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

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 AMI, 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 EU. (C) 2001 Academic Press.