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WO2016159178A1 - Procédé de prédiction de l'efficacité d'une thérapie basée sur l'interféron, et composition médicamenteuse destinée aux patients souffrant d'hépatite b l'utilisant - Google Patents

Procédé de prédiction de l'efficacité d'une thérapie basée sur l'interféron, et composition médicamenteuse destinée aux patients souffrant d'hépatite b l'utilisant Download PDF

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WO2016159178A1
WO2016159178A1 PCT/JP2016/060553 JP2016060553W WO2016159178A1 WO 2016159178 A1 WO2016159178 A1 WO 2016159178A1 JP 2016060553 W JP2016060553 W JP 2016060553W WO 2016159178 A1 WO2016159178 A1 WO 2016159178A1
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concentration
interferon
ifn
hbs antigen
value
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Japanese (ja)
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雅史 溝上
一素 村田
真也 杉山
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • 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
    • 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

Definitions

  • the present invention relates to an interferon therapeutic effect prediction method and a pharmaceutical composition for treating hepatitis B patients using the same. According to the present invention, the therapeutic effect of interferon can be predicted in advance.
  • hepatitis B virus HBV
  • hepatitis B virus infection with hepatitis B virus causes acute and chronic hepatitis (hepatitis B), and further causes cirrhosis and liver cancer.
  • hepatitis B chronic hepatitis
  • 300,000 people die from hepatitis B-related diseases every year.
  • interferon or nucleic acid analog preparations are used as therapeutic agents for hepatitis B virus.
  • nucleic acid analog preparation lamivudine, Adefovir pivoxil, entecavir, tenofovir disoproxil fumarate, tervivudine, or clevudine are used in Japan or overseas.
  • Non-patent Document 1 the nucleic acid analog preparation cannot be stopped to maintain the virus reduction.
  • interferon can reduce the viral load of HBV and further reduce the HBs antigen.
  • side effects such as fever, general malaise, joint pain, or muscle pain are observed in interferon (Non-patent Document 2).
  • an object of the present invention is to provide a method for predicting patients in which sequential therapy with interferon therapy after treatment with a nucleic acid analog preparation is likely to be effective.
  • the present invention [1] (1) A step of measuring the IFN- ⁇ 3 concentration and HBs antigen concentration of a specimen derived from an HBV-infected patient, and (2) a predetermined cutoff value for each of the measured IFN- ⁇ 3 concentration and HBs antigen concentration.
  • An interferon therapeutic effect prediction method comprising: [2] (1) A step of measuring the IFN- ⁇ 3 concentration and HBs antigen concentration of a specimen derived from an HBV-infected patient, and (2) comparing the measured HBs antigen concentration with a preset cut-off value, Predicts that interferon therapy is likely to be effective when is below the cut-off value or below the cut-off value, and if the HBs antigen concentration exceeds the cut-off value, the measured IFN- ⁇ 3 concentration Comparing with a preset cut-off value, and predicting that interferon treatment is likely to be effective when the IFN- ⁇ 3 concentration is equal to or higher than the cut-off value or exceeds the cut-off value.
  • the cutoff value of the IFN- ⁇ 3 concentration is any one of 10 pg / mL to 25 pg / mL, and the cutoff value of the HBs antigen concentration is 2.5 LogIU / mL to 4.0 LogIU / mL
  • the cutoff value of the IFN- ⁇ 3 concentration is 15 pg / mL or 20 pg / mL, and the cutoff value of the HBs antigen concentration is 2.9 Log IU / mL, 3.0 Log IU / mL, or 3.5 Log IU / mL.
  • the interferon therapeutic effect prediction method according to any one of [1] to [3], [5]
  • the interferon therapeutic effect prediction method according to any one of [1] to [4], wherein the HBV-infected patient is a patient administered with adefovir or tenofovir, [6] It is administered to a patient infected with hepatitis B virus that is predicted to be highly likely to be effective in the interferon treatment by the method for predicting the effect of interferon treatment according to any one of [1] to [5].
  • a pharmaceutical composition for treating hepatitis B comprising interferon
  • An interferon therapeutic effect prediction kit comprising an IFN- ⁇ 3 concentration measuring reagent and an HBs antigen concentration measuring reagent, About.
  • interferon therapeutic effect prediction method or the interferon therapeutic effect prediction kit of the present invention patients with high sequential therapy effects can be predicted with high probability. Therefore, for patients with low efficacy of sequential therapy, sufficient explanation can be provided to determine whether to perform interferon treatment or continue with a nucleic acid analog preparation. Moreover, the treatment cost of interferon treatment can be suppressed by those judgments. Furthermore, since the pharmaceutical composition for treating hepatitis B containing the interferon of the present invention is administered to patients with hepatitis B who are highly likely to be effective in interferon therapy, the therapeutic effect is high.
  • serum IFN- ⁇ 3 In patients with chronic hepatitis or cirrhosis who received adefovir or tenofovir treatment, serum IFN- ⁇ 3 increased in many patients. On the other hand, serum IFN- ⁇ 3 hardly increased in patients receiving lamivudine and entecavir. Most cases with high serum IFN- ⁇ 3 were taking adefovir or tenofovir. In sequential therapy, serum IFN- ⁇ 3 and HBs antigen at the time of discontinuation of nucleic acid analog preparation were measured. mL) or higher indicates a decrease in HBs antigen at the end of treatment.
  • Serum IFN- ⁇ 3 and HBs antigen are measured and if the HBs antigen shows a cut-off value (2.9 Log IU / mL), the HBs antigen is decreased and the HBs antigen is cut-off (2.9 Log IU / mL) )
  • IFN- ⁇ 3 shows a cut-off value (15 pg / mL) or more, it is a graph showing that the HBs antigen has decreased.
  • Interferon therapeutic effect prediction method [1-1] First embodiment of interferon therapeutic effect prediction method
  • One embodiment of the interferon therapeutic effect prediction method of the present invention includes (1) IFN of a specimen derived from an HBV-infected patient. A step of measuring the - ⁇ 3 concentration and the HBs antigen concentration, and (2) comparing the measured IFN- ⁇ 3 concentration and the HBs antigen concentration with respective preset cutoff values, and the IFN- ⁇ 3 concentration is equal to or higher than the cutoff value. Or a step of predicting that interferon treatment is likely to be effective when the cutoff value is exceeded and the HBs antigen concentration is below the cutoff value or below the cutoff value. That is, the interferon therapeutic effect is predicted by combining the IFN- ⁇ 3 concentration and the HBs antigen concentration of the specimen derived from an HBV-infected patient.
  • the interferon treatment capable of predicting the therapeutic effect by the interferon therapeutic effect prediction method of the present invention is not particularly limited, and examples thereof include interferon- ⁇ , PEGylated interferon- ⁇ , interferon ⁇ , and interferon ⁇ . Particularly preferred is PEGylated interferon- ⁇ .
  • the administration schedule of interferon is not particularly limited. For example, Peg-IFN- ⁇ 2a (180 ⁇ g) is administered once a week and subcutaneously for 48 weeks.
  • the interferon treatment may be interferon treatment of interferon alone, but sequential treatment is preferred in which interferon treatment is performed after treatment with the nucleic acid analog preparation. This is because treatment with a nucleic acid analog preparation may increase the concentration of IFN- ⁇ 3 having an anti-HBV effect in HBV-infected patients.
  • Nucleic acid analog preparations used in sequential therapy can include lamivudine, Adefovir pivoxil, entecavir, tenofovir disoproxil fumarate, tervivudine, or clevudine Is preferably adefovir or tenofovir.
  • Step of measuring IFN- ⁇ 3 concentration and HBs antigen concentration In the step of measuring IFN- ⁇ 3 concentration and HBs antigen concentration, IFN- ⁇ 3 concentration and HBs antigen concentration are measured. And may be measured simultaneously or individually.
  • the specimen used is not particularly limited as long as it is a specimen derived from an HBV-infected patient and capable of measuring the IFN- ⁇ 3 concentration and the HBs antigen concentration.
  • urine, blood, serum, plasma, lymph, tissue fluid, cerebrospinal fluid, saliva, urine, or sweat can be mentioned.
  • blood, serum, Or plasma is preferred.
  • IFN- ⁇ 3 concentration measurement The method for measuring IFN- ⁇ 3 concentration used in the method for predicting the therapeutic effect of interferon according to the present invention is not particularly limited as long as it can specifically measure IFN- ⁇ 3.
  • IFN- ⁇ 3 is also referred to as IL-28B.
  • IL-28B (IFN- ⁇ 3) has 96% amino acid homology with the IFN- ⁇ family IL-28A. Therefore, most antibodies that bind to IL-28B (IFN- ⁇ 3) also bind to IL-28A, and most antibodies that bind to IL-28A also bind to IL-28B (IFN- ⁇ 3).
  • the difference in amino acid sequence from IL-28A is only 6 amino acids, and the difference in amino acid sequence between major IL-28B (IFN- ⁇ 3) and IL-28A is only 7 amino acids. Therefore, the conventional IL-28B immunoassay does not specifically measure IL-28B (IFN- ⁇ 3), but measures IL-28B (IFN- ⁇ 3) and IL-28A. However, the IL-28B-specific immunoassay described in Patent Document 1 does not substantially measure IL-28A but specifically measures IL-28B (IFN- ⁇ 3). This is preferred as a method for measuring IFN- ⁇ 3 concentration in the invention.
  • IL28B (IFN- ⁇ 3) includes minor IL-28B (IFN- ⁇ 3) and major IL-28B (IFN- ⁇ 3), and the difference between these amino acids is one amino acid.
  • the anti-IL-28B monoclonal antibody (A) used in the IL-28B-specific immunoassay described in Patent Document 1 is major IL-28B (IFN- ⁇ 3) and minor IL-28B (IFN- ⁇ 3).
  • IL-28B (IFN- ⁇ 3) can be specifically measured.
  • Such antigen-binding fragments of antibodies can also be used in the same manner as antibodies.
  • Patent Document 1 also describes an anti-IL-28B monoclonal antibody (B) that binds to major IL-28B (IFN- ⁇ 3) and does not bind to minor IL-28B (IFN- ⁇ 3) and IL-28A.
  • IFN- ⁇ 3 major IL-28B
  • IFN- ⁇ 3 minor IL-28B
  • IL-28B (IFN- ⁇ 3) can be specifically measured with this monoclonal antibody.
  • the IFN- ⁇ 3 concentration measurement method used in the interferon therapeutic effect prediction method of the present invention is not particularly limited as long as it has a detection sensitivity equal to or lower than the cut-off value for determining the therapeutic effect. By having a detection sensitivity equal to or lower than the cut-off value for determining the therapeutic effect, the interferon therapeutic effect can be accurately predicted.
  • the IFN- ⁇ 3 concentration measurement method used in the present invention is not particularly limited as long as it can measure the IFN- ⁇ 3 concentration.
  • enzyme immunoassay, latex agglutination immunoassay, chemiluminescence immunoassay A measurement method or a radioimmunoassay method can be mentioned, but a sandwich-type enzyme immunoassay method or a chemiluminescence immunoassay method using two or more kinds of antibodies is preferable.
  • an immunoassay that can measure major IL-28B (IFN- ⁇ 3) and minor IL-28B (IFN- ⁇ 3) may be used, and only major IL-28B (IFN- ⁇ 3) is specifically detected.
  • An immunoassay that can be measured may be used.
  • the method for measuring the concentration of HBs antigen used in the method for predicting the therapeutic effect of interferon of the present invention is not particularly limited as long as it can specifically measure the HBs antigen. That is, those containing an anti-HBs antigen antibody that specifically binds to the HBs antigen are preferred.
  • the HBs antigen concentration measurement method used in the interferon therapeutic effect prediction method of the present invention is not particularly limited as long as it has a detection sensitivity equal to or lower than the cut-off value for determining the therapeutic effect. By having a detection sensitivity equal to or lower than the cut-off value for determining the therapeutic effect, the interferon therapeutic effect can be accurately predicted.
  • the HBs antigen concentration measurement method used in the present invention is not particularly limited as long as it can measure HBs antigen concentration measurement.
  • enzyme immunoassay latex agglutination immunoassay, chemiluminescence immunoassay Or a sandwich immunoassay using two or more antibodies or a chemiluminescent immunoassay is preferred.
  • kit for measuring the HBs antigen concentration a commercially available kit can be used.
  • HBsAgQT Abbott Japan
  • Lumipulse II HBsAg Flujirebio
  • Cobas Core HBsAgII-EIA Roche Diagnostics
  • Enzygnost HBsAg5.0 Dade Bering
  • the predicted IFN- ⁇ 3 concentration and HBs antigen concentration are compared with respective preset cutoff values, and the IFN- ⁇ 3 concentration is determined in advance. It is predicted that there is a high possibility that interferon treatment is effective when the cut-off value is equal to or higher than the set cut-off value or exceeds the cut-off value and the HBs antigen concentration is less than or equal to the preset cut-off value or less than the cut-off value.
  • the interferon therapeutic effect prediction method of the present invention as shown in the Examples, when the IFN- ⁇ 3 concentration is high and the HBs antigen concentration is low, it is predicted that interferon treatment is likely to be effective.
  • the number of infected patients can be improved.
  • interferon can be effective when the cutoff value of IFN- ⁇ 3 concentration is 20 pg / mL or more and the cutoff value of HBs antigen concentration is less than 3.0 Log IU / mL.
  • the number of HBV-infected patients judged to be high in nature was 5, and 4 of them were actually effective for interferon treatment.
  • interferon can be effective when the cutoff value of the IFN- ⁇ 3 concentration is 20 pg / mL or more and the cutoff value of the HBs antigen concentration is less than 3.5 Log IU / mL.
  • the number of HBV-infected patients judged to be high is 11 and 7 of them were actually effective for interferon treatment. Therefore, although there are variations in the accuracy (specificity) of prediction and the number of HBV-infected patients (sensitivity) that are predicted to have a high therapeutic effect by interferon depending on the setting of the cutoff value, for example, the cutoff value of IFN- ⁇ 3 concentration
  • the cutoff value of IFN- ⁇ 3 concentration Treatment of interferon with a concentration of any one of 10 pg / mL to 25 pg / mL and a cutoff value of HBs antigen concentration of any one of 2.5 Log IU / mL to 4.0 Log IU / mL It is possible to predict the effect.
  • the cutoff value can be selected and determined as appropriate depending on whether priority is given to specificity or sensitivity.
  • the cutoff value of the IFN- ⁇ 3 concentration is 10 pg / mL to 25 pg / mL. Any one concentration is preferable, and any one concentration of 15 pg / mL to 20 pg / mL is more preferable.
  • the cut-off value of the HBs antigen concentration is preferably any one of 2.5 Log IU / mL to 4.0 Log IU / mL, and any one of 3.0 Log IU / mL to 3.5 Log IU / mL. It is more preferable.
  • the cutoff value of the IFN- ⁇ 3 concentration is, for example, 10 pg / mL, 11 pg / mL, 12 pg / mL, 13 pg / mL, 14 pg / mL, 15 pg / mL, 16 pg / mL, 17 pg / mL, It is possible to select from the group consisting of 18 pg / mL, 19 pg / mL, 20 pg / mL, 21 pg / mL, 22 pg / mL, 23 pg / mL, 24 pg / mL, and 25 pg / mL, and cut off the HBs antigen concentration Values are, for example, 2.5 Log IU / mL, 2.6 Log IU / mL, 2.7 Log IU / mL, 2.8 Log IU / mL, 2.9 Logs anti
  • the interferon therapeutic effect prediction method of the present invention can be used as an auxiliary method for predicting interferon therapeutic effect. That is, the method of the present invention can be used as an assisting method for predicting the therapeutic effect for a doctor to treat interferon. Moreover, the interferon therapeutic effect prediction method of the present invention is performed in vitro using a sample isolated from an HBV-infected patient. That is, the interferon therapeutic effect prediction method is not a diagnostic method performed using a living body but an inspection method performed outside the living body.
  • the IFN- ⁇ 3 concentration and the HBs antigen concentration As a prediction method that combines the IFN- ⁇ 3 concentration and the HBs antigen concentration, it can be performed as follows. First, the IFN- ⁇ 3 concentration and HBs antigen concentration of blood derived from an HBV-infected patient who is being treated with a nucleic acid analog preparation (particularly adefovir and tenofovir) are measured. It can be predicted that interferon therapy is likely to be effective for HBV-infected patients whose IFN- ⁇ 3 concentration is above or above the cutoff and above the cutoff and the HBs antigen concentration is below the cutoff or below the cutoff. Therefore, interferon treatment is recommended for these patients.
  • HBV-infected patient whose antigen concentration is above the cut-off or exceeds the cut-off can be used as a material for determining whether or not to perform the interferon treatment by informing that there is a possibility that the interferon treatment is effective.
  • the interferon treatment effect prediction method of the present invention can be used as a policy decision method for interferon treatment. Therefore, interferon treatment can be performed following prediction by the interferon therapeutic effect prediction method of the present invention.
  • a method for treating a hepatitis B virus-infected patient can be carried out, comprising the step of (3) administering an interferon to an HBV-infected patient whose interferon therapeutic effect is predicted.
  • the HBV-infected patient is preferably an HBV-infected patient determined to have a high possibility of effective interferon treatment effect.
  • Interferon therapeutic effect prediction method second embodiment Another embodiment of the interferon therapeutic effect prediction method of the present invention includes (1) measurement of IFN- ⁇ 3 concentration and HBs antigen concentration in a specimen derived from an HBV-infected patient. And (2) comparing the measured HBs antigen concentration with a preset cut-off value, and if the HBs antigen concentration is below the cut-off value or below the cut-off value, interferon treatment may be effective. If the HBs antigen concentration is predicted to be high and exceeds the cut-off value, the measured IFN- ⁇ 3 concentration is further compared with a preset cut-off value, and the IFN- ⁇ 3 concentration is greater than or equal to the cut-off value.
  • interferon therapy Predicting that interferon therapy is likely to be effective if an off-value is exceeded.
  • it can be carried out in the same manner as the “interferon treatment”, “sequential therapy”, and “(1) measuring step of IFN- ⁇ 3 concentration and HBs antigen concentration” in the first embodiment.
  • interferon treatment is effective when the HBs antigen concentration is lower than the cut-off value or less than the cut-off value compared to the previously set cut-off value.
  • the measured IFN- ⁇ 3 concentration is further compared with a preset cutoff value, and IFN- ⁇ 3
  • the setting of the cut-off value and the like can be performed in the same manner except that it is predicted that there is a high possibility that the interferon treatment is effective when the concentration is equal to or higher than the cut-off value or exceeds the cut-off value.
  • composition for treatment of hepatitis B The pharmaceutical composition for treatment of hepatitis B of the present invention is predicted to have high possibility that the interferon treatment is effective by the interferon treatment effect prediction method of the present invention. It is administered to patients with hepatitis virus infection.
  • the pharmaceutical composition for treating hepatitis B contains interferon as an active ingredient.
  • the interferon contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used for the treatment of hepatitis B, and examples include interferon- ⁇ , PEGylated interferon- ⁇ , interferon ⁇ , or interferon ⁇ . Particularly preferably PEGylated interferon- ⁇
  • the dose of the pharmaceutical composition for treating hepatitis B of the present invention is not particularly limited.
  • 50 ⁇ g to 400 ⁇ g / week can be administered by injection.
  • the administration period is not particularly limited, but is, for example, 12 to 72 weeks, more preferably 24 to 60 weeks, and further preferably 36 to 48 weeks.
  • the dosage form of the pharmaceutical composition for treating hepatitis B of the present invention is not particularly limited.
  • powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts Oral agents such as pills or pills, or injections, and the like for example, in the preparation of an injection, in addition to the active ingredient, for example, a water-soluble solvent such as physiological saline or Ringer's solution, a water-insoluble solvent such as vegetable oil or fatty acid ester, an isotonic agent such as glucose or sodium chloride, Solubilizers, stabilizers, preservatives, suspending agents, or emulsifiers can be optionally used.
  • a water-soluble solvent such as physiological saline or Ringer's solution
  • a water-insoluble solvent such as vegetable oil or fatty acid ester
  • an isotonic agent such as glucose or sodium chloride
  • the pharmaceutical composition for treating hepatitis B according to the present invention is not limited, but is preferably used in sequential therapy in which interferon treatment is performed after treatment with a nucleic acid analog preparation. This is because administration of a nucleic acid analog preparation, particularly adefovir or tenofovir, increases IFN- ⁇ 3 concentration in HBV-infected patients. That is, the pharmaceutical composition for treating hepatitis B of the present invention is preferably used as a method for administering interferon after administration of adefovir and tenofovir.
  • Interferon can be used in a method for treating hepatitis B.
  • the method for treating hepatitis B includes a step of administering interferon to a patient infected with hepatitis B virus, which is predicted to be highly likely to be effective in interferon treatment by the IFN treatment effect prediction method.
  • interferon is produced by the method for predicting therapeutic effect of interferon, and a pharmaceutical composition for treating hepatitis B to be administered to a patient infected with hepatitis B virus, which is predicted to be highly effective for interferon therapy.
  • the interferon of the present invention is an interferon for use in a method for treating a patient infected with hepatitis B virus, which is predicted to have a high possibility that the interferon treatment is effective by the interferon treatment effect prediction method.
  • the interferon therapeutic effect prediction kit of the present invention includes an IFN- ⁇ 3 concentration measurement reagent and an HBs antigen concentration measurement reagent.
  • an IFN- ⁇ 3 concentration measuring reagent an anti-IL-28B monoclonal antibody that binds to major IL-28B and minor IL-28B and does not bind to IL-28A as described in the column of [1] Interferon therapeutic effect prediction method above (A) or an antigen-binding fragment thereof, or an anti-IL-28B monoclonal antibody (B) that binds to major IL-28B and does not bind to minor IL-28B and IL-28A (B) or an antigen-binding fragment thereof is preferred.
  • the monoclonal antibody may be bound to a carrier or dissolved in a buffer according to the measurement method of the kit.
  • examples of the carrier include sepharose, cellulose, or agarose.
  • the shape of the carrier is not particularly limited, but carriers in the form of particulate beads, plates, gels and the like can be used.
  • the method for analyzing the IFN- ⁇ 3 concentration measuring reagent is an immunological method using a labeled antibody (eg, enzyme immunoassay, chemiluminescence immunoassay, fluorescent antibody method, or radioimmunoassay).
  • the antibody can be contained in the form of a labeled antibody or a labeled antibody fragment labeled with a labeling substance.
  • Specific examples of the labeling substance include peroxidase, alkaline phosphatase, ⁇ -D-galactosidase and the like as enzymes.
  • an enzyme, a chemiluminescent substance, or the like it is not possible to provide a measurable signal by itself, and therefore it is preferable to select and include a corresponding appropriate substrate.
  • the IL-28B (IFN- ⁇ 3) concentration measuring reagent can contain IL-28B (IFN- ⁇ 3) as a standard substance. Further, the reagent of the present invention can be used to specify that major and minor IL-28B (IFN- ⁇ 3) can be specifically measured, or to measure major IL-28B (IFN- ⁇ 3) specifically. Can be included. Such a description may be attached to the container of the kit.
  • the reagent for measuring the HBs antigen concentration may be a reagent having the same structure as the reagent for measuring the concentration of IL-28B except that it contains an anti-HBs antigen antibody that specifically binds to the HBs antigen instead of the anti-IL-28B monoclonal antibody. it can. Kits for HBs antigen concentration measurement methods are commercially available. For example, Architect HBsAgQT (Abbott Japan), Lumipulse II HBsAg (Fujirebio), Cobascore HBsAgII-EIA (Roche Diagnostics), Enzygnost HBsAg5.0 ( Can be used as a reagent for measuring HBs antigen concentration.
  • anti-IL-28B antibody and anti-HBs antibody can be used for the production of an interferon therapeutic effect prediction kit.
  • IFN- ⁇ 3 The measurement of IFN- ⁇ 3 was performed as follows according to Example 6 of JP2013-136530A.
  • Monoclonal antibody TA2602 was diluted with 10 mM HEPES buffer (pH 7.4: hereinafter referred to as HBS buffer) containing 150 mM NaCl to a final concentration of 2 ⁇ g / mL, and 96 well microplate (manufactured by NUNK) per well Dispense 100 ⁇ L each. After standing overnight at 4 ° C., the plate was washed twice with 400 ⁇ L of HBS buffer, and 400 ⁇ L of HBS buffer containing 0.1% casein-Na (hereinafter referred to as blocking solution) was added. Let stand for 30 minutes.
  • the plate was washed twice with 400 ⁇ L of an HBS buffer solution (hereinafter referred to as a washing solution) containing 0.05% Tween20.
  • a washing solution containing 0.05% Tween20.
  • dilution buffer containing 0.1% casein-Na, 1% mouse serum, 1% BSA, and 0.05% Tween20
  • the solution was diluted to 50 mL per well and reacted at room temperature for 1 hour with stirring.
  • the concentration of IFN- ⁇ 3 is 0 pg / mL or more and less than 1 pg / mL, 1 pg / mL or more and less than 5 pg / mL, 5 pg / mL or more and less than 20 pg / mL, and The graph was divided into 20 pg / mL or more (FIG. 2). As a result, many of the patients whose IFN- ⁇ 3 concentration was 20 pg / mL were patients who received adefovir or tenofovir treatment.
  • Example 1 IFN- ⁇ 3 was measured in 83 HBV-infected patients who had been treated with nucleic acid analog preparations after treatment with nucleic acid analog preparations (immediately before administration of PEG-IFN) according to Reference Example 1 above.
  • HBsAg was measured using HBsAg QT. After discontinuing the nucleic acid analog preparation as a sequential therapy, subcutaneous injection of PEG-IFN ⁇ , 90-180 ⁇ g once a week was continued for 48 weeks. HBsAg was measured at the end of PEG-IFN to determine the effect. The results are shown in Table 1-1 and Table 1-2.
  • Example 2 In this example, the cutoff value of the IFN ⁇ 3 concentration was 20 pg / mL, and the cutoff value of the HBs antigen concentration was less than 3 LogIU / mL.
  • the results are shown in FIG. In HBV-infected patients with an IFN- ⁇ 3 concentration of 20 pg / mL or higher and an HBs antigen concentration of less than 3 Log IU / mL, 4 out of 5 patients had HBs antigen decreased to less than 2 Log IU / mL at the end of PEG-IFN.
  • Example 3 In this example, the cutoff value of the IFN ⁇ 3 concentration was 20 pg / mL, and the cutoff value of the HBs antigen concentration was less than 3.5 Log IU / mL.
  • the results are shown in FIG.
  • 7 of 11 patients had HBs antigen decreased to less than 2 Log IU / mL at the end of PEG-IFN.
  • Example 4 the prognosis of treatment, and IFN ⁇ 3 and other parameters were analyzed for 69 patients who were further subjected to sequential therapy using PEG-IFN.
  • the decrease in HBs antigen was analyzed in two groups of 0.6 log IU / mL / year or more or less than 0.6 log IU / mL / year.
  • HBs antigen 5 shows the reduction of HBs antigen by dividing HBs antigen into 4 combinations of less than 2.9 log IU / mL, or more than 2.9 log IU / mL, and IFN- ⁇ 3 level less than 15 pg / mL, or more than 15 pg / mL. Of 0.6 log IU / mL / year or more was effective. When the HBs antigen was less than 2.9 log IU / mL, both groups with IFN- ⁇ 3 levels less than 15 pg / mL and IFN- ⁇ 3 levels greater than 15 pg / mL showed an effective rate of therapeutic effect of about 40%. .
  • the group having an IFN- ⁇ 3 level of 15 pg / mL or more showed an effective rate of the therapeutic effect of about 40%.
  • the group with IFN- ⁇ 3 levels less than 15 pg / mL had an effective rate of treatment effect of 10% or less.
  • the therapeutic effect of interferon can be estimated beforehand, and the judgment material of whether to perform an interferon treatment or to continue a nucleic acid analog formulation can be provided.
  • the treatment cost of interferon treatment can be suppressed.

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Abstract

L'objet de la présente invention est de pourvoir à un procédé permettant de prédire les patients chez lesquels il est fortement probable qu'une thérapie séquentielle impliquant une thérapie basée sur l'interféron à la suite d'une thérapie basée sur des analogues d'acides nucléiques soit efficace. La solution selon l'invention porte sur un procédé permettant de prédire l'efficacité thérapeutique de l'interféron, qui est caractérisé en ce qu'il comprend : (1) une étape de mesure de la concentration en IFN-λ3 et de la concentration en antigènes HBs dans un analyte dérivé d'un patient infecté par le VHC ; et (2) une étape de comparaison de la concentration en IFN-λ3 et de la concentration en antigènes HBs à des valeurs de coupure respectivement prédéfinies, et, dans le cas où la concentration en IFN-λ3 n'est pas inférieure, ou est supérieure à la valeur de coupure, et où la concentration en antigènes HBs n'est pas supérieure, ou est inférieure à la valeur de coupure, la prédiction selon laquelle il est fortement probable que la thérapie par l'interféron soit efficace.
PCT/JP2016/060553 2015-03-30 2016-03-30 Procédé de prédiction de l'efficacité d'une thérapie basée sur l'interféron, et composition médicamenteuse destinée aux patients souffrant d'hépatite b l'utilisant Ceased WO2016159178A1 (fr)

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JP2017510154A JP6738319B2 (ja) 2015-03-30 2016-03-30 インターフェロン治療効果予測方法及びそれを用いたｂ型肝炎患者の治療用医薬組成物

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JP2015-068502 2015-03-30

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CN115466802A (zh) * 2022-10-28 2022-12-13 北京大学 Tp53bp2在调控干扰素信号通路及抗病毒中的用途

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115466802A (zh) * 2022-10-28 2022-12-13 北京大学 Tp53bp2在调控干扰素信号通路及抗病毒中的用途
CN115466802B (zh) * 2022-10-28 2023-12-12 北京大学 Tp53bp2在调控干扰素信号通路及抗病毒中的用途

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