Mechanisms of allergy and clinical immunology
Anti–IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels

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Background

Anti–IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized.

Objective

We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects.

Methods

The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filtration. Immunoreactive IL-5 fraction and plasma samples were subsequently precipitated with saturating concentrations of protein A/G.

Results

Twenty-three patients responded to anti–IL-5 therapy with a decrease in blood eosinophil counts and a reduced percentage of CCR3+ cells by 20- and 13-fold, respectively (P < .0001). Responsiveness was not related to the levels of baseline plasma IL-5 or the presence of FIP1L1-PDGFRA fusion gene. Persistently decreased blood eosinophilia remained for 3 months after final infusion in 76% of subjects. Therapy was associated with a large increase in blood IL-5 levels, likely because of a circulating IL-5/mepolizumab complex precipitated with protein A/G, a significant increase in eosinophil IL-5 receptor α expression, and increased percentage of CD4+ and CD8+ cells producing intracellular IL-5 (P < .05). Additionally, anti-IL-5 therapy decreased eotaxin-stimulated eosinophil shape change ex vivo.

Conclusions

Anti–IL-5 therapy induces a dramatic and sustained decrease in blood eosinophilia (including CCR3+ cells), decreased eosinophil activation, and increased circulating levels of IL-5 in a variety of eosinophilic disorders. Increased levels of IL-5 receptor α and lymphocyte IL-5 production after anti–IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.

Section snippets

Inclusion and exclusion criteria

Twenty-five subjects (13 male and 12 female subjects 18-57 years of age) were enrolled in an open-label phase I/II trial designed to assess the safety of mepolizumab and to delineate the effect of neutralizing endogenous IL-5 activity in patients with eosinophilic disorders, as previously described.18, 20

Subject characteristics

Of the 25 subjects enrolled, 18 were diagnosed with a diverse set of HESs, as defined by a recent workshop (Table I).22 Six subjects were diagnosed with EE. Of these subjects, 4 subjects with

Effect of anti–IL-5 therapy (mepolizumab) on peripheral blood eosinophil levels

Subjects (Table I) were observed, stabilized, or both for 8 weeks, subsequently infused with 3 doses of intravenous mepolizumab at 4-week intervals (weeks 8, 12, and 16), and monitored thereafter for an additional 12 weeks (Fig 1, A). Mepolizumab therapy was generally well tolerated (Table I).

During the first 8 weeks, the mean eosinophil level ranged from 1183 ± 2073 cells/mm3 at baseline to 1400 ± 2179 cells/mm3 (mean ± SD, P = .15). After mepolizumab therapy, a marked and sustained decrease

Discussion

Eosinophilic disorders are a heterogeneous group of diseases characterized by blood eosinophilia, tissue eosinophilia, or both with end organ damage. Current therapies for these disorders are often unsatisfactory because of their inefficiency to abate the eosinophilia, their toxicity, or both. Herein we report the immunologic and hematologic effects of antiIL-5 (mepolizumab) in 25 patients with diverse eosinophilic disorders. Our findings establish that (1) mepolizumab is effective in

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Supported by Food and Drug Administration grant no. FD-R 002313, the Burroughs Wellcome Fund, the CURED (Campaign Urging Research for Eosinophilic Diseases) Foundation, and the Buckeye Foundation. We are grateful to the Translational Research Office at CCHMC for their assistance and the General Clinical Research Center at CCHMC (supported by USPHS GCRC grant no. M01 RR 08084 from the National Center for Research Resources, National Institutes of Health). Miguel L. Stein is a recipient of a fellowship from the American Physicians Fellowship for Medicine in Israel.

Disclosure of potential conflict of interest: A. H. Assa'ad has consulting arrangements with and has received research support from GlaxoSmithKline and has served as an expert witness in food allergy and anaphylaxis litigation. M. E. Rothenberg has consulting arrangements with Merck, Ception Therapeutics, and Medacorp; is on the speakers' bureau for Merck; has received research support from the National Institutes of Health, the Food Allergy and Anaphylaxis Network, Ception Therapeutics, and Merck; and is on the advisory board for the National Institutes of Health and the American Partnership for Eosinophilic Disorders. The rest of the authors have declared that they have no conflict of interest.

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