# US 2019/0167641 A1 · Use of vcp inhibitor and oncolytic virus in the preparation of an anti-tumor drug

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- Number: US 2019/0167641 A1
- Document ID: US20190167641A1
- Status: Published application
- Kind: A1
- Application number: 16/325,960
- Filed: 2017-08-18
- Published: 2019-06-06
- Earliest claimed: 2016-08-18
- Assignees: Guangzhou Virotech Pharmaceutical Co., Ltd.
- Applicants: Guangzhou Virotech Pharmaceutical Co., Ltd.
- Inventors: Guangmei YAN; Haipeng ZHANG; Yuan LIN; Suizhen LIN; Jing CAI; Shoufang GONG; Jun HU; Xiao XIAO; Kai LI; Jiankai LIANG; Yaqian TAN; Wenbo ZHU; Wei YIN
- Web page: https://patentgrep.com/patent/US20190167641A1

## CPC

- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 9/7023: {Transdermal patches and similar drug-containing composite devices, e.g. cataplasms (galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006)}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 35/768: Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61P 35/00: Antineoplastic agents
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- C12N 2770/36132: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention belongs to the field of biomedicine and relates to use of VCP (valosin-containing protein, VCP) inhibitor and oncolytic virus in the preparation of an anti-tumor drug. The present invention firstly discovers that VCP inhibitor can be used in the preparation of an anti-tumor synergist for oncolytic virus. Meanwhile, the present invention relates to a pharmaceutical composition comprising VCP inhibitor and oncolytic virus, a pharmaceutical kit comprising VCP inhibitor and oncolytic virus, and use of VCP inhibitor and oncolytic virus for treating tumor, especially a tumor that is not sensitive to oncolytic virus. The present invention also relates to an anti-tumor administration system, characterized in that, comprising oncolytic virus and a reagent for detecting the expression level of VCP.

## Claims

### Claim at position 1

1-3. (canceled)

### Claim 4

A pharmaceutical composition or a kit, comprising:
(a) at least one VCP inhibitor; and
(b) at least one oncolytic virus;
preferably, said composition or kit is a composition for treating tumors.

### Claim 5 (depends on 4)

The kit of claim 4, wherein the at least one VCP inhibitor and the at least one oncolytic virus are present as separate components.

### Claim 6

(canceled)

### Claim 7 (depends on 4)

The composition/kit according to claim 4, wherein said VCP inhibitor is Eeyarestatin I, NMS-873, CB-5083 or combination thereof.

### Claim 8 (depends on 4)

The composition/pharmaceutical kit according to claim 4, wherein said tumor is a solid tumor or a blood tumor.

### Claim 9 (depends on 4)

The composition/kit according to claim 4, wherein the ratio of Eeyarestatin I, NMS-873 or CB-5083 with oncolytic virus is 0.01˜200 mg: 103˜109 PFU; preferably 0.1˜200 mg: 104˜109 PFU; more preferably 0.1˜100 mg: 105˜′109 PFU;
preferably, the doses are used as follows: Eeyarestatin I, NMS-873 or CB-5083 is used in a range from 0.01 mg/kg to 200 mg/kg, while oncolytic virus is used in a titer such that MOI ranges from 103 to 109 (PFU/kg);
preferably, Eeyarestatin I, NMS-873 or CB-5083 is used in a range from 0.1 mg/kg to 200 mg/kg, while oncolytic virus is used in a titer such that MOI ranges from 104 to 109 (PFU/kg);
more preferably, Eeyarestatin I, NMS-873 or CB-5083 is used in a range from 0.1 mg/kg to 100 mg/kg, while oncolytic virus is used in a titer such that MOI ranges from 105 to 109 (PFU/kg).

### Claim 10 (depends on 4)

The pharmaceutical composition according to claim 4, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier; preferably said carrier is preferably selected from lyophilized powder, injection, tablet, capsule, kit or patch.

