WO2019069980A1 - Procédé de détection du cancer colorectal - Google Patents

Procédé de détection du cancer colorectal Download PDF

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Publication number
WO2019069980A1
WO2019069980A1 PCT/JP2018/037040 JP2018037040W WO2019069980A1 WO 2019069980 A1 WO2019069980 A1 WO 2019069980A1 JP 2018037040 W JP2018037040 W JP 2018037040W WO 2019069980 A1 WO2019069980 A1 WO 2019069980A1
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igg
amount
red blood
blood cells
bound
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PCT/JP2018/037040
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Japanese (ja)
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晋一郎 川本
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晋一郎 川本
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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
    • 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
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

Definitions

  • the present invention relates to a method for detecting colon cancer.
  • Colorectal cancer is a generic term for carcinomas that occur in the large intestine (colon, rectum, anus). Methods of detection of colorectal cancer include fecal occult blood test and endoscopy, which have been shown to be useful in randomized controlled trials. However, since the fecal occult blood test detects cancer based on hemorrhage, it may miss colon cancer that does not accompany hemorrhage, and for the subject, it is complicated to collect stool prior to the test. Endoscopic examination is generally performed as a detailed examination of colon cancer, but it requires food restriction and pretreatment with laxative before the examination, and subjects such as inserting an endoscope into the intestine and biopsy accompanied by invasion, etc.
  • Non-patent Document 1 a method for detecting DNA from blood and stools
  • ELISA enzyme-linked immunosorbent assay
  • Senescent cell antigen is immunologically related to band 3. Proc. Natl. Acad. Sci. USA 1983; 80; Lutz HU. Naturally Occurring Anti-Band 3 Antibodies in Clearance of Senescent and Oxidatively Stressed Human Red Blood Cells. Transfus Med Hemother. 2012 Oct; 39 (5): 321-327.
  • An object of the present invention is to provide a simple method for detecting colorectal cancer that can replace or complement conventional detection methods.
  • the inventors of the present invention conducted intensive studies to solve the above problems and found that in colon cancer patients, the amount of immunoglobulin IgG bound on the erythrocyte membrane is significantly higher than in other cancer patients and healthy people.
  • the present invention has been achieved.
  • the present application provides a method of detecting colon cancer in a subject, comprising measuring the amount of immunoglobulin G (IgG) bound to red blood cells in a sample from the subject.
  • IgG immunoglobulin G
  • the present application provides a detection kit for colon cancer, which comprises a labeled anti-IgG antibody for measuring the amount of IgG bound to erythrocytes.
  • bonded with the erythrocyte in the colon cancer patient group, the stomach cancer patient group, and the healthy subject group by the flow cytometry method is shown. It is the ROC curve obtained by the logistic regression etc. which used the result of having measured the quantity of IgG couple
  • the results of the Coombs test for a group of healthy people are shown.
  • the results of the Coombs test on gastric cancer patient groups are shown.
  • the results of the Coombs test for a group of colon cancer patients are shown.
  • the inventor has clarified the following matters as a result of measuring the amount of IgG bound to erythrocytes in blood samples of patients with colon cancer, stomach cancer and healthy subjects using flow cytometry. I made it. (1) The amount of IgG bound to erythrocytes of colorectal cancer patients is significantly higher than the amount of IgG in healthy subjects. (2) The amount of IgG bound to erythrocytes of colorectal cancer patients is significantly higher than that of gastric cancer patients. (3) There is no significant difference between the amount of IgG in gastric cancer patients and the amount of IgG in healthy subjects.
  • Anion exchanger 1 (AE1, also called band 3) is a membrane transport protein abundant in erythrocyte membranes. Usually, AE1 detects the carbon dioxide dissolved in blood on the erythrocyte membrane and functions to accelerate the release of oxygen from the hemoglobin in the erythrocyte. It is known that this AE1 is ectopically expressed in colon cancer cells (Non-patent Document 3).
  • AIHA Autoimmune hemolytic anemia
  • red blood cells circulate in the body while being exposed to oxidative stress, are aged, and are finally captured by macrophages.
  • One of the mechanisms defining the life span of this red blood cell is opsonization by the reaction of AE1 with a natural antibody in the serum that recognizes it.
  • a natural antibody (anti-AE1 IgG) in serum binds to AE1 on the cell membrane of senescent red blood cells, and senescent red blood cells are fed by macrophages having a receptor for the antibody (non-patent documents 4 and 5).
  • autoantibodies bind to AE1 present in the erythrocyte membrane of colon cancer patients based on the finding that autoantibodies (IgG) against AE1 are produced in colon cancer patients, and as a result colon cancer patients It is inferred that IgG bound to the erythrocyte membrane is increasing.
  • the estimation of the mechanism does not limit the present invention.
  • the invention provides a method of detecting colon cancer in a subject comprising measuring the amount of IgG bound to red blood cells in a sample from the subject.
  • the subject in the method of the present invention is not particularly limited, and is preferably a mammal, more preferably a human.
  • Such subjects may include, for example, those who have not been diagnosed with cancer (eg, those who have no disease being treated, or patients with diseases other than cancer) and those who have cancer other than colon cancer.
