Fresh frozen plasma and platelet concentrates may increase plasma anti-diphtheria toxin IgG concentrations: implications for diphtheria fusion protein therapy

Abstract

We are developing two fusion proteins consisting of a diphtheria toxin (DT) linked to either granulocyte macrophage colony stimulating factor (DT₃₈₈-GMCSF) or interleukin-3 (DT₃₈₈-IL3). In trials, patients with anti-DT IgG concentrations >2.5 μg/ml had significantly lower concentrations of either fusion protein. DT₃₈₉-IL2 is currently FDA approved for the treatment of cutaneous T-cell lymphomas. We noted increased concentrations of anti-DT IgG after administration of platelet concentrates (PC). Because many of these patients require transfusions, we measured the anti-DT IgG content of FFP and PC. We assayed 14 bags of FFP and 12 bags of single-donor PCs for anti-DT IgG by an enzymoimmunoassay against DT₃₈₉-IL2, DT₃₈₈-IL3, DT₃₈₈-GMCSF. The median (percent of samples positive) of anti-DT IgG concentrations in PC against DT₃₈₈-GMCSF, DT₃₈₈-IL3, DT₃₈₉-IL2 was 0.8 μg/ml (83%), 0.7 μg/ml (83%), and 0.3 μg/ml (58%), respectively. The median (percent of samples positive) anti-DT IgG concentration in FFP against DT₃₈₈-GMCSF, DT₃₈₈-IL3, and DT₃₈₉-IL2 was 2.1 μg/ml (86%), 1.9 μg/ml (93%), and 1.4 μg/ml (86%), respectively. There was a strong association between anti-DT₃₈₉IL2 IgG, anti-DT₃₈₈IL3 IgG, and anti-DT₃₈₈GMCSF IgG concentrations in both the FFP (95.6%) and PC (76.3%). Assuming a plasma volume of 3 l in a 70 kg patient, a single FFP unit would increase the plasma anti-DT₃₈₉IL2 IgG, anti-DT₃₈₈IL3 IgG, and anti-DT₃₈₈GMCSF IgG by 0.13 μg/ml, 0.17 μg/ml, and 0.19 μg/ml, respectively. For PC, a single unit would increase plasma anti-DT₃₈₉-IL2 IgG, anti-DT₃₈₈-IL3 IgG, and anti-DT₃₈₈-GMCSF IgG by 0.03 μg/ml, 0.06 μg/ml, and 0.07 μg/ml, respectively. In conclusion, a single FFP or PC appears to minimally increase anti-DT IgG concentrations, but multiple units may significantly do such.