WO2021193081A1 - Virus de l'herpès simplex de type 1 - Google Patents

Virus de l'herpès simplex de type 1 Download PDF

Info

Publication number
WO2021193081A1
WO2021193081A1 PCT/JP2021/009720 JP2021009720W WO2021193081A1 WO 2021193081 A1 WO2021193081 A1 WO 2021193081A1 JP 2021009720 W JP2021009720 W JP 2021009720W WO 2021193081 A1 WO2021193081 A1 WO 2021193081A1
Authority
WO
WIPO (PCT)
Prior art keywords
type
virus
herpes simplex
rev
simplex virus
Prior art date
Application number
PCT/JP2021/009720
Other languages
English (en)
Japanese (ja)
Inventor
英樹 粕谷
吉則 直江
繁 松村
イブラヒム ラガブ ナシー エイッサ
Original Assignee
国立大学法人東海国立大学機構
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人東海国立大学機構 filed Critical 国立大学法人東海国立大学機構
Priority to JP2022509899A priority Critical patent/JPWO2021193081A1/ja
Publication of WO2021193081A1 publication Critical patent/WO2021193081A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/763—Herpes virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C12N15/869—Herpesviral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof

Definitions

  • the present invention relates to type 1 herpes simplex virus and the like.
  • Malignant tumor (cancer) (hereinafter sometimes referred to simply as "tumor”) is the number one factor in the mortality rate of Japanese people, but if early treatment by early diagnosis is possible, the mortality rate. Is said to be able to be significantly reduced.
  • treatments for tumors include surgical excision, radiation, and treatment with anticancer agents. Further, in recent years, tumor treatment using an oncolytic virus that specifically proliferates in tumor cells is also known.
  • C-REV is an oncolytic herpes simplex virus (HSV), a mutant virus that selectively destroys tumors and exerts antitumor effects.
  • HSV herpes simplex virus
  • the virus spreads from the tumor destroyed by the virus infection, and the released cancer antigen causes activation of tumor-specific lymphocytes. This activated lymphocyte has strong tumor immunity.
  • Non-Patent Document 1 when C-REV is administered to a tumor, it is applied not only to the tumor cells actually infected with C-REV, but also to the tumor cells surrounding the tumor cells destroyed by C-REV, and to the tumor cells that have distantly metastasized. Is also known to exert an antitumor effect by tumor-specific lymphocytes rather than virus infection (Non-Patent Document 1).
  • An object of the present invention is to provide a virus having a higher antitumor effect.
  • the present inventor has found that a type 1 herpes simplex virus containing an IL21 expression cassette in the viral genome can solve the above problems.
  • the present inventor has completed the present invention as a result of further research based on this finding. That is, the present invention includes the following aspects.
  • Item 1 Type 1 herpes simplex virus containing an IL21 expression cassette in the viral genome.
  • Item 2. The type 1 herpes simplex virus according to Item 1, which contains an expression cassette of CCL19 in the viral genome.
  • Item 3. Item 2.
  • Item 4. Item 2. The type 1 herpes simplex virus according to Item 2 or 3, wherein all the expression cassettes are controlled by a single promoter.
  • Item 5. Item 4. The type 1 herpes simplex virus according to any one of Items 1 to 4, which has cancer cell selectivity.
  • Item 6. Item 2.
  • Item 7. A drug comprising the type 1 herpes simplex virus according to any one of Items 1 to 6.
  • Item 8. Item 2. The drug according to Item 7, which is a drug.
  • Item 9. Item 2. The agent according to Item 7, which is an anticancer agent.
  • Item A A method for treating cancer, which comprises administering the type 1 herpes simplex virus according to any one of Items 1 to 6 to an animal.
  • Item B Item 1. The type 1 herpes simplex virus according to any one of Items 1 to 6 for use in the treatment of cancer.
  • Item C Use of the type 1 herpes simplex virus according to any one of Items 1 to 6 for the production of an anticancer drug.
  • Item D Use of the type 1 herpes simplex virus according to any one of Items 1 to 6 for the treatment of cancer.
  • the present invention it is possible to provide a virus having a higher antitumor effect. Furthermore, the virus of the present invention can exert an antitumor effect on a tumor distant from the administration site.
  • FIG. 1 It is a schematic diagram which shows the structure of the cytokine expression cassette in the cytokine-mounted C-REV (Example 1), and the position where the cytokine expression cassette is mounted in the viral genome.
  • the results of Elisa measurement of cytokine expression levels are shown (Example 1).
  • the vertical axis shows the IL21 concentration, and in the horizontal axis, MOCK indicates the case of non-virus infection, and the others indicate the virus species infecting the cells.
  • the results of tumor size measurement in the antitumor effect evaluation test 1 (Example 2) are shown.
  • the vertical axis shows the tumor size, and the horizontal axis shows the number of days elapsed since the start of virus administration.
  • the graph on the left shows the tumor size on the administration side, and the graph on the right shows the tumor size on the non-administration side.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered.
  • the results of body weight measurement in the antitumor effect evaluation test 1 (Example 2) are shown.
  • the vertical axis shows the body weight, and the horizontal axis shows the number of days elapsed from the start of virus administration.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered.
  • the results of tumor size measurement in the antitumor effect evaluation test 2 (Example 3) are shown.
  • the vertical axis shows the tumor size
  • the horizontal axis shows the number of days elapsed since the start of virus administration.
  • the graph on the left shows the tumor size on the administration side
  • the graph on the right shows the tumor size on the non-administration side.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered.
  • the results of body weight measurement in the antitumor effect evaluation test 2 (Example 3) are shown.
  • the vertical axis shows the body weight
  • the horizontal axis shows the number of days elapsed from the start of virus administration.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered.
  • the results of tumor size measurement in the antitumor effect evaluation test 3 are shown.
