MEDI-563, a humanized anti–IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function

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• 作者：Rol ; Kolbeck ; Alex ; er Kozhich ; Masamichi Koike ; Li Peng ; Cecilia K. Andersson ; Melissa M. Damschroder ; Jennifer L. Reed ; Robert Woods ; William W. Dall'Acqua ; Geoffrey L. Stephens ; Jonas S. Erjefalt ; L
• 关键词：Asthma ; eosinophil ; antibody-dependent cell-mediated cytotoxicity ; Fcγ ; RIIIα ; basophil ; IL-5 ; IL-5 receptor ; monoclonal antibody
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2010
• 出版时间：June 2010
• 年：2010
• 卷：125
• 期：6
• 页码：1344-1353.e2
• 全文大小：1200 K

文摘

lass=""h4"">Background

Peripheral blood eosinophilia and lung mucosal eosinophil infiltration are hallmarks of bronchial asthma. IL-5 is a critical cytokine for eosinophil maturation, survival, and mobilization. Attempts to target eosinophils for the treatment of asthma by means of IL-5 neutralization have only resulted in partial removal of airway eosinophils, and this warrants the development of more effective interventions to further explore the role of eosinophils in the clinical expression of asthma.

lass=""h4"">Objective

We sought to develop a novel humanized anti–IL-5 receptor α (IL-5Rα) mAb with enhanced effector function (MEDI-563) that potently depletes circulating and tissue-resident eosinophils and basophils for the treatment of asthma.

lass=""h4"">Methods

We used surface plasmon resonance to determine the binding affinity of MEDI-563 to FcγRIIIa. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5Rα was determined by using site-directed mutagenesis. The consequences of MEDI-563 administration on peripheral blood and bone marrow eosinophil depletion was investigated in nonhuman primates.

lass=""h4"">Results

MEDI-563 binds to an epitope on IL-5Rα that is in close proximity to the IL-5 binding site, and it inhibits IL-5–mediated cell proliferation. MEDI-563 potently induces antibody-dependent cell-mediated cytotoxicity of both eosinophils (half-maximal effective concentration = 0.9 pmol/L) and basophils (half-maximal effective concentration = 0.5 pmol/L) in vitro. In nonhuman primates MEDI-563 depletes blood eosinophils and eosinophil precursors in the bone marrow.

lass=""h4"">Conclusions

MEDI-563 might provide a novel approach for the treatment of asthma through active antibody-dependent cell-mediated depletion of eosinophils and basophils rather than through passive removal of IL-5.