Abstract
The (6-maleimidocaproyl)hydrazone of doxorubicin was synthesized and conjugated to several mAbs, including chimeric BR96, via a Michael addition reaction to thiol-containing mAbs. DTT reduction of disulfides present in the mAb was a reliable and general method for generating a consistent number of reactive SH groups. The conjugates, after purification by Bio-Beads, were free of unreacted linker and/or doxorubicin. All conjugates released doxorubicin under acidic conditions that mimic the lysosomal environment, while they were relatively stable at neutral pH. BR96 conjugates showed antigen-specific cytotoxicity.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / immunology
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Animals
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Antibodies, Monoclonal / metabolism
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Cross-Linking Reagents / chemical synthesis*
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Cross-Linking Reagents / chemistry
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Dithiothreitol / chemistry
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Doxorubicin / analogs & derivatives*
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Doxorubicin / chemical synthesis
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Doxorubicin / chemistry
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Doxorubicin / metabolism
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Doxorubicin / toxicity*
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Drug Stability
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Epitopes
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Humans
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Hydrazones / chemical synthesis*
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Hydrazones / chemistry
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Immunotoxins / chemistry*
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Immunotoxins / metabolism
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Immunotoxins / toxicity*
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Lung Neoplasms / drug therapy
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Lung Neoplasms / immunology
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Mice
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Oxidation-Reduction
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Sulfhydryl Compounds / chemistry
Substances
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Antibodies, Monoclonal
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Cross-Linking Reagents
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Epitopes
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Hydrazones
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Immunotoxins
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Sulfhydryl Compounds
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doxorubicin(6-maleimidocaproyl)hydrazone
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Doxorubicin
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Dithiothreitol