Therapeutic antibody targeting of individual Notch receptors

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 Shelton, Scott Stawicki, Ryan J. Watts, Jeff Zhang, Robert Choy, Peter Howard, Lisa Kadyk, Minhong Yan, Jiping Zha, Christopher A. Callahan, Sarah G. Hymowitz and Christian W. Siebel ()
Additional contact information
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,
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,

Nature, 2010, vol. 464, issue 7291, 1052-1057

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.

Date: 2010
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DOI: 10.1038/nature08878

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