Antibody response to DT-GM, a novel fusion toxin consisting of a truncated diphtheria toxin (DT) linked to human granulocyte-macrophage colony stimulating factor (GM), during a phase I trial of patients with relapsed or refractory acute myeloid leukemia

Philip D. Hall, Gabriel Virella, Tony Willoughby, Daniel H. Atchley, Robert J. Kreitman, Arthur E. Frankel

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Abstract

We are conducting a Phase I trial of a fusion toxin (DT-GM) for the treatment of relapsed or refractory acute myeloid leukemia (AML). The fusion toxin consists of a truncated diphtheria toxin (DT) linked to human granulocyte-macrophage colony stimulating factor (GM). Prior to beginning the Phase I trial, our first goal was to determine whether healthy controls and adult AML patients had preexisting antibodies able to inhibit DT-GM. Sera from 5 of the 9 controls completely neutralized DT-GM by an in vitro bioassay to assess the inhibition of DT-GM. Sera from 43 patients with AML were tested by bioassay and a specific enzymoimmunoassay (EIA) for anti-DT-GM antibodies. Forty-two of 43 samples were positive by EIA, and 5 patients (11.6%) showed complete neutralization of DT-GM in the bioassay. Anti-DT-GM concentrations were significantly higher in samples demonstrating neutralization than in samples demonstrating no neutralization (P = 0.003). In the Phase I trial of DT-GM prior to therapy, none of 28 patients exhibited neutralization by bioassay, but 89% were positive by EIA. After the first course of DT-GM, 23% developed neutralizing antibodies by the bioassay, and 64% of patients exhibited an increase in their anti-DT-GM antibody concentrations by EIA. Further studies are needed to determine the clinical impact of the anti-DT-GM antibodies and whether the neutralization bioassay can be replaced by our EIA.

Original languageEnglish (US)
Pages (from-to)191-197
Number of pages7
JournalClinical Immunology
Volume100
Issue number2
DOIs
StatePublished - 2001

Fingerprint

Diphtheria Toxin
Granulocyte-Macrophage Colony-Stimulating Factor
Acute Myeloid Leukemia
Antibody Formation
Biological Assay
Antibodies
Neutralizing Antibodies
Serum

Keywords

  • Antibody
  • huGMCSF diphtheria toxin fusion protein
  • Myeloid leukemia

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Pathology and Forensic Medicine

Cite this

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title = "Antibody response to DT-GM, a novel fusion toxin consisting of a truncated diphtheria toxin (DT) linked to human granulocyte-macrophage colony stimulating factor (GM), during a phase I trial of patients with relapsed or refractory acute myeloid leukemia",
abstract = "We are conducting a Phase I trial of a fusion toxin (DT-GM) for the treatment of relapsed or refractory acute myeloid leukemia (AML). The fusion toxin consists of a truncated diphtheria toxin (DT) linked to human granulocyte-macrophage colony stimulating factor (GM). Prior to beginning the Phase I trial, our first goal was to determine whether healthy controls and adult AML patients had preexisting antibodies able to inhibit DT-GM. Sera from 5 of the 9 controls completely neutralized DT-GM by an in vitro bioassay to assess the inhibition of DT-GM. Sera from 43 patients with AML were tested by bioassay and a specific enzymoimmunoassay (EIA) for anti-DT-GM antibodies. Forty-two of 43 samples were positive by EIA, and 5 patients (11.6{\%}) showed complete neutralization of DT-GM in the bioassay. Anti-DT-GM concentrations were significantly higher in samples demonstrating neutralization than in samples demonstrating no neutralization (P = 0.003). In the Phase I trial of DT-GM prior to therapy, none of 28 patients exhibited neutralization by bioassay, but 89{\%} were positive by EIA. After the first course of DT-GM, 23{\%} developed neutralizing antibodies by the bioassay, and 64{\%} of patients exhibited an increase in their anti-DT-GM antibody concentrations by EIA. Further studies are needed to determine the clinical impact of the anti-DT-GM antibodies and whether the neutralization bioassay can be replaced by our EIA.",
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author = "Hall, {Philip D.} and Gabriel Virella and Tony Willoughby and Atchley, {Daniel H.} and Kreitman, {Robert J.} and Frankel, {Arthur E.}",
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AU - Hall, Philip D.

AU - Virella, Gabriel

AU - Willoughby, Tony

AU - Atchley, Daniel H.

AU - Kreitman, Robert J.

AU - Frankel, Arthur E.

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