Binding agents that modulate the hippo pathway and uses thereof

A technology of pathways and reagents, applied in the field of disease, which can solve the problem of not identifying cell surface receptors, etc.

Inactive Publication Date: 2015-05-06
ONCOMED PHARMA
View PDF40 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no cell surface receptors have been identified for the mammalian Hippo pathway

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Binding agents that modulate the hippo pathway and uses thereof
  • Binding agents that modulate the hippo pathway and uses thereof
  • Binding agents that modulate the hippo pathway and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0282] Expression of YAP in OMP tumors

[0283] Microarray gene expression analysis of patient-derived tumors in the OncoMed tumor bank was performed to determine YAP expression levels. 101 tumors were evaluated, including bladder (2), brain (2), breast (15), colon (25), liver (1), lung (19), melanoma (11), ovary (9), and pancreas tumor. Total RNA was isolated from these tumors that had been serially transplanted into NOD / SCID mice. RNA quality was monitored using Bioanalyzer (Agilent, Santa Clara CA). Purified RNA was processed using established Affymetrix procedures. Samples were hybridized to Affymetrix HG-U133plus 2.0 microarrays (Affymetrix, Santa Clara, CA) according to the manufacturer's technical manual. After hybridization, the microarray is washed, scanned and analyzed. Scanned arrays were background adjusted and signal intensity normalized using the GCRMA algorithm (Bioconductor, www.bioconductor.org )conduct. Such as figure 1As shown, about 80% of tumors s...

Embodiment 2

[0285] Inhibition of tumor growth by dominant-negative YAP

[0286] A mutant YAP gene encoding a dominant-negative human YAP (dnYAP) was designed and synthesized. The dnYAP protein comprises a YAP TEAD binding domain, two WW domains and a PDZ domain (SEQ ID NO:68). The YAP activation domain was deleted and the serine at amino acid 127 was replaced by an alanine residue (S127A). This substitution eliminates a critical phosphorylation site and allows dnYAP to translocate from the cytoplasm to the nucleus.

[0287] To express dnYAP in tumor cells in vitro and in vivo, the dnYAP gene was cloned into a lentiviral vector containing an immediate-early CMV enhancer. This lentiviral vector also contains an IRES-GFP moiety that allows visualization and selection of transduced cells. Lentiviral vectors are HIV-1-derived, replication-deficient, tat-independent, self-inactivating '3rd generation' vectors (see, eg, Durand et al., Viruses, 2011, 3:132-159). The lentiviral vector expressi...

Embodiment 3

[0293] Microarray Analysis of Tumor Cells Expressing dnYAP

[0294] As described in Example 2, the tumor cells of colon tumor OMP-C18, colon tumor OMP-C37, pancreas tumor OMP-PN7 and lung tumor OMP-LU52 were treated with dnYAP-lentivirus (LOM420, CMV-dnYAP-IRES-GFP) Or GFP-lentivirus (LOM92, CMV-IRES-GFP) transduction as a control. Transduced cells were cultured for 3 days and FACS sorted for GFP expression. The gene expression profiles of these transduced tumor cells were determined by microarray analysis. RNA was isolated from transduced cells and processed using established Affymetrix programs. Samples were hybridized to Affymetrix HG-U133 plus 2.0 microarrays (Affymetrix, Santa Clara, CA) according to the manufacturer's technical manual. After hybridization, the microarray is washed, scanned and analyzed. Scanned arrays were background adjusted and signal intensity normalized using the GCRMA algorithm (Bioconductor, www.bioconductor.org )conduct. Gene expression pro...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The present invention relates to agents that modulate the Hippo pathway and Hippo pathway signaling, such as antibodies and soluble receptors, as well as to methods of using the agents for the treatment of diseases such as cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 61 / 656,249, filed June 6, 2012, U.S. Provisional Application No. 61 / 737,390, filed December 14, 2012, and U.S. Provisional Application No. 61, filed March 14, 2013 / 783,190, each of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates generally to agents, such as antibodies and soluble receptors, that modulate the Hippo pathway and Hippo pathway signaling, and to methods of using said agents to treat diseases such as cancer. Background technique [0004] The Hippo pathway is a signaling pathway that regulates cell proliferation and cell death and determines organ size. This pathway is believed to function as a tumor suppressor in mammals, and dysregulation of this pathway is commonly detected in human cancers. This pathway is involved in and / or can regulate the self-renewal and differentiation of stem...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K38/00A61P35/00C12Q1/02
CPCA61K38/1774C07K2319/30C07K16/2803A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P25/00A61P35/00A61P43/00Y02A50/30A61K39/395A61K39/3955A61K45/06G01N33/5008G01N33/582
Inventor 奥斯丁·L·格尼C·沙尔捷-库尔托
Owner ONCOMED PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap