WO2018143336A1 - 膵臓癌の検査方法 - Google Patents
膵臓癌の検査方法 Download PDFInfo
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- WO2018143336A1 WO2018143336A1 PCT/JP2018/003394 JP2018003394W WO2018143336A1 WO 2018143336 A1 WO2018143336 A1 WO 2018143336A1 JP 2018003394 W JP2018003394 W JP 2018003394W WO 2018143336 A1 WO2018143336 A1 WO 2018143336A1
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- sugar chain
- antibody
- pancreatic cancer
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
- A61B5/4222—Evaluating particular parts, e.g. particular organs
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- 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
- G01N33/5436—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand physically entrapped within the solid phase
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- 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
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
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- 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
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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- 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
- G01N33/6854—Immunoglobulins
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- C—CHEMISTRY; METALLURGY
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- G01N2400/02—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates involving antibodies to sugar part of glycoproteins
Definitions
- the present invention relates to a pancreatic cancer test method, a pancreatic cancer test drug, and the like.
- pancreatic cancer The annual number of deaths from pancreatic cancer is the fifth highest among men and fourth among women (2014), and the number is increasing.
- One reason for the large number of deaths from pancreatic cancer is that early detection is difficult. Pancreatic cancer has no characteristic symptoms at an early stage, and early detection is difficult. For this reason, when pancreatic cancer is diagnosed, the cancer has already progressed and is often difficult to treat.
- An object of the present invention is to provide a method for examining pancreatic cancer. Furthermore, this invention makes it a subject to provide the test
- the serum anti-sugar chain antibody (anti-sialyl lactose sugar chain antibody and anti- (LN) 3 sugar chain antibody) value tends to be lower in pancreatic cancer patients, and Based on the finding that the possibility of suffering from pancreatic cancer can be determined by using the anti-sugar chain antibody value as an index.
- the present invention includes the following embodiments as one embodiment: Item 1.
- a method for examining the possibility of suffering from pancreatic cancer comprising: (1) selected from the group consisting of an anti-3-sialyllactose sugar chain antibody and an anti- (LN) 3 sugar chain antibody in a biological sample collected from a subject Measuring the amount or concentration of at least one anti-sugar chain antibody, wherein the anti-3-sialyl lactose sugar chain antibody is converted into a sugar chain represented by Neu5Ac ⁇ (2 ⁇ 3) Gal ⁇ (1 ⁇ 4) Glc.
- an antibody capable of binding or an antibody that recognizes the sugar chain and the anti- (LN) 3 sugar chain antibody is capable of binding to a sugar chain represented by Gal ⁇ 1 ⁇ 3GlcNAc ⁇ 1 ⁇ 3Gal ⁇ 1 ⁇ 4GlcNAc or A method, which is an antibody that recognizes a sugar chain.
- the step (1) comprises (1a) at least one compound selected from the group consisting of a compound 1 containing a 3-sialyllactose sugar chain structure and a compound 2 containing a (LN) 3 sugar chain structure;
- the method according to Item 1 comprising a step of contacting the compound and (1b) a step of measuring the amount of the anti-sugar chain antibody bound to the compound.
- step (3c) measuring the amount or concentration of the glycan pancreatic cancer marker in the biological sample, and the measured value of the amount or concentration of the glycan pancreatic cancer marker is set in advance
- the method according to Item 1 or 2 comprising a step of determining that the subject is highly likely to have pancreatic cancer based on the provisional determination.
- Item 6 the preliminary determination that the subject is highly likely to suffer from pancreatic cancer in either or both of the temporary determination in the step (2c) and the temporary determination in the step (3c) 6.
- the method according to Item 5 wherein it is determined that the subject is highly likely to have pancreatic cancer.
- the cut-off value of the amount or concentration of the anti-sugar chain antibody is an average value, percentile value, or value of the amount or concentration of the anti-sugar chain antibody in a biological sample collected from a subject not suffering from pancreatic cancer, or Item 7.
- Item 8. The method according to any one of Items 5 to 7, wherein the sugar chain pancreatic cancer marker is at least one selected from the group consisting of CA19-9 and DUPAN-2.
- Item 11 The method according to any one of Items 1 to 9, wherein the anti-sugar chain antibody is IgG.
- Item 11. The method according to any one of Items 1 to 10, wherein the biological sample is a body fluid or a sample derived from a body fluid.
- Item 12. The method according to Item 11, wherein the body fluid is at least one selected from the group consisting of whole blood, serum, and plasma.
- Item 13. Item 13. The method according to any one of Items 1 to 12, wherein the pancreatic cancer to be examined is stage 0 to 2 pancreatic cancer.
- this invention also includes the following aspect as another aspect: Item 15.
- a method for assisting in the determination of the possibility of suffering from pancreatic cancer comprising: (1) from a group consisting of an anti-3-sialyllactose sugar chain antibody and an anti- (LN) 3 sugar chain antibody in a biological sample collected from a subject Measuring the amount or concentration of at least one anti-sugar chain antibody selected.
- a method for measuring the amount or concentration of an anti-sugar chain antibody in a subject comprising (1) an anti-3-sialyllactose sugar chain antibody and an anti- (LN) 3 sugar chain antibody in a biological sample collected from the subject Measuring the amount or concentration of at least one anti-sugar chain antibody selected from the group.
- step (1) the amount or concentration of only one anti-sugar chain antibody selected from the group consisting of an anti-sialyl lactose sugar chain antibody and an anti- (LN) 3 sugar chain antibody is measured as the anti-sugar chain antibody.
- Step (1) Fixing at least one compound selected from the group consisting of Compound 1 containing 3-sialyllactose sugar chain structure and Compound 2 containing (LN) 3 sugar chain structure to a solid phase; Contacting the compound immobilized on the solid phase with a biological sample collected from the subject; Washing the solid phase on which the compound brought into contact with the biological sample is fixed with a solution containing trishydroxymethylaminomethane and / or an ether type nonionic surfactant; A step of adding a blocking solution containing bovine serum albumin and further containing trishydroxymethylaminomethane and / or an ether type nonionic surfactant to the washed solid phase, and an antibody bound to the compound immobilized on the solid phase Item 18.
- Item 19 A method for diagnosing pancreatic cancer in a subject comprising: (1) Measure the amount or concentration of at least one anti-sugar chain antibody selected from the group consisting of anti-sialyl lactose sugar chain antibody and anti- (LN) 3 sugar chain antibody in a biological sample collected from a subject The process of (2a) When the amount or concentration value of the anti-glycan antibody measured in the step (1) is not more than a preset cutoff value, the subject may be suffering from pancreatic cancer And (3a) a method of applying a method for diagnosing pancreatic cancer to a subject determined to have a high possibility of suffering from pancreatic cancer in the step (2a) .
- Item 20 The diagnostic method for pancreatic cancer applied in the step (3a) is at least one selected from the group consisting of a biopsy method, a PET test method, a CT test method, and an ultrasonic test method. the method of. Item 21.
- a method for diagnosing and treating pancreatic cancer in a subject comprising: (1) Measure the amount or concentration of at least one anti-sugar chain antibody selected from the group consisting of anti-sialyl lactose sugar chain antibody and anti- (LN) 3 sugar chain antibody in a biological sample collected from a subject The step of: (2a) When the amount or concentration value of the anti-glycan antibody measured in the step (1) is not more than a preset cutoff value, the subject may be suffering from pancreatic cancer Or (3b) the amount or concentration of the anti-glycan antibody measured in the step (1) (test anti-glycan antibody value) is a preset cutoff value
- a process of treating pancreatic cancer for a subject Including a method.
- Item 22 At least one selected from the group consisting of Compound 1 containing a 3-sialyllactose sugar chain structure and Compound 2 containing a (LN) 3 sugar chain structure for use as a test for the possibility of developing pancreatic cancer Compound.
- Item 23 Use of at least one compound selected from the group consisting of Compound 1 containing a 3-sialyllactose sugar chain structure and Compound 2 containing a (LN) 3 sugar chain structure for examining the possibility of suffering from pancreatic cancer .
- Item 24 Use of at least one compound selected from the group consisting of Compound 1 containing a 3-sialyllactose sugar chain structure and Compound 2 containing a (LN) 3 sugar chain structure for examining the possibility of suffering from pancreatic cancer .
- a method for examining pancreatic cancer can be provided. According to the test method of the present invention, it becomes possible to test the possibility of suffering from pancreatic cancer (preferably earlier pancreatic cancer) with higher sensitivity, and to detect pancreatic cancer earlier. .
- Anti-glycan antibody (anti-sialyl lactose sugar chain antibody and anti- (LN) 3 sugar chain antibody) concentration in the serum of healthy human samples and pancreatic cancer patient samples measured and calculated in Reference Example 1 (b) (Anti-sugar chain antibody value) is shown.
- the vertical axis of each graph represents the anti-sugar chain antibody value (the unit is fluorescence intensity value / IgG amount ( ⁇ g)).
- “Healthy” indicates the result of the healthy human specimen
- Pancreatic cancer indicates the result of the pancreatic cancer patient specimen
- N indicates the number of specimens.
- the determination result of pancreatic cancer morbidity for each stage performed in Example 1 and Comparative Example 1 is shown.
- the vertical axis represents the determination index.
- the horizontal axis shows the stage of pancreatic cancer.
- the horizontal line in the graph indicates a preset cutoff value.
- the fraction in the graph indicates (sensitivity of the number of specimens determined to be highly likely to have pancreatic cancer / number of specimens of pancreatic cancer patients).
- the anti-sialyl lactose sugar chain antibody concentration in the serum of healthy human samples and pancreatic cancer patient samples measured in Reference Example 2 and Example 2 is shown.
- the ROC curve is shown for the anti-sialyl lactose sugar chain antibody concentration ( ⁇ g / mL) in the serum of healthy human samples and pancreatic cancer patient samples measured in Reference Example 2 and Example 2.
- the vertical axis represents sensitivity.
- the horizontal axis represents a value obtained by subtracting% specificity from 100% (100% -specificity%).
- the present invention is a method for examining the possibility of pancreatic cancer, comprising: (1) anti-3-sialyl lactose in a biological sample collected from a subject.
- a method comprising a step (step (1)) of measuring the amount or concentration of at least one anti-sugar chain antibody selected from the group consisting of a sugar chain antibody and an anti- (LN) 3 sugar chain antibody; It may be indicated as “inspection method of the present invention”). This will be described below.
- the pancreatic cancer to be examined is not particularly limited, and includes pancreatic cancer of all types and stages.
- Examples of the type of pancreatic cancer to be examined include pancreatic duct cancer, pancreatic endocrine tumor, intraductal papillary mucinous tumor, mucinous cystic tumor, acinar cell cancer, and preferably pancreatic duct cancer.
- Stages of pancreatic cancer to be examined include stage 0, stage 1, stage 2, stage 3, and stage 4 (stage 4a, stage 4b) in order from the earlier stage.
- the inspection method of the present invention is useful in that it can be determined even for early pancreatic cancer.
- stage of pancreatic cancer to be examined is preferably stages 0 to 3, more preferably stages 0 to 2, and further preferably stages 1 to 2.
- the subject is a control organism of the test method of the present invention, and its species is not particularly limited.
- Examples of the biological species of the subject include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, and preferably humans.
- the state of the subject relating to pancreatic cancer is not particularly limited.
- specimens include specimens that are unclear whether they have pancreatic cancer, specimens that have no history of pancreatic cancer, specimens that have a history of pancreatic cancer and have been treated for pancreatic cancer, and are affected by pancreatic cancer by other methods.
- the biological sample is not particularly limited as long as it can contain an anti-sugar chain antibody.
- biological samples include body fluids such as whole blood, serum, plasma, saliva, spinal fluid, joint fluid, urine, tissue fluid, sweat, tears, saliva, and samples derived from these body fluids.
- the sample derived from the body fluid is not particularly limited as long as it is a sample prepared from the body fluid.
- an antibody contained in the body fluid preferably an anti-sugar chain antibody, more preferably an anti 3-sialyl lactose sugar chain antibody.
- the body fluid preferably includes whole blood, serum, plasma and the like.
- a biological sample may be employed singly or in combination of two or more.
- a biological sample can be collected from a subject by methods known to those skilled in the art.
- whole blood can be collected by blood collection using a syringe or the like.
- blood collection is preferably performed by medical personnel such as doctors and nurses.
- Serum is a part obtained by removing blood cells and a specific blood coagulation factor from blood, and can be obtained, for example, as a supernatant after coagulating the blood.
- Plasma is a portion obtained by removing blood cells from blood, and can be obtained, for example, as a supernatant when subjected to centrifugation under conditions that do not coagulate blood.
- the 3-sialyllactose sugar chain is a sugar chain represented by Neu5Ac ⁇ (2 ⁇ 3) Gal ⁇ (1 ⁇ 4) Glc, that is, the hydroxy group at the 2-position of neuraminic acid (Neu5Ac) and the 3-position of galactose (Gal). It is a sugar chain in which a hydroxy group is linked by an ⁇ -glycoside bond, and a hydroxy group at the 1-position of galactose (Gal) and a hydroxy group at the 4-position of glucose (Glc) are linked by a ⁇ -glycoside bond.
- the structural formula of 3-sialyllactose sugar chain the following formula (A) [wherein Ac represents an acetyl group. ].
- the (LN) 3 sugar chain is a sugar chain represented by Gal ⁇ 1 ⁇ 3GlcNAc ⁇ 1 ⁇ 3Gal ⁇ 1 ⁇ 4GlcNAc, ie, galactose (Gal, sometimes referred to as “galactose A” for convenience) and the 1-position hydroxy group and N-acetyl.
- the hydroxy group at the 3-position of glucosamine (GlcNAc, sometimes referred to as “N-acetylglucosamine A” for convenience) is linked by a ⁇ -glycosidic bond, so that the hydroxy group at the 1-position of the N-acetylglucosamine A is separate from galactose A.
- galactose (Gal, sometimes referred to as “galactose B” for convenience) is linked by a ⁇ -glycosidic bond, and the 1-position hydroxy group of galactose B and N-acetylglucosamine A
- This is a sugar chain in which the hydroxy group at the 4-position of another N-acetylglucosamine is linked by a ⁇ glycoside bond.
- (LN) 3 sugar chain the following formula (B) [wherein Ac represents an acetyl group. ].
- Anti-sialyl lactose sugar chain antibody is an antibody that can bind (preferably specifically) to 3-sialyl lactose sugar chain and / or an antibody that recognizes (preferably specifically) 3-sialyl lactose sugar chain.
- Anti- (LN) 3 sugar chain antibody is an antibody that can bind (preferably specifically) to (LN) 3 sugar chain and / or an antibody that specifically recognizes (preferably) (LN) 3 sugar chain
- these may be collectively referred to as “the anti-sugar chain antibody of the present invention”.
- step (1) the amount or concentration of at least one antibody selected from the group consisting of an anti-3-sialyllactose sugar chain antibody and an anti- (LN) 3 sugar chain antibody is measured.
- step (1) from the viewpoint of the efficiency of the test, the amount of only one kind selected from the group consisting of anti-sialyl lactose sugar chain antibody and anti- (LN) 3 sugar chain antibody as an anti-sugar chain antibody or It is desirable to measure the concentration.
- the isotype of the anti-sugar chain antibody of the present invention to be detected is not particularly limited.
- Examples of the isotype include IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA, IgD, IgE, and the like.
- IgG and the like are preferable from the viewpoint that the possibility of suffering from pancreatic cancer can be examined with higher accuracy.
- the method of measuring the amount or concentration of the anti-glycan antibody is not particularly limited as long as it can measure the amount and / or concentration of the antibody.
- the method include immunoassay.
- the immunoassay can be widely adopted regardless of direct method, indirect method, homogeneous method, heterogeneous method, competitive method, non-competitive method, and the like.
- an immunoassay for example, ELISA (for example, direct method, indirect method, sandwich method, competitive method, etc.), radioimmunoassay (RIA), immunoradiometric assay (IRMA), enzyme immunoassay (EIA), sandwich EIA, Examples include immunochromatography, Western blot, immunoprecipitation, slot or dot blot assay, immunohistochemical staining, fluorescent immunoassay, immunoassay using avidin-biotin or streptavidin-biotin system, and immunoassay using surface plasmon resonance (SPR) method.
- the detection method may be employed singly or in combination of two or more.
- the type of label in the label used for detecting the antibody is not particularly limited.
- the label include fluorescent substances, luminescent substances, dyes, enzymes, gold colloids, and radioisotopes.
- enzyme labels such as peroxidase and alkaline phosphatase are preferable from the viewpoints of safety, economy, detection sensitivity, and the like.
- step (1) the amount or concentration of the anti-sugar chain antibody of the present invention in a biological sample collected from a subject can be measured and calculated. Details of the measurement and calculation methods will be described in the following preferred embodiment of step (1).
- step (1) (1a) at least one compound selected from the group consisting of a compound 1 containing a 3-sialyllactose sugar chain structure and a compound 2 containing a (LN) 3 sugar chain structure
- a step including a step of contacting a biological sample collected from a subject (step (1a)) and (1b) a step of measuring the amount of antibody bound to the compound (step (1b)) Can do.
- the compound 1 containing 3-sialyl lactose sugar chain structure is a compound containing 3-sialyl lactose sugar chain itself or 3-sialyl lactose sugar chain as a partial structure.
- the structure other than the 3-sialyllactose sugar chain structure is not particularly limited, and may be a structure having no antigenicity or a structure having antigenicity. Examples of the structure having no antigenicity include a structure that serves as a spacer when a sugar chain array is prepared.
- Compound 1 is preferably a sugar chain containing a 3-sialyllactose sugar chain structure (for example, 3 to 30, preferably 3 to 10, more preferably 3 to 5, more preferably 3 sugar residues)
- a synthetic polymer for example, polyacrylamide, polylysine, polystyrene, polyethylene, polyester, polyvinyl chloride, polyurethane, etc.
- the sugar chain is serum
- examples include glycoproteins covalently bound to albumin and mucin, glycopeptides whose sugar chains are covalently bonded to peptides, sugar chain dendrimers, sugar chains labeled using reductive amination reaction
- the compound 2 containing the (LN) 3 sugar chain structure is a compound containing the (LN) 3 sugar chain itself or the (LN) 3 sugar chain as a partial structure.
- the structure other than the (LN) 3 sugar chain structure is not particularly limited, and may be a structure having no antigenicity or a structure having antigenicity. Examples of the structure having no antigenicity include a structure that serves as a spacer when a sugar chain array is prepared.
- Compound 2 is preferably a sugar chain containing (LN) 3 sugar chain structure (for example, the number of sugar residues is 4 to 30, preferably 4 to 6, more preferably 4 to 5, and still more preferably 4), (LN) A sugar chain polymer in which a sugar chain containing a three sugar chain structure is covalently bonded to a synthetic polymer (eg, polyacrylamide, polylysine, polystyrene, polyethylene, polyester, polyvinyl chloride, polyurethane, etc.). Examples include glycoproteins covalently bound to albumin and mucin, glycopeptides whose sugar chains are covalently bonded to peptides, sugar chain dendrimers, sugar chains labeled using reductive amination reaction, and the like.
- LN sugar chain containing (LN) 3 sugar chain structure
- LN A sugar chain polymer in which a sugar chain containing a three sugar chain structure is covalently bonded to a synthetic polymer (eg, polyacrylamide, polylysine, poly
- Compound 2 may be synthesized according to a known method, or various commercially available products such as Gal ⁇ 1 ⁇ 3GlcNAc ⁇ 1 ⁇ 3Gal ⁇ 1 ⁇ 4GlcNAc-PAA (manufactured by GlycoTech Corporation, catalog number: 08-096) may be used.
- the mode of contact in step (1a) is not particularly limited, and an appropriate mode can be selected according to the type of the above-described method for measuring the amount or concentration of the anti-sugar chain antibody (for example, various immunoassays).
- a contact mode for example, a mode in which only one of an antibody and a sugar chain antigen (compound 1 and / or compound 2) in a biological sample is contacted with the solid phase, both of which are not fixed to the solid phase.
- the aspect etc. made to contact in a state are mentioned.
- an embodiment in which only a sugar chain antigen (compound 1 and / or compound 2) is preferably immobilized on a solid phase is mentioned.
- the solid phase is not particularly limited as long as it can fix an antibody or a sugar chain antigen (compound 1 and / or compound 2) in a biological sample.
- the solid phase include plates, slides, and membranes containing polystyrene, glass, nitrocellulose and the like as main components.
- the solid phase is a component for more easily immobilizing an antibody or sugar chain antigen (compound 1 and / or compound 2) in a biological sample, such as a readily reactive compound (for example, a compound having a readily reactive group, a gold colloid, etc. ).
- the compound having an easily reactive group is a group capable of forming a covalent bond with a sugar chain or a sugar chain derivative, such as a (1H-imidazol-1-yl) carbonyl group, a succinimidyloxycarbonyl group, Epoxy group, aldehyde group, amino group, thiol group, carboxyl group, azide group, cyano group, active ester group (1H-benzotriazol-1-yloxycarbonyl group, pentafluorophenyloxycarbonyl group, paranitrophenyloxycarbonyl group Etc.), or a compound having a carbonyl halide group (carbonyl chloride group, carbonyl fluoride group, carbonyl bromide group, carbonyl iodide group) and the like.
- a (1H-imidazol-1-yl) carbonyl group such as a (1H-imidazol-1-yl) carbonyl group, a succinimidyloxycarbon
- Examples of the compound having an easily reactive group include epoxy silane and polylysine.
- the easily reactive compound When using a solid phase coated with a readily reactive compound, it is preferable to block the easily reactive compound with a bovine serum albumin (BSA) buffer, and the blocking time is preferably 60 minutes or longer.
- BSA bovine serum albumin
- the blocking liquid preferably further contains trishydroxymethylaminomethane (Tris) and / or an ether type nonionic surfactant.
- Tris trishydroxymethylaminomethane
- the aspect of measuring the amount or concentration of the antibody in step (1b) is not particularly limited, and is appropriate depending on the type of the above-described method for measuring the amount or concentration of the anti-glycan antibody (for example, various immunoassays). Can be selected.
- the measurement can be performed, for example, by quantifying a signal derived from the label of the label used.
- a labeled antibody is brought into contact with an antibody bound to a sugar chain antigen (compound 1 and / or compound 2), and a signal derived from the label of the bound labeled antibody is quantified. be able to.
- Standard antibodies can be prepared from commercially available antibodies, for example, by affinity purification using biotin-labeled sugar chain antigen and streptavidin-agarose resin. First, a well of an appropriate ELISA plate is coated with a sugar chain antigen and then blocked with a BSA buffer. Next, each concentration of standard antibody or specimen is added to the well and allowed to stand for a certain period of time, and then the well is washed. A secondary antibody labeled with peroxidase is added to the well and allowed to stand for a certain period of time.
- a peroxidase substrate is added to the well and allowed to stand for a certain period of time for color development.
- a reaction stop solution such as sulfuric acid
- the absorbance is measured using a plate reader.
- the concentration of the anti-sugar chain antibody in the sample is quantified based on the standard curve.
- the amount of the anti-sugar chain antibody of the present invention can be calculated based on the obtained signal amount.
- the obtained signal amount can be directly used as the amount of the anti-sugar chain antibody of the present invention.
- the amount of signal obtained and the amount of the anti-sugar chain antibody of the present invention are in an inversely proportional relationship, and therefore, from the amount of signal obtained based on this relationship, The amount of the anti-sugar chain antibody of the present invention can be calculated.
- the amount of the anti-sugar chain antibody of the present invention is divided by the amount of the biological sample and the amount of components in the biological sample (for example, the total amount of antibody, the total amount of the antibody of the same isotype as the anti-glycan antibody of the present invention to be detected). By doing so, the concentration of the anti-sugar chain antibody of the present invention can be calculated.
- test method of the present invention including the step (1), it is possible to provide a test anti-glycan antibody value that is a detection index of pancreatic cancer disease, thereby determining the possibility of pancreatic cancer disease, etc. Can assist.
- the test method of the present invention further includes (2a) when the value of the amount or concentration of the anti-glycan antibody of the present invention measured in step (1) is not more than a preset cutoff value.
- “possibility of suffering from pancreatic cancer” means “possibility of suffering from pancreatic cancer at the time of biological sample collection”.
- the test method of the present invention including the step (2a) it is possible to determine the possibility of suffering from pancreatic cancer. Further, since the test method of the present invention can determine the possibility of suffering from pancreatic cancer with higher sensitivity, the test method of the present invention including this step (2a) can be used to determine whether the patient is truly suffering from pancreatic cancer. The specimen can be more reliably determined to be “affected by pancreatic cancer” (ie, the possibility of being erroneously determined to be “not affected by pancreatic cancer” can be further reduced).
- the cut-off value can be appropriately set by those skilled in the art from the viewpoint of sensitivity, specificity, positive predictive value, negative predictive value, etc.
- a biological sample collected from a subject not suffering from pancreatic cancer The average value, percentile value, or minimum value of the amount or concentration of the anti-glycan antibody of the present invention in FIG. More specifically, for example, the amount or concentration of the anti-sugar chain antibody of the present invention in a subject suffering from pancreatic cancer and a biological sample collected from a subject suffering from pancreatic cancer is measured. Then, using the measured value, statistical analysis based on analysis of a receiver operating characteristic (Receiver Operating Characteristic, ROC) curve or the like (more specifically, a method using Youden index is exemplified).
- Receiveiver Operating Characteristic Receiveiver Operating Characteristic
- the cut-off value is, for example, a 10 to 90 percentile value, preferably a 30 to 70 percentile value of the amount or concentration of the anti-glycan antibody of the present invention in a biological sample collected from a subject not suffering from pancreatic cancer.
- the 40th percentile value is more preferable, and the 45th to 55th percentile value is more preferable.
- the value of the amount or concentration of the anti-sugar chain antibody in a biological sample collected from the same subject before a certain period of time can be used as a cutoff value.
- the “predetermined period” is not particularly limited as long as the amount or concentration of the anti-sugar chain antibody of the present invention can be changed within the same subject. For example, the period is about 1 month to 10 years, 2 months to 5 years, 3 months to 2 years, 4 months to 1 year.
- step (2b) As a modification of the test method of the present invention, instead of the above step (2a), the amount or concentration value of the anti-sugar chain antibody of the present invention measured in (2b) step (1) is from the same subject.
- the “certain period” is not particularly limited as long as the amount or concentration of the anti-sugar chain antibody of the present invention can be changed within the same subject.
- the period is about 1 month to 10 years, 2 months to 5 years, 3 months to 2 years, 4 months to 1 year.
- the level of “low” is not particularly limited, but the amount or concentration of the anti-glycan antibody of the present invention measured in step (1) is the same in a biological sample collected from the same subject before a certain period of time. Examples thereof include 90% or less, 70% or less, 50% or less, or 30% or less of the amount or concentration of the anti-sugar chain antibody of the invention.
- step (2c) As another aspect of the inspection method of the present invention, instead of the step (2a), (2c) When the amount or concentration of the anti-glycan antibody measured in the step (1) is not more than a preset cutoff value, the subject may be suffering from pancreatic cancer Process (step (2c)) that is temporarily determined to be high (3c) Measure the amount or concentration of the glycan pancreatic cancer marker in the biological sample, and the measured amount or concentration of the glycan pancreatic cancer marker is equal to or higher than a preset cutoff value, Based on the step of tentatively determining that the subject is likely to have pancreatic cancer (step (3c)), and (3d) the tentative determination of step (2c) and the tentative determination of step (3c) Determining that the subject is likely to have pancreatic cancer (step (3d)) The method containing is mentioned.
- the possibility of suffering from pancreatic cancer is examined by the test method including the steps (2c), (3c), and (3d).
- the test method of the present invention comprising the steps (2c), (3c) and (3d) is an early pancreatic cancer, specifically, pancreatic cancer earlier than stage 2 or stage 2, particularly pancreas of stage 1 or 2 Cancer morbidity can be determined with higher accuracy than known methods.
- the subject is highly likely to suffer from pancreatic cancer in one or both of the temporary determination in the step (2c) and the temporary determination in the step (3c). If it is a tentative determination, it is determined that the subject is highly likely to have pancreatic cancer, so that a subject suffering from pancreatic cancer is erroneously described as “not suffering from pancreatic cancer”. The possibility of determination can be further reduced.
- sugar chain pancreatic cancer marker examples include CA19-9, DUPAN-2, Span-1, CA50, CA242, TAG-72, SLX, STN and the like, preferably CA19-9, DUPAN-2 and the like. More preferably, CA19-9 is used.
- the sugar chain pancreatic cancer marker for example, one or more selected from the group consisting of CA19-9 and DUPAN-2 may be used in combination.
- the test method of the present invention further includes (3a) Higher accuracy by combining the step of applying a diagnostic method for pancreatic cancer (step (3a)) to a subject determined to have a high possibility of suffering from pancreatic cancer in step (2a) It is possible to diagnose pancreatic cancer. Further, since the test method of the present invention can determine the possibility of suffering from pancreatic cancer with higher sensitivity, combining the test method (3a) with the test method of the present invention truly suffers from pancreatic cancer. The subject can be more reliably diagnosed as “affected by pancreatic cancer” (ie, possibly misdiagnosed as “not affected by pancreatic cancer”, and excluded from the diagnosis target in step (3a)) Can be further reduced).
- the method for diagnosing pancreatic cancer employed in step (3a) is not particularly limited, and various known diagnostic methods can be employed.
- the diagnostic method include a biopsy method, a PET test method, a CT test method, an ultrasonic test method, a pancreatic cancer marker (eg, CA19-9, DUPAN-2, CEA, CA50, etc.) test method, and the like.
- a biopsy method, a PET examination method, a CT examination method, an ultrasonic examination method and the like are preferable. Diagnostic methods may be employed singly or in combination of two or more.
- step (4) When it is determined that the subject is highly likely to have pancreatic cancer by the test method of the present invention including the pancreatic cancer treatment step (2a), or the subject is pancreatic cancer in step (3a) If diagnosed, (4) to a subject who is determined to be highly likely to have pancreatic cancer in step (2a), or to a subject who has been diagnosed as having pancreatic cancer in step (3a) By performing the pancreatic cancer treatment step (step (4)), it becomes possible to treat the pancreatic cancer of the subject.
- the method further includes a step of the test method of the present invention or a combination of the test method of the present invention and the step (3a)
- a subject truly suffering from pancreatic cancer can be treated more reliably (ie, a subject who is truly suffering from pancreatic cancer is more likely to be excluded from the treatment subject). Can be reduced).
- the method for treating pancreatic cancer is not particularly limited, and various known treatment methods can be employed. Examples of treatment methods include chemotherapy, surgical treatment, radiotherapy, immunotherapy, and the like. These can be carried out according to known methods.
- the therapeutic agent used for chemotherapy is not particularly limited, and various anticancer agents can be used.
- the anticancer agent include an alkylating agent, an antimetabolite, a microtubule inhibitor, an antibiotic anticancer agent, a topoisomerase inhibitor, a platinum preparation, a molecular target drug, a hormonal agent, and a biological preparation.
- the alkylating agent include cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, and ranimustine.
- Antimetabolites include, for example, enositabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nelarabine, fluorouracil, fludarabetine, pemetrexed, pentotrexet
- Examples include cladribine, doxyfluridine, hydroxycarbamide, mercaptopurine and the like.
- the microtubule inhibitor include alkaloid anticancer agents such as vincristine and taxane anticancer agents such as docetaxel and paclitaxel.
- Antibiotic anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, aclarubicin, idarubicin, pirarubicin, pepromycin, mitoxantrone, amrubicin, dinostatin stimaramer and the like.
- the topoisomerase inhibitor include CPT-11 having a topoisomerase I inhibitory action, irinotecan, nogitane, etoposide having a topoisomerase II inhibitory action, and sobuzoxane.
- platinum preparation examples include cisplatin, nedaplatin, oxaliplatin, carboplatin and the like.
- hormonal agent for example, dexamethasone, finasteride, tamoxifen, astrozole, exemestane, ethinylestradiol, chlormadinone, goserelin, bicalutamide, flutamide, brednisolone, leuprorelin, letrozole, estramustine, toremifene, phosfestol, mitotane
- Examples include methyltestosterone, medroxyprogesterone, and mepithiostane.
- biologics include interferon ⁇ , ⁇ and ⁇ , interleukin 2, ubenimex, and dry BCG.
- molecular target drugs include rituximab, alemtuzumab, trastuzumab, cetuximab, panitumumab, imatinib, dasatinib, nilotinib, gefitinib, erlotinib, temsirolimus, bevacizumab, VEGF trap, sunitinib, totemizumab, , Ibritumomab tiuxetan, tamibarotene, tretinoin and the like.
- human epidermal growth factor receptor 2 inhibitor In addition to the molecular target drugs specified here, human epidermal growth factor receptor 2 inhibitor, epidermal growth factor receptor inhibitor, Bcr-Abl tyrosine kinase inhibitor, epidermal growth factor tyrosine kinase inhibitor, mTOR inhibition Drugs, inhibitors targeting angiogenesis such as vascular endothelial growth factor receptor 2 inhibitor ( ⁇ -VEGFR-2 antibody), various tyrosine kinase inhibitors such as MAP kinase inhibitor, inhibitors targeting cytokines, Molecular target drugs such as proteasome inhibitors and antibody-anticancer drug combinations can also be included. These inhibitors also include antibodies.
- pancreatic cancer therapeutic agents include gemcitabine, TS-1, erlotinib, a combination drug of gemcitabine and erlotinib, a combination drug of gemcitabine and albumin-binding paclitaxel, four drugs (oxaliplatin, levofolinate, irinotecan, and Fluorouracil) and the like.
- the present invention relates to at least one compound selected from the group consisting of Compound 1 having a 3-sialyllactose sugar chain structure and Compound 2 having a (LN) 3 sugar chain structure.
- the present invention relates to a pancreatic cancer test drug (also referred to as “the test drug of the present invention” in the present specification). This will be described below.
- the test drug of the present invention is a drug for testing the possibility of suffering from pancreatic cancer.
- the test agent of the present invention is in the form of a composition comprising at least one compound selected from the group consisting of Compound 1 having a 3-sialyllactose sugar chain structure and Compound 2 having a (LN) 3 sugar chain structure. May be.
- the composition may contain other components as necessary. Examples of other components include a base, a carrier, a solvent, a dispersant, an emulsifier, a buffer, a stabilizer, an excipient, a binder, a disintegrant, a lubricant, a thickener, a moisturizer, a colorant, and a fragrance. And chelating agents.
- the test agent of the present invention is in the form of a kit containing at least one compound selected from the group consisting of Compound 1 containing a 3-sialyllactose sugar chain structure and Compound 2 containing a (LN) 3 sugar chain structure. Also good.
- the kit may contain instruments, reagents, and the like that can be used to carry out the inspection method of the present invention.
- instruments include test tubes, microtiter plates, agarose particles, latex particles, purification columns, epoxy-coated slide glasses, and gold colloid-coated slide glasses.
- reagents include labeled antibodies and standard samples (positive control, negative control).
- labeled antibody various commercially available antibodies can be used depending on the isotype of the anti-sugar chain antibody of the present invention to be detected.
- the anti-sugar chain antibody of the present invention is used as a standard sample.
- the anti-sugar chain antibody of the present invention is obtained by purifying the culture supernatant after obtaining a hybridoma that produces an antibody that binds to 3-sialyl lactose sugar chain or (LN) 3 sugar chain using, for example, hybridoma technology. be able to.
- the anti-sugar chain antibody of the present invention can be obtained as follows. First, lymphocytes are prepared from lymph nodes or spleen, and fused with myeloma cells such as SPM4-0 and cultured. Four weeks after the fusion, the hybridoma culture supernatant is collected, and a hybridoma of the culture supernatant that reacts with 3-sialyl lactose sugar chain or (LN) 3 sugar chain is selected.
- the anti-sugar chain antibody of the present invention can be obtained from the supernatant obtained by culturing the selected hybridoma in a large amount by a salting-out method and an affinity purification method using a Protein-G column.
- Reference example 1 Anti-glycan antibody value in serum
- a Preparation of sugar chain array 3′-sialyl lactose-PAA (manufactured by GlycoTech Corporation, catalog number: 08-038) and Gal ⁇ 1 ⁇ 3GlcNAc ⁇ 1 ⁇ 3Gal ⁇ 1 ⁇ 4GlcNAc-PAA (manufactured by GlycoTech Corporation, Catalog No. 08-096) is diluted with a solution (hereinafter also referred to as “spot solution”) in which purified water and Spotting Solution (manufactured by Matsunami Glass Industry, catalog No .: DSP0050) are mixed in equal amounts. A diluted solution of 0.5 mg / mL was prepared.
- 1 ⁇ L of a diluted solution containing 3′-sialyl-lactose-PAA and 1 ⁇ L of a diluted solution containing Gal ⁇ 1 ⁇ 3GlcNAc ⁇ 1 ⁇ 3Gal ⁇ 1 ⁇ 4GlcNAc-PAA are each coated with epoxysilane so as to have a diameter of 1 mm.
- the solution was dropped onto a slide (manufactured by Schott AG, catalog number: 1066643) and allowed to stand at room temperature for 16 hours.
- each glass slide was washed 3 times with a washing solution (25 mM Tris-HCl (pH 7.4), 0.8% NaCl, 1% Triton-X 100) to remove an excess spot solution, and a blocking solution (25 mM) Tris-HCL (pH 7.4), 0.8% NaCl, 1% Triton-X 100, 4% BSA) was added and allowed to stand at room temperature for 1 hour to protect the unreacted epoxy group of epoxysilane.
- a sugar chain array containing 3′-sialyl-lactose-PAA and a sugar chain array containing Gal ⁇ 1 ⁇ 3GlcNAc ⁇ 1 ⁇ 3Gal ⁇ 1 ⁇ 4GlcNAc-PAA were prepared. These sugar chain arrays were stored refrigerated until use.
- sample dilution solution 25 mM Tris-HCL (pH 7.4), 0.8% NaCl, 1% Triton-X 100, 1 mM MnCl 2 , 1 mM CaCl 2 , 1% BSA
- sample dilution solution 25 mM Tris-HCL (pH 7.4), 0.8% NaCl, 1% Triton-X 100, 1 mM MnCl 2 , 1 mM CaCl 2 , 1% BSA
- 80 ⁇ L including serum equivalent to 0.8 ⁇ L
- Cy3 registered trademark fluorescent dye-labeled goat anti-human IgG antibody (Jackson ImmunoResearch Laboratories) was added to each sugar chain array to which serum diluted with the sample dilution solution was added, and allowed to stand at room temperature for 1 hour. After that, the plate was washed three times with a washing solution, and a fluorescence image was obtained using a fluorescence detector FLA-5100.
- the fluorescence intensity of each spot was measured using Image J (http://imagej.nih.gov/ij/), and the fluorescence intensity value in each serum was obtained.
- the serum of each specimen was diluted 200,901 times, and the amount of human IgG contained in the serum equivalent to 0.8 ⁇ L was measured.
- Example 1 16 pancreatic cancer patients (Stage 1: 1) obtained in Pancreatic Cancer Test Reference Example 1 (b) using the anti-sialyl lactose sugar chain antibody or anti- (LN) 3 sugar chain antibody as an index (Stage 2: 6 specimens, Stage 3: 2 specimens, Stage 4: 7 specimens) and compare the anti-glycan antibody value in each serum with the cutoff value, Pancreatic cancer (positive) was determined.
- the cut-off value was the 50% percentile value of the anti-sugar chain antibody value of 25 healthy subjects obtained in Reference Example 1.
- the cut-off value of anti-3-sialyllactose sugar chain antibody is 63.16 (fluorescence intensity value / IgG amount ( ⁇ g)), and the cut-off value of anti- (LN) 3 sugar chain antibody is 13.09 (fluorescence intensity value / IgG Amount ( ⁇ g)).
- FIG. 2 shows the results for each stage of pancreatic cancer.
- stage 1 and 2 The percentage of patients with early pancreatic cancer (stage 1 and 2) patients who were positive (highly likely to have pancreatic cancer) was 6 when the antibody value of anti-3-sialyllactose sugar chain antibody was used. / 7, and 6/7 when the antibody value of anti- (LN) 3 sugar chain antibody was adopted.
- Comparative Example 1 Similar to Reference Example 1 for pancreatic cancer testing using known markers as indicators , each serum of 16 pancreatic cancer patients (Stage 1: 1 specimen, Stage 2: 6 specimens, Stage 3: 2 specimens, Stage 4: 7 specimens) The concentration of CA19-9 was measured using a commercially available kit (manufactured by ALPCO, catalog number: 25-199HU-E01).
- the obtained CA19-9 concentration was compared with a cutoff value, and a specimen having a higher value than the cutoff value was determined to be pancreatic cancer (positive).
- the cut-off value was a commonly used value (37 U / mL).
- FIG. 2 shows the results for each stage of pancreatic cancer.
- stage 1 and 2 The percentage of patients with early pancreatic cancer (stage 1 and 2) patients who were positive (highly likely suffering from pancreatic cancer) was 3/7.
- Example 1 From the results of Example 1 and Comparative Example 1, the accuracy of determining the morbidity of early pancreatic cancer (stages 1 and 2) is higher than that using the CA19-9 concentration. It was shown that the antibody or anti- (LN) 3 sugar chain antibody antibody value was higher.
- this resin was packed in a Poly-Prep (registered trademark) empty column (manufactured by BIO-RAD, catalog number: 731-1550) to prepare a 3′-sialyl lactose-PAA-immobilized column.
