Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies

被引：133

作者：

Ettenberg, Seth A. ^{[1
]}

Charlat, Olga ^{[1
]}

Daley, Michael P. ^{[1
]}

Liu, Shanming ^{[1
]}

Vincent, Karen J. ^{[1
]}

Stuart, Darrin D. ^{[1
]}

Schuller, Alwin G. ^{[1
]}

Yuan, Jing ^{[1
]}

Ospina, Beatriz ^{[1
]}

Green, John ^{[1
]}

Yu, Qunyan ^{[1
]}

Walsh, Renee ^{[1
]}

Li, Sharon ^{[1
]}

Schmitz, Rita ^{[1
]}

Heine, Holger ^{[1
]}

Bilic, Sanela ^{[1
]}

Ostrom, Lance ^{[1
]}

Mosher, Rebecca ^{[1
]}

Hartlepp, K. Felix ^{[2
]}

Zhu, Zhenping ^{[1
]}

Fawell, Stephen ^{[1
]}

Yao, Yung-Mae ^{[1
]}

Stover, David ^{[1
]}

Finan, Peter M. ^{[1
]}

Porter, Jeffery A. ^{[1
]}

Sellers, William R. ^{[1
]}

Klagge, Ingo M. ^{[2
]}

Cong, Feng ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] MorphoSys AG, D-82152 Martinsried, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 35期

关键词：

antibody therapeutics; cancer; RECEPTOR-RELATED PROTEIN-5; BONE-MASS; STEM-CELLS; EPIGENETIC INACTIVATION; MUTATION; SOST; ACTIVATION; PATHWAY; DISEASE; CANCER;

D O I：

10.1073/pnas.1007428107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Disregulated Wnt/beta-catenin signaling has been linked to various human diseases, including cancers. Inhibitors of oncogenic Wnt signaling are likely to have a therapeutic effect in cancers. LRP5 and LRP6 are closely related membrane coreceptors for Wnt proteins. Using a phage-display library, we identified anti-LRP6 antibodies that either inhibit or enhance Wnt signaling. Two classes of LRP6 antagonistic antibodies were discovered: one class specifically inhibits Wnt proteins represented by Wnt1, whereas the second class specifically inhibits Wnt proteins represented by Wnt3a. Epitope-mapping experiments indicated that Wnt1 class-specific antibodies bind to the first propeller and Wnt3a class-specific antibodies bind to the third propeller of LRP6, suggesting that Wnt1- and Wnt3a-class proteins interact with distinct LRP6 propeller domains. This conclusion is further supported by the structural functional analysis of LRP5/6 and the finding that the Wnt antagonist Sclerostin interacts with the first propeller of LRP5/6 and preferentially inhibits the Wnt1-class proteins. We also show that Wnt1 or Wnt3a class-specific anti-LRP6 antibodies specifically block growth of MMTV-Wnt1 or MMTV-Wnt3 xenografts in vivo. Therapeutic application of these antibodies could be limited without knowing the type of Wnt proteins expressed in cancers. This is further complicated by our finding that bivalent LRP6 antibodies sensitize cells to the nonblocked class of Wnt proteins. The generation of a biparatopic LRP6 antibody blocks both Wnt1- and Wnt3a-mediated signaling without showing agonistic activity. Our studies provide insights into Wnt-induced LRP5/6 activation and show the potential utility of LRP6 antibodies in Wnt-driven cancer.

引用

页码：15473 / 15478

页数：6

共 34 条

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An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells [J].