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  • [Bioconjug Chem.] FRET Reagent Reveals the Intracellular Processing of Peptide-Linked Antibody-Drug Conjugates.

    Genentech / 이병철, Richard Vandlen*

  • 출처
    Bioconjug Chem.
  • 등재일
    2018 Jun 13. doi: 10.1021/acs.bioconjchem.8b00362.
  • 저널이슈번호
  • 내용

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    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.

     


    Author information

    Lee BC1, Chalouni C2, Doll S1,2, Nalle SC3, Darwish M1, Tsai SP4, Kozak KR4, Del-Rosario G5, Yu SF5, Erickson H1, Vandlen R1.
    1
    Department of Protein Chemistry , Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
    2
    Department of Pathology , Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
    3
    Department of Cancer Immunology , Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
    4
    Department of Biochemical and Cellular Pharmacology , Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
    5
    Department of Translational Oncology , Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.

  • 편집위원

    종양치료분야에서 최근 활발히 사용 중인 항체-약물결합체(antibody-drug conjugates, ADCs)의 효과와는 별개로 그 작동 정보가 부족한 상황이다. 따라서 이 논문은 ADC의 활성 메커니즘 연구를 위하여 두 종류의 형광물질이 가까운 거리에 있을 때 공명에 의해 에너지를 전달하는 현상인 FRET (Fluorescence Resonance Energy Transfer) 기술을 이용하여 ADC의 종양치료 메커니즘을 연구한 것으로, 더 효과적인 ADC 개발 연구자들에게 도움을 줄 수 있을 것이다.

    2018-07-12 15:23:46

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