Modified vaccinia vectors

A carrier, vaccinia technology, applied in the field of immunotherapy, which can solve problems such as limited clinical success

Pending Publication Date: 2021-02-02
OTTAWA HOSPITAL RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the use of vaccinia virus as a clinical oncolytic vector is a promising cancer treatment paradigm, most current clinical candidates have shown only limited clinical efficacy due to toxicity in patients such as pox lesions and immunosuppressive side effects. success

Method used

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  • Modified vaccinia vectors
  • Modified vaccinia vectors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0198] Example 1 - Production of CopMD5p3p "SKV-B8R+" Recombinant Vaccinia Virus

[0199] The open reading frames (ORFs) from 59 poxvirus strains were clustered into orthologs and aligned at the amino acid level (see figure 1 phylogenetic analysis). Bayesian analysis was performed to determine the relatedness of all strains. Poxviruses are very diverse in terms of genetic content and host range. There are several naturally occurring wild strains of vaccinia, which differ from each other.

[0200] Five vaccinia wild strains (Copenhagen, TianTan, Lister, Wyeth, and Western Reserve) were mixed with equal plaque-forming unit counts and sequenced by NGS (inoculation library (Inputpool) )). The resulting mixture was passaged three times in different cancer cell lines (HeLa, 786-O, HT29, MCF7). The final population was sequenced by NGSillumina sequencing. Reads (short DNA fragments) were assigned to individual strains based on sequence identity and used to calculate the percent...

Embodiment 2

[0207] Example 2 - Cancer Cell Death

[0208] Cancer cells were infected with CopMD5p3p at a range of MOI (1 to 0.01 ) in 4 replicates in 24-well plates. Two days after virus infection, plates were stained with crystal violet. Crystal violet stain was dissolved in SDS and read spectrophotometrically. Data are expressed as a percentage of uninfected cells (see Figure 9). The data show that most cancer cell lines die more rapidly when exposed to the CopMD5p3p virus.

[0209] Figure 26 ,27 The ability of wild-type vaccinia Copenhagen virus and several modified vaccinia Copenhagen virions to induce anti-tumor immune responses and to proliferate in various cancer cell lines is also shown in and 29-35.

Embodiment 3

[0210] Example 3 - Growth in Cancer Cells

[0211] Four cancer cell lines were infected with CopMD5p3p at low MOI (0.001) and at different time points in 24-well plates in triplicate, and viruses were collected and titered. Time 0h represents inoculation. Figure 10 Growth curves for HeLa, 786-O, HT-29 and MCF7 are shown. This data shows that the in vitro growth ability of the modified CopMD5p3p virus is not impaired. This indicates that the virus is replication competent, even in the presence of an interferon response. The ability to replicate in mammalian cell lines provides another important advantage. As such, viruses with high speed and efficiency can be produced.

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Abstract

The disclosure relates to modified vaccinia virus vectors derived from the Copenhagen strain of vaccinia virus, as well as methods of using the same for the treatment of various cancers. The disclosure provides modified Copenhagen-derived vaccinia virus vectors that exhibit various beneficial therapeutic activities, including enhanced oncolytic activity, spread of infection, immune evasion, tumorpersistence, capacity for incorporation of exogenous DNA sequences, amenability for large scale manufacturing, and safety.

Description

technical field [0001] The invention relates to the field of immunotherapy, for example, for the treatment of abnormalities in cell proliferation, such as cancer. In particular, the invention relates to genetically modified vaccinia viruses and methods of making and using said vaccinia viruses. [0002] Background of the invention [0003] The immune system can be stimulated to recognize tumor cells and target them for destruction. Immunotherapy using oncolytic vaccinia viruses is a rapidly developing field in cancer research. New approaches are needed to engineer and / or improve the tumor selectivity of oncolytic viruses to maximize efficiency and safety. This selectivity is particularly important when adding potentially toxic therapeutic agents or genes to viruses. [0004] Although the use of vaccinia virus as a clinical oncolytic vector is a promising cancer treatment paradigm, most current clinical candidates have shown only limited clinical efficacy due to toxicity in...

Claims

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Application Information

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IPC IPC(8): C12N15/863A61K35/768A61P35/00C07K14/07C12N15/39C12N5/10C12N7/01
CPCA61K35/768A61P35/00C12N15/86C07K14/005C12N2710/24122C12N2710/24132A61P31/20A61K39/285
Inventor 约翰·C·贝尔法布里斯·勒伯夫迈克尔·S·许马修·Y·唐布莱恩·安德鲁·凯勒阿德里安·佩林
Owner OTTAWA HOSPITAL RES INST
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