《Nature》封面文章 首次获得抗癌性跨膜蛋白抗体

　　

生物通报道，来自Genentech公司结构生物学部门，肿瘤研究部门，抗体工程等多个部门的科学家联手首次合成Notch跨膜蛋白抗体，在癌症治疗方面取得新进展，相关成果文章Therapeutic antibody targeting of individual Notch receptors公布在最新一期的Nature杂志上，并且别列为该期的封面文章。

 

Notch信号传导途径在无脊椎动物和脊椎动物中广泛存在且高度保守。此途径介导由局部细胞间相互作用而产生的、对多种不成熟细胞分化的抑制信号, 在胚胎发育中起重要作用。在多细胞生物的发育中, 需要通过邻近细胞间的相互作用对各谱系细胞分化潜能进行精确的调控。哺乳类动物中Notch途径的功能复杂多样, 参与造血、T细胞发育、血管生成等重要生理过程，Notch信号作用的缺陷与很多癌症相关，包括急性淋巴细胞白血病。

 

Notch家族的4个受体是广泛表达的跨膜蛋白，哺乳动物细胞通过它们进行沟通，来调控细胞命运和生长。

 

Genentech公司结研究小组利用“噬菌体呈现技术”（ phage display technology），生成了合成抗体，它们是Notch1 和Notch2的强效和特异性拮抗剂。

 

抗Notch1的抗体在临床前小鼠模型中表现出抗肿瘤活性，能抑制癌细胞生长和血管生成，并且在体外培养实验中也表现出针对人类癌细胞的活性。

 

Notch1和Notch2的同时抑制会引起小肠毒性，而只抑制其中一个能在很大程度上避免这一效应，这是相对“泛Notch”抑制药物来说的一个潜在治疗优势。

 

 

由来自Salamander Design Studios的Gregóire Vion提供的本期封面图片描绘了一个配体表达细胞（右）和一个相邻细胞之间的通信——前一个细胞刺激后一个中的Notch信号作用。受体-细胞膜表达Notches 1 和 2（红色和蓝色）；特异性拮抗剂的作用意味着，只有蓝色信号被传导到细胞核。

（生物通 小茜）

最新Acumen eX3高通量平台广泛应用癌症研究领域

生物通推荐原文检索

Nature 464, 1052-1057 (15 April 2010) | doi:10.1038/nature08878; Received 30 June 2009; Accepted 28 January 2010

 

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

 

Department of Antibody Engineering,

Department of Molecular Biology,

Department of Pathology,

Department of Translational Oncology,

Department of Tumor Biology and Angiogenesis,

Department of Neurodegeneration,

Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

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

These authors contributed equally to this work.

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

Correspondence to: Christian W. Siebel2 Correspondence and requests for materials should be addressed to C.W.S. (Email: [e-mail]).

【Abstract】

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.