Pharmacokinetics and microdistribution of polyethylene glycol-modified humanized A33 antibody targeting colon cancer xenografts Journal Article
| Authors: | Deckert, P. M.; Jungbluth, A.; Montalto, N.; Clark, M. A.; Finn, R. D.; Williams, C. Jr; Richards, E. C.; Panageas, K. S.; Old, L. J.; Welt, S. |
| Article Title: | Pharmacokinetics and microdistribution of polyethylene glycol-modified humanized A33 antibody targeting colon cancer xenografts |
| Abstract: | Therapeutic proteins have been conjugated with polyethylene glycol (PEGylation) to reduce immunogenicity and enhance circulating dose. Here we have investigated the effect of PEGylation on immunogenicity, pharmacokinetics, and histologic microdistribution of tumor-targeting antibodies with humanized A33 antibody (huA33) as a model system. Conjugation of huA33 with methoxy-PEG of M(r) 5,000 (32%-34% of primary amines modified) or M(r) 20,000 (16%-18% modification) preserved >50% of native huA33 binding to SW1222 colon cancer cells. In mice, both PEGylated forms cleared from serum moderately slower than native huA33. After repeated immunization with PEG-huA33, anti-antibody titers in immunocompetent mice were <5% of those in huA33-treated controls. Both PEG-huA33 forms reached approx. 75% of the maximum tumor dose of huA33 in SW1222-xenografted mice, but their tumor:blood ratios were considerably reduced. To demonstrate immunologic specificity of PEG-huA33 targeting in SW1222 tumor-bearing mice, antigenic sites were presaturated by injecting excess native huA33. This reduced subsequent uptake of PEG-huA33 by up to 80%, whereas presaturation with hu3S193 control antibody had no significant effect. To assess the microdistribution of antibody uptake in the same xenograft model, tumor tissue resected at different time points after antibody administration was examined for human IgG by immunohistochemistry. Both PEG preparations achieved the same peak staining intensity and homogeneity as native huA33 with a delay of several hours. Given the measured reduction in immunoreactivity in vitro, these results demonstrate that the tumor targeting potential of huA33 in vivo is preserved at PEGylation levels sufficient to suppress immunogenicity. (C) 2000 Wiley-Liss, Inc. |
| Keywords: | immunohistochemistry; adolescent; controlled study; unclassified drug; human cell; nonhuman; adenocarcinoma; mouse; animals; mice; animal tissue; animal model; colonic neoplasms; tumor xenograft; drug specificity; immunoenzyme techniques; antibodies, monoclonal; antigens, neoplasm; immunoglobulin g; drug distribution; tissue distribution; iodine radioisotopes; mice, nude; membrane glycoproteins; colon cancer; immunogenicity; transplantation, heterologous; antibody specificity; neoplasm transplantation; molecular weight; macrogol; drug conjugation; half-life; polyethylene glycols; immunization; cancer antibody; radioimmunodetection; plasma clearance; humans; human; female; priority journal; article; monoclonal antibody a33 |
| Journal Title: | International Journal of Cancer |
| Volume: | 87 |
| Issue: | 3 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2000-08-01 |
| Start Page: | 382 |
| End Page: | 390 |
| Language: | English |
| DOI: | 10.1002/1097-0215(20000801)87:3<382::aid-ijc12>3.0.co;2-p |
| PUBMED: | 10897044 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
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