Pharmacokinetics of tumor-reactive immunotoxins in tumor-bearing mice

Effects 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

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Abstract

The blood clearance and tissue distribution of immunotoxins composed of either intact of 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 BCL1 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 (α 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 aproximately 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 125I-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 - 1988

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Ricin
Immunotoxins
Pharmacokinetics
Antibodies
Neoplasms
Immunoglobulin Fab Fragments
Immunoglobulin G
Injections
Rho(D) Immune Globulin
Antigens
Propionates
Tissue Distribution

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{742780669a15498d862daf5e30cd5188,
title = "Pharmacokinetics of tumor-reactive immunotoxins in tumor-bearing mice: Effects of antibody valency and deglycosylation of the ricin A chain on clearance and tumor localization",
abstract = "The blood clearance and tissue distribution of immunotoxins composed of either intact of 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 BCL1 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 (α 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 aproximately 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 125I-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.",
author = "Fulton, {R. J.} and Tucker, {T. F.} and Vitetta, {E. S.} and Uhr, {J. W.}",
year = "1988",
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T1 - Pharmacokinetics of tumor-reactive immunotoxins in tumor-bearing mice

T2 - Effects of antibody valency and deglycosylation of the ricin A chain on clearance and tumor localization

AU - Fulton, R. J.

AU - Tucker, T. F.

AU - Vitetta, E. S.

AU - Uhr, J. W.

PY - 1988

Y1 - 1988

N2 - The blood clearance and tissue distribution of immunotoxins composed of either intact of 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 BCL1 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 (α 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 aproximately 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 125I-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.

AB - The blood clearance and tissue distribution of immunotoxins composed of either intact of 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 BCL1 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 (α 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 aproximately 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 125I-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.

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