Antibodies and methods for Wnt pathway-related diseases

An antibody and antigen technology, applied in the field of antibodies binding to ZNRF3 protein or RNF43 protein, can solve the problem of less protein

Active Publication Date: 2014-10-01
NOVARTIS AG
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  • Abstract
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Problems solved by technology

[0008] Although many proteins are involved in the Wnt signaling pathway, few proteins have been identified as druggable targets in this pathway, especially those upstream in the β-catenin pathway in the Wnt pathway

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  • Antibodies and methods for Wnt pathway-related diseases
  • Antibodies and methods for Wnt pathway-related diseases
  • Antibodies and methods for Wnt pathway-related diseases

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Embodiment Construction

[0030] The present invention provides the following: First, ZNRF3 and RNF43 are cell surface proteins, so it is possible to use them as drug targets after the antibody binds to ZNRF3 or RNF43. Second, ZNRF3 and RNF43 are negative regulators of β-catenin and Wnt signaling pathways. Inhibition of ZNRF3 by using siRNA or by expressing a dominant negative mutant ZNRF3 protein resulted in increased Wnt signaling. Third, RNF43 is a functional homologue of ZNRF3. Fourth, an anti-ZNRF3 antibody that binds to the extracellular domain of the protein mimics inhibition of ZNRF3 either by using siRNA or by expressing a dominant negative mutant ZNRF3 protein, resulting in enhanced Wnt signaling. Fifth, various types of anti-ZNRF3 or RNF43 antibodies that bind to the extracellular domain of proteins can be produced by known methods for producing antibodies with specific binding. Sixth, inhibition of ZNRF3 enhances Wnt / β-catenin signaling and disrupts Wnt / PCP signaling in vivo. Seventh, th...

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Abstract

The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 are negative regulators of [beta]-catenin and the Wnt signaling pathway in eukaryotic cells. The activity of ZNRF3 can be modulated by antibody binding to its extracellular domain, thus causing an increase in Wnt signaling. The ZNRF3 antagonizing antibodies can be used to treat diseases with low Wnt signaling, such as short bowel syndrome, osteoporosis, diabetes, neurodegenerative diseases, and mucositis. In addition, the antagonizing antibodies of the invention can be used to enhance Wnt signaling for tissue repair and wound healing.

Description

technical field [0001] The present invention relates broadly to monoclonal antibodies that bind to receptors, and more particularly to antibodies that bind to ZNRF3 protein or RNF43 protein. Background technique [0002] The Wnt signaling pathway is a protein network in eukaryotic cells that is important for regulating cell growth and differentiation. Logan CY and Nusse R, "The Wnt signaling pathway in development and disease." Annu. Rev. Cell. Dev. Biol. 20:781-810 (2004); Nusse R., "Wnt signaling in disease and in development." Cell Res. 15(1):28-32 (January 2005); Clevers H, "Wnt / beta-catenin signaling in development and disease." Cell 127(3):469-80 (3Nov.2006). Wnt signaling is critical for regulating cell growth and differentiation during embryonic development. In adults, Wnt signaling promotes tissue homeostasis. [0003] Dysregulation of Wnt signaling has been linked to many human diseases. Abnormal overactivation of the Wnt pathway may be involved in the oncogene...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61K39/395
CPCC12N9/93C07K16/40A61K39/3955C12Y603/02019A61K45/06A61K38/53A61K31/40A61P1/04A61P1/12A61P11/00A61P17/02A61P17/16A61P19/08A61P19/10A61P25/00A61P3/00A61P31/04A61P35/00A61P43/00A61P9/00A61P3/10A61K2300/00
Inventor F·从H·郝L·B·科立克斯泰恩R-F·孔A·泰勒Y·谢
Owner NOVARTIS AG
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