Abstract
Bivalent doxorubicin (DOX)-dipeptides (16a-c) were prepared and conjugated to the monoclonal antibody BR96. The dipeptides are cleaved by lysosomal proteases following internalization of the resulting immunoconjugates. Conjugate 18b demonstrated antigen-specific in vitro tumor cell killing activity (IC(50)=0.2 microM) that was equipotent to DOX with a near doubling of drug molecules/MAb. Size exclusion chromatography showed 18b to be a noncovalent dimer that was formed immediately upon conjugation.
MeSH terms
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Antibodies, Monoclonal / chemistry*
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Binding Sites
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Cathepsin B / blood
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Cathepsin B / metabolism
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Chromatography, Gel
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Dimerization
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Dipeptides / chemistry*
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Dipeptides / pharmacology
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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 / immunology
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Doxorubicin / pharmacology
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Half-Life
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Humans
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Immunoconjugates / chemistry
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Immunoconjugates / immunology
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Immunoconjugates / pharmacology
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Inhibitory Concentration 50
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Lung Neoplasms / drug therapy
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Lysosomes / enzymology
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Stereoisomerism
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Sulfhydryl Compounds / chemistry
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / immunology
Substances
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Antibodies, Monoclonal
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BR96-doxorubicin immunoconjugate
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Dipeptides
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Immunoconjugates
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Sulfhydryl Compounds
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Doxorubicin
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Cathepsin B