WO2006054806A1 - Autoantigène associé à la maladie de crohn - Google Patents

Autoantigène associé à la maladie de crohn Download PDF

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Publication number
WO2006054806A1
WO2006054806A1 PCT/JP2005/021937 JP2005021937W WO2006054806A1 WO 2006054806 A1 WO2006054806 A1 WO 2006054806A1 JP 2005021937 W JP2005021937 W JP 2005021937W WO 2006054806 A1 WO2006054806 A1 WO 2006054806A1
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WIPO (PCT)
Prior art keywords
disease
ube4a
crohn
antibody
protein
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PCT/JP2005/021937
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English (en)
Japanese (ja)
Inventor
Toshio Sakiyama
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Locomogene, Inc.
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Publication of WO2006054806A1 publication Critical patent/WO2006054806A1/fr

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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
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/9015—Ligases (6)

Definitions

  • the present invention relates to a diagnostic marker for Crohn's disease comprising an antibody against ubiquitination factor E4A protein or a fragment thereof, and a method for diagnosing or prognosing Crohn's disease using the diagnostic marker.
  • Crohn's disease is an inflammatory disease of the gastrointestinal tract.
  • Crohn's disease is considered to be an autoimmune disease caused by impaired immune system regulation. Dysregulation of the immune system is thought to play a central role in the pathogenesis of Crohn's disease, but the clear cause of the persistent inflammatory response in Crohn's disease patients has not yet been elucidated. Disclosure of the invention
  • An object of the present invention is to provide a Crohn's disease diagnostic marker containing an antibody against the ubiquitination factor E4A protein or a fragment thereof, and a method for diagnosing or prognosing Crohn's disease.
  • the present inventor has changed the constituent molecules of ubiquitination factors in serum collected from Crohn's disease patients and healthy subjects in comparison with Crohn's disease patients and healthy subjects. We examined whether there was something. As a result, the inventor has found that autoantibodies to ubiquitination factors are useful markers in the diagnosis of Crohn's disease, and have completed the present invention.
  • a diagnostic marker for clone disease including an antibody against ubiquitination factor E4A protein or a fragment thereof.
  • a clone disease detection reagent comprising an antibody against ubiquitination factor E4A protein or a fragment thereof.
  • a method for detecting or diagnosing whether or not a subject suffers from Crohn's disease comprising the following steps:
  • a method for evaluating whether or not the disease has progressed in a patient suffering from Crohn's disease comprising the following steps:
  • step (c) The step of associating the measurement result of step (b) with the progression of the disease
  • the sample includes, but is not limited to, serum, blood, cells and tissues.
  • Figure 1 is a photograph showing the serum response of a patient with Crohn's disease (CD) to UBE4A.
  • FIG. 2 is a photograph showing that recombinant UBE4A protein was prepared.
  • Figure 3 shows the results of ELISA using CD patients, ulcerative colitis (UC) patients, and healthy subjects. It is the graph which quantified UBE4A specific IgG in the serum of the best form for carrying out the invention
  • the present invention relates to a Crohn's disease (CD) diagnostic marker containing an antibody against the ubiquitinating factor E4A protein or a fragment thereof, and to the diagnosis or prognosis of Crohn's disease using the marker.
  • CD Crohn's disease
  • Crohn's disease is an autoimmune disease whose main symptoms are inflammatory diseases of the gastrointestinal tract, and the immune system's dysregulation is closely related to the pathogenesis of Crohn's disease.
  • the present invention identified ubiquitination factor E4A (UBE4A) as a target self-antigen in Crohn's disease, and found that autoantibodies against ubiquitination factor in the serum of Crohn's disease patients would be useful markers in Crohn's disease diagnosis. And completed.
  • UBE4A ubiquitination factor E4A
  • Molecular identification of self-antigens helps to elucidate immune abnormalities in Crohn's disease.
  • the inventor collected normal human ileal tissue and created a typical cDNA expression library for human. From there, the inventor conducted immunoscreening and identified an immunoreactive cDNA (C-terminal fragment) encoding ubiquitination factor E4A (UBE4A). IgG autoantibodies were quantitated by ELISA using a 12.3% recombinant C-terminal fragment corresponding to 12.3% of the C-terminal UBE4A protein.
  • the antigen (UBE4A) or its immunoreactive fragment and a sample collected from a subject in need of diagnosis were used to bind UBE4A in the sample. It is possible to detect, diagnose, or diagnose prognosis of Crohn's disease by measuring the antibody to be combined and performing immunological analysis to detect the presence of the antibody used for Crohn's disease diagnosis.
  • the method of the present invention provides a method for detecting an antibody against UBE4A in a sample, for example, in a non-specific embodiment or a specific embodiment,
  • the method After binding to UBE4A, the method includes detecting the non-specific binding or specific binding.
