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.
authors.affiliation: College of Pharmacy, Hollings Cancer Center, Charleston, South Carolina 29425, USA. hallpd@musc.edu
authors.forename: P D
authors.initials: PD
authors.lastname: Hall
authors.forename: G
authors.initials: G
authors.lastname: Virella
authors.forename: T
authors.initials: T
authors.lastname: Willoughby
authors.forename: D H
authors.initials: DH
authors.lastname: Atchley
authors.forename: R J
authors.initials: RJ
authors.lastname: Kreitman
authors.forename: A E
authors.initials: AE
authors.lastname: Frankel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000097:blood / Q000276:immunology; D000918:Antibody Specificity; D004167:Diphtheria Toxin / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D004167:Diphtheria Toxin; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor