WO2014104305A1 - Diagnostic de la maladie inflammatoire chronique de l'intestin par la mesure de la présepsine - Google Patents

Diagnostic de la maladie inflammatoire chronique de l'intestin par la mesure de la présepsine Download PDF

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WO2014104305A1
WO2014104305A1 PCT/JP2013/085128 JP2013085128W WO2014104305A1 WO 2014104305 A1 WO2014104305 A1 WO 2014104305A1 JP 2013085128 W JP2013085128 W JP 2013085128W WO 2014104305 A1 WO2014104305 A1 WO 2014104305A1
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patient
inflammatory bowel
scd14
bowel disease
concentration
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PCT/JP2013/085128
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Japanese (ja)
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白川　嘉門
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持田製薬株式会社
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases
    • G01N2800/065—Bowel diseases, e.g. Crohn, ulcerative colitis, IBS

Definitions

  • the present invention relates to a method for detecting inflammatory bowel disease unresponsive to a biologic by sCD14-ST (also known as preceptin), a method for selecting a patient with inflammatory bowel disease unresponsive to a biologic, an antibiotic, etc. (An antibiotic and / or a new therapeutic agent for inflammation (for example, anti-CD14 antibody fusion protein, particularly MR1007). The same shall apply hereinafter.)
  • a method for selecting a patient with inflammatory bowel disease to be administered Alternatively, the present invention relates to a method for determining the end timing of administration of the antibiotics or the like in patients with inflammatory bowel disease to which antibiotics or the like are administered.
  • IBD Inflammatory Bowel Disease
  • UC ulcerative colitis
  • This disease has the characteristic that inflammation is chronically repeated, and as a result of repeated remission and relapse, it causes trait abnormalities such as colon cancer and colon perforation.
  • medical treatment at the inflammatory stage is the most important issue because the large intestine excision by surgery is finally necessary.
  • Non-patent Document 3 In addition, in patients who used Humira for a long time, 70% (16 of 23 cases) eventually stopped using (6 invalid cases, 8 diminished effects, 1 side effect, 1 remission after 6 months) There is also a report that the cumulative cancellation rate was 50% at 6 months, 65% at 12 months, and 72% at 24 months (Non-patent Document 3).
  • treatment with a biological product may be performed by switching from a biological product that has no or no therapeutic effect to another biological product.
  • Biological products that are used in the treatment of IBD and that have been tried to be used in clinical trials, etc. target cytokines such as TNF- ⁇ and ⁇ 4 integrins.
  • cytokines such as TNF- ⁇ and ⁇ 4 integrins.
  • BT Bacterial Translocation
  • Antibiotics are not a common choice in the treatment of IBD, but are used for patients with inflammation around the anus and as a combination therapy. Antibiotics are also used in IBD patients suspected of being caused by luminal bacteria. Although antibiotics with a broad antibacterial spectrum are used especially when the causative bacteria are not specified, there is a report that it worsens the intestinal bacterial flora and promotes diarrhea, which is one of the main symptoms of IBD ( Non-patent document 4).
  • Bosani et al. “Biologic targeting in the treatment of inflammatory bowel diseases", Biologics 3 (1): 77-97, July 13, 2009 (Published online).
  • Assa et al. “Long-term outcome of tumor necrosis factor alpha antagonist's treatment in pediatric Crohn's disease”, Journal of Crohn's and Colitis, April 6, 2012 (Published online).
  • McDermott et al. “Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis", Journal of Crohn's and Colitis, April 20, 2012 (Published online).
  • Perencevich & Burakoff "Use of Antibiotics in the Treatment of Inflammatory Bowel Disease", Inflammatory Bowel Disease 12 (7): 651-664, 2006.
  • the initial symptom of IBD patients is inflammation, and general inflammatory markers (CRP, IL-6) are increased.
  • CRP general inflammatory markers
  • IL-6 general inflammatory markers
  • intestinal abnormalities are present but not accompanied by bacterial infection, so an increase in these markers serves as an indicator of the degree of inflammation but does not indicate bacterial infection.
  • SCD14-ST soluble CD14 antigen subtype, also known as preceptin
  • sCD14-ST soluble CD14 antigen subtype, also known as preceptin
  • sCD14-ST is produced in the process of phagocytic cells phagocytosing and digesting foreign microorganisms and foreign substances, and in diseases such as arthritis where local autoimmune reactions and phagocytosis associated with infection occur. It has been reported that it is possible to detect an increase in the sCD14-ST concentration (WO 2009/142303).
  • sCD14-ST is useful as a marker to be used in a method for appropriately selecting patients who should be administered antibiotics in IBD patients and further optimizing the period of administration of antibiotics was investigated. It never happened.
  • An object of the present invention is to appropriately select an IBD patient who needs a new treatment for antimicrobial removal or inflammation (including treatment with anti-CD14 antibody fusion protein, particularly MR1007) in addition to the usual treatment. Moreover, it is providing the method of optimizing the administration period of antibiotics. That is, it aims at solving the subject of proper use of antibiotics etc. in IBD.
  • the present inventors for a normal human, normal inflammatory bowel disease (IBD) patients and biologicals (Remicade (R), the common name infliximab) does not react to (unresponsiveness) 3 groups of IBD patients, blood sample SCD14-ST concentrations were measured and compared. Then, there is no difference in the sCD14-ST concentration between the normal group and the normal IBD patient group, but between the normal group and the normal IBD patient group and the IBD patient group that does not respond to the biologics. A difference was observed in the sCD14-ST concentration in the blood sample, and it was also found that the preceptin concentration in the remicade-unresponsive IBD patient was as high as that in the sepsis patient.
  • IBD normal inflammatory bowel disease
  • R biologicals
  • Presepsin is useful as a new indicator for selecting a subject to be used such as antibiotics among IBD patients, when to end treatment, and for selecting other treatments.
  • the present invention uses the sCD14-ST concentration in a blood sample as an indicator, detection of inflammatory bowel disease unresponsive to a biological product, selection of an inflammatory bowel disease patient unresponsive to a biological product,
  • the present invention provides a method for selecting an inflammatory bowel disease patient to be administered with an antibiotic or the like, or determining the administration end timing of the antibiotic or the like in an inflammatory bowel disease patient receiving an antibiotic or the like. More specifically, the present invention is as described below, for example.
  • the present invention provides, for example, the detection method, selection method, determination method or treatment method described below.
  • (1-1) A method for detecting inflammatory bowel disease unresponsive to a biologic, using the sCD14-ST concentration in a blood sample derived from a subject as an index.
  • (1-2) A method for detecting inflammatory bowel disease unresponsive to a biologic, comprising a step of measuring the sCD14-ST concentration in a blood sample derived from a subject.
  • a method for detecting inflammatory bowel disease unresponsive to a biologic comprising the following steps: 1) a step of measuring the sCD14-ST concentration in a blood sample derived from a subject; 2) comparing the measured value of the sCD14-ST concentration with a reference value; and 3) determining whether the measured value is higher than the reference value.
  • (1-5) The detection method according to any one of (1-1) to (1-4) above, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
  • the biological product is selected from the group consisting of anti-TNF ⁇ antibody, soluble TNF receptor, anti-IL-6 receptor antibody, anti-IL-2 receptor antibody, anti- ⁇ integrin antibody and antisense NF ⁇ B.
  • the detection method according to any one of (1-1) to (1-6), which is at least one of (1-8) The detection method according to any one of (1-1) to (1-7), wherein the reference value is a normal value.
  • (1-10) The detection method according to any one of (1-3) to (1-9), wherein the reference value is 500 pg / mL.
  • (2-1) A method for selecting an inflammatory bowel disease patient to be administered with an antibiotic and / or MR1007, using sCD14-ST concentration in a blood sample derived from the patient as an index.
  • (2-2) A method for selecting an inflammatory bowel disease patient to be administered with an antibiotic and / or MR1007, comprising a step of measuring the sCD14-ST concentration in a blood sample derived from a patient.
  • a method for selecting an inflammatory bowel disease patient to be administered with an antibiotic and / or MR1007 comprising the following steps: 1) a step of measuring the sCD14-ST concentration in a blood sample derived from a patient; 2) comparing the measured value of the sCD14-ST concentration with a reference value; and 3) determining whether the measured value is higher than the reference value.
  • a method for selecting a patient to be administered an antibiotic and / or MR1007 among patients with inflammatory bowel disease comprising the following steps: 1) a step of measuring the sCD14-ST concentration in a blood sample derived from a patient; 2) comparing the measured value of the sCD14-ST concentration with a reference value; and 3) determining whether the measured value is higher than the reference value.
  • the biological product is selected from the group consisting of anti-TNF ⁇ antibody, soluble TNF receptor, anti-IL-6 receptor antibody, anti-IL-2 receptor antibody, anti- ⁇ integrin antibody and antisense NF ⁇ B.
  • the selection method according to (2-7) or (2-8), which is at least one of (2-10) The selection method according to any one of (2-3) to (2-9), wherein the reference value is 500 pg / mL.
  • (3-1) Timing of completion of administration of the antibiotic and / or MR1007 in an inflammatory bowel disease patient to which an antibiotic and / or MR1007 is administered, using the sCD14-ST concentration in a blood sample derived from the patient as an index Decision method.
  • (3-2) Completion of administration of the antibiotic and / or MR1007 in an inflammatory bowel disease patient to which an antibiotic and / or MR1007 has been administered, comprising the step of measuring the sCD14-ST concentration in a blood sample derived from a patient How to determine timing.
  • (3-3) A method for determining the end timing of administration of the antibiotic and / or MR1007 in a patient with inflammatory bowel disease to which an antibiotic and / or MR1007 is administered, comprising the following steps: 1) a step of measuring the sCD14-ST concentration in a blood sample derived from a patient; 2) comparing the measured value of the sCD14-ST concentration with a reference value; and 3) determining whether the measured value is less than or equal to the reference value. (3-4) The determination method according to (3-3), further including the following steps: 4) A step of determining the end of administration of the antibiotic and / or MR1007 to the patient when the measured value is not more than the reference value.
  • the determination method according to (3-6) or (3-7), which is at least one of (3-9) The determination method according to any one of (3-1) to (3-8), wherein the reference value is a normal value.
  • (4-1) A method for treating inflammatory bowel disease unresponsive to a biologic, comprising administering an antibiotic and / or MR1007 using the sCD14-ST concentration in a blood sample derived from a patient as an index.
  • (4-2) A method of treating inflammatory bowel disease, comprising the following steps: 1) measuring sCD14-ST in a blood sample derived from a patient; 2) a step of selecting a patient to be administered with an antibiotic and / or MR1007 using the measured value of sCD14-ST in the sample as an index, and 3) a step of administering an antibiotic and / or MR1007 to the selected patient.
  • the above (4-2), wherein the step of selecting a patient to be administered with an antibiotic and / or MR1007 using the measured value of sCD14-ST in the sample as an index includes the following steps: Method described in: 1) a step of comparing a measured value of sCD14-ST in a sample with a reference value; and 2) a step of selecting a patient as an administration target of an antibiotic and / or MR1007 if the measured value of the sample is higher than the reference value.
  • (4-4) The method according to any one of (4-1) to (4-3) above, further comprising the following steps: 1) measuring sCD14-ST in a blood sample derived from a patient to whom an antibiotic and / or MR1007 is administered over time, 2) a step of comparing the measured value of sCD14-ST in the sample with a predetermined reference value, and 3) if the measured value of the sample falls below the predetermined reference value, the end of administration of the antibiotic and / or MR1007 is determined.
  • Process. (4-5) The method according to any one of (4-1) to (4-4) above, wherein the reference value is a normal value.
  • kits for detecting inflammatory bowel disease unresponsive to a biologic comprising a device for measuring the concentration of sCD14-ST in a blood sample.
  • a kit for detecting inflammatory bowel disease unresponsive to a biologic comprising a device for measuring the concentration of sCD14-ST in a blood sample.
  • the use of the method for measuring the sCD14-ST concentration in a blood sample described below is provided.
  • a method of using a method for measuring sCD14-ST concentration for detecting inflammatory bowel disease unresponsive to a biologic is provided.
  • a method of using a method for measuring sCD14-ST concentration for selecting a patient with inflammatory bowel disease unresponsive to a biologic is provided.
  • a method for treating inflammatory bowel disease by administering an antibiotic comprising administering an antibiotic, comprising the following steps. 1) measuring sCD14-ST in a blood sample derived from a patient; 2) a step of selecting a patient to be administered an antibiotic using the measured value of sCD14-ST in the sample as an index; and 3) a step of administering an antibiotic to the selected patient.
  • (10-2) The method according to (10-1) above, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
  • the inflammatory bowel disease is an inflammatory bowel disease unresponsive to a biological product, and the biological product comprises an anti-TNF ⁇ antibody, a soluble TNF receptor, an anti-IL-6 receptor antibody,
  • a method for treating inflammatory bowel disease by administering MR1007. (11-1) A method for treating inflammatory bowel disease, comprising administering MR1007, comprising the following steps. 1) measuring sCD14-ST in a blood sample derived from a patient; 2) a step of selecting a patient to be administered an antibiotic using the measured value of sCD14-ST in the sample as an index; and 3) a step of administering MR1007 to the selected patient.
  • the inflammatory bowel disease is an inflammatory bowel disease unresponsive to a biological product, and the biological product comprises an anti-TNF ⁇ antibody, a soluble TNF receptor, an anti-IL-6 receptor antibody,
  • FIG. 1 is a diagram showing the measurement results of preceptin concentration in blood samples of 20 normal subjects, 5 inflammatory bowel disease (IBD) patients, and 5 IBD patients who did not respond to remicade treatment.
  • IBD inflammatory bowel disease
  • sCD14-ST soluble CD14 antigen subtype, also known as presepsin
  • sCD14-ST is one of the molecular species of soluble CD14, characterized in that it migrates to a molecular weight of 13 ⁇ 2 kDa in SDS-PAGE under non-reducing conditions, It holds the N end of CD14.
  • sCD14-ST has an amino acid sequence that is greatly deleted on the C-terminal side compared to full-length CD14, and both are different in three-dimensional structure, and thus show different immunogenicity.
  • sCD14-ST has the property of specifically binding to an antibody prepared using a peptide consisting of 16 amino acid residues described in SEQ ID NO: 2 as an antigen.
  • sCD14-ST specifically binds to an antibody that binds to a peptide consisting of the 17th to 26th amino acids of SEQ ID NO: 3, does not bind to 3C10 antibody, and does not bind to MEM-18 antibody.
  • it additionally has any one or more of the characteristics that it has no LPS binding ability and can be obtained from human blood.
  • sCD14-ST has a feature that it has the amino acid sequence of SEQ ID NO: 1 at the N-terminal sequence. More specifically, it is specified by the feature that the N-terminus is position 1 of the amino acid sequence shown in SEQ ID NO: 3 and the C-terminus is any one of positions 59 to 90 of the amino acid sequence shown in SEQ ID NO: 3. Can do. sCD14-ST is disclosed in detail in WO 2005/108429. In the present specification, sCD14-ST means human sCD14-ST unless otherwise specified.
  • Measurement of sCD14-ST in a blood sample can be performed by a known method or a known device.
  • an immunoassay system that specifically detects sCD14-ST disclosed in International Publication No. 2004/044005 or International Publication No. 2005/108429 can be used.
  • An antibody prepared by using a peptide consisting of 16 amino acid residues described in SEQ ID NO: 2 as an antigen is an antibody that specifically detects sCD14-ST. Therefore, sCD14-ST may be measured using this antibody.
  • a sandwich immunoassay system using a combination with an antibody that competes with F1106-13-3 antibody or F1031-8-3 antibody is preferable.
  • the antibody produced using a peptide consisting of 16 amino acid residues described in SEQ ID NO: 2 as an antigen is also an antibody that specifically binds to a peptide consisting of 16 amino acid residues described in SEQ ID NO: 2.
  • any of a quantitative value, a semi-quantitative value, or a qualitative value may be used.
  • the sCD14-ST concentration can be displayed in stages such as 0, 1, 2, 3 or-, +, ++, +++. Since this stage correlates with the quantitative sCD14-ST concentration, whether or not the sCD14-ST concentration is equal to or higher than a predetermined reference value depends on the correlation between the semi-quantitative step display and the quantitative sCD14-ST concentration.
  • less than the reference value may be set to a stage such as 0 or ⁇ .
  • it may be set to be negative when the value is less than the reference value and positive when the value is equal to or more than the reference value.
  • the blood sample is not particularly limited, and any of whole blood, plasma, and serum may be used.
  • the blood sample may be a sample to which an anticoagulant such as EDTA, heparin, or citric acid is added after blood collection.
  • the sCD14-ST concentration in a blood sample derived from a subject or a patient may be measured over time. This is because detection, selection, or determination can be performed at a more appropriate timing by performing measurement over time.
  • timing of measurement when it is suspected that the biologic product is unresponsive, or when it is necessary to determine the start, end or continuation of antibiotic administration, from the first sCD14-ST concentration measurement day, every day, What is necessary is just to set suitably every 2nd day or the 3rd day, the 5th day, and / or the 7th day.
  • the biological preparation is not particularly limited as long as it can be used for the treatment of inflammatory bowel disease.
  • examples of the biological preparation include Remicade (R) (generic name: Infliximab: Mitsubishi Tanabe Pharma, St.
  • Humira (generic name: adalimumab: Abbott Laboratories), Simpony (R) (generic name: Golimumab: Janssen Pharma) ), Simdia (R) (generic name: Centrizumab Pegor: UCB Pharma) and other TNF ⁇ antibodies; Embrel (R) (generic name: Etanercept: Weiss) and other soluble TNF receptors; Actemra (R) (generic name: Tocilizumab: Chugai pharmaceutical) anti-IL-6 receptor antibody such as; Simulect (R) (generic name basiliximab: anti IL-2 receptor antibody of Novartis Pharma), and the like; TYSABRI (R) (generic name natalizumab: Elan Pharma International) anti such ⁇ 4 integrin antibody; Orencia (R (Generic name abatacept: Bristol-Myers Squibb) CD28-CD80 / 86 interaction inhibitors such
  • an immunosuppressive agent is preferable, and it is selected from the group consisting of anti-TNF ⁇ antibody, soluble TNF receptor, anti-IL-6 receptor antibody, anti-IL-2 receptor antibody, anti- ⁇ integrin antibody and antisense NF ⁇ B. More preferred is at least one selected.
  • the anti-TNF ⁇ antibody is preferably an anti-human TNF ⁇ monoclonal antibody or a PEGylated derivative thereof. Specific examples of the PEGylated derivative include a derivative obtained by binding polyethylene glycol (PEG) to a Fab ′ fragment excluding the Fc region of the anti-human TNF ⁇ monoclonal antibody.
  • Soluble TNF receptors include TNFR derivatives, and specifically, a fusion protein of the extracellular domain of human TNFR-II and the Fc region of human IgG1 is preferred.
  • anti-TNF ⁇ antibodies include Remicade (R) (generic name: infliximab; Human TNF ⁇ monoclonal antibody formulation), Humira (R) (generic name adalimumab; human anti-human TNF ⁇ monoclonal antibody formulation) or Simdia (R) (generic name centrizumab pegol; PEGylated anti-human TNF ⁇ monoclonal antibody formulation) are preferred, soluble TNF
  • the receptor is preferably usinel (R) (generic name etanercept; fully human soluble TNF ⁇ / LT ⁇ receptor preparation), and the anti- ⁇ 4 integrin antibody is
  • the inflammatory bowel disease is preferably Crohn's disease or ulcerative colitis.
  • Crohn's disease may be diagnosed according to conventionally known diagnostic criteria. However, longitudinal ulcers, paving stones, or non-drying characteristics are confirmed by X-ray examinations (barium small bowel and barium enema examinations) and endoscopic examinations. Preferably, characteristic findings such as epithelioid granuloma are observed.
  • the method for evaluating the severity of Crohn's disease is not particularly limited, but it is preferable to use an IOIBD assessment score or CDAI (Crohn's disease activity index).
  • CDAI consists of (1) number of watery or loose stools, (2) degree of abdominal pain, (3) subjective general condition, (4) presence of extraintestinal complications, (5) use of antidiarrheal drugs, (6 It is an index obtained by scoring and adding the weight of abdominal mass, (7) hematocrit, and (8) body weight.
  • 150-220 is mild
  • 220-300 is moderate
  • 300-450 is severe
  • 450 or more is severe.
  • Diagnosis and severity of ulcerative colitis Diagnosis of ulcerative colitis may be performed according to conventionally known diagnostic criteria, but other enteritis is based on clinical symptoms, endoscopic findings, enema X-ray findings, pathological findings (cell examination). It is preferably performed by excluding (infectious enteritis, drug enteritis, radiation enteritis, ischemic enteritis, Crohn's disease, etc.).
  • the method for evaluating the severity of ulcerative colitis is not particularly limited, but it is preferable to make a determination based on, for example, the degree of bloody stool and diarrhea, the presence or absence of fever, tachycardia and anemia, and blood tests.
  • the reference values are a group of patients with inflammatory bowel disease unresponsive to biological products, and normal and normal IBD patients (not “people with inflammatory bowel disease unresponsive to biological products”). This is the sCD14-ST concentration in the blood sample that is set in advance to distinguish it from the population of IBD patients).
  • the reference value may be set to a value with good screening efficiency so that a balance between false positives and false negatives can be achieved, and the frequency of occurrence of inflammatory bowel disease patients who have not responded to biologics has rapidly increased.
  • the starting value may be set, a pathologically or physiologically theoretical value may be set, or a statistically determined value may be set.
  • the reference value is obtained, for example, by calculating an average value and a standard deviation (SD) of measured values of sCD14-ST concentration in a blood sample of a medically healthy person, and a range of the average value +0.5 SD to +5 SD
  • the average value + SD, the average value + 2SD, the average value + 3SD, etc. may be set, or the average value of 5 to 95, 10 to 90, 15 to 85, or 25 to 75 percentile value may be set. May be.
  • the reference value is preferably set to the average value + 2SD or the average value + 3SD. Specific numerical values include 500 pg / mL or 600 pg / mL, preferably 600 pg / mL, but are not limited thereto.
  • Antibiotics are not particularly limited, for example, penicillin, penem, carbapenem, cephem, monobactam, fosfomycin, glycopeptide, amino acid glycoside, macrolide, ketolide, lincomycin, Antibiotics such as tetracyclines, new quinolones, sulfonamides, oxazolidinones, streptogramins, and azoles can be used, and one or more of these antibiotics can be appropriately selected and used.
  • an anti-CD14 antibody fusion protein preferably MR1007 (Nakamura et al., Critical Care 11 (Supp. 4): P4, 2012 ) And / or anti-IL-6 antibodies (Mudter & Neurath, Inflammatory & Bowel & Disease < 13 (8) > 1016-1023, 2007).
  • the anti-CD14 antibody fusion protein is a fusion protein containing an anti-CD14 antibody and a proteolytic enzyme inhibitor, and the MR1007 comprises an anti-CD14 antibody and a modified light chain (serine protease inhibitory active fragment) of an inter- ⁇ inhibitor. It is a fusion protein.
  • the anti-CD14 fusion protein may have an effect of preventing the severity of bacterial infection by targeting membrane-bound CD14 and blood coagulation protease.
  • IL-6 is an inflammatory cytokine similar to TNF ⁇ , and has various actions such as activation of T cells and B cells and induction of C-reactive protein (CRP). If inflammation is present, the concentration of IL-6 will increase along with CRP. In active IBD patients, serum and intestinal mucosa, especially intestinal mucosa, have increased IL-6 concentrations, which have been suggested for some time to be associated with disease states. In addition, when IL-6 binds to a receptor, a signal is transmitted into the cell through the JAK-STAT pathway, but it has been proved that dysregulation of the JAK-STAT pathway is involved in inflammation and carcinogenesis. Therefore, inhibition of excessive signal transduction with an anti-IL-6 antibody may prevent not only the improvement of IBD but also the occurrence of colorectal cancer.
  • CRP C-reactive protein
  • an anti-CD14 fusion protein or MR1007 or anti-IL-6 antibody is administered instead of or together with an antibiotic
  • selection of these administration subjects using the sCD14-ST concentration as an index, Administration start, administration end and / or continuation of administration can be determined.
  • Antibiotics and MR1007 are preferably formulations with the following information: 1) A preparation that is administered to a patient with inflammatory bowel disease that is unresponsive to a biological preparation, using the sCD14-ST concentration in a blood sample derived from a subject as an index. 2) A preparation for detecting an inflammatory bowel disease patient who is unresponsive to a biological preparation, using the sCD14-ST concentration in a blood sample derived from the subject as an index, and administering it to the patient. 3) A preparation for measuring a sCD14-ST concentration in a blood sample derived from a patient with inflammatory bowel disease, selecting a patient with inflammatory bowel disease to be administered, and administering it to the patient.
  • the above information can be provided in the package insert, interview form, brochure, instructions, etc. of the formulation, and can be provided simultaneously with the formulation or separately.
  • Detection method, selection method, determination method and treatment method 1. Method for Detecting Inflammatory Bowel Disease Unresponsive to Biological Product
  • a biologic agent which uses sCD14-ST concentration in a blood sample derived from a subject as an index
  • a method for detecting a disease is provided.
  • this detection method it is possible to perform efficient screening by detecting inflammatory bowel disease unresponsive to biological products using sCD14-ST concentration in a blood sample derived from a subject as an index. Inflammatory bowel disease unresponsive to biologics can be detected earlier. As a result, appropriate treatment can be performed earlier and an improvement in the overall outcome can be expected.
  • the subject is not particularly limited, and inflammatory bowel disease may or may not be diagnosed.
  • a subject who has been diagnosed with inflammatory bowel disease may be referred to as a patient.
  • the patient is a patient who needs treatment with a biological product or is actually receiving treatment with a biological product.
  • Calprotectin measurement may be used to identify patients with inflammatory bowel disease.
  • the inflammatory bowel disease unresponsive to a biological product is not particularly limited as long as it is an inflammatory bowel disease unresponsive to at least one biological product, and may not respond from the start of treatment. However, the reaction may have occurred at the start of the treatment, but the effect may be reduced due to the continuation of treatment and the reaction may stop.
  • an inflammatory bowel disease that is unresponsive to a biological product is treated with a biological product, even if it is not actually treated with the biological product.
  • Inflammatory bowel disease which may be unresponsive to active formulations. It may also be an inflammatory bowel disease with bacterial infection.
  • the method for detecting inflammatory bowel disease unresponsive to the biological preparation of the present invention preferably comprises a step of measuring the sCD14-ST concentration in a blood sample derived from a subject. 1) In a blood sample derived from a subject measuring the sCD14-ST concentration; 2) comparing the measured value of the sCD14-ST concentration with a reference value; and 3) determining whether the measured value is higher than the reference value. More preferably, further comprising 4) a step of determining that an unresponsive inflammatory bowel disease is detected in the biological product when the measured value is higher than the reference value. .
  • a step of preparing a blood sample derived from the subject may be provided before the step of measuring the sCD14-ST concentration in the blood sample derived from the subject.
  • the detection method of the present invention can be performed in vitro.
  • a normal value set based on the measured value of sCD14-ST in a blood sample of a healthy person can be used.
  • an average value of sCD14-ST measurement results in a blood sample of a healthy person or a value obtained by standardizing the measurement results by setting a range, for example, can be used.
  • the background value in the measurement system is a measurement value when a buffer or an assay solution is added to the measurement system instead of a specimen.
  • the values obtained by standardizing the measured values of the specimens derived from the subjects are the average value of healthy individuals +0.5 SD to +5 SD (SD is the standard deviation), and the measured values of healthy persons 5 to 95, 10 to 90, 15 to 85, or 25 to A 75th percentile value or the like can be used. Preferably, it is the average value of healthy individuals + SD, + 2SD or + 3SD.
  • the method for detecting IBD that is unresponsive to the biological product of the present invention can be paraphrased as a method for selecting an IBD patient who is unresponsive to the biological product to which antibiotics and / or MR1007 are administered.
  • a subject in whom an IBD that is unresponsive to a biologic is detected is a patient likely to be an IBD that is unresponsive to the biologic and is a suitable subject for antibiotic and / or MR1007 administration.
  • antibiotics and / or MR1007 should be administered if the IBD is unresponsive to the biologic.
  • an IBD patient who does not respond to a biological product to which an antibiotic and / or MR1007 is administered is characterized by measuring sCD14-ST in a blood sample derived from a patient.
  • a method is provided. In the method for selecting an IBD patient who does not respond to a biological product to which the antibiotic of the present invention and / or MR1007 is administered, the embodiment in the method for detecting IBD not responding to a biological product can be applied as it is.
  • antibiotics and the like using sCD14-ST concentration in a blood sample derived from a patient as an index.
  • a therapeutic agent against inflammation for example, anti-CD14 antibody fusion protein, particularly MR1007.
  • this selection method by selecting sCD14-ST concentration in a blood sample derived from a patient as an index, by selecting an inflammatory bowel disease patient to be administered an antibiotic or the like from inflammatory bowel disease patients, Subjects to which antibiotics and the like should be administered can be appropriately selected. As a result, patients who need treatment with antibiotics are treated. Survival rate, incidence of complications, incidence of infectious diseases and side effects, occurrence of surgical procedures (colectomy, etc.) Improvements in rates, patient functional health, patient QOL, treatment satisfaction, etc. can be expected.
  • the patient is not particularly limited as long as it is a patient with inflammatory bowel disease, and may or may not be treated with a biologic.
  • the patient is a patient in need of treatment with a biologic or is actually undergoing treatment with a biologic.
  • the method for selecting an inflammatory bowel disease patient to be administered with the antibiotic of the present invention preferably comprises a step of measuring the sCD14-ST concentration in a patient-derived blood sample.
  • a patient-derived blood sample Measuring the sCD14-ST concentration therein; 2) comparing the measured value of the sCD14-ST concentration with a reference value; and 3) determining whether the measured value is higher than the reference value
  • a step of preparing a patient-derived blood sample may be provided before the step of measuring the sCD14-ST concentration in the patient-derived blood sample.
  • the measured value of sCD14-ST in the sample is an indicator of whether or not the IBD patient is unresponsive to the biological product
  • the measured value of the sCD14-ST concentration is compared with a predetermined reference value.
  • the normal value set based on the measured value of sCD14-ST in the blood sample of a healthy person described in the embodiment can be used as the reference value.
  • the reference value For example, the average value of healthy individuals + SD, + 2SD, or + 3SD. If the measured value of sCD14-ST falls within the normal range, it can be considered that the IBD has been cured or ameliorated to a level equivalent to that of a healthy person.
  • a cut-off value set so that the sensitivity and / or specificity of detection can be optimized can be used as a reference value. For example, 500 pg / mL or 600 pg / mL is mentioned, Preferably it is 600 pg / mL, However It is not limited to these.
  • the method for selecting an inflammatory bowel disease patient to be administered with the antibiotic or the like of the present invention is the above-mentioned “4)
  • the patient is administered with the antibiotic or the like.
  • the step of selecting as a target to be performed “when the measured value is higher than the reference value, the step of selecting the patient as a patient to start administration of an antibiotic etc.”
  • the same description is “the step of determining the start of administration of antibiotics to the patient when the measured value is higher than the reference value”, so that the timing of the start of administration of antibiotics, etc. in IBD patients It can be paraphrased as a determination method.
  • antibiotics using sCD14-ST concentration in a blood sample derived from a patient as an index Etc refers to antibiotics and / or therapeutic agents for inflammation (for example, anti-CD14 antibody fusion protein, particularly MR1007)) in patients with inflammatory bowel disease
  • an index Etc refers to antibiotics and / or therapeutic agents for inflammation (for example, anti-CD14 antibody fusion protein, particularly MR1007)) in patients with inflammatory bowel disease
  • this determination method it is possible to determine an appropriate timing for terminating antibiotic administration in patients with inflammatory bowel disease to which antibiotics or the like are administered, using the sCD14-ST concentration in the blood sample derived from the patient as an index.
  • treatment with antibiotics is terminated at an appropriate time, and unnecessary antibiotics are not administered, resulting in the survival rate, incidence of complications, incidence of infections and side effects in the patient. Improvements in the incidence of surgical procedures (such as colectomy), functional health of patients, patient QOL, treatment satisfaction, etc. can be expected.
  • the patient is not particularly limited as long as it is an inflammatory bowel disease patient to whom an antibiotic or the like is administered, and may or may not be treated with a biologic.
  • the patient is preferably a patient who has been administered antibiotics and needs to be treated with a biologic or is actually receiving treatment with a biologic.
  • the method for determining the end timing of administration of an antibiotic or the like in an inflammatory bowel disease patient to which an antibiotic or the like of the present invention is administered comprises a step of measuring the sCD14-ST concentration in a blood sample derived from the patient. 1) a step of measuring the sCD14-ST concentration in a blood sample derived from a patient; 2) a step of comparing the measured value of the sCD14-ST concentration with a reference value; and 3) the measured value is less than or equal to the reference value It is more preferable to include a step of determining whether or not, and 4) a step of determining the end of administration of the antibiotic or the like to the patient when the measured value is lower than the reference value. Is more preferable.
  • a step of preparing a patient-derived blood sample may be provided before the step of measuring the sCD14-ST concentration in the patient-derived blood sample.
  • the measured value of sCD14-ST in the sample is an indicator of whether or not the IBD patient is unresponsive to the biological product. Therefore, by comparing the measured value of the specimen with a predetermined reference value, it is possible to determine the end timing of administration of the antibiotic or the like in the inflammatory bowel disease patient who is being treated with the antibiotic or the like. More specifically, when the measured value falls below the reference value, it can be determined that an IBD that has not responded to a biologic is in remission, severity is no longer severe, or no longer active, such as antibiotics The end of administration can be determined.
  • the reference value used in the method for determining the end timing of administration of the antibiotic of the present invention may be any value that can confirm the success of the antibiotic.
  • a value such as 1/2, 1/5, or 1/10 of the measured value of sCD14-ST measured from before administration of antibiotics to 24 hours after the start of administration can be set as the reference value.
  • the normal value set based on the measured value of sCD14-ST in the blood sample of a healthy person described in the embodiment can be used as the reference value.
  • the measured value of sCD14-ST in the blood sample of a healthy person, an IBD patient who is not responsive to the biological product, and an IBD patient who is not responsive to the biological product can be used as a reference value.
  • 500 pg / mL or 600 pg / mL is mentioned, Preferably it is 600 pg / mL, However It is not limited to these.
  • the method for selecting an inflammatory bowel disease patient to be administered with the antibiotic or the like of the present invention is the above-mentioned “4)
  • the antibiotic for the patient when the measured value is lower than the reference value is the above-mentioned “4)
  • the step of determining the end of administration such as “when the measured value is lower than the reference value
  • the step of selecting the patient as a patient to end the administration of antibiotics is the same description as “a step of selecting the patient as a patient to continue administration of antibiotics when the measured value is higher than the reference value”.
  • it can be paraphrased as a method of selecting patients with inflammatory bowel disease.
  • a method of treating IBD uses a measured value of sCD14-ST in a blood sample derived from a subject as an index, in addition to the usual treatment, a new treatment method (anti-CD14 antibody fusion protein, particularly MR1007) for removal of bacteria by antibiotics and inflammation.
  • a method of treating IBD by administering an antibiotic or the like to the selected patient Specifically, as described in 2. above. An IBD patient to be administered an antibiotic or the like is selected by the method described in the embodiment, and the antibiotic or the like is administered to the selected patient. In addition, the 3. By determining the end timing of administration of antibiotics or the like by the method described in the embodiment, more efficient treatment can be performed.
  • Antibiotics and the like used in the embodiment described in 1) are not particularly limited, but antibiotics that can be used at least for IBD are suitable. Examples include penicillins, penems, carbapenems, cephems, monobactams, fosfomycins, glycopeptides, amino acid glycosides, macrolides, ketolides, lincomycins, tetracyclines, new quinolones, sulfonamides And antibiotics such as oxazolidinone, streptogramin, and azole. One or more of these antibiotics can be appropriately selected and used. Preference is given to the new quinolone series used in IBD, in particular ciprofloxacin (Ciproxan (R) ), or the azole series, especially metronidazole (Frazil (R) ).
  • an anti-CD14 antibody fusion protein (see International Publication No. 2006/1229849), preferably MR1007 (Nakamura et al., Critical Care 11 (Supp. 4): P4, 2012 ) And / or anti-IL-6 antibodies (Mudter & Neurath, Inflammatory Bowel Disease 13 (8): 1016-1023, 2007).
  • the anti-CD14 antibody fusion protein is a fusion protein containing an anti-CD14 antibody and a proteolytic enzyme inhibitor, and the MR1007 comprises an anti-CD14 antibody and a modified light chain (serine protease inhibitory active fragment) of an inter- ⁇ inhibitor. It is a fusion protein.
  • the anti-CD14 fusion protein may have an effect of preventing the severity of bacterial infection by targeting membrane-bound CD14 and blood coagulation protease.
  • Kit comprising a device for measuring the concentration of sCD14-ST in a blood sample
  • detection of inflammatory bowel disease unresponsive to a biological product comprising a device for measuring the concentration of sCD14-ST in a blood sample
  • a kit is provided.
  • the detection kit of the present invention comprises, as desired, an antibody (anti-preceptin antibody) prepared using a peptide consisting of 16 amino acid residues described in SEQ ID NO: 2 as an antigen, from the 17th to 26th amino acid sequences described in SEQ ID NO: 3. And at least one selected from the group consisting of an antibody that binds to the peptide, a multiwell plate, and a spectrophotometer.
  • This kit preferably measures the sCD14-ST concentration in a blood sample by a sandwich immunoassay.
  • Method for detecting inflammatory bowel disease unresponsive to biological products are administered. This is a method (use) of using a method for measuring the concentration of sCD14-ST in a blood sample in a method for selecting an IBD patient who does not respond to a biologic.
  • ulcerative colitis requires attention to responsiveness to medical treatment, complications due to drugs, etc. for severe cases and intermediate cases with systemic disorders.
  • unnecessary drug therapy can be suppressed, which is useful.
  • a fatal course may occur due to side effects (such as opportunistic infections such as MRSA infection) caused by therapeutic agents having an immunosuppressive effect. Therefore, it is highly useful to perform treatment effect determination etc. at an early stage by the method of the present invention.
  • PROSEP (R) -A Protein A column
  • the collected non-adsorbed fraction was concentrated and purified by gel filtration (Superdex 75, GE Healthcare) to separate the contained F (ab ′) 2 and Fab.
  • the obtained F (ab ′) 2 was concentrated and dialyzed against 10 mM carbonate buffer (pH 9.5).
  • 2 Next, according to the method of Nakane et al. (J. Histochem. Cytochem., 22, 1084, 1974), 1 mg of peroxidase (Toyobo) was dissolved in distilled water, and 100 mM periodic acid dissolved in distilled water was dissolved. The mixture was added and reacted at 25 ° C. for 15 minutes. After completion of the reaction, 1.5% ethylene glycol was added, reacted at 25 ° C.
  • Table 1 shows the specimen number, diagnosis (diagnostic disease name), symptom, condition (disease activity), and IBD treatment history for 5 IBD patients and 5 IBD patients who did not respond to Remicade.
  • diagnosis diagnosis
  • symptom diagnosis
  • condition diagnosis activity
  • IBD treatment history for 5 IBD patients and 5 IBD patients who did not respond to Remicade.
  • sandwich ELISA system prepared in “1. Preparation of blood presepsin measurement system”, each purchased specimen was diluted 20 times and the preceptin concentration was measured.
  • Table 1 shows the preceptin concentrations of 5 IBD patients and 5 IBD patients who did not respond to remicade.
  • the preceptin concentration of 465 ⁇ 105 pg / mL (mean value ⁇ SD) of IBD patients (5 cases) was comparable to the preceptin concentration of 346 ⁇ 109 pg / mL (mean value ⁇ SD) of normal patients (20 cases).
  • the preceptin concentration of Remicade unresponsive patients (5 cases) was as high as 13441 ⁇ 23623 pg / mL (mean value ⁇ SD, range 513 to 55562 pg / mL).
  • Antibiotic treatment in IBD patients is not used as a general treatment method.
  • by measuring the preceptin concentration in the specimen for example, by adopting a cutoff value of 600 pg / mL as reported by Endo et al. (Infect Chemother. 2012 Jun 13) as a reference value, in the diagnosis of infection in IBD patients, and It has been shown that it can be used to select, use and / or discontinue treatment methods such as antibiotics.
  • the concentration of presepsin is generally low, but by measuring the blood presepsin concentration, in IBD that is not classified as an infectious disease, severe infection caused by infection It could be used to detect IBD patients and to select IBD patients whose bacterial infection is related to aging, relapse of disease or activity.
  • an IBD patient to be administered an antibiotic or the like refers to an antibiotic and / or a therapeutic agent for inflammation (for example, anti-CD14 antibody fusion protein, particularly MR1007)).
  • an antibiotic and / or a therapeutic agent for inflammation for example, anti-CD14 antibody fusion protein, particularly MR1007
  • the administration period of antibiotics can be shortened by determining the timing of the end of administration of antibiotics etc. using the sCD14-ST concentration in the blood sample as an index.

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Abstract

L'invention concerne un procédé de détection d'une maladie inflammatoire chronique de l'intestin insensible à des préparations biologiques ; un procédé de sélection d'un patient atteint d'une maladie inflammatoire chronique de l'intestin insensible à des préparations biologiques ; un procédé de détermination du temps d'achèvement de l'administration d'un antibiotique, etc., à un patient ayant une maladie inflammatoire chronique de l'intestin, ledit patient étant soumis à l'administration de l'antibiotique, etc. ; ou une méthode de traitement d'un patient atteint d'une maladie inflammatoire chronique de l'intestin insensible à des préparations biologiques, ladite méthode comprenant l'administration d'un antibiotique, etc., chaque procédé utilisant la concentration de sCD14-ST (également connu en tant que présepsine) dans un échantillon sanguin comme indice.
PCT/JP2013/085128 2012-12-28 2013-12-27 Diagnostic de la maladie inflammatoire chronique de l'intestin par la mesure de la présepsine WO2014104305A1 (fr)

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