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DIAGNOSTIC OF RHEUMATOID ARTHRITIS

Foreign code F190009769
File No. (S2017-0877-N0)
Posted date May 7, 2019
Country WIPO
International application number 2018JP025020
International publication number WO 2019009231
Date of international filing Jul 2, 2018
Date of international publication Jan 10, 2019
Priority data
  • P2017-132888 (Jul 6, 2017) JP
  • P2018-005038 (Jan 16, 2018) JP
Title DIAGNOSTIC OF RHEUMATOID ARTHRITIS
Abstract Provided are: a method for diagnosis of rheumatoid arthritis in a subject; a method for auxiliary diagnosis of rheumatoid arthritis; and a method for monitoring disease activity of rheumatoid arthritis and/or a therapeutic effect of a rheumatoid arthritis drug, each method being characterized by comprising detecting citrullination of an arginine residue in inter-α-trypsin inhibitor heavy chain (ITIH) 4 in a biological sample derived from the subject. Also provided are: a citrullinated protein, wherein, in a protein having the amino acid sequence represented by SEQ ID NO: 1 or 5, the 438-th arginine residue has been modified into a citrulline residue, or a fragment of said protein; an antibody capable of binding to the citrullinated protein; and a diagnostic of rheumatoid arthritis which comprises the antibody.
Outline of related art and contending technology BACKGROUND ART
(Rheumatoid Arthritis, RA) is rheumatoid arthritis, joint pain and swelling occurs, further deformation of the joint, and then proceeds to the destruction of the autoimmune disease is an inflammatory. Is RA, joint pain and swelling, the presence or absence of an inflammatory response, the duration of the arthritis, and total blood test values or the like described later are diagnosed, it may not be determined previously and arthritis long known that the presence of pre-clinical stage, the development of RA is the environmental risk factors and genetic risk factors have been reported to be involved in the (non-patent document 1).
RA is the body of the patient anti-citrullinated protein binds to citrullinated peptide antibody (anti-citrullinated protein antibodies, ACPA) is known to exist (non-patent document 2). In addition, in the RA of the patient's joint is increased and a plurality of types of citrullinated protein and, which may be involved in the RA has been suggested (Non-Patent Document 3-5). However, major serum proteins citrulline, and its role in the pathogenesis of relevance is not clear.
For treatment of RA, inflammation and pain drug treatment, surgery, rehabilitation and the like are performed, in recent years, anti-cytokine therapy to onset of clinical remission can be obtained from the reported cases, early diagnosis, early treatment are required.
Comprehensive clinical symptoms of RA as an index, for example the evaluation of the joint 28 has been used widely DAS(Disease Activity Score) 28. DAS28 In, blood laboratory values inflammatory response C-reactive protein (CRP) as those used in DAS28-CRP. Other, rheumatoid factor and an index value of the ACPA blood test for the diagnosis of RA have been used to, rheumatoid factor is compared to the high accuracy of the ACPA detected by the (non-patent document 6).
Scope of claims (In Japanese)請求の範囲 [請求項1]
 被験体由来の生物学的サンプル中のインターαトリプシンインヒビター重鎖(ITIH)4のアルギニン残基のシトルリン化を検出することを特徴とする、被験体における関節リウマチの診断方法、又は関節リウマチの診断を補助する方法。

[請求項2]
 被験体由来の生物学的サンプル中のインターαトリプシンインヒビター重鎖(ITIH)4のアルギニン残基のシトルリン化を検出することを特徴とする、被験体における関節リウマチの疾患活動性及び/又は関節リウマチ薬による治療効果のモニタリング方法。

[請求項3]
 アルギニン残基が配列番号1又は5に示すアミノ酸配列中438番目のアルギニン残基である、請求項1又は2記載の方法。

[請求項4]
 生物学的サンプルが、被験体から採取された全血、血漿、血清、皮膚、又は関節組織である、請求項1~3のいずれか1項記載の方法。

[請求項5]
 シトルリン化の検出が、シトルリンを含むタンパク質を認識する質量分析法、ウェスタンブロット法、免疫組織学的検出法、免疫沈降法、又はELISA法である、請求項1~4のいずれか1項記載の方法。

[請求項6]
 シトルリン化の検出が、配列番号1又は5に示すアミノ酸配列中438番目のアルギニンがシトルリンに改変された改変タンパク質又は該シトルリンを含むペプチド断片に結合する抗体との結合を介するものである、請求項1~5のいずれか1項記載の方法。

[請求項7]
 配列番号1若しくは5に示すアミノ酸配列を有するタンパク質において、438番目のアルギニン残基のシトルリン残基への改変を有するシトルリン化タンパク質、又は該シトルリン残基を有するその断片。

[請求項8]
 請求項7記載のシトルリン化タンパク質又はその断片を含む、関節リウマチの診断のためのバイオマーカー。

[請求項9]
 請求項7記載のシトルリン化タンパク質又はその断片に結合し、非シトルリン化タンパク質には結合しない抗体。

[請求項10]
 請求項9記載の抗体を含む、関節リウマチ診断薬。

[請求項11]
 関節リウマチの診断又は診断の補助のために使用されるキットであって、請求項9記載の抗体を含む、上記キット。

[請求項12]
 関節リウマチの診断又は診断の補助のために使用されるキットであって、質量分析における内部標準として請求項7記載のシトルリン残基を有する断片を含む、上記キット。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • UNIVERSITY OF TSUKUBA
  • Inventor
  • MATSUMOTO Isao
  • SUMIDA Takayuki
  • KAWAGUCHI Hoshimi
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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