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A Diphtheria Toxin-Interleukin 3 Fusion Protein Is Cytotoxic to Primitive Acute Myeloid Leukemia Progenitors But Spares Normal Progenitors¹

Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3 Canada [M. F-B., B. G., D. E. H.], and Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 [A. E. F., R. L. A.]

The relative cytotoxicity of a diphtheria toxin (DT) human interleukin 3(IL3) fusion protein (DT₃₈₈IL3) was tested against primitive normal (n = 3)and acute myeloid leukemia (AML) progenitors (n = 7). After 24-h culture with 50 ng/ml DT₃₈₈IL3, the mean percentages of kill of AML colony-forming cells (CFCs), long-term culture-initiating cells (LTC-ICs), and suspension culture-ICs (SC-ICs) were 82% (range, 47–100), 56% (range, 28–91), and 74% (range, 43–87), respectively, with most surviving progenitors being cytogenetically normal. Engraftment of DT₃₈₈IL-3-treated AML cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice followed for 16 weeks was eradicated for two of these samples. In contrast, with normal bone marrow, mean percentages of CFC kill of 49 and 64% were seen with 50 or 250 ng/ml DT₃₈₈IL3, respectively, whereas no significant kills were observed in the LTC-IC and SC-IC assays. The NOD/SCID mouse repopulating cell (RC) frequency in normal BM cells was also not reduced by DT₃₈₈IL3 treatment. In subsequent experiments, NOD/SCID mice that received AML blasts i.v. followed in 24 h by 0.045 µg/g DT₃₈₈IL3 daily i.p. x 5 showed mean percentages of reduction in AML engraftment of 83% (range, 14–100) and 57% (range, 0–98) after 4 and 12 weeks, respectively (n = 6). No evidence of leukemia was detected with two of six AML samples 12 weeks after one 5-day course of DT₃₈₈IL3. Repeating the DT₃₈₈IL3 treatment every 4 weeks enhanced its effectiveness against two additional samples. Thus, DT₃₈₈IL3 kills primitive leukemic progenitors from a proportion of AML patients but shows no significant toxicity against equivalent normal cells.

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