EP2255195A2 - Séquences de marqueurs de la polyarthrite rhumatoïde et leur utilisation - Google Patents

Séquences de marqueurs de la polyarthrite rhumatoïde et leur utilisation

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Publication number
EP2255195A2
EP2255195A2 EP08829479A EP08829479A EP2255195A2 EP 2255195 A2 EP2255195 A2 EP 2255195A2 EP 08829479 A EP08829479 A EP 08829479A EP 08829479 A EP08829479 A EP 08829479A EP 2255195 A2 EP2255195 A2 EP 2255195A2
Authority
EP
European Patent Office
Prior art keywords
marker sequences
rheumatoid arthritis
case
marker
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP08829479A
Other languages
German (de)
English (en)
Inventor
Jens Beator
Angelika LÜKING
Axel Kowald
Helmut E. Meyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Protagen GmbH
Original Assignee
Protagen GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE200710041656 external-priority patent/DE102007041656A1/de
Priority claimed from DE200710041654 external-priority patent/DE102007041654A1/de
Application filed by Protagen GmbH filed Critical Protagen GmbH
Priority to EP14164520.0A priority Critical patent/EP2884278A3/fr
Publication of EP2255195A2 publication Critical patent/EP2255195A2/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • 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
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • the present invention relates to novel marker sequences for rheumatoid arthritis and their diagnostic use, including a method of screening for potential drugs for rheumatoid arthritis by means of these marker sequences. Furthermore, the invention relates to a diagnostic device containing such marker sequences for rheumatoid arthritis, in particular a protein biochip and its use.
  • Protein biochips are gaining increasing industrial importance in analytics and diagnostics as well as in pharmaceutical development. Protein biochips have become established as screening tools.
  • cDNA of a particular tissue in a bacterial or a eukaryotic expression vector, such as yeast is cloned.
  • the ones used for the expression Vectors are generally characterized by carrying inducible promoters that control the timing of protein expression.
  • expression vectors have sequences for so-called affinity epitopes or proteins, which on the one hand allow the specific detection of the recombinant fusion proteins by means of an antibody directed against the affinity epitope, on the other hand, the specific purification via affinity chromatography (IMAC) allows.
  • affinity epitopes or proteins which on the one hand allow the specific detection of the recombinant fusion proteins by means of an antibody directed against the affinity epitope, on the other hand, the specific purification via affinity chromatography (IMAC) allows.
  • IMAC affinity chromatography
  • Antibody arrays An embryonic but growing technology, DDT, 7, 143-149, Kusnezow et al., (2003) Antibody microarrays: An evaluation of production parameters, proteomics, 3, 254-264).
  • indication-specific diagnostic devices such as a protein biochip.
  • the object of the present invention is therefore the provision of marker sequences and their diagnostic use.
  • the invention relates to the use of marker sequences for the diagnosis of rheumatoid arthritis, wherein at least one marker sequence of a cDNA selected from the group SEQ 1-488 or in each case a protein coding therefor or in each case a partial sequence or fragment thereof
  • marker sequences according to the invention to or from a patient to be examined.
  • the marker sequences according to the invention could be identified by differential screening of samples from healthy subjects with patient samples with rheumatoid arthritis.
  • rheumatoid arthritis is defined, for example, by Pschyrembel, de Gruyter, 261st edition (2007), Berlin According to the invention, "juvenile idiopathic arthritis” (ICD-10: M08.-, abbr .: JIA Older people
  • Juvenile rheumatoid arthritis Juvenile chronic arthritis, Still's disease or more popular: childhood rheumatism
  • Juvenile Juvenile rheumatoid arthritis
  • Juvenile chronic arthritis Still's disease or more popular: childhood rheumatism
  • This is a polygenic disease which can be diagnosed particularly advantageously by means of the marker sequences according to the invention, preferably of the marker sequences SEQ 401-488.
  • At least 2 to 5 or 10 preferably 30 to 50 marker sequences or 50 to 100 or more marker sequences are determined on or from a patient to be examined.
  • the marker sequences of SEQ 1-20 are particularly preferred, the marker sequences are preferably SEQ 21-50 and further preferred are the marker sequences SEQ 51-100.
  • marker sequences SEQ 1-10 and SEQ 11-20 and also preferably SEQ 21-30, SEQ 31-40 or SEQ 41-50.
  • marker sequences SEQ 401-488 for the diagnosis of juvenile rheumatoid arthritis in particular, SEQ ID Nos. 401-420, SEQ ID NO 421-440, SEQ ID NOs 441-460 and SEQ ID NOs 461-488.
  • the marker sequences according to the invention can also be combined, supplemented, fused or extended with known biomarkers for this indication.
  • the determination of the marker sequences takes place outside the human body and the determination takes place in an ex vivo / in vitro diagnosis.
  • the invention relates to the use of marker sequences as diagnostic agents, wherein at least one marker sequence of a cDNA selected from the group SEQ 1 - 488 or in each case a protein coding therefor or in each case a partial sequence or fragment thereof.
