title: 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.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: T L
authors.initials: TL
authors.lastname: Cheng
authors.forename: B M
authors.initials: BM
authors.lastname: Chen
authors.forename: J W
authors.initials: JW
authors.lastname: Chern
authors.forename: M F
authors.initials: MF
authors.lastname: Wu
authors.forename: S R
authors.initials: SR
authors.lastname: Roffler
mesh_terms: D000816:Aniline Mustard / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D004926:Escherichia coli / Q000201:enzymology; D005966:Glucuronidase / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics*; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007457:Iodine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004337:Drug Carriers; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D011355:Prodrugs; C071879:p-hydroxyaniline mustard glucuronide, tetra-n-butyl ammonium salt; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D000816:Aniline Mustard; D005966:Glucuronidase