Anti-angiogenic adenovirus

A technology of recombinant adenovirus and angiostatin, which is applied in the fields of molecular biology and virology, can solve the problem of cancer being incurable

Pending Publication Date: 2020-07-24
EPICENTRX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Despite extensive understanding of the underlying molecular mechanisms leading to cancer, the majority of advanced cancers remain incurable with current chemotherapy and radiation therapies

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0135] Example 1: Construction of Adenovirus Expressing Endostatin or Angiostatin

[0136] This example describes the construction of recombinant adenovirus type 5 (Ad5) expressing endostatin and / or angiostatin.

[0137] A plasmid carrying the 5' portion of the adenovirus type 5 genome sequence was modified to carry a deletion of the region of nucleotides -304 to -255 upstream of the Ela initiation site to render E1a expression cancer-selective (as previously described in U.S. Pat. No. 9,073,980). The modified plasmid is hereinafter referred to as a TAV plasmid, and any viral particles produced therefrom are hereinafter referred to as TAV adenovirus.

[0138] The TAV plasmid was further modified to carry a SalI site at the beginning of the E1b-19k region and an XhoI site 200 bp 3' to the SalI site to facilitate insertion of the therapeutic transgene. To delete the E1b-19k region 200 bp, the plasmid was cut with SalI and XhoI and self-ligated. The nucleotide sequence of the ...

Embodiment 2

[0147] Example 2: Construction of Adenovirus Expressing Endostatin and / or Angiostatin

[0148] This example describes the construction of recombinant adenovirus type 5 (Ad5) expressing endostatin and / or angiostatin.

[0149] A plasmid carrying the 5' portion of the adenovirus type 5 genome sequence was modified to carry a deletion of the region of nucleotides -304 to -255 upstream of the Ela initiation site to render E1a expression cancer-selective (as previously described in U.S. Pat. No. 9,073,980). The modified plasmid is hereinafter referred to as a TAV plasmid, and any viral particles produced therefrom are hereinafter referred to as TAV adenovirus.

[0150] The TAV plasmid was further modified to carry a SalI site at the beginning of the E1b-19k region and an XhoI site 200 bp 3' to the SalI site to facilitate insertion of the therapeutic transgene. To delete the E1b-19k region 200 bp, the plasmid was cut with SalI and XhoI and self-ligated. The nucleotide sequence of ...

Embodiment 3

[0167] Example 3: Anticancer Activity of Adenoviruses Expressing Endostatin or Angiostatin

[0168] This example describes the anticancer activity of recombinant adenoviruses expressing endostatin or angiostatin prepared as described in Example 1.

[0169] On days 0, 4 and 8, at 1x10 9 PFU / dose three intratumoral injections of buffer, TAV-Δ19k, TAV-Endo, or TAV-Ang adenovirus, and / or four intraperitoneal injections of phosphate-buffered saline (PBS) or shellfish on days 1, 5, 9, and 13 The mouse homologue of valtumab (Bev) was used to treat ADS-12 tumor-bearing 129S4 mice. Figure 1-3 Initial results, including tumor volume and progression-free survival, are depicted in . Figure 4-6 Further results after tracking mice for a longer period of time are depicted in .

[0170] These results demonstrate that endostatin- and angiostatin-expressing adenoviruses are effective in reducing tumor volume, and that endostatin- and angiostatin-expressing adenoviruses and bevacizumab act ...

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Abstract

The invention relates to a recombinant adenovirus that expresses endostatin, angiostatin, or a combination of endostatin and angiostatin. The invention also relates to method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination of (i) a recombinant adenovirus and (ii) an anti-angiogenic agent to treat the cancer inthe subject.

Description

[0001] Cross References to Related Applications [0002] This patent application claims the benefit of priority of US Provisional Application Serial No. 62 / 510,647 filed May 24, 2017 and US Provisional Application Serial No. 62 / 510,647 filed June 2, 2017. technical field [0003] The field of the invention is molecular biology and virology, particularly recombinant adenoviruses and methods of using recombinant adenoviruses to treat cancer. Background technique [0004] Despite extensive understanding of the underlying molecular mechanisms that lead to cancer, most advanced cancers remain incurable with current chemotherapy and radiation therapies. Oncolytic viruses have now emerged as a platform technology with the potential to significantly improve the current standard of care for a variety of malignancies (Kumar, S. et al. (2008) CURRENTOPINION IN MOLECULAR THERAPEUTICS 10(4): 371-379; Kim, D. (2001) EXPERT OPINION ON BIOLOGICAL THERAPY 1(3):525-538; Kim D. (2000) ONCOGEN...

Claims

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Application Information

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IPC IPC(8): C12N7/01C12N15/861A61K35/761A61P35/00A61P9/00
CPCA61K35/761A61P9/00A61P35/00C12N15/86C12N2710/10332C12N2710/10343C07K14/78C12N9/6435Y02A50/30A61K39/3955C12N7/00C12N2710/00032C12N2710/00043C12N2710/10021
Inventor 克里斯托弗·拉森托尼·R·雷德布莱恩·T·奥兰斯基
Owner EPICENTRX
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