Method for diagnosis of cancer

Abstract

The present invention provides an examination method, which is a method for examining cancer in a subject, comprising measuring the concentration of an active macrophage apoptosis inhibiting factor (AIM) in blood from the subject, and when the concentration of the active AIM in the blood from the subject is higher than the concentration in a healthy person, determining the concentration of the active AIM in the blood from the subject, and if the concentration of the active AIM in the blood from the subject is lower than the concentration in the healthy person, determining the cancer in the subject. It is determined that the subject has a likelihood of suffering from at least one type of cancer selected from the group consisting of biliary tract cancer and pancreatic cancer.

Description

Technical Field

[0001] The present invention relates to a method for diagnosing cancer using an inhibitor of macrophage apoptosis. Background Art

[0002] Macrophage apoptosis inhibitory factor (AIM, also known as CD5 antigen-like protein (CD5L)) is a protein in the blood produced by tissue macrophages. It is the first protein identified by the inventors as a substance that supports the survival of macrophages. AIM is now recognized as a molecule that induces repair processes in many diseases (non-patent literature 1 to 3). AIM is composed of three cysteine-rich domains (called SRCR domains), and within the third SRCR domain located at the carboxyl terminus, there is a unique cluster of positively charged amino acids. This cluster forms a charge-based interaction with dead cells that are strongly negatively charged due to the high levels of phosphatidylserine exposed on their surface (non-patent literature 1, 2). AIM is efficiently taken up into phagocytes via multiple scavenger receptors, so this binding strongly promotes the phagocytosis of dead cells by phagocytes (non-patent literature 3).

[0003] In humans, AIM exists in the state combined with IgM pentamer usually, but if acute kidney injury etc. occurs, then it is separated into free AIM from IgM pentamer, by combining with dead cells or fragments and promoting their removal. The related mechanism is preserved in most mammals, but it is known that in felines, the combination of AIM and IgM pentamer is very stable, so the related mechanism can't fully play a role (non-patent literature 4). Therefore, in felines, the removal of the dead cell debris in the nephron can't be fully carried out. As a result, felines grow with age, and the dead cell debris is accumulated in the nephron, and renal function is reduced thus, and finally severe chronic renal failure occurs, and uremia occurs and causes death as a result.

[0004] In consideration of such background, the present inventors reported a means for treating or preventing kidney diseases in humans or felines by administering AIM (Patent Document 1).

[0005] However, the association of AIM with cancer has not been reported to date.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: International Publication No. 2015 / 119253

[0009] Non-patent literature

[0010] Non-patent literature 1: Arai, S. et al., Nat Med. 2016 Feb; 22(2): 183-93.

[0011] Non-patent document 2: Tomita, T. et al., Sci Rep. 2017 Jul 25; 7(1): 6450

[0012] Non-patent literature 3: Arai, S. and Miyazaki, T., Semin Immunopathol. 2018 Nov; 40(6): 567-575

[0013] Non-patent document 4: Sugisawa R. et al., Sci Rep. 2016 Oct 12; 6: 35251 Summary of the Invention

[0014] Problems to be solved by the invention

[0015] The present invention aims to provide a novel medical application method of AIM.

[0016] Means for solving problems

[0017] The present inventors measured the concentrations of active AIM and inactive AIM in the blood of patients with various cancers and discovered that whether a subject has a specific cancer can be determined by (1) significantly increasing the amount of active AIM in the blood or (2) determining the ratio of active AIM to the total amount of AIM in the blood (i.e., the amount of active AIM + inactive AIM). Based on these findings, the inventors conducted further studies and completed the present invention.

[0018] That is, the present invention is as follows.

[0019] [1] A method for examining cancer in a subject, comprising measuring the concentration of activated macrophage apoptosis inhibitory factor (AIM) in blood from the subject,

[0020] Here, when the concentration of active AIM in the blood of the subject is higher than that in healthy people, it is determined that the subject is likely to suffer from at least one selected from biliary tract cancer and pancreatic cancer.

[0021] [2] The examination method described in [1], wherein when the concentration of active AIM in the blood from the subject is higher than a cutoff value, it is determined that the subject is likely to suffer from at least one of biliary tract cancer and pancreatic cancer.

[0022] [3] A method for detecting cancer in a subject, comprising measuring the concentrations of activated macrophage apoptosis inhibitory factor (AIM) and inactive AIM in blood from the subject,

[0023] Here, when the ratio of active AIM to total AIM in the blood of a subject is higher than that in a healthy person, the subject is determined to be likely to suffer from at least one selected from the group consisting of pancreatic cancer, biliary tract cancer, squamous cell lung carcinoma, large cell lung carcinoma, multiple myeloma, non-Hodgkin's lymphoma, and esophageal cancer.

[0024] [4] The examination method described in [3], wherein when the ratio of active AIM to total AIM in the blood of the subject is higher than a cutoff value, the subject is determined to be likely to suffer from at least one of pancreatic cancer, biliary tract cancer, squamous cell carcinoma of the lung, large cell carcinoma of the lung, multiple myeloma, non-Hodgkin's lymphoma and esophageal cancer.

[0025] [5] The inspection method according to any one of [1] to [4], wherein the subject is a human.

[0026] Effects of the Invention

[0027] According to the present invention, it is possible to easily examine whether a subject has a specific cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] [ Figure 1 ] Figure 1 It is a diagram showing the structures of active AIM (free AIM) and inactive AIM. DETAILED DESCRIPTION

[0029] The present invention will be described in detail below.

[0030] 1. Cancer screening methods 1

[0031] The present invention provides an examination method (hereinafter sometimes referred to as "examination method 1 of the present invention"), which is a method for examining cancer in a subject, comprising measuring the concentration of activated macrophage apoptosis inhibitory factor (AIM) in blood from the subject, wherein when the concentration of activated AIM in the blood from the subject is higher than the concentration in a healthy person, it is determined that the subject is likely to suffer from at least one selected from biliary tract cancer and pancreatic cancer.

[0032] In the inspection method 1 of the present invention, AIM refers to a protein having an amino acid sequence shown in SEQ ID NO: 1 in humans, for example. AIM exists in active and inactive forms. Figure 1As shown, inactive AIM exists in the blood in the form of binding to IgM pentamers and becomes active AIM by being released from the IgM pentamers. In this specification, "active AIM" is also referred to as "free AIM".

[0033] The method for measuring the concentration of the active AIM present in the blood is not particularly limited, as long as the method known to itself is used to carry out.For example, the concentration of the active AIM contained in the quantitative blood can be measured by using anti-AIM antibodies to carry out ELISA or Western blotting from the serum collected from the experimenter's blood, but is not limited to this. It should be noted that anti-AIM antibodies can be manufactured by the method known to itself. In addition, anti-AIM antibodies can use commercially available antibodies.

[0034] In one embodiment of Method 1 of the present invention, the concentration of active AIM in blood is measured without using an anti-IgM antibody.

[0035] In one embodiment of the examination method 1 of the present invention, a cutoff value can be used to determine whether a subject has a possibility of having cancer.

[0036] The cutoff value that can be used for determination is not particularly limited as long as the desired effect can be obtained, but the following cutoff values can be used:

[0037] [Bile tract cancer]

[0038] Typically 1.00 μg / mL or higher (e.g., 1.10 μg / mL or higher, 1.11 μg / mL or higher, 1.12 μg / mL or higher, 1.13 μg / mL or higher, 1.14 μg / mL or higher, 1.15 μg / mL or higher, 1.16 μg / mL or higher, 1.17 μg / mL or higher, 1.18 μg / mL or higher, 1.19 μg / mL or higher);

[0039] Preferably, it is 1.20 μg / mL or more (e.g., 1.21 μg / mL or more, 1.22 μg / mL or more, 1.23 μg / mL or more, 1.24 μg / mL or more);

[0040] More preferably, it is 1.25 μg / mL or more.

[0041] [Pancreatic cancer]

[0042] Typically 1.00 μg / mL or higher (e.g., 1.10 μg / mL or higher, 1.11 μg / mL or higher, 1.12 μg / mL or higher, 1.13 μg / mL or higher, 1.14 μg / mL or higher, 1.15 μg / mL or higher, 1.16 μg / mL or higher, 1.17 μg / mL or higher, 1.18 μg / mL or higher, 1.19 μg / mL or higher);

[0043] Preferably, it is 1.20 μg / mL or more (e.g., 1.21 μg / mL or more, 1.22 μg / mL or more, 1.23 μg / mL or more, 1.24 μg / mL or more, 1.25 μg / mL or more, 1.26 μg / mL or more, 1.27 μg / mL or more, 1.28 μg / mL or more, 1.29 μg / mL or more);

[0044] More preferably, it is 1.30 μg / mL or more (eg, 1.32 μg / mL or more).

[0045] When the concentration of active AIM in the blood of a subject is above the relevant cutoff value, it can be determined that the subject is likely to suffer from at least one of biliary tract cancer and pancreatic cancer. It should be noted that, in this specification, biliary tract cancer includes bile duct cancer and gallbladder cancer.

[0046] In the inspection method 1 of the present invention, the subject is not particularly limited as long as it is an organism that can suffer from biliary tract cancer or pancreatic cancer. It is usually a primate (such as a human, chimpanzee, macaque, marmoset, etc.), preferably a human.

[0047] 2. Cancer screening methods 2

[0048] The present invention also provides a test method (hereinafter sometimes referred to as "test method 2 of the present invention") for testing a subject for cancer, comprising measuring the concentrations of activated macrophage apoptosis inhibitory factor (AIM) and inactive AIM in blood from the subject, wherein when the ratio of the active AIM to the total AIM amount in the blood from the subject is higher than that in a healthy person, the subject is determined to be likely to have at least one selected from the group consisting of pancreatic cancer, biliary tract cancer, squamous cell lung carcinoma, large cell lung carcinoma, multiple myeloma, non-Hodgkin's lymphoma, and esophageal cancer.

[0049] The AIM, active AIM and its measurement method, inactive AIM, etc. in the inspection method 2 of the present invention are the same as those described in the inspection method 1 of the present invention.

[0050] In the inspection method 2 of the present invention, the concentration of inactive AIM is measured in addition to the active AIM present in the blood.

[0051] The method for measuring the concentration of inactive AIM in blood is not particularly limited, and any known method may be used. For example, the concentration of inactive AIM in blood can be quantified by ELISA or Western blotting, but the method is not limited thereto.

[0052] In one embodiment of Method 2 of the present invention, the concentrations of active AIM and inactive AIM present in the blood are measured without using anti-IgM antibodies.

[0053] In one embodiment of the examination method 2 of the present invention, a cutoff value is used to determine whether a subject has a possibility of having cancer.

[0054] The cutoff value (%) that can be used for determination is not particularly limited as long as the desired effect can be obtained, but the following cutoff values can be used:

[0055] [Pancreatic cancer]

[0056] Typically 16.0% or more (e.g., 16.1% or more, 16.2% or more, 16.3% or more, 16.4% or more, 16.5% or more, 16.6% or more, 16.7% or more, 16.8% or more, 16.9% or more, 17.0% or more, 17.1% or more, 17.2% or more, 17.3% or more, 17.4% or more, 17.5% or more, 17.6% or more, 17.7% or more, 17.8% or more, 17.9% or more);

[0057] Preferably, it is 18.0% or more (e.g., 18.1% or more, 18.2% or more, 18.3% or more, 18.4% or more, 18.5% or more, 18.6% or more, 18.7% or more, 18.8% or more, 18.9% or more, 19.0% or more, 19.1% or more, 19.2% or more, 19.3% or more, 19.4% or more, 19.5% or more, 19.6% or more, 19.7% or more, 19.8% or more, 19.9% or more);

[0058] More preferably, it is 20.0% or more (for example, 20.1% or more, 21.0% or more, 22.0% or more, 23.0% or more, 24.0% or more, or 25.0% or more).

[0059] [Bile tract cancer]

[0060] Typically 20.0% or more (e.g., 20.1% or more, 20.2% or more, 20.3% or more, 20.4% or more, 20.5% or more, 20.6% or more, 20.7% or more, 20.8% or more, 20.9% or more, 21.0% or more, 21.1% or more, 21.2% or more, 21.3% or more, 21.4% or more, 21.5% or more, 21.6% or more, 21.7% or more, 21.8% or more, 21.9% or more);

[0061] Preferably, it is 22.0% or more (e.g., 22.1% or more, 22.2% or more, 22.3% or more, 22.4% or more, 22.5% or more, 22.6% or more, 22.7% or more, 22.8% or more, 22.9% or more, 23.0% or more, 23.1% or more, 23.2% or more, 23.3% or more, 23.4% or more, 23.5% or more, 23.6% or more, 23.7% or more, 23.8% or more, 23.9% or more);

[0062] More preferably, it is 24.0% or more (for example, 24.1% or more, 24.2% or more, 24.3% or more, 24.4% or more, 24.5% or more, 24.6% or more, 24.7% or more, 24.8% or more, 24.9% or more, or 25.0% or more).

[0063] [Squamous cell carcinoma of the lung]

[0064] Typically 16.0% or more (e.g., 16.1% or more, 16.2% or more, 16.3% or more, 16.4% or more, 16.5% or more, 16.6% or more, 16.7% or more, 16.8% or more, 16.9% or more, 17.0% or more, 17.1% or more, 17.2% or more, 17.3% or more, 17.4% or more, 17.5% or more, 17.6% or more, 17.7% or more, 17.8% or more, 17.9% or more);

[0065] Preferably, it is 18.0% or more (e.g., 18.1% or more, 18.2% or more, 18.3% or more, 18.4% or more, 18.5% or more, 18.6% or more, 18.7% or more, 18.8% or more, 18.9% or more, 19.0% or more, 19.1% or more, 19.2% or more, 19.3% or more, 19.4% or more, 19.5% or more, 19.6% or more, 19.7% or more, 19.8% or more, 19.9% or more);

[0066] More preferably, it is 20.0% or more (for example, 20.1% or more, 21.0% or more, 22.0% or more, 23.0% or more, 24.0% or more, or 25.0% or more).

[0067] Or, in another embodiment,

[0068] Typically 27.0% or more (e.g., 27.1% or more, 27.2% or more, 27.3% or more, 27.4% or more, 27.5% or more, 27.6% or more, 27.7% or more, 27.8% or more, 27.9% or more, 28.0% or more, 28.1% or more, 28.2% or more, 28.3% or more, 28.4% or more, 28.5% or more, 28.6% or more, 28.7% or more, 28.8% or more, 28.9% or more);

[0069] Preferably, it is 29.0% or more (e.g., 29.1% or more, 29.2% or more, 29.3% or more, 29.4% or more, 29.5% or more, 29.6% or more, 29.7% or more, 29.8% or more, 29.9% or more, 30.0% or more, 30.1% or more, 30.2% or more, 30.3% or more, 30.4% or more, 30.5% or more, 30.6% or more, 30.7% or more, 30.8% or more, 30.9% or more);

[0070] More preferably, it is 31.0% or more (eg, 31.1% or more).

[0071] [Large cell lung carcinoma]

[0072] Typically 16.0% or more (e.g., 16.1% or more, 16.2% or more, 16.3% or more, 16.4% or more, 16.5% or more, 16.6% or more, 16.7% or more, 16.8% or more, 16.9% or more, 17.0% or more, 17.1% or more, 17.2% or more, 17.3% or more, 17.4% or more, 17.5% or more, 17.6% or more, 17.7% or more, 17.8% or more, 17.9% or more);

[0073] Preferably, it is 18.0% or more (e.g., 18.1% or more, 18.2% or more, 18.3% or more, 18.4% or more, 18.5% or more, 18.6% or more, 18.7% or more, 18.8% or more, 18.9% or more, 19.0% or more, 19.1% or more, 19.2% or more, 19.3% or more, 19.4% or more, 19.5% or more, 19.6% or more, 19.7% or more, 19.8% or more, 19.9% or more);

[0074] More preferably, it is 20.0% or more (for example, 20.5% or more, 21.0% or more, 22.0% or more, 23.0% or more, 24.0% or more, or 25.0% or more).

[0075] [Multiple Myeloma]

[0076] Typically 16.0% or more (e.g., 16.1% or more, 16.2% or more, 16.3% or more, 16.4% or more, 16.5% or more, 16.6% or more, 16.7% or more, 16.8% or more, 16.9% or more);

[0077] Preferably, it is 17.0% or more (e.g., 17.1% or more, 17.2% or more, 17.3% or more, 17.4% or more, 17.5% or more, 17.6% or more, 17.7% or more, 17.8% or more, 17.9% or more, 18.0% or more, 18.1% or more, 18.2% or more, 18.3% or more, 18.4% or more, 18.5% or more, 18.6% or more, 18.7% or more, 18.8% or more, 18.9% or more);

[0078] More preferably, it is 19.0% or more (for example, 19.2% or more, 20.0% or more, 21.0% or more, 22.0% or more, 23.0% or more, 24.0% or more, or 25.0% or more).

[0079] [Non-Hodgkin's lymphoma]

[0080] Typically 16.0% or more (e.g., 16.1% or more, 16.2% or more, 16.3% or more, 16.4% or more, 16.5% or more, 16.6% or more, 16.7% or more, 16.8% or more, 16.9% or more);

[0081] Preferably, it is 17.0% or more (e.g., 17.1% or more, 17.2% or more, 17.3% or more, 17.4% or more, 17.5% or more, 17.6% or more, 17.7% or more, 17.8% or more, 17.9% or more, 18.0% or more, 18.1% or more, 18.2% or more, 18.3% or more, 18.4% or more, 18.5% or more, 18.6% or more, 18.7% or more, 18.8% or more, 18.9% or more);

[0082] More preferably, it is 19.0% or more (for example, 19.1% or more, 20.0% or more, 21.0% or more, 22.0% or more, 23.0% or more, 24.0% or more, or 25.0% or more).

[0083] [Esophageal cancer]

[0084] Typically 16.0% or more (e.g., 16.1% or more, 16.2% or more, 16.3% or more, 16.4% or more, 16.5% or more, 16.6% or more, 16.7% or more, 16.8% or more, 16.9% or more);

[0085] Preferably, it is 17.0% or more (e.g., 17.1% or more, 17.2% or more, 17.3% or more, 17.4% or more, 17.5% or more, 17.6% or more, 17.7% or more, 17.8% or more, 17.9% or more, 18.0% or more, 18.1% or more, 18.2% or more, 18.3% or more, 18.4% or more, 18.5% or more, 18.6% or more, 18.7% or more, 18.8% or more, 18.9% or more);

[0086] More preferably, it is 19.0% or more (for example, 19.2% or more, 20.0% or more, 21.0% or more, 22.0% or more, 23.0% or more, 24.0% or more, or 25.0% or more).

[0087] When the ratio of active AIM to total AIM in the blood of the subject is greater than or equal to the relevant cutoff value, the possibility of suffering from at least one selected from pancreatic cancer, biliary tract cancer, squamous cell lung carcinoma, large cell lung carcinoma, multiple myeloma, non-Hodgkin's lymphoma, and esophageal cancer can be determined.

[0088] In the inspection method 2 of the present invention, the subject is not particularly limited as long as it is an organism that may suffer from pancreatic cancer, biliary tract cancer, squamous cell carcinoma of the lung, large cell carcinoma of the lung, multiple myeloma, non-Hodgkin's lymphoma or esophageal cancer, but is usually a primate (such as humans, chimpanzees, macaques, marmosets, etc.), preferably humans.

[0089] 3. Cancer treatment methods

[0090] The present invention also provides a method for treating cancer in a subject (hereinafter sometimes referred to as "the therapeutic method of the present invention"), comprising the steps of determining whether the subject has cancer using the examination method 1 or 2 of the present invention, and applying a cancer treatment method to the subject determined to have cancer.

[0091] In the therapeutic methods of the present invention, the cancer treatment method is not particularly limited as long as it can treat cancer in a subject. In one embodiment, examples of cancer treatment methods include, but are not limited to, anticancer drug therapy, radiotherapy, and surgery. Preferably, the cancer treatment method is anticancer drug therapy.

[0092] Examples of anticancer agents include, but are not limited to, chemotherapeutic agents, immune checkpoint inhibitors, PARP inhibitors, T cell activation agonists, and angiogenesis inhibitors.

[0093] Examples of chemotherapeutic agents include, but are not limited to, metabolic antagonists, alkaloids, and platinum preparations.

[0094] Examples of metabolic antagonists include, but are not limited to, enocitabine, capecitabine, carmofur, gemcitabine, cytarabine, tegafur, tegafur / uracil, nelarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, and methotrexate. Particularly preferred examples of metabolic antagonists include gemcitabine.

[0095] As an example of an alkaloid, a plant alkaloid can be cited. Preferred examples of a plant alkaloid include irinotecan, etoposide, sobuzoxane, docetaxel, nogitecan, paclitaxel, vinorelbine, vincristine, vindesine, and vinblastine, but are not limited thereto. Preferably, a topoisomerase inhibitor can be cited.

[0096] Preferred examples of platinum preparations include, but are not limited to, oxaliplatin, carboplatin, cisplatin, and nedaplatin. Preferably, carboplatin and cisplatin are mentioned.

[0097] As immune checkpoint inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-TIM3 antibodies or anti-LAG3 antibodies can be mentioned, but are not limited thereto. For example, as examples of anti-PD-1 antibodies, pembrolizumab (CAS accession number: 1374853-91-4), nivolumab (CAS accession number: 946414-94-4), MEDI0680, PDR001, BGB-A317, REGN2810, SHR-1210, PF-0680159I or various known anti-PD-1 antibodies can be mentioned. Examples of anti-PD-L1 antibodies include atezolizumab (CAS Reg. No. 1380723-44-3), avelumab (CAS Reg. No. 1537032-82-8), durvalumab (CAS Reg. No. 1428935-60-7), MDX-1105, and various known anti-PD-L1 antibodies. Examples of anti-CTLA-4 antibodies include ipilimumab (CAS Reg. No. 477202-00-9), tremelimumab (CAS Reg. No. 745013-59-6), and various known anti-CTLA-4 antibodies. Examples of anti-TIM3 antibodies include MBG452 and various known anti-TIM3 antibodies. Examples of anti-LAG3 antibodies include BMS-986016s LAG525 and various known anti-LAG3 antibodies, preferably anti-PD-L1 antibodies.

[0098] Examples of PARP inhibitors include Olaparib, Rucaparib, Niraparib, Veliparib, Pamiparib, and Talazoparib. Preferably, Olaparib is used.

[0099] As T cell activation agonist, the agonist antibody of TNF receptor superfamily (TNFRSF) or the agonist antibody of costimulatory molecule can be enumerated, but is not limited thereto. As the target molecule of " agonist antibody of TNF receptor superfamily ", as long as it is the factor of the cell (such as T cell or NK cell etc.) that activates and expresses TNF receptor superfamily, it is not particularly limited, preferably belongs to " TNF superfamily " or " TNF receptor superfamily " factor. As the factor belonging to " TNF superfamily " or " TNF receptor superfamily ", it is known to contribute to the receptor (Nat.Rev.Immunol., 2012,12,339-51) of the trimeric structure that the ligand with the activation of various immune cells and the trimer structure that the ligand is combined. As factors belonging to the TNF superfamily or the TNF receptor superfamily, for example, CD137, CD137L, CD40, CD40L, OX40, OX40L, CD27, CD70, HVEM, LIGHT, RANK, RANKL, CD30, CD153, GITR, GITRL, TNFRSF25, and TL1A can be mentioned. Preferably, CD137 can be mentioned. For example, as an example of a CD137 agonist antibody, Urelumab (CAS accession number: 934823-49-1), PF-05082566, or various known CD137 agonist antibodies can be mentioned.

[0100] As a preferred example of angiogenesis inhibitor, VEGFR2 antibodies can be cited, but are not limited thereto. Angiogenesis inhibitors prevent the large-scale growth of blood vessels (angiogenesis) required for tumor survival. For example, angiogenesis promoted by tumor cells in order to meet the increased nutritional and oxygen requirements of tumor cells can be blocked by targeting various molecules. As examples of angiogenesis inhibitors, bevacizumab, sorafenib, everolimus, temsirolimus or various well-known angiogenesis inhibitors can be cited.

[0101] The present invention is further specifically described in the following examples, but the present invention is not limited to these examples.

[0102] Example

[0103] [Example 1] Amounts of active AIM in blood from healthy individuals and patients with various cancers and active AIM Ratio relative to the total AIM amount

[0104] To investigate the relationship between AIM in blood and various cancers, the concentrations of active AIM and total AIM in blood from healthy individuals and patients with various cancers were measured.

[0105] [Measurement method]

[0106] The levels of active AIM in serum samples were determined by ELISA using mouse anti-human AIM monoclonal antibodies (clones #11 and #12, produced by the present inventors, that specifically recognize active AIM). For total AIM (i.e., active AIM + inactive AIM), mouse anti-human AIM monoclonal antibodies (clones #6 and #7, produced by the present inventors, that specifically recognize total AIM, available from Immuno-Biological Research Institute, Gunma, Japan) were used. The limits of quantification (LOQ; CV < 30%) for active AIM and total AIM in the above ELISA system were 0.17971936 ng / ml and 0.198454825 ng / ml, respectively. Each step was performed using a Biomek i7 Automated Workstation (Beckman Coulter) and a BioTek 405LS washer (BioTek Instruments, Agilent Technologies).

[0107] Next, the amount of active AIM in serum (μg / mL) or the ratio of active AIM to total AIM (concentration ratio (μg / mL / μg / mL) %) was calculated for the presence (patients) or absence (healthy subjects) of various cancers to create an ROC curve. The cutoff point (cutoff value) was the point on the ROC curve closest to (0, 1) (i.e., the point with complete sensitivity and specificity).

[0108] The results of the measurement of active AIM (non-IgM AIM) are shown in Table 1, and the results of the measurement of the ratio of active AIM to the total AIM amount (%F / T) are shown in Table 2. In addition, the results of the numerical analysis of active AIM are shown in Table 3, and the results of the numerical analysis of the ratio of active AIM to the total AIM amount are shown in Table 4. It should be noted that "*" in Tables 1 and 2 means statistically significant.

[0109] [Table 1] No IgMAIM

[0110]

[0111] [Table 2] %F / T

[0112]

[0113] [Table 3] No IgMAIM

[0114]

[0115] [Table 4] %F / T

[0116]

[0117] As shown in Table 1, it was confirmed that the concentration of active AIM in the blood was significantly higher in patients with biliary tract cancer or pancreatic cancer than in healthy subjects.

[0118] Furthermore, as shown in Table 2, it was confirmed that the ratio of the amount of active AIM to the total amount of AIM in the blood was significantly higher in patients with pancreatic cancer, biliary tract cancer, squamous cell lung carcinoma, large cell lung carcinoma, multiple myeloma, non-Hodgkin's lymphoma, and esophageal cancer compared to healthy subjects.

[0119] Industrial applicability

[0120] According to the present invention, whether a subject has a specific cancer can be easily examined. Therefore, the present invention is extremely useful in medical fields such as cancer screening.

[0121] This application is based on Japanese Patent Application No. 2023-001743 (filing date: January 10, 2023) filed in Japan, the entire contents of which are incorporated herein by reference.

Claims

1. A method for detecting cancer in a subject, comprising measuring the concentration of activated macrophage apoptosis inhibitory factor (AIM) in blood from the subject, Here, when the concentration of active AIM in the blood of the subject is higher than that in healthy people, it is determined that the subject is likely to suffer from at least one selected from biliary tract cancer and pancreatic cancer.

2. The inspection method according to claim 1, wherein when the concentration of active AIM in the blood of the subject is higher than a cutoff value, the subject is determined to have a possibility of suffering from at least one selected from biliary tract cancer and pancreatic cancer.

3. A method for detecting cancer in a subject, comprising measuring the concentrations of activated macrophage apoptosis inhibitory factor (AIM) and inactive AIM in blood from the subject, Here, when the ratio of active AIM to total AIM in the blood of a subject is higher than that in a healthy person, the subject is determined to be likely to suffer from at least one selected from the group consisting of pancreatic cancer, biliary tract cancer, squamous cell lung carcinoma, large cell lung carcinoma, multiple myeloma, non-Hodgkin's lymphoma, and esophageal cancer.

4. The testing method according to claim 3, wherein when the ratio of active AIM to total AIM in the blood of the subject is higher than a cutoff value, the subject is determined to be likely to have at least one selected from the group consisting of pancreatic cancer, biliary tract cancer, squamous cell lung carcinoma, large cell lung carcinoma, multiple myeloma, non-Hodgkin's lymphoma, and esophageal cancer.

5. The inspection method according to any one of claims 1 to 4, wherein the subject is a human.

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