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Notch家族的4個(gè)受體是廣泛表達(dá)的跨膜蛋白，哺乳動(dòng)物細(xì)胞通過它們進(jìn)行溝通，來調(diào)控細(xì)胞命運(yùn)和生長。Notch信號作用的缺陷與很多癌癥相關(guān)，包括急性淋巴細(xì)胞白血病。利用“噬菌體呈現(xiàn)技術(shù)”，“基因科技公司”一個(gè)多學(xué)科小組了合成抗體，它們是Notch1 和Notch2的強(qiáng)效和特異性拮抗劑?？筃otch1的抗體在臨床前小鼠模型中表現(xiàn)出抗腫瘤活性，能抑制癌細(xì)胞生長和血管，并且在培養(yǎng)中也表現(xiàn)出針對人類癌細(xì)胞的活性。

Notch1和Notch2的同時(shí)抑制會(huì)引起小腸毒性，而只抑制其中一個(gè)能在很大程度上避免這一效應(yīng)，這是相對“泛Notch”抑制藥物來說的一個(gè)潛在治療優(yōu)勢。

由來自Salamander Design Studios的Gregóire Vion提供的本期封面圖片描繪了一個(gè)配體表達(dá)細(xì)胞（右）和一個(gè)相鄰細(xì)胞之間的通信——前一個(gè)細(xì)胞刺激后一個(gè)中的Notch信號作用。受體-細(xì)胞膜表達(dá)Notches 1 和 2（紅色和藍(lán)色）；特異性拮抗劑的作用意味著，只有藍(lán)色信號被傳導(dǎo)到細(xì)胞核。

原文出處：

Nature doi:10.1038/nature08878

Therapeutic antibody targeting of individual Notch receptors
Yan Wu1,9, Carol Cain-Hom2,9, Lisa Choy2, Thijs J. Hagenbeek2, Gladys P. de Leon7, Yongmei Chen1, David Finkle4, Rayna Venook4, Xiumin Wu5, John Ridgway5, Dorreyah Schahin-Reed6, Graham J. Dow2,10, Amy Shelton2, Scott Stawicki1, Ryan J. Watts6, Jeff Zhang8, Robert Choy8, Peter Howard8, Lisa Kadyk8, Minhong Yan5, Jiping Zha3, Christopher A. Callahan3, Sarah G. Hymowitz7  &  Christian W. Siebel2

   1. Department of Antibody Engineering,
   2. Department of Molecular Biology,
   3. Department of Pathology,
   4. Department of Translational Oncology,
   5. Department of Tumor Biology and Angiogenesis,
   6. Department of Neurodegeneration,
   7. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
   8. Exelixis Inc., 210 East Grand Avenue, PO Box 511, South San Francisco, California 94083-0511, USA
   9. These authors contributed equally to this work.
  10. Present address: Department of Biology, Stanford University, Stanford, California 94305, USA.

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 growth1, 2. Ligand binding triggers a conformational change in the receptor negative regulatory region （NRR） that enables ADAM protease cleavage3, 4  at a juxtamembrane site that otherwise lies buried within the quiescent NRR5, 6. Subsequent intramembrane proteolysis catalysed by the γ-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 cancer7, making the Notch pathway a compelling target for new drugs. Although γ-secretase inhibitors （GSIs） have progressed into the clinic8, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways9  and cause intestinal toxicity10, 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.