WO2008065752A1 - Agent immunothérapeutique contenant un arndi en tant que principe actif - Google Patents

Agent immunothérapeutique contenant un arndi en tant que principe actif Download PDF

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WO2008065752A1
WO2008065752A1 PCT/JP2007/001315 JP2007001315W WO2008065752A1 WO 2008065752 A1 WO2008065752 A1 WO 2008065752A1 JP 2007001315 W JP2007001315 W JP 2007001315W WO 2008065752 A1 WO2008065752 A1 WO 2008065752A1
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dirna
strain
immunotherapeutic agent
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measles virus
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PCT/JP2007/001315
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Japanese (ja)
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Tsukasa Seya
Misako Matsumoto
Masashi Shingai
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National University Corporation Hokkaido University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4613—Natural-killer cells [NK or NK-T]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/17—Immunomodulatory nucleic acids
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18411—Morbillivirus, e.g. Measles virus, canine distemper
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18411—Morbillivirus, e.g. Measles virus, canine distemper
    • C12N2760/18432—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent

Definitions

  • Immunotherapy drugs containing di RNA as an active ingredient containing di RNA as an active ingredient
  • the present invention relates to an immunotherapy drug comprising as an active ingredient a diRNA having a measles virus-derived RNA sequence, and a tumor immunotherapy composition comprising the diRNA and a cell wall skeleton of a Gram-positive bacterium.
  • One of the cancer treatment methods is so-called cancer immunotherapy that induces cancer regression by enhancing the immunity of the patient's own cancer cells.
  • the method of administering a peptide vaccine as a cancer antigen is the mainstream, but according to Rosenberg et al. (Non-Patent Document 1), the effectiveness of this method is said to be 2.5 ⁇ 1 ⁇ 2. .
  • Patent Document 1 As a method for increasing the effective rate of this cancer immunotherapy, a method has been proposed in which an adjuvant that activates dendritic cells is simultaneously administered simultaneously with the administration of a cancer antigen (Patent Document 1).
  • the adjuvant disclosed in Patent Document 1 is a cell wall skeleton (hereinafter referred to as BGG and GWS) of the gram-positive bacterium Mycobacterium mupovis Calmette and Guerin, and immature dendritic cells are matured dendritic cells.
  • BGG and GWS cell wall skeleton
  • immature dendritic cells are matured dendritic cells.
  • GTL cytotoxic T lymphocytes
  • BGG— GWS has the advantage of improving the 5-year survival rate by more than 10% by actually administering it to cancer patients and showing few side effects.
  • BGG-GWS is a ligand that activates TLR (Toll Like Receptor) 2 and 4. This fact is based on the fact that BGG- GWS is an adjuvant that has neither the ability to induce type I interferon (referred to as type I interferon I FN-S) or the ability to enhance NK activity in human dendritic cells. Matches.
  • GTL induced by single administration of BGG-GWS cannot kill cancers with low MHG class I protein expression levels. Therefore, although it has better anti-cancer effect than the peptide vaccine of Rosenberg et al. Is considered difficult.
  • Patent Document 1 W001 / 048154
  • Non-Patent Document 1 Rosenberg et al., Nat. Med., 2004, 10, 9, 909-92, p. 5
  • the present invention provides an immunotherapeutic agent that exhibits a further excellent anticancer effect by using it instead of or at the same time as BGG-GWS, and particularly usable for immunotherapy of cancer. It is an object of the present invention to provide a substance exhibiting an immunostimulatory action useful for immunotherapy of cancer, particularly a substance that induces the production of IFNyS and / or enhances NK activity.
  • the present inventors have surprisingly confirmed the presence of a substance having a desired activity in measles virus, particularly acclimated measles virus strain and measles virus vaccine strain, and the substance is diRNA. Ascertaining that it is (also called defective interference RNA, defective interfering, or loop RNA), the following inventions were completed.
  • An immunotherapeutic agent comprising, as an active ingredient, diRNA having a measles virus-derived RNA sequence.
  • the measles virus is an acclimated virus strain or a vaccine strain, (1) or (
  • the immunotherapeutic agent according to 2).
  • the acclimated virus strain is an Edmonston strain, a Nagahata strain, or an lchinose_V strain.
  • diRNA comprising any RNA sequence represented by SEQ ID NOs: 9 to 15
  • a composition for tumor immunotherapy comprising the immunotherapeutic agent according to any one of (1) to (7) and a cell wall skeleton of a Gram-positive bacterium.
  • composition for tumor immunotherapy according to (8), wherein the cell wall skeleton of the Gram-positive bacterium is BGG-GWS.
  • Medicament for promoting interferon expression and / or enhancing NK activity comprising diRNA having measles virus-derived RNA sequence as an active ingredient (1 1) Measles virus acclimatized The medicament according to (10), which is a virus strain or a vaccine strain.
  • diR whose diRNA is composed of any RNA sequence shown in SEQ ID NOs: 9 to 15
  • the immunotherapeutic agent of the present invention can enhance the immune defense power of chicks against foreign substances such as bacteria or neoplastic tumors such as cancer, and can be used as an anticancer agent or a tumor immunotherapeutic agent. is there. Furthermore, by using the immunotherapeutic agent of the present invention in combination with BGG-GWS, a pharmaceutical composition (tumor immunity therapeutic composition) effective for immunotherapy of cancer can be obtained.
  • the diRNA according to the present invention does not show toxicity even when administered subcutaneously (100 ⁇ g) to mice and humans and can be a safe pharmaceutical.
  • FIG. 1 is an electrophoretogram showing the detection results of diRNA of each measles virus strain.
  • FIG. 2 shows a schematic diagram of p (+) MV Dl GFP plasmid.
  • FIG. 3 shows a schematic diagram of diRNA-IGV-G.
  • FIG. 4 shows the amount of fluorescence of luciferase from HEK cells into which di RNA-IGV-G has been introduced.
  • FIG. 5 shows the regression effect of transplanted cancer-bearing cancer by administration of diRNA-IGV-G.
  • FIG. 6 It shows the increase in cytotoxic activity of NK cells by [ ⁇ --6 administration (_ ⁇ _)]. The letter indicates the control.
  • the diRNA is a double-stranded RNA having a stem-and-loop structure, as contained in, for example, measles virus, in particular, acclimatized measles virus or measles virus strain.
  • measles virus vaccine strains diRNA is a contaminant and has been reported to be a non-infectious RNA produced during viral replication (Robert et al., Cell, 1981, 26, 145-154).
  • DiRNA has been confirmed to exist in measles virus vaccine strains and acclimated measles virus, but is considered to be a completely unnecessary substance for replication of measles virus. It is a substance that has received little attention for its effects.
  • measles virus particularly measles vaccine virus
  • the present invention is an invention based on the fact that a substance that enhances immunity against cancer exists in such measles virus vaccine, and that the substance is confirmed to be diRNA.
  • the diRNA has a combination of either a trailer sequence and a leader sequence, or a trailer sequence and a sequence complementary to the trailer sequence, and has a stem-and-loop structure formed thereby.
  • RNA A trailer sequence is present at the 5 'end of the virus genome and a leader sequence is present at the 3' end, each of which is a specific sequence essential for transcription, replication, etc. of the measles virus genome.
  • the trailer sequence and the leader sequence are almost complementary sequences, and when they are aligned, a diRNA stem-and-loop structure is formed.
  • DiRNAs having a trailer sequence and a complementary sequence of the trailer sequence are also By ringing, a stem and loop structure is formed.
  • the viral genomes of the habituated measles virus strains Edmonston (ED) strain, lchi nose-V (ICV) strain, and vaccine strains Schwarz strain and Tanabe strain are the RNA shown in SEQ ID NO: 1. It has a trailer array consisting of an array.
  • the Nagahata (NV) strain, a habituated measles virus strain has a trailer sequence consisting of the RNA sequence shown in SEQ ID NO: 2 in which only the 15th base of the RNA sequence shown in SEQ ID NO: 1 is mutated from guanine to adenine. Have.
  • the IGV strain which is an acclimated measles virus strain, has a leader sequence consisting of the RNA sequence shown in SEQ ID NO: 3
  • the Edmonston (ED) strain is a leader sequence consisting of the RNA sequence shown in SEQ ID NO: 4.
  • the Schwarz strain which is a vaccine strain, has a leader sequence consisting of the RNA sequence shown in SEQ ID NO: 5, respectively.
  • Each leader sequence shown in SEQ ID NOs: 3 to 5 has the same RNA sequence except that the 26th, 42nd, 50th and 50th bases are different.
  • Di RNA derived from measles virus has a variation in RNA sequence and number of bases, and includes a trailer sequence and a leader sequence, or a trailer sequence and a sequence complementary to the trailer. It also has the structural feature of forming a & loop structure. Therefore, the present invention is not limited to diRNA containing any of the specific RNA sequences shown in SEQ ID NOs: 1 to 5 above, but includes measles virus-derived RNA, which retains the stem-and-loop structure, and is As long as the function of enhancing immunity against cancer is maintained, diRNAs comprising RNA sequences in which a plurality of, preferably several to several tens of bases are substituted, deleted, added, etc. in the above RNA sequence are also included.
  • the di RNA according to the present invention is conventionally known as reported to Robert et al. According to the method of Maniatis et al. (Molecular Cloning, 1989, Go Id Spring Harbor Laboratory Press), it can be isolated and purified from measles virus, particularly acclimated measles virus or measles virus vaccine strains widely supplied to the parties concerned. Acclimatized measles virus strains ED, NV, and IG-V can be obtained from the National Institute of Infectious Diseases. Schwarz and Tanabe strains are available from Takeda Pharmaceutical Co., Ltd. and Tanabe Seiyaku Co., Ltd., respectively.
  • diRNA obtained from the above strains or diRNA obtained by artificially recombining part of the RNA sequence based on them can be produced using a general genetic recombination technique.
  • an appropriate expression vector incorporating a DNA containing a base sequence complementary to any RNA sequence shown in SEQ ID NOs: 1 to 5 is expressed in a host cell to produce diRNA, Collect it.
  • RNA may be produced in vitro by collecting a DNA containing a base sequence complementary to any of the RNA sequences shown in SEQ ID NOs: 1 to 5 in a cage shape and recovering it.
  • gene expression systems such as expression vectors and promoters that can be used in the present invention, the types of recombinant host cells, in vitro transcription systems, and RNA recovery methods. Any available method can be used.
  • the composition for tumor immunotherapy of the present invention comprises an immunotherapeutic drug containing the above-described diRNA as an active ingredient and a cell wall skeleton of Gram-positive bacteria.
