WO1999067388A1 - Oligonucleotide antisens inhibant l'expression de la proteine il-10 - Google Patents

Oligonucleotide antisens inhibant l'expression de la proteine il-10 Download PDF

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Publication number
WO1999067388A1
WO1999067388A1 PCT/JP1999/003315 JP9903315W WO9967388A1 WO 1999067388 A1 WO1999067388 A1 WO 1999067388A1 JP 9903315 W JP9903315 W JP 9903315W WO 9967388 A1 WO9967388 A1 WO 9967388A1
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WIPO (PCT)
Prior art keywords
seq
antisense oligonucleotide
protein
sequence
cells
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PCT/JP1999/003315
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English (en)
Japanese (ja)
Inventor
Hidetoshi Arima
Seishi Tsuchiya
Takahiro Hirata
Katsuhiko Akiyama
Takeshi Goto
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Hisamitsu Pharmaceutical Co., Inc.
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Application filed by Hisamitsu Pharmaceutical Co., Inc. filed Critical Hisamitsu Pharmaceutical Co., Inc.
Publication of WO1999067388A1 publication Critical patent/WO1999067388A1/fr

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    • 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
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to an antisense oligonucleotide which specifically hybridizes to a chromosome DNA and / or mRNA which encodes an IL-10 (human interleukin-1) protein and inhibits the expression of IL-10 protein.
  • the present invention relates to a remedy for diseases such as atopic dermatitis containing the same as an active ingredient.
  • Atopic dermatitis is a disease in which pruritus eczema is the main lesion, with repeated bad and remissions. Its morbidity is thought to account for 3-10% of the total population (Hiroshi Ueda: Dermatology MOOK atopic dermatitis, Kinbara Shuppan, 12—18, 1985). Although the pathogenic mechanism of arthritis dermatitis has not yet been elucidated, it is said that not only allergic reactions mediated by IgE but also factors such as skin irritability are greatly involved in the pathogenesis of the disease.
  • Treatment for atopic dermatitis includes steroids and nonsteroidal drugs, and steroid drugs are the mainstay of drug treatment. Long-term treatment The side effects of drugs are a major problem. It is necessary to pay attention to systemic side effects, such as suppression of adrenal function, bone marrow suppression, and S opportunistic infection, when steroid drugs are administered orally. Also, side effects of topical steroid drugs include so-called steroidoid skin such as capillary dilation, steroid flushing and skin atrophy, skin mycosis such as candida and ringworm, purulent dermatitis such as bunches, and simple dermatitis. Skin infections such as herpes simplex and other viral diseases may be induced or exacerbated. In addition, the tapering of the dose needs to be done carefully, paying attention to the rebound. Because of these side effects, there is a strong demand for the development of new treatments to replace current treatments.
  • IL-10 protein is a cytokine produced by Thiorentino et al. In 1989 from Th2 cells and identified as a factor that suppresses cytokine production from Th1 cells (Fiorentino D., et al. 1., J. Ex p. Med., 170, 2081, 1989), and subsequently produced in mice by Th2 cells, CD5-positive B cells, macrophages, keratinocytes, and mast cells. Th0 cells, Th2 cells, activated T cells, monocytes, macrophages, activated B cells, and many other types of cells have been shown to be produced (Ishida H., Jpn.J.C lin. Pathol., 42, 843, 1994).
  • WO 97/31532 discloses IL-110 antisense technology for the treatment of AIDS-related B-cell lymphoma and chronic lymphocytic leukemia, but the mRNA sequence of human IL-10 protein is disclosed. Among them, it only discloses that antisense to 315-342 has an inhibitory effect on the autocrine action of IL-10 protein excessively produced from B cells of the above patients. No sequence is described at all.
  • dermatitis is an IL-10 that is excessively produced from monocytes or macrophages. Since protein is considered to be the etiology, development of a novel anti-IL110 preparation for the treatment of atopic dermatitis is desired.
  • an object of the present invention is to inhibit the production of IL_10 protein and cause diseases caused by IL-11 protein, for example, atopic dermatitis, allergic skin disease, systemic E. tomato-des (SLE)
  • Another object of the present invention is to provide an antisense oligonucleotide capable of treating Epstein-Barr virus (EB) virus infection, lymphoma and the like, and a therapeutic agent containing the antisense oligonucleotide or a derivative thereof as an active ingredient.
  • EB Epstein-Barr virus
  • the present inventors have searched for an effective therapeutic agent for intractable diseases caused by IL-10 protein produced from monocytes or macrophages.
  • the present inventors have discovered an antisense oligonucleotide sequence that strongly suppresses the production of 10 proteins, and have completed the present invention.
  • This antisense oligonucleotide sequence is a sequence completely different from the antisense oligonucleotide for 315-342 of the mRNA sequence disclosed in the aforementioned W097 / 315332.
  • the present invention specifically hybridizes with chromosomal DNA and / or mRNA encoding human interleukin-10 (IL-10) protein and inhibits the expression of IL-10 protein.
  • An antisense oligonucleotide comprising any one or more of the following sequences:
  • a therapeutic agent for atopic dermatitis, allergic dermatitis, SLE, EB virus infection or lymphoma comprising the antisense oligonucleotide or a derivative thereof as an active ingredient.
  • the antisense oligonucleotide of the present invention contains one or more of the sequences of SEQ ID NOS: 1 to 7 shown in the sequence listing.
  • the antisense oligonucleotide of SEQ ID NO: 1 has a nucleotide sequence complementary to the nucleotide sequence of 176 to 193 of human IL-10mRNA,
  • the antisense oligonucleotide described in SEQ ID NO: 2 has a nucleotide sequence complementary to the nucleotide sequence of 181-198 of human IL_10 mRNA,
  • the antisense oligonucleotide described in SEQ ID NO: 3 has a nucleotide sequence complementary to the nucleotide sequence of 367 to 384 of human IL-1 OmRNA
  • the antisense oligonucleotide described in SEQ ID NO: 4 has a nucleotide sequence complementary to the nucleotide sequence of 637 to 654 of human IL_10 mRNA
  • the antisense oligonucleotide described in SEQ ID NO: 5 has a nucleotide sequence complementary to the nucleotide sequence of 915 to 932 of human IL_10 mRNA,
  • the antisense oligonucleotide of SEQ ID NO: 6 is a nucleotide sequence complementary to the nucleotide sequence of 1246 to 1263 of human IL-10 mRNA
  • the antisense oligonucleotide of SEQ ID NO: 7 is Human IL—A nucleotide sequence complementary to the nucleotide sequence of 1249 to 1266 of 10 mRNA.
  • the antisense oligonucleotide of the present invention may include only one of the nucleotide sequences of SEQ ID NOS: 1 to 7, or may include two or more nucleotide sequences in combination.
  • the antisense oligonucleotide of the present invention effectively suppresses the expression of IL-10 produced by the macrophage without damaging the macrophage.
  • SEQ ID NOs: 1, 3, 4, 5, and 6 are excellent, and SEQ ID NOs: 3 and 4 are particularly excellent.
  • the antisense oligonucleotides represented by SEQ ID NOs: 1 to 7 may have an antisense oligonucleotide having one or two or more shorter 5′-side and Z or 3′-side bases, Although the activity of suppressing protein production is not lost, the antisense described in SEQ ID NOs: 1 to 7 must be used in order to maintain the specificity for human IL-11 O mRNA and not to affect other genes. It is preferred to use oligonucleotides as the minimum unit.
  • the antisense oligonucleotide has one or two or more bases on the 5 ′ side and / or 3 ′ side of the antisense oligonucleotides of SEQ ID NOS: 1 to 7, IL_10
  • the antisense oligonucleotides described in SEQ ID NOs: 1 to 7 increase the cost of synthesis when the antisense oligonucleotide is chemically synthesized, because the longer the nucleotide length, the higher the synthesis cost.
  • it is used at the length of the oligonucleotide.
  • the method for synthesizing the antisense oligonucleotide of the present invention is not particularly limited, and a phosphoramidite method, a phosphorothioate method, a phosphotriester method, or the like using an ordinary oligonucleotide synthesizer can be used.
  • the hydroxyl group of the phosphate group or ribose moiety is replaced with another stable group within a range that does not significantly reduce the activity. It is also possible to use it as a derivative.
  • Specific examples of such antisense oligonucleotide derivatives include those in which a phosphate group is replaced with a thiophosphate group, a methylphosphonate group, or the like, a hydroxyl group in a ribose moiety, an alkoxy group such as methoxydiaryloxy, or the like. Examples thereof include those substituted with an amino group or a fluorine atom. Of these, those in which the phosphate ester group is substituted with a thiophosphate ester group are preferred from the viewpoint of the effect of inhibiting IL-10 protein production.
  • the antisense oligonucleotide of the present invention can be expected to have an inhibitory effect on the production of IL-10 protein, whether it is of the DNA type or the RNA type, but the DNA type has a higher stability when administered to a living body. Is preferred.
  • the antisense oligonucleotide of the present invention has a sequence complementary and specific to mRNA encoding human IL-10 protein, and functions of mRNA or DNA, ie, translation into protein. It can inhibit any of the transport into the cytoplasm, or any other activity required for its overall biological function. Furthermore, the treatment can be performed safely and effectively without the serious side effects seen when using steroids.
  • the antisense oligonucleotide of the present invention suppresses the expression of IL-10 in monocytes or macrophages, a disease considered to be one of the causes due to overexpression of IL-10 protein in monocytes or macrophages
  • a disease considered to be one of the causes due to overexpression of IL-10 protein in monocytes or macrophages For example, atopic dermatitis, allergic skin disease, SLE, EB virus infection, lymphoma and the like can be effectively treated.
  • the antisense oligonucleotide of the present invention can be administered alone, but can also be administered as a formulation by mixing with a pharmaceutically acceptable substance.
  • the antisense oligonucleotide of the present invention when used as an injection, can be prepared by dissolving it in water, physiological saline, a glucose solution, or the like. If necessary, a buffer, a preservative, or a stabilizing agent can be used. And the like.
  • the antisense oligonucleotide of the present invention can be prepared by dissolving or dispersing the antisense oligonucleotide of the present invention in an oily, emulsifying, or water-soluble base. It may contain a regulator, a plasticizer, an emulsifier, a surfactant, a solubilizer, a wetting agent, a preservative, a preservative, a solvent or an absorption enhancer.
  • the antisense oligonucleotide of the present invention can be prepared by dissolving or dispersing the antisense oligonucleotide in an aqueous phase and emulsifying with an oil phase component such as a hydrocarbon or a higher alcohol. It may contain stabilizers, pH adjusters, plasticizers, emulsifiers, surfactants, solubilizers, wetting agents, preservatives, preservatives, solvents or absorption enhancers.
  • an oil phase component such as a hydrocarbon or a higher alcohol. It may contain stabilizers, pH adjusters, plasticizers, emulsifiers, surfactants, solubilizers, wetting agents, preservatives, preservatives, solvents or absorption enhancers.
  • the antisense oligonucleotide of the present invention can be prepared by dissolving or dispersing it in a solvent. If necessary, stabilizers, pH regulators, emulsifiers, A suspending agent, a surfactant, a solubilizing agent, a wetting agent, a preservative, a preservative, an absorption enhancer, and the like may be contained.
  • the preparation can be prepared by incorporating the antisense oligonucleotide of the present invention into a conductive gel or a drug storage tank in a device, and the like. If necessary, stabilizers, pH regulators, surfactants, solubilizers, wetting agents, preservatives, preservatives, absorption enhancers, and the like may be added.
  • compositions may contain other pharmacologically acceptable and therapeutically useful ingredients.
  • Carriers include, for example, liposomes, lipid emulsions, micelles, and other lipid-based carriers, peptide carriers such as polylysine and polyordinine, polyethyleneimine, and polylactic acid-Z-glycolic acid copolymer.
  • the carrier include a molecular carrier, and among these, a carrier having a cationic charge is preferable.
  • those obtained by modifying the above carriers for the purpose of promoting uptake into cells and enhancing directivity to target cells can also be used.
  • plasmid virus vector designed to express the antisense oligonucleotide sequence of the present invention is useful as a vector for gene therapy.
  • the mixture of the antisense oligonucleotide or the antisense oligonucleotide of the present invention and a carrier can be administered in any manner, including, but not limited to, oral administration, intravenous administration, transdermal administration, topical administration, and intraperitoneal administration. It is preferable to select an administration method that is more effective against the disease. For example, in the treatment of atopic dermatitis, transdermal administration, for example, administration by iontophoresis, or administration as an external preparation such as a cream or ointment is preferred. For SLE, intravenous administration is preferred.
  • lmgZkg to 1 g / kg per body weight, preferably 5 mg / kg to 500 mg / kg, More preferably from 1 Omg / kg
  • FIG. 1 is a graph showing the effect of the antisense oligonucleotide of the present invention on expression of IL-10 protein.
  • SEQ ID NO: 9 shows the cDNA base sequence of human IL-10 protein (DNADatBaBankofJapann: DDBJ, Accession No. M57627).
  • SEQ ID NOS: 1 to 7 are antisense oligonucleotide chains of the human IL_10 gene
  • SEQ ID NO: 1 corresponds to +176 to +193 of SEQ ID NO: 9
  • SEQ ID NO: 2 corresponds to + of SEQ ID NO: 9.
  • 18 1 to 1098 SEQ ID NO: 3 to +367 to 10384 of SEQ ID NO: 9, SEQ ID NO: 4 to +637 to 10654 of SEQ ID NO: 9, SEQ ID NO: 5 to +637 of SEQ ID NO: 9 No. 91 to No. 932
  • SEQ ID No. 6 corresponds to +1246 to No. 1024 of SEQ ID No. 9
  • SEQ ID No. 7 corresponds to +1 249 to No.
  • SEQ ID NO: 8 is the sequence of the antisense oligonucleotide chain of the mouse IL-10 protein gene.
  • SEQ ID NO: 9 Yes (Comparative Example 1).
  • the antisense oligonucleotides used in the examples were all phosphorothioate-type oligonucleotides and were synthesized by contract with Pharmacia Biotech. (Example 1)
  • Antisense oligonucleotides of SEQ ID NOS: 1 to 8 in the sequence listing were synthesized using a DNA synthesizer O1goPi1otII (Pharmacia Biotech). It was synthesized based on the phosphorothioate method, and purified based on the ion exchange FPLC method using FPLC directosymstem (manufactured by Pharmacia Biotech).
  • the cells used were human monocyte macrophage U933 cells (Dainippon Pharmaceutical) at 37 ° C and 5% C02 at 10% fetal calf serum (FCS: Sanko Junyaku). ) And an antibiotic (100 units / m 1 penicillin (GIB CO) and 100 ⁇ m 1 streptomycin (GIB CO)) in RPMI-164 medium (stock) (Manufactured by Nikken Biomedical Research Laboratories) (hereinafter referred to as FCS-containing medium).
  • phorbol myristate acetate the (PMA manufactured by Wako Pure Chemical Industries, Ltd.) 1 0 n gZm 1 become as And cultured for 12 hours (differentiation induction).
  • PBS phosphate buffer solution
  • FCS drug suspension period
  • the human IL-10 protein in the culture supernatant collected from the culture solution obtained in the above (A) was quantified by ELISA.
  • a 50 ⁇ 1 anti-IL-10 monoclonal antibody (1 g / m10.1 MNa2HPO4 solution, pH 9: manufactured by Pharmingen) was placed in a 96-well plate (sum ito mo H-type ) And left overnight at 4 ° C. The plate was washed four times with PBS containing BST (0.05% (V / V) Tween _ 20). To prevent nonspecific adsorption, add a B lockingbuffer (PBS containing l% BSA) to each well.
  • PBS containing BST 0.05% (V / V) Tween _ 20
  • the antisense oligonucleotide of the present invention can effectively suppress the expression of IL-10 protein, and thus is used for intractable diseases caused by IL-10 protein, such as atopic skin. It is effective against inflammation, allergic skin disease, SLE, EB virus infection, lymphoma, etc.

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Abstract

La présente invention concerne un oligonucléotide antisens comprenant une séquence spécifique, qui est caractérisé en ce qu'il peut être hybridé avec un ADN et/ou un ARNm chromosomique codant la protéine IL-10 et en ce qu'il peut par conséquent inhiber l'expression de ladite protéine IL-10. L'invention concerne également des remèdes contre la dermatite atopique, la dermatite allergique, les infections virales dues au SLE, à l'EBV ou les lymphomes, qui contiennent comme principe actif l'oligonucléotide antisens susmentionné.
PCT/JP1999/003315 1998-06-24 1999-06-22 Oligonucleotide antisens inhibant l'expression de la proteine il-10 WO1999067388A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/177188 1998-06-24
JP10177188A JP2000004883A (ja) 1998-06-24 1998-06-24 Ｉｌ−１０蛋白の発現を阻害するアンチセンスオリゴヌクレオチド

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WO1999067388A1 true WO1999067388A1 (fr) 1999-12-29

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EP1562635A4 (fr) * 2002-11-07 2007-12-19 Chang Lung Ji Cellules dendritiques modifiees

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ARIMA H, ET AL.: "SPECIFIC INHIBITION OF INTERLEUKIN-10 PRODUCTION IN MURINE MACROPHAGE-LIKE CELLS BY PHOSPHOROTHIOATE ANTISENSE OLIGONUCLEOTIDES", ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT., MARY ANN LIEBERT, INC., NEW YORK., US, vol. 08, 1 August 1998 (1998-08-01), US, pages 319 - 327, XP002926349, ISSN: 1087-2906 *

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