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Inhibitor of HMGB protein-mediated immune response activation, and screening method

外国特許コード F130007604
整理番号 AF22-02WO
掲載日 2013年8月9日
出願国 アメリカ合衆国
出願番号 201113823913
公報番号 20130183348
公報番号 9186371
出願日 平成23年9月14日(2011.9.14)
公報発行日 平成25年7月18日(2013.7.18)
公報発行日 平成27年11月17日(2015.11.17)
国際出願番号 JP2011071023
国際公開番号 WO2012036215
国際出願日 平成23年9月14日(2011.9.14)
国際公開日 平成24年3月22日(2012.3.22)
優先権データ
  • 特願2010-209587 (2010.9.17) JP
  • 特願2011-138825 (2011.6.22) JP
  • 2011JP071023 (2011.9.14) WO
発明の名称 (英語) Inhibitor of HMGB protein-mediated immune response activation, and screening method
発明の概要(英語) Provided are an inhibitor of activation of an immune response mediated by an HMGB protein, the inhibitor containing at least one compound selected from the group consisting of a phosphorothioate oligonucleotide and a derivative thereof, and a method of screening for an inhibitor or enhancer of activation of an immune response mediated by an HMGB protein, the method including a mixing step of mixing an HMGB protein and a labeled nucleic acid in the presence and absence of a test substance; a quantifying step of quantifying the HMGB protein bound to the labeled nucleic acid; and a determination step of determining that the test substance is an inhibitor of activation of an immune response mediated by the HMGB protein when the amount of the HMGB protein bound to the labeled nucleic acid in the presence of the test substance is less than the amount of the HMGB protein bound to the labeled nucleic acid in the absence of the test substance and determining that the test substance is an enhancer of activation of an immune response mediated by the HMGB protein when the amount of the HMGB protein bound to the labeled nucleic acid in the presence of the test substance is higher than the amount of the HMGB protein bound to the labeled nucleic acid in the absence of the test substance.
従来技術、競合技術の概要(英語) BACKGROUND ART
In immune response and its control, discrimination between self and nonself is the basis.
The innate immune system and the adaptive immune system carry out this discrimination by the respective specific mechanisms and establish and maintain each mechanism not to response to self, so-called immune tolerance.
Since activation of the innate immune response is known to be also involved in induction of the adaptive immune response, inhibition of the innate immune response is known to be also effective for inhibition of the adaptive immune response.
It has been revealed that in the adaptive immune system, after construction of a lymphocyte repertoire expressing random antigen receptors, the majority of autoreactive lymphocytes are eliminated by a central tolerance mechanism and the autoreactive lymphocytes still remaining at periphery are inhibited by a peripheral tolerance mechanism.
Though the recognition of an antigen by the adaptive immune system is characterized by the recognition of a specific molecular structure by a lymphocyte antigen receptor, the innate immune system is regarded to recognize the molecular pattern possessed by, for example, a pathogen, and many innate immune activating receptors including a Toll-like receptor (TLR) are known.
In particular, the innate immune activation by nucleic acid is important for elimination of pathogens such as viruses and is simultaneously regarded to be involved in onset and exacerbation of various immune pathological conditions and is therefore drawing much interest.
However, there are many unknown aspects in the discrimination mechanism by nucleic acid in the innate immune system, though receptor molecular groups, such as Toll-like receptor (TLR) 3, TLR7, TLR9, RIG-1-like receptor, DAI, and AIM2, have been identified as molecular groups carrying out immune responses activated by nucleic acid, the whole picture is still unclear (see, e.g., Non Patent Literatures 1 to 3).
In HMGB (high-mobility group box) proteins, it is known that HMGB1, HMGB2 and HMGB3 are present.
These HMGB proteins are abundantly present in nuclei and are believed to be involved in chromatin structure and in control of transcription.
In addition, they are known to be also present in cytoplasms and outside cells.
Patent Literature 1 describes a synthetic double-stranded nucleic acid or a nucleic acid analog molecule that inhibits binding between an extracellularly secreted HMGB1 protein and an advanced glycation end product receptor (RAGE) on a cell surface.
Patent Literature 2 describes a HMGB1 antagonist that inhibits interaction between the extracellularly secreted HMGB1 protein and the RAGE.
Non Patent Literature 4 describes that a base-free phosphorothioate deoxyribose homopolymer has a high affinity to TLR9 and TLR7 and acts as an antagonist of these TLRs.
Non Patent Literature 5 describes that though administration of a phosphorothioate oligonucleotide including a nucleotide sequence of 5'-TCCATGACGTTCCTGATGCT-3' (SEQ ID NO: 37) to a mouse induces an IFN (interferon)-gamma response, a phosphorothioate oligonucleotide including a nucleotide sequence of 5'-TCCATGAGCTTCCTGATGCT-3' (SEQ ID NO: 38) does not cause such a response.

CITATION LIST

Patent Literature
Patent Literature 1: National Publication of International Patent Application No. 2008-504335
Patent Literature 2: National Publication of International Patent Application No. 2009-517404

Non Patent Literature
Non Patent Literature 1: Kawai T. et al., Nat. Rev. Immunol 7: 131-137, 2006
Non Patent Literature 2: Yoneyama et al., J. Biol. Chem. 282: 15315-15318, 2007
Non Patent Literature 3: Burckstummer T. et al., Nat. Immunol. 10: 266-272, 2009
Non Patent Literature 4: Haas T. et al., Immunity, 28: 315-323, 2008
Non Patent Literature 5: Cowdery J S. et al., J. Immunol. 156: 4570-4575, 1996

特許請求の範囲(英語) [claim1]
1. A method of inhibiting activation of an immune response mediated by a high-mobility group box (HMGB) protein, the method comprising administering to a subject in need thereof a phosphorothioate oligonucleotide of 20 to 40 nucleotides in length in an amount effective to inhibit an immune response in the subject, wherein
the phosphorothioate oligonucleotide binds to HMGB protein,
the phosphorothioate oligonucleotide does not have an unmethylated CG sequence, and
the phosphorothioate oligonucleotide does not have a methylated guanine.
[claim2]
2. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide consisting of: a nucleotide sequence as set forth in SEQ ID NO: 40; or
a nucleotide sequence having deletion, substitution, or addition of one or more nucleotides in the nucleotide sequence as set forth in SEQ ID NO: 40 and having a binding ability to an HMGB protein.
[claim3]
3. The method according to claim 1, wherein the phosphorothioate oligonucleotide inhibits a binding between a nucleic acid activating the immune response and the HMGB protein in a cell.
[claim4]
4. The method according to claim 1, wherein the activation of an immune response mediated by an HMGB protein is selected from the group consisting of antigen-specific adaptive immune system, multiple sclerosis, excessive immune response to a dead cell, organ transplant rejection, autoimmune disease, inflammatory bowel disease, allergy, septicemia, tumor growth by inflammation and inflammatory disease caused by a nucleic acid-containing pathogen.
[claim5]
5. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide consisting of: a nucleotide sequence as set forth in SEQ ID NO: 40; or
a nucleotide sequence having deletion, substitution, or addition of one to five nucleotides in the nucleotide sequence as set forth in SEQ ID NO: 40 and having a binding ability to an HMGB protein.
[claim6]
6. The method according to claim 1, wherein the activation of an immune response mediated by an HMGB protein causes multiple sclerosis or septicemia.
[claim7]
7. The method according to claim 5, wherein the activation of an immune response mediated by an HMGB protein causes multiple sclerosis or septicemia.
[claim8]
8. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide consisting of: a nucleotide sequence as set forth in SEQ ID NO: 40; or
a nucleotide sequence having deletion, substitution, or addition of one to three nucleotides in the nucleotide sequence as set forth in SEQ ID NO: 40 and having a binding ability to an HMGB protein.
[claim9]
9. The method according to claim 8, wherein the activation of an immune response mediated by an HMGB protein causes multiple sclerosis or septicemia.
[claim10]
10. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide consisting of a nucleotide sequence as set forth in SEQ ID NO: 40.
[claim11]
11. The method according to claim 10, wherein the activation of an immune response mediated by an HMGB protein causes multiple sclerosis or septicemia.
[claim12]
12. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide comprising: a nucleotide sequence as set forth in SEQ ID NO: 40; or
a nucleotide sequence having deletion, substitution, or addition of one or more nucleotides in the nucleotide sequence as set forth in SEQ ID NO: 40 and having a binding ability to an HMGB protein.
[claim13]
13. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide comprising: a nucleotide sequence as set forth in SEQ ID NO: 40; or
a nucleotide sequence having deletion, substitution, or addition of one to five nucleotides in the nucleotide sequence as set forth in SEQ ID NO: 40 and having a binding ability to an HMGB protein.
[claim14]
14. The method according to claim 13, wherein the activation of an immune response mediated by an HMGB protein causes multiple sclerosis or septicemia.
[claim15]
15. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide comprising: a nucleotide sequence as set forth in SEQ ID NO: 40; or
a nucleotide sequence having deletion, substitution, or addition of one to three nucleotides in the nucleotide sequence as set forth in SEQ ID NO: 40 and having a binding ability to an HMGB protein.
[claim16]
16. The method according to claim 15, wherein the activation of an immune response mediated by an HMGB protein causes multiple sclerosis or septicemia.
[claim17]
17. The method according to claim 1, wherein the phosphorothioate oligonucleotide is a phosphorothioate oligonucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 40.
[claim18]
18. The method according to claim 17, wherein the activation of an immune response mediated by an HMGB protein causes multiple sclerosis or septicemia.
[claim19]
19. The method according to claim 1, wherein the activation of an immune response mediated by an HMGB protein causes an inflammatory disease.
[claim20]
20. The method according to claim 1, wherein the phosphorothioate oligonucleotide is unmethylated.
[claim21]
21. The method according to claim 1, wherein the phosphorothioate oligonucleotide does not comprise a CG sequence.
  • 発明者/出願人(英語)
  • TANIGUCHI TADATSUGU
  • YANAI HIDEYUKI
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
国際特許分類(IPC)
米国特許分類/主・副
  • 424/278.1
  • 435/375
  • 436/501
参考情報 (研究プロジェクト等) CREST Etiological Basics of and Techniques for Treatment of Allergic and Autoimmune Diseases AREA
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