  • the invention relates to a method for the diagnosis of rheumatoid arthritis, wherein a.) At least one marker sequence of a cDNA selected from the group SEQ 1-488 or a respective coding protein or a partial sequence or fragment thereof is applied to a solid support and b .) is brought into contact with body fluid or tissue extract of a patient and c.) the detection of an interaction of the body fluid or tissue extract with the marker sequences from a.).
  • the invention also relates to diagnostic agents for the diagnosis of rheumatoid arthritis each selected from the group SEQ 1 - 488 or each a protein coding therefor or in each case a partial sequence or fragment thereof.
  • the detection of such an interaction can be carried out for example by a probe, in particular by an antibody.
  • the invention also has the object of providing a diagnostic device or assay, in particular a protein biochip, which allows for diagnosis or examination of rheumatoid arthritis.
  • the invention relates to a method for stratifying, in particular for risk stratification and / or therapy control of a patient with rheumatoid arthritis, wherein at least one marker sequence of a cDNA selected from the group SEQ 1 - 488 or in each case a protein coding therefor is determined on a patient to be examined.
  • therapy control also includes the classification of patients into responders and non-responders with regard to a therapy or its course of therapy.
  • Diagnosis in the sense of this invention means the positive determination of rheumatoid arthritis by means of the marker sequences according to the invention and the assignment of the patients to rheumatoid arthritis.
  • diagnosis includes medical diagnosis and investigations in this regard, in particular in vitro diagnostics and laboratory diagnostics Proteomics and Nucleic Acid Blots Further investigation may be required to confirm and exclude other diseases, therefore, the term diagnosis also includes the differential diagnosis of rheumatoid arthritis using the marker sequences of the present invention as well as the prognosis of rheumatoid arthritis.
  • Stratification also: stratification or therapy control
  • stratification means that the method according to the invention allows decisions for the treatment and therapy of the patient, be it hospitalization of the patient, use, effect and / or dosage of one or more drugs, a therapeutic measure or the monitoring of a disease course as well as the course of therapy or etiology or classification of a disease, for example into a new or existing subtype or the differentiation of diseases and their patients.
  • the term “stratification” includes in particular the risk stratification with the prognosis of an "outcome” of an adverse health event.
  • patient is understood to mean any subject - human or mammal - with the proviso that the subject is being examined for rheumatoid arthritis.
  • marker sequences in the sense of this invention means that the cDNA or the respective polypeptide or protein obtainable therefrom are significant for rheumatoid arthritis
  • the cDNA or the respectively obtainable polypeptide or protein can interact with substances from the body fluid or tissue extract of a Patients with rheumatoid arthritis (eg antigen (epitope) / antibody (paratope) interaction)
  • "at least one marker sequence of a cDNA selected from the group SEQ 1-488 or a protein coding therefor or in each case a partial sequence or Fragment thereof is determined on a patient to be examined "that an interaction between the body fluid or tissue extract of a patient and the marker sequences according to the invention is detected.
  • Such an interaction is eg a bond, in particular a binding substance on at least one marker sequence according to the invention or in the case of a cDNA the hybridization with a suitable substance under selected conditions, in particular stringent conditions (eg as defined in J. Sambrook, EF Fritsch, T. Maniatis (1989), Molecular cloning: A laboratory manual, 2nd Edition, CoId Spring Habor Laboratory Press, CoId Spring Habor, USA or Ausubel, "Current Protocols in Molecular Biology", Green Publishing Associates and Wiley Interscience, NY (1989)).
  • stringent conditions eg as defined in J. Sambrook, EF Fritsch, T. Maniatis (1989), Molecular cloning: A laboratory manual, 2nd Edition, CoId Spring Habor Laboratory Press, CoId Spring Habor, USA or Ausubel, "Current Protocols in Molecular Biology", Green Publishing Associates and Wiley Interscience, NY (1989)).
  • stringent conditions eg as defined in J. Sambrook, EF Fritsch,
  • Hybridization conditions are: hybridization in 4 x SSC at 65 ° C (alternatively in 50% formamide and 4X SSC at 42 ° C), followed by several washes in 0.1 x SSC at 65 ° C for a total of about one hour.
  • An example of less stringent hybridization conditions is hybridization in 4 x SSC at 37 ° C, followed by several washing steps in 1 x SSC at room temperature.
  • Such substances are part of a body fluid according to the invention, in particular blood, whole blood, blood plasma, blood serum, patient serum, urine, cerebrospinal fluid,
  • the marker sequences according to the invention may be present in a significantly higher or lower expression rate or concentration that indicates the rheumatoid arthritis.
  • the relative expression rates ill / healthy of the marker sequences according to the invention for rheumatoid arthritis are determined by means of proteomics or nucleic acid blots.
  • the marker sequences have, in another embodiment of the invention, a recognition signal which is addressed to the substance to be bound (e.g., antibody, nucleic acid).
  • the recognition signal for a protein is preferably an epitope and / or paratope and / or hapten and, for a cDNA, a hybridization or binding region.
  • the marker sequences according to the invention are the subject of Table A and can be identified unambiguously by the respectively cited database entry (also by means of the Internet: http://www.ncbi.nlm.nih.gov/) (see Table A: Accession No. there).
  • the marker sequences also include such modifications of the cDNA sequence and the corresponding amino acid sequence, such as chemical modification, such as citrullination, acetylation, phosphorylation, glycosylation or polyA strand and other modifications known to those skilled in the art.
  • partial sequences or fragments of the marker sequences according to the invention are also included.
  • those partial sequences which have an identity of 95%, 90%, in particular 80% or 70% with the marker sequences according to the invention are also included.
  • the respective marker sequence can be introduced in different amounts into or be represented on a solid support several areas. This allows a variation of the sensitivity.
  • the regions can each have an entirety of marker sequences, ie a sufficient number of different marker sequences, in particular 2 to 5 or 10 or more and, if appropriate, further nucleic acids and / or proteins, in particular biomarkers. However, at least 96 to 25,000 (numerically) or more are preferred from different or identical marker sequences and further nucleic acids and / or proteins, in particular biomarkers. Also preferred are more than 2,500, more preferably 10,000 or more different or identical marker sequences and, if appropriate, further nucleic acids and / or proteins, in particular biomarkers.
  • Another object of the invention relates to an array of marker sequences containing at least one marker sequence of a cDNA selected from the group SEQ 1-488 or in each case a protein coding therefor.
  • the array contains at least 2 to 5 or 10, preferably 30 to 50 marker sequences or 50 to 100 or more marker sequences.
  • “arrangement” synonymously means “array” and insofar as this "array” is used to identify substances to marker sequences, this is to be understood as an “assay” or diagnostic device.
  • the arrangement is such that the marker sequences represented on the array are in the form of a grid on a solid support.
  • Such arrangements are preferred which allow a high density array of protein binders and spotting the marker sequences.
  • Such high density spotted assemblies are disclosed, for example, in WO 99/57311 and WO 99/57312, and may be advantageously used in a robotic automated high throughput method.
  • the term "assay” or diagnostic device also encompasses such embodiments of a device as ELISA (eg individual wells of a microtiter plate are coated with the marker sequences of the invention or combinations of marker sequences, optionally robotically supported in the individual wells of the microtiter plate
  • ELISA eg individual wells of a microtiter plate are coated with the marker sequences of the invention or combinations of marker sequences, optionally robotically supported in the individual wells of the microtiter plate
  • diagnostic ELISA kits from Phadia or Multiplex ELISA kits "Searchlight” from Pierce / Thermo Fisher Scientific
  • bead-based assay are coated with marker sequences / combinations of marker sequences.
  • the patient sample is incubated with this bead population and bound (auto) antibodies are detected by means of another fluorescence-labeled secondary antibody / detection reagent by measuring the fluorescence, eg Borrelia IgG kit or Athena Multilyte from the company Multimetrix), Line Assay (Mar kersequences or combinations of marker sequences are robotically immobilized on membranes which are examined / incubated with the patient sample; Example "Euroline” from Euroimmun AG), Western blot (example “Euroline-WB” from Euroimmun AG), immortror ⁇ atographische method (eg lateral flow immunoassays, marker sequences / combinations of marker sequences are on test strips (membranes, US 5,714,389 etc.) immobilized, for example, One Step HBsAg Test Device from Acon Laboratories) or similar immunological single or multiplex detection methods.
  • fluorescence eg Borrelia IgG kit or Athena Multilyte from
  • the marker sequences of the assembly are fixed to a solid support, but preferably spotted or immobilized even printed, i. applied reproducibly.
  • One or more marker sequences may be present several times in the totality of all marker sequences and be present in different amounts relative to one spot. Furthermore, the
  • Marker sequences on the solid support to be standardized (eg by means of serial dilution series of eg Human globulins as internal calibrators for data normalization and quantitative evaluation).
  • the invention relates to an assay or protein biochip consisting of an array containing marker sequences according to the invention.
  • the marker sequences are present as clones.
  • Such clones can be obtained, for example, by means of a cDNA expression library according to the invention (Büssow et al., 1998 (supra)).
  • expression libraries containing clones are obtained by means of expression vectors from an expressing cDNA library consisting of the cDNA marker sequences.
  • These expression vectors preferably contain inducible promoters. Induction of expression may be e.g. by means of an inductor, such as IPTG. Suitable expression vectors are described in Terpe et al. (Terpe T Appl Microbiol Biotechnol 2003 Jan; 60 (5): 523-33).
  • expression libraries which are tissue specific (e.g., human tissue, particularly human organs).
  • tissue specific e.g., human tissue, particularly human organs.
  • expression libraries are also included according to the invention, which can be obtained by exon trapping. Instead of expression library can be spoken synonymously from an expression bank.
  • UnicloneCD library protein biochips or corresponding expression libraries which have no redundancy
  • UnicloneCD library protein biochips or corresponding expression libraries which have no redundancy
  • the clones may not be such as transformed bacteria, recombinant phage or transformed cells of mammals, insects, fungi, yeasts or plants.
  • the clones are fixed on a solid support, spotted or immobilized.
  • the invention relates to an arrangement wherein the marker sequences are present as clones.
  • the marker sequences may be in the form of a fusion protein containing, for example, at least one affinity epitope or "tag".
  • the tag may be one such as c-myc, His-tag, Arg-tag, FLAG, alkaline phosphatase, V5 tag, T7 tag or
  • Strep tag HAT tag, NusA, S-tag, SBP tag, thioredoxin, DsbA, a fusion protein, preferably a cellulose binding domain, green fluorescent protein, maltose binding protein, calmodulin binding protein, glutathione S-transferase or lacZ contain.
  • a marker sequence can also be composed of several individual marker sequences. This may involve cloning individual fragments into a large common fragment and expressing this combined fragment.
  • the term "solid support” includes embodiments such as a filter, a membrane, a magnetic or fluorophore-labeled bead, a silicon wafer, glass, metal, plastic, a chip, a mass spectrometric target, or a matrix.
  • a filter is preferred according to the invention.
  • nitrocellulose or nylon is further preferred (eg Immobilon P Millipore, Protran Whatman f Hybond N + ⁇ mersham).
  • this corresponds to a grid having the size of a microtiter plate (8-12 wells strips, 96 wells, 384 wells or more), a silicon wafer, a chip, a mass spectrometric target or a matrix.
  • the invention relates to an assay or protein biochip for identifying and characterizing a substance for rheumatoid arthritis, characterized in that an arrangement or assay according to the invention is brought into contact with a.) At least one substance to be investigated and b.) Detects a binding success becomes.
  • the invention further relates to a method for identifying and characterizing a substance for rheumatoid arthritis, characterized in that an arrangement or assay according to the invention is brought into contact with a.) At least one substance to be investigated and b.) A binding success is detected.
  • the substance to be assayed may be any native or non-native biomolecule, synthetic chemical molecule, mixture or substance library.
  • the evaluation of the binding success is carried out, for example, using commercially available image analysis software (GenePix Pro (Axon Laboratories), Aida (Raytest), ScanArray (Packard Bioscience).
  • the visualization of protein-protein interactions according to the invention can be carried out in a customary manner, for example by means of fluorescence labeling, biotinization, radio-isotope labeling or colloidal gold or latex particle labeling.
  • Detection of bound antibodies is carried out with the aid of secondary antibodies labeled with commercial reporter molecules (eg Cy, Alexa, Dyomics, FITC or similar fluorescent dyes, colloidal gold or latex particles), or with reporter enzymes such as alkaline phosphatase, horseradish peroxidase, etc.
  • the invention relates to a drug / drug or prodrug for rheumatoid arthritis developed and obtainable by the use of the assay or protein biochip according to the invention.
  • the invention also relates to the use of a device according to the invention or an assay for the screening of drugs for rheumatoid arthritis.
  • the invention also relates to a target for the treatment and therapy of rheumatoid arthritis in each case selected from the group SEQ 1 - 488 or in each case a protein coding therefor.
  • the invention likewise relates to the use of the marker sequences according to the invention, preferably in the form of an arrangement, as an affinity material for carrying out apheresis or, respectively, for the same.
  • a blood wash wherein substances from body fluids of a patient with rheumatoid arthritis, such as blood or plasma, bind to the marker sequences of the invention and thus the body fluid can be selectively withdrawn.
  • Ten or more patient samples were individually screened against a cDNA expression library.
  • the rheumatoid arthritis-specific expression clones were determined by comparison with ten or more healthy samples.
  • FIG. 1 shows the differential screening between two protein biochips from in each case one cDNA expression bank of a patient and one healthy subject.
  • the differential clones are detected by fluorescence labeling and evaluated bioinformatorisch.

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

Abstract

L'invention concerne de nouvelles séquences de marqueurs de la polyarthrite rhumatoïde et leur utilisation diagnostique ainsi qu'un procédé pour cribler des principes actifs potentiels, pouvant être utilisés contre la polyarthrite rhumatoïde, au moyen de ces séquences de marqueurs. L'invention concerne en outre un dispositif diagnostique contenant de telles séquences de marqueurs de la polyarthrite rhumatoïde, notamment une biopuce à protéines et son utilisation.
EP08829479A 2007-09-03 2008-09-03 Séquences de marqueurs de la polyarthrite rhumatoïde et leur utilisation Ceased EP2255195A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14164520.0A EP2884278A3 (fr) 2007-09-03 2008-09-03 Séquences de marqueurs pour l'arthrite rhumatoïde et leur utilisation

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE200710041656 DE102007041656A1 (de) 2007-09-03 2007-09-03 Markersequenzen für rheumatoide Arthritis und deren Verwendung
DE200710041654 DE102007041654A1 (de) 2007-09-03 2007-09-03 Markersequenzen für juvenile idiopathische Arthritis und deren Verwendung
PCT/DE2008/001547 WO2009030226A2 (fr) 2007-09-03 2008-09-03 Séquences de marqueurs de la polyarthrite rhumatoïde et leur utilisation

Related Child Applications (1)

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EP14164520.0A Division EP2884278A3 (fr) 2007-09-03 2008-09-03 Séquences de marqueurs pour l'arthrite rhumatoïde et leur utilisation

Publications (1)

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EP2255195A2 true EP2255195A2 (fr) 2010-12-01

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EP08829479A Ceased EP2255195A2 (fr) 2007-09-03 2008-09-03 Séquences de marqueurs de la polyarthrite rhumatoïde et leur utilisation
EP14164520.0A Withdrawn EP2884278A3 (fr) 2007-09-03 2008-09-03 Séquences de marqueurs pour l'arthrite rhumatoïde et leur utilisation

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US (3) US20100261881A1 (fr)
EP (2) EP2255195A2 (fr)
CN (1) CN101842705A (fr)
AU (1) AU2008295292A1 (fr)
CA (1) CA2698437A1 (fr)
WO (1) WO2009030226A2 (fr)

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JP5996429B2 (ja) * 2009-09-03 2016-09-21 ジェネンテック， インコーポレイテッド 関節リウマチの治療、診断及びモニターするための方法
EP2644704A1 (fr) 2012-03-27 2013-10-02 Protagen AG Séquences de marqueurs pour l'arthrite rhumatoïde
WO2013170994A1 (fr) 2012-03-27 2013-11-21 Protagen Ag Séquences marqueurs de la polyarthrite rhumatoïde
EP3436828A1 (fr) 2016-04-02 2019-02-06 Protagen AG Séquences de marqueurs pour la polyarthrite rhumatoïde
EP3258268A1 (fr) 2016-06-15 2017-12-20 Protagen AG Sequences de marqueurs pour la commande de therapie de patients atteints de polyarthrite rhumatoïde
DE102021205638A1 (de) 2021-06-02 2022-12-08 Volkswagen Aktiengesellschaft Fahrzeugscheibenanordnung, Fahrzeug

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Also Published As

Publication number Publication date
US20150087548A1 (en) 2015-03-26
AU2008295292A1 (en) 2009-03-12
EP2884278A2 (fr) 2015-06-17
CA2698437A1 (fr) 2009-03-12
EP2884278A3 (fr) 2015-10-07
US20170009300A1 (en) 2017-01-12
US20100261881A1 (en) 2010-10-14
WO2009030226A3 (fr) 2009-07-23
CN101842705A (zh) 2010-09-22
WO2009030226A2 (fr) 2009-03-12

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