WO2006112482A1 - Prediction de pronostic de maladie du foie associee avec l’infection par le virus de l’hepatite c - Google Patents

Prediction de pronostic de maladie du foie associee avec l’infection par le virus de l’hepatite c Download PDF

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Publication number
WO2006112482A1
WO2006112482A1 PCT/JP2006/308233 JP2006308233W WO2006112482A1 WO 2006112482 A1 WO2006112482 A1 WO 2006112482A1 JP 2006308233 W JP2006308233 W JP 2006308233W WO 2006112482 A1 WO2006112482 A1 WO 2006112482A1
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WIPO (PCT)
Prior art keywords
peptide
hepatitis
progression
amino acid
virus
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PCT/JP2006/308233
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English (en)
Japanese (ja)
Inventor
Kyogo Itoh
Michio Sata
Shigeru Yutani
Nobukazu Komatsu
Akira Yamada
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Green Peptide Co., Ltd.
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Publication date
Application filed by Green Peptide Co., Ltd. filed Critical Green Peptide Co., Ltd.
Priority to JP2007528175A priority Critical patent/JP4615567B2/ja
Publication of WO2006112482A1 publication Critical patent/WO2006112482A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/576—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis
    • G01N33/5767—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis non-A, non-B hepatitis

Definitions

  • the present invention relates to a prognostic prediction of liver disease associated with hepatitis C virus infection. More specifically, the present invention relates to liver disease associated with hepatitis C virus infection, from hepatitis to cirrhosis.
  • the present invention relates to a method for predicting progression to hepatocellular carcinoma and a kit for use in a powerful method.
  • Carriers of hepatitis C virus are estimated to be 2 million in Japan and 200 million worldwide.
  • HCV-infected persons have symptoms of chronic hepatitis.
  • Chronic hepatitis C if left untreated, progresses to cirrhosis at an annual rate of 2-3%, and those patients further transition to liver cancer (hepatocellular carcinoma) at an annual rate of 5-7%.
  • Screening methods include first-generation antibody testing using only the recombinant antigen (C100-3) corresponding to NS3,4 region of HCV, core region, NS3, NS4, NS5 (3rd generation only) Second- and third-generation antibody tests using recombinant antigens have been used. There is also a viral antigen gene identification method as a definitive method.
  • hepatitis C virus-related liver diseases can be diagnosed by examining liver function tests using various types of markers such as serum ALT and AST levels in patients, measurement of tumor markers AFP and PIVKA II, measurement of viral load, And methods of diagnosing the transition to fibrosis and canceration by biopsy are used.
  • markers such as serum ALT and AST levels in patients, measurement of tumor markers AFP and PIVKA II, measurement of viral load, And methods of diagnosing the transition to fibrosis and canceration by biopsy are used.
  • IgG antibodies against the NS5A-2132 peptide show high values in cured cases and chronic hepatitis in the early stages of HCV, but it decreases as the disease progresses. (WO2005Z028503). Since the serum levels of the above-mentioned anti-C35 peptide antibodies correlate with persistent infection, it is possible to diagnose HCV infection and determine prognosis, that is, predict the transition to liver cancer by monitoring antibody titers against these two peptides. It was shown that
  • Patent Document 1 WO03 / 025569
  • Patent Document 2 WO2005Z028503
  • An object of the present invention is to provide a novel marker that can be used for predicting the prognosis of liver disease associated with hepatitis C virus infection.
  • the present inventors have found that the antibody titer against the HCV core protein 30-39 peptide increases in patients with hepatitis C virus infection as the liver lesion progresses, and thus completed the present invention.
  • the present invention measures the antibody titer of an antibody against a peptide consisting of eight or more consecutive amino acids including amino acid Gly32 of hepatitis C virus core protein in the blood of a subject.
  • the HCV peptides are numbered sequentially from the N-terminal side to the amino acid sequence of the entire translation region encoded by the consensus sequence of the HCVlb virus genome.
  • the amino acid sequence encoded by the consensus sequence is shown in FIG.
  • Anti-HCV antibody means an antibody capable of binding to a peptide derived from hepatitis C virus. Anti-HCV antibodies can be detected in the serum of patients infected with HCV.
  • Liver disease associated with hepatitis C virus infection refers to liver disease caused by hepatitis C virus infection and includes, for example, hepatitis, cirrhosis and hepatocellular carcinoma. The progression of liver disease is typically progression from chronic hepatitis to cirrhosis, and further from cirrhosis to liver cancer.
  • the antibody titer against a peptide consisting of 8 or more consecutive amino acids including amino acid Arg2132 of non-structural protein NS5A of hepatitis C virus is measured in the blood of the subject. To do.
  • the antibody titer against a peptide having 8 or more consecutive amino acid strengths among Gly33 to Val48 amino acids of the hepatitis C virus core protein is also measured.
  • the present invention includes a peptide recognized by an anti-HCV antibody capable of binding to a peptide consisting of eight or more consecutive amino acids including amino acid Gly32 of hepatitis C virus core protein.
  • a kit is provided to predict the progression of liver disease associated with hepatitis C virus infection.
  • the kit of the present invention contains a peptide having a power of 8 or more consecutive amino acids including amino acid Gly32 of hepatitis C virus core protein.
  • the kit of the present invention comprises a peptide selected from the group consisting of IVGGVYLLPR (SEQ ID NO: 1), VGGVYLLPRR (SEQ ID NO: 2) and GGV YLLPRRG (SEQ ID NO: 3).
  • the kit of the present invention further comprises a peptide recognized by an antibody capable of binding to a peptide having a power of 8 or more consecutive amino acids including the amino acid Arg2132 of the nonstructural protein NS5A of hepatitis C virus.
  • the kit of the present invention further comprises a C type. It includes peptides that are recognized by antibodies that can bind to a peptide consisting of 8 or more consecutive amino acids among the amino acids from Gly33 to Val48 of the hepatitis virus core protein.
  • the present invention not only positive / negative of viral infection can be determined, but also the prognosis of diseases associated with hepatitis C virus infection can be predicted.
  • the method of the present invention enables prediction of prognosis more accurately by combining with the conventional liver function test.
  • FIG. 1 shows antibody titers against C30-39 peptide, NS5A-2132-2140 peptide, and C33-42 peptide in the serum of subjects.
  • FIG. 2 shows antibody titers against C30-39 peptide, C31-40 peptide, and C32-41 peptide in the serum of subjects.
  • FIG. 3 shows antibody titers against C33-42 peptide, C34-43 peptide, C35-44 peptide, C36-45 peptide and C37-46 peptide in the serum of subjects.
  • Figure 4 shows the ratio of antibody titer against C30-39 peptide and antibody titer against C35-44 peptide in the serum of subjects.
  • FIG. 5 shows the numbering of the amino acid sequences of all translation regions encoded by the consensus sequence of the HCVlb virus genome, sequentially from the N-terminal side. The amino acid sequence encoded by the consensus sequence is shown. In the figure, the C30-39 peptide and the NS 5A-2132-2140 peptide are underlined.
  • FIGS. 6-1 to 6-16 show the homology of the amino acid sequences of various isolates of HCVlb.
  • the present invention relates to HCV infection, comprising measuring the antibody titer of an antibody against a peptide consisting of 8 or more consecutive amino acids including amino acid Gly32 of hepatitis C virus core protein in the blood of a subject. Methods for predicting the progression of associated liver disease are provided.
  • Liver disease associated with hepatitis C virus infection means liver disease caused by hepatitis C virus infection, and includes, for example, hepatitis, cirrhosis and hepatocellular carcinoma.
  • the progression of liver disease typically progresses from chronic hepatitis to cirrhosis, and further from cirrhosis to liver cancer. Line.
  • the antibody titer in the blood of a subject can be measured using an antigen-antibody reaction well known in the art.
  • an antigen-antibody reaction well known in the art.
  • the measurement can be performed as follows.
  • the antigen peptide is bound to a conventional ELISA plate such as 96well, and the plate is appropriately blocked to prevent nonspecific adsorption.
  • the serum prepared by the subject's blood force is diluted as appropriate and added to each well of the plate, and reacted for a predetermined time. After washing the plate to remove unbound components, add an antibody that can bind to a human antibody (eg, a rabbit anti-human antibody). If it is desired to detect IgG, ⁇ -chain specific anti-HgG can be used.
  • the plate After reacting for the specified time, the plate is washed and detectably labeled antibody (eg anti-rabbit IgG) is added. Labeling can be performed by methods known to those skilled in the art using enzymes, fluorescent dyes, chemiluminescent substances, piotin, radiation compounds and the like. After reacting the plate for a specified time, the label is detected by adding an appropriate substrate and measuring the decrease in substrate or increase in product, or by measuring fluorescence, luminescence, or radioactivity. In this way, the amount of antibody against a specific peptide in the serum of a subject can be measured.
  • labeled antibody eg anti-rabbit IgG
  • xMAP technology is a flowmetry measurement method developed by Luminex using a fluorescent microbead array system. Microbeads to which peptides are bound are brought into contact with serum, and then a fluorescently labeled secondary antibody is bound to the flow. Measure fluorescence intensity by measurement. Details of antibody titer measurement using this method are shown in the examples below.
  • an immunochromatography method can be used.
  • a portion in which the antigen (or antibody) is linearly distributed is made on the test paper, and the complex of the antibody in the sample and the antigen labeled with the colored particles moves on the test paper.
  • Qualitative analysis is based on the presence or absence of colored lines that appear by intensive capture by antigens (or antibodies). Using this method, results can be obtained in a short time (within 20 to 30 minutes) with simple equipment.
  • the peptide used for detection in the present invention is based on the known gene sequence of hepatitis C virus, and may be 8 or more consecutive amino acids including the amino acid Gly32 of the core protein. Can be obtained from the above. Particularly preferred for the present invention! / ⁇ peptides are C30 peptide: IVGGVYLLPR (SEQ ID NO: 1), C31 peptide: VGGVY LLPRR (SEQ ID NO: 2) and C32 peptide: GGVYLLPRRG (SEQ ID NO: 3). These peptides only need to have the above sequence to the extent that the effects of the present invention are exhibited, and may contain additional sequences.
  • N-terminal side and the C-terminal side would have the N-terminal side and the C-terminal side to obtain a desired effect as an antigen peptide for detecting an antibody, that is, to be able to specifically bind to the target antibody.
  • an amino acid sequence convenient for expressing a peptide as a fusion protein and an amino acid sequence convenient for peptide production and purification are added to the N-terminal side and the Z- or C-terminal side of the peptide according to the present invention. May be.
  • the peptide according to the present invention may be chemically modified or a polymer or sugar chain may be added as long as the specificity of binding to the antibody is not lost.
  • the antibody titer against 2132 peptide: RYAPACKPL (SEQ ID NO: 4) is measured.
  • Antibodies to this peptide show high levels in cases of HCV infection-related liver disease and chronic hepatitis in the early stages of HCV, but are known to decrease as the disease progresses! Therefore, by combining with the above-described method of the present invention, a more reliable prognosis can be predicted.
  • a peptide comprising 8 or more consecutive amino acids of Gly33 to Val48 of hepatitis C virus core protein in the blood of the subject, for example, C33 Peptide: GVYLLPRRGP (SEQ ID NO: 5) , C34 peptide: VYLLPRRGPR (SEQ ID NO: 6) or C35 peptide: YLLPRRGPR L (SEQ ID NO: 7).
  • Antibodies to these peptides are high in the plasma of patients with chronic hepatitis, cirrhosis and liver cancer associated with HCV infection, and are found in the plasma of patients with chronic hepatitis associated with hepatitis B virus.
  • Peptides used as antigens in the method of the present invention can be obtained by a conventional chemical synthesis method or a gene recombination technique using a host transformed to express a base sequence encoding a target amino acid sequence. Obtainable.
  • a target peptide When a target peptide is produced by a chemical synthesis method, it can be produced by a method commonly used in normal peptide chemistry. For example, using a peptide synthesizer, It can be synthesized by a solid phase synthesis method.
  • the crude peptides thus obtained can be purified by purification methods commonly used in protein chemistry, such as salting out, ultrafiltration, reverse phase chromatography, ion exchange chromatography, -Teak It can be purified by a method such as mouth-matography.
  • a DNA fragment encoding the target amino acid sequence is incorporated into an appropriate expression vector, and microorganisms and animal cells are used using this expression vector.
  • the desired peptide can be obtained by culturing the resulting transformant after transformation.
  • expression vectors that can be used plasmids, virus vectors, and the like known in the art can be used.
  • techniques for expressing peptides as fusion proteins are also well known in the art.
