Targeting myeloid leukemia with a DT390-mIL-3 fusion immunotoxin: ex vivo and in vivo studies in mice

The IL-3 receptor was expressed on a high frequency of myeloid leukemia cel ls and also on hematopoietic and vascular cells. We previously showed that a recombinant IL-3 fusion immunotoxin (DT390IL-3) expressed by splicing the murine IL-3 gene to a truncated diphtheria toxin (DT390) gene selectively killed IL-3R(+) expressing cells and was not uniformly toxic to uncommited BM progenitor cells (Chan,C.-H,, Blazar,B,R., Greenfield,L., Kreitman,R.J. and Vallera,D.A., 1996, Blood, 88, 1445-1456), Thus, we explored the feasab ility of using DT390IL-3 as an antileukemia agent. DT390IL-3 was toxic when administered to mice at doses as low as 0.1 mu g/day, The dose limiting to xicity appeared to be related to platelet and bleeding effects of the fusio n toxin, Because of these effects, DT390IL-3 was Studied ex vivo as a means of purging contaminating leukemia cells from BM grafts in a murine autolog ous BM transplantation. In this setting, as few as 1000 IL-3R-expressing, b cr/abl transformed myeloid 32Dp210 leukemia cells were lethal, An optimal p urging interval of 10 nM/l for 8 h eliminated leukemia cells from 32Dp210/B M: mixtures given to lethally irradiated (8 Gy) C3H/HeJ syngeneic mice. Mic e given treated grafts containing BM and a lethal dose of 32Dp210 cells sur vived over 100 days while mice given untreated grafts did not survive (P < 0.00001). DT390IL-3 may prove highly useful for ex vivo purging of lethal m alignant leukemia cells from autologous BM grafts.