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J. Biol. Chem., Vol. 269, Issue 1, 86-93, Jan, 1994
JP Brakenhoff, FD de Hon, V Fontaine, E ten Boekel, H Schooltink, S Rose-John, PC Heinrich, J Content and LA Aarden
Neutralizing monoclonal antibodies specific for human interleukin-6 (IL- 6)
bind two distinct sites on the IL-6 protein (sites I and II). Their
interference with IL-6 receptor binding suggested that site I is a
receptor-binding site of IL-6, whereas site II is important for signal
transduction. Mutagenesis of site II could therefore result in the
isolation of IL-6 receptor antagonists. To test this hypothesis, a panel of
IL-6 mutant proteins was constructed that did not bind to a site
II-specific monoclonal antibody. One such site II mutant protein (with
double substitution of Gln-160 with Glu and Thr-163 with Pro) was found to
be an antagonist of human IL-6. It was inactive on human CESS cells, weakly
active on human HepG2 cells, but active on mouse B9 cells. It could
specifically antagonize the activity of wild-type IL-6 on CESS and HepG2
cells. The binding affinity of this variant for the 80-kDa IL-6 receptor
was similar to that of wild-type IL-6. High affinity binding to CESS cells,
however, was abolished, suggesting that the mutant protein is inactive
because the complex of the 80-kDa IL-6 receptor and the mutant protein
cannot associate with the signal transducer gp130. The human IL-6
antagonist protein may be potentially useful as a therapeutic agent.
Development of a human interleukin-6 receptor antagonist
Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam.
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