  • detection means to relate the amount of IgG bound to erythrocytes to the possibility of colon cancer in a subject. For example, based on the amount of IgG bound to erythrocytes, it is determined that the subject has or is likely to have colon cancer, or that cancer other than colon cancer has metastasized to colon or is likely to have it. Means
  • the method of the present invention can be used to examine the possibility of having colon cancer, for example, at a health checkup, in persons who have not been diagnosed with cancer. In those who have cancer other than colon cancer, the method of the present invention can be used to investigate the possibility that the cancer has metastasized to the large intestine.
  • the sample derived from the subject used in the method of the present invention is not particularly limited as long as it is collected from the subject and contains red blood cells.
  • Preferred examples include blood and lymph, and more preferably blood.
  • the state is not particularly limited as long as “red blood cells” have a binding site of IgG, and examples thereof include red blood cells in which red blood cells are hemolyzed in addition to red blood cells. It may be a ghost. Red blood cells or erythrocyte ghosts may be disrupted to obtain the amount of IgG in the state of erythrocyte membranes obtained.
  • the method for measuring the amount of IgG bound to erythrocytes is not particularly limited, and can be carried out by methods known to those skilled in the art. As long as the purpose of the present method for detecting colon cancer can be achieved, the method of measuring the amount of IgG bound to the red blood cells may be a quantitative method or a qualitative method. It is desirable to have.
  • Examples of the method of measuring the amount of the IgG include immunological methods, such as radioimmunoassay (RIA), immunofluorescence assay (FIA), immunoluminescence assay, enzyme immunoassay (eg, Enzyme immunoassay) Immunoassay (EIA), Enzyme-linked Immunosorbent assay (ELISA), immunochromatography, latex particle agglutination), flow cytometry (with immunological techniques), Western blotting, and the like.
  • immunological methods such as radioimmunoassay (RIA), immunofluorescence assay (FIA), immunoluminescence assay, enzyme immunoassay (eg, Enzyme immunoassay) Immunoassay (EIA), Enzyme-linked Immunosorbent assay (ELISA), immunochromatography, latex particle agglutination), flow cytometry (with immunological techniques), Western blotting, and the like.
  • preferred methods include ELISA and flow cytometry. Specific operating conditions of each measurement method
  • Radioactive substances that can be used for labeling in radioimmunoassay include, for example, 125 I, 131 I, 14 C, 3 H, 35 S, and 32 P.
  • fluorescent substances that can be used for labeling in immunofluorescence assay (FIA) include Eu (Europium), FITC, TMRITC, Cy3, PE, Texas-Red, and the like.
  • luminescent materials that can be used for labeling in immunoluminescence measurement include luminol, luminol derivatives, luciferin and the like.
  • HRP horseradish peroxidase
  • ALP alkaline phosphatase
  • GO glucose oxidase
  • FITC fluorescein isothiocyanate
  • PE phycoerythrin
  • APC Allophycocyanin
  • PerCP-Cy5.5, PE-Cy7, APC-H7 and the like can be mentioned.
  • a biotin-avidin system can also be used to bind an antibody or an antigen to these labeled substances.
  • anti-IgG antibodies may be used when immunological methods are used.
  • Anti-IgG antibodies can be prepared by methods known to those skilled in the art, and may be commercially available.
  • An anti-IgG antibody labeled with the above-mentioned labeling substance can be used, and such an anti-IgG antibody can be prepared by methods well known to those skilled in the art, and may be commercially available.
  • the anti-IgG antibody may be a polyclonal antibody or a monoclonal antibody, but in view of high sensitivity, the polyclonal antibody is desirable. Examples of preferred anti-IgG antibodies include polyclonal anti-human IgG-FITC (manufactured by DAKO, code-Nr. F0202).
  • Flow cytometry method In one embodiment of the method of the present invention, when the sample derived from the subject is blood, and flow cytometry is employed, for example, blood to plasma component layer, prior to flow cytometry.
  • the white blood cell layer and the platelet layer are removed, and phosphate buffered saline (PBS) is added to the red blood cell layer to obtain a red blood cell suspension, which can be treated with, for example, an anti-IgG antibody labeled with FITC.
  • PBS phosphate buffered saline
  • the method for treating red blood cells with anti-IgG antibody is not particularly limited, and various treatment conditions such as the amount of red blood cells, treatment time of anti-IgG antibody, treatment temperature and the like may be appropriately determined according to flow cytometry conditions etc. it can.
  • the fluorescent dye and the fluorescent substance can be appropriately selected, for example, from the above examples, depending on the number of red blood cells to be detected, the setting of conditions of flow cytometry, and the like. By these operations, a suspension of red blood cells treated with anti-IgG antibody is obtained.
  • flow cytometry is performed using a suspension of red blood cells treated with anti-IgG antibody as a sample.
  • the operating method, operating conditions, and analysis conditions of the flow cytometer can be appropriately adjusted according to the flow cytometer and sample to be used.
  • FSC-A forward scattered light pulse area
  • SSC-A side scattered light pulse area
  • MFI mean fluorescence intensity
  • treating refers to selecting only a cell population of interest in a sample and creating a histogram of only the cells (also referred to as “setting a gate”).
  • the method may further comprise the step of correlating the amount of IgG bound to red blood cells with the likelihood of colon cancer in the subject.
  • the determination of the colon cancer potential of the subject may be performed by, for example, comparing the measured value of the IgG with a reference value or a preset cutoff value. It can be done by
  • the reference value is a measurement value of IgG bound to red blood cells in a sample (normal sample) derived from a non-colorectal cancer person to be compared.
  • non-colorectal cancer persons include healthy persons (persons with no disease being treated), persons with diseases other than cancer, and persons with cancer other than colon cancer and have not been pointed out for anemia Is preferred. It is preferable to use an average value of samples of a plurality of persons (more is preferable) for calculation of the reference value, for example, 2 or more persons, preferably 5 or more persons.
  • the subject has, for example, colon cancer or that cancer has metastasized to the colon.
  • the subject has, for example, a colon cancer when the measured value of IgG bound to erythrocytes of the subject is within a range consisting of a combination of appropriately selecting the upper limit value and the lower limit value below with respect to the reference value.
  • cancer has metastasized to the large intestine.
  • Upper limit 102%, 105%, 110%, 120%, 130%, 140%, 150%, 160%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900% ; Lower limit values: 101%, 102%, 105%, 110%, 120%, 130%, 140%, 150%, 160%, 200%, 300%, 400%, 500%, 600%.
  • the cutoff value can be determined, for example, as follows. First, the amount of IgG bound to red blood cells in a sample from a colorectal cancer patient is measured. At this time, it is preferable that the number of colorectal cancer patients to be targeted is large, for example, 2 or more, 5 or more, 10 or more, 20 or more, or 100 or more. It is also preferable to measure the amount of IgG bound to red blood cells in two or more non-colorectal cancer-derived samples (normal samples), and the number of non-colorectal cancer subjects targeted is, for example, two or more, There are 5 or more, 10 or more, 20 or more, or 100 or more.
  • the cutoff value of the amount of IgG bound to red blood cells is determined by statistical processing from the whole including both the sample group derived from colon cancer patients and the normal sample group. Examples of statistical processing include Youden Index and the like. When the measured value of IgG bound to erythrocytes of the subject is higher than the cut-off value, the subject may be judged to have, for example, colon cancer or that cancer has metastasized to the colon.
  • the amount of IgG bound to red blood cells in the blood sample is determined by flow cytometry, the amount of IgG can be calculated as the mean fluorescence intensity and has colon cancer
  • the cutoff value that distinguishes (or is likely to have) a person who does not have (or is likely to have) colon cancer is, for example, an average fluorescence intensity of 20 or more, 25 or more, 30 or more, 35 It may be 40 or more, 45 or more, 50 or more, 60 or more, or 65 or more. Alternatively, the cutoff value may be included within the following range: mean fluorescence intensity 20-65, 25-60, or 30-55, 32-40.
  • the cutoff value may be included in a range consisting of a combination of appropriately selecting the following upper limit value and lower limit value.
  • Upper limit average fluorescence intensity 65, 60, 55, 45, 40, 35, 32.3, 32;
  • Lower limit average fluorescence intensity 40, 32.3, 32, 30, 25, 20.
  • An example of a preferred cutoff value is mean fluorescence intensity 32.3.
  • the step of correlating the amount of IgG bound to erythrocytes with the likelihood of colon cancer in the subject comprises measuring the amount of IgG bound to erythrocytes from the same subject measured over time. You may do by comparing. For example, relative to the amount of said IgG measured in advance, compared with the amount of said IgG measured at intervals (eg after 1, 2, 3, 6, 12, 18 months, 2 years, 3 years) If there is a significant increase, the subject can be determined to have, for example, colon cancer or that cancer has metastasized to the colon.
  • the present application provides a detection kit for colon cancer comprising a labeled anti-IgG antibody for measuring the amount of IgG bound to erythrocytes.
  • the labeled anti-IgG antibody contained in the present detection kit is, for example, labeled with the labeling substance exemplified above according to the measuring method.
  • the kit of the present invention may contain, in addition to the labeled anti-IgG antibody, a container for a reagent or a test sample, and a label for which the kit has been shown to be used for detection of colon cancer. In addition, it may further include instructions for use in the method of detecting colon cancer using the labeled anti-IgG antibody.
  • Example 1 Measurement of the Amount of IgG Bound to Erythrocytes by Flow Cytometry There are no colorectal cancer patients (23), gastric cancer patients (11), and healthy people (20 years of age or older) Blood was collected from (5 persons) who did not indicate anemia, and the amount of IgG bound to erythrocytes was measured by the following method.
  • Example 2 Coombs test Colorectal cancer patients (23), gastric cancer patients (11), and healthy persons (persons 20 years of age or older who have no disease currently being treated and have not been pointed out for anemia) (5 Blood was collected from the n.) And IgG bound to erythrocytes was detected by agglutination reaction.
  • Test Tube Method 1. Test Tube Method (1) Put one drop of subject's red blood cells in 10 mL of phosphate buffered saline. (2) After mixing, centrifuge at 3,000 rpm for 2 to 5 minutes. (3) Remove the supernatant and resuspend the pellet in 10 mL of phosphate buffered saline. (4) After mixing, centrifuge at 3,000 rpm for 2 to 5 minutes. (5) Repeat (3) and (4) three times. (6) After removing the supernatant as much as possible, make 3-5% erythrocyte suspension with phosphate buffered saline. (7) Prepare one test tube for anti-IgG antibody, one for anti-C3d antibody, and one for negative control.

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Abstract

La présente invention concerne un procédé pour détecter un cancer colorectal chez un sujet, ledit procédé comprenant la mesure de la quantité d'immunoglobuline G (IgG) qui est liée à des globules rouges dans un échantillon prélevé du sujet.
PCT/JP2018/037040 2017-10-04 2018-10-03 Procédé de détection du cancer colorectal WO2019069980A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112394175A (zh) * 2019-08-15 2021-02-23 中山大学附属第六医院 IgG3检测试剂在制备结直肠癌诊断剂方面的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006516088A (ja) * 2002-09-18 2006-06-22 ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア 細胞上および生物学的混合物中の抗原の検出のための組成物、方法およびキット
JP2010078374A (ja) * 2008-09-24 2010-04-08 Olympus Corp 抗赤血球抗体の検出方法
WO2015158722A1 (fr) * 2014-04-15 2015-10-22 Université D'aix-Marseille Méthode de diagnostic ou de suivi d'un cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006516088A (ja) * 2002-09-18 2006-06-22 ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア 細胞上および生物学的混合物中の抗原の検出のための組成物、方法およびキット
JP2010078374A (ja) * 2008-09-24 2010-04-08 Olympus Corp 抗赤血球抗体の検出方法
WO2015158722A1 (fr) * 2014-04-15 2015-10-22 Université D'aix-Marseille Méthode de diagnostic ou de suivi d'un cancer

Non-Patent Citations (2)

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Title
KAWAMOTO, S ET AL.: "Ectopic expression of band 3 anion transport protein in colorectal cancer revealed in an antoimmune hemolytic anemia patient", HUMAN PATHOLOGY, vol. 83, 28 July 2018 (2018-07-28), pages 193 - 198, XP055590106 *
OGURA TAKESHI ET AL.: "recurrent autoimmune hemolytic anemia induced by XELOX chemotherapy for colon cancer", JOURNAL OF JAPANESE SOCIETY OF GASTROENTEROLOGY, vol. 1, no. 108, 2011, pages 1712 - 1719 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112394175A (zh) * 2019-08-15 2021-02-23 中山大学附属第六医院 IgG3检测试剂在制备结直肠癌诊断剂方面的应用
CN112394175B (zh) * 2019-08-15 2023-02-14 中山大学附属第六医院 IgG3检测试剂在制备结直肠癌诊断剂方面的应用

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