CONSTITUENTS OF AUTOCRINE IL-6 LOOPS IN MYELOMA CELL-LINES AND THEIR TARGETING FOR SUPPRESSION OF NEOPLASTIC GROWTH BY ANTIBODY STRATEGIES

We examined the constitution and biological relevance of an autocrine IL-6/IL6-receptor (r) loop in 7 multiple myeloma and plasma-cell leuke mia lines in order to determine its biological role and potential ther apeutic impact on antibody strategies. The expression and constitution of the IL-br [i.e. membrane-bound gp-80, soluble (s)gp-55 and the gp- 130 IL-6 signal-transducing element (str)], the binding capacity of th e membrane-associated receptor(s) for IL-6, the production and secreti on of IL-6 by neoplastic plasma cells, and the effect of IL-6 on tumor -cell proliferation were investigated. In the U-266 cell line, the gro wth-inhibitory effects of antibodies (Abs) against IL-6 and the IL-6-b inding subunit of its receptor were compared with each other. From our results the following conclusions may be drawn: (i) Substantial diffe rences in the quantificative assembly of the IL-br constituents and in the response to recombinant (r) human (h) IL-6 became evident in the 7 myeloma cell lines. (ii) The components of an autocrine IL-6 loop ma y be regulated in an independent and, in the case of IL-6 and sgp-55, probably counteractive manner. (iii) The level of endogenous IL-6 and the reservoir of recruitable sgp-55 were important for the response to exogenous rhIL-6. (iv) Apart from IL-6, other growth factors are impo rtant for the propagation of myeloma cells but at least some of them e xert their effect through an IL-6-dependent pathway. Their growth-prom oting activity, as well as that of IL-6, may be successfully targeted by immunological means, with Abs against the IL-6r being more efficien t than those against the ligand. (C) 1996 Wiley-Liss, Inc.