### Claim 11

An anti-tumor administration system comprising a VCP detecting reagent or detecting system, and oncolytic virus;
preferably said oncolytic virus is one or more selected from the group consisting of alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and herpes simplex virus;
preferably, said alphavirus is at least one selected from M1 virus and Getah virus;
preferably, said tumor is a solid tumor or a blood tumor;
more preferably, said solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer.

### Claim 12

A method for treating a subject with a tumor, the method comprising administering to the subject at least one VCP inhibitor and at least one oncolytic virus.

### Claim 13 (depends on 12)

The method of claim 12, wherein the tumor is a solid tumor or a blood tumor.

### Claim 14 (depends on 12)

The method of claim 12, wherein said oncolytic virus is one or more selected from the group consisting of alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and herpes simplex virus.

### Claim 15 (depends on 12)

The method of claim 12, wherein at least one VCP inhibitor is a substance that inhibits VCP.

### Claim 16 (depends on 4)

The pharmaceutical composition or the kit according to claim 4, wherein said VCP inhibitor is a synthetic VCP inhibitor, or
said VCP inhibitor is a substance for inhibiting the activity of VCP protein, or a substance for degrading VCP protein, or a genetic tool for reducing the level of VCP protein;
preferably, said substance for inhibiting the activity of VCP protein is selected from a compound, more preferably, said compound is one or more selected from Eeyarestatin I, NMS-873 and CB-5083;
or preferably, said genetic tool for reducing the level of VCP protein is RNA interference, microRNA, gene editing or gene knockout material;
more preferably, said VCP inhibitor is a tumor targeted VCP inhibitor.

### Claim 17 (depends on 4)

The pharmaceutical composition or the kit according to claim 4, wherein said oncolytic virus is one or more selected from the group consisting of alphavirus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus and herpes simplex virus.

### Claim 18 (depends on 17)

The pharmaceutical composition or the kit according to claim 17, wherein said alphavirus is at least one selected from M1 virus and Getah virus;
preferably, said alphavirus has at least 97.8% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423; more preferably, said alphavirus has at least 100% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423.

### Claim 19 (depends on 8)

The pharmaceutical composition or the kit according to claim 8, wherein said solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer; or
said tumor is a tumor that is not sensitive to oncolytic virus; or said tumor is a tumor with high expression of VCP;
preferably, said tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer, which is not sensitive to oncolytic virus;
or said tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer, which is of high expression of VCP.

### Claim 20 (depends on 12)

The method of claim 12, wherein said tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer; preferably, the tumor is a liver cancer; or
said tumor is a tumor that is not sensitive to oncolytic virus;
preferably, said tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer, which is not sensitive to oncolytic virus.

### Claim 21 (depends on 14)

The method of claim 14, wherein said alphavirus is at least one selected from M1 virus and Getah virus;
optionally, said M1 virus have a genome as described in Genbank Accession No. EF011023, or have a genome that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, identical to the genomic nucleotide sequence set forth in Genbank Accession No. EF011023;
optionally, said Getah virus have a genome as described in Genbank Accession No. EU015062, or have a genome that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, identical to the genomic nucleotide sequence set forth in Genbank Accession No. EU015062;
or optionally, said M1 virus has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423;
or optionally, said alphavirus has at least 97.8% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423; more preferably, said alphavirus has at least 100% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423.

### Claim 22 (depends on 15)

The method of claim 15, wherein said at least one VCP inhibitor is a substance inhibits the activity of VCP protein, a substance that degrades VCP protein, or a genetic tool that reduces the level of VCP protein;
preferably, said at least one VCP inhibitor is a low molecular weight compound;
preferably, said substance that inhibits the activity of VCP protein is selected from a compound;
more preferably, the compound is one or more selected from the group consisting of Eeyarestatin I, NMS-873 and CB-5083;
or preferably, said genetic tool that reduces the level of VCP protein is RNA interference, microRNA or gene editing or gene knockout material.

### Claim 23 (depends on 22)

The method of claim 22, wherein said VCP inhibitor is an siRNA, an shRNA, or an antibody.