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WO2010039137A1 - Composés oligonucléotidiques de régulation immune (ori) permettant de moduler une réponse immune reposant sur les récepteurs de type toll - Google Patents

Composés oligonucléotidiques de régulation immune (ori) permettant de moduler une réponse immune reposant sur les récepteurs de type toll Download PDF

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Publication number
WO2010039137A1
WO2010039137A1 PCT/US2008/078539 US2008078539W WO2010039137A1 WO 2010039137 A1 WO2010039137 A1 WO 2010039137A1 US 2008078539 W US2008078539 W US 2008078539W WO 2010039137 A1 WO2010039137 A1 WO 2010039137A1
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WO
WIPO (PCT)
Prior art keywords
virus
nucleotide
iro
hepatitis
tlr
Prior art date
Application number
PCT/US2008/078539
Other languages
English (en)
Inventor
Ekambar R. Kandimalla
Daqing Wang
Yukui Li
Dong Yu
Fugang Zhu
Lakshmi Bhagat
Sudhir Agrawal
Original Assignee
Idera Pharmaceuticals, Inc.
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 Idera Pharmaceuticals, Inc. filed Critical Idera Pharmaceuticals, Inc.
Priority to PCT/US2008/078539 priority Critical patent/WO2010039137A1/fr
Publication of WO2010039137A1 publication Critical patent/WO2010039137A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • TLRs are a key means by which mammals recognize and mount an immune response to foreign molecules and also provide a means by which the innate and adaptive immune responses are linked (Akira, S. et al. (2001) Nature Immunol. 2:675-680; Medzhitov, R. (2001) Nature Rev. Immunol. 1 :135-145). TLRs have also been shown to play a role in the pathogenesis of many diseases, including autoimmunity, infectious disease, and inflammation (Cook, D.N. et al. (2004) Nature Immunol. 5:975-979) and the regulation of TLR-mediated activation using appropriate agents may provide a means for disease intervention.
  • TLRs have been shown to play a role in the pathogenesis of many diseases, including autoimmunity, infectious disease and inflammation (Papadimitraki et al.
  • N m - N 3 N 2 N 1 CGN 1 N 2 N 3 - N m -3' wherein CG is an oligonucleotide motif and C is cytosine or a pyrimidine nucleotide derivative or non-nucleotide linkage, and G is guanosine a purine nucleotide derivative or non-nucleotide linkage; N 1 -N 3 and N !
  • Figure 6 depicts the TLR9 inhibitory activity of an IRO in human cells treated according to Example 7.
  • TLR4, TLR5, TLR7, TLR8, and TLR9 following in vivo administration according to
  • FIG. 12 depicts early inhibitory activity of an IRO on TLR2, TLR3,
  • IRO compounds of the invention are useful in combination with, for example, DNA vaccines, antigens, antibodies, antiviral agents, antimalarial drugs (for example, chloroquine and hydroxychloroquine) and allergens; and in combination with chemotherapeutic agents (both traditional chemotherapy and modern targeted therapies) and/or antisense oligonucleotides for prevention and treatment of diseases.
  • DNA vaccines for example, DNA vaccines, antigens, antibodies, antiviral agents, antimalarial drugs (for example, chloroquine and hydroxychloroquine) and allergens
  • chemotherapeutic agents both traditional chemotherapy and modern targeted therapies
  • antisense oligonucleotides for prevention and treatment of diseases.
  • analog or “derivative” can be used interchangeable to generally refer to any purine and/or pyrimidine nucleotide or nucleoside that has a modified base and/or sugar.
  • a modified base is a base that is not guanine, cytosine, adenine, thymine or uracil.
  • a modified sugar is any sugar that is not ribose or 2 'deoxyribose and can be used in the backbone for an oligonucleotide.
  • the non-nucleotide linker may include, but are not limited to, those listed in Table 2.
  • IRO compounds may comprise at least two oligonucleotides non- covalently linked, such as by electrostatic interactions, hydrophobic interactions, ⁇ -stacking interactions, hydrogen bonding and combinations thereof.
  • Non-limiting examples of such non-covalent linkage includes Watson-Crick base pairing, Hoogsteen base pairing and base stacking.
  • pyrimidine nucleosides in the immune regulatory oligonucleotides used in the compositions and methods according to the invention have the structure (II):
  • D' is selected from the group consisting of hydrogen, hydrogen bond donor, hydrogen bond acceptor, hydrophilic group, hydrophobic group, electron withdrawing group and electron donating group;
  • C57BL/6 mice were injected s.c. at left underarm with 0.25 mg/kg stimulating IMO 3 and 1 mg/kg IRO 5 or 5 '-CTATCTCACCTTCTCTGT-S ' (non- CpG non-stimulatory control; oligo/SEQ ID NO 4) at right under arm either one hour before (-Ih) or at the same time as stimulating IMO (Oh).
  • Serum samples were taken at 2 hours after IMO injection and determined IL- 12 levels by ELISA.
  • the results in Figure 4 A demonstrate a decrease in serum IL- 12 levels after administration of IRO 5 or (oligo 4) either one hour before (-Ih) or at the same time as stimulating IMO (Oh).
  • mice were subcutaneously injected with 10 mg/kg IRO in their right flank seventy- two hours (-72h) before subcutaneous administration of a TLR agonist (as described above) to the left flank. Serum samples were taken at 2 hours after administration of the TLR agonist and were analyzed as described above. The results are shown in Figures 13-15. These results demonstrate pre-administration administration of an IRO was able to inhibit TLR agonist, and that the inhibitory activities of IRO were effective even when administered 72 hours prior to the administration of the agonist.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'oligonucléotides de régulation immune (ORI) en tant qu’antagonistes des récepteurs de type toll (TLR) pour la prévention et le traitement d'une maladie causée par un agent pathogène, par exemple un virus à ADN ou à ARN.
PCT/US2008/078539 2008-10-02 2008-10-02 Composés oligonucléotidiques de régulation immune (ori) permettant de moduler une réponse immune reposant sur les récepteurs de type toll WO2010039137A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2008/078539 WO2010039137A1 (fr) 2008-10-02 2008-10-02 Composés oligonucléotidiques de régulation immune (ori) permettant de moduler une réponse immune reposant sur les récepteurs de type toll

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2008/078539 WO2010039137A1 (fr) 2008-10-02 2008-10-02 Composés oligonucléotidiques de régulation immune (ori) permettant de moduler une réponse immune reposant sur les récepteurs de type toll

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WO2010039137A1 true WO2010039137A1 (fr) 2010-04-08

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103370417A (zh) * 2010-12-23 2013-10-23 莫洛根股份公司 非编码免疫调节dna构建体
US8840308B2 (en) 2010-11-19 2014-09-23 Saint-Gobain Performance Plastics Corporation Adhesive film for bushings
WO2015124614A1 (fr) 2014-02-18 2015-08-27 Mologen Ag Construction d'adn immunomodulateur non codant fermée de facon covalente
GB2542425A (en) * 2015-09-21 2017-03-22 Mologen Ag Means for the treatment of HIV
US11578331B2 (en) 2015-09-09 2023-02-14 Gilead Sciences, Inc. Combination comprising immunostimulatory oligonucleotides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070264284A1 (en) * 2004-05-19 2007-11-15 Stephen Locarnini Therapeutic, Prophylactic and Diagnostic Agents for Hepatitis B
US20080089883A1 (en) * 2006-10-12 2008-04-17 Idera Pharmaceuticals, Inc. Immune regulatory oligonucleotide (iro) compounds to modulate toll-like receptor based immune response

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070264284A1 (en) * 2004-05-19 2007-11-15 Stephen Locarnini Therapeutic, Prophylactic and Diagnostic Agents for Hepatitis B
US20080089883A1 (en) * 2006-10-12 2008-04-17 Idera Pharmaceuticals, Inc. Immune regulatory oligonucleotide (iro) compounds to modulate toll-like receptor based immune response

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8840308B2 (en) 2010-11-19 2014-09-23 Saint-Gobain Performance Plastics Corporation Adhesive film for bushings
CN103370417A (zh) * 2010-12-23 2013-10-23 莫洛根股份公司 非编码免疫调节dna构建体
KR20160113332A (ko) 2010-12-23 2016-09-28 몰로젠 아게 비-코딩 면역조절 dna 구조체
CN107299101A (zh) * 2010-12-23 2017-10-27 莫洛根股份公司 非编码免疫调节dna 构建体
WO2015124614A1 (fr) 2014-02-18 2015-08-27 Mologen Ag Construction d'adn immunomodulateur non codant fermée de facon covalente
US11578331B2 (en) 2015-09-09 2023-02-14 Gilead Sciences, Inc. Combination comprising immunostimulatory oligonucleotides
GB2542425A (en) * 2015-09-21 2017-03-22 Mologen Ag Means for the treatment of HIV
US11583581B2 (en) 2015-09-21 2023-02-21 Gilead Sciences, Inc. Methods of treating a retroviral infection

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