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Oncolytic adenoviruses with mutations in immunodominant adenovirus epitopes and their use in cancer treatment

An oncolytic adenovirus and adenovirus technology, applied in the field of oncolytic adenovirus, can solve problems such as accelerated virus rapid release, accelerated virus transmission, and low total virus yield

Active Publication Date: 2018-03-27
VCN BIOSCI SL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This premature apoptosis usually results in lower total virus yields in many infected cell lines; however, it facilitates a rapid release of virus, which in turn accelerates virus dissemination in cell culture

Method used

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  • Oncolytic adenoviruses with mutations in immunodominant adenovirus epitopes and their use in cancer treatment
  • Oncolytic adenoviruses with mutations in immunodominant adenovirus epitopes and their use in cancer treatment
  • Oncolytic adenoviruses with mutations in immunodominant adenovirus epitopes and their use in cancer treatment

Examples

Experimental program
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Embodiment

[0176] It should be understood that the examples and implementations described herein are for illustrative purposes only, and various modifications or changes may be made by those skilled in the art, and shall be included within the spirit and scope of the present application.

[0177] Examples 1-4 demonstrate the immunological shift of the immune response from anti-adenovirus to anti-tumor by deletion of immunodominant T cell epitopes of adenovirus. ICO15K-TD-gp100-tyr (which is an HAd5 oncolytic adenovirus containing mutations in the three immunodominant T cell epitopes of the hexon and the human tumor epitope gp100-tyr inserted in the hexon) was used , demonstrated that mice treated with ICO15K-TD-gp100-tyr had attenuated overall resistance to adenovirus compared to mice treated with ICO15K-gp100-tyr, a control virus lacking the three hexon mutations immune response, while showing a higher immune response to the tyr tumor epitope.

Embodiment 5

[0178] Example 5 shows that ICO15K-TD-gp100-tyr induces more potent antitumor activity than ICO15K-gp100-tyr in murine tumor-bearing animals. Specifically, animals injected with ICO15K-TD-gp100-tyr were less likely to form tumors than animals treated with ICO15K-gp100-tyr.

[0179] Examples 6-8 show the effect of immunotransfer on antitumor activity in the absence of tumor epitopes. Specifically, the quadruple-deleted (QD) ICOVIR15K adenovirus (ICOVIR15K-QD) induced more potent antitumor activity than ICO15K in murine tumor-bearing animals, where the quadruple-deleted (QD ) ICOVIR15K adenovirus (ICOVIR15K-QD) lacks human tumor epitopes and introduces additional hexon epitope mutations.

Embodiment 1

[0181] Generation of oncolytic adenovirus ICOVIR15K-TD and its derivative ICO15K-TD-gp100-tyr with triple deletion (TD) using restricted-library method

[0182]The literature was searched for immunodominant epitopes restricted by human lymphocyte antigen-A2.1 (HLA-A2.1) of adenovirus 5 through PubMed. HLA-A2.1 was chosen because it is the major histocompatibility complex (MHC) class I ( Gonzalez‐Galarza, F.F., et al., Nucleic Acids Res. 2011 Jan; 39 (Database issue): D913-9). Each epitope has two major anchor sites for HLA-A2.1 at positions 2 and 9 of the peptide, and two minor anchor sites at positions 1 and 3. The hexon is considered to be the most immunogenic protein of human adenovirus 5, and the following three epitopes are based on different studies (Leen, A.M., et al., Blood. 2004 Oct 15; 104(8): 2432 -40; Leen, A.M., et al., J Virol.2008Jan; 82(1):546-54; Olive, M., et al., Hum Gene Ther.2002Jul 1; 13(10):1167-78; Tang , J., et al., Virology.2006 Jul 5; 350(2):312-2...

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Abstract

The present invention relates to oncolytic adenoviruses with functional deletions of immunodominant T-cell epitopes of adenovirus proteins, as well as to methods of using the oncolytic adenoviruses for the treatment of diseases, such as cancer. The oncolytic adenoviruses may also contain one or more heterologous nucleic acid sequences each encoding a tumor antigen or epitope. The oncolytic adenoviruses may also contain other mutations and insertions of DNA sequences used to confer selectivity and antitumor potency. The invention has application in the field of cancer therapy.

Description

technical field [0001] The field of the invention relates generally to an oncolytic adenovirus having a functional deletion of an immunodominant T cell epitope of an adenoviral protein, and methods of using the oncolytic adenovirus to treat diseases such as cancer. Background technique [0002] Currently, cancer treatment is mainly based on chemotherapy, radiotherapy and surgery. Despite the high success rate of early treatment, most advanced disease is incurable due to the inability to remove the tumor surgically or the dose of radiation and chemotherapy that can be administered is limited by the toxicity to normal cells. To alleviate this problem, biotechnological strategies pursuing higher selectivity and potency have been developed. Among them, gene therapy and virotherapy use viruses that have therapeutic targets for cancer. In gene therapy, viruses are modified to avoid their replication and used as vehicles or carriers of therapeutic genetic material. Virotherapy, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/705C12N7/00A61K39/00A61K39/235
CPCA61K2039/57C07K14/005C12N2710/10322C12N2710/10332A61K35/761A61P35/00A61K2039/572C07K14/075
Inventor 莱蒙·阿莱马尼拉鲁·吉尔米里阿姆·巴赞
Owner VCN BIOSCI SL
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