Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:132

Article

Laviolette, Michel¹  Gossage, David L.²  Gauvreau, Gail³  Leigh, Richard⁴  Olivenstein, Ron⁵  Katial, Rohit⁶  Busse, William W.⁷  Wenzel, Sally⁸  Wu, Yanping²  Datta, Vivekananda²  Kolbeck, Roland²  Molfino, Nestor A.² 

[1] Univ Laval, Dept Med, Fac Med, Quebec City, PQ G1K 7P4, Canada

[2] MedImmune LLC, Clin Dev, Gaithersburg, MD USA

[3] McMaster Univ, Dept Med, Div Respirol, Hamilton, ON, Canada

[4] Univ Calgary, Dept Med, Div Resp, Calgary, AB, Canada

[5] McGill Univ, Ctr Hlth, Montreal Chest Inst, Montreal, PQ, Canada

[6] Natl Jewish Hlth, Dept Med, Denver, CO USA

[7] Univ Wisconsin, Dept Med, Madison, WI USA

[8] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA

关键词: Eosinophils;    IL-5;    IL-5 receptors;    asthma;    antibody-dependent cell-mediated cytotoxicity;   

DOI  :  10.1016/j.jaci.2013.05.020

来源: Elsevier

【 摘 要 】

Background: Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor alpha, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity. Objectives: We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood. Methods: In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive. Results: The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 1 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts. Conclusion: Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients.

【 授权许可】

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