Pharmacokinetics of Tumor-Reactive Immunotoxins in Tumor-Bearing Mice: Effect of Antibody Valency and Deglycosylation of the Ricin a Chain on Clearance and Tumor Localization

R. J. Fulton, T. F. Tucker, E. S. Vitetta, J. W. Uhr

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

The blood clearance and tissue distribution of immunotoxins composed of either intact or Fab' fragments of tumor-reactive, monoclonal rat anti-murine immunoglobulin D (anti-δ) or nonreactive, normal rat immunoglobulin G and ricin A chain (native or chemically deglycosylated) were determined in BCL, tumor-bearing mice. In the presence of accessible target cells, neither the valency of the antibody nor deglycosylation of the A chain affect the initial rate of clearance (a phase) of immunotoxins from the blood; however, both factors affect the levels of tumor-specific and nonspecific localization of the immunotoxins. Thus, the use of immunotoxins with deglycosylated A chain greatly reduced the levels of nonspecific uptake by the liver and concomitantly increased tumor-specific localization. Immunotoxins prepared with Fab' fragments of anti-δ antibody and deglycosylated A chain were twice as effective at localizing to splenic tumor than immunotoxins prepared with intact immunoglobulin G and deglycosylated A chain. Approximately 90% of tumor-specific localization of anti-δ immunotoxins occurred within 1 h after injection and less than 5% of the immunotoxin remained in the circulation 4 h after injection. In addition, the antigen-binding capacity of the remaining circulating immunotoxins decreased in a linear manner over the first 10 h to approximately 20% of the initial binding activity. Thus, by 10 h after injection, only 2-3% of injected immunotoxin remained in the circulation and this material expressed little antigen reactivity. Analysis of the in vivo stability of circulating 125 I-labeled immunotoxins in tumor-bearing mice demonstrated that Fab' immunotoxins are more stable than IgG immunotoxins prepared with N-succinimidyl-3-(2-pyridylthio)propionate. In BCL1-bearing mice, significant splitting of the anti-δ immunotoxins did not occur until tumor localization was virtually complete.

Original languageEnglish (US)
Pages (from-to)2618-2625
Number of pages8
JournalCancer research
Volume48
Issue number9
StatePublished - May 1988

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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