- 50 mg of healthy human serum-derived freeze-dried IgG (manufactured by Wako Pure Chemicals, code number: 289-95341, lot number: WDN9152) is dissolved in 5 mL of PBS containing 0.1% Tween-20 and fixed with 3 ⁇ -sialyl lactose-PAA Added to the column. Then, the column was sealed and reacted at 4 ° C. with stirring for 12 hours.
- the column was released to elute non-adsorbed components. After washing the column with 4 mL of PBS, add 1 mL of 3 mM 3 ⁇ -sialyl lactose (Tokyo Kasei Kogyo, catalog number: S0885) PBS (-) solution, and seal the column at 4 ° C for 3 hours. The reaction was carried out with stirring. After the reaction, the column was released, and anti-sialyl lactose sugar chain antibody (human IgG) was eluted.
- 3 mM 3 ⁇ -sialyl lactose Tokyo Kasei Kogyo, catalog number: S0885
- washing solution After washing each well with 300 ⁇ l of washing solution, add 100 ⁇ l of anti 3-sialyl lactose sugar chain antibody solution (0, 6.25, 12.5, 25, 50, 100, 250 ng / ml) and let stand at room temperature for 2 hours. did. Then, each well was washed 5 times with 300 ⁇ L of washing solution and diluted to 200 times peroxidase-labeled goat anti-human IgG antibody (manufactured by SeraCare Life Sciences, catalog number: 04-10-06).
- Serum of each specimen is diluted 750 times with a specimen dilution solution (1% BSA and 1% Triton-X 100), and 100 ⁇ L of diluted serum is added to a MaxiSorp 96-well plate pre-adsorbed with 3 ⁇ -sialyl lactose-PAA. Added. Absorbance at 450 nm was measured in the same manner as shown in Reference Example (a), and the anti-3-sialyllactose sugar chain antibody concentration in each serum was calculated based on the standard curve.
- Example 2 Examination of pancreatic cancer using anti-3-sialyllactose sugar chain antibody concentration as an index Based on the results of Reference Example 2, the vertical axis represents sensitivity (positive rate) (%), and the horizontal axis represents 100% to specificity (%).
- An ROC curve with a value obtained by subtracting (100% -specificity (%)) (false positive rate) was created using the medical statistical software GraphPad Prism and is shown in FIG.
- the sensitivity indicates a ratio at which pancreatic cancer (stages 1, 2, 3, and 4) patient specimens are determined as positive
- the specificity indicates a ratio at which healthy human specimens are determined as negative.
- this test method had a sensitivity of 76% and a specificity of 92%.
- Example 3 Similar to Reference Example 2 (b) for early pancreatic cancer testing using a combination of known markers, 13 healthy subjects and 55 pancreatic cancer patients (Stage 1:15, Stage 2:15, Stage 3:11) The concentration of CA19-9 in each serum of the specimen (stage 4:14 specimen) was measured using a commercially available kit (Abnova, catalog number: KA0207). The cut-off value with the Youden index as an index was calculated from the measured values, and found to be 24.80 U / mL. For patients with early pancreatic cancer (stage 1 and 2) patients, the number of cases judged to be negative (highly likely not suffering from pancreatic cancer) based on this value was counted (number of false negative cases). .
- pancreatic cancer incidence using the anti-3-sialyllactose sugar chain antibody concentration as an index and the determination of pancreatic cancer incidence using the CA19-9 as an index positive in either or both of the determination of pancreatic cancer incidence using the anti-3-sialyllactose sugar chain antibody concentration as an index and the determination of pancreatic cancer incidence using the CA19-9 as an index (see Example 2) “Positive” is an example in which it is determined that the patient is likely to have pancreatic cancer), pancreatic cancer is determined using anti-sialyllactose sugar chain antibody concentration as an index, and CA19-9 as an index The number of cases determined to be negative (highly likely not suffering from pancreatic cancer) in any determination of cancer incidence was counted as the number of cases of false negative determination.
- the test method of the present invention can determine the possibility of suffering from early pancreatic cancer with higher accuracy than existing test methods. By measuring the antibody value of the anti-sugar chain antibody of the present invention, it is possible to monitor the progression of pancreatic cancer and the effectiveness of anticancer agents.
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Abstract
Description
項1. 膵臓癌の罹患の可能性を検査する方法であって、(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程を含み、前記抗3-シアリルラクトース糖鎖抗体がNeu5Acα(2→3)Galβ(1→4)Glcで表される糖鎖に結合することができる抗体又は前記糖鎖を認識する抗体であり、且つ前記抗(LN)3糖鎖抗体がGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される糖鎖に結合することができる抗体又は前記糖鎖を認識する抗体である、方法.
項2. 前記工程(1)が、(1a)3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物と、前記生体試料とを接触させる工程、並びに(1b)前記化合物に結合した抗糖鎖抗体の量を測定する工程を含む、項1に記載の方法.
項3. さらに、(2a)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程を含む、項1又は2に記載の方法.
項4. 前記カットオフ値が、膵臓癌に罹患していない被検体から採取された生体試料における前記抗糖鎖抗体の量又は濃度の値の平均値、パーセンタイル値、又は最小値である、項3に記載の方法.
項5. さらに、(2c)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと仮判定する工程、(3c)前記生体試料における糖鎖膵臓癌マーカーの量又は濃度を測定し、測定された前記糖鎖膵臓癌マーカーの量又は濃度の値が、予め設定されたカットオフ値以上である場合に、前記被検体が膵臓癌に罹患している可能性が高いと仮判定する工程、並びに(3d)前記工程(2c)の仮判定及び前記工程(3c)の仮判定に基づき、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程を含む、項1又は2に記載の方法.
項6. 前記工程(3d)において、前記工程(2c)の仮判定及び前記工程(3c)の仮判定のいずれか又は両方で、前記被検体が膵臓癌に罹患している可能性が高いとの仮判定である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する、項5に記載の方法.
項7. 前記抗糖鎖抗体の量又は濃度のカットオフ値が、膵臓癌に罹患していない被検体から採取された生体試料における前記抗糖鎖抗体の量又は濃度の値の平均値、パーセンタイル値、又は最小値である、項5又は6に記載の方法.
項8. 前記糖鎖膵臓癌マーカーが、CA19-9及びDUPAN-2からなる群より選択される少なくとも1種である、項5~7のいずれかに記載の方法.
項9. 前記糖鎖膵臓癌マーカーがCA19-9である、項8に記載の方法.
項10. 前記抗糖鎖抗体がIgGである、項1~9のいずれかに記載の方法.
項11. 前記生体試料が体液又は体液由来の試料である、項1~10のいずれかに記載の方法.
項12. 前記体液が全血、血清、及び血漿からなる群より選択される少なくとも1種である、項11に記載の方法.
項13. 検査対象である前記膵臓癌がステージ0~2の膵臓癌である、項1~12のいずれかに記載の方法.
項14. 3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物を含み、前記3-シアリルラクトース糖鎖構造がNeu5Acα(2→3)Galβ(1→4)Glcで表される糖鎖構造であり、且つ前記(LN)3糖鎖構造がGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される糖鎖構造である、膵臓癌の検査薬。
項15. 膵臓癌の罹患の可能性の判定を補助する方法であって、(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程を含む、方法.
項16. 被検体における抗糖鎖抗体の量又は濃度を測定する方法であって、(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程を含む、方法.
項17. 工程(1)において、抗糖鎖抗体として抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される1種の抗糖鎖抗体のみの量又は濃度を測定する、項16に記載の方法.
項18. 工程(1)が、
3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物を、固相に固定する工程、
固相に固定された化合物と、被検体から採取された生体試料とを接触させる工程、
生体試料と接触させた化合物が固定された固相を、トリスヒドロキシメチルアミノメタン及び/又はエーテル型非イオン界面活性剤を含む溶液で洗浄する工程、
洗浄された固相に、ウシ血清アルブミンを含み、さらにトリスヒドロキシメチルアミノメタン及び/又はエーテル型非イオン界面活性剤を含むブロッキング溶液を添加する工程、並びに
固相に固定された化合物に結合した抗体の量又は濃度を測定する工程を含む、項16又は17に記載の方法.
項19. 被検体における膵臓癌を診断する方法であって、
(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程、
(2a)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程、並びに
(3a)前記工程(2a)で膵臓癌に罹患している可能性が高いと判定された被験者に対して膵臓癌の診断方法を適用する工程を含む、方法.
項20. 前記工程(3a)において適用される膵臓癌の診断方法が、生検法、PET検査法、CT検査法、及び超音波検査法からなる群より選択される少なくとも1種である、項19に記載の方法.
項21. 被検体における膵臓癌を診断及び治療する方法であって、
(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程;
(2a)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程、又は
(3b)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値(被検抗糖鎖抗体値)が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程、及び膵臓癌に罹患している可能性が高いと判定された被験者に対して膵臓癌の診断方法を適用する工程;並びに
(4)前記工程(2a)で膵臓癌に罹患している可能性が高いと判定された被験者、又は前記工程(3b)で膵臓癌に罹患していると診断された被験者に対して膵臓癌治療を行う工程、
を含む、方法.
項22. 膵臓癌罹患の可能性の検査薬としての使用のための、3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物.
項23. 膵臓癌の罹患の可能性を検査するための、3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物の使用.
項24.膵臓癌罹患の可能性の検査薬の製造のための、3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物の使用.
本発明は、その一態様において、膵臓癌の罹患の可能性を検査する方法であって、(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程(工程(1))を含む方法(本明細書において、「本発明の検査方法」と示すこともある。)に関する。以下、これについて説明する。
検査対象である膵臓癌は、特に制限されず、あらゆる種類、ステージなどの膵臓癌を包含する。検査対象である膵臓癌の種類としては、例えば膵管癌、膵内分泌腫瘍、膵管内乳頭粘液性腫瘍、粘液性嚢胞腫瘍、腺房細胞癌などが挙げられ、好ましくは膵管癌などが挙げられる。検査対象である膵臓癌のステージとしては、より早期のステージから順に、ステージ0、ステージ1、ステージ2、ステージ3、及びステージ4(ステージ4a、ステージ4b)が挙げられる。本発明の検査方法は、初期の膵臓癌であっても判定できる点で有用である。本発明の検査方法では、ステージ2又はステージ2より初期の膵臓癌、特にステージ1又は2の膵臓癌において公知の方法より高い精度で判定できる。
この観点から、検査対象である膵臓癌のステージは、好ましくはステージ0~3、より好ましくはステージ0~2、さらに好ましくはステージ1~2である。
血漿は、血液から血球を除去した部分であり、例えば、血液を凝固させない条件下で遠心分離に供した際の上澄みとして得ることができる。
本発明の検査方法は、一態様として、さらに、(2a)工程(1)で測定された本発明の抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程(工程(2a))を含むことが好ましい。ここで、「膵臓癌に罹患している可能性」とは、「生体試料採取時に膵臓癌に罹患している可能性」を意味する。
本発明の検査方法の変法として、上記工程(2a)に代えて、(2b)工程(1)で測定された本発明の抗糖鎖抗体の量又は濃度の値が、同一の被検体から一定期間前に採取された生体試料における本発明の抗糖鎖抗体の量又は濃度の値よりも低い場合に、前記被検体が将来膵臓癌に罹患する可能性が高いと判定する工程(工程(2b))を含む方法が挙げられる。該工程(2b)を含む前記検査方法により、将来における膵臓癌罹患リスクを判定する。
本発明の検査方法の別の一態様として、上記工程(2a)に代えて、
(2c)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと仮判定する工程(工程(2c))、
(3c)前記生体試料における糖鎖膵臓癌マーカーの量又は濃度を測定し、測定された前記糖鎖膵臓癌マーカーの量又は濃度の値が、予め設定されたカットオフ値以上である場合に、前記被検体が膵臓癌に罹患している可能性が高いと仮判定する工程(工程(3c))、並びに
(3d)前記工程(2c)の仮判定及び前記工程(3c)の仮判定に基づき、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程(工程(3d))
を含む方法が挙げられる。該工程(2c)、(3c)、(3d)を含む前記検査方法により、膵臓癌の罹患の可能性を検査する。前記工程(2c)、(3c)、(3d)を含む本発明の検査方法は、初期の膵臓癌、具体的には、ステージ2又はステージ2より初期の膵臓癌、特にステージ1又は2の膵臓癌の罹患について、公知の方法より高い精度で判定できる。
工程(2a)を含む本発明の検査方法により、被検体が膵臓癌に罹患している可能性が高いと判定された場合、本発明の検査方法に、さらに(3a)工程(2a)で膵臓癌に罹患している可能性が高いと判定された被験者に対して膵臓癌の診断方法を適用する工程(工程(3a))を組み合わせることによって、より高い精度で膵臓癌の罹患を診断することができる。また、本発明の検査方法はより高い感度で膵臓癌に罹患している可能性を判断できるので、本発明の検査方法に工程(3a)を組み合わせることによって、真に膵臓癌に罹患している被検体を、より確実に「膵臓癌に罹患している」と診断できる(すなわち、「膵臓癌に罹患していない」と誤診断する可能性、及び工程(3a)の診断対象から除外する可能性をより低減することができる)。
工程(2a)を含む本発明の検査方法により被検体が膵臓癌に罹患している可能性が高いと判定された場合、又は工程(3a)により被検体が膵臓癌であると診断された場合、さらに(4)工程(2a)で膵臓癌に罹患している可能性が高いと判定された被験者、又は工程(3a)で膵臓癌に罹患していると診断された被験者に対して膵臓癌治療を行う工程(工程(4))を行うことによって、被検体の膵臓癌を治療することが可能となる。また、本発明の検査方法はより高い感度で膵臓癌に罹患している可能性を判断できるので、本発明の検査方法又は本発明の検査方法と工程(3a)との組み合わせに対してさらに工程(4)を組み合わせることによって、真に膵臓癌に罹患している被検体を、より確実に治療できる(すなわち、真に膵臓癌に罹患している被検体を治療対象から除外する可能性をより低減することができる)。
本発明は、その一態様において、3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物を含む、膵臓癌の検査薬(本明細書において、「本発明の検査薬」と示すこともある。)に関する。以下、これについて説明する。
(a)糖鎖アレイの作製
3´-sialyl lactose-PAA(GlycoTech Corporation製、カタログ番号:08-038)及びGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAc-PAA(GlycoTech Corporation製、カタログ番号:08-096)を、それぞれ精製水とSpotting Solution(松浪硝子工業製、カタログ番号:DSP0050)を等量に混和した溶液(以下「スポット溶液」と示すこともある。)で希釈して、0.5 mg/mLの希釈溶液を作製した。
生体試料として、健常人25検体、及び膵臓癌患者16検体(ステージ1:1検体、ステージ2:6検体、ステージ3:2検体、ステージ4:7検体)の血清を、和光純薬工業を介して2箇所の病院から入手した。
(抗糖鎖抗体値)=(蛍光強度値)/(血清0.8μL相当に含まれるヒトIgG量)
その結果、図1に示すように健常人に比して膵臓癌患者では、血清中の抗糖鎖抗体値が明らかに低く、膵臓癌の罹患とこれらの抗糖鎖抗体値とが相関していることが示された。
参考例1(b)で求めた、膵臓癌患者16検体(ステージ1:1検体、ステージ2:6検体、ステージ3:2検体、ステージ4:7検体)の各血清中の各抗糖鎖抗体値と、カットオフ値とを比較して、カットオフ値よりも低値の検体を膵臓癌(陽性)と判断した。
参考例1と同様に、膵臓癌患者16検体(ステージ1:1検体、ステージ2:6検体、ステージ3:2検体、ステージ4:7検体)の各血清中のCA19-9の濃度を、市販のキット(ALPCO製、カタログ番号:25-199HU-E01)を用いて測定した。
(a)標準曲線の作製
ビオチン標識3´-sialyl lactose-PAA 0.5 mgを0.8 mLのPBS(リン酸緩衝生理食塩水)に溶解し、全量を0.8 mLのストレプトアビジン-アガロース樹脂(Thermo Scientific製、カタログ番号:20353)に添加し、4℃で12時間攪拌しながら反応させた。反応後、この樹脂をPoly-Prep(登録商標)エンプティーカラム(BIO-RAD製、カタログ番号:731-1550)に充填し、3´-sialyl lactose-PAA固定化カラムを作製した。50mgの健常人血清由来凍結乾燥IgG(和光純薬製、コード番号:289-95341、ロット番号:WDN9152)を5mLの0.1%Tween-20を含むPBSに溶解させ、3´-sialyl lactose-PAA固定化カラムに添加した。その後、カラムを密閉し、4℃で12時間攪拌しながら反応させた。反応後、カラムを解放し、非吸着成分を溶出させた。さらに、カラムを4 mLのPBSで洗浄後、3 mMの 3´-sialyl lactose(東京化成工業製、カタログ番号:S0885)PBS(-)溶液を1mL加えてカラムを密閉し、4℃で3時間攪拌しながら反応させた。反応後、カラムを解放し、抗3-シアリルラクトース糖鎖抗体(ヒトIgG)を溶出させた。さらに、カラムに3mMの 3´-sialyl lactose PBS(-)溶液4mLを添加し、溶出液を回収後、前述の抗3-シアリルラクトース糖鎖抗体溶出液と合わせた。この溶出液を、Amicon(登録商標) Ultra 15 mL(NMWL of 50 kDa, Millipore製、コード番号:UFC905024 )を用いて限外ろ過し、IgG濃度を測定後、抗3-シアリルラクトース糖鎖抗体の標準品とした。
(抗3-シアリルラクトース糖鎖抗体濃度)=372.27x(吸光度)
生体試料として、健常人13検体、及び膵臓癌患者55検体(ステージ1:15検体、ステージ2:15検体、ステージ3:11検体、ステージ4:14検体)の血清を、和光純薬工業を介して米国の病院から入手した。
前記参考例2の結果に基づき、縦軸を感度(陽性率)(%)とし、横軸を100%から特異度(%)を減じた値(100%-特異度(%))(偽陽性率)とするROC曲線を医学統計ソフトGraphPad Prismを用いて作成し、図4に示した。曲線下面積(Area Under the Curve, AUC)は0.87と高値を示し、Youden indexを指標とするカットオフ値は50.08μg/mL(感度=76.36%、特異度=92.31%)であった。ここで、感度とは、膵臓癌(ステージ1、2、3及び4)患者検体を陽性と判定する割合を示し、特異度とは、健常人検体を陰性と判定する割合を示す。この値を基に判定した結果、本検査法は感度76%、特異度92%であった。
参考例2(b)と同様に、健常人13検体、及び膵臓癌患者55検体(ステージ1:15検体、ステージ2:15検体、ステージ3:11検体、ステージ4:14検体)の各血清中のCA19-9の濃度を、市販のキット(Abnova製、カタログ番号:KA0207)を用いて測定した。得られた測定値から、Youden indexを指標とするカットオフ値を算出したところ、24.80 U/mLであった。初期の膵臓癌(ステージ1及び2)患者検体について、この値を基にして陰性(膵臓癌に罹患していない可能性が高い)と判定した例数(偽陰性判定の例数)を数えた。一方、実施例2.で示した、抗3-シアリルラクトース糖鎖抗体濃度を指標とした膵臓癌罹患の判定と前記CA19-9を指標とした膵臓癌罹患の判定のいずれか又は両方において陽性(膵臓癌に罹患している可能性が高い)と判定された例を「陽性」とし、抗3-シアリルラクトース糖鎖抗体濃度を指標とした膵臓癌罹患の判定とCA19-9を指標とした膵臓癌罹患の判定のいずれにおいても陰性(膵臓癌に罹患していない可能性が高い)と判定された例数を偽陰性判定の例数として数えた。
Claims (20)
- 膵臓癌の罹患の可能性を検査する方法であって、
(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程
を含み、
前記抗3-シアリルラクトース糖鎖抗体がNeu5Acα(2→3)Galβ(1→4)Glcで表される糖鎖に結合することができる抗体又は前記糖鎖を認識する抗体であり、且つ
前記抗(LN)3糖鎖抗体がGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される糖鎖に結合することができる抗体又は前記糖鎖を認識する抗体である、方法。 - 前記工程(1)が、
(1a)3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物と、前記生体試料とを接触させる工程、並びに
(1b)前記化合物に結合した抗糖鎖抗体の量を測定する工程
を含む、請求項1に記載の方法。 - さらに、(2a)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程
を含む、請求項1又は2に記載の方法。 - 前記カットオフ値が、膵臓癌に罹患していない被検体から採取された生体試料における前記抗糖鎖抗体の量又は濃度の値の平均値、パーセンタイル値、又は最小値である、請求項3に記載の方法。
- さらに、(2c)前記工程(1)で測定された前記抗糖鎖抗体の量又は濃度の値が、予め設定されたカットオフ値以下である場合に、前記被検体が膵臓癌に罹患している可能性が高いと仮判定する工程、
(3c)前記生体試料における糖鎖膵臓癌マーカーの量又は濃度を測定し、測定された前記糖鎖膵臓癌マーカーの量又は濃度の値が、予め設定されたカットオフ値以上である場合に、前記被検体が膵臓癌に罹患している可能性が高いと仮判定する工程、並びに
(3d)前記工程(2c)の仮判定及び前記工程(3c)の仮判定に基づき、前記被検体が膵臓癌に罹患している可能性が高いと判定する工程を含む、請求項1又は2に記載の方法. - 前記工程(3d)において、前記工程(2c)の仮判定及び前記工程(3c)の仮判定のいずれか又は両方で、前記被検体が膵臓癌に罹患している可能性が高いとの仮判定である場合に、前記被検体が膵臓癌に罹患している可能性が高いと判定する、請求項5に記載の方法.
- 前記抗糖鎖抗体の量又は濃度のカットオフ値が、膵臓癌に罹患していない被検体から採取された生体試料における前記抗糖鎖抗体の量又は濃度の値の平均値、パーセンタイル値、又は最小値である、請求項5又は6に記載の方法.
- 前記糖鎖膵臓癌マーカーが、CA19-9及びDUPAN-2からなる群より選択される少なくとも1種である、請求項5~7のいずれか1項に記載の方法.
- 前記糖鎖膵臓癌マーカーがCA19-9である、請求項8に記載の方法.
- 前記抗糖鎖抗体がIgGである、請求項1~9のいずれか1項に記載の方法。
- 前記生体試料が体液又は体液由来の試料である、請求項1~10のいずれか1項に記載の方法。
- 前記体液が全血、血清、及び血漿からなる群より選択される少なくとも1種である、請求項11に記載の方法。
- 検査対象である前記膵臓癌がステージ0~2の膵臓癌である、請求項1~12のいずれか1項に記載の方法。
- 被検体における抗糖鎖抗体の量又は濃度を測定する方法であって、
(1)被検体から採取された生体試料における抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される少なくとも1種の抗糖鎖抗体の量又は濃度を測定する工程を含み、
前記抗3-シアリルラクトース糖鎖抗体がNeu5Acα(2→3)Galβ(1→4)Glcで表される糖鎖に結合することができる抗体又は前記糖鎖を認識する抗体であり、且つ
前記抗(LN)3糖鎖抗体がGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される糖鎖に結合することができる抗体又は前記糖鎖を認識する抗体である、方法。 - 工程(1)において、抗糖鎖抗体として抗3-シアリルラクトース糖鎖抗体及び抗(LN)3糖鎖抗体からなる群より選択される1種の抗糖鎖抗体のみの量又は濃度を測定する、請求項14に記載の方法。
- 工程(1)が、
3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物を、固相に固定する工程、
固相に固定された化合物と、被検体から採取された生体試料とを接触させる工程、
生体試料と接触させた化合物が固定された固相を、トリスヒドロキシメチルアミノメタン及び/又はエーテル型非イオン界面活性剤を含む溶液で洗浄する工程、
洗浄された固相に、ウシ血清アルブミンを含み、さらにトリスヒドロキシメチルアミノメタン及び/又はエーテル型非イオン界面活性剤を含むブロッキング溶液を添加する工程、並びに
固相に固定された化合物に結合した抗体の量又は濃度を測定する工程を含む、請求項14又は15に記載の方法。 - 3-シアリルラクトース糖鎖構造を含む化合物1及び(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物を含み、
前記3-シアリルラクトース糖鎖構造がNeu5Acα(2→3)Galβ(1→4)Glcで表される糖鎖構造であり、且つ
前記(LN)3糖鎖構造がGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される糖鎖構造である、膵臓癌の検査薬。 - 膵臓癌罹患の可能性の検査薬としての使用のための、Neu5Acα(2→3)Galβ(1→4)Glcで表される3-シアリルラクトース糖鎖構造を含む化合物1及びGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物。
- 膵臓癌の罹患の可能性を検査するための、Neu5Acα(2→3)Galβ(1→4)Glcで表される3-シアリルラクトース糖鎖構造を含む化合物1及びGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物の使用。
- 膵臓癌罹患の可能性の検査薬の製造のための、Neu5Acα(2→3)Galβ(1→4)Glcで表される3-シアリルラクトース糖鎖構造を含む化合物1及びGalβ1→3GlcNAcβ1→3Galβ1→4GlcNAcで表される(LN)3糖鎖構造を含む化合物2からなる群より選択される少なくとも1種の化合物の使用。
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