  • the cell wall skeleton of a Gram-positive bacterium is an insoluble residue obtained through a refinement process such as denucleation, protein removal, and degreasing after physically pulverizing the Gram-positive bacterium, and is described in detail in Patent Document 1.
  • Examples of cell wall skeletons of Gram-positive bacteria in the present invention include cell wall skeletons such as Mycobacterium bacteria, Nocardia bacteria, Corynebacterium bacteria, and the like. (BGG—GWS) is preferred.
  • the composition for tumor immunotherapy of the present invention comprising the cell wall skeleton of Gram-positive bacteria and diRNA derived from measles virus is a type of cancer, in particular, an MHG class I protein. Regardless of current level, it has the effect of reducing cancer.
  • the composition for tumor immunotherapy of the present invention comprises various excipients, carriers, and other pharmaceutical compositions depending on the administration route to the living body, dosage form, etc. It can be adjusted by blending other ingredients.
  • the administration route of the composition for tumor immunotherapy of the present invention is not particularly limited, but oral administration, subcutaneous administration, vascular administration, and transmucosal administration are preferable.
  • the diRNA according to the present invention has a function of inducing IFN-; 3 expression to human cells and enhancing the NK activity of NK cells as described above. It can also be used as a medicament for promoting S expression and / or enhancing NK activity.
  • measles virus vaccines are known to weaken the immunity of living organisms, but diRNA contained in measles virus vaccines promotes the expression of IFN-3; It was an unexpected finding that it had a function to enhance immune defense ability.
  • the pharmaceutical for promoting the expression of interferon containing diRNA and / or enhancing NK activity depends on the administration route to the living body and the dosage form in addition to diRNA as an active ingredient.
  • Various excipients, carriers, other pharmaceutical ingredients and other ingredients can be blended and adjusted. There are no particular restrictions on the route of administration, but oral administration, subcutaneous administration, and vascular administration are preferred.
  • P1 5′-TATAAGCTTACCAGACAAAGCTGGGAATAGAAACTTCG-3 ′ (SEQ ID NO: 6)
  • P2 5′-CGAAGATATTCTGGTGTAAGTCTAGTA-3 ′ (SEQ ID NO: 7) Primers for the control reaction indicating that the PGR reaction is in progress used P1 and P3. [0040] P3: 5'-TTTATCCAGAATCTCAARTCCGG-3 '(SEQ ID NO: 8)
  • RNA-ED Sequence
  • diRNA_ED, diRNA-ICV, diRNA-SH, diRNA-TAU diRNA_TA2, diRNA_TA3 include the trailer sequence shown in SEQ ID NO: 1 and a sequence complementary to the trailer sequence, and diRNA-NV in SEQ ID NO: 2. The trailer sequence shown and the sequence complementary to the trailer sequence were included.
  • a plasmid (Takeda et al., Viro, 2000, 74, 6643-6647) having a genomic sequence of the IG-V strain incorporated with a DNA encoding a GFP fluorescent protein p (+ ) MV323GFP plasmid (Singai et al., J. I country unol., 2005, Vol. 175, No. 5, pp.
  • 3252-3261 is a saddle type, and a leader sequence (SEQ ID NO: 3) and trailer from the plasmid
  • the plasmid p (+) MV DI GFP from which the genomic sequence of the IG-V strain excluding the sequence (SEQ ID NO: 1) was deleted was converted to PGR using primers (P4, P5) consisting of the following base sequences: (Fig. 2).
  • P4 5′-GCCATCGATTATTACTTGTACAGCTCGTCC-3 ′ (SEQ ID NO: 16)
  • p (+) MV DI GFP is a cocoon type, and one leader sequence is one GFP—one trailer sequence in the opposite direction to the ⁇ type.
  • p (-) MV DI GFP was prepared by the PGR method using the following two sets of primers-(P6 and P7, and P8 and P9).
  • P6 5′-GGCCGGCATGGTCCCAGCCTCCTCGCT-3 ′ (SEQ ID NO: 1 8)
  • P7 5'-TATAGTGAGTCGTATTACGCGCGCTT-3 '(SEQ ID NO: 1 9)
  • P8 5'-ACCAAACAAAGTTGGGTAAGGATAGATCAATCAATGATCAT-3' (SEQ ID NO: 2)
  • diRNA-IGV-G (which has a stem-and-loop structure in which the region encoding GFP fluorescent protein is looped over Figure 3) was prepared in vitro.
  • a plSRE_Luc plasmid (Stratagene) that incorporates a nucleotide sequence that codes for luciferase fluorescent protein downstream of the nucleotide sequence that codes for IFN-stimulated response element (ISRE), a transcription factor that induces IFN production.
  • ISRE IFN-stimulated response element
  • mice G57BL / 6 inbred mice were transplanted with B16 melanoma cells (distributed from the Osaka Prefectural Center for Adult Diseases) 1 x 10 6 cel ls, and changes in tumor size over time were measured (Fig. 5). ) Since B16 melanoma cells do not express MHG class I molecules, activation of killer T cells is not induced, and only by the activity of NK cells enhanced by interferon. The mammary tumor regresses.
  • BGG-GWS 25 g / 0.1 m prepared by the method described in Patent Document 1 MALP-2 ( Oncologics Inc., Nagoya Japan) B16 melanoma cell cancer antigen EP with physiological saline containing di RNA-1 CV-G 10 g / ml as an adjuvant.
  • TRP2_pep8 distributed by Rosenberg S.
  • 0.1 mg was administered intraperitoneally three times every other week before transplantation of B16 melanoma cells and three times every other week after transplantation (indicated by the arrow in FIG. 5).
  • diRNA-IGV-G was administered, a marked cancer regression effect (proliferation inhibitory effect) was observed.
  • Lymphocytes were extracted using Lympho I yte-M (Cederlane Laboratory) from the three types of mice administered with the adjuvant in Example 3, and then negative for NK preparation using MACS beads (Mi Itenyi Biotec) NK cells were obtained by selection. NK cells and B16 melanoma cells were co-cultured using RPM-1640 medium, and the cytotoxic activity of NK cells was measured by 5 iCr-re lease assay. As shown in Fig. 6, NK cells derived from mice treated with diRNA-IGV-G showed a marked increase in cytotoxic activity compared to NK cells derived from mice administered with saline (control). It was.

