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Variant Diphtheria Toxin–Interleukin-3 Fusion Proteins with Increased Receptor Affinity Have Enhanced Cytotoxicity against Acute Myeloid Leukemia Progenitors

Authors' Affiliations: ¹ Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada and ² Department of Medicine, Scott and White Hospital, Temple, Texas

Requests for reprints: Donna E. Hogge, Terry Fox Laboratory, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3. Phone: 604-675-8138; Fax: 604-877-0712; E-mail: dhogge{at}bccancer.bc.ca.

A fusion protein linking a truncated form of diphtheria toxin (DT₃₈₈) to human interleukin-3 (DT₃₈₈IL3) kills malignant progenitors from some patients with acute myeloid leukemia (AML) while sparing normal progenitors. This study evaluated two variants of DT₃₈₈IL3 with increased affinity for the IL-3 receptor (IL-3R) for their cytotoxicity to AML progenitors and determined the ability of quantitative reverse transcription-PCR assessment of expression of the IL-3R subunits to predict the effectiveness of wild-type DT₃₈₈IL3 and its variants. Both the IL-3 deletion variant (125-133) and the amino acid substitution variant (K116W) showed enhanced toxicity against AML colony-forming cells (AML-CFC; but not normal CFC) compared with wild-type DT₃₈₈IL3 with the K116W variant achieving >90% AML-CFC kill with 17 of 23 patient samples. This variant was also more effective against AML cells engrafting in nonobese diabetic severe combined immunodeficient mice. There was a significant correlation between the expression of the and, particularly, the common ß subunit of the IL-3R on AML blasts detected by quantitative reverse transcription-PCR and AML-CFC kill. Thus, the combined use of IL-3R expression to select patients most likely to respond to DT₃₈₈IL3 and the improved cytotoxicity of the K116W DT₃₈₈IL3 variant against leukemic progenitors may enhance the clinical usefulness of these fusion proteins.

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				L. Yalcintepe, A. E. Frankel, and D. E. Hogge Expression of interleukin-3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin interleukin-3 fusion protein against malignant progenitors that engraft in immunodeficient mice Blood, November 15, 2006; 108(10): 3530 - 3537. [Abstract] [Full Text] [PDF]