  • the vertical axis shows the tumor size, and the horizontal axis shows the number of days elapsed since the start of virus administration.
  • the graph on the left shows the tumor size on the administration side, and the graph on the right shows the tumor size on the non-administration side.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered.
  • the results of body weight measurement in the antitumor effect evaluation test 3 (Example 4) are shown.
  • the vertical axis shows the body weight, and the horizontal axis shows the number of days elapsed from the start of virus administration.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered.
  • the results of tumor size measurement in the antitumor effect evaluation test 4 (Example 5) are shown.
  • the vertical axis shows the tumor size, and the horizontal axis shows the number of days since virus administration.
  • the graph on the left shows the tumor size on the administration side, and the graph on the right shows the tumor size on the non-administration side.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered.
  • the serum IL-21 measurement result in the safety test (Example 6) is shown.
  • the vertical axis shows the IL-21 concentration
  • the horizontal axis shows the number of days elapsed since virus administration.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered. It is a figure which represented the content of FIG. 10 by a heat map.
  • the results of serum CCL19 measurement in the safety test (Example 6) are shown.
  • the vertical axis shows the CCL19 concentration, and the horizontal axis shows the number of days elapsed since virus administration.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered. It is a figure which represented the content of FIG. 12 by a heat map.
  • the serum IL-7 measurement result in the safety test (Example 6) is shown.
  • the vertical axis shows the IL-7 concentration
  • the horizontal axis shows the number of days elapsed since virus administration.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered. It is a figure which represented the content of FIG. 14 by a heat map.
  • the serum IL-15 measurement result in the safety test (Example 6) is shown.
  • the vertical axis shows the IL-15 concentration, and the horizontal axis shows the number of days elapsed since virus administration.
  • Control indicates the case of non-administration of virus, and the others indicate the type of virus administered. It is a figure which represented the content of FIG. 16 by a heat map.
  • the "identity" of an amino acid sequence refers to the degree of coincidence of two or more comparable amino acid sequences with respect to each other. Therefore, the higher the match between two amino acid sequences, the higher the identity or similarity of those sequences.
  • the level of amino acid sequence identity is determined, for example, using FASTA, a sequence analysis tool, using default parameters.
  • FASTA a sequence analysis tool
  • the algorithm BLAST by Karlin and Altschul Karlin S, Altschul SF. “Methods for assessing the statistical significance of molecular sequence features by using general scoring schemes” Proc Natl Acad Sci USA.
  • substitution between amino acid residues having a basic side chain such as lysine, arginine, and histidine is a conservative substitution.
  • Other amino acid residues with acidic side chains such as aspartic acid and glutamic acid; amino acid residues with non-charged polar side chains such as glycine, asparagine, glutamine, serine, threonine, tyrosine and cysteine; alanine, valine, leucine, isoleucine, Amino acid residues with non-polar side chains such as proline, phenylalanine, methionine and tryptophan; amino acid residues with ⁇ -branched side chains such as threonine, valine and isoleucine; with aromatic side chains such as tyrosine, phenylalanine, tryptophan and histidine Substitution between amino acid residues is also a conservative substitution.
  • polynucleotides such as DNA and RNA may be subjected to known chemical modifications as illustrated below.
  • Substituting the phosphate residue (phosphate) of each nucleotide with a chemically modified phosphate residue such as phosphorothioate (PS), methylphosphonate, or phosphorodithionate to prevent degradation by hydrolytic enzymes such as nucleases. Can be done.
  • the hydroxyl group at the 2-position of the sugar (ribose) of each ribonucleotide is changed to -OR (R is, for example, CH3 (2'-O-Me), CH2CH2OCH3 (2'-O-MOE), CH2CH2NHC (NH) NH2, It may be replaced with CH2CONHCH3, CH2CH2CN, etc.).
  • R is, for example, CH3 (2'-O-Me), CH2CH2OCH3 (2'-O-MOE), CH2CH2NHC (NH) NH2, It may be replaced with CH2CONHCH3, CH2CH2CN, etc.
  • the base moiety pyrimidine, purine
  • examples thereof include those in which the phosphoric acid moiety and the hydroxyl moiety are modified with biotin, an amino group, a lower alkylamine group, an acetyl group and the like, but the present invention is not limited thereto.
  • BNA LNA
  • the "coding sequence” is a base sequence encoding an amino acid sequence of a protein, and is not particularly limited as long as it is.
  • the present invention relates to a type 1 herpes simplex virus (sometimes referred to herein as "the virus of the present invention"), which comprises an IL21 expression cassette in the viral genome. This will be described below.
  • Type 1 herpes simplex virus is mainly composed of core protein, viral genome (DNA), capsid, segment protein, and envelope.
  • Type 1 herpes simplex virus invades the cells of the host animal, replicates within the cells, and eventually destroys / lyses the infected cells. Therefore, type 1 herpes simplex virus can exhibit oncolytic virus by infecting cancer cells.
  • Type 1 herpes simplex virus preferably has cancer cell selectivity.
  • the cancer cell selectivity include a property of specifically proliferating in cancer cells, a property of infecting cancer cells specifically, and a property of exhibiting cytolysis specifically in cancer cells. Among these, the property of specifically proliferating in cancer cells is preferable.
  • the type 1 herpes simplex virus having cancer cell selectivity may be either a naturally isolated virus strain or an artificially modified (for example, introduced with a heterologous gene) virus strain.
  • the type 1 herpes simplex virus having cancer cell selectivity is preferably Canerpaturev (C-REV: former name: HF10).
  • C-REV is an attenuated mutant of herpes simplex virus type 1 that carries the functional ⁇ 1 34.5 gene without artificial modification, and its antitumor effect can be obtained by local administration to the tumor. Be done.
  • C-REV is provided by Takara Bio Inc. for joint research purposes.
  • C-REV is WO2002 / 092826 International Pamphlet, Hepato-Gastroenterology 2003; 50: 961-966, Microbes Infect. 2007; 1-8, Current Gene Therapy. 2008 Jun; 8 (3): It is a simple herpes virus reported in 208-21 or Front Oncol. 2017; 7,149, etc.
  • type 1 herpes simplex virus having cancer cell selectivity examples include talimogene laherparepvec (T-VEC: Immunotherapy. 2015, 7, (6): 611-9.).
  • T-VEC is an oncolytic virus derived from type 1 herpes simplex virus carrying the GM-CSF gene, and has been approved as a drug by the US Food and Drug Administration.
  • G47 ⁇ is also an oncolytic virus produced by modifying the gene of type 1 herpes simplex virus, and its composition has also been reported (Proc Natl Acad Sci U S A. 2001, 98 (11): 6396). -401).
  • JS1 / 34.5- / 47- / mGM-CSF is a type 1 herpes simplex virus that lacks ICP34.5 and ICP47 and has a gene encoding mGM-CSF inserted, and has strong oncolytic virus. It has been reported (Gene Therapy 2003,10 (4); 292-303).
  • type 1 herpes simplex virus having cancer cell selectivity in addition to the above, those obtained by screening, those obtained by gene modification, etc. can be used.
  • a part of the endogenous gene is deleted (in the present specification, "deficiency” includes inactivation of the gene, for example, loss of function due to a frame shift).
  • deficiency includes inactivation of the gene, for example, loss of function due to a frame shift.
  • some endogenous genes eg UL56, UL43, UL49.5, UL55, etc.
  • the virus of the present invention is a mutant virus in the above-mentioned "type 1 herpes simplex virus" containing an IL21 expression cassette in the viral genome.
  • IL21 is one of the cytokines expressed in various animals.
  • the species from which IL21 is derived is not particularly limited.
  • the organism is not particularly limited, and examples thereof include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer.
  • human-derived IL21 includes a protein consisting of the amino acid sequence shown in SEQ ID NO: 1 (NCBI Accession Number: NP_068575) and a protein consisting of the amino acid sequence shown in SEQ ID NO: 2 (NCBI Accession Number: NP_068575). NCBI Accession Number: NP_001193935), these mature proteins (for example, proteins obtained by cleaving signal peptides) and the like can be mentioned.
  • mouse-derived IL21 (NCBI Gene ID: 60505), a protein consisting of the amino acid sequence shown in SEQ ID NO: 3 (NCBI Accession Number: NP_001277970) and a protein consisting of the amino acid sequence shown in SEQ ID NO: 4 (NCBI Accession Number:) NP_068554), these mature proteins (for example, proteins obtained by cleaving signal peptides) and the like can be mentioned.
  • IL21 may have mutations such as amino acid substitutions, deletions, additions, and insertions with respect to wild-type IL21 as long as the properties as cytokines are not significantly reduced. Mutations include preferably substitutions, more preferably conservative substitutions. When IL21 has an amino acid mutation, for example, 85% or more, preferably 90% or more, more preferably 95% or more, still more preferably 98% or more, still more preferably 99% with respect to the amino acid sequence of wild-type IL21. It has the above identity.
  • IL21 include the protein described in (a) below and the protein described in (b) below: (A) A protein consisting of a wild-type IL21 amino acid sequence (for example, the amino acid sequence shown in any of SEQ ID NOs: 1 to 4 or a mature sequence thereof), and (b) A wild-type IL21 amino acid sequence (for example, any of SEQ ID NOs: 1 to 4). At least one selected from the group consisting of proteins consisting of an amino acid sequence having 85% or more identity with the amino acid sequence shown in (1) or its mature sequence) can be mentioned.
  • the identity is preferably 90% or more, more preferably 95% or more, still more preferably 98% or more.
  • the number of amino acids mutated in (b) above is, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 2.
  • IL21 may be added with a protein or peptide such as a known protein tag or signal sequence.
  • a protein tag such as a known protein tag or signal sequence.
  • the protein tag include His tag, FLAG tag, Halo tag, MBP tag, HA tag, Myc tag, V5 tag, PA tag and the like.
  • the IL21 expression cassette is not particularly limited as long as it is a polynucleotide capable of expressing IL21 in the cell.
  • Typical examples of IL21 expression cassettes include promoters and polynucleotides containing the IL21 coding sequence placed under the control of the promoter. Further, if necessary, it may have another sequence such as a polyadenylation signal sequence, a reporter protein (for example, a fluorescent protein, etc.) coding sequence and the like.
  • the promoter contained in the IL21 expression cassette is not particularly limited, and can be appropriately selected according to the target cancer cells.
  • various pol II promoters can be used.
  • the polII promoter is not particularly limited, but for example, CMV promoter, EF1 promoter, SV40 promoter, MMTV promoter, MSCV promoter, hTERT promoter, ⁇ -actin promoter, CAG promoter, CEA promoter, AFP promoter, tyrosinase promoter, albumin promoter, etc.
  • Examples include the HSVUL29 promoter and the HSVUL39 promoter.
  • the reporter protein examples include a luminescent (color-developing) protein that reacts with a specific substrate to emit (color) the substrate, a fluorescent protein that fluoresces due to excitation light, and the like, and is not particularly limited.
  • luminescent (color-developing) proteins include luciferase, ⁇ -galactosidase, chloramphenicol acetyltransferase, ⁇ -glucuronidase, etc.
  • fluorescent proteins examples include GFP, Azami-Green, ZsGreen, GFP2, HyPer, Sirius, BFP, etc.
  • Examples include CFP, Turquoise, Cyan, TFP1, YFP, Venus, ZsYellow, Banana, KusabiraOrange, RFP, DsRed, AsRed, Strawberry, Jred, KillerRed, Cherry, HcRed, mPlum and the like.
  • the virus of the present invention preferably contains an expression cassette of CCL19 in the viral genome in the above-mentioned "type 1 herpes simplex virus".
  • CCL19 (C-C motif chemokine ligand 19) is one of the cytokines expressed in various animals.
  • the species from which CCL19 is derived is not particularly limited.
  • the organism is not particularly limited, and examples thereof include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer.
  • the amino acid sequences of various CCL19 are known. For example, it can be obtained from a known database (for example, NCBI: https://www.ncbi.nlm.nih.gov/). Specifically, for example, as human-derived CCL19 (NCBI Gene ID: 6363), a protein consisting of the amino acid sequence shown in SEQ ID NO: 5 (NCBI Accession Number: NP_006265) and this mature protein (for example, a signal peptide are cleaved). Protein) and the like.
  • NCBI Gene ID: 6363 a protein consisting of the amino acid sequence shown in SEQ ID NO: 5 (NCBI Accession Number: NP_006265) and this mature protein (for example, a signal peptide are cleaved). Protein
  • mouse-derived CCL19 (NCBI Gene ID: 24047) includes a protein consisting of the amino acid sequence shown in SEQ ID NO: 6 (NCBI Accession Number: NP_036018), this mature protein (for example, a protein obtained by cleaving a signal peptide), and the like. Can be mentioned.
  • CCL19 may have mutations such as amino acid substitutions, deletions, additions, and insertions with respect to wild-type CCL19 as long as the properties as cytokines are not significantly reduced. Mutations include preferably substitutions, more preferably conservative substitutions. When CCL19 has an amino acid mutation, for example, 85% or more, preferably 90% or more, more preferably 95% or more, still more preferably 98% or more, still more preferably 99% with respect to the amino acid sequence of wild-type CCL19. It has the above identity.
  • CCL19 examples include the protein described in (c) below and the protein described in (d) below:
  • C A protein consisting of a wild-type CCL19 amino acid sequence (for example, the amino acid sequence shown in any of SEQ ID NOs: 5 to 6 or a mature sequence thereof), and (d) a wild-type CCL19 amino acid sequence (for example, any of SEQ ID NOs: 5 to 6).
  • At least one selected from the group consisting of proteins consisting of an amino acid sequence having 85% or more identity with the amino acid sequence shown in (1) or its mature sequence can be mentioned.
  • the identity is preferably 90% or more, more preferably 95% or more, still more preferably 98% or more.
  • the number of amino acids mutated in (d) above is, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 2.
  • CCL19 may be added with a protein or peptide such as a known protein tag or signal sequence.
  • a protein tag such as a known protein tag or signal sequence.
  • the protein tag include His tag, FLAG tag, Halo tag, MBP tag, HA tag, Myc tag, V5 tag, PA tag and the like.
  • the CCL19 expression cassette is the same as the IL21 expression cassette.
  • the virus of the present invention preferably contains at least one expression cassette selected from the group consisting of an IL7 expression cassette and an IL15 expression cassette in the virus genome.
  • a CCL19 expression cassette and at least one expression cassette selected from the group consisting of an IL7 expression cassette and an IL15 expression cassette are included.
  • the expression cassette of CCL19 and the expression cassette of IL7 may be included. preferable.
  • IL7 (interleukin 7) is one of the cytokines expressed in various animals.
  • the species from which IL7 is derived is not particularly limited.
  • the organism is not particularly limited, and examples thereof include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer.
  • IL7 amino acid sequences are known. For example, it can be obtained from a known database (for example, NCBI: https://www.ncbi.nlm.nih.gov/). Specifically, for example, as human-derived IL7 (NCBI Gene ID: 3574), a protein consisting of the amino acid sequence shown in SEQ ID NO: 7 (NCBI Accession Number: NP_000871) and a protein consisting of the amino acid sequence shown in SEQ ID NO: 8 (NCBI Accession Number: NP_000871).
  • NCBI Accession Number: NP_001186815 protein consisting of the amino acid sequence shown in SEQ ID NO: 9 (NCBI Accession Number: NP_001186816), protein consisting of the amino acid sequence shown in SEQ ID NO: 10 (NCBI Accession Number: NP_001186817), these Examples include mature proteins (for example, proteins obtained by cleaving a signal peptide).
  • mouse-derived IL7 (NCBI Gene ID: 16196), a protein consisting of the amino acid sequence shown in SEQ ID NO: 11 (NCBI Accession Number: NP_001300817) and a protein consisting of the amino acid sequence shown in SEQ ID NO: 12 (NCBI Accession Number: NP_001300818), a protein consisting of the amino acid sequence shown in SEQ ID NO: 13 (NCBI Accession Number: NP_001300819), a protein consisting of the amino acid sequence shown in SEQ ID NO: 14 (NCBI Accession Number: NP_032397), these mature proteins (for example, A protein obtained by cleaving a signal peptide) and the like.
  • NCBI Gene ID: 16196 a protein consisting of the amino acid sequence shown in SEQ ID NO: 11 (NCBI Accession Number: NP_001300817) and a protein consisting of the amino acid sequence shown in SEQ ID NO: 12 (NCBI Accession Number: NP_001300818), a protein consisting of the
  • IL7 may have mutations such as amino acid substitutions, deletions, additions, and insertions with respect to wild-type IL7 as long as the properties as cytokines are not significantly reduced. Mutations include preferably substitutions, more preferably conservative substitutions. When IL7 has an amino acid mutation, for example, 85% or more, preferably 90% or more, more preferably 95% or more, still more preferably 98% or more, still more preferably 99% with respect to the amino acid sequence of wild-type IL7. It has the above identity.
  • IL7 include the protein described in (e) below and the protein described in (f) below: (E) A protein consisting of a wild-type IL7 amino acid sequence (for example, the amino acid sequence shown in any of SEQ ID NOs: 7 to 14 or a mature sequence thereof), and (f) A wild-type IL7 amino acid sequence (for example, any of SEQ ID NOs: 7 to 14). At least one selected from the group consisting of proteins consisting of an amino acid sequence having 85% or more identity with the amino acid sequence shown in (1) or its mature sequence) can be mentioned.
  • the identity is preferably 90% or more, more preferably 95% or more, still more preferably 98% or more.
  • the number of amino acids mutated in (f) above is, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 2.
  • IL7 may be added with a protein or peptide such as a known protein tag or signal sequence.
  • a protein tag such as a known protein tag or signal sequence.
  • the protein tag include His tag, FLAG tag, Halo tag, MBP tag, HA tag, Myc tag, V5 tag, PA tag and the like.
  • the IL7 expression cassette is the same as the IL21 expression cassette.
  • IL15 is one of the cytokines expressed in various animals.
  • the species from which IL15 is derived is not particularly limited.
  • the organism is not particularly limited, and examples thereof include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer.
  • the amino acid sequences of various IL15 are known. For example, it can be obtained from a known database (for example, NCBI: https://www.ncbi.nlm.nih.gov/). Specifically, for example, as human-derived IL15 (NCBI Gene ID: 3600), a protein consisting of the amino acid sequence shown in SEQ ID NO: 15 (NCBI Accession Number: NP_000576) and a protein consisting of the amino acid sequence shown in SEQ ID NO: 16 (NCBI Accession Number: NP_751915), these mature proteins (for example, proteins obtained by cleaving a signal peptide) and the like can be mentioned.
  • NCBI Gene ID: 3600 a protein consisting of the amino acid sequence shown in SEQ ID NO: 15
  • NP_751915 a protein consisting of the amino acid sequence shown in SEQ ID NO: 16
  • these mature proteins for example, proteins obtained by cleaving a signal peptide
  • mouse-derived IL15 (NCBI Gene ID: 16168), a protein consisting of the amino acid sequence shown in SEQ ID NO: 17 (NCBI Accession Number: NP_001241676) and a protein consisting of the amino acid sequence shown in SEQ ID NO: 18 (NCBI Accession Number NP_ 032383)
  • These mature proteins for example, proteins obtained by cleaving a signal peptide
  • IL15 may have mutations such as amino acid substitutions, deletions, additions, and insertions with respect to wild-type IL15 as long as the properties as cytokines are not significantly reduced. Mutations include preferably substitutions, more preferably conservative substitutions. When IL15 has an amino acid mutation, for example, 85% or more, preferably 90% or more, more preferably 95% or more, still more preferably 98% or more, still more preferably 99% with respect to the amino acid sequence of wild-type IL15. It has the above identity.
  • IL15 include the protein described in (g) below and the protein described in (h) below: (G) A protein consisting of a wild-type IL15 amino acid sequence (for example, the amino acid sequence shown in any of SEQ ID NOs: 15 to 18 or a mature sequence thereof), and (h) A wild-type IL15 amino acid sequence (for example, any of SEQ ID NOs: 15 to 18). At least one selected from the group consisting of proteins consisting of an amino acid sequence having 85% or more identity with the amino acid sequence shown in (1) or its mature sequence) can be mentioned.
  • the identity is preferably 90% or more, more preferably 95% or more, still more preferably 98% or more.
  • the number of amino acids mutated in (h) above is, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 2.
  • IL15 may be added with a protein or peptide such as a known protein tag or signal sequence.
  • a protein tag such as a known protein tag or signal sequence.
  • the protein tag include His tag, FLAG tag, Halo tag, MBP tag, HA tag, Myc tag, V5 tag, PA tag and the like.
  • the IL15 expression cassette is the same as the IL21 expression cassette.
  • each cytokine gene expression is independent.
  • a plurality of expression cassettes controlled by a promoter may be used, or an expression cassette in which a plurality of gene expressions are controlled by a single promoter may be used.
  • each expression cassette does not have a promoter, but the IL21 expression cassette and the CCL19 expression cassette typically have a promoter.
  • a polynucleotide containing the IL21 coding sequence and the CCL19 coding sequence placed under the control of the promoter more specifically, from the 5'side, the promoter, the IL21 coding sequence, the CCL19 coding sequence (or The promoter, the coding sequence of CCL19, and the coding sequence of IL21) can be the polynucleotides arranged in this order.
  • self-cleaving peptide means a peptide sequence with cleavage activity that occurs between two amino acid residues within the peptide sequence itself.
  • self-cleaving peptides include 2A peptides and 2A-like peptides. For example, in 2A peptides or 2A-like peptides, cleavage occurs between glycine residues and proline residues on these peptides.
  • the ribosome skipping mechanism prevents the formation of normal peptide bonds between glycine residues and proline residues during translation, and does not affect downstream translation.
  • the ribosome skip mechanism is known in the art and is used for the expression of multiple proteins encoded by a single molecule of messenger RNA (mRNA).
  • mRNA messenger RNA
  • the self-cleaving peptide used in the present invention can be obtained from a viral 2A peptide or a 2A-like peptide having an equivalent function.
  • 2A peptide derived from foot-and-mouth disease virus (FMDV)
  • 2A peptide E2A
  • E2A horse rhinitis A virus
  • P2A Porcine teschovirus
  • TaV Thosea signavirus
  • the above-mentioned expression cassette is included in the locus of the deficient endogenous gene. This makes it possible to reduce the influence of cis elements in the viral genome on transcription from the expression cassette, and facilitates control of transcription from the expression cassette based on the configuration of the expression cassette.
  • the virus of the present invention can be easily produced according to a known genetic engineering method. For example, it can be prepared by using PCR, restriction enzyme cleavage, DNA ligation technology, or the like.
  • the virus of the present invention has oncolytic properties. Therefore, the virus of the present invention is more specifically effective as an active ingredient of a drug, a reagent, etc. (sometimes referred to as "the drug of the present invention” in the present specification), more specifically, an anticancer agent, etc. It can be used as an ingredient.
  • the agent of the present invention is not particularly limited as long as it contains the virus of the present invention, and may further contain other components if necessary.
  • the other components are not particularly limited as long as they are pharmaceutically acceptable components.
  • Other components include additives as well as components having a pharmacological action. Additives include, for example, bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, moisturizers, colorants, fragrances, etc. Examples include a chelating agent.
  • the drug of the present invention can be used as a drug for cancer treatment (anticancer drug).
  • the agent of the present invention can be used in combination with other anticancer agents.
  • the other anticancer agent is not particularly limited, and various anticancer agents can be used.
  • the anticancer agent include alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum preparations, molecular targeting agents, hormone agents, biological preparations and the like, which are preferable.
  • examples include antimetabolites, antibiotic anticancer agents, platinum preparations and the like.
  • alkylating agent examples include cyclophosphamide, iphosphamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, and ranimustine.
  • Antimetabolites include, for example, enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nelarabine, fluorouracil, fludalabine, pemetrexed.
  • Examples include cladribine, doxifluridine, hydroxycarbamide, mercaptopurine and the like.
  • Examples of the microtubule inhibitor include alkaloid anticancer agents such as vincristine and taxane anticancer agents such as docetaxel and paclitaxel.
  • Antibiotics Anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, acralubicin, idarubicin, pirarubicin, peplomycin, mitoxantrone, amurubicin, dinostatin stimalamar and the like.
  • topoisomerase inhibitor examples include CPT-11 having a topoisomerase I inhibitory action, irinotecan, nogitecan, and etoposide and sobzoxane having a topoisomerase II inhibitory action.
  • platinum preparation examples include cisplatin, nedaplatin, oxaliplatin, carboplatin and the like.
  • Hormonal agents include, for example, dexamethasone, finasteride, tamoxifen, astrosol, exemestane, ethinyl estradiol, chlormadinone, goseleline, bicalutamide, flutamide, bredonizolone, leuprorelin, letrozole, estramustine, tremiphen, fosfestrol, mitotan, Examples thereof include methyltestosterone, medroxyprogesterone, and mepitiostane.
  • Biopharmaceuticals include, for example, interferon ⁇ , ⁇ and ⁇ , interleukin 2, ubenimex, dried BCG and the like.
  • Molecular-targeted drugs include, for example, rituximab, alemtuzumab, trastuzumab, cetuximab, panitummab, imatinib, dasatinib, nirotinib, gefitinib, elrotinib, temsirolimus, bebashizumab, temshirolimus, bebashizumab, vEGF trap , Ibritumomab tiuxetan, tamibarotene, tretinoin, etc.
  • human epithelial growth factor receptor 2 inhibitor In addition to the molecular-targeted drugs specified here, human epithelial growth factor receptor 2 inhibitor, epithelial growth factor receptor inhibitor, Bcr-Abl tyrosine kinase inhibitor, epithelial growth factor tyrosine kinase inhibitor, mTOR inhibition Agents, inhibitors targeting angiogenesis such as vascular endothelial growth factor receptor 2 inhibitors ( ⁇ -VEGFR-2 antibody), various tyrosine kinase inhibitors such as MAP kinase inhibitors, inhibitors targeting cytokines, Molecular-targeted drugs such as proteasome inhibitors, antibody-anticancer drug formulations, etc. can also be included. These inhibitors also include antibodies.
  • the agent of the present invention is used in combination with an oncolytic virus different from the virus of the present invention, or a drug (cell medicine) containing cells such as cytotoxic T cells, natural killer cells, and antigen-presenting cells as active ingredients. You can also do it.
  • the cell medicine include artificially modified cells, for example, T cells (CAR-T) into which a chimeric antigen receptor gene has been introduced and T cells (TCR-T) into which a T cell receptor gene has been introduced.
  • the usage mode of the drug of the present invention is not particularly limited, and an appropriate usage mode can be adopted according to the type of the drug.
  • the agent of the present invention can be used, for example, in vitro (for example, added to the medium of cultured cells) or in vivo (for example, administered to an animal). You can also.
  • the application target of the agent of the present invention is not particularly limited, and examples of mammals include humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer.
  • examples of cells include animal cells and the like.
  • the type of cell is not particularly limited, and for example, blood cell, hematopoietic stem cell / precursor cell, sperm (sperm, egg), fibroblast, epithelial cell, vascular endothelial cell, nerve cell, hepatocyte, keratin-producing cell, muscle cell. , Epidermal cells, endocrine cells, ES cells, iPS cells, tissue stem cells, cancer cells and the like.
  • the target cancer is not particularly limited, and for example, ovarian cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract. Cancer, colon cancer, skin cancer, malignant melanoma, osteosarcoma, squamous epithelial cancer of the head and neck, gastric cancer, prostate cancer, breast cancer, lung cancer, colon cancer, lymphoma, liver cancer, mesenteric cancer, black Tumors, stellate cell tumors, oligodendroglioma, meningeal tumors, neurofibromas, glioblastomas, coat cell tumors, nerve sheath tumors, neurofibrosarcoma, neuromyelblastoma, fibrosarcoma, squamous epithelium Examples include cell cancer, neuroendoblast cell cancer, thyroid tumor, pituitary tumor, epidermoid cancer and the like. Among these, solid cancer is preferable.
  • the agent of the present invention can be used in any dosage form, for example, tablets (including medially disintegrating tablets, chewable tablets, effervescent tablets, troches, jelly-like drops, etc.), rounds, granules, fine granules, powders, etc.
  • Oral formulation forms such as hard capsules, soft capsules, dry syrups, liquids (including drinks, suspensions, and syrups), jelly, and injection formulations (eg, drip injections (eg, intravenous drip)).
  • intravenous injections intramuscular injections, subcutaneous injections, intradermal injections
  • external preparations eg, ointments, paps, lotions
  • suppository inhalants e.g., ointments, paps, lotions
  • suppository inhalants e.g., ophthalmic agents, eye ointments, dots
  • Parenteral preparation forms such as nasal preparations, ear drops, and liposome preparations can be taken.
  • the route of administration of the agent of the present invention is not particularly limited as long as a desired effect can be obtained, and is locally administered to tumor tissue; oral administration, tube feeding, enema administration, etc.
  • Parenteral administration such as arterial administration, intramuscular administration, intracardiac administration, subcutaneous administration, intradermal administration, and intraperitoneal administration can be mentioned.
  • the agent of the present invention is locally administered to tumor tissue as an injection.
  • the liquid medium for preparing the injection is not particularly limited as long as it is a liquid solvent that does not affect the living body, and a known medicinal liquid medium can be used. In addition, it can contain various components that are permitted for use in injections.
  • the number of viruses of the present invention in the agent of the present invention depends on the mode of use, the target of application, the state of the target of application, and the like, and is not limited.
  • the number of viruses is, for example, 10 3 or more, 2 ⁇ 10 3 or more, 5 ⁇ 10 3 or more, 10 4 or more, 2 ⁇ 10 4 or more, 5 ⁇ 10 4 or more, 10 5 or more, 2 ⁇ 10 5 or more, 5 ⁇ 10 5 or more, 10 6 or more, 2 ⁇ 10 6 or more, 5 ⁇ 10 6 or more, 10 7 or more, 2 ⁇ 10 7 or more, 5 ⁇ 10 7 or more, 10 8 or more, 2 ⁇ 10 8 or more, 5 ⁇ 10 8 or more, 10 9 or more, 2 ⁇ 10 9 or more, 5 ⁇ 10 9 or more, 10 10 or more.
  • the upper limit is not particularly limited, but is, for example, 10 12 or less and 10 11 or less.
  • the administration schedule is not particularly limited, and can be, for example, only once, or twice or more (for example, 2 to 10 times) at a frequency of once a day to once a month. It can be appropriately adjusted according to the usage mode, application target, state of application target, and the like.
  • Example 1 Cytokine-loaded C-REV production
  • a cytokine gene was introduced into the UL43 locus where a gene defect (function loss due to frameshift) was observed in C-REV.
  • the expression of the cytokine gene was regulated by the CMV promoter, and the green fluorescent protein (Green) was also expressed via IRES.
  • a plasmid was constructed at both ends of a cytokine expression cassette transcriptionally regulated by the CMV promoter, sandwiched in the same base sequence as the UL43 gene of 500 bases each.
  • the cytokines to be introduced are mouse IL7 (SEQ ID NO: 19), mouse IL15 (SEQ ID NO: 20), mouse IL21 (SEQ ID NO: 21), and mouse CCL19 (SEQ ID NO: 22).
  • FIG. 1 shows a schematic diagram showing the configuration of the cytokine expression cassette and the position of the cytokine expression cassette in the viral genome.
  • Cytokine production from cytokine-loaded C-REV was confirmed as follows. In vitro, mouse squamous cell carcinoma cell SCC7 was infected with 1 MOI of various cytokine-loaded C-REVs, and 24 hours later, the expression level of cytokines was measured by RT-qPCR method and ELISA method. As a result, it was confirmed that the loaded cytokine was expressed. A part of the result is shown in FIG.
  • Example 2 Antitumor effect evaluation test 1 Mouse pancreatic cancer cell Pan02 is transplanted subcutaneously into mice, and virus (C-REV or cytokine-loaded C-REV (C-REV-IL7CCL19IL21 or C-REV-IL15CCL19IL21)) is administered. The antitumor effect was examined. Specifically, it is as follows. One tumor was transplanted subcutaneously into the bilateral abdomen of the mouse with a tumor transplant needle (bilateral abdominal transplant model). When the size of the tumor reached 100 mm 3 , grouping was performed and administration of the virus was started.
  • virus C-REV or cytokine-loaded C-REV (C-REV-IL7CCL19IL21 or C-REV-IL15CCL19IL21)
  • the antitumor effect was examined. Specifically, it is as follows. One tumor was transplanted subcutaneously into the bilateral abdomen of the mouse with a tumor transplant needle (bilateral abdominal transplant model). When the size of the tumor reached 100 mm 3
  • C-REV or cytokine-carrying C-REV 5x10 5 pfu was administered into one tumor 3 times every 3 days (Day 0, 3, 6). Twice a week, the tumor size and body weight on the treated side and the non-treated side were measured to evaluate the antitumor effect.
  • the tumor growth was also suppressed in the tumors on the non-administered side, but the effects of C-REV-IL7CCL19IL21 and C-REV-IL15CCL19IL21 were clearly stronger than those of C-REV. In addition, the effects of C-REV-IL7CCL19IL21 and C-REV-IL15CCL19IL21 were equivalent. There was no difference in body weight of the treated mice between the groups.
  • Example 3 Antitumor effect evaluation test 2 The test was carried out in the same manner as in Example 2 except that C-REV-IL21, C-REV-IL7IL21 and C-REV-IL7CCL19IL21 were used as viruses.
  • Example 4 Antitumor effect evaluation test 3 C-REV-GMCSF and C-REV-IL7CCL19IL21 were used as viruses and tested in the same manner as in Example 2 except that the administration schedule was 4 times every 2 days (Day 0, 2, 4, 6). ..
  • Example 5 Antitumor effect evaluation test 4 C-REV-IL7CCL19IL21 and C-REV-IL15CCL19IL21 were used as viruses, and the test was carried out in the same manner as in Example 2 except that the virus was administered only once (Day 0, dose: 1x10 7 pfu).
  • Example 6 Antitumor effect evaluation test 5 The test was carried out in the same manner as in Example 5 except that mouse squamous cell carcinoma cell SCC7 was used as the cell to be transplanted into the mouse. As a result, it was found that C-REV-IL7CCL19IL21 and C-REV-IL15CCL19IL21 also exert an antitumor effect on squamous cell carcinoma cells.
  • Example 7 Safety evaluation test Cytokine-loaded C-REV was administered, and the blood expression of the loaded cytokine was measured. Specifically, for tumor-transplanted mice obtained in the same manner as in Example 2 except that the tumor was transplanted only subcutaneously on one side of the abdomen of the mouse, a virus (C-REV or cytokine-loaded C-REV (C-)) was used. REV-IL7CCL19IL21 or C-REV-IL15CCL19IL21)) 1x10 7 pfu was administered intratumorally only once (Day 0), 1 day (Day 1), 3 days (Day 3), and 7 days (Day 7) after administration. ), The concentration of each cytokine in the serum was measured by the ELISA method.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Biochemistry (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Public Health (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne un virus ayant un effet antinéoplasique plus puissant.　L'invention concerne un virus de l'herpès simplex de type 1 dont le génome comprend une cassette d'expression d'IL21.
PCT/JP2021/009720 2020-03-23 2021-03-11 Virus de l'herpès simplex de type 1 WO2021193081A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022509899A JPWO2021193081A1 (fr) 2020-03-23 2021-03-11

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020-051489 2020-03-23
JP2020051489 2020-03-23

Publications (1)

Publication Number Publication Date
WO2021193081A1 true WO2021193081A1 (fr) 2021-09-30

Family

ID=77891707

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/009720 WO2021193081A1 (fr) 2020-03-23 2021-03-11 Virus de l'herpès simplex de type 1

Country Status (2)

Country Link
JP (1) JPWO2021193081A1 (fr)
WO (1) WO2021193081A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019500909A (ja) * 2016-01-08 2019-01-17 レプリミュン リミテッド 腫瘍溶解性ウイルス株
WO2019062234A1 (fr) * 2017-09-26 2019-04-04 杭州康万达医药科技有限公司 Poxvirus oncolytique recombiné isolé, composition pharmaceutique, et utilisation associée dans le traitement de tumeurs et/ou du cancer
WO2019073973A1 (fr) * 2017-10-10 2019-04-18 国立大学法人山口大学 Amplificateur pour lymphocytes t ou lymphocytes b ayant une fonction de mémoire, inhibiteur de récurrence de tumeur maligne, et inducteur pour induire une fonction de mémoire dans des lymphocytes t ou des lymphocytes b

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019500909A (ja) * 2016-01-08 2019-01-17 レプリミュン リミテッド 腫瘍溶解性ウイルス株
JP2019501670A (ja) * 2016-01-08 2019-01-24 レプリミュン リミテッド 改変された腫瘍溶解性ウイルス
WO2019062234A1 (fr) * 2017-09-26 2019-04-04 杭州康万达医药科技有限公司 Poxvirus oncolytique recombiné isolé, composition pharmaceutique, et utilisation associée dans le traitement de tumeurs et/ou du cancer
WO2019073973A1 (fr) * 2017-10-10 2019-04-18 国立大学法人山口大学 Amplificateur pour lymphocytes t ou lymphocytes b ayant une fonction de mémoire, inhibiteur de récurrence de tumeur maligne, et inducteur pour induire une fonction de mémoire dans des lymphocytes t ou des lymphocytes b

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CAI LINKANG, HU HAN, DUAN HAIXIAO, LI YUYING, ZOU ZONGXING, LUO KAILUN, ZHANG ZIYI, YANG JUNHAN, JIN JING, CHEN YING, KE ZONGHUANG: "The construction of a new oncolytic herpes simplex virus expressing murine interleukin‐15 with gene‐editing technology", JOURNAL OF MEDICAL VIROLOGY, JOHN WILEY & SONS, INC., US, vol. 92, no. 12, 1 December 2020 (2020-12-01), US , pages 3617 - 3627, XP055858838, ISSN: 0146-6615, DOI: 10.1002/jmv.25691 *
LI, JUN ET AL.: "Expression of CCL19 from Oncolytic Vaccinia Enhances Immunotherapeutic Potential while Maintaining Oncolytic Activity", NEOPLASIA, vol. 14, no. 12, 2012, pages 1115 - 1121, XP055330932, DOI: 10.1593/neo.121272 *
LI, YANG ET AL.: "CCL21/ IL 21-armed oncolytic adenovirus enhances antitumor activity against TERT-positive tumor cells", VIRUS RESEARCH, vol. 220, 2016, pages 172 - 178, XP029572600, DOI: 10.1016/j.virusres.2016.05.002 *
THIRUNAVUKARASU P ET AL.: "Chemokine CCL19 expressing poxvirus enhances safety and efficacy of oncolytic therapy through differential biodistribution and synergism with Cytokine-induced killer cell immunotherapy", ANNALS OF SURGICAL ONCOLOGY, vol. 18, no. 1, 2011 *

Also Published As

Publication number Publication date
JPWO2021193081A1 (fr) 2021-09-30

Similar Documents

Publication Publication Date Title
JP6959258B2 (ja) 改変された腫瘍溶解性ウイルス
US8076460B2 (en) Antibody and inhibitor, and transfection method or kit using them
CN105483093A (zh) Ⅱ型单纯疱疹病毒突变体在治疗癌症中的用途
CN112601547A (zh) 使用溶瘤病毒的治疗
US20060052322A1 (en) Combination treatment of cancer with elicitor of gene product expression and gene-product targeting agent
AU2017405929B2 (en) Programmable oncolytic virus vaccine system and application thereof
CN107557337B (zh) 一种抗ror1安全型嵌合抗原受体修饰的免疫细胞及其应用
CN107475275B (zh) 嵌合抗原受体及其表达基因、双抗原调节的嵌合抗原受体修饰的t细胞及其应用
CN108300699A (zh) 修饰的nk细胞及其用途
Kottke et al. Subversion of NK-cell and TNFα immune surveillance drives tumor recurrence
WO2015148879A1 (fr) Compositions d'immunothérapie du cancer et méthodes associées
CN111526894B (zh) 将chi3l1抑制剂作为有效成分的用于预防或治疗癌症的肺转移的药物组合物
Wu et al. ING4 expressing oncolytic vaccinia virus promotes anti-tumor efficiency and synergizes with gemcitabine in pancreatic cancer
Kottke et al. Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy
CN115552019A (zh) 在髓样细胞和小胶质细胞中特异性表达治疗性蛋白的病毒载体
US20110189237A1 (en) Therapeutic Agent for Malignant Mesothelioma and Immunostimulant
WO2021193081A1 (fr) Virus de l'herpès simplex de type 1
JP5887413B2 (ja) 非小細胞肺癌におけるｔｍ４ｓｆ４の発現または活性を調節することによって癌細胞の放射線耐性ならびに増殖、転移および浸潤を低減させる方法
CN109419818B (zh) 一种用于治疗肿瘤的埃可病毒
CN112996802A (zh) 用于制备抗肿瘤沙粒病毒的方法以及沙粒病毒突变体
CN116836283B (zh) 具有多种免疫调节因子的增强型溶瘤病毒及其制备方法和应用
US20240139345A1 (en) Nucleic acid vectors and methods of use
RU2774677C2 (ru) Рнк для терапии рака
CN116769011A (zh) 一种视网膜母细胞瘤蛋白突变体及其制备方法和应用
Zhang et al. Molecular cloning of duck CD40 and its immune function research

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21775011

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022509899

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21775011

Country of ref document: EP

Kind code of ref document: A1