PMID- 20393564
OWN - NLM
STAT- MEDLINE
DCOM- 20100602
LR  - 20220318
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 464
IP  - 7291
DP  - 2010 Apr 15
TI  - Therapeutic antibody targeting of individual Notch receptors.
PG  - 1052-7
LID - 10.1038/nature08878 [doi]
AB  - The four receptors of the Notch family are widely expressed transmembrane 
      proteins that function as key conduits through which mammalian cells communicate 
      to regulate cell fate and growth. Ligand binding triggers a conformational change 
      in the receptor negative regulatory region (NRR) that enables ADAM protease 
      cleavage at a juxtamembrane site that otherwise lies buried within the quiescent 
      NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase 
      complex liberates the intracellular domain (ICD) to initiate the downstream Notch 
      transcriptional program. Aberrant signalling through each receptor has been 
      linked to numerous diseases, particularly cancer, making the Notch pathway a 
      compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have 
      progressed into the clinic, GSIs fail to distinguish individual Notch receptors, 
      inhibit other signalling pathways and cause intestinal toxicity, attributed to 
      dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of 
      Notch1 and Notch2 and develop clinically relevant inhibitors that reduce 
      intestinal toxicity, we used phage display technology to generate highly 
      specialized antibodies that specifically antagonize each receptor paralogue and 
      yet cross-react with the human and mouse sequences, enabling the discrimination 
      of Notch1 versus Notch2 function in human patients and rodent models. Our 
      co-crystal structure shows that the inhibitory mechanism relies on stabilizing 
      NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in 
      pre-clinical models through two mechanisms: inhibition of cancer cell growth and 
      deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes 
      severe intestinal toxicity, inhibition of either receptor alone reduces or avoids 
      this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our 
      studies emphasize the value of paralogue-specific antagonists in dissecting the 
      contributions of distinct Notch receptors to differentiation and disease and 
      reveal the therapeutic promise in targeting Notch1 and Notch2 independently.
FAU - Wu, Yan
AU  - Wu Y
AD  - Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San 
      Francisco, California 94080, USA.
FAU - Cain-Hom, Carol
AU  - Cain-Hom C
FAU - Choy, Lisa
AU  - Choy L
FAU - Hagenbeek, Thijs J
AU  - Hagenbeek TJ
FAU - de Leon, Gladys P
AU  - de Leon GP
FAU - Chen, Yongmei
AU  - Chen Y
FAU - Finkle, David
AU  - Finkle D
FAU - Venook, Rayna
AU  - Venook R
FAU - Wu, Xiumin
AU  - Wu X
FAU - Ridgway, John
AU  - Ridgway J
FAU - Schahin-Reed, Dorreyah
AU  - Schahin-Reed D
FAU - Dow, Graham J
AU  - Dow GJ
FAU - Shelton, Amy
AU  - Shelton A
FAU - Stawicki, Scott
AU  - Stawicki S
FAU - Watts, Ryan J
AU  - Watts RJ
FAU - Zhang, Jeff
AU  - Zhang J
FAU - Choy, Robert
AU  - Choy R
FAU - Howard, Peter
AU  - Howard P
FAU - Kadyk, Lisa
AU  - Kadyk L
FAU - Yan, Minhong
AU  - Yan M
FAU - Zha, Jiping
AU  - Zha J
FAU - Callahan, Christopher A
AU  - Callahan CA
FAU - Hymowitz, Sarah G
AU  - Hymowitz SG
FAU - Siebel, Christian W
AU  - Siebel CW
LA  - eng
SI  - PDB/3L95
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies)
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (NOTCH2 protein, human)
RN  - 0 (Notch1 protein, mouse)
RN  - 0 (Notch2 protein, mouse)
RN  - 0 (Peptide Library)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Receptor, Notch2)
RN  - 0 (Receptors, Notch)
SB  - IM
CIN - Nat Rev Drug Discov. 2010 Jun;9(6):431. PMID: 20514065
MH  - Angiogenesis Inhibitors/immunology/pharmacology/therapeutic use
MH  - Animals
MH  - Antibodies/adverse effects/immunology/*pharmacology/*therapeutic use
MH  - Antibody Specificity/immunology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Goblet Cells/drug effects/pathology
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - NIH 3T3 Cells
MH  - Neoplasms/blood supply/*drug therapy/*metabolism/pathology
MH  - Neovascularization, Pathologic/drug therapy
MH  - Peptide Library
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug 
      therapy/metabolism/pathology
MH  - Receptor, Notch1/antagonists & inhibitors/immunology
MH  - Receptor, Notch2/antagonists & inhibitors/immunology
MH  - Receptors, Notch/*antagonists & inhibitors/genetics/immunology/metabolism
MH  - Signal Transduction/drug effects
EDAT- 2010/04/16 06:00
MHDA- 2010/06/03 06:00
CRDT- 2010/04/16 06:00
PHST- 2009/06/30 00:00 [received]
PHST- 2010/01/28 00:00 [accepted]
PHST- 2010/04/16 06:00 [entrez]
PHST- 2010/04/16 06:00 [pubmed]
PHST- 2010/06/03 06:00 [medline]
AID - nature08878 [pii]
AID - 10.1038/nature08878 [doi]
PST - ppublish
SO  - Nature. 2010 Apr 15;464(7291):1052-7. doi: 10.1038/nature08878.