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Infectivity-enhanced conditionally-replicative adenovirus and uses thereof

a technology of adenovirus and replicative vector, which is applied in the field of adenovirus vectors, can solve the problems of poor infectability of primary tumors, affecting the efficiency of replicative vectors, and clinical trials that are less than optimal, so as to increase the infectivity of adenoviruses, improve the efficiency of replicative vectors, and improve the infectivity of primary tumors

Inactive Publication Date: 2012-08-16
BOARD OF RGT THE UNIV OF TEXAS SYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0021]It is a goal of the present invention to improve the infectivity and specificity of conditional replicative vectors, thereby improving their therapeutic utility and efficacy.
[0022]One object of the present invention is to provide adenoviral vectors that possess enhanced infectivity to a specific cell type (i.e., that are not limited to CAR-dependent cell entry) and that replicate with high efficiency in only those cell types.

Problems solved by technology

Despite the promise of adenoviral vectors, results from experimental models and clinical trials have been less than optimal.
One limitation lies in the poor infectability of primary tumors due to low levels of the primary adenovirus receptor CAR.
A second limitation that particularly affects the efficiency of replicative vectors is related to the lack of tumor-specific replication achieved using promoters or mutations.

Method used

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  • Infectivity-enhanced conditionally-replicative adenovirus and uses thereof
  • Infectivity-enhanced conditionally-replicative adenovirus and uses thereof
  • Infectivity-enhanced conditionally-replicative adenovirus and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Enhanced Tumor Transduction with Adenoviral Vectors Modified with an Antibody Conjugate

[0078]As a first approach towards enhancing the infectivity of adenoviral vectors and to demonstrate the tumor transduction advantage of vectors with altered tropism over unmodified vectors, an anti-fiber antibody conjugated to fibroblast growth factor (FGF2) was used. The Fab portion of the anti-knob antibody, 1D6.14, which is capable of blocking the interaction of the fiber with its cognate cellular receptor, was chemically conjugated to FGF2. The resulting Fab-FGF2 conjugate was complexed with adenoviral vectors expressing luciferase or β-galactosidase reporter genes to compare the transduction efficiency of the modified and unmodified vectors. Vector modification increased the level of gene expression more than 9-fold, as measured by luciferase activity (FIG. 1A), largely due to transduction of a greater percentage of target cells as seen by β-galactosidase staining (FIG. 1B). This experiment ...

example 2

Genetic Modification of the Hi Loop of the Fiber Provides Enhanced Infectivity to Adenoviral Vectors

[0080]The Fab-ligand conjugation method described in Example 1 only modifies the tropism of the vector prepared for inoculation. In the context of a replicative vector, it is advantageous to modify the tropism of the vector that replicates in the tumor as well. With this rationale, a genetic modification of the fiber is necessary for replicative vectors because it is carried over to the progeny. As a simple and potent strategy for retargeting, the sequence of the fiber was genetically modified. Based on the three-dimensional model of the fiber knob, targeting ligands were inserted into the HI loop of the fiber (FIG. 3). This loop is flexible, exposed on the outside of the knob, is not involved in fiber trimerization and its variable length in different Ad serotypes suggests that insertions or substitutions would not affect the fiber stability.

[0081]As a ligand to introduce into the HI...

example 3

Enhanced Tumor Transduction Via RDG-Fiber Modification

[0085]To determine if the RGD sequence incorporated into the HI loop of the fiber could increase the infectivity of tumors, the ability of the modified vector to deliver genes to cultured human ovarian cancer cells was examined. Characterization of two cell lines, SKOV3.ipl and OV-4, by flow cytometry showed that they both express moderate-to-high levels of ανβ3 and ανβ35 integrins. SKOV3.ipl also expresses a high level of CAR, whereas OV-4 only modestly expresses CAR.

[0086]The incorporation of recombinant RGD-containing fiber protein in the Ad5lucRGD vector dramatically improved the ability of the virus to efficiently transduce these cells (FIG. 4A). At different MOIs tested, Ad5lucRGD-transduced cultures of SKOV3.ipl cells showed 30-fold to 60-fold increase in luciferase activity compared to cells transduced with control virus. Interestingly, while the purified fiber knob blocked over 90% of AdCMVLuc-mediated gene transfer, it ...

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Abstract

A modified adenovirus capable of overcoming the problem of low level of coxsackie-adenovirus receptor (CAR) expression on tumor cells and methods of using such adenovirus are provided. The fiber protein of the adenovirus is modified by insertion or replacement so as to target the adenovirus to tumor cells, and the replication of the modified adenovirus is limited to tumor cells due to specific promoter control or mutations in E1a or E1b genes.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation of prior application U.S. Ser. No. 10 / 697,535, filed on Aug. 20, 2003, now abandoned, which claims the benefit of priority to U.S. Ser. No. 09 / 569,789, filed May 12, 2000, now U.S. Pat. No. 6,824,2004, which claims benefit of provisional patent application Ser. No. 60 / 133,634, filed May 12, 1999, now abandoned; wherein each application is hereby incorporated by reference in its entirety.FEDERAL FUNDING LEGEND[0002]This invention was produced in part using funds obtained through a grant from the National Institutes of Health. Consequently, the federal government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates generally to adenoviral vectors. More specifically, the present invention relates to infectivity-enhanced conditionally replicative adenovirus vectors.[0005]2. Description of the Related Art[0006]Surgery, chemotherapy a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/76A61P35/00C12N7/01A61K45/06A61K48/00C07K16/08C12NC12N7/00C12N15/861
CPCA61K45/06A61K48/0058C07K16/081C07K2317/55C07K2319/00C12N7/00C12N15/86C12N2710/10321C12N2710/10343C12N2710/10345C12N2810/40C12N2810/405C12N2810/6018C12N2810/851C12N2810/859C12N2830/008A61K48/00A61K35/761A61K2300/00A61P35/00
Inventor FUEYO, JUANGOMEZ-MANZANO, CANDELARIA
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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