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Human interleukin-6 receptor super-antagonists with high potency and wide
spectrum on multiple myeloma cells
E Sporeno, R Savino, L Ciapponi, G Paonessa, A Cabibbo, A Lahm, K Pulkki, RX Sun, C Toniatti and B Klein
Istituto di Richerche di Biologia Molecolare (IRBM)- P. Angeletti, Pomezia,
Rome, Italy.
Interleukin-6 (IL-6) is the major growth factor for myeloma cells and is
believed to participate in the pathogenesis of chronic autoimmune diseases
and postmenopausal osteoporosis. IL-6 has been recently shown to possess
three topologically distinct receptor binding sites: site 1 for binding to
the subunit specific chain IL-6R alpha and sites 2 and 3 for the
interaction with two subunits of the signaling chain gp130. We have
generated a set of IL-6 variants that behave as potent cytokine receptor
super-antagonists carrying substitutions that abolish interaction with
gp130 at either site 2 alone (site 2 antagonist) or at both sites 2 and 3
(site 2 + 3 antagonist). In addition, substitutions have been introduced in
site 1 that lead to variable increases in binding for IL-6R alpha up to
70-fold. IL-6 super-antagonists inhibit wild-type cytokine activity with
efficacy proportional to the increase in receptor binding on a variety of
human call lines of different origin, and the most potent molecules display
full antagonism at low molar excess to wild-type IL-6. When tested on a
representative set of IL-6-dependent human myeloma cell lines, although
site 2 super- antagonists were in general quite effective, only the site 2
+ 3 antagonist Sant7 showed antagonism on the full spectrum of cells
tested. In conclusion, IL-6 super-antagonists are a useful tool for the
study of myeloma in vitro and might constitute, in particular Sant7,
effective IL-6 blocking agents in vivo.
Volume 87,
Issue 11,
pp. 4510-4519,
06/01/1996
Copyright © 1996 by The American Society of Hematology
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