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Abstract

L'invention concerne une substance exerçant une action immunostimulatrice utile pour l'immunothérapie du cancer, en particulier une substance qui induit la production d'IFN-β et/ou favorise l'activité NK dans des cellules associées à l'immunité humaine. L'invention concerne également un agent immunothérapeutique contenant en tant que principe actif, un ARNdi comprenant de l'ARN dérivé du virus de la rougeole, et une composition immunothérapeutique pour lutter contre les tumeurs contenant l'agent immunothérapeutique ainsi qu'une structure de parois cellulaires bactériennes à Gram positif. L'agent immunothérapeutique de l'invention peut être un médicament extrêmement sûr qui peut renforcer une capacité de défense immunitaire humaine contre des substances étrangères telles que des bactéries ou des tumeurs néoplasiques telles que le cancer.
PCT/JP2007/001315 2006-11-30 2007-11-29 Agent immunothérapeutique contenant un arndi en tant que principe actif WO2008065752A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012014945A1 (fr) 2010-07-28 2012-02-02 国立大学法人北海道大学 Nouvel acide nucléique ayant une activité d'adjuvant et son utilisation
WO2016088784A1 (fr) * 2014-12-02 2016-06-09 国立大学法人北海道大学 Composition d'adjuvant
WO2017221076A1 (fr) * 2016-06-24 2017-12-28 Institut Pasteur Prévention de maladies infectieuses par l'utilisation de composés faits à partir particules interférentes dysfonctionnelles du virus de la rougeole (vr).
WO2018021400A1 (fr) 2016-07-27 2018-02-01 国立大学法人北海道大学 Adjuvant immunitaire contre le cancer.

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