  • Such methods are not illustrative of the only methods by which those skilled in the art of medicine, microbiology or immunology can use the present invention. Any method of detecting the presence of an antibody against UBE4A in a sample is useful in the present invention, as any immune system interaction with UBE4A can be detected.
  • the Crohn's disease diagnosis of a patient suspected of having Crohn's disease, or the severity or progression of Crohn's disease in a patient already diagnosed as having Crohn's disease is done by detecting the immune response to UBE4A in samples from patients in need of diagnosis.
  • antibody detection generally and preferably, antibodies that bind to UBE 4 A in the patient sample are detected. Detection of antibodies that bind to UBE 4 A
  • detection of an antibody that binds to UBE 4 A can be performed by indirect detection of an antibody against UBE4A.
  • Direct detection of binding means that the label or indicator that is the final measured entity is on the antibody to UBE4A.
  • Indirect detection of binding means that there is no label or indicator on the antibody against UBE4A that is ultimately present to be measured.
  • UBE4A or “ubiquitination factor E4A” means U-box ubiquitin ligase, and is essentially described as an E4 ubiquitination factor.
  • UBE4A is a budding yeast 03 ⁇ 4cc / 2flra "C cerevisiae) It is a mammalian homologue of Ufd2.
  • the UBE4A gene is located in the human chromosome lq23.3 region, which is a critical region involved in cancer such as neuroblastoma. Northern blot analysis of fetal and mature human tissues confirms that a single transcription band of approximately 7.5 kb can be obtained.
  • UBE4A is present in skeletal muscle, kidney and liver.
  • the ubiquitination factor E4A (UBE4A) is a target autoantigen in Crohn's disease and a protein consisting of 1073 amino acids. As mentioned above, UBE4A is useful as an index in the diagnosis of Crohn's disease.
  • the base sequence of the gene encoding the UBE4A protein is known, and the sequence can be easily obtained through a public database such as GenBank (GenBank Accession No.
  • NM_004788 The nucleotide sequence of the gene encoding UBE4A is shown in SEQ ID NO: 1, and the amino acid sequence of UBE4A is shown in SEQ ID NO: 2.
  • the UBE4A protein fragment of the present invention may be any fragment as long as it contains a region having immunoreactivity in the UBE4A protein.
  • a DNA fragment containing the 2953-3348th nucleotide site of SEQ ID NO: 1 covering the C-terminal 132 amino acids (12.3%) of SEQ ID NO: 2 can be mentioned.
  • Clones containing the above DNA fragments exhibit a strong reaction with sera collected from patients with Crohn's disease and are useful in the diagnosis of Crohn's disease.
  • an antibody against the above-mentioned fragment is particularly preferred as the Crohn's disease diagnostic marker of the present invention.
  • UBE4A or its immunoreactive fragment reacts with autoantibodies useful for the diagnosis of Crohn's disease
  • the above-mentioned UBE4A or its immunoreactive fragment is described below. It can be used as a diagnosis of Crohn's disease.
  • the diagnostic marker for Crohn's disease of the present invention is an autoantibody against UBE4A or an immunoreactive fragment thereof (hereinafter sometimes referred to as “antibody against UBE4A etc.”).
  • An autoantibody reacts with an autoantigen that is an antigen component of an individual's own constituents caused by abnormalities in the immune response caused by the proliferation of in vivo lymphoid tissues.
  • the term “antibody” includes both natural antibodies and biologically active antibody derivatives such as Fab, F (ab ′) 2 , and Fv as well as single domain and single chain antibodies. Means. Biologically active antibody derivatives possess antigen-binding ability.
  • the antibody of the present invention specifically means the whole antibody molecule capable of binding to UBE4A or a partial fragment thereof.
  • Subjects with antibodies to UBE4A have a high prevalence of Crohn's disease.
  • 42.1% (16/38) of patients with Crohn's disease and 7.1% (2/28) of ulcerative colitis patients have the above-mentioned DNA fragment containing the 2953-3348th nucleotide sites of SEQ ID NO: 1. 3.8% (2/52) of the healthy people are watching.
  • the prevalence of anti-UBE4A antibody in patients with Crohn's disease is significantly higher than that of Crohn's disease (Fisher's direct probability test: P ⁇ 0.05) and healthy subjects (PO.001).
  • the antibody is useful as a serum marker (diagnostic force) for diagnosing whether Crohn's disease is present or for evaluating the degree of progression of symptoms in Crohn's disease patients.
  • the anti-UBE4A antibody in a sample collected from a subject is detected or the amount of the antibody is measured by an immunological analysis method. Can be done by.
  • Subjects include humans and mammals such as dogs, cats, rats, and mice.
  • Samples include, but are not limited to, blood, serum, tissue, urine, mucus and the like.
  • antibodies against UBE4A in patient samples such as blood, serum, and tissue can be detected in immunoassays where the antigen can be utilized in a liquid layer or bound to a solid carrier.
  • Many commonly used immunological analysis methods can be used to detect antibodies against UBE4A and the like.
  • the amount of antibody or antigen-antibody complex in a patient's sample, particularly blood, serum or tissue sample is detected by chemical or physical means, and this is detected in a known amount of substance. Including standard Any method may be used as long as it is a measurement method calculated from a calibration curve created using a solution.
  • an antigen-sensitized plate is reacted with an antibody in a sample, and the antibody to be detected captured on the surface of the plate is detected with an antibody bound to a labeling substance having a specific antigen is detected by the antibody. It is the most popular method for immunological analysis (Immunochemistry, 8: 871-879, 1971).
  • a method is also known in which latex particles adsorbed with an antigen are mixed with a sample and an antibody is detected as an immunological agglutination reaction (Am. J. Med., 21: 888-892, 1956).
  • Immunological particle agglutination is a method that allows rapid analysis with a single reagent and is suitable for large-scale screening.
  • Specific measurement methods include, for example, radioimmunoassay, enzyme immunoassay (ELISA), or immunofluorescence measurement for preferable immunological analysis for detecting antibodies against UBE4A used in the method of the present invention.
  • measurement methods known in the art such as chemiluminescence measurement method or bioluminescence measurement method are included, but from the viewpoint of sensitivity and specificity, ELISA is particularly preferable.
  • a sample (containing the antibody to be quantified) is added to the insolubilized UBE4A or a fragment thereof to react (primary reaction), and then a labeled secondary antibody is reacted (secondary reaction) and then insolubilized.
  • primary reaction and the secondary reaction may be performed in reverse order, may be performed simultaneously, or may be performed at different times.
  • Radioisotopes that are particularly useful in the analysis include 1H, 125 I, 131 I, 32 P, 35 S, 14 51 , 36 C1, 57 Co, 59 Fe, 75 Se, and 152 Eu. Radiolabeling is one example.
  • UBE4A or its antibody can also be used as a labeling agent used in a measurement method that uses a labeling substance, such as fluorescent labeling, enzyme labeling, free radicals using techniques known in the art. It can be labeled using a label or an avidin-piotin label. The case where an enzyme is used for labeling as described above is called ELISA.
  • Typical enzymes include alkaline phosphatase, ⁇ -galactosidase, glucose-6-phosphate dehydrogenase, malate dehydrogenase, glucose oxidase, urease and peroxidase, ⁇ -galatato Sidase etc. are included.
  • the fluorescent material include fluorescamine, fluorescein thiothionate, and the like.
  • luminescent substances include / reciferin, norecigenin, noreminol, and / reminol derivatives.
  • UBE4A or a fragment thereof For insolubilization of UBE4A or a fragment thereof, physical adsorption may be used, or a method using a chemical bond usually used to insolubilize or immobilize proteins or enzymes may be used.
  • synthetic resins such as polystyrene, polyacrylamide, and silicon, insoluble polysaccharides such as agarose, dextran, and cellulose, or glass is used.
  • the reaction medium may include a buffer solution that provides optimum conditions for the reaction or stabilizes the reaction product, and a stabilizer for the reaction material.
  • the antibody detection means those capable of detecting the above-mentioned label such as a spectroscope, a radiation detector, and a light scattering detector can be used, but are not limited thereto.
  • the amount of antibody can be measured by measuring the absorbance.
  • An antibody against UBE4A or the like in a sample can be detected by using the detection method as described above, or the amount of the antibody can be measured.
  • whether or not a subject suffers from Crohn's disease can be diagnosed by analyzing the OD value (absorbance at 450 nm) of the amount of anti-UBE4A antibody. For example, when measuring the OD value of an antibody using a spectrophotometer, if the obtained OD value is 0.31 or more, the subject can be diagnosed as having Crohn's disease. In addition, when assessing the degree of progression in patients with Crohn's disease (ie, associating with disease progression), for example, if the OD value is 0.26 or greater, it is assessed that the symptoms of Crohn's disease patients are progressing can do.
  • an autoantigen that has generated an autoantibody can also be detected.
  • an antibody (autoantibody) against UBE4A etc. Can be used as a reagent, but caused autoantibody production
  • the amount of UBE4A protein or fragment thereof can also be used as an indicator for Crohn's disease detection.
  • the above substance can be combined with another solvent or solute to form a composition.
  • distilled water, pH buffer reagent, salt, protein, surfactant, etc. can be combined.
  • the antibody such as UBE4A of the present invention, or UBE4A protein or a fragment thereof is applied to an immunological measurement method
  • special conditions and operations are not required, and according to normal conditions and operations in each method. Done.
  • a suitable measurement system can be constructed by adding modifications well known to those skilled in the art.
  • the most convenient and efficient measurement is to make the above reagent into a kit.
  • Such a kit enables efficient quantification in a normal laboratory or laboratory without the need for special analytical equipment, skilled operation, or advanced knowledge.
  • the configuration and form of the assembly kit for carrying out the above-described various diagnostic methods or treatment determination methods are not particularly limited, and the content thereof is not limited as long as a predetermined purpose can be achieved.
