TREATMENT OF ACUTE MYELOCYTIC-LEUKEMIA WITH INTERLEUKIN-6 PSEUDOMONASEXOTOXIN FUSION PROTEIN IN A RAT LEUKEMIA MODEL

We studied the applicability of interleukin-6 Pseudomonas exotoxin fus ion protein (IL-6PE4E) for treatment of acute myelocytic leukemia (AML ). Leukemic cells from five out of 10 AML patients studied expressed I L-6 receptor (IL-6R) and proliferation in vitro was Inhibited in four of these cases, The potential of this approach in vivo was tested in a pre-clinical model for AML; the Brown Norway acute myelocytic leukemi a (BNML). To obtain IL-6R expression levels on BNML cells comparable t o the numbers expressed on human AML, human IL-6R gene transfectants o f the BNML sub-line LT12 (LT12/IL-6R) were generated. IL-6PE4E is cyto toxic in vitro to LT12/IL-6R expressing 1400 high affinity IL-6R per c ell with 50% inhibition of DNA synthesis at 1 ng/ml, In vivo treatment of leukemic rats carrying LT12/IL-6R leukemia indicated that the maxi mal tolerated dose of IL-6PE4E was 275+/-25 mu g/kg/day, when continuo usly administered for 7 days and resulted in a 90% reduction in leukem ic cell load. AT this dose level of IL-6PE4E no reduction of normal he mopoietic progenitors was seen in non-leukemic rats. At higher dose le vels (350-1050 mu g/kg/day) severe systemic toxicity was encountered. On the basis of these pre-clinical studies the feasibility of growth f actor-toxins for selective in vivo targeting to AML cells is evaluated .