Elsevier

The Lancet

Volume 356, Issue 9248, 23–30 December 2000, Pages 2144-2148
The Lancet

Early Report
Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsìveness, and the late asthmatic response

https://doi.org/10.1016/S0140-6736(00)03496-6Get rights and content

Summary

Background

Interleukin-5 (IL-5) is essential for the formation of eosinophils, which are thought to have a major role in the pathogenesis of asthma and other allergic diseases. We aimed to assess the effects of monoclonal antibody to IL-5 on blood and sputum eosinophils, airway hyperresponsiveness, and the late asthmatic reaction to inhaled allergen in patients with mild asthma.

Methods

We did a double-blind randomised placebo-controlled trial, in which a single intravenous infusion of humanised (IgG-k) monoclonal antibody to IL-5 (SB-240563) was given at doses of 2·5 mg/kg (n=8) or 10·0 mg/kg (n=8). The effects of treatment on responses to inhaled allergen challenge, sputum eosinophils, and airway hyper-responsiveness to histamine were measured at weeks 1 and 4 with monitoring of blood eosinophil counts for up to 16 weeks.

Findings

Monoclonal antibody against IL-5 lowered the mean blood eosinophil count at day 29 from 0·25x109/L (95% CI 0·16-0·34) in the placebo group to 0·04x109/L (0·00-0·07) in the 10 mg/kg group (p<0·0001), and prevented the blood eosinophilia that follows allergen challenge. After inhaled allergen challenge, 9 days after treatment, the percentage sputum eosinophils were 12·2% in the placebo group and lowered to 0·9% (−1·2 to 3·0; p=0·0076) in the 10 mg/kg group, and this effect persisted at day 30 after the dose. There was no significant effect of monoclonal antibody to IL-5 on the late asthmatic response or on airway hyperresponsiveness to histamine.

Interpretation

A single dose of monoclonal antibody to IL-5 decreased blood eosinophils for up to 16 weeks and sputum eosinophils at 4 weeks, which has considerable therapeutic potential for asthma and allergy. However, our findings question the role of eosinophils in mediating the late asthmatic response and causing airway hyper-responsiveness.

Introduction

Asthma is a chronic inflammatory disease of the airways in which eosinophils are prominent in sputum, bronchoalveolar lavage, and mucosal biopsy samples.1 These tissue eosinophils are terminally differentiated myeloid leucocytes with characteristic secondary granules2 that have the capacity to cause airway hyperresponsiveness in bronchial smooth-muscle.3 Furthermore, eosinophils could mediate some of the structural changes comprising airways remodelling, including epithelial shedding, sub-basement membrane collagen deposition, and smooth-muscle hypertrophy.4

Within the bone marrow, interleukin-5 (IL-5) is the major haematopoietin responsible for terminal differentiation of human eosinophils.5 This cytokine could be involved in eosinophilic inflammation in asthma6 since there are raised concentrations of IL-5 in serum7 and bronchial biopsy samples.8 In addition, raised serum IL-5 and blood eosinophils are associated with the fall in forced expiratory volume in 1 s (FEV1) that constitutes the late asthmatic reaction.9

Direct evidence that IL-5 might be harmful in asthma is that inhalation of IL-5 by patients with asthma causes airway hyper-responsiveness and sputum eosinophilia.10 Monoclonal antibodies to IL-5 administered to animals with allergic asthma cause long-term inhibition of pulmonary eosinophilia and airway hyper-responsiveness.11, 12 Furthermore, mice in which the IL-5 gene has been deleted failed to develop pulmonary eosinophilia and airway hyper-responsiveness after allergen challenge.13

We aimed to describe the effect of a single intravenous infusion of humanised monoclonal antibody against IL-5 on blood and sputum eosinophils, and the responses to inhaled allergen in patients with atopic asthma. In particular, our study was designed to assess the tolerability and activity of a potent and specific anti-eosinophil treatment.

We recruited 24 non-smoking men (mean age 27, range 18-45 years) with mild allergic asthma (as defined by the American Thoracic Society)14 and a history of episodic wheeze and shortness of breath. The patients were atopic, as defined by positive skin tests in response to common airborne allergens (Dermatophagoides pteronyssinus, mixed grass pollen, and cat hair) and were maintained on shortacting inhaled β2-agonist treatment as required (table 1). Patients had neither worsening asthma nor a respiratory infection in the preceding 6 weeks. FEV1 at baseline was at least 70% of the predicted value and there was a documented airway hyper-responsiveness to histamine, with a provocation concentration causing a 20% reduction in FEV1 (PC20) <8 mg/mL. Patients had documented early and late asthmatic responses (defined as a ⩾ 15% reduction in FEV1 on at least three occasions between 4 and 10 h after allergen) to inhaled incremental allergen challenge between 3 and 6 weeks before the study treatment was given. We obtained approval from relevant national regulatory agencies, local ethics committees, and written informed patient consent.

This study was a double-blind, randomised, placebocontrolled, single dose, parallel group study in three centres. At screening (28 days before the dose), a full medical history, examination, and investigations were done to ensure eligibility for the study. We examined stool specimens for absence of parasites. 14 days before the dose, patients had a histamine challenge followed 2 h later by an inhaled allergen challenge, with a bolus dose equal to the sum of the incremental doses that produced the screening late asthmatic reaction. 22 h after allergen inhalation, a further histamine challenge was done and sputum was induced 1 h later. On day 1, patients were randomly assigned intravenous infusion of humanised monoclonal antibody to IL-5 (SB 240563) or placebo. Allocation to active treatment or placebo was in a 2:1 ratio for the 2·5 mg/kg and 10 mg/kg groups (n=12 for each group, eight receiving monoclonal antibody to IL-5 and four receiving placebo). A 30 min intravenous infusion of either study treatment or placebo was done, with continuous electrocardiographic monitoring, and measurement of blood pressure and lung function at regular intervals. 24 h after the infusion, patients were discharged, but they returned on 2 successive days for blood analysis and lung function testing. On day 8 and 29 after the dose, all patients had a histamine challenge followed 2 h later by an inhaled allergen challenge with another histamine challenge, and sputum induction the next day. Further visits were made at intervals up to 16 weeks after the dose for assessment of airway hyperresponsiveness and blood eosinophil counts.

All the 24 patients assigned placebo in both dose groups completed all of the visits up to day 30. One patient in the 2·5 mg/kg group withdrew for personal reasons at week 12 after the dose (figure 1).

We analysed blood eosinophil counts with automated haematology analysers at each of the participating centres. For bolus allergen challenge, a single volume of relevant allergen (ALK, Reading, UK) was diluted with saline to make up a single dose, which was equal to the sum of the incremental doses inhaled by the patient to cause the early phase during the screening allergen challenge.15 We measured airway hyper-responsiveness using inhalation of doubling concentrations of histamine according to standard challenge protocols.16

Before sputum induction, all patients inhaled 200 μg of salbutamol via a metered dose inhaler. The patients inhaled hypertonic saline to induce sputum, and selected sputum was analysed.17 Cytospins of sputum cells were prepared, fixed with methanol, and stained by May-Grunwald-Giemsa.

We analysed baseline variables by analysis of variance. For the primary variable of late asthmatic response, the maximum percentage change in FEV1 from the dose at 4 to 10 h after allergen challenge was calculated for days -14, 8, and 29. An analysis of covariance (ANCOVA) model accounting for baseline value (−14 days), group (placebo, 2·5 mg/kg, and 10 mg/kg), time (day 8 and day 29), and interaction between group and time was used. Least squares means for day 8 and day 29 and the mean differences between placebo and the two treated groups on day 8 and day 29 are reported along with the 95% CIs. We did similar analyses separately for blood eosinophils, sputum eosinophils, provocative concentration of histamine preallergen challenge and postallergen challenge, but eosinophils were analysed on the square root scale whereas histamine was analysed on the log scale. For these transformed variables, the least squares means, mean differences, and the associated CIs are backtransformed to the original scale, and these are reported (table 2).

Section snippets

Results

In the 24 patients who participated in the study (table 1), treatment with monoclonal antibody treatment to IL-5 at baseline (day - 14) caused no clinically relevant adverse events. Antibodies to IL-5 did not develop during the 16 week study period.

At baseline (day -14) for FEV (% predicted) the difference between the placebo and the 2·5 mg/kg groups was not significant, but there was a small significant difference between the placebo and the 10 mg/kg groups (p=0·0494). There was a signficant

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