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

The F(ab')(2) fragment of the anti-TAG-72 antibody, B72.3, was covalently l inked to Escherichia coli-derived P-glucuronidase that was modified with me thoxypoly(ethylene glycol). The conjugate (B72.3-beta G-PEG) localized to a peak concentration in LS174T xenografts within 48 h after injection, but e nzyme activity persisted in plasma such that prodrug administration had to be delayed for at least 4 days to avoid systemic prodrug activation and ass ociated toxicity. Conjugate levels in tumors decreased to 36% of peak level s at this time. Intravenous administration of AGP3, an IgM mAb against meth oxypoly(ethylene glycol), accelerated clearance of conjugate from serum and increased the tumor/blood ratio of B72.3-beta G-PEG from 3.9 to 29.6 witho ut significantly decreasing the accumulation of conjugate in tumors. Treatm ent of nude mice bearing established human colon adenocarcinoma xenografts with B72.3-beta G-PEG followed 48 h later with AGP3 and a glucuronide prodr ug of p-hydroxyaniline mustard significantly (p less than or equal to 0.000 5) delayed tumor growth with minimal toxicity compared to therapy with a co ntrol conjugate or conventional chemotherapy.