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


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


METHODS
We used surface plasmon resonance to determine the binding affinity of MEDI-563 to FcgammaRIIIa. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5Ralpha 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.


RESULTS
MEDI-563 binds to an epitope on IL-5Ralpha 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.


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.
Kolbeck
Roland
R
Department of Respiratory, Inflammation & Autoimmunity, MedImmune, LLC, Gaithersburg, MD 20878, USA. KolbeckR@medimmune.com
Kozhich
Alexander
A
Koike
Masamichi
M
Peng
Li
L
Andersson
Cecilia K
CK
Damschroder
Melissa M
MM
Reed
Jennifer L
JL
Woods
Robert
R
Dall'acqua
William W
WW
Stephens
Geoffrey L
GL
Erjefalt
Jonas S
JS
Bjermer
Leif
L
Humbles
Alison A
AA
Gossage
David
D
Wu
Herren
H
Kiener
Peter A
PA
Spitalny
George L
GL
Mackay
Charles R
CR
Molfino
Nestor A
NA
Coyle
Anthony J
AJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000915:Antibody Affinity; D000920:Antibody-Dependent Cell Cytotoxicity; D002452:Cell Count; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018604:Epitope Mapping; D000939:Epitopes / Q000378:metabolism*; D005260:Female; D006801:Humans; D053666:Interleukin-5 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D016297:Mutagenesis, Site-Directed; D015202:Protein Engineering; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020349:Surface Plasmon Resonance
D000911:Antibodies, Monoclonal; D000939:Epitopes; C496124:FCGR3A protein, human; D053666:Interleukin-5 Receptor alpha Subunit; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins