Simultaneous antagonism of interleukin-5, granulocyte-macrophage colony- stimulating factor, and interleukin-3 stimulation of human eosinophils by targetting the common cytokine binding site of their receptors

Q. Sun, K. Jones, Barbara McClure, B. Cambareri, B. Zacharakis, P. O. Iversen, F. Stomski, J. M. Woodcock, C. J. Bagley, R. D'Andrea, A. F. Lopez

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52 Citations (Scopus)

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 α chain and a shared subunit (β(c)). Although binding of IL-5, GM-CSF, and IL-3 to their respective receptor α chains is the first step in receptor activation, it is the recruitment of β(c) that allows high-affinity binding and signal transduction to proceed. Thus, β(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 β(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 125I-IL-5, 125I-GM-CSF, and 125I-IL-3 to purified human eosinophils and that it bound to the major cytokine binding site of β(c). Interestingly, epitope analysis using several β(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 β(c), suggesting that ligand contact with β(c) is a prerequisite for recruitment of β(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.

Original languageEnglish
Pages (from-to)1943-1951
Number of pages9
JournalBlood
Volume94
Issue number6
Publication statusPublished - 15 Sep 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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