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Oncolytic adenoviral vector and methods of use

An adenovirus and vector technology, applied in the field of oncolytic adenovirus vector and application, can solve problems such as unclear clinical response

Pending Publication Date: 2021-11-26
安利舒免疫溶瘤技术公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oncolytic adenoviruses have shown some promise in targeting ovarian cancer in Phase I clinical studies (see, e.g., Kimball et al., Clin. Cancer Res., 16(21):5277-87 (2010); Cerullo et al., Cancer Res., 70(11):4297-309(2010); and Koski et al., Mol.Ther., 18(10):1874-84(2010)); however, the clinical response to these treatments remains unclear, and the host's secondary immune response may inhibit its efficacy

Method used

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  • Oncolytic adenoviral vector and methods of use
  • Oncolytic adenoviral vector and methods of use
  • Oncolytic adenoviral vector and methods of use

Examples

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Embodiment 1

[0071] This example describes the construction and characterization of serotype 5 adenovirus according to the present disclosure.

[0072]UIO-523 (also known as AdSΔ15-40L.BBL-HV5 / 3-F5 / 3 and UIO-522OP in U.S. Provisional Application No. 62 / 808,694) is a conditionally replicable form of human serotype 5 containing the DNA sequence of the SPARC promoter Adenoviral (CRAd) vector (Δ15E1A, E1B-, E3+, HV5 / 3, F5 / 3) with a promoter modified to contain three hypoxia response elements (HRE) and 12 nuclear factor kappa B (NFκB) responsive Element (κBRE). HRE acts as a regulator of the hypoxic environment, while κBRE acts as a trigger of inflammation. Hypoxia and inflammation are hallmarks of the tumor microenvironment. The SPARC promoter is highly expressed in cancer-associated fibroblasts and endothelial cells that are in close contact with the malignant cellular compartment. A modified SPARC promoter drives a mutant ElA gene encoding a protein with defective retinoblastoma (Rb) bind...

Embodiment 2

[0077] This example describes the in vivo expression of CD40L and 41BBL in a xenogeneic model of human SKOV3 ovarian cancer.

[0078] Administer 4.5X10 to 6-8 week old nude mice 6 SKOV3.Luc cells. Once the tumor reaches an average of 150mm 3 , inject (i.t.) 1x10 10 v.p. / mouse or the same volume of PBS (30 μl).

[0079] Twenty-four hours later, tumors were excised and protein extracts were prepared. 100 μg of protein extracts were separated in 12% SDS-PAGE and transferred to nitrocellulose membranes (Bio-Rad Laboratories). Membranes were probed with anti-h4-1-BBL antibody (ab68185 Abcam, Cambridge, UK) or anti-CD40L antibody (ab2391 Abcam, Cambridge, UK). Anti-β-actin antibody (A4700; Sigma, St. Louis, MO) and anti-α-tubulin (12g10DSHB) were used as loading controls. Signals were detected using enhanced chemiluminescent reagents following the manufacturer's instructions (Amersham, Little Chalfont, UK). CD40L is expressed in Figure 4 shown in . Evaluation of 41BBL expr...

Embodiment 3

[0081] This example describes the pharmacology studies of UIO-523 in a subcutaneous xenograft mouse model of ovarian cancer.

[0082] A murine xenograft model of ovarian cancer based on subcutaneous (s.c.) implantation of the human ovarian cancer cell line SKOV3 was used to evaluate UIO-523 (armed with human CD40L and 4-1BBL). By placing the 5×10 6 SKOV3 cells / 200 μL were injected into the flanks of 6-8 week-old nude mice (n=10 mice / group) to establish subcutaneous tumors. On day 10 of tumor establishment, 5×10 of AR2011 or UIO-523 10 vp were injected intratumorally (i.t.) in 400 μL PBS. PBS administration served as a negative control. Virus was injected on days 1, 3 and 5 after tumor establishment as described (Lopez et al., Molecular Therapy, 20:2222-33 (2012)). Tumor imaging was performed on day -1 before treatment and then weekly until the end of the experiment. Mice received food and water ad libitum and were followed closely to avoid any signs of wasting or other vi...

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Abstract

Provided herein is a conditionally-replicating serotype 5 adenovirus or adenoviral vector expressing a mutant E1A protein under control of a promoter that is responsive to hypoxia and inflammation and one or more immune modulators under control of a tumor-specific promoter. The adenovirus or adenoviral vector also comprises serotype 3 fiber and hexon proteins. Also provided is a method of inducing cytotoxicity in tumor cells using a composition containing the adenovirus or adenoviral vector.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 808,694, filed February 21, 2019, the disclosure of which is incorporated herein by reference. [0003] Incorporation by reference of electronically submitted material [0004] Incorporated herein by reference in its entirety is the computer readable nucleotide / amino acid sequence listing filed herewith and identified as follows: Created on February 21, 2020 entitled "2020-02-21_37394-601_SQL_ST25.TXT" A 2,371-byte ASCII (text) file of . [0005] Background of the invention [0006] Oncolytic virotherapy (OV) is a promising and exciting new approach to cancer treatment. Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming normal tissues. In addition to its primary role of cell killing, OV stimulates the immune system. Oncolytic virus immunotherapy involve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/861A61K35/761C07K14/075C12N15/09C12N5/10
CPCA61K45/06A61P35/00C12N15/86C12N2710/10322C12N2710/10332A61K35/761C12N7/00C07K14/005A61K48/00C12N2710/10043C12N2710/10022
Inventor D·T·库里尔O·波哈塞尔M·V·罗佩斯
Owner 安利舒免疫溶瘤技术公司
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