INTERLEUKIN-6 RECEPTOR SUPERANTAGONISTS ARE POTENT INDUCERS OF HUMAN MULTIPLE-MYELOMA CELL-DEATH

Interleukin-6 (IL-6) plays a central role in the pathogenesis of multi ple myeloma, acting as both a growth and a survival factor for myeloma cells, A series of IL-6 receptor antagonists that are IL-6 variants h as been recently obtained, the affinity of which for the ligand-specif ic receptor chain IL-6R alpha has been maintained or even increased, b ut the signaling of which is impaired by not being able to bind and/or dimerize the signaling chain gp130. Although IL-6 antagonists have be en shown to inhibit the growth of IL-6-dependent myeloma, no informati on has been gathered on their ability to induce myeloma cell death, We show here that IL-6 receptor antagonists are pro-apoptotic factors fo r the IL-6-dependent human myeloma cell line XG-1, Their capacity to i nduce cell death is in direct relation to their affinity for IL-6R alp ha, degree of gp130 binding impairment, and efficiency to inhibit intr acellular signaling events, Interestingly, the most potent pro-apoptot ic molecule, Sant7, counteracts the protective autocrine effect exerci sed by the limited amounts of IL-6 produced by XG-1 cells and is thus able to induce cell death at higher rate than just IL-6 deprivation, T hese findings are particularly relevant for the therapy of multiple my eloma.