Triggered Drug Release from an Antibody–Drug Conjugate Using Fast “Click-to-Release” Chemistry in Mice

The use of a bioorthogonal reaction for the selective cleavage of tumor-bound antibody–drug conjugates (ADCs) would represent a powerful new tool for ADC therapy, as it would not rely on the currently used intracellular biological activation mechanisms, thereby expanding the scope to noninternalizin...

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Veröffentlicht in:Bioconjugate chemistry 2016-07, Vol.27 (7), p.1697-1706
Hauptverfasser: Rossin, Raffaella, van Duijnhoven, Sander M. J, ten Hoeve, Wolter, Janssen, Henk M, Kleijn, Laurens H. J, Hoeben, Freek J. M, Versteegen, Ron M, Robillard, Marc S
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Sprache:eng
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Zusammenfassung:The use of a bioorthogonal reaction for the selective cleavage of tumor-bound antibody–drug conjugates (ADCs) would represent a powerful new tool for ADC therapy, as it would not rely on the currently used intracellular biological activation mechanisms, thereby expanding the scope to noninternalizing cancer targets. Here we report that the recently developed inverse-electron-demand Diels–Alder pyridazine elimination reaction can provoke rapid and self-immolative release of doxorubicin from an ADC in vitro and in tumor-bearing mice.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.6b00231