WO2023040910A1 - Réactif de détection de l'hépatite c et du cancer hépatique, et son application dans la détection de l'hépatite c et du cancer hépatique - Google Patents

Réactif de détection de l'hépatite c et du cancer hépatique, et son application dans la détection de l'hépatite c et du cancer hépatique Download PDF

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WO2023040910A1
WO2023040910A1 PCT/CN2022/118795 CN2022118795W WO2023040910A1 WO 2023040910 A1 WO2023040910 A1 WO 2023040910A1 CN 2022118795 W CN2022118795 W CN 2022118795W WO 2023040910 A1 WO2023040910 A1 WO 2023040910A1
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reagent
hepatitis
liver cancer
cancer detection
preparation
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PCT/CN2022/118795
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English (en)
Chinese (zh)
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陈翠英
王蕾
谈宗男
苏瑞
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江苏先思达生物科技有限公司
先思达（南京）生物科技有限公司
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Publication of WO2023040910A1 publication Critical patent/WO2023040910A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/924—Hydrolases (3) acting on glycosyl compounds (3.2)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/978—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2440/00—Post-translational modifications [PTMs] in chemical analysis of biological material
    • G01N2440/38—Post-translational modifications [PTMs] in chemical analysis of biological material addition of carbohydrates, e.g. glycosylation, glycation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/08—Hepato-biliairy disorders other than hepatitis
    • G01N2800/085—Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin

Definitions

  • the invention belongs to the technical field of biomedicine and relates to a detection method of hepatitis C liver cancer, in particular to a detection method of hepatitis C liver cancer based on the specific fingerprint of serum glycoprotein oligosaccharide chain detection (G-Test).
  • G-Test serum glycoprotein oligosaccharide chain detection
  • Hepatitis C virus referred to as hepatitis C for short, is a kind of viral hepatitis caused by hepatitis C virus (HCV) infection, which is mainly transmitted through blood transfusion, acupuncture, drug abuse and other ways.
  • HCV hepatitis C virus
  • the pathological changes of hepatitis C are very similar to those of hepatitis B, with liver cell necrosis and lymphocyte infiltration being the main ones.
  • Fibrous tissue proliferation in the portal area can occur in chronic hepatitis, leading to chronic inflammation, necrosis and fibrosis of the liver, and some patients may develop liver cirrhosis or even hepatocellular carcinoma (HCC).
  • Hepatitis C is closely related to the occurrence of liver cancer, and the transition between the two is a relatively long process, which is divided into four stages: acute infection - chronic infection - liver cirrhosis - liver cancer.
  • the initial stage of HCV infection (2 to 12 weeks) is the acute stage, and the infected person may have no obvious symptoms. 1 to 3 weeks after infection with HCV, HCV RNA can be detected in peripheral blood, and only a few people can clear the virus by themselves and recover.
  • hepatitis C antibody is the main indicator for the diagnosis of hepatitis C virus.
  • the anti-HCV antibody appears slowly, usually 2 to 6 months after the onset, or even 1 year before turning positive, so it cannot be used as an early diagnosis method.
  • ALT single alanine aminotransferase
  • Liver function including serum ALT, aspartate aminotransferase (AST), total bilirubin, direct bilirubin, indirect bilirubin, albumin, globulin, cholinesterase , alkaline phosphatase, transpeptidase, etc.
  • AST aspartate aminotransferase
  • Hepatitis C virus antibody against HCV 3.
  • liver imaging Abdominal ultrasonography of liver, gallbladder and spleen to check whether there is chronic damage to the liver. If necessary, perform abdominal enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) examination to understand the degree of damage. 5.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • Liver transient elastic wave scanning is a non-invasive examination that can be used to evaluate the degree of liver fibrosis in patients with chronic hepatitis C. Assessment of liver fibrosis in patients with hepatitis C is important for determining treatment options. 6.
  • Liver biopsy is the gold standard for assessing liver inflammation grade and fibrosis stage.
  • HCV-RNA in blood can be directly detected by polymerase chain reaction (PCR), which can be used for early diagnosis of HCV infection.
  • HCV-RNA and anti-HCV antibody are positive or HCV-RNA positive alone can be diagnosed as hepatitis C virus.
  • patients with chronic hepatitis C belong to the high-risk group of liver cancer.
  • the high-risk group of liver cancer refers to those who are over 35 years old, have serological evidence of HBV or HCV infection, or have a history of chronic hepatitis.
  • Alpha-fetoprotein (AFP) detection + liver ultrasound examination is used for early detection of liver cancer.
  • AFP detection and liver ultrasonography it is easy to cause false negatives and delay the diagnosis. Therefore, there is an urgent need for methods with high sensitivity and high specificity for the early detection of hepatitis C liver cancer.
  • Protein glycosylation is the most common post-translational modification of proteins. It is a process in which sugars are transferred to proteins and special amino acid residues on proteins to form glycosidic bonds under the action of glycosyltransferases. Most glycoproteins are secreted proteins, widely present in cell membranes, interstitial cells, plasma, and mucus. Some enzymes and hormones are glycoproteins. Glycoproteins have a variety of biological functions. Some glycoproteins such as trocollagen are structural proteins.
  • glycoproteins are glycoproteins
  • fiber Proproteins are glycoproteins
  • Lectins have the ability to aggregate cells, and sugar chains can also stabilize peptide chains. Another important function of glycoprotein is to directly or indirectly participate in various recognition phenomena on the cell surface.
  • sugar chains Due to the importance of sugar chains in glycoproteins for maintaining biological functions of the body, changes in sugar chains help to elucidate the molecular mechanisms of abnormal biobehaviors such as inflammation, tumor cell invasion and metastasis of surrounding tissues. At present, changes in N-glycan chains have been found in various tumors.
  • Sugar chains are important bioinformatics molecules that play unique roles in many physiological and pathological processes.
  • the sugar chain structure is very complex and has microscopic heterogeneity. Its analysis and structural elucidation have always been the bottleneck of glycobiology research.
  • the analysis methods of sugar chain structure are developing rapidly, mainly including: (1) High performance liquid chromatography (HPLC): high resolution, fast detection speed, high repeatability, high performance liquid chromatography column can be used repeatedly, but column efficiency will decrease It becomes lower with the increase of the number of uses, and the mobile phase is toxic, and the operation of the equipment requires strictly trained professionals, and the equipment is relatively expensive, and the solvent needs to be strictly purified; (2) mass spectrometry (MS): mass spectrometry has high sensitivity, It can obtain a variety of structural information and is suitable for the analysis of mixtures.
  • HPLC High performance liquid chromatography
  • MS mass spectrometry
  • capillary electrophoresis capillary electrophoresis is low in cost, high in column efficiency, high in sensitivity, fast in speed, and easy to inject. The amount is small and the operation is simple, but the repeatability is not high and the stability is not as good as HPLC.
  • the G-Test detection method is based on the capillary microelectrophoresis technology (DSA-FACE) of the DNA analyzer. After the N-sugar chain of the glycoprotein in the prostatic fluid sample is fluorescently labeled, it is separated by capillary microelectrophoresis. The content of the N-oligosaccharide chain obtained by measuring the fluorescent signal is the fingerprint spectrum (G-Test spectrum for short).
  • This detection technology has the advantages of high sensitivity, simple operation, trace volume (2 ⁇ L serum), high repeatability, good stability, high throughput (96-well plate) and other sugar chain analysis technologies, and is suitable for general laboratory departments. It is expected to be used in clinical promotion.
  • the purpose of the present invention is to provide a detection reagent for hepatitis C liver cancer.
  • the reagent measures the glycome profile in serum, quantifies the peak value, and performs statistical analysis, thereby providing a method for establishing a model of the serum glycome profile of hepatitis C liver cancer.
  • a hepatitis C liver cancer detection reagent which is formed by mixing the following reagents:
  • Reagent A prepared by adding SDS with a mass concentration of 0.5 to 5% in ammonium bicarbonate solution with a concentration of 10 mM;
  • Reagent B It is prepared by mixing 0.01 ⁇ 10U/10 ⁇ L glucosamidase and 0.01 ⁇ 10U/10 ⁇ L sialidase, and the pH value of the mixed solution is 4 ⁇ 9;
  • Reagent C Prepared by dissolving 8-aminopyrene-1,3,6-trisulfonic acid in DMSO, the concentration is 0.01mM ⁇ 1M;
  • Reagent D stop solution.
  • the volume ratio of the reagent A, reagent B and reagent C is 2:2:1.
  • a preparation method of hepatitis C liver cancer detection reagent comprising the following steps:
  • Step 3 Separation and analysis of oligosaccharide chains
  • the denaturation temperature in the preparation of the step 1 oligosaccharide is not lower than 75°C, and the incubation temperature is not lower than 25°C.
  • the temperature of fluorescent labeling in the second step is 50-90°C.
  • composition detects hepatitis C liver cancer through the ratio of (NGA2F+NA2F)/NA3.
  • the invention provides a method for establishing a serum glycoprotein N-glycan group pattern model of hepatitis C liver cancer, and performs statistical analysis by measuring the specific fingerprint pattern of the serum glycoprotein oligosaccharide chain G-Test.
  • Test samples Serum from patients with hepatitis C liver cancer caused by hepatitis C virus and normal controls.
  • Reagent A prepared by adding SDS with a mass concentration of 0.5 to 5% in ammonium bicarbonate solution with a concentration of 10 mM;
  • Reagent B It is prepared by mixing 0.01 ⁇ 10U/10 ⁇ L glucosamidase and 0.01 ⁇ 10U/10 ⁇ L sialidase, and the pH value of the mixed solution is 4 ⁇ 9;
  • Reagent C Prepared by dissolving 8-aminopyrene-1,3,6-trisulfonic acid in DMSO, the concentration is 0.01mM ⁇ 1M;
  • Reagent D stop solution.
  • Step 3 Separation and analysis of oligosaccharide chains
  • the composition detects hepatitis C liver cancer through the ratio of (NGA2F+NA2F)/NA3.
  • the method of the present invention adopts the G-Test detection method with high sensitivity, simple operation, only needs a small amount of sample, high repeatability, good stability and high throughput, and has established a significant difference between patients with hepatitis C liver cancer and normal controls.
  • -Model of the glycome map In subsequent applications, the N-glycan profile of the serum to be tested is calculated using the profile model established by this method, which can detect whether the sample has hepatitis C liver cancer. Compared with the prior art, it has higher accuracy, and the AUC area of the ROC curve for the hepatitis C liver cancer detection model reaches 0.864.
  • the N-glycan map model constructed based on the method of the present invention can allow many patients to receive routine and non-invasive testing, and help doctors and patients detect the occurrence and progression of liver cancer caused by hepatitis C virus in a timely manner, and it is expected to be widely used in clinical practice .
  • Figure 1 is the serum glycoprotein N-glycan map of the normal control group and the hepatitis C liver cancer group; the abbreviations of the oligosaccharides in the map are respectively expressed as: NGA2F, galactose missing two antennae containing core fucose (Agalacto core- ⁇ -1 , 6-fucosylated biantennary); NA2F, Bigalacto core- ⁇ -1, 6-fucosylated biantennary); NA3, triantennary.
  • Test samples Serum from patients with hepatitis C liver cancer caused by hepatitis C virus and normal controls.
  • Reagent A prepared by adding SDS with a mass concentration of 0.5 to 5% in ammonium bicarbonate solution with a concentration of 10 mM;
  • Reagent B It is prepared by mixing 0.01 ⁇ 10U/10 ⁇ L glucosamidase and 0.01 ⁇ 10U/10 ⁇ L sialidase, and the pH value of the mixed solution is 4 ⁇ 9;
  • Reagent C Prepared by dissolving 8-aminopyrene-1,3,6-trisulfonic acid in DMSO, the concentration is 0.01mM ⁇ 1M;
  • Reagent D stop solution.
  • Step 3 Separation and analysis of oligosaccharide chains
  • G-Test detection technology was used to process the collected serum samples of 66 cases of hepatitis C liver cancer patients and normal control group, including 36 cases of serum samples of hepatitis C liver cancer patients and 30 cases of serum samples of normal control group. Statistical analysis was carried out on the N-glycan profile obtained from samples measured by G-Test detection technology.
  • the serum N-glycan profile shows about 9 N-glycan peaks, and the sugar chains show different mobility due to different molecular sizes, that is, the Different peaks represent different oligosaccharide chains, and the measured peak heights represent the relative concentration of oligosaccharide chains.
  • Figure 1A is the normal control group
  • Figure 1B is the hepatitis C liver cancer group.
  • the composition of the N-glycan profile detects hepatitis C liver cancer by the ratio of (NGA2F+NA2F)/NA3.

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  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne un réactif de détection de l'hépatite C et du cancer hépatique et son procédé de préparation. Le réactif de détection est fabriqué en mélangeant les réactifs suivants, le réactif A, préparé en ajoutant du SDS possédant une concentration massique de 0,5 à 5,0 % dans une solution de bicarbonate d'ammonium ayant une concentration de 10 mM ; le réactif B, préparé en mélangeant 0,01 à 10 U / 10 μL de glycosaminoacylase avec 0,01 à 10 U/ 10 μL de sialidase, la solution mélangée possédant une valeur de pH de 4 à 9 ; le réactif C, préparé en dissolvant de l'acide 8-aminopyrène-1,3,6-trisulfonique dans du diméthylsulfoxyde (DMSO), la concentration étant de 0,01 mM à 1 M ; et le réactif D, qui est une solution d'arrêt ; un graphique de glucome d'un sérum est déterminé au moyen du réactif de détection, un pic est quantifié et une analyse statistique est effectuée, et un procédé pour construire un modèle de graphique de glucome de sérum d'hépatite C et de cancer hépatique est présenté pour détecter l'hépatite C et le cancer hépatique.
PCT/CN2022/118795 2021-09-15 2022-09-14 Réactif de détection de l'hépatite c et du cancer hépatique, et son application dans la détection de l'hépatite c et du cancer hépatique WO2023040910A1 (fr)

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