –7.1 to 6.5. Working back from the CI to get the SD of 8.15, we estimate that you would need 11,660 patients per group to give the study 80% power to detect this (non)difference in LAR. With regard to airway responsiveness to histamine, we accept that our study was inadequately powered to assess any subtle influence on this outcome, even when assessed as change in airway responsiveness. Interpretation of the effects of anti–IL-5 on inhaled allergen challenge must be made with caution, because even though eosinophil numbers in blood and sputum were markedly reduced by anti–IL-5, there were still residual eosinophils in the airways and these could be activated and surrounded by released eosinophil granule proteins. To address this issue of incomplete eosinophil antagonism, we eagerly await the results of a study currently being undertaken by Barry Kay and colleagues (at the National Heart and Lung Institute in the United Kingdom) in which they will assess the effects of anti–IL-5 on tissue eosinophils and their granule proteins in bone marrow, blood, bronchial mucosal biopsy specimens, nasal scrapings, and skin biopsy specimens from asthmatic patients. Inhalation of allergen constitutes an artificial situation, and effects on clinical symptoms and lung function in patients with symptomatic asthma need to be measured. There is a preliminary report that a different humanized mAb against IL-5 (SCH55700) also caused a pronounced reduction in circulating eosinophils in severe asthma but did not cause any significant effects on symptoms or lung function.4Kips JC O'Connor BJ Langley J Woodcock A Kerstjens HAM Postma DS et al.Results of a phase I trial with SCH55700, a humanized anti-IL-5 antibody in severe persistent asthma.Am J Respir Crit Care Med. 2000; 161: A505Crossref Scopus (192) Google Scholar In addition, SB240563 administered in 3 separate doses over 12 weeks has been studied in patients with asthma receiving inhaled corticosteroids, and there was no evidence of efficacy across a range of different pulmonary function and symptomatic endpoints—this despite a decrease in circulating eosinophil numbers (Dr C. Compton, oral presentation, American Thoracic Society, San Francisco, April 2001). In conclusion, we would like to stress that despite the initial negative clinical studies, there is a need to carry out further assessment of anti–IL-5, as well as eotaxin chemokine receptor 3 (CCR3) antagonists, to elucidate the potential of eosinophil-directed therapy in asthma and allergy. The eosinophil still represents an important target for novel therapeutics for asthma and allergic disease, and further clinical studies are needed to elucidate the role of this cell in airways remodeling, airway hyperresponsiveness, and exacerbations of asthma.