  • the above sample consists of instructions for interpreting the results obtained by performing the immunological method, reaction reagents, reaction medium in which the reaction is performed, and a substrate that provides a place for the experiment. Is done. Furthermore, if desired, a reference sample for use as a reference for comparison or for creating a calibration curve, a detector, etc. may be included.
  • the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.
  • CD Crohn's disease
  • XgtU phage library is seeded on LB agar medium, cultured at 42 ° C for 7 hours, and then 20 mM isopropyl ⁇ -D-thiogalatatopyranoside (IPTG) (Nacalai tesque, Kyoto, Japan)-containing nitrocellulose membrane ( Schleicher and Schuell, Dassel, Germany) and overlaid at 37 ° C for 7 hours. 5% Cw / v) After blocking with skim milk / Tris buffered saline (TBS), incubate the membrane with serum and dilute them with TBS. And preabsorbed with a lysate of E. coli strain Y1090 for 15 hours.
  • IPTG isopropyl ⁇ -D-thiogalatatopyranoside
  • TBS Tris buffered saline
  • Membranes were incubated for 1 hour at 22 ° C with Western anther-sabiperoxidase (HRP) -conjugated goat anti-human IgG (ICN Pharmaceuticals, Aurora, OH, USA) and 4-black mouthed-1-naphthol (Nacalai Testa) was used to detect antibody reactive phage plaques. After incubation, the membrane was washed 3 times with TBS containing 0.05% Tween 20. Positive clones were isolated in the second and third screens in the same way as the first screen. Sequence analysis of cDNA clones
  • the 30-cycle cDNA fragment was sequenced using ABIPrism310 (PE Applied Biosystems, Foster, CA, USA). Sequence alignment was performed using software and a search program provided by the National Center for Biotechnology Information (NCBI, http://www.ncbi.nlm.nih.gov). Recombinant ubiquitination factor E4A (TJBE4A) protein preparation
  • the construct used to make the GST ubiquitination factor E4A (UBE4A) fusion protein is a PCR preparation (cleaved with JECORI and pGEX-6P-1). Prepared by ligating to the EcoRI-XJiol ⁇
  • the primers and PCR conditions used were as follows.
  • composition of the reaction solution is the same as that used in the sequence analysis of the above cDNA clone. Temperature and cycle conditions
  • the lower fountain sequence was designed for subcloning into the EcoRI-Xhol site of the pGEX-6P-1 vector.
  • This UBE4A fragment covers the C-terminal 132 amino acids (12.3%) of all UBE4A consisting of 1073 amino acids.
  • this vector was transformed into E. coli BL21 strain using 0.1 mM IPTG.
  • the GST-UBE4A fusion protein was purified using the B-PER GST fusion protein purification kit (Pierce Biotechnology, Rockford, IL, USA) according to the manufacturer's protocol.
  • Recombinant C-terminal UBE4A tamper by cleaving GST-UBE4A using PreScission protease (Amersham Biosciences) Enzyme-linked immunosorbent assay (ELISA)
  • the purpose of this example is to identify immunoreactive cDNA clones.
  • a cDNA expression library was constructed from normal sites in the ileum, which are sites of frequent inflammation in CD patients.
  • a total of 5 ⁇ 10 5 phage plaques were screened from a pool of sera collected from 3 randomly selected CD patients.
  • UBE4A accesion
  • FIG. 1 shows the response of CD patients and healthy subjects to UBE4A.
  • Fig. 1 gtll phage without fragments was mixed equally to make a negative control.
  • A represents the serum of a CD patient
  • B represents the serum of a healthy person.
  • Example 2 Search for UBE4A-specific antibody in serum of CD patient by ELISA The purpose of this example is to search for UBE4A-specific antibody in serum of CD patient using ELISA.
  • Lane 1 is a purified GST-UBE4A fusion protein
  • Lane 2 is a recombinant UBE4A protein produced by cleavage with PreScission protease
  • Lane 3 is dartathione with reduced dartathione after cleavage with PreScission protease. Shows effluent from Sepharose. Samples were reduced by SDS-PAGE (12.5%).
  • Serum anti-UBE4A IgG antibody titers were measured using ELISA.
  • the average OD value of anti-UBE4A antibody in CD patients was very high compared to UC patients and healthy subjects (ANOVA; P 0.001) (Fig. 3).
  • Fig. 3 is a graph quantifying UBE4A-specific IgG in the serum of CD patients, ulcerative colitis (UC) patients, and healthy individuals by ELISA. The average for each group is indicated by a long horizontal line, and the standard error is indicated by a short horizontal line.
  • the fraction of OD value for the positivity of anti-UBE4A antibody is It was defined as an OD value of + 2SD or higher, which is higher than the average value of healthy subjects (> 0.271). The broken line indicates the fraction level.
  • Anti-UBE4A antibodies were found in 42.1% (16/38) of CD patients, 7.1% (2/28) of UC patients, and 3.8% (2/52) of healthy individuals.
  • the prevalence of anti-UBE4A IgG antibodies in CD patients was significantly higher than in UC patients (Fisher's direct probability test: PO.05) and healthy individuals ( ⁇ ⁇ 0 ⁇ 001).
  • a Crohn's disease diagnostic marker containing an antibody against UBE4A protein or a fragment thereof (UBE4A protein etc.) and an antibody against UBE4A protein etc. or a Crohn's disease diagnostic reagent containing UBE4A protein or a fragment thereof are provided.
  • UBE4A protein etc. an antibody against UBE4A protein etc.
  • a Crohn's disease diagnostic reagent containing UBE4A protein or a fragment thereof are provided.

