Targeting myeloid leukemia with a DT(390)-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 cells and also on hematopoietic and vascular cells. We previously showed that a recombinant IL-3 fusion immunotoxin (DT(390)IL-3) expressed by splicing the murine IL-3 gene to a truncated diphtheria toxin (DT(390)) gene selectively killed IL-3R(+) expressing cells and was not uniformly toxic to uncommitted 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 feasibility of using DT(390)IL-3 as an anti-leukemia agent. DT(390)IL-3 was toxic when administered to mice at doses as low as 0.1 microg/day. The dose limiting toxicity appeared to be related to platelet and bleeding effects of the fusion toxin. Because of these effects, DT(390)IL-3 was studied ex vivo as a means of purging contaminating leukemia cells from BM grafts in a murine autologous BM transplantation. In this setting, as few as 1000 IL-3R-expressing, bcr/abl transformed myeloid 32Dp210 leukemia cells were lethal. An optimal purging interval of 10 nM/l for 8 h eliminated leukemia cells from 32Dp210/BM mixtures given to lethally irradiated (8 Gy) C3H/HeJ syngeneic mice. Mice given treated grafts containing BM and a lethal dose of 32Dp210 cells survived over 100 days while mice given untreated grafts did not survive (P < 0.00001). DT(390)IL-3 may prove highly useful for ex vivo purging of lethal malignant leukemia cells from autologous BM grafts.
Vallera
D A
DA
University of Minnesota Cancer Center, Department of Therapeutic Radiology (Section on Experimental Cancer Immunology) Minneapolis, MN 55455, USA.
Seo
S Y
SY
Panoskaltsis-Mortari
A
A
Griffin
J D
JD
Blazar
B R
BR
D000818:Animals; D016465:Bone Marrow Purging; D004167:Diphtheria Toxin / Q000235:genetics*; D005434:Flow Cytometry; D006470:Hemorrhage / Q000139:chemically induced; D000922:Immunotoxins / Q000009:adverse effects / Q000627:therapeutic use*; D007377:Interleukin-3 / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*
D004167:Diphtheria Toxin; D000922:Immunotoxins; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins