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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Mustard / analogs & derivatives
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Aniline Mustard / chemistry
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Aniline Mustard / therapeutic use
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Aniline Mustard / toxicity
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Animals
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Antibodies, Monoclonal / chemistry
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Antibodies, Monoclonal / pharmacokinetics*
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Antibodies, Monoclonal / therapeutic use
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Agents / toxicity
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Cell Survival / drug effects
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Disease Models, Animal
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Drug Carriers / chemistry
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Drug Carriers / pharmacokinetics
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Escherichia coli / enzymology
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Glucuronidase / chemistry
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Glucuronidase / immunology
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Glucuronidase / pharmacokinetics*
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Humans
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Immunoenzyme Techniques / methods
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Immunoglobulin Fab Fragments / chemistry
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Iodine Radioisotopes
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Transplantation
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Polyethylene Glycols / chemistry
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Polyethylene Glycols / pharmacokinetics*
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Prodrugs / chemistry
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Prodrugs / pharmacokinetics*
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Prodrugs / therapeutic use
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Tissue Distribution
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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Antibodies, Monoclonal
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Antineoplastic Agents
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Drug Carriers
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Immunoglobulin Fab Fragments
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Iodine Radioisotopes
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Prodrugs
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p-hydroxyaniline mustard glucuronide, tetra-n-butyl ammonium salt
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Polyethylene Glycols
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monomethoxypolyethylene glycol
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Aniline Mustard
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Glucuronidase