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Abstract

L'invention concerne un marqueur de diagnostic pour la maladie de Crohn lequel contient un anticorps contre la protéine UBE4A ou son fragment (protéine UBE4A ou similaire) et un réactif de diagnostic pour la maladie de Crohn lequel contient un anticorps contre la protéine UBE4A ou similaire, ou la protéine UBE4A ou son fragment. L'invention concerne également un procédé consistant à évaluer si un patient souffre ou non de la maladie de Crohn lequel comprend : (a) de recueillir un échantillon chez le patient ; (b) de détecter la présence ou l'absence d'un anticorps contre la protéine E4A de facteur d'ubiquitination ou son fragment ; et (c) d'estimer que le patient souffre de la maladie de Crohn dans le cas où l'anticorps est détecté dans l'échantillon.
PCT/JP2005/021937 2004-11-22 2005-11-22 Autoantigène associé à la maladie de crohn WO2006054806A1 (fr)

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US10080808B2 (en) 2012-10-11 2018-09-25 Uti Limited Partnership Methods and compositions for treating multiple sclerosis and related disorders
US10124045B2 (en) 2013-11-04 2018-11-13 Uti Limited Partnership Methods and compositions for sustained immunotherapy
US10172955B2 (en) 2010-11-12 2019-01-08 Uti Limited Partnership Compositions and methods for the prevention and treatment of cancer
US10988516B2 (en) 2012-03-26 2021-04-27 Uti Limited Partnership Methods and compositions for treating inflammation

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
US10172955B2 (en) 2010-11-12 2019-01-08 Uti Limited Partnership Compositions and methods for the prevention and treatment of cancer
US11000596B2 (en) 2010-11-12 2021-05-11 UTI Limited Parttiership Compositions and methods for the prevention and treatment of cancer
US10988516B2 (en) 2012-03-26 2021-04-27 Uti Limited Partnership Methods and compositions for treating inflammation
US10080808B2 (en) 2012-10-11 2018-09-25 Uti Limited Partnership Methods and compositions for treating multiple sclerosis and related disorders
US10905773B2 (en) 2012-10-11 2021-02-02 Uti Limited Partnership Methods and compositions for treating multiple sclerosis and related disorders
US10124045B2 (en) 2013-11-04 2018-11-13 Uti Limited Partnership Methods and compositions for sustained immunotherapy
US11338024B2 (en) 2013-11-04 2022-05-24 Uti Limited Partnership Methods and compositions for sustained immunotherapy

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