Interleukin-6 (IL-6) plays a central role in the pathogenesis of
multiple myeloma, acting both as a growth and a survival factor for myeloma cells.
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 separate subunits of the signalling chain gp130. We have generated a set of
IL-6 receptor 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 were 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 site 2+3 antagonist
Sant7 showed full antagonism on the entire spectrum of cells tested. Moreover,
IL-6 receptor antagonists were also pro-apoptotic factors for myeloma cells. Their capacity to induce cell death was directly related to the impairment of binding to gp130 and to their ability to fully block intracellular signalling. In fact, the most potent inducer of apoptosis was again
Sant7, which also counteracted the protective autocrine effect excercised by the endogenously produced
IL-6. On the basis of these results we propose the super-antagonist
Sant7 as a possible candidate for the
immunotherapy of
multiple myeloma.