EP1955064A1 - Marqueur polypeptidique pour diagnostiquer et evaluer la stenose du meat de l'uretre - Google Patents

Marqueur polypeptidique pour diagnostiquer et evaluer la stenose du meat de l'uretre

Info

Publication number
EP1955064A1
EP1955064A1 EP06819862A EP06819862A EP1955064A1 EP 1955064 A1 EP1955064 A1 EP 1955064A1 EP 06819862 A EP06819862 A EP 06819862A EP 06819862 A EP06819862 A EP 06819862A EP 1955064 A1 EP1955064 A1 EP 1955064A1
Authority
EP
European Patent Office
Prior art keywords
markers
sample
marker
polypeptide
polypeptide marker
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.)
Withdrawn
Application number
EP06819862A
Other languages
German (de)
English (en)
Inventor
Harald Mischak
Stefan Wittke
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.)
Mosaiques Diagnostics and Therapeutics AG
Original Assignee
Mosaiques Diagnostics and Therapeutics AG
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 Mosaiques Diagnostics and Therapeutics AG filed Critical Mosaiques Diagnostics and Therapeutics AG
Priority to EP06819862A priority Critical patent/EP1955064A1/fr
Publication of EP1955064A1 publication Critical patent/EP1955064A1/fr
Withdrawn legal-status Critical Current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
    • G01N33/68—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
    • G01N2800/34—Genitourinary disorders

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 evaluation of the severity of Ureterausgangsstenose (UAS) and a method for diagnosing and assessing Ureterabgangsstenose, wherein the presence or absence of the or the peptide marker (s) is indicative of the severity of a UAS.
  • UAS Ureterausgangsstenose
  • Diagnosis may be prenatal only sonographically, postnatally sonographically and e.g. be carried out by diuresis load.
  • the decisive factor for the course of therapy is the question of when a severity level is reached that makes an operative intervention necessary. In dilatation and no further increase in the enlargement of the renal medullary system after diuresis load no surgery is necessary according to the current state. On the other hand, if there is evidence of obstruction (persistent or progressive enlargement of the renal medullary system following diuresis loading) or other functional impairment, surgery is required. All stages between these two conditions do not allow a clear decision for or against surgery, which may be associated with severe complications in newborns or infants.
  • an object of the present invention is the use of the presence or absence of at least one, ideally more polypeptide marker (s) in a sample of an individual for the diagnosis of ureteral stenosis, said polypeptide marker (s) being selected from polypeptide labels Nos. 1 to No. 308, which are characterized by the molecular masses given in Table 1 and their migration times.
  • Table 1 Polypeptide markers for the diagnosis of ureteral stenosis and its molecular masses and migration times (CE time in minutes):
  • the migration time is determined by means of capillary electrophoresis (CE), as described in Example 2, for example.
  • CE capillary electrophoresis
  • a 90 cm long glass capillary with an inner diameter (ID) of 50 ⁇ m and an outer diameter (OD) of 360 ⁇ m is operated at an applied voltage of 30 kV.
  • the eluent used is 30% methanol, 0.5% formic acid in water.
  • CE migration time can vary. Nevertheless, the order in which the polypeptide labels elute is typically the same for each CE system used under the conditions indicated. To compensate for any differences in migration time, the system can be normalized using standards for which migration times are known. These standards may e.g. be the polypeptides given in the examples (see example point 3).
  • the characterization of the polypeptides shown in Tables 1 to 3 was determined by capillary electrophoresis mass spectrometry (CE-MS), a method which was described e.g. in detail by Neuhoff et al. (Rapid Communications in mass spectrometry, 2004, Vol. 20, pages 149-156).
  • CE-MS capillary electrophoresis mass spectrometry
  • the variation of molecular masses between individual measurements or between different mass spectrometers is relatively small with exact calibration, typically in the range of ⁇ 0.1%, preferably in the range of ⁇ 0.05%, more preferably ⁇ 0.03%, even more preferably ⁇ 0.01%.
  • 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 glycolization, phosphorylation, alkylation or disulfide bridging, or by other reactions, e.g. in the context of mining, to be changed. In addition, the polypeptide markers may also be chemically altered as part of the purification of the samples, e.g. oxidized, be.
  • polypeptides of the invention are used to diagnose the severity of UAS. Diagnosis is the process of gaining knowledge by assigning symptoms or phenomena to a disease or injury. In the present case, the presence or absence of certain polypeptide markers is indicative of the severity of UAS.
  • the polypeptide markers of the invention are determined in a sample of an individual, their presence or absence suggesting the degree of UAS. 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 the degree of UAS (frequency marker).
  • UAS degree of UAS
  • polypeptide markers that are present in patients with severe UAS such as polypeptide marker Nos. 250 to 277, but are not or only rarely present in patients without UAS (control).
  • the amplitude markers indicated in Table 3 can also be used for the diagnosis of ureteral stenosis (number 278-308). Amplitude markers 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 Essence of the signal in both groups decides. Table 3 shows the mean amplitudes of the respective signals (characterized by mass and migration time) over all the samples measured. To achieve comparability between differently concentrated samples or different measurement methods, all peptide signals of a sample are normalized to a total amplitude of 1 million counts. The respective mean amplitudes of the single markers are therefore given as parts per million (ppm).
  • All groups used consist of at least 20 individual patient or control samples to obtain a reliable mean amplitude.
  • the decision to make a diagnosis depends on the level of the respective polypeptide markers in the patient sample compared to the mean amplitudes in the control group or the UAS group, respectively, from the presence of a ureter outlet stenosis if it is more likely to be equivalent to the mean amplitudes of the control group, it can not be assumed that it is an UAS.
  • a more precise definition should be given using marker no. 298 (Table 3).
  • the mean amplitude of the marker is markedly increased in severe UAS (4428 ppm versus 1983 ppm in the control group).
  • this sample belongs to the control group. If the value is 4428 ppm, or 20% lower, or higher, ie between 3542 ppm and very high values, a severe ureter outlet stenosis can be assumed.
  • the individual from whom the sample is derived, in which the presence or absence of one or more polypeptide markers is determined may be any individual who may suffer from UAS.
  • the subject is a mammal, most preferably a human.
  • a frequency marker is a variant of the amplitude marker, in which the amplitude is low in some samples. It is possible to convert such frequency markers into amplitude markers, in which the amplitude is calculated in accordance with the With a very small amplitude - in the range of the detection limit - the sample will be included in the calculation.
  • a polypeptide marker not only a polypeptide marker, but a combination of markers is used to diagnose the degree of UAS. It is concluded by their presence or absence on the degree of UAS. By comparing a plurality of polypeptide markers, the falsification of the overall result can be reduced or avoided by individual deviations from the typical probability of presence in the patient or control individual.
  • 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 (severe UAS or not).
  • the sample may be blood, urine, synovial fluid, tissue fluid, body secretions, sweat, cerebrospinal fluid, lymph, intestinal, gastric, pancreatic, bile, tears, tissue, sperm, vaginal fluid, or a stool sample.
  • a liquid sample Preferably, it is a liquid sample.
  • the sample is a urine sample or a blood sample, where a blood sample may be a serum (blood) or plasma (blood) sample.
  • Urine samples may be known as known in the art.
  • a mid-beam 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.
  • Blood samples may be taken by methods known in the art, for example from a vein, artery or capillary.
  • a blood sample is obtained by giving venous blood to an individual by means of a blood test Syringe eg is removed from the arm.
  • the term blood sample also includes samples obtained from blood by further purification and separation techniques known in the art, such as blood plasma or blood serum.
  • the presence or absence 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 mass spectrometry or indirect methods such as by ligands.
  • the sample of the individual e.g. the urine or blood sample
  • pretreated prior to measuring the presence or absence of the polypeptide marker (s) by any suitable means e.g. be cleaned or separated.
  • the treatment may e.g. a purification, separation, dilution or concentration.
  • the methods may be, for example, centrifugation, filtration, ultrafiltration, dialysis, precipitation or chromatographic methods such as affinity separation or separation by ion exchange chromatography, or electrophoretic separation.
  • the sample is separated by electrophoresis prior to its measurement, purified by means of ultracentrifugation and / or by means of Ultrafiltration in fractions containing Polypeptidmarker certain molecular size, separated.
  • a mass spectrometric method is used to determine the presence or absence 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, ie 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 most commonly used to measure ions from liquid samples, whereas the matrix assisted laser desorption / ionization (MALDI) technique is used to measure ions from sample crystallized with a matrix.
  • MALDI matrix assisted laser desorption / ionization
  • TOF time-of-flight
  • electrospray ionization (ESI) the molecules present in solution are sprayed, inter alia, under the influence of high voltage (eg 1-8 kV), forming charged droplets, which become smaller due to evaporation of the solvent.
  • 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 process is described in detail, for example, in German patent application DE 10021737, in Kaiser et al. (J. Chromatogr. A 1 2003, Vol. 1013: 157-171, and Electrophoresis, 2004, 25: 2044-2055) and in Wittke et al. (J. Chromatogr. A 1 2003, 1013: 173-181).
  • 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 made. This can be compared with reference patterns of ill or healthy individuals.
  • CE-MS a CE-MS method which includes CE coupled online to an ESI-TOF-MS.
  • suitable solvents include acetonitrile, methanol and the like.
  • the solvents may be diluted with water and treated with a weak acid (eg 0.1% to 1% formic acid) 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 surface-to-volume ratio, which results in a good removal of the Joule heat arising during the current flow allows. 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.
  • polypeptide markers can be used for the diagnosis of UAS in the method according to the invention.
  • at least three polypeptide markers may be used, for example, markers 1, 2 and 3; 1, 2 and 4; etc.
  • Urine was used to detect polypeptide markers for the diagnosis of UAS. Urine was withdrawn from healthy donors (peer group) and from patients with severe UAS.
  • CE-MS measurements were carried out using a Beckman Coulter capillary electrophoresis system (P / ACE MDQ system, Beckman Coulter Ine, Fullerton, USA) and Bruker ESI-TOF mass spectrometer (micro-TOF MS, Bruker Daltonik, Bremen, D).
  • the CE capillaries were purchased from Beckman Coulter, having an ID / OD of 50/360 ⁇ m 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, here with a flow rate of 2 ⁇ l / min.
  • the coupling of CE and MS was realized by a CE-ESI-MS sprayer kit (Agilent Technologies, Waldbronn, DE).
  • the duration of the injection was 99 seconds. With these parameters were about 150 nl the Sample 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 sec (at 1 psi) prior to sample injection, and after injection of the sample for 5 sec, a 2M formic acid solution is injected. After applying the separation voltage (30 kV), the analytes are automatically concentrated between these solutions.
  • CE separation was performed with a pressure method: 0 psi for 40 minutes, 0.1 psi for 2 minutes, 0.2 psi for 2 minutes, 0.3 psi for 2 minutes, 0.4 psi for 2 minutes, finally 32 min at 0.5 psi.
  • the total duration of a separation run was thus 80 minutes.
  • the "Nebulizer gas” was set to the lowest possible value.
  • the voltage applied to the spray needle to generate the electrospray was 3700 - 4100 V.
  • the other settings on the mass spectrometer were optimized according to the instructions of the manufacturer for peptide detection. The spectra were recorded over a mass range of m / z 400 to m / z 3000 and accumulated every 3 seconds.
  • ELM sequence: ELMTGELPYSHINNRDQIIFMVGR 23.4 min
  • GIVLY sequence: GIVLYELMTGELPYSHIN 36.8 min The proteins / polypeptides are each used in a concentration of 10 pmol / ⁇ l in water. "REV”, “ELM”, “KINCON” and “GIVLY” represent synthetic peptides.
  • 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 comigrate under such conditions.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un procédé permettant de diagnostiquer la sténose du méat de l'urètre (VE), selon lequel il est prévu de déterminer la présence ou l'absence d'au moins un marqueur polypeptidique dans un échantillon, le marqueur polypeptidique étant sélectionné parmi les marqueurs 1 à 277 (marqueurs de fréquence), ou de déterminer l'amplitude d'au moins un marqueur polypeptidique, sélectionné parmi les marqueurs 278-308 (marqueurs d'amplitude), qui sont caractérisés par les valeurs des masses moléculaires et le temps de migration (temps CE).
EP06819862A 2005-11-30 2006-11-30 Marqueur polypeptidique pour diagnostiquer et evaluer la stenose du meat de l'uretre Withdrawn EP1955064A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06819862A EP1955064A1 (fr) 2005-11-30 2006-11-30 Marqueur polypeptidique pour diagnostiquer et evaluer la stenose du meat de l'uretre

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102005057383 2005-11-30
EP06110498 2006-02-28
PCT/EP2006/069098 WO2007063090A1 (fr) 2005-11-30 2006-11-30 Marqueur polypeptidique pour diagnostiquer et evaluer la stenose du meat de l'uretre
EP06819862A EP1955064A1 (fr) 2005-11-30 2006-11-30 Marqueur polypeptidique pour diagnostiquer et evaluer la stenose du meat de l'uretre

Publications (1)

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EP1955064A1 true EP1955064A1 (fr) 2008-08-13

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EP06819862A Withdrawn EP1955064A1 (fr) 2005-11-30 2006-11-30 Marqueur polypeptidique pour diagnostiquer et evaluer la stenose du meat de l'uretre

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Country Link
US (1) US20100062537A1 (fr)
EP (1) EP1955064A1 (fr)
JP (1) JP2009517677A (fr)
WO (1) WO2007063090A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060286602A1 (en) * 2004-05-10 2006-12-21 Harald Mischak Method and markers for the diagnosis of renal diseases
JP5351773B2 (ja) * 2007-03-07 2013-11-27 モザイクヴェス ディアグノシュティクス アンド テラポイティクス アクチェン ゲゼルシャフト 尿試料中の検体の濃度を正規化するための方法
EP1972940A1 (fr) * 2007-03-14 2008-09-24 mosaiques diagnostics and therapeutics AG Procédé et marqueur destinés à diagnostiquer des maladies des reins
AU2008309605A1 (en) * 2007-10-09 2009-04-16 Mosaiques Diagnostics And Therapeutics Ag Polypeptide marker for the diagnosis of prostate cancer
EP2051078A1 (fr) * 2007-10-19 2009-04-22 mosaiques diagnostics and therapeutics AG Procédé et marqueur destinés à diagnostiquer le diabète sucré
WO2009115570A2 (fr) * 2008-03-19 2009-09-24 Mosaiques Diagnostics And Therapeutics Ag Procédé et marqueur permettant de diagnostiquer des maladies et dommages tubulaires rénaux
EP2105736A1 (fr) * 2008-03-28 2009-09-30 Novartis Ag Analyse ADN au moyen d'électrophorèse capillaire
US20110214990A1 (en) * 2008-09-17 2011-09-08 Mosaiques Diagnostics And Therapeutics Ag Kidney cell carcinoma

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JP2948649B2 (ja) * 1990-10-26 1999-09-13 日本臓器製薬株式会社 生体内物質測定法
JP3147953B2 (ja) * 1991-10-23 2001-03-19 日本臓器製薬株式会社 生体内物質測定法
JP2001174459A (ja) * 1999-12-17 2001-06-29 Nippon Zoki Pharmaceut Co Ltd 腎機能検査法
US20030198959A1 (en) * 2002-03-28 2003-10-23 Kurnit David M. Methods and compositions for analysis of urine samples in the diagnosis and treatment of kidney diseases
AU2004225472B2 (en) * 2003-03-27 2011-02-10 Children's Hospital Medical Center A method and kit for detecting the early onset of renal tubular cell injury
CA2473814A1 (fr) * 2004-07-13 2006-01-13 Mosaiques Diagnostics And Therapeutics Ag Methode et marqueurs de diagnostic des maladies renales

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Title
See references of WO2007063090A1 *

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JP2009517677A (ja) 2009-04-30
WO2007063090A1 (fr) 2007-06-07
US20100062537A1 (en) 2010-03-11

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