Reducing anti-DT IgG concentrations to improve the efficacy of a diphtheria fusion protein

Philip D. Hall, Kathryn L. Beagle, Elizabeth Garrett-Mayer, Arthur E. Frankel

Research output: Contribution to journalArticle

Abstract

Preformed antidiphtheria toxin (anti-DT) IgG limits the development of diphtheria fusion proteins because the anti-DT IgG binds and removes the diphtheria fusion protein from the circulation. In our phase I trial of DT-granulocyte macrophage colony stimulating factor (GMCSF), a truncated DT linked to human GMCSF, in relapsed or refractory acute myeloid leukemia, patients with high concentrations of preexisting anti-DT IgG (>2.5 μg/ml) had significantly lower DT-GMCSF concentrations. This study details the fate of anti-DT IgG during the patient's treatment with DT-GMCSF and describes how we could lower anti-DT IgG concentrations and increase the patient's exposure to DT-GMCSF. Using an enzyme immunoassay, we measured anti-DT IgG concentrations before the first cycle of treatment (baseline) and on day 2 (after one dose of DT-GMCSF) and on day 5 (after four doses of DT-GMCSF). Thirty-three patients with relapsed or refractory acute myeloid leukemia in the phase 1 trial received DT-GMCSF at doses from 1 to 5 μg/kg/day intravenously for 5 days. The mean anti-DT IgG concentration pretherapy was 1.3 μg/ml (range: undetectable to 7.8) and significantly decreased to a mean concentration of 0.7 μg/ml on day 2 (P=0.007) and to 0.5 μg/ml on day 5 (P<0.0001). In two individuals in whom we measured DT-GMCSF concentrations on day 1 and day 5, we observed that a decrease in anti-DT IgG concentrations was associated with an increase in DT-GMCSF concentrations. No relationship was observed between dose of DT-GMCSF and the absolute change in anti-DT IgG concentrations on day 2 (r= -0.01, P=0.98) or day 5 (r= -0.12, P=0.53). For patients with high baseline anti-DT IgG concentrations, a single dose of DT-GMCSF could be used to lower the anti-DT IgG concentrations and potentially result in a significant increase in DT-GMCSF concentrations and efficacy.

Original languageEnglish (US)
Pages (from-to)1007-1011
Number of pages5
JournalAnti-Cancer Drugs
Volume19
Issue number10
DOIs
StatePublished - Nov 2008

Keywords

  • Acute myeloid leukemia
  • Diphtheria antibodies
  • Diphtheria fusion proteins

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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