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Therapeutic antibody targeting of individual Notch receptors

Author

Listed:
  • Yan Wu

    (Department of Antibody Engineering,)

  • Carol Cain-Hom

    (Department of Molecular Biology,)

  • Lisa Choy

    (Department of Molecular Biology,)

  • Thijs J. Hagenbeek

    (Department of Molecular Biology,)

  • Gladys P. de Leon

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Yongmei Chen

    (Department of Antibody Engineering,)

  • David Finkle

    (Department of Translational Oncology,)

  • Rayna Venook

    (Department of Translational Oncology,)

  • Xiumin Wu

    (Department of Tumor Biology and Angiogenesis,)

  • John Ridgway

    (Department of Tumor Biology and Angiogenesis,)

  • Dorreyah Schahin-Reed

    (Department of Neurodegeneration,)

  • Graham J. Dow

    (Department of Molecular Biology,
    Present address: Department of Biology, Stanford University, Stanford, California 94305, USA.)

  • Amy Shelton

    (Department of Molecular Biology,)

  • Scott Stawicki

    (Department of Antibody Engineering,)

  • Ryan J. Watts

    (Department of Neurodegeneration,)

  • Jeff Zhang

    (Exelixis Inc., 210 East Grand Avenue, PO Box 511, South San Francisco, California 94083-0511, USA)

  • Robert Choy

    (Exelixis Inc., 210 East Grand Avenue, PO Box 511, South San Francisco, California 94083-0511, USA)

  • Peter Howard

    (Exelixis Inc., 210 East Grand Avenue, PO Box 511, South San Francisco, California 94083-0511, USA)

  • Lisa Kadyk

    (Exelixis Inc., 210 East Grand Avenue, PO Box 511, South San Francisco, California 94083-0511, USA)

  • Minhong Yan

    (Department of Tumor Biology and Angiogenesis,)

  • Jiping Zha

    (Department of Pathology,)

  • Christopher A. Callahan

    (Department of Pathology,)

  • Sarah G. Hymowitz

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Christian W. Siebel

    (Department of Molecular Biology,)

Abstract

Direct action: antitumour potential of Notch receptor antagonists The four receptors of the Notch family are widely expressed transmembrane proteins through which mammalian cells communicate to regulate cell fate and growth. Defects in Notch signalling are linked to many cancers, including acute lymphoblastic leukaemia. Using phage display technology, a multi-department team at Genentech has produced synthetic antibodies that act as potent and specific antagonists of Notch1 and Notch2. Anti-Notch1 shows antitumour activity in pre-clinical mouse models, inhibiting both cancer cell growth and angiogenesis, and is active against human cancer cells in culture. Inhibition of Notch1 and 2 together causes intestinal toxicity, whereas inhibition of each singly largely avoids this effect, a potential therapeutic advantage over 'pan-Notch' inhibitors.

Suggested Citation

  • Yan Wu & Carol Cain-Hom & Lisa Choy & Thijs J. Hagenbeek & Gladys P. de Leon & Yongmei Chen & David Finkle & Rayna Venook & Xiumin Wu & John Ridgway & Dorreyah Schahin-Reed & Graham J. Dow & Amy Shelt, 2010. "Therapeutic antibody targeting of individual Notch receptors," Nature, Nature, vol. 464(7291), pages 1052-1057, April.
    • Handle: RePEc:nat:nature:v:464:y:2010:i:7291:d:10.1038_nature08878
    DOI: 10.1038/nature08878
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    Citations

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    Cited by:

    1. Songbai Zhang & Ayako Miyakawa & Malin Wickström & Cecilia Dyberg & Lauri Louhivuori & Manuel Varas-Godoy & Kati Kemppainen & Shigeaki Kanatani & Dagmara Kaczynska & Ivar Dehnisch Ellström & Lotta Elf, 2022. "GIT1 protects against breast cancer growth through negative regulation of Notch," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Mayra Cruz Tleugabulova & Sandra P. Melo & Aaron Wong & Alexander Arlantico & Meizi Liu & Joshua D. Webster & Julia Lau & Antonie Lechner & Basak Corak & Jonathan J. Hodgins & Venkata S. Garlapati & M, 2024. "Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Wenxue Ma & Alejandro Gutierrez & Daniel J Goff & Ifat Geron & Anil Sadarangani & Christina A M Jamieson & Angela C Court & Alice Y Shih & Qingfei Jiang & Christina C Wu & Kang Li & Kristen M Smith & , 2012. "NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-14, June.

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