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WO2003069343A2 - Procede de detection dans les selles des marqueurs tumoraux cea, ca19.9 ou ca72.4 pour reconnaitre des tumeurs gastro-intestinales - Google Patents

Procede de detection dans les selles des marqueurs tumoraux cea, ca19.9 ou ca72.4 pour reconnaitre des tumeurs gastro-intestinales Download PDF

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Publication number
WO2003069343A2
WO2003069343A2 PCT/EP2003/001504 EP0301504W WO03069343A2 WO 2003069343 A2 WO2003069343 A2 WO 2003069343A2 EP 0301504 W EP0301504 W EP 0301504W WO 03069343 A2 WO03069343 A2 WO 03069343A2
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Prior art keywords
cea
stool
tumor
receptor
detection
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PCT/EP2003/001504
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German (de)
English (en)
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WO2003069343A3 (fr
Inventor
Hans Scheefers
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Schebo Biotech Aktiengesellschaft
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Application filed by Schebo Biotech Aktiengesellschaft filed Critical Schebo Biotech Aktiengesellschaft
Priority to AU2003210274A priority Critical patent/AU2003210274A1/en
Publication of WO2003069343A2 publication Critical patent/WO2003069343A2/fr
Publication of WO2003069343A3 publication Critical patent/WO2003069343A3/fr

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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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57446—Specifically defined cancers of stomach or intestine

Definitions

  • the invention relates to methods for the qualitative and / or quantitative detection of CEA, CA19.9, CA72.4 or parts thereof, which are used as tumor markers in human or animal stool for detecting malignancy in the gastrointestinal tract and the abdominal cavity (esophagus, stomach, small intestine, Biliary tract, pancreas and colon).
  • CEA, CA19.9 and CA72.4 are tumor markers that are used in a variety of tumor diseases in body fluids, e.g. in serum or plasma (see e.g. Review: Anticancer Research 19: 2785-2820, 1999)
  • Tumor markers are macromolecules or antigens that occur in blood, serum, or other body fluids, and their changes in concentration are somewhat related to the development and growth of an individual's malignant tumors. Criteria for the quality of tumor markers
  • the "ideal tumor marker” should have the following properties: high specificity, i.e. undetectable in benign diseases and healthy people; high sensitivity, i.e. it can be detected in a high percentage of tumor patients .; Organ specificity; good correlation with tumor stages or tumor mass; - Relation to the forecast: reliable forecast values.
  • pyruvate kinase isoenzymes There are four pyruvate kinase isoenzymes (L, R, M 1 and M2) in higher organisms. Scientific studies have shown that malignant tumors have a special isoenzyme subclass of pyruvate kinase type M2, the tumor M2-PK.
  • GIT gastrointestinal tract
  • CEA is the best and most widely used marker for colon cancer.
  • the markers CEA, CA 1 9.9, CA72.4 and tumor M2-PK can be detected in all tumor diseases in the serum or blood plasma of patients, the type and location of the affected organ or tissue in the patient's body is not possible. Furthermore