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Oncolytic tumor viruses and methods of use

An adenovirus, tumor cell technology, applied in oncolytic tumor virus and its application field

Pending Publication Date: 2018-05-22
SALK INST FOR BIOLOGICAL STUDIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, an important challenge lies in designing viruses that can replicate selectively in cancer cells

Method used

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  • Oncolytic tumor viruses and methods of use
  • Oncolytic tumor viruses and methods of use
  • Oncolytic tumor viruses and methods of use

Examples

Experimental program
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Effect test

Embodiment 1

[0343] Example 1: Oncolytic Adenoviruses Selectively Replicate in Tumor Cells with Dysregulated E2F Activity

[0344] Modified adenoviruses were prepared from the components mentioned below according to the methods described in PCT Publication No. WO 2012 / 024351, incorporated herein by reference. The Gateway pDONR vector was used. The El module was obtained from human Ad5 DNA by PCR and inserted into the vector pDONR P1P4 using SLIC. The pDONR P1P4 vector backbone including attL1 and attL4 recombination sites was amplified using PCR and combined with the Ad5 E1 module using SLIC. The E3 module was obtained by PCR to generate a product flanked by attB5 and attB3r recombination sites. The product was inserted into pDONR P5P3r vector by Gateway BP reaction. The E4 module was obtained by PCR to generate a product flanked by attB3 and attB2 recombination sites. The product was inserted into pDONR P3P2 vector by Gateway BP reaction. The attR5-ccdB-Cm(r)-attR2 fragment from the ...

Embodiment 2

[0377]Example 2: Oncolytic Adenoviruses with Modifications in El, L3, E3 and / or E4

[0378] This example describes other recombinant adenoviruses with tumor selectivity. Exemplary recombinant viruses are listed in Table 2 and the genome sequences of these viruses are shown in SEQ ID NO: 25-31.

[0379] Table 2. Adenoviruses with modifications in E1, L3, E3 and / or E4

[0380]

[0381] AdSyn-CO312, AdSyn-CO313, and AdSyn-CO335 are rapamycin- and / or rapamycin analog (AP21967)-dependent EFGR-targeting viruses (see PCT Publication No. WO2013 / 138505, for which targeting The description of the method is hereby incorporated by reference in its entirety). Each of these recombinant viruses included deletions of the E3-RIDα / β and E3-14.7k coding sequences, as well as EGFRVHH-FKBP fusion proteins and FRB*-fibrils (Ad5 fibers fused to mutant FRB, which can bind rapamycin or rapamycin insertion of rapamycin analogues) or FRB-fibers (Ad5 fibers fused to wild-type FRB, which can only bi...

Embodiment 3

[0388] Example 3: Recombinant Adenovirus Expressing Chimeric Fiber Protein

[0389] This example describes recombinant adenoviruses expressing chimeric fibril proteins directed to infect specific cell types.

[0390] While Ad5 and many other serotypes have been shown to bind to the coxsackie adenovirus receptor (CAR) for cell attachment, other serotypes have been shown to use CD46, desmoglein 2, sialic acid, or others. Since Adsembly / AdSLIC (see PCT Publication No. WO 2012 / 024351, incorporated herein by reference) allows rapid generation of chimeric viruses, an initial set of six fiber chimeric viruses was generated to examine alternate cellular targets of various serotypes ability. Since the spherical nodule at the C-terminus of fibrin is generally responsible for receptor binding, chimeras were generated by replacing the Ad5 fibrous nodule with those from Ad3, Ad9, Ad11, Ad12, or Ad34 (FIGS. 23A23C; Table 3). Each virus generated had the same E1 module containing an E1A / E1...

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Abstract

Recombinant adenoviruses that selectively replicate in E2F deregulated tumor cells are described. The recombinant adenoviruses have a genome encoding a modified El A protein, a modified or deleted E4orf 1 protein, a modified or deleted E4orf6 / 7 protein, or any combination thereof, such that the recombinant adenoviruses exhibit replication defects in normal cells compared to tumor cells. In some instances, the recombinant adenovirus genomes encode additional modifications that target the recombinant adenoviruses to specific cell types, detarget the viruses from the liver, inhibit viral replication in the liver, and / or evade pre-existing neutralizing antibodies.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 054,724, filed September 24, 2014, which is incorporated herein by reference in its entirety. technical field [0003] The present disclosure relates to recombinant adenoviruses that selectively undergo lytic replication in tumor cells, comprising one or more modifications in E1A, E4orf1 and / or E4orf6 / 7. The recombinant adenovirus optionally has one or more modifications in the fiber, hexon or capsid proteins to allow systemic delivery and uptake in tumor cells. [0004] government support [0005] This invention was made with Government support under Grant No. 5T32GM007240-35 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0006] Cancer is a complex and debilitating disease that kills more than half a million people each year. There is a profound need for more effective...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N7/01A61K35/761A61P35/00
CPCA61K38/00A61K35/00C12N2710/10322C12N2710/10332C12N2710/10343C12N2810/6018C12N2810/855A61K35/761A61K31/436A61P35/00A61P35/02C12N15/86C12N7/00A61K48/005C07K14/005
Inventor C·奥谢S·米亚克-斯托纳
Owner SALK INST FOR BIOLOGICAL STUDIES
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