Renal dysfunction accounts for the dose limiting toxicity of DT390anti-CD3sFv, a potential new recombinant anti-GVHD immunotoxin

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Abstract

The toxicity of a highly selective, recombinant fusion immunotoxin, DT390anti-CD3sFv, was examined in mice. The protein was expressed from a hybrid gene in which the single chain Fv of the anti-murine CD3 epsilon antibody cDNA was spliced to truncated diphtheria toxin cDNA. DT390anti-CD3sFv, previously shown to have significant anti-GVHD effects when administered to mice given transplants of allogeneic MHC-disparate donor T cells, preferentially localized to kidney and had profound renal toxicity as assessed by histology and serum levels of blood urea nitrogen (BUN), and creatinine. Kidney effects were more severe than liver effects at the maximum tolerated dose (MTD) of 10 μg/day BID given over a six day interval. Toxic injury was attributed in part to the toxin moiety since DT390 administered alone was more toxic than equivalent doses of DT390 given in the context of DT390anti-CD3sFv fusion protein. The presence of anti-CD3sFv ligand reduced toxicity since DT390anti-CD3sFv was twice as toxic to severe combined immunodeficiency disease (scid) mice which do not have CD3epsilon expressing T cells as compared to their normal counterparts. Together, these findings further our understanding of the toxicities limiting the in vivo administration of DT fusion immunotoxins in mice and provide a foundation for future genetic modifications which should be directed at reducing these effects.

Original languageEnglish (US)
Pages (from-to)1071-1076
Number of pages6
JournalProtein Engineering
Volume10
Issue number9
DOIs
StatePublished - 1997

Keywords

  • Diphtheria toxin
  • Fusion protein
  • Graft-versus-host-disease
  • Immunotoxin
  • Toxicity

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