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Modulation of adenoviral tropism

An adenovirus and targeting agent technology, applied in the field of adenovirus, can solve the fundamental problems that remain to be elucidated

Inactive Publication Date: 2011-04-13
安德鲁·贝克 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Adenoviruses based on human serotype 5 have been extensively studied, but fundamental questions about the mechanisms of infection, especially in vivo, remain to be elucidated

Method used

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  • Modulation of adenoviral tropism
  • Modulation of adenoviral tropism
  • Modulation of adenoviral tropism

Examples

Experimental program
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Effect test

Embodiment

[0281] The FX Gla domain is essential for Ad5 binding

[0282] FX is the zymogen of a vitamin K-dependent serine protease with a Gla (γ-carboxylated glutamate)-EGF1 (epidermal growth factor-like)-EGF2-SP (serine protease) domain structure ( figure 1 A), FX circulates in plasma at a concentration of 8 μg / ml. FX is converted to its active serine protease by a single proteolytic cleavage that produces a disulfide-bonded two-chain molecule consisting of a light chain (LC; Gla-EGF1-EGF2) and a heavy chain (HC; SP ) composed of molecules. There are three calcium ion binding sites in the FX molecule: the Gla domain coordinates seven calcium ions, and the EGF 1 and SP domains each bind a single calcium ion. The FX-Ad5 interaction is calcium dependent (Parker et al., 2006). We attempted to identify the domain responsible for Ad5 binding. To determine whether the N-terminal Gla-EGF1 component of FX binds to Ad5, we evaluated the binding of full-length activated human FX (FXa; Gla-EG...

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Abstract

The invention provides materials and methods for modulating adenoviral tropism for hepatocytes and other cell types such as splenocytes. It relates to the findings that hypervariable regions (HVRs) of the viral hexon protein interact with the Gla domain of the blood clotting factor FX as part of the infective process in vivo. The invention provides means to disrupt the interaction between hexon and FX, thus reducing infection of hepatocytes and splenocytes, as well as use of targeting agents comprising the Gla domain or a fragment thereof to direct adenoviral vectors to desired target cell or tissue types.

Description

field of invention [0001] The present invention relates to adenoviruses, and in particular to methods of reducing the tropism of adenoviruses for hepatocytes. Background of the invention [0002] Adenoviruses are common pathogens used for gene delivery and as vaccine vectors experimentally as well as in completed and ongoing clinical trials in oncology, cardiovascular, regenerative medicine (Schenk-Braat et al., 2007; Kawabata et al., 2006). Much work has demonstrated the potential benefits and limitations of adenovirus-mediated gene therapy both preclinically and clinically, the latter being introduced by Jesse Gelsinger in 1999 due to the extremely high doses of adenovirus type 5 (Ad5) delivered directly into the hepatic artery. ) has attracted attention (Raper et al., 2003). This significantly highlights the need to fully understand the virological and biological aspects that define the liver infectivity and in vivo toxicity of adenoviruses before the vectors can be ful...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/16A61K35/58C07K16/06A61K48/00G01N33/569G01N33/68A61K38/48C12N15/861
CPCA61K38/4846G01N2333/745G01N33/56983C12N2710/10322G01N2333/075C12N2810/6018C12N15/86A61K48/00G01N2500/02A61K38/162C07K14/005C12N7/00C12N2810/857A61K35/58C12N2710/10345
Inventor 安德鲁·贝克西蒙·沃丁顿约翰·麦克维
Owner 安德鲁·贝克
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