WO2013150132A2 - Marqueurs polypeptidiques pour diagnostiquer et évaluer des accidents vasculaires cérébraux - Google Patents

Marqueurs polypeptidiques pour diagnostiquer et évaluer des accidents vasculaires cérébraux Download PDF

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Publication number
WO2013150132A2
WO2013150132A2 PCT/EP2013/057182 EP2013057182W WO2013150132A2 WO 2013150132 A2 WO2013150132 A2 WO 2013150132A2 EP 2013057182 W EP2013057182 W EP 2013057182W WO 2013150132 A2 WO2013150132 A2 WO 2013150132A2
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markers
polypeptide
sample
absence
amplitude
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PCT/EP2013/057182
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German (de)
English (en)
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WO2013150132A3 (fr
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Harald Mischak
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Mosaiques Diagnostics And Therapeutics Ag
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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
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7019—Ischaemia

Definitions

  • the present invention relates to the use of the presence or absence of one or more peptide markers in a sample of an individual for the diagnosis and assessment of ischemic stroke and transistoric, ischemic attacks as well as a method for the diagnosis and assessment of ischemic stroke and transistoric ischemic attacks or absence of the peptide marker (s) is indicative of ischemic stroke and of transient ischemic attacks.
  • a transient ischemic attack is a circulatory disorder of the brain that causes neurological deficits that completely regress within 24 hours.
  • Typical symptoms include hemiplegia of the arm and / or leg, speech problems and - possibly half-sided - visual disturbances. Especially in the case of TIA, some of the symptoms have already subsided during hospital admission.
  • the diagnosis is essentially based on imaging techniques.
  • the sensitivity of magnetic resonance imaging with diffusion weighting was 83%, while computed tomography without contrast medium had only a sensitivity of 16%.
  • the false-negative rate of magnetic resonance imaging is still 17%.
  • the ability or ability to easily and reliably detect and assess a stroke, especially a minor stroke or a TIA would have many advantages.
  • the object of the present invention was to provide a method with which this diagnosis can take place, in particular also the severity of a stroke can be assessed.
  • the object is achieved by a method for diagnosing a stroke, comprising the step of determining the presence or absence or amplitude of at least three polypeptide markers in a urine sample, the polypeptide markers being selected from the markers shown in Table 1 by values for the molecular masses, the migration time and / or optionally their peptide sequence are characterized.
  • the evaluation of the measured polypeptides can be based on the presence or absence and / or amplitude of the markers taking into account the following reference or regulation values.
  • the specified logarithm of the amplitude is a measure of a higher or lower occurrence of a marker in the respective groups.
  • the control group is a group of patients who did not have a stroke.
  • markers are used whose sequence is given in Table 3.
  • Specificity is defined as the number of actual negative samples divided by the sum of the number of actual negatives and the number of false positives. A specificity of 100% means that a test identifies all healthy persons as healthy, i. no healthy person is identified as ill. This does not say anything about how well the test detects sick patients.
  • Sensitivity is defined as the number of actual positive samples divided by the sum of the number of actual positives and the number of false negatives. A sensitivity of 100% means that the test detects all patients. He does not say how well the test detects healthy people.
  • markers according to the invention it is possible to detect IS or TIA with a specificity of at least 60, preferably at least 70, more preferably 80, even more preferably at least 90 and most preferably at least 95%.
  • markers according to the invention it is possible to detect IS or TIA with a sensitivity of at least 60, preferably at least 70, more preferably 80, even more preferably at least 90 and most preferably at least 95%.
  • Migration time is determined by capillary electrophoresis (CE) - e.g. executed in point 2 - determined.
  • CE time capillary electrophoresis
  • the eluent used is, for example, 30% methanol, 0.5% formic acid in water or 20% acetonitrile, 0.25% formic acid. All percentages in% by volume.
  • CE migration time can vary. However, the order in which the polypeptide labels elute is typically the same for any CE system used under the conditions indicated. To the- To compensate for any remaining differences in migration time, the system can be normalized using standards for which migration times are well known. These standards can be, for example, the polypeptides given in the examples (see Example 3), or certain known peptides from urine, as described, for example, in Jantos-Siwy et al. (Quantitative Urinary Proteome Analysis for Biomarker Evaluation in Chronic Kidney Disease, J. Proteome Res., 8: 268-281 (2009)).
  • CE-MS capillary electrophoresis mass spectrometry
  • polypeptide markers according to the invention are proteins or peptides or degradation products of proteins or peptides. They may be chemically modified, e.g. by post-translational modifications such as glycation, phosphorylation, alkylation or disulfide bridging, or by other reactions, e.g. in the context of mining, to be changed. Based on the parameters that determine the polypeptide markers (molecular mass and migration time), it is possible to identify the sequence of the corresponding polypeptides by methods known in the art.
  • the polypeptides of the invention are used to diagnose IS or TIA. Diagnosis is the process of the recognition Winning by assigning symptoms or phenomena to a disease or injury. The presence or absence of a polypeptide marker can be measured by any method known in the art. Methods that can be used are exemplified below.
  • a polypeptide marker is present when its reading is at least as high as the threshold. If its reading is below that, the polypeptide marker is absent.
  • the threshold value can either be determined by the sensitivity of the measurement method (detection limit) or defined based on experience.
  • the threshold is preferably exceeded when the sample reading for a given molecular mass is at least twice that of a blank (e.g., only buffer or solvent).
  • the polypeptide marker (s) is / are used to measure its presence or absence, the presence or absence being indicative of IS or TIA.
  • polypeptide markers that are typically present in individuals with IS or TIA, but are less common or absent in individuals without IS or TIA.
  • polypeptide markers which are present in patients with IS or TIA but are absent or only rarely present in patients without IS or TIA.
  • the frequency with which a marker appears in the group with IS or TIA or in the control group is given in Table 2 as frequency.
  • the amplitudes can also be used for diagnosis.
  • the amplitudes are used in such a way that it is not the presence or absence that is decisive, but the height of the signal (the amplitude) when the signal is present in both groups.
  • a nomination procedure makes sense in order to achieve comparability between differently concentrated samples or different measurement methods.
  • collagen fragments are preferably used, as in Jantos Siwy et al. (Quantitative Urinary Proteome Analysis for Biomarker Evaluation in Chronic Kidney Disease, J. Proteome Res., 8: 268-281 (2009)). wrote.
  • the decision to make a diagnosis depends on how high the amplitude of the respective polypeptide markers in the patient sample is compared to the mean amplitudes in the control group or the "sick" group. If the value is close to the mean amplitude of the "sick" group, it is to be assumed that the occurrence of a stroke, it corresponds more to the mean amplitudes of the control group, is not to assume a stroke.
  • the distance to the mean amplitude can be interpreted as a probability of belonging to a group. Alternatively, the distance between the measured value and the mean amplitude may be considered as a probability of belonging to a group.
  • both the frequency and the amplitude are used for the evaluation.
  • the p-value is a measure of the likelihood that the association of the markers with the two groups (IS or TIA and control) is based on a random distribution that is not related to IS or TIA.
  • the individual from whom the sample is derived, in which the presence or absence or amplitude of one or more polypeptide markers is determined, may be any individual who may be suffering from IS or TIA.
  • the subject is a mammal, most preferably a human.
  • the sample measuring the presence or absence of the polypeptide marker (s) of the invention may be any sample recovered from the subject's body.
  • the sample is a sample having a polypeptide composition suitable for making statements about the condition of the individual.
  • it may be blood, urine, synovial fluid, tissue fluid, body secretions, sweat, cerebrospinal fluid, lymph, intestinal, gastric, pancreatic, bile, tear fluid, tissue sample, sperm, vaginal fluid or stool sample ,
  • it is a liquid sample.
  • the sample is a urine sample.
  • Urine samples may be known as known in the art.
  • a mid-jet urine sample is used.
  • the urine sample may e.g. by means of a catheter or also with the aid of a urination apparatus, as described in WO 01/74275.
  • the presence or absence or amplitude of a polypeptide marker in the sample can be determined by any method known in the art suitable for measuring polypeptide markers. Those skilled in such methods are known. In principle, the presence or absence of a polypeptide marker can be determined by direct methods such as e.g. Mass spectrometry, or indirect methods, such as by ligands or specific probes such as antibodies.
  • the sample of the subject eg, the urine sample
  • the treatment may include, for example, purification, separation, dilution or concentration.
  • the methods may include, for example, centrifugation, filtration, ultrafiltration, dialysis, precipitation or chromatographic methods such as affinity separation or separation by ion exchange chromatography, or electrophoretic separation.
  • a mass spectrometric method is used to determine the presence or absence or amplitude of a polypeptide marker, which method may precede purification or separation of the sample.
  • the mass spectrometric analysis has the advantage over current methods that the concentration of many (> 100) polypeptides of a sample can be determined by a single analysis. Any type of mass spectrometer can be used. With mass spectrometry, it is possible to routinely measure 10 fmoles of a polypeptide marker, that is, 0.1 ng of a 10 kDa protein with a measurement accuracy of approximately ⁇ 0.01% from a complex mixture. In mass spectrometers, an ion-forming unit is coupled to a suitable analyzer.
  • electrospray ionization (ESI) interfaces are commonly used to measure ions from liquid samples
  • matrix assisted laser desorption / ionization (MALDI) technique is used to measure ions from sample crystallized with a matrix
  • ESI electrospray ionization
  • MALDI matrix assisted laser desorption / ionization
  • quadrupoles ion traps or time-of-flight (TOF) analyzers are used.
  • TOF time-of-flight
  • electrospray ionization the molecules present in solution are sprayed, inter alia, under the influence of high voltage (eg 1-8 kV), resulting in charged droplets formed by evaporation of the solvent get smaller.
  • high voltage eg 1-8 kV
  • Coulomb explosions lead to the formation of free ions, which can then be analyzed and detected.
  • TOF analyzers have a very high scanning speed and achieve a very high resolution.
  • Preferred methods for determining the presence or absence of polypeptide markers include gas phase ion spectrometry, such as laser desorption / ionization mass spectrometry, MALDI-TOF-MS, SELDI-TOF-MS (surface enhanced laser desorption ionization), LC-MS (liquid chromatography mass spectrometry), 2D-PAGE-MS and capillary electrophoresis mass spectrometry (CE-MS). All of the methods mentioned are known to the person skilled in the art.
  • gas phase ion spectrometry such as laser desorption / ionization mass spectrometry, MALDI-TOF-MS, SELDI-TOF-MS (surface enhanced laser desorption ionization), LC-MS (liquid chromatography mass spectrometry), 2D-PAGE-MS and capillary electrophoresis mass spectrometry (CE-MS). All of the methods mentioned are known to the person skilled in the art.
  • CE-MS in which capillary electrophoresis is coupled with mass spectrometry. This method is described in detail e.g. in German patent application DE 10021737, in Kaiser et al. (J. Chromatogr. A, 2003, Vol. 1013: 157-171, and Electrophoresis, 2004, 25: 2044-2055), in Wittke et al. (J. Chromatogr. A, 2003, 1013: 173-181) and Ref.
  • the CE-MS technique allows to determine the presence of several hundreds of polypeptide markers of a sample simultaneously in a short time, a small volume and high sensitivity. After a sample has been measured, a pattern of the measured polypeptide markers is prepared (see below). This can be compared with reference patterns of ill or healthy individuals. In most cases it is sufficient to use a limited number of polypeptide markers for the diagnosis of diseases. More preferred is a CE-MS method which includes CE coupled online to an ESI-TOF-MS.
  • the use of volatile solvents is preferred, and it is best to work under substantially salt-free conditions. conditions.
  • suitable solvents include acetonitrile, methanol and the like.
  • the solvents may be diluted with water and an acid (eg 0.1% to 1% formic acid) added to protonate the analyte, preferably the polypeptides.
  • Capillary electrophoresis makes it possible to separate molecules according to their charge and size. Neutral particles migrate at the rate of electroosmotic flow upon application of a current, cations are accelerated to the cathode and anions are retarded.
  • the advantage of capillaries in electrophoresis is the favorable ratio of surface area to volume, which enables a good removal of the Joule heat arising during the current flow. This in turn allows the application of high voltages (usually up to 30 kV) and thus a high separation efficiency and short analysis times.
  • quartz glass capillaries with internal diameters of typically 50 to 75 ⁇ m are normally used. The used lengths are 30-100 cm.
  • the capillaries usually consist of plastic-coated quartz glass.
  • the capillaries may be both untreated, i. on the inside show their hydrophilic groups, as well as be coated on the inside. A hydrophobic coating can be used to improve the resolution.
  • a pressure which is typically in the range of 0-1 psi may also be applied. The pressure can also be created during the separation or changed during the process.
  • the markers of the sample are separated by capillary electrophoresis, then directly ionized and transferred online to a mass spectrometer coupled thereto for detection.
  • several polypeptide markers can advantageously be used for diagnostics. Preferred is the use of at least 5, 6, 8, or 10 markers. In one embodiment, 20 to 50 markers are used.
  • the biomarkers identified according to the invention can also be used to determine the severity of the stroke.
  • the biomarkers show correlation with the National Institute of Health Stroke Scale (NIHSS).
  • NIHSS National Institute of Health Stroke Scale
  • the combination of the normalized amplitudes of the individual biomarkers can thus be used to determine the severity of the stroke, thus giving valuable information on the therapy.
  • Urine was used to detect polypeptide markers for diagnosis. Urine was collected from healthy donors (peer group) and from patients who had a stroke. For the subsequent CE-MS measurement, those also had to be in urine of patients in higher concentration occurring proteins such as albumin and immunoglobulins are separated by ultrafiltration. For this purpose, 700 .mu.l of urine were removed and treated with 700 .mu.l Filtrationspuffer (2M urea, lOmM ammonia, 0.02% SDS). These 1.4 ml sample volumes were ultrafiltered (20 kDa, Sartorius, Göttingen, DE). The UF was carried out at 3000 rpm in a centrifuge until 1.1 ml ultrafiltrate was obtained.
  • the CE-MS measurements were performed with a capillary electrophoresis system from Beckman Coulter (P / ACE MDQ System, Beckman Coulter Inc, Fullerton, USA) and a Bruker ESI-TOF mass spectrometer (micro-TOF MS, Bruker Daltonik, Bremen, D).
  • the CE capillaries were purchased from New Objective, they had an ID / OD of 50/360 ⁇ and a length of 90 cm.
  • the mobile phase for the CE separation consisted of 20% acetonitrile and 0.25% formic acid in water. 30% isopropanol with 0.5% formic acid was used for the "sheath flow" at the MS, here with a flow rate of 20 ⁇ / h.
  • CE-ESI-MS sprayer kit (Agilent Technologies, Waldbronn, DE).
  • the duration of the injection was 99 seconds. With these parameters about 300 nl of the sample were injected into the capillary, this corresponds to about 10% of the capillary volume.
  • a "stacking" technique was used. An IM NH 3 solution is injected for 7 seconds (at 1 psi) prior to sample injection. After applying the separation voltage (25 kV), the analytes are automatically concentrated between these solutions.
  • CE separation was performed with a pressure method: 0 psi for 30 minutes, 0.1 psi for 1 min, 0.2 psi for 1 min, 0.3 psi for 1 min, 0.4 psi for 1 min, and 0.5 psi for 35 min.
  • the total duration of a separation run was thus 70 minutes.
  • no "Nebulizer gas” was used.
  • the voltage applied to the spray needle to generate the electrospray was 4000-4800 V.
  • the remaining settings on the mass spectrometer were optimized as instructed by the manufacturer of peptide detection. The spectra were recorded over a mass range of m / z 400 to m / z 3000 and accumulated every 3 seconds.
  • the proteins / polypeptides are each used in a concentration of 10 pmol / ⁇ in water.
  • REV amino acid sequence
  • ELM amino acid sequence polypeptide
  • KINCON amino acid sequence polypeptides
  • a further peptide (peptide 2) is selected from the measurement and attempts to identify a suitable polypeptide marker, again taking into account a corresponding time window. If, in turn, several markers can be found with a corresponding mass, the most probable assignment is that in which there is a substantially linear relationship between the shift for the peptide 1 and for the peptide 2.
  • further proteins from his sample for the assignment, for example ten proteins.
  • migration times are either lengthened or shortened by certain absolute values, or upsets or knocks occur throughout the course. Co-migrating peptides also co-migrate under such conditions.
  • the urine samples are analyzed according to Carty DM et al. (Urinary proteomics for predication of preeclampsia, Hypertension 2011; 57: 561-9) with a Dionex Ultimate 3000 RSLS nanoflous system (Dionex, Camberley, UK) (LC / MS). Samples (5 ⁇ ) were spun at a flow rate of 5 ⁇ / min in 0.1% formic acid and 2% acetonitrile onto a Dionex C18 nano trap. Column (0.1 x 20 mm, 5 ⁇ m) abandoned.
  • the sample was eluted at a flow rate of 0.3 ⁇ / min onto an Acclaim-PepMap C18 nano-column (75 ⁇ m x 15cm, 2 ⁇ m, 100%), the trap column and the nanofluid column were opened
  • the mass spectrometer was operated in the MS / MS mode with a scan range from m / z 380 to 2000 amu.
  • the 10 largest multiply charged ions were selected from each scan for MS / MS analysis; the fragmentation method was HCD with 35% collision energy.
  • the ions were selected by a data-dependent method with a repetition number of 1 and an exclusion time of 15 s for MS2.
  • the ion dissolution was 60000 in MSI and 7500 for HCD-MS2.
  • the files were used for a search against the human non-redundant IPI database using the Open Mass Spectrometry Search Algorithm (OMSSA, see pubchem.ncbi.nlm.nih.gov/omssa) and SEQUEST (using the Thermo Proteome Discoverer), without any enzyme specificity. No fixed modification and oxidation of methionine and proline were chosen as variable modifications. The permissible mass error window for MS or MS / MS was 10 ppm or 0.05 Da. In the case of SEQUEST, the peptide data were extracted using high peptide-confidence and top-one peptide rank filters. 1% FDR was used as the threshold for identifying identified peptides.
  • OMSSA Open Mass Spectrometry Search Algorithm
  • SEQUEST using the Thermo Proteome Discoverer
  • Sample 14289 and Sample 14238 were classified with a classifier based on the biomarkers of the invention in a blinded assay. When all 229 biomarkers were used, the scoring for subject was 14289-0788, so no stroke, the scoring for subject 14238 was 1,058, so positive for stroke.
  • Marker 123902 has an amplitude of 2.35 in the control group and an amplitude of 1.86 in the stroke group. The subject found an amplitude of 2.62, i. still above the amplitude for the control group. This results in a negative score for the patient.
  • Marker 70413 has an amplitude of 2.16 in the control group and a score of 3.02 in the stroke group. The found amplitude is 2.85; this is closer to the group for stroke. He gets a positive score.
  • Marker 4609 has a score of 0.06 in the healthy group and a score of 1.27 in the stroke group. The amplitude of 2.31 is still above the amplitude of the sick group. This gives a strong positive score. This results in a total score for subject 14238 of +0.910.
  • Marker 70413 has an amplitude of 2.48. The score is slightly closer to the healthy than to the sick group, so there is a small negative score.
  • Marker 4906 was not found in the sample. The marker is rare in the control (3%) and also with small amplitudes. His absence is a strong negative score.
  • subject 14289 was found to be the urine sample of a patient who did not have a stroke, while subject 14238 was from a stroke patient, so in both cases the diagnosis was correct.

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Abstract

L'invention concerne un procédé pour diagnostiquer et évaluer des accidents vasculaires cérébraux ischémiques et des accidents ischémiques transitoires, consistant à déterminer une présence ou une absence ou une amplitude d'au moins trois marqueurs polypeptidiques dans un échantillon d'urine, les marqueurs polypeptidiques étant choisis parmi les marqueurs caractérisés dans le tableau 1 par des valeurs pour les masses moléculaires et la durée de migration.
PCT/EP2013/057182 2012-04-05 2013-04-05 Marqueurs polypeptidiques pour diagnostiquer et évaluer des accidents vasculaires cérébraux WO2013150132A2 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074275A1 (fr) 2000-03-30 2001-10-11 Orde Levinson Appareil de miction
DE10021737A1 (de) 2000-05-04 2001-11-15 Hermann Haller Verfahren und Vorrichtung zur qualitativen und/oder quantitativen Bestimmung eines Protein-und/oder Peptidmusters einer Flüssigkeitsprobe, die dem menschlichen oder tierischen Körper entnommen wird

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2046807B1 (fr) * 2006-07-13 2012-03-28 University of Iowa Research Foundation Procedes et reactifs pour le traitement et le diagnostic de troubles vasculaires et de la degenerescence maculaire liee a l'age
WO2011029954A2 (fr) * 2009-09-14 2011-03-17 Mosaiques Diagnostics And Therapeutics Ag Polypeptide marqueur pour le diagnostic et l'évaluation de maladies vasculaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074275A1 (fr) 2000-03-30 2001-10-11 Orde Levinson Appareil de miction
DE10021737A1 (de) 2000-05-04 2001-11-15 Hermann Haller Verfahren und Vorrichtung zur qualitativen und/oder quantitativen Bestimmung eines Protein-und/oder Peptidmusters einer Flüssigkeitsprobe, die dem menschlichen oder tierischen Körper entnommen wird

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Title
ANDERSEN ET AL.: "Urinary proteome analysis enables assessment of renoprotective treatment in type 2 diabetic patients with microalbuminuria", BMC NEPHROL., vol. 11, 2010, pages 29
CARTY DM ET AL.: "Urinary proteomics for prediction of preeclampsia", HYPERTENSION, vol. 57, 2011, pages 561 - 9
DAKNA ET AL., BMC BIOINFORMATICS, vol. 11, 2010, pages 594
ELECTROPHORESIS, vol. 25, 2004, pages 2044 - 2055
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JANTOS-SIWY ET AL.: "Quantitative Urinary Proteome Analysis for Biomarker Evaluation in Chronic Kidney Disease", J. PROTEOME. RES., vol. 8, 2009, pages 268 - 281
KAISER ET AL., J. CHROMATOGR. A, vol. 1013, 2003, pages 157 - 171
MISCHAK, H. ET AL.: "Capillary electrophoresis-mass spectrometry as a powerful tool in biomarker discovery and clinical diagnosis: An update of recent developments", MASS SPECTROM. REV., vol. 28, 2009, pages 703 - 724
MISCHAK, H. ET AL.: "Comprehensive human urine standards for comparability and standardization in clinical proteome analysis", PROTEOMICS CLIN APPL., vol. 4, 2010, pages 464 - 478
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