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Oncolytic virus therapy with induced anti-tumor immunity

A technology of anti-tumor immunity and oncolytic virus, which is applied in the field of viral tumor therapy and can solve the problems of limited oncolytic activity and other issues

Pending Publication Date: 2022-07-15
休斯敦系统大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current oncolytic viral therapies are limited by suboptimal oncolytic activity, susceptibility to innate or adaptive immune effector suppression, and limited ability to induce tumor-specific immune responses, especially to neoantigens

Method used

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  • Oncolytic virus therapy with induced anti-tumor immunity
  • Oncolytic virus therapy with induced anti-tumor immunity
  • Oncolytic virus therapy with induced anti-tumor immunity

Examples

Experimental program
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Effect test

Embodiment 1

[0065] Construction of the exposed instance

[0066] Figure 1A and Figure 1B The design of exemplary affibosome-PLs and their in vivo mechanisms of action in the tumor microenvironment are described. Affibody molecules are short peptides of 58 amino acids in length and are based on triple alpha-helical Z domain scaffolds that can be selected from combinatorial libraries to bind specific protein targets with strong affinity and specificity. See Feldwisch J, et al. "Engineering of affibody molecules for therapy and diagnostics" Methods Mol Biol. 899 (2012) 103-26. Examples of suitable affibodies selected for strong binding affinity to HER2 are available. See Orlova A, et al. "Tumor imaging using a picomolar affinity HER2 binding affibody molecule" Cancer Res. 66(8)(2006) 4339-48; Steffen AC, et al. "Affibody-mediated tumor targeting of HER-2 expressing xenografts in mice" Eur J Nucl Med Mol Imaging 33(6) (2006) 631-8. The coding sequences from the five immunoglobulin bindi...

Embodiment 2

[0072] Affibody-PL engagement of innate immune cells

[0073] Efforts were made to demonstrate that Affibody-PL can actively engage innate immune cells to attack tumor cells when tested in vitro. First, the ability of Affibody-PL to selectively bind to HER2-expressing tumor cells was examined. The plasmid or control plasmid (pcDNA3-EGFP from Addgene) containing the gene cassette pcDNA-Affibody-PL constructed by inserting Affibody-PL into the pcDNA3 plasmid was transfected into 293 cells for 24 hours (hr) Then collect the supernatant. Supernatants (100 μl) were added to three tumor cell lines (Skov3, from serous cystadenocarcinoma; MCF7; and MDA-MB-231) expressing varying levels of HER2 to allow Affibody-PL to bind tumors first HER2 on the cell surface. After washing, FITC-conjugated anti-HA-tagged antibody was added. The stained cells were then analyzed by flow cytometry and the results were shown in image 3 middle. As shown, Affibody-PL efficiently bound Skov3 cells ex...

Embodiment 3

[0076] Insertion of Affibody-PL coding sequences into oncolytic HSV and in vitro identification of the equipped virus.

[0077] Next, by techniques previously described in certain inventors' publications (see Fu, X et al.), by methods such as Figure 2A and Figure 2B Homologous recombination shown inserts the Affibody-PL coding sequence into the genome of the HSV-2 based oncolytic virus FusOn-H2. FusOn-H2 is a herpes simplex virus type 2 mutant that lacks the protein kinase domain of the ICP10 gene and is a potent oncolytic virus (Mol Ther. 13(5) (2006) 882-90; Fu X, et al. “Construction of anoncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells" Mol Ther. 20(2)(2012) 339-46); each of which is incorporated herein by reference. The complete sequence of the derived FusOn-Affibody-PL is provided in SEQ ID NO:17. Expression of Affibody-PL from the novel virus FusOn-PL was confirmed by Western blot analysis of supernatants collected from virus-inf...

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Abstract

Provided herein are improved oncolytic viruses with increased oncolytic cell killing and induced anti-tumor immunity. An oncolytic virus includes an oncolytic herpesvirus backbone genetically modified to encode a tumor cell binding component and an immunoglobulin (Ig) binding component.

Description

[0001] Field of Invention [0002] The present invention generally relates to methods and constructs for viral tumor therapy. [0003] Background of the Invention [0004] Without limiting the scope of the invention, the background of the invention is described in conjunction with existing oncolytic virus therapeutics. Oncolytic virus therapy for cancer relies on the use of oncolytic viruses, defined by their ability to selectively replicate and destroy tumor cells in tumor cells without damaging normal cells. [0005] Oncolytic viruses can kill cancer cells in a number of different ways, ranging from direct virus-mediated cytolysis to various cytotoxic immune effector mechanisms. However, current oncolytic virus therapies are limited by suboptimal oncolytic activity, susceptibility to inhibition by innate or adaptive immune effectors, and limited ability to induce tumor-specific immune responses, especially to neoantigens . [0006] Therefore, genetic engineering has been e...

Claims

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Application Information

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IPC IPC(8): A61K35/763C12N15/869C07K14/315
CPCC12N15/86C12N2710/16632C12N2710/16643C07K2319/00C07K2319/02C07K2319/33C07K2319/74C07K2318/20C12N2830/50A61K35/763C07K14/195A61P35/00C07K14/485C07K16/32C12N2710/16622C12N2710/16662C12N2710/16671
Inventor 张小留付新平
Owner 休斯敦系统大学
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