Efficient clearance of poly(ethylene glycol)-modified immunoenzyme with anti-PEG monoclonal antibody for prodrug cancer therapy.

Abstract

The F(ab')(2) fragment of the anti-TAG-72 antibody, B72.3, was covalently linked to Escherichia coli-derived beta-glucuronidase that was modified with methoxypoly(ethylene glycol). The conjugate (B72.3-betaG-PEG) localized to a peak concentration in LS174T xenografts within 48 h after injection, but enzyme activity persisted in plasma such that prodrug administration had to be delayed for at least 4 days to avoid systemic prodrug activation and associated toxicity. Conjugate levels in tumors decreased to 36% of peak levels at this time. Intravenous administration of AGP3, an IgM mAb against methoxypoly(ethylene glycol), accelerated clearance of conjugate from serum and increased the tumor/blood ratio of B72. 3-betaG-PEG from 3.9 to 29.6 without significantly decreasing the accumulation of conjugate in tumors. Treatment of nude mice bearing established human colon adenocarcinoma xenografts with B72. 3-betaG-PEG followed 48 h later with AGP3 and a glucuronide prodrug of p-hydroxyaniline mustard significantly (p< or =0.0005) delayed tumor growth with minimal toxicity compared to therapy with a control conjugate or conventional chemotherapy.

• Authors: T L Cheng, B M Chen, J W Chern, M F Wu, S R Roffler
• Journal: Bioconjugate chemistry (Bioconjug Chem) 2000 Mar-Apr Vol. 11 Issue 2 Pg. 258-66 ISSN: 1043-1802 [Print] United States
• PMID: 10725103 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Drug Carriers
• Immunoglobulin Fab Fragments
• Iodine Radioisotopes
• Prodrugs
• p-hydroxyaniline mustard glucuronide, tetra-n-butyl ammonium salt
• Polyethylene Glycols
• monomethoxypolyethylene glycol
• Aniline Mustard
• Glucuronidase

Topics

• Aniline Mustard (analogs & derivatives, chemistry, therapeutic use, toxicity)
• Animals
• Antibodies, Monoclonal (chemistry, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (chemistry, therapeutic use, toxicity)
• Cell Survival (drug effects)
• Disease Models, Animal
• Drug Carriers (chemistry, pharmacokinetics)
• Escherichia coli (enzymology)
• Glucuronidase (chemistry, immunology, pharmacokinetics)
• Humans
• Immunoenzyme Techniques (methods)
• Immunoglobulin Fab Fragments (chemistry)
• Iodine Radioisotopes
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Polyethylene Glycols (chemistry, pharmacokinetics)
• Prodrugs (chemistry, pharmacokinetics, therapeutic use)
• Tissue Distribution
• Transplantation, Heterologous
• Tumor Cells, Cultured