In vitro and in vivo antitumor effects of the recombinant immunotoxin IL6(T23)-PE38KDEL in multiple myeloma

Abstract

IL6(T23)-PE38KDEL is a chimeric molecule composed of interleukin 6 (IL6), missing the N-terminal 23 amino acids, and fused to a truncated mutant form of Pseudomonas exotoxin (PE38KDEL). The aim of this study was to evaluate this recombinant immunotoxin in terms of its specific cytotoxicity to IL6R-overexpressing multiple myeloma (MM) cells in vitro, as well as its antitumor effects and side effects in vivo. IL6(T23)-PE38KDEL was expressed in Escherichia coli, refolded and purified from inclusion bodies. The purified IL6(T23)-PE38KDEL was found to be selectively cytotoxic to IL6 receptor-positive tumor cells in vitro. IC 50 values of IL6(T23)-PE38KDEL were evaluated by MTS assay. Toxicity and maximum-tolerated dose of IL6(T23)-PE38KDEL were determined in mice. The antitumor activity of IL6(T23)-PE38KDEL was evaluated in mice with MM through intravenous injection and interventional therapy. Intravenous administration of IL6(T23)-PE38KDEL caused a significantly increased survival time in treated mice, and exhibited dose- and time-dependent antitumor effects against MM mice. Moreover, complete tumor regression was observed in 30 and 80% of mice treated intravenously and intraperitoneally, respectively, with 0.4 mg/kg/day for 10 days. These results demonstrated that the recombinant immunotoxin IL6(T23)-PE38KDEL kills IL6R-overexpressing cancer cells, and causes significant tumor regression.