EP3827022A1 - Auto-anticorps se liant au facteur e d'allongement négatif (nelf-e) pour le diagnostic de la sarcoïdose - Google Patents

Auto-anticorps se liant au facteur e d'allongement négatif (nelf-e) pour le diagnostic de la sarcoïdose

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Publication number
EP3827022A1
EP3827022A1 EP18755184.1A EP18755184A EP3827022A1 EP 3827022 A1 EP3827022 A1 EP 3827022A1 EP 18755184 A EP18755184 A EP 18755184A EP 3827022 A1 EP3827022 A1 EP 3827022A1
Authority
EP
European Patent Office
Prior art keywords
nelf
sarcoidosis
subject
antibodies against
risk
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.)
Pending
Application number
EP18755184.1A
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German (de)
English (en)
Inventor
Niklas BAERLECKEN
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.)
Individual
Original Assignee
Individual
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
Application filed by Individual filed Critical Individual
Publication of EP3827022A1 publication Critical patent/EP3827022A1/fr
Pending legal-status Critical Current

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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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells

Definitions

  • the present invention relates to methods for diagnosing the presence or the risk of development or the therapy control of sarcoidosis in human subjects.
  • the present invention relates to test kits for use in the diagnosis of the presence or the risk of development, or for the therapy control of sarcoidosis in human subjects.
  • the present invention relates to a method for diagnosing the presence or the risk of development, or for the therapy control of sarcoidosis, in a subject testing for the presence of antibodies against Negative elongation factor E (NELF-E)(RNA-binding protein RD) or a NELF-E analog protein, preferably bacterial NELF-E analog protein, or immune-reactive peptides thereof, in a subject.
  • NELF-E Negative elongation factor E
  • RD RNA-binding protein RD
  • NELF-E analog protein preferably bacterial NELF-E analog protein, or immune-reactive peptides thereof
  • the presence of antibodies against NELF-E or immunoreactive peptides thereof is indicative for the presence or the risk of development, or for the therapy control of sarcoidosis. That is, detection of the presence of antibodies against NELF-E or immunoreactive peptides thereof, allows early diagnosis of sarcoidosis.
  • Sarcoidosis belongs to multisystemic inflammatory orphan diseases (lannuzzi M, Rybicki BA, Teirsten AS. Sacoidosis. Nejm 2007;375(21 ):2153-2165.). Sarcoidosis is characterized by noncaseeating granulomatous infiltrations of the soft tissue. It affects younger adults between 20 and 40 years (yrs) and older adults beyond the age of 50yrs. Its incidence varies between 10 and 50/100.000. In Germany, the prevalence is 40/100.00 and its incidence is 12/100.000.
  • the diagnossis of sarkoidosis relies on the typical symptomatic trias, known as Loffgren trias, or positive biopsy in combination with radiologic findings or typical clinical findings, however exclusion of malignancies, infectious diseases and other inflammatory diseases is necessary.
  • the present invention provides a diagnostic method for the presence or the risk of developing sarcoidosis, as well as for therapy control of sarcoidosis in a subject. That is, the present inventors recognized that subjects suffering from sarcoidosis have antibodies directed against NELF-E or immunoreactive peptides thereof, preferably human NELF-E or bacterial homologs, or
  • a first embodiment of the present invention relates to a method for diagnosing the presence or the risk of development, or for the therapy control of sarcoidosis in a subject comprising
  • the biological sample is one from a human subject.
  • the presence of antibodies against human NELF-E i.e. autoantibodies, and/or bacterial NELF-E homologs, or immunoreactive peptides thereof, are detected.
  • antibodies against bacterial NELF- E homologs or immune reactive peptides thereof, are detected.
  • the detection of antibodies is conducted using immunoassays, like ELISA.
  • the biological sample to be tested is obtained from blood, in particular serum.
  • the diagnostic method according to the present invention represents the first method allowing positive diagnosis of sarcoidosis in a subject via antibody markers. Diagnosis is possible at an early stage of the disease.
  • Another embodiment of the present invention relates to a test kit for use in a method according to the present invention, namely for diagnosing the presence or the risk of a development as well as for therapy control of sarcoidosis in a subject comprising means of determining antibodies against NELF-E and
  • test kit is an ELISA assay.
  • Fig. 1 The figure shows the titers of IgG-antibodies against the NELF-E (Seq.
  • titer in different diseases.
  • the titer is considered positive, if it is the same or higher than the cut off serum. From the left to the right the different test groups are listed: Sarcoidosis, small vessel vasculitis (SVV), systemic lupus erythematosus (SLE), febrile infectious diseases (FID), and blood donors (BD).
  • SVV small vessel vasculitis
  • SLE systemic lupus erythematosus
  • FID febrile infectious diseases
  • BD blood donors
  • Fig.2 In figure 1 the positive patients for the human IgG anti-NELF-E antibodies and the positive patients for the human IgA anti-NELF-E (using Seq. ID. No.1 ) in sarcoidosis versus febrile infectious diseases (FID) are shown. In addition, a chi- squared distribution table shows the sensitivity and sensitivity.
  • Fig.3 In In figure 1 , the positive patients for the human IgG anti-NELF-E antibodies are shown, here the peptide of Seq. ID. No. 2, using different diseases: Sarcoidosis, systemic lupus erythematosus (SLE) and blood donors (BD).
  • Fig.4 In figure 1 , the positive patients for the human IgG anti-NELF-E antibodies are shown, here the peptide of Seq. ID. No. 3, using different diseases:
  • Sarcoidosis systemic lupus erythematosus (SLE), febrile infectious diseases (FID), lung diseases (including lung fibrosis, COPD, bronchial cancer) and blood donors (BD).
  • SLE systemic lupus erythematosus
  • FID febrile infectious diseases
  • BD blood donors
  • Fig.5 In figure 1 , the positive patients for the human lgG4 anti-NELF-E
  • the present invention relates to a method for diagnosing the presence or the risk of development, or for the therapy control of sarcoidosis in a subject comprising
  • the present invention is based on the observation of the present inventor that subjects afflicted with sarcoidosis have antibodies against NELF-E, typically against the NELF-E, or immunoreactive peptides thereof.
  • NELF-E includes also fragments of NELF-E containing an immuno reactive peptide.
  • the NELF-E peptide may be NELF-E derived from eukaryotes or prokaryotes.
  • the NELF-E may be human NELF-E, non-human eukaryotic or prokaryotic NELF-E which is a analog of the eukaryotic NELF-E, like bacterial NELF-E, or immunoreactive peptides derived from eukaryotic or prokaryotic NELF-E.
  • Immunoreactive peptides are peptides of at least 7 amino acid residues, like 8 to 1 1 amino acid residues or longer. Immunoreactive peptides of NELF-E comprise an epitop of an anti-NELF-E antibody, like an autoantibody.
  • NELF-E is part of the NELF complex.
  • the NELF complex negatively influences the elongation of transcription by RNA polymerase II.
  • NELF-E shows the strongest RNA binding activity of the NELF complex and may start recruiting the NELF complex to RNA.
  • NELF a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation.
  • NELF-E or immunoreactive peptides thereof represents an entity to which antibodies can be found in subjects afflicted with sarcoidosis.
  • determining the presence of antibodies against NELF-E e.g. human NELF-E alone, bacterial NELF-E alone or a combination of both
  • NELF-E antibodies against NELF-E and/or the prokaryotic analog thereof, or immune reactive peptides thereof, e.g. against the protein sequence(s) according to Seq. ID No. 1 and/or Seq. ID No. 2 and/or Seq. ID No. 3 are detected.
  • the determination of antibodies against at least one of these molecules allows to identify individuals suffering from sarcoidosis.
  • the immunoreactive peptide of NELF-E is derived from the NELF-E, preferably of human NELF-E, or its analogs in prokaryotes.
  • the NELF-E peptide is any one of Seq. ID No. 1 .
  • determining the presence of antibodies against NELF-E allows a specific diagnosis of sarcoidosis, in particular, at early stages.
  • said diseases can be diagnosed by extensive and cost-intensive diagnosis or exclusion of other diseases, disorders or conditions, only.
  • the present invention allows to identify the therapy regimen of an individual in need thereof. That is, identifying the presence of antibodies against NELF-E or immune reactive peptides thereof, suggests a therapy comprising 13- cell depletion, inducing tolerance in T-cells or to any other therapy in order to eliminate NELF-E specific antibodies.
  • the presence of antibodies against both, human NELF-E and bacterial protein is determined. That is, by determining the presence of antibodies against both, human NELF-E, and bacterial homologs, or immunoreactive peptides thereof, the specificity of diagnosing sarcoidosis.
  • patient and“subject” are used interchangeably and refer to patients and subjects of humans or other mammals and includes any individual it is desired to examine or treat using the methods of the invention. However, it will be understood that“patient” does not imply that symptoms are present.
  • biological sample refers to a sample that may be extracted, untreated, treated, isolated, concentrated from a patient.
  • the biological sample is selected from any part of the patient’s body, including but not limited to hair, skin, nails, tissues or body fluids, such as saliva, synovia and blood. It is preferred that the samples are from the blood of said individual, like from the sera.
  • the word “comprise” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.
  • the term“obtained from” is meant that a sample such as, for example serum is isolated from or derived from a particular source of the subject.
  • the extract can be obtained from tissue or a body fluid isolated directly from the subject.
  • diagnosis refers to methods by which a skilled artisan can estimate and even determine whether or not a subject is suffering from a given disease, disorder or condition.
  • diagnosis on the basis of one or more diagnostic indicators, namely antibodies, the amount (including presence or absence) of which is indicator for the presence, severity, or absence of the condition.
  • “making a diagnosis” or“diagnosing” as used herein may further include making a prognosis, which can provide for predicting a clinical outcome, selecting an appropriate treatment, or monitoring current treatment and
  • determining refers to assessing the presence, absence, quantity, level or amount of the respective antibodies within the subject derived sample, including qualitative or quantitative concentration levels of said substances otherwise evaluating the values or categorisation of a subject clinical parameter.
  • multiple determinations of the antibodies over time can be made to facilitate stratification, diagnosis and/or prognosis.
  • detecting, determining or analyzing the presence of the antibodies in the sample can include binding the antibodies to antigen and then detecting either the binding event or the presence of the antibody isolated from the biological sample.
  • Exemplary techniques for detecting the antibodies include, but are not limited to, enzyme-linked
  • immunoassay immunoprecipitation and immunoblotting (including for example western blotting and dot blotting).
  • the skilled person is well aware of useful immunodetection methods allowing analyzing the sample for the presence or absence of antibodies against N ELF-E, in particular heavy chain N ELF-E, or immunoreactive peptides thereof.
  • the biological sample obtained from the subject is contacted with an antigen, namely with N ELF-E or oligo-, polypeptide or protein containing the antibody immunoreactive peptide including a NELF-E epitope, thus, allowing binding of the antibody to said peptide.
  • the term“polypeptide” or“protein” which are used interchangeably herein, refer to a polymer of amino acids heaving a length of at least 50 aa.
  • oligopeptide refers to a polymer of amino acids heaving a length of from 5 to 49 aa.
  • the term“peptide” include polypeptides, oligopeptides as well as proteins.
  • a label or marker such as any radioactive, fluorescent, biological or enzymatic tags or labels of standard use in the art.
  • a secondary binding ligand such as a second antibody or a biotine/avidine (streptavidine) ligand binding arrangement as it is known in the art.
  • the primary immune complex can be detected by a second binding ligand that has binding affinity for the antigen or the antibody presented in the sample, for example reactivity to the Fc region of the antibodies or having reactivity to a region of the antigen different to the binding region of the antibody.
  • the second binding ligand can be linked to a detectable label or marker molecule.
  • the second binding ligand is itself often an antibody which may thus be termed a secondary antibody.
  • the primary immune complexes are contacted with the labelled, secondary binding ligand or antibody, under conditions effective and for a period of time sufficient to allow the formation of secondary immune complexes.
  • the secondary immune complexes are then generally washed to remove off any unbound labelled secondary antibodies or ligands, and the remaining label in the secondary immune complex is then detected.
  • the second binding ligand such as an antibody, having binding activity for either the antigen or antibody, may also be used to bind to the primary immune complexes.
  • the second binding ligand contains an enzyme capable of
  • the biological sample is a body fluid, preferably blood.
  • the biological sample is serum of the subject to be
  • the methods according to the present invention allows for the stratification of the therapeutic regimen of a subject afflicted with sarcoidosis or being at risk of developing sarcoidosis.
  • the present invention allows to identify the status of disease, in particular, the active state of the disease in a subject afflicted with sarcoidosis.
  • the antibodies to be detected may be of the IgA, IgM, IgE, IgD and/or IgG type or IgG 1 , lgG2, lgG3, lgG4 subtype. That is, it is possible to determine the presence of the IgA, IgM, IgE, IgD and/or IgG type or lgG1 , lgG2, lgG3, lgG4 antibodies in the biological sample obtained from the subject.
  • IgA, IgM, IgE, IgD and/or IgG type or IgG 1 , lgG2, lgG3, lgG4 antibodies it is preferred that IgA and IgG and lgG4 antibodies against NELF-E are detected.
  • the subject is a human and the antibodies are human
  • the presently disclosed subject matter provides test kits or diagnostic kits for the use in a method according to the present invention.
  • immunological kits for use in detecting antibodies in biological samples allowing diagnosis of sarcoidosis. That is, the present invention provides a test kit for use in a method according to the present invention for diagnosing the presence of the risk of a development as well as for the therapy control of sarcoidosis, in a subject comprising means or determining antibodies against NELF-E or immunoreactive peptides derived from NELF-E in a biological sample of a subject to be tested and instructions on how to use the test kit.
  • said test kit is an ELISA.
  • kits can generally comprise or more antigens, namely oligo- or polypeptides of NELF-E that can immunoreact with the antibodies.
  • the immunodetection kits will comprise in suitable container(s), one or more antibody immunoreactive peptide antigens derived from NELF-E.
  • Said antigens useful in the presently claimed methods and test kits may be the full NELF-E or
  • the antigen can be provided bound to a solid support, such as for example a column matrix or a well of a microtiter plate, a membrane, beads, dip sticks or the like.
  • a solid support such as for example a column matrix or a well of a microtiter plate, a membrane, beads, dip sticks or the like.
  • the support can be provided as a separate element of the kit.
  • the test kit according to the present invention for diagnosing sarcoidosis includes beside the antigen a detection agent for the antibodies which may be an antibody, antibody fragment etc.
  • the kit may comprise more than one detection agent.
  • the kit further comprises substrate and further means for allowing reaction with an enzyme used as label for the detecting agent which may be an antibody.
  • the immunodetection agents of the kit can include detectable labels that are associated with or linked to the given detecting agent, in particular, the detecting antibody. Detectable labels that are associated with or attached to a secondary binding ligand are also contemplated. Detectable labels include dyes,
  • illuminescent or fluorescent molecules biotin, radiolabels or enzymes.
  • suitable labels include commonly known fluorescent molecules, like rhodamine, fluorescein, green fluorescent protein or luciferase, or alkaline phosphatase and horseradish peroxidase as examples for suitable enzymes.
  • kits further comprise positive and negative controls for verifying the results obtained when using the kit.
  • the components of the kits can be packaged either in aqueous medium or lyophilised form and, in addition, the kits comprise one or more containers allowing to conduct the detection.
  • the test kit comprises instructions for use of the kit.
  • the present invention relates to the use of NELF-E, immune reactive sequences or analogs thereof in the diagnosis, risk assessment or therapy control of sarcoidosis.
  • the present invention relates to the use of peptides derived from NELF-E including immune reactive peptides in prophylaxis and/or treatment of
  • NELF-E including the immune reactive peptides of said molecules allow to induce tolerance, thus, being useful in prophylaxis and therapy of sarcoidosis.
  • NELF-E, immunoreactive peptides thereof may be used for systemic or local therapy of diseases, disorders or conditions which are associated with an immunoreaction against said
  • the administration thereof may be effected orally, parenterally or via mucosal membranes.
  • the present invention provides pharmaceutically compositions containing NELF-E molecules including immunoreactive peptides for use in the prophylaxis and treatment of the disease identified herein as well as in diseases, disorders or conditions associated with an immune reaction against these compounds.
  • the pharmaceutical composition may be provided in a suitable form. The skilled person is well aware of useful forms, dosages etc.
  • Sera of patients with different inflammatory and rheumatic diseases were screened via protein array technology. New markers of sarcoidosis have been identified which have been evaluated further for frequency and association by different ELISA.
  • the evaluation was performed with sera of patients with sarcoidosis and with sera of controls (blood donors, patients with systemic lupus erythematosus, malignant diseases, different lung diseases, infectious diseases, HIV infected persons and small vessel vasculitis).
  • the patients had been well characterized with regard to the disease activity, demographic data and treatment.
  • the sera of the patients and of the controls had been stored in a -20°C freezer until use.
  • 96 well plates (Nunc Maxisorb) were coated with 10 pg recombinant NELF-E (amino acids, purchased from Abeam, Cambridge, UK)(Seq. ID. No. 1 ), or with 100 pg of peptide consisting of the NELF-E peptid I (synthesized by Biomatik, U.S.A.)(Seq. ID. No.2) or with 100 pg of the NELF-E peptid II (synthesized by Biomatik, U.S.A.)(Seq. ID. No. 3).
  • the plates were incubated with sera in a 1 :100 dilution in PBS for 30 to 60 minutes at room temperature.
  • a serum of a patient with active sarcoidosis was used.
  • the concentration of antibodies in this serum was defined as 1 AU for IgG- type antibodies against NELF-E and the NELF-E peptides as well as for IgA-type NELF-E antibodies.
  • the plates were washed 3 times with PBS.
  • IgG-type antibodies against NELF-E protein and against the NELF-E peptide I and mycobacterial homolog sequence NELF-E II (“NELF-E analog protein”) had a sensitivity for sarcoidosis of 48%, 56% and 50%, respectively, and a specificity (considering only the non-autoimmune controls) of 90%, 97% and 96%.
  • IgG- type antibodies against NELF-E peptide II showed a specificity of 94% considering the infectious diseases and of 95% considering non-sarcoidosis lung diseases.
  • IgG- type antibodies against NELF-E peptide II showed a specificity considering only the systemic lupus erythematosus patients of 89%.
  • the test for lgG4-subtype antibodies against NELF-E had a sensitivity for sarcoidosis of 31 % and a specificity (considering only the non-autoimmune controls) of 96% and (considering only the infectious diseases) 96%, respectively.

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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

La présente invention concerne d'une manière générale un procédé permettant de diagnostiquer la présence ou le risque de développement ou le contrôle thérapeutique de la sarcoïdose chez un sujet, en particulier chez des mammifères. La présente invention concerne également des kits de test destinés à être utilisés dans le diagnostic de la présence ou du risque de développement ou du contrôle thérapeutique de la sarcoïdose chez un sujet. La présente invention concerne, plus particulièrement un procédé permettant de diagnostiquer la présence ou le risque de développement ou le contrôle thérapeutique de la sarcoïdose chez un sujet par la recherche de la présence d'anticorps contre NELF-E ou des peptides immunoréactifs de ceux-ci ou une protéine d'un analogue de NELF-E, de préférence, une protéine d'un analogue bactérien, ou des peptides immunoréactifs de celle-ci, chez un sujet. La présence d'anticorps contre NELF-E ou des peptides immunoréactifs de ceux-ci indique la présence ou le risque de développement, ou le contrôle thérapeutique de la sarcoïdose. En particulier, la détection de la présence d'anticorps contre la sarcoïdose ou de peptides immunoréactifs de ceux-ci permet un diagnostic précoce de la sarcoïdose.
EP18755184.1A 2018-08-11 2018-08-11 Auto-anticorps se liant au facteur e d'allongement négatif (nelf-e) pour le diagnostic de la sarcoïdose Pending EP3827022A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2018/071843 WO2020035123A1 (fr) 2018-08-11 2018-08-11 Auto-anticorps se liant au facteur e d'allongement négatif (nelf-e) pour le diagnostic de la sarcoïdose

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EP3827022A1 true EP3827022A1 (fr) 2021-06-02

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Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4512828B2 (ja) * 2005-04-12 2010-07-28 国立大学法人 千葉大学 肺サルコイドーシスおよび眼サルコイドーシスの検出マーカー及び検出キット
WO2011156766A2 (fr) * 2010-06-11 2011-12-15 The Regents Of The University Of California Biomarqueurs associés aux maladies auto-immunes du poumon
EP2620770B1 (fr) * 2010-09-22 2017-04-26 National University Corporation Chiba University Nouvelle méthode de test pour angéite
JP5574348B2 (ja) * 2012-05-31 2014-08-20 国立大学法人 千葉大学 肺サルコイドーシスおよび眼サルコイドーシスの検出マーカー及び検出キット
GB201411060D0 (en) * 2014-06-20 2014-08-06 Oncimmune Ltd Improved immunoassay method
GB201411037D0 (en) * 2014-06-20 2014-08-06 Immatics Biotechnologies Gmbh Novel immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemai (CLL)

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