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|Title:||Simultaneous antagonism of interleukin-5, granulocyte-macrophage colony-stimulting factor, and interleukin-3 stimulation of human eosinophils by targetting the common cytokine binding site of their receptors|
|Citation:||Blood, 1999; 94(6):1943-1951|
|Publisher:||AMER SOC HEMATOLOGY|
|Q. Sun, K. Jones, B. McClure, B. Cambareri, B. Zacharakis, P.O. Iversen, F. Stomski, J.M. Woodcock, C.J. Bagley, R. D’Andrea, and A.F. Lopez|
|Abstract:||Human interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3 are eosinophilopoietic cytokines implicated in allergy in general and in the inflammation of the airways specifically as seen in asthma. All 3 cytokines function through cell surface receptors that comprise a ligand-specific alpha chain and a shared subunit (beta(c)). Although binding of IL-5, GM-CSF, and IL-3 to their respective receptor alpha chains is the first step in receptor activation, it is the recruitment of beta(c) that allows high-affinity binding and signal transduction to proceed. Thus, beta(c) is a valid yet untested target for antiasthma drugs with the added advantage of potentially allowing antagonism of all 3 eosinophil-acting cytokines with a single compound. We show here the first development of such an agent in the form of a monoclonal antibody (MoAb), BION-1, raised against the isolated membrane proximal domain of beta(c). BION-1 blocked eosinophil production, survival, and activation stimulated by IL-5 as well as by GM-CSF and IL-3. Studies of the mechanism of this antagonism showed that BION-1 prevented the high-affinity binding of (125)I-IL-5, (125)I-GM-CSF, and (125)I-IL-3 to purified human eosinophils and that it bound to the major cytokine binding site of beta(c). Interestingly, epitope analysis using several beta(c) mutants showed that BION-1 interacted with residues different from those used by IL-5, GM-CSF, and IL-3. Furthermore, coimmunoprecipitation experiments showed that BION-1 prevented ligand-induced receptor dimerization and phosphorylation of beta(c), suggesting that ligand contact with beta(c) is a prerequisite for recruitment of beta(c), receptor dimerization, and consequent activation. These results demonstrate the feasibility of simultaneously inhibiting IL-5, GM-CSF, and IL-3 function with a single agent and that BION-1 represents a new tool and lead compound with which to identify and generate further agents for the treatment of eosinophil-dependent diseases such as asthma.|
|Keywords:||Leukocytes; Eosinophils; Neutrophils; Monocytes; CHO Cells; Animals; Humans; Granulocyte Macrophage Colony-Stimulating Factors, Recombinant; Interleukin-3; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Receptors, Interleukin-3; Receptors, Interleukin; Recombinant Proteins; Interleukin-5; Transfection; Lymphocyte Activation; Cell Survival; Binding Sites; Kinetics; Cricetinae; Receptors, Interleukin-5|
|Rights:||Copyright © 1999 The American Society of Hematology|
|Appears in Collections:||Medicine publications|
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