Immune deficiencies, infection, and systemic immune disordersMEDI-563, a humanized anti–IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function
Section snippets
Epitope mapping of MEDI-563
Extracellular IL-5Rα knockout mutants were engineered by substituting regions of full-length human IL-5Rα with corresponding segments of murine IL-5Rα and vice versa for knock-in mutants. Mutants were transiently expressed in HEK293F cells. HEK293F transfectants were incubated with 1 μg/mL MEDI-563 for 1 hour on ice in phosphate-buffered saline (PBS). After washing, cells were incubated with goat anti-human IgG–fluorescein isothiocyanate (Jackson ImmunoResearch Laboratories, West Grove, Pa) and
MEDI-563 interaction with IL-5Rα
MEDI-563 bound to recombinant human and cynomolgus monkey IL-5Rα extracellular domains with a dissociation constant of 11 and 42 pmol/L, respectively, whereas the F(ab) fragment bound with an approximately 100-fold lower affinity, as assessed by means of surface plasmon resonance (Table I). Consistent with the specific expression of IL-5Rα on human eosinophils and basophils among a large variety of hematopoietic cell types (Fig 1, A), MEDI-563 exclusively stained peripheral blood eosinophils
Discussion
IL-5 blockade in subjects with asthma has failed to improve parameters of lung function in response to allergen challenge despite rapid and near-complete depletion of eosinophils from peripheral blood and sputum.14, 15, 16, 17 However, a causal link between reduced eosinophil numbers and a reduction in exacerbation frequency and prednisone requirement has recently been demonstrated in subjects with severe refractory eosinophilic asthma.16, 17 Interestingly, results from 2 independent clinical
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Supported by MedImmune, LLC, Gaithersburg, Md, and Biowa, Inc, Princeton, NJ.
Disclosure of potential conflict of interest: R. Kolbeck, A. Kozhich, L. Peng, M. M. Damschroder, R. Woods, W. W. Dall'Acqua, G. L. Stephens, A. A. Humbles, D. Gossage, H. Wu, P. A. Kiener, N. A. Molfino, and A. J. Coyle are employed by MedImmune, LLC. J. L. Reed's husband is employed by MedImmune, LLC. C. R. Mackay is the Founder and Director of G2 Therapies. M. Koike and G.L. Spitalny are employed by Biowa, Inc. The rest of the authors have declared that they have no conflict of interest.
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J. L. Reed is currently affiliated with the US Food and Drug Administration, Center for Biologics Evaluation and Research, Rockville, Md.
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P. A. Kiener is currently employed by Zyngenia, Inc, Gaithersburg, Md.
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C. R. Mackay is currently affiliated with the Immunology and Stem Cell Labs, Faculty of Medicine, Nursing and Health Sciences, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.