  • a conventional method such as a calcium chloride method, a calcium phosphate coprecipitation method, a DEAE dextran method, a lipofectin method, or an electopore position method may be used. It can. Purification of the resulting peptide Can be performed from the cell extract or culture supernatant recovered from the cultured medium by the purification method described above.
  • Antibody titers against the following peptides were measured using sera of HCV-infected and healthy individuals with various liver diseases:
  • GGVYLLPRRG SEQ ID NO: 3
  • NS5A-2132-2140 RYAPACKPL (SEQ ID NO: 4)
  • VYLLPRRGPR SEQ ID NO: 6
  • Specimens used were a group of patients diagnosed with liver disease (chronic hepatitis (CH) 21 cases, cirrhosis (LC) 21 cases, liver cancer (HCC) 27 cases), and healthy subjects (HD) 20 cases. It was. Peptides were purchased from Thermo with a purity of over 90%.
  • the filter plate was washed with 0.05% Tween—20ZPBS. Place 100 / zl of carboxy beads (Luminex) into each well of the filter plate and suck at some point, and wash with 0.1 M MES (2-morpholinoethanesulfonic acid) buffer (pH 7.0). 0.1M MES buffer of 1 Solution (pH 7.0) was added. EDC (Nethyl N,-(3 dimethylaminopropyl) -force rubodiimide hydrochloride) (lOmgZmlZO. 1M MES buffer (pH 7.0)) was added to each of the tubes one by one.
  • Each peptide was dissolved in dimethyl sulfoxide at 10 mg / ml to obtain a peptide solution.
  • EDC (lmg / ml / 0.1M MES buffer (pH 7.0)) was added at a rate of 10 / zl of each well and allowed to react for 20 minutes in the dark. Furthermore, EDC (lmgZmlZ 0.1M MES buffer (pH 7.0)) was added to each well 101 and allowed to react for 20 minutes in the dark. After aspirating the filter plate, 1M Tris-HCl buffer (pH 7.0) was added to each well 1001 and allowed to react for 15 minutes at room temperature in the dark. Next, each bead of each tool was washed with 0.05% Tween-20ZPBS, and collected with a storage solution prepared by adding 0.05% sodium chloride to Block Ace (registered trademark).
  • Serum that also obtained subject strength was diluted 100-fold with 10% Block Ace (registered trademark) ZPBS.
  • the filter plate was washed with 0.05% Tween-20ZPBS, and the previously prepared peptide-bound beads were added with 51 Zwell.
  • the beads were washed with 0.05% Tween-20ZPBS, and diluted serum was covered with 100 1Z wells and reacted at room temperature for 2 hours.
  • the beads were washed with 0.05% Tween-20ZPBS, added with 100 ⁇ lZ piotylated goat anti-human IgG ( ⁇ ) antibody, and reacted at room temperature for 1 hour.
  • Figure 1 shows C30—39: IVGGVYLLPR (SEQ ID NO: 1), NS5A—2132-2140: RYAP ACKPL (SEQ ID NO: 4), and C33—42: GVYLLPRRGP ( The result of having plotted the antibody titer with respect to sequence number 5) according to the disease progression degree is shown. It can be seen that the antibody titer against C30-39 increases with disease progression (CH ⁇ LC ⁇ HCC), whereas the antibody titer against NS5A-2132-2140 decreases with disease progression. Furthermore, the antibody titer against C33-42 is high in HCV-infected individuals regardless of disease progression, but is low in healthy donors.
  • Figure 2 shows antibody titers against C30—39: IVGGVYLLPR (SEQ ID NO: 1), C31—40: VGGVYLLPRR (SEQ ID NO: 2), and C32—41: GGVYLLPRRG (SEQ ID NO: 3) in the serum of subjects.
  • IVGGVYLLPR SEQ ID NO: 1
  • C31—40 VGGVYLLPRR
  • C32—41 GGVYLLPRRG (SEQ ID NO: 3) in the serum of subjects.
  • the results plotted according to the degree of disease progression are shown.
  • Antibody titers against C31 and C32 were shown to increase with disease progression, as did antibody titers against C30.
  • FIG. 3 shows C33—42: GVYLLPRRGP (SEQ ID NO: 5), C34—4 3: VYLLPRRGPR (SEQ ID NO: 6), C35—44: YLLPRRGPRL (SEQ ID NO: 7), C36 45: The result of having plotted the antibody titer with respect to LLPRRGPRLG (sequence number 8) and C37-46: LPRRGPRLGV (sequence number 9) according to the disease progression degree is shown. Antibody titers against any of these peptides are high in HCV-infected individuals regardless of disease progression, but are low in healthy donors. In other words, by combining the antibody titers against these peptides with the antibody titers against the C30, C31 or C32 peptides described above, a more accurate prognosis of HCV infection-related liver disease can be predicted.
  • C30ZC35 is similar between HCC patients and healthy donors, but the antibody titer against C35 is significantly lower in healthy donors. CC patients and healthy donors can be easily distinguished. In other words, by combining the antibody titer against C30 peptide and the antibody titer against C35 peptide, a more accurate prognosis of HCV infection-related liver disease can be predicted.
  • the present invention is useful for diagnosis of liver diseases associated with hepatitis C virus infection and prediction of prognosis.

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Abstract

L’invention porte sur un procédé pour la prédiction de l’évolution d’une maladie du foie associée avec l’infection par le virus de l’hépatite C, le procédé comprenant la détermination du titre d’anticorps d’un anticorps contre un peptide comprenant une séquence d’acides aminés composée de 8 ou plus de 8 résidus d’acides aminés contigus contenant l’acide aminé Gly 32 d’une protéine de coeur de virus d’hépatite C dans le sang d’un sujet. Ensuite, le titre de l’anticorps contre le peptide NS5A-2132 du virus de l’hépatite C et le titre de l’anticorps contre le peptide C33 ou C35 de la protéine du cœur du virus de l’hépatite C sont aussi déterminés. Sur la base de la combinaison de ces résultats, il devient possible de prédire l'évolution avec une fiabilité plus élevée. L’invention concerne aussi une trousse pour une utilisation dans la prédiction de la progression d’une maladie du foie associée avec l’infection par le virus de l’hépatite C, la trousse comprenant un peptide qui peut être reconnu au moyen d’un anticorps anti-VHC capable de se lier à un peptide comprenant une séquence d’acides aminés composée de 8 ou plus de 8 résidus d’acides aminés contigus contenant l’acide aminé Gly 32 de la protéine du cœur du virus de l’hépatite C.
PCT/JP2006/308233 2005-04-19 2006-04-19 Prediction de pronostic de maladie du foie associee avec l’infection par le virus de l’hepatite c WO2006112482A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059221A3 (fr) * 2005-11-11 2007-12-06 Vertex Pharma Variantes du virus de l'hepatite c
US7705138B2 (en) 2005-11-11 2010-04-27 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
WO2010050181A1 (fr) * 2008-10-27 2010-05-06 株式会社グリーンペプタイド Vaccin destiné à prévenir l’apparition et la récurrence du cancer du foie induit par le virus de l’hépatite c
US7884199B2 (en) 2003-10-27 2011-02-08 Vertex Pharmaceuticals Incorporated HCV NS3-NS4 protease resistance mutants

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04121193A (ja) * 1990-09-07 1992-04-22 Chemo Sero Therapeut Res Inst 非ａ非ｂ型肝炎ウイルス融合ペプチドおよびその製法
JPH06247997A (ja) * 1992-08-07 1994-09-06 Boehringer Mannheim Gmbh Ｈｃｖ ペプチド抗原及びｈｃｖ の測定方法
WO2005028503A1 (fr) * 2003-09-22 2005-03-31 Green Peptide Co., Ltd. Peptide provenant du virus de l'hepatite c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04121193A (ja) * 1990-09-07 1992-04-22 Chemo Sero Therapeut Res Inst 非ａ非ｂ型肝炎ウイルス融合ペプチドおよびその製法
JPH06247997A (ja) * 1992-08-07 1994-09-06 Boehringer Mannheim Gmbh Ｈｃｖ ペプチド抗原及びｈｃｖ の測定方法
WO2005028503A1 (fr) * 2003-09-22 2005-03-31 Green Peptide Co., Ltd. Peptide provenant du virus de l'hepatite c

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7884199B2 (en) 2003-10-27 2011-02-08 Vertex Pharmaceuticals Incorporated HCV NS3-NS4 protease resistance mutants
WO2007059221A3 (fr) * 2005-11-11 2007-12-06 Vertex Pharma Variantes du virus de l'hepatite c
US7705138B2 (en) 2005-11-11 2010-04-27 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
US8501450B2 (en) 2005-11-11 2013-08-06 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
WO2010050181A1 (fr) * 2008-10-27 2010-05-06 株式会社グリーンペプタイド Vaccin destiné à prévenir l’apparition et la récurrence du cancer du foie induit par le virus de l’hépatite c

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