title: Reducing anti-DT IgG concentrations to improve the efficacy of a diphtheria fusion protein.
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 microg/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 microg/kg/day intravenously for 5 days. The mean anti-DT IgG concentration pretherapy was 1.3 microg/ml (range: undetectable to 7.8) and significantly decreased to a mean concentration of 0.7 microg/ml on day 2 (P=0.007) and to 0.5 microg/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.
authors.affiliation: Department of Clinical Pharmacy and Outcome Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, 274 Calhoun Street, Charleston, SC 29425, USA. hallpd@musc.edu
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hall
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Beagle
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004167:Diphtheria Toxin / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012189:Retrospective Studies
chemical_list: D004167:Diphtheria Toxin; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor