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• W2124409897 abstract "Tumor therapy by the preferential activation of a prodrug at tumor cells targeted with an antibody−enzyme conjugate may allow improved treatment efficacy with reduced side effects. We examined antibody-mediated clearance of poly(ethylene glycol)-modified β-glucuronidase (βG−sPEG) as a method to reduce serum concentrations of enzyme and minimize systemic prodrug activation. Enzyme-linked immunosorbent assay and immunoblot analysis of two monoclonal antibodies generated by immunization of BALB/c mice with an antibody−βG−sPEG conjugate showed that mAb 1E8 (IgG1) bound βG and βG−sPEG whereas mAb AGP3 (IgM) bound poly(ethylene glycol). Neither antibody affected the βG activity. mAb 1E8 and AGP3 were modified with 36 and 208 galactose residues (1E8−36G and AGP3−208G) with retention of 72 and 48% antigen-binding activity, respectively, to target immune complexes to the asialoglycoprotein receptor on liver cells. mAb 1E8 and AGP3 cleared βG−PEG from the circulation of mice as effectively as 1E8−36G and AGP3−208G, respectively. mAb AGP3, however, cleared βG−sPEG more completely and rapidly than 1E8, reducing the serum concentration of βG−sPEG by 38-fold in 8 h. AGP3 also reduced the concentration of an antibody−βG−sPEG conjugate in blood by 280-fold in 2 h and 940-fold in 24 h. AGP3-mediated clearance did not produce obvious damage to liver, spleen, or kidney tissues. In addition, AGP3 clearance of βG−sPEG before administration of BHAMG, a glucuronide prodrug of p-hydroxyaniline mustard, prevented toxicity associated with systemic activation of the prodrug based on mouse weight and blood cell numbers. AGP3 should be generally useful for accelerating the clearance of PEG-modified proteins as well as for improving the tumor/blood ratios of antibody−βG−PEG conjugates for glucuronide prodrug therapy of cancer." @default.
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• W2124409897 date "1999-04-17" @default.
• W2124409897 modified "2023-10-14" @default.
• W2124409897 title "Accelerated Clearance of Polyethylene Glycol-Modified Proteins by Anti-Polyethylene Glycol IgM" @default.
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• W2124409897 doi "https://doi.org/10.1021/bc980143z" @default.
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