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METHOD FOR DETECTING HCV IN BLOOD, AND METHOD FOR DETERMINING EFFECT OF ANTI-HCV TREATMENT

Foreign code F140007999
File No. S2012-1115-C0
Posted date Oct 28, 2014
Country WIPO
International application number 2013JP074859
International publication number WO 2014046045
Date of international filing Sep 13, 2013
Date of international publication Mar 27, 2014
Priority data
  • P2012-204395 (Sep 18, 2012) JP
Title METHOD FOR DETECTING HCV IN BLOOD, AND METHOD FOR DETERMINING EFFECT OF ANTI-HCV TREATMENT
Abstract The present invention relates to a method for detecting hepatitis-C virus (HCV) in blood of a test subject, the method including detecting a C4γ fragment in a blood sample generated by HCV NS3/4A protease cleavage of complement C4.
Outline of related art and contending technology BACKGROUND ART
C-type hepatitis virus belonging to the Flaviviridae family (Hepatitis C Virus; HCV) is a positive stranded RNA virus, and human host-specific, becoming a cause of hepatitis C has been known. Simmonds et al. system according to the analysis, the genotype of the HCV genotypes are classified into 1-6, and in addition they are classified into several subtypes (Non-Patent Document 1). HCV RNA genome of, one region 4 to the structural proteins (Core, E1, E2, p7) and one non-structural protein region 6 (NS2, NS3, NS4A, NS4B, NS5A, NS5B) 1 precursor protein consisting of one encoding (polyprotein) (Non-Patent Document 2). Precursor protein is post-translationally, in a host cell which is hydrolyzed by proteases and protease, respectively and the mature protein of 10.
HCV infection of a patient suffering from acute hepatitis, chronic persistent infection is 70% is called to. Many of the persistently infected liver disorders such as chronic hepatitis with a peak value of ALT and, eventually cirrhosis, hepatoma and travels to the liver failure. Major HCV antiviral therapy, interferon - α - β interferon monotherapy or in addition, alpha and ribavirin combination therapy with the standard therapy has been established. However to those used in anti-viral treatments, the overall treatment of only about 60% was observed to have a therapeutic effect, even if the virus had negative example after the completion of the treatment is large. The therapeutic effect of interferon, the genotype of HCV associated with large, an effect of genotype 1 to 4 or, 2, 3, 5, 6 effect is high with respect to a genotype thereof.
A method of treating hepatitis C is the current, a method for the administration of a drug over a period of weeks 24-72 HCV antiviral therapy is mainly performed. To complete the drug administration period after the negative serum HCV RNA, to week 24 follow-up is performed to reduce the negative serum HCV RNA was observed, the therapeutic effect thereof, patients with persistent viruses (sustained virological response; SVR) is determined. Hepatitis C treatment current finally points to the SVR. On the other hand, serum HCV RNA at the end of the drug administration is negative, then in the case of serum HCV RNA positive, it is determined that the therapeutic effect may be had. And the predetermined drug administration period and serum HCV RNA was completed when the negative, the treatment is found to be invalid. Classical anti-viral therapy, to determine the effect of antiviral therapy for HCV and HCV RNA quantitatively detect the amount of an index. TaqMan AMPLICORE method or the detection of HCV RNA is used in the method, and at an earlier stage of the virus-negative in order to confirm that a more precise, more sensitive HCV detection method is demanded.
HCV NS4A and NS3 of the enzyme is a serine protease activity of NS3/4A, an important role in HCV replication functions as, a direct acting antiviral agent (direct-acting antiviral agents; DAA) already become one of the target (non-patent documents 3 and 4, such as Patent Document 1). DAA is one of the protease inhibitor is NS3/4A, in recent years, a dramatic improvement in the therapeutic effect on HCV to, 3 + alpha + NS3/4A protease inhibitors ribavirin combination therapy agents, refractory genotype 1 HCV has been referred to as a chronic hepatitis C virus and high in a patient in an amount, which leads to high viral quenching effect. However NS3/4A the mechanism of anti-viral effect of protease inhibitors has been solved sufficiently and it is not considered.
Is a persistent infection of HCV, HCV inhibitory to the host immune response can be applied in the suggested that the (non-patent document 5), the mechanism has not been elucidated sufficiently. In addition, in a HCV-infected persons, liver cirrhosis and progresses to the individual difference in speed, in particular HCV chronic infection but to maintain normal ALT ALT value of the duration of the HCV infected persons normally (HCV carrier with persistent normal ALT; PNALT) is, a high value of ALT as compared to patients in chronic hepatitis, the slow speed of the hepatic fibrosis have been reported (Non-Patent Document 6). These clinical difference is that, due to the host immune reaction can be surmised, the reason for the difference of the reaction is not yet been elucidated sufficiently.
The present inventors have found a technique using the proteomics far, mainly from the serum of patients with liver disease can be a marker of liver cancer who has made an attempt to identify a protein (non-patent document 7-10). But the function of a protein in vivo in the context of the disease state of the patients with liver disease has not been elucidated sufficiently.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 補体C4のHCV NS3/4Aプロテアーゼ切断により生成される、血液検体中のC4γ切断断片を検出することを含む、被験者の血液中のC型肝炎ウイルス(HCV)の検出方法。

[請求項2]
 前記C4γ切断断片が、配列番号1で示されるアミノ酸配列の1583位のシステインと1584位のセリンの間、又は1590位のシステインと1591位のアラニンの間のNS3/4Aプロテアーゼ切断によりC4γ鎖から生成される17kDa又は15kDaのタンパク質である、請求項1に記載の方法。

[請求項3]
 被験者が、C型肝炎ウイルス感染者又は感染既往者である、請求項1又は2に記載の方法。

[請求項4]
 被験者が、C型肝炎ウイルスに対する抗ウイルス治療中又は抗ウイルス治療終了後の患者である、請求項3記載の方法。

[請求項5]
 請求項3又は4に記載の方法を用いてC型肝炎ウイルスを経時的に測定することを含む、被験者におけるC型肝炎ウイルス量のモニタリング方法。

[請求項6]
 請求項4又は5に記載の方法を用いてC型肝炎ウイルスを測定し、その測定結果を抗ウイルス治療の効果の指標とすることを含む、抗ウイルス治療効果の判定方法。

[請求項7]
 補体C4のHCV NS3/4Aプロテアーゼ切断により生成されるC4γ切断断片に結合する抗体を含む、C型肝炎ウイルス検出試薬。

[請求項8]
 前記C4γ切断断片が、配列番号1で示されるアミノ酸配列の1583位のシステインと1584位のセリンの間、又は1590位のシステインと1591位のアラニンの間のNS3/4Aプロテアーゼ切断によりC4γ鎖から生成される17kDa又は15kDaのタンパク質である、請求項7に記載のC型肝炎ウイルス検出試薬。

[請求項9]
 請求項7又は8に記載のC型肝炎ウイルス検出試薬を含む、C型肝炎ウイルス検出用キット。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • KAGOSHIMA UNIVERSITY
  • Inventor
  • UTO Hirofumi
  • TSUBOUCHI Hirohito
  • MAWATARI Seiichi
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 DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS KE KG KN KP KR KZ LA LC LK LR LS LT 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 TD TG
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