WO2018021624A1 - Biomarqueurs pour le diagnostic de la polyarthrite rhumatoïde - Google Patents

Biomarqueurs pour le diagnostic de la polyarthrite rhumatoïde Download PDF

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Publication number
WO2018021624A1
WO2018021624A1 PCT/KR2016/013260 KR2016013260W WO2018021624A1 WO 2018021624 A1 WO2018021624 A1 WO 2018021624A1 KR 2016013260 W KR2016013260 W KR 2016013260W WO 2018021624 A1 WO2018021624 A1 WO 2018021624A1
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WIPO (PCT)
Prior art keywords
rheumatoid arthritis
antibody
protein
interleukin
urine
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PCT/KR2016/013260
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English (en)
Korean (ko)
Inventor
김완욱
박윤정
유승아
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가톨릭대학교 산학협력단
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Publication of WO2018021624A1 publication Critical patent/WO2018021624A1/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
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • 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
    • 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
    • G01N33/6854—Immunoglobulins
    • 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
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/521—Chemokines
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5412—IL-6
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5421—IL-8
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints

Definitions

  • the present invention is characterized in that it is a diagnostic marker for rheumatoid arthritis that can be detected in a urine sample.
  • Figure 6 shows the ROC curve to test the severity [a: comparison of the prediction of bone fracture after 3 years with IL-6, ESR, and CRP, b: comparison of the prediction of bone destruction after 3 years with CCL2, ESR, and CRP, c: Comparison of prediction of bone destruction after 3 years with IL-8, ESR and CRP].
  • the present invention provides IL-6, CCL-2 and / or IL-8 as diagnostic markers of rheumatoid arthritis.
  • the present invention can determine the current disease activity of the patient non-invasively without having to evaluate the rheumatoid arthritis activity, such as the conventional DAS28, based on this to determine the optimal treatment regimen and determine whether the appropriate treatment response is shown in the treatment To provide objective disease activity markers.
  • the term "predicting the severity prognosis of rheumatoid arthritis” refers to the possibility of bone fracture or joint deformation due to high disease activity when assessing the general degree of inflammation, bone fracture, or progression of rheumatoid arthritis in patients with rheumatoid arthritis.
  • DAS Disease Activity Score
  • DAS28 Disease Activity Score 28
  • DAS28 is a composite index consisting of the number of tenderness joints, swelling joints, erythrocyte sedimentation rate, and systemic evaluation of the patients. 28 joints include both shoulder joints, elbow and wrist joints, and metacarpal joints. , Muscle joints, knee joints, and the like.
  • Rheumatoid arthritis disease activity surveyed with DAS28 can be calculated from 0 to a maximum of 9.4. Generally, if the DAS28 score is less than 2.6, there is little disease activity (Remission). Low Disease Activity is defined as Moderate Disease Activity (severity) of 3.2 or more and less than 5.1, and High Disease Activity (Severe) of 5.1 or more.
  • the present invention provides IL-6 as a predictor of severity prognosis in rheumatoid arthritis patients.
  • IL-6 is an index for predicting the disease state of rheumatoid arthritis, and it can be predicted that the risk of osteoporosis of rheumatoid arthritis increases when IL-6 concentration is increased in the urine sample of the patient.
  • IL-6 showed a similar level of power to C-reactive protein (CRP), a known risk factor for bone destruction.
  • CRP C-reactive protein
  • a protein expressing a specific expression difference was selected from urine samples of patients with rheumatoid arthritis (RA) and normal persons, and proteins of IL-6, CCL-2 and / or IL-8. The amount was found to be significantly higher in RA patients than normal (FIG. 1). These proteins have proven to be urine protein biomarkers for the diagnosis of rheumatoid arthritis because of constant changes in proteome profile.
  • the results of the ROC analysis to compare with the well-known serum index in RA patients (DAS28 ⁇ 5.1) with high rheumatoid arthritis activity the result of the area under curve (AUC) of serum CRP was 0.669 (95% confidence interval; CI [0.614-0.765]), AUC of IL-6 in urine was 0.657 [0.572-0.742], AUC of CCL-2 was 0.642 [0.551-0.734], and AUC of IL-8 Showed 0.546 [0.457-0.636] not inferior to CRP (FIG. 4).
  • the agent for measuring the expression level of the protein may be an antibody specific for IL-6, CCL-2 and / or IL-8.
  • antibody means a protein molecule specific for an antigenic site.
  • an antibody means an antibody that specifically binds to the marker proteins IL-6, CCL-2 and / or IL-8, and includes all monoclonal antibodies, polyclonal antibodies and recombinant antibodies.
  • Monoclonal antibodies are well known in the art by hybridoma methods (Kohler and Milstein (1976) European journal og Immunology 6: 511-519), or phage antibody libraries (Clarkson et al, Nature, 352: 624-628, 1991; Marks et al, J. Mol. Biol., 222: 58, 1-597, 1991).
  • Polyclonal antibodies can be produced by methods well known in the art for injecting the above described protein antigens into animals and collecting blood from the animals to obtain serum comprising the antibodies.
  • Such polyclonal antibodies can be prepared from any animal species host, such as goats, rabbits, sheep, monkeys, horses, pigs, cattle, dogs, and the like.
  • the antibodies used in the present invention include functional fragments of antibody molecules as well as complete forms having two full length light chains and two full length heavy chains.
  • the functional fragment of an antibody molecule means the fragment which has at least antigen binding function, and can illustrate Fab, F (ab '), F (ab') 2, Fv etc.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne des biomarqueurs pour le diagnostic de la polyarthrite rhumatoïde, l'évaluation de l'activité de la polyarthrite rhumatoïde et/ou la prédiction de la gravité et le pronostic de la polyarthrite rhumatoïde ; et une utilisation de ceux-ci.
PCT/KR2016/013260 2016-07-29 2016-11-17 Biomarqueurs pour le diagnostic de la polyarthrite rhumatoïde WO2018021624A1 (fr)

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KR10-2016-0097185 2016-07-29
KR20160097185 2016-07-29

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WO2018021624A1 true WO2018021624A1 (fr) 2018-02-01

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102333499B1 (ko) * 2019-06-17 2021-12-01 고려대학교 산학협력단 대사체 분석을 이용한 류마티스 관절염 중증도 예측 또는 구분용 바이오마커
KR102481470B1 (ko) * 2019-11-07 2022-12-28 가톨릭대학교 산학협력단 류마티스 관절염의 질병활성도 평가용 바이오마커 및 이의 이용
WO2022031006A1 (fr) * 2020-08-05 2022-02-10 가톨릭대학교 산학협력단 Composition pour diagnostiquer l'arthrose, et procédé pour fournir des informations pour diagnostiquer l'arthrose

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070072237A1 (en) * 2004-02-27 2007-03-29 Norbert Wild Method of assessing rheumatoid arthritis by measuring rheumatoid factor and interleukin-6
US20090142792A1 (en) * 2007-06-21 2009-06-04 Robinson William H Biomarkers for the diagnosis of autoimmune disease
US20110256636A1 (en) * 2010-04-16 2011-10-20 Abbott Japan Co., Ltd. Methods and reagents for diagnosing rheumatoid arthrtis
US20140142861A1 (en) * 2010-11-06 2014-05-22 Oklahoma Medical Research Foundation Biomarkers For Predicting Progressive Joint Damage

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006008183A1 (fr) * 2004-07-23 2006-01-26 Novartis Ag Biomarqueurs de la polyarthrite rhumatoide (pr)
KR100937144B1 (ko) 2007-10-11 2010-01-15 경북대학교 산학협력단 Ｄｎａ-메틸전이효소-3ｂ를 이용한 류마티스 관절염 예후진단용 마커 및 이를 이용한 류마티스 관절염 중증도 예측및 판단 방법
EP2488659B1 (fr) * 2009-10-15 2019-12-11 Crescendo Bioscience, Inc. Biomarqueurs et procédés de mesure et de surveillance de l'activité d'une maladie inflammatoire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070072237A1 (en) * 2004-02-27 2007-03-29 Norbert Wild Method of assessing rheumatoid arthritis by measuring rheumatoid factor and interleukin-6
US20090142792A1 (en) * 2007-06-21 2009-06-04 Robinson William H Biomarkers for the diagnosis of autoimmune disease
US20110256636A1 (en) * 2010-04-16 2011-10-20 Abbott Japan Co., Ltd. Methods and reagents for diagnosing rheumatoid arthrtis
US20140142861A1 (en) * 2010-11-06 2014-05-22 Oklahoma Medical Research Foundation Biomarkers For Predicting Progressive Joint Damage

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BECETTI: "Urinary albumin excretion is increased in patients with rheumatoid arthritis and associated with arterial stiffness", THE JOURNAL OF RHEUMATOLOGY, vol. 42, 2015, pages 593 - 598 *
PARK: "Urinary interleukin-6 as a predictor of radiographic progression in rheumatoid arthritis: A 3-year evaluation", SCIENTIFIC REPORTS, vol. 6, 12 October 2016 (2016-10-12), pages 1 - 9, XP055604712 *

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KR20180014419A (ko) 2018-02-08

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