Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/101845
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Type: Journal article
Title: CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common β chain of the IL-3, GM-CSF and IL-5 receptors
Other Titles: CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common beta chain of the IL-3, GM-CSF and IL-5 receptors
Author: Panousis, C.
Dhagat, U.
Edwards, K.M.
Rayzman, V.
Hardy, M.P.
Braley, H.
Gauvreau, G.M.
Hercus, T.R.
Smith, S.
Sehmi, R.
McMillan, L.
Dottore, M.
McClure, B.J.
Fabri, L.J.
Vairo, G.
Lopez, A.F.
Parker, M.W.
Nash, A.D.
Wilson, N.J.
Wilson, M.J.
et al.
Citation: mAbs, 2016; 8(3):436-453
Publisher: Taylor & Francis Group
Issue Date: 2016
ISSN: 1942-0862
1942-0870
Statement of
Responsibility: 
Con Panousis, Urmi Dhagat, Kirsten M. Edwards, Veronika Rayzman, Matthew P. Hardy, Hal Braley, Gail M. Gauvreau, Timothy R. Hercus, Steven Smith, Roma Sehmi, Laura McMillan, Mara Dottore, Barbara J. McClure, Louis J. Fabri, Gino Vairo, Angel F Lopez, Michael W. Parker, Andrew D. Nash, Nicholas J. Wilson, Michael J. Wilson and Catherine M. Owczarek
Abstract: The β common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific α and shared β common (βc, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human βc receptor. The binding epitope of CSL311 on the βc receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human βc receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 β common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human βc receptor is central to pathogenesis. The coordinates for the βc/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).
Keywords: Affinity maturation
GM-CSF
IL-3
IL-5
asthma
cytokine
eosinophil
myeloid
phage display
therapeutic antibody
β common receptor
Rights: Published with license by Taylor & Francis Group, LLC © Recombinant Proteins This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.o rg/licenses/by-nc/3.0/), which permits unre- stricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the nam ed author(s) have been asserted.
DOI: 10.1080/19420862.2015.1119352
Published version: http://dx.doi.org/10.1080/19420862.2015.1119352
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