THE RECEPTOR SUPER-ANTAGONIST SANT7 - A POTENT AND SAFE INHIBITOR OF IL-6 ON HUMAN MYELOMA CELLS (REVIEW)

Interleukin-6 (IL-6) plays a central role in the pathogenesis of multi ple myeloma, acting both as a growth and a survival factor for myeloma cells. IL-6 has been recently shown to possess three topologically di stinct receptor binding sites: site 1 for binding to the subunit speci fic chain IL-6R alpha and sites 2 and 3 for the interaction with two s eparate subunits of the signalling chain gp130. We have generated a se t of IL-6 receptor antagonists carrying substitutions that abolish int eraction with gp130 at either site 2 alone (site 2 antagonist) or at b oth sites 2 and 3 (site 2+3 antagonist). In addition, substitutions we re introduced at site 1 that increased affinity for IL-6R alpha. When tested as growth inhibitors on a representative set of IL-6-dependent human myeloma cell lines (XG-1, XG-2, XG-4 and XG-6), although site 2 antagonists were effective on 3 out of 4 of the cell lines, only the s ite 2+3 antagonist Sant7 showed full antagonism on the entire spectrum of cells tested. Moreover, IL-6 receptor antagonists were also pro-ap optotic factors for myeloma cells. Their capacity to induce cell death was directly related to the impairment of binding to gp130 and to the ir ability to fully block intracellular signalling. In fact, the most potent inducer of apoptosis was again Sant7, which also counteracted t he protective autocrine effect excercised by the endogenously produced IL-6. On the basis of these results we propose the super-antagonist S ant7 as a possible candidate for the immunotherapy of multiple myeloma .