Monoclonal Antibody Conjugates of Doxorubicin Prepared with Branched Linkers: A Novel Method for Increasing the Potency of Doxorubicin Immunoconjugates
| Autor: | Karl Erik Hellström, Yurgaitis D, David Willner, King Hd, Pamela A. Trail, Raymond A. Firestone, Yang Mb, Shirley J. Lasch |
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| Rok vydání: | 1999 |
| Předmět: |
Immunoconjugates
Lung Neoplasms Cell Survival medicine.drug_class Stereochemistry Biomedical Engineering Pharmaceutical Science Hydrazone Bioengineering Monoclonal antibody Mice Tumor Cells Cultured medicine Animals Humans Cytotoxic T cell Doxorubicin Cytotoxicity Pharmacology chemistry.chemical_classification Chemistry Hydrolysis Organic Chemistry Hydrazones Antibodies Monoclonal Hydrogen-Ion Concentration In vitro Kinetics Immunoglobulin G Indicators and Reagents Lysosomes Linker Biotechnology Conjugate medicine.drug |
| Zdroj: | Bioconjugate Chemistry. 10:279-288 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc980100i |
| Popis: | Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novel series of branched hydrazone linkers. Since each linker bound to the mAb carries two DOX molecules, the DOX/mAb molar ratios of these conjugates were approximately 16, twice that of those previously prepared with single-chain hydrazone linkers. The conjugates were stable at a physiological pH of 7, but released DOX rapidly at lysosomal pH 5. The branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a DOX (4-14-fold) and mAb (7-23-fold) basis. The results suggest that, by using the branched linker methodology, it is possible to significantly reduce the amount of mAb required to achieve antigen-specific cytotoxic activity. In this paper, the synthesis and in vitro biology of branched chain immunoconjugates are described. |
| Databáze: | OpenAIRE |
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