title: The receptor super-antagonist Sant7.
abstract: 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.
authors: IRBM,I-00040 POMEZIA,ROME,ITALY. IRCCS,IDI,BIOCHEM LAB,ROME,ITALY. UNIV AQUILA,I-67100 LAQUILA,ITALY. CNRS,INST MOL GENET,F-34033 MONTPELLIER 1,FRANCE.
authors: R
authors: R
authors: Savino
authors: A
authors: A
authors: Demartis
authors: L
authors: L
authors: Ciapponi
authors: E
authors: E
authors: Sporeno
authors: C
authors: C
authors: Toniatti
authors: F
authors: F
authors: Bernassola
authors: G
authors: G
authors: Melino
authors: B
authors: B
authors: Klein
authors: G
authors: G
authors: Ciliberto