WO1998022503A2 - Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed against said peptide, a combinatorial antigen, and a method of detecting auto-immune antibodies - Google Patents
Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed against said peptide, a combinatorial antigen, and a method of detecting auto-immune antibodies Download PDFInfo
- Publication number
- WO1998022503A2 WO1998022503A2 PCT/NL1997/000624 NL9700624W WO9822503A2 WO 1998022503 A2 WO1998022503 A2 WO 1998022503A2 NL 9700624 W NL9700624 W NL 9700624W WO 9822503 A2 WO9822503 A2 WO 9822503A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- peptide
- antibody
- reactive
- antigen
- rheumatoid arthritis
- Prior art date
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- 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
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
-
- 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
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
-
- 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
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/24—Immunology or allergic disorders
Definitions
- Peptide derived from an antigen recognized by auto- antibodies from patients with rheumatoid arthritis antibody directed against said peptide, a combinatorial antigen, and a method of detecting auto-immune antibodies
- the present invention relates to a peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, which peptide is reactive with autoimmune antibodies from a patient suffering from rheu- matoid arthritis.
- a peptide is known from the European patent application 0 511 116 (Clonatec S.A.). This application describes an antigen comprising a filaggrin or pro- filaggrin fragment .
- the peptide is recognized by rheuma- toid arthritis-specific autoimmune antibodies.
- Rheumatoid arthritis (RA) is a systemic autoimmune disease. It is the most commonly occurring inflammatory disease of the joints, it is chronic and may lead to severe physical disablement .
- the object of the present is to provide a peptide which is reactive with autoimmune antibodies from a patient suffering from rheumatoid arthritis, which peptide is suitable for diagnostic research with increased specificity while also being useful for other purposes such as obtaining (raising, selecting and isolating) poly- and monoclonal antibodies.
- the peptide according to the invention is characterized in that the derived peptide that is reactive with autoimmune antibodies, corresponds to a part of a mRNA molecule coding for the antigen, said part comprising a codon for an arginine residue, and the arginine residue in the derived peptide, which is reactive with autoimmune antibodies, is a modified arginine residue.
- the peptide according to the inven- tion that possesses a modified arginine residue proved to be very suitable for the specific diagnosis of rheumatoid arthritis.
- no specific serological test is available for RA. The only test frequently employed is based on the determination of rheumatoid factors (RF; Ref . l) which are found in 70% of the RA patients.
- RF rheumatoid factors
- this test is not very specific and is characterized by a relatively large number of false positives. For patients suffering from systemic lupus erythematosus the percentage of false positives is approximately 20% and for healthy individuals approximately 5%.
- the peptide is characterized in that the modified arginine residue's side chain is a side chain according to Formula I on the formula sheet, in which
- X NH 2 , CH 3 , NHCH 3 or N(CH 3 ) 2 ;
- a preferred peptide is the peptide selected from the group of peptides having the Formula II - X on the formula sheet .
- the peptide is a cyclic peptide, for instance, due to the presence of a cystine residue.
- such a cyclic peptide exhibits an increased immunological affinity.
- the preferred cyclic peptide is the peptide having the Formula XI on the formula sheet.
- the peptide is a synthetic peptide.
- the reactive peptide according to the invention can be obtained pure and in large quantities by means of organic synthesis, making immunological testing on a large scale possible.
- the peptide in accordance with the invention is characterized in that the peptide is obtained by the proteolytic treatment of (pro) filaggrin, separation of peptide fragments formed by proteolysis and subsequent selection on the presence of a modified arginine residue in a peptide which was formed during the proteolytic treatment.
- peptides can be identified which can increase the sensitivity of a rheumatoid arthritis test.
- the term sensitivity is in the present application to be understood to mean the ability of a test to properly identify a patient suffering from rheumatoid arthritis.
- the antigen is (pro) filaggrin
- the peptide is reactive with a rheumatoid arthritis patient's autoimmune antibodies which are reactive with (pro) filaggrin.
- the peptide has been shown to be very suitable for high-specificity testing (few false positives) for rheumatism.
- the present invention also relates to an antibody which is cross-reactive with an antibody raised against a peptide according to the invention.
- an antibody is useful for the indication of rheumatoid arthritis by analysing sections of biopsy samples and immunological tests of the sandwich type.
- the antibody is preferably a monoclonal antibody. According to another preferred embodiment, the antibody is obtained by using as antigen a peptide in accordance with the invention.
- a suitable antibody according to the invention is characterized in that it is cross-reactive with the antibody as produced by Escherichia coli TGI with plasmid RA3 , deposited at the Centraalbureau voor Schimmelcultures, at Baarn, the Netherlands under accession number CBS143.96.
- the invention further relates to an organic compound comprising a part that is able to compete with a peptide according to one of the claims 1 to 9 for binding to an antibody which is specific for said peptide, wherein at least said part of the organic compound can be prepared by means of combinationary chemistry.
- organic compounds are found by competitive selection wherein a peptide of the invention competes for recognition by an antibody of the invention, such as the antibody produced by E . coli CBS143.96.
- the organic compounds which are often cheaper to produce than antigens that are prepared solely on the basis of amino acids that may or may not comprise side chains, are suitable for immunological kits for diagnosing RA. Also, after coupling to a solid carrier, said organic compounds could be applied to lower, through adsorption, the level of autoimmune antibodies in the blood of patients suffering from RA.
- the invention relates to a method of detecting autoimmune antibodies against rheumatoid arthritis.
- the method according to the invention is character- ized in that in an immunological test at least one immunologically active molecule selected from the group consisting of i) a peptide according to the invention; ii) a recombinatory organic molecule according to the invention; and iii) an antibody according to the invention is used.
- the peptides mentioned on the formula sheet may also be part of other oligopeptides. They may be provided at one or both ends with one or more other amino acids while also, two or more peptides according to the invention may be part of one oligopeptide. It is also possible to shorten the peptides by one or more amino acids, provided this does not have a significantly adverse effect on the reactivity.
- peptides and organic compounds according to the invention may optionally be labelled or be coupled to a carrier, and how on the basis of such antigens an immuno- logical test may be developed, using the standard techniques well-known in the field.
- Peptide synthesis Peptides were selected for synthesis on the basis of amino acid sequences derived from known cDNA sequences of human profilaggrin (Ref. 2; Ref. 3). The peptides were synthesized on solid phase using the method described by Schellekens et al. (Ref. 4) . The peptides were at least 95% pure, as determined by the elution profile by means of reversed phase chromatography and the relative absorption at 214 nm. The composition of the peptides was confirmed by means of mass spectrometry (MALDI- MS). All peptides were synthesized as peptide amides.
- MALDI- MS mass spectrometry
- peptide names starting with "cf” are based on the C- terminal end (amino acids 306-324) ; and the peptide names staring with “nf” are based on the sequence near the N- terminal end (amino acids 18-32 for nfcl) .
- the peptides were covalently coupled to the wells of 96-well microtitre plates (Costar amide binding plates) in an amount of 1 ⁇ g/well. Coupling took place for 16 hours at 4EC and pH 9.0. The plates were blocked for 1 hour with 2% bovine serum albumin. The sera were diluted 200 times in a diluent (0.3% BSA, 350 mM NaCl, 10 mM Tris-HCl pH 7.6 , 1% vol. /vol. Triton X-100, 0.5% w./vol. Na-deoxycholate, 0.1% SDS) supplemented with 10% normal rabbit serum, and incubated for one hour at room temperature.
- a diluent (0.3% BSA, 350 mM NaCl, 10 mM Tris-HCl pH 7.6 , 1% vol. /vol. Triton X-100, 0.5% w./vol. Na-deoxycholate, 0.1% SDS
- Control sera are from patients suffering from rheumatic diseases other than RA.
- SLE is systemic lupus erythematosus .
- pSS is primary Sj ⁇ gren's syndrome.
- SSC is systemic scleroderma.
- PM/DM is polymyositis/dermatomyositis.
- Sera from patients suffering from various infectious diseases (Borrelia, syphilis, malaria, endocarditis, Legionella, tuberculosis, mycoplasma, Yersinia, salmonella, parvovirus B19, Epstein-Barr virus, rubella, schistosomiasis, Toxoplasma, leishmaniasis, Chagas' disease) were tested for the presence of antibodies reactive with cfcl. Of the 308 tested sera 9 were positive. This means that the specificity was 97%, a considerable improvement compared with the RF test .
- a second citrulline-substituted peptide (nfcl) was shown to be specifically reactive with 10% of the RA sera, but not with the control peptide nf, which does not comprise citrulline. Of the RA sera reactive with nfcl, some were not reactive with cfcl to cfc9. Therefore, it is possible to increase the sensitivity of a test for rheumatoid arthritis by applying more peptides comprising a modified arginine residue.
- a peptide may comprise several modified arginine residues, but the peptide may also comprise one or more non-modified arginine residues.
- modified amino acids in particular those derived from arginine residues, could possibly also play a role in other autoimmune diseases .
- the invention is also aimed at peptides comprising modified amino acids that are reactive with auto-antibodies from patients suffering from autoimmune diseases other than RA.
- Said peptides are useful for the development of monoclonal antibodies against these diseases as well as for diagnosing the respective autoimmune diseases, in particular for the detection of autoimmune antibodies in body fluid such as blood, plasma and serum of patients who are suspected of suffering from the autoimmune disease.
- the peptides and antibodies offer the possibility of developing an organic compound with the aid of combinatorial chemistry, which compound is comprised within the scope of the invention.
- the recombinant monoclonal antibody described by applicants is reactive with peptide cfcl but not with the control peptides cfA, cfE, cfQ or cf.
- the commercially available monoclonal antibody AKH1 (Ref. 5), directed against human filaggrin, is not reactive with any of the peptides described herein and is therefore not cross- reactive with an antibody raised against a peptide according to the invention.
- the polyclonal serum anti-54 kD (Ref. 5), raised against filaggrin is not reactive with any of the peptides described herein and is therefore not cross-reactive with an antibody reactive with a peptide according to the invention. This suggests that in a normal immune reaction antibodies that are cross-reactive with an antibody raised against a peptide according to the invention, are not necessarily formed.
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP52350198A JP4197743B2 (en) | 1996-11-15 | 1997-11-14 | Peptides derived from antigens recognized by autoantibodies from patients with rheumatoid arthritis, antibodies directed against said peptides, methods of detecting antigens and autoimmune antibodies |
AU49707/97A AU741850B2 (en) | 1996-11-15 | 1997-11-14 | Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed against said peptide, a combinatorial antigen, and a method of detecting auto-immune antibodies |
DE69737292T DE69737292T2 (en) | 1996-11-15 | 1997-11-14 | PEPTIDE DERIVED FROM AN ANTIGEN RECOGNIZED BY ANTIBODIES FROM PATIENTS WITH RHEUMATOID ARTHRITIS, ANTIBODIES TO THIS PEPTIDE AND A METHOD FOR DETECTING AUTOIMMUNANTIC BODIES |
EP97912577A EP0941244B1 (en) | 1996-11-15 | 1997-11-14 | Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed against said peptide and a method of detecting auto-immune antibodies |
DK97912577T DK0941244T3 (en) | 1996-11-15 | 1997-11-14 | Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed to said peptide, and a method for detecting autoimmune antibodies |
CA002272573A CA2272573C (en) | 1996-11-15 | 1997-11-14 | Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed against said peptide, a combinatorial antigen, and a methodof detecting auto-immune antibodies |
BR9712955-0A BR9712955A (en) | 1996-11-15 | 1997-11-14 | Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed against said peptide, combinatorial antigen and method of detecting autoimmune antibodies |
US09/308,150 US6858438B2 (en) | 1996-11-15 | 1997-11-14 | Peptides immunoreactive with autoantibodies from patients with rheumatoid arthritis |
US11/059,775 US7335724B2 (en) | 1996-11-15 | 2005-02-16 | Peptides immunoreactive with autoantibodies from patients suffering from rheumatoid arthritis |
US11/165,085 US7288634B2 (en) | 1996-11-15 | 2005-06-23 | Isolated antibodies immunoreactive with synthetic peptides used to detect rheumatoid arthritis |
US11/834,557 US8772448B2 (en) | 1996-11-15 | 2007-08-06 | Peptides immunoreactive with autoantibodies from patients suffering from rheumatoid arthritis |
US14/285,577 US20140342378A1 (en) | 1996-11-15 | 2014-05-22 | Peptides immunoreactive with autoantibodies from patients suffering from rheumatoid arthritis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL1004539A NL1004539C2 (en) | 1996-11-15 | 1996-11-15 | Peptide derived from an antigen recognized by autoantibodies of patients with rheumatoid arthritis, antibody to it and method for detecting autoimmune antibodies. |
NL1004539 | 1996-11-15 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09308150 A-371-Of-International | 1997-11-14 | ||
US09/308,150 A-371-Of-International US6858438B2 (en) | 1996-11-15 | 1997-11-14 | Peptides immunoreactive with autoantibodies from patients with rheumatoid arthritis |
US11/059,775 Continuation US7335724B2 (en) | 1996-11-15 | 2005-02-16 | Peptides immunoreactive with autoantibodies from patients suffering from rheumatoid arthritis |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1998022503A2 true WO1998022503A2 (en) | 1998-05-28 |
WO1998022503A3 WO1998022503A3 (en) | 1998-08-27 |
Family
ID=19763876
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NL1997/000624 WO1998022503A2 (en) | 1996-11-15 | 1997-11-14 | Peptide derived from an antigen recognized by autoantibodies from patients with rheumatoid arthritis, antibody directed against said peptide, a combinatorial antigen, and a method of detecting auto-immune antibodies |
Country Status (13)
Country | Link |
---|---|
US (5) | US6858438B2 (en) |
EP (1) | EP0941244B1 (en) |
JP (1) | JP4197743B2 (en) |
AT (1) | ATE352560T1 (en) |
AU (1) | AU741850B2 (en) |
BR (1) | BR9712955A (en) |
CA (1) | CA2272573C (en) |
DE (1) | DE69737292T2 (en) |
DK (1) | DK0941244T3 (en) |
ES (1) | ES2281095T3 (en) |
NL (1) | NL1004539C2 (en) |
PT (1) | PT941244E (en) |
WO (1) | WO1998022503A2 (en) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999028344A2 (en) * | 1997-11-28 | 1999-06-10 | Innogenetics N.V. | Synthetic peptides containing citrulline recognized by rheumatoid arthritis sera as tools for diagnosis and treatment |
FR2773078A1 (en) * | 1997-12-30 | 1999-07-02 | Univ Toulouse | USE OF CITRULLIN PEPTIDES DERIVED FROM FILAGGRIN FOR THE TREATMENT OF RHUMATOID POLYARTHRITIS |
FR2795735A1 (en) * | 1999-07-01 | 2001-01-05 | Univ Toulouse | CITRULLIN FIBRIN DERIVATIVES AND THEIR USE FOR DIAGNOSIS OR TREATMENT OF RHUMATOID POLYARTHRITIS |
WO2001046222A2 (en) * | 1999-12-21 | 2001-06-28 | Innogenetics N.V. | Peptides designed for the diagnosis and treatment of rheumatoid arthritis |
WO2003050542A2 (en) * | 2001-12-11 | 2003-06-19 | Stichting Voor De Technische Wetenschappen | Method of detecting autoantibodies from patients suffering from rheumatoid arthritis, a peptide and an assaykit |
EP1980855A1 (en) | 2004-02-27 | 2008-10-15 | Roche Diagnostics GmbH | Method of assessing rheumatoid arthritis by measuring anti-CCP and serum amyloid A |
WO2008132264A1 (en) * | 2007-04-30 | 2008-11-06 | Consejo Superior De Investigaciones Científicas | Citrulinated fibrin-filaggrin chimeric polypeptide capable of detecting the antibodies generated in rheumatoid arthritis |
WO2009070875A1 (en) * | 2007-12-03 | 2009-06-11 | Sqi Diagnostics Systems Inc. | Synthetic peptides immuno-reactive with rheumatoid arthritis auto-antibodies |
WO2009103988A1 (en) | 2008-02-20 | 2009-08-27 | Axis-Shield Diagnostics Ltd. | Assay method for antibodies against cyclic citrullinated peptide |
WO2010072673A1 (en) | 2008-12-23 | 2010-07-01 | Max-Planck Gesellschaft Zur Förderung Der Wissenschaften E.V | Diagnostic prediction of rheumatoid arthritis and systemic lupus erythematosus |
US7846674B2 (en) | 2003-12-23 | 2010-12-07 | Roche Diagnostics Operations, Inc. | Assessing rheumatoid arthritis by measuring anti-CCP and interleukin 6 |
EP2325195A1 (en) | 2009-11-23 | 2011-05-25 | Toscana Biomarkers S.r.l. | Viral citrullinated peptides and uses thereof |
WO2011070172A1 (en) | 2009-12-10 | 2011-06-16 | Modiquest B.V. | Anti-inflammatory agents directed against citrullinated epitopes |
EP2336769A1 (en) | 2009-12-18 | 2011-06-22 | F. Hoffmann-La Roche AG | Trigger assay for differentiating between rheumatic and non-rheumatic disorders |
US8058013B2 (en) | 2006-09-29 | 2011-11-15 | Roche Diagnostics Operations, Inc. | Assessing risk of disease progression in rheumatoid arthritis patients |
EP2402368A1 (en) | 2010-07-02 | 2012-01-04 | Toscana Biomarkers S.r.l. | Histone citrullinated peptides and uses thereof |
EP2527841A1 (en) | 2011-05-25 | 2012-11-28 | Toscana Biomarkers S.r.l. | Methods for the diagnosis of rheumatoid arthritis |
US8323656B2 (en) | 2007-06-25 | 2012-12-04 | Yijun Xu | Antigen determinant of rheumatoid arthritis-specific autoantibody and use thereof |
WO2013014312A1 (en) * | 2011-07-28 | 2013-01-31 | Consejo Superior De Investigaciones Científicas (Csic) | Chimeric polypeptides derived from the vimentin protein, suitable for use in the diagnosis of rheumatoid arthritis |
EP3056904A1 (en) | 2015-02-13 | 2016-08-17 | F. Hoffmann-La Roche AG | Method of assessing rheumatoid arthritis by measuring anti-CCP and anti-MCM3 |
EP3056903A1 (en) | 2015-02-13 | 2016-08-17 | F. Hoffmann-La Roche AG | Method of assessing rheumatoid arthritis by measuring anti-CCP and anti-Casp8 |
WO2016128348A1 (en) | 2015-02-13 | 2016-08-18 | F. Hoffmann-La Roche Ag | Method of assessing rheumatoid arthritis by measuring anti-ccp and anti-pik3cd |
US10266568B2 (en) * | 2015-03-26 | 2019-04-23 | Korea Institute Of Science And Technology | Cyclic citrullinated peptide, rheumatoid arthritis diagnosis composition including the same, rheumatoid arthritis diagnosis method using the peptide or the composition, and method of screening diagnostic marker for rheumatoid arthritis |
US10703822B2 (en) | 2008-06-04 | 2020-07-07 | Modiquest B.V. | Anti-inflammatory agents |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL1004539C2 (en) * | 1996-11-15 | 1998-05-20 | Stichting Tech Wetenschapp | Peptide derived from an antigen recognized by autoantibodies of patients with rheumatoid arthritis, antibody to it and method for detecting autoimmune antibodies. |
WO2004082617A2 (en) * | 2003-03-14 | 2004-09-30 | Ppd Biomarker Discovery Sciences, Llc | Biological markers for diagnosing rheumatoid arthritis |
US20060141547A1 (en) * | 2004-11-16 | 2006-06-29 | Das Hasi R | Novel diagnostic marker, a diagnostic kit and a method for diagnosis of rheumatoid arthritis |
WO2009115612A1 (en) * | 2008-03-21 | 2009-09-24 | Universiteit Hasselt | Biomarkers for rheumatoid arthritis |
WO2012096893A2 (en) * | 2011-01-10 | 2012-07-19 | Opko Pharmaceuticals, Llc | Antigen surrogates in autoimmune disease |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0511116A1 (en) * | 1991-04-26 | 1992-10-28 | Clonatec S.A. | Antigens recognized by polyarthrits rheumatoid antibodies, preparation and applications |
FR2752842A1 (en) * | 1996-08-30 | 1998-03-06 | Biomerieux Sa | ANTIGENS DERIVED FROM FILAGGRINS AND THEIR USE FOR THE DIAGNOSIS OF RHUMATOID POLYARTHRITIS |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6100377A (en) * | 1994-06-10 | 2000-08-08 | The Trustees Of The University Of Pennsylvania | Constrained peptides |
NL1004539C2 (en) * | 1996-11-15 | 1998-05-20 | Stichting Tech Wetenschapp | Peptide derived from an antigen recognized by autoantibodies of patients with rheumatoid arthritis, antibody to it and method for detecting autoimmune antibodies. |
FR2773405B1 (en) * | 1998-01-08 | 2000-09-29 | France Telecom | METHOD AND SYSTEM FOR CONTROLLING ACCESS TO A RESOURCE LIMITED TO CERTAIN TIME RANGES |
-
1996
- 1996-11-15 NL NL1004539A patent/NL1004539C2/en not_active IP Right Cessation
-
1997
- 1997-11-14 CA CA002272573A patent/CA2272573C/en not_active Expired - Lifetime
- 1997-11-14 EP EP97912577A patent/EP0941244B1/en not_active Expired - Lifetime
- 1997-11-14 US US09/308,150 patent/US6858438B2/en not_active Expired - Lifetime
- 1997-11-14 ES ES97912577T patent/ES2281095T3/en not_active Expired - Lifetime
- 1997-11-14 BR BR9712955-0A patent/BR9712955A/en not_active Application Discontinuation
- 1997-11-14 AT AT97912577T patent/ATE352560T1/en active
- 1997-11-14 AU AU49707/97A patent/AU741850B2/en not_active Expired
- 1997-11-14 JP JP52350198A patent/JP4197743B2/en not_active Expired - Lifetime
- 1997-11-14 PT PT97912577T patent/PT941244E/en unknown
- 1997-11-14 DK DK97912577T patent/DK0941244T3/en active
- 1997-11-14 DE DE69737292T patent/DE69737292T2/en not_active Expired - Lifetime
- 1997-11-14 WO PCT/NL1997/000624 patent/WO1998022503A2/en active IP Right Grant
-
2005
- 2005-02-16 US US11/059,775 patent/US7335724B2/en not_active Expired - Fee Related
- 2005-06-23 US US11/165,085 patent/US7288634B2/en not_active Expired - Fee Related
-
2007
- 2007-08-06 US US11/834,557 patent/US8772448B2/en not_active Expired - Fee Related
-
2014
- 2014-05-22 US US14/285,577 patent/US20140342378A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0511116A1 (en) * | 1991-04-26 | 1992-10-28 | Clonatec S.A. | Antigens recognized by polyarthrits rheumatoid antibodies, preparation and applications |
FR2752842A1 (en) * | 1996-08-30 | 1998-03-06 | Biomerieux Sa | ANTIGENS DERIVED FROM FILAGGRINS AND THEIR USE FOR THE DIAGNOSIS OF RHUMATOID POLYARTHRITIS |
Non-Patent Citations (6)
Title |
---|
G. SCHELLEKENS ET AL.: "The modified arginine residue citrulline is the major constituent of epitopes recognized by autoantibodies in sera from rheumatoid arthitis patients." ARTHRITIS AND RHEUMATISM, vol. 40, no. 9 suppl., 8 - 12 November 1997, NEW YORK, NY, USA, page S276 XP002067877 * |
M. SEBBAG ET AL.: "The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies." THE JOURNAL OF CLINICAL INVESTIGATION, vol. 95, no. 6, June 1995, NEW YORK, NY, VS, pages 2672-2679, XP002038025 * |
M. SIMON ET AL.: "The cytokeratin filament-aggregating protein filaggrin is the target of the so-called "antikeratin antibodies", autoantibodies specific for rheumatoid arthritis." THE JOURNAL OF CLINICAL INVESTIGATION, vol. 92, no. 3, September 1993, NEW YORK, NY, VS, pages 1387-1393, XP002038026 * |
R. HOET ET AL.: "Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the perinuclear factor and profilaggrin." ANNALS OF THE RHEUMATIC DISEASES, vol. 50, no. 9, September 1991, LONDEN, GB, pages 611-618, XP002038024 * |
S-Q. GAN ET AL.: "Organization, structure and polymorphisms of the human profilaggrin gene." BIOCHEMISTRY, vol. 29, no. 40, 9 October 1990, VS, pages 9432-9440, XP002038027 cited in the application * |
Y. MISAKI ET AL.: "The 56K autoantigen is identical to human annexin XI." THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 269, no. 6, 11 February 1994, BALTIMORE, MD, VS, pages 4240-4246, XP002038028 * |
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Also Published As
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AU741850B2 (en) | 2001-12-13 |
NL1004539C2 (en) | 1998-05-20 |
BR9712955A (en) | 1999-12-07 |
CA2272573C (en) | 2010-02-02 |
CA2272573A1 (en) | 1998-05-28 |
US20060039924A1 (en) | 2006-02-23 |
US20020137092A1 (en) | 2002-09-26 |
US20050186201A1 (en) | 2005-08-25 |
JP4197743B2 (en) | 2008-12-17 |
US20140342378A1 (en) | 2014-11-20 |
AU4970797A (en) | 1998-06-10 |
WO1998022503A3 (en) | 1998-08-27 |
US8772448B2 (en) | 2014-07-08 |
PT941244E (en) | 2007-02-28 |
US20080050841A1 (en) | 2008-02-28 |
JP2001513753A (en) | 2001-09-04 |
DK0941244T3 (en) | 2007-04-30 |
US6858438B2 (en) | 2005-02-22 |
EP0941244A2 (en) | 1999-09-15 |
US7335724B2 (en) | 2008-02-26 |
US7288634B2 (en) | 2007-10-30 |
DE69737292T2 (en) | 2007-06-28 |
ATE352560T1 (en) | 2007-02-15 |
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