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Journal Article

FRET Reagent Reveals the Intracellular Processing of Peptide-Linked Antibody-Drug Conjugates

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Doll,  Sophia
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Lee, B.-C., Chalouni, C., Doll, S., Nalle, S. C., Darwish, M., Tsai, S. P., et al. (2018). FRET Reagent Reveals the Intracellular Processing of Peptide-Linked Antibody-Drug Conjugates. Bioconjugate Chemistry, 29(7), 2468-2477. doi:10.1021/acs.bioconjchem.8b00362.


Abstract
Despite the recent success of antibody-drug conjugates (ADCs) in cancer therapy, a detailed understanding of their entry, trafficking, and metabolism in cancer cells is limited. To gain further insight into the activation mechanism of ADCs, we incorporated fluorescence resonance energy transfer (FRET) reporter groups into the linker connecting the antibody to the drug and studied various aspects of intracellular ADC processing mechanisms. When comparing the trafficking of the antibody FRET drug conjugates in various different model cells, we found that the cellular background plays an important role in how the antigen mediated antibody is processed. Certain tumor cells showed limited cytosolic transport of the payload despite efficient linker cleavage. Our FRET assay provides a facile and robust assessment of intracellular ADC activation that may have significant implications for the future development of ADCs.