Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors

Donna E. Hogge, Leman Yalcintepe, Siaw Hui Wong, Brigitte Gerhard, Arthur E. Frankel

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

A fusion protein linking a truncated form of diphtheria toxin (DT 388) 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 (Δ125-133) 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 áand, particularly, the common β 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.

Original languageEnglish (US)
Pages (from-to)1284-1291
Number of pages8
JournalClinical Cancer Research
Volume12
Issue number4
DOIs
StatePublished - Feb 15 2006

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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