Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells

Elisabetta Sporeno, Rocco Savino, Laura Ciapponi, Giacomo Paonessa, Andrea Cabibbo, Armin Lahm, Kari Pulkki, Ren Xiao Sun, Carlo Toniatti, Bernard Klein, G. Ciliberto

Research output: Contribution to journalArticlepeer-review


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 I for binding to the subunit specific chain IL-6Rα 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 IL6Rα 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 cell 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.

Original languageEnglish
Pages (from-to)4510-4519
Number of pages10
Issue number11
Publication statusPublished - Jun 1 1996

ASJC Scopus subject areas

  • Hematology


Dive into the research topics of 'Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells'. Together they form a unique fingerprint.

Cite this