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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1943-1951
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,
B. McClure,
B. Cambareri,
B. Zacharakis,
P.O. Iversen,
F. Stomski,
J.M. Woodcock,
C.J. Bagley,
R. D'Andrea, and
A.F. Lopez
From the Hanson Centre for Cancer Research, the Institute of Medical
and Veterinary Science, Adelaide, Australia.
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 
chain and a shared subunit ( c). Although binding of
IL-5, GM-CSF, and IL-3 to their respective receptor chains is the
first step in receptor activation, it is the recruitment of
c that allows high-affinity binding and signal
transduction to proceed. Thus, 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 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 c. Interestingly,
epitope analysis using several 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 c, suggesting that ligand contact
with c is a prerequisite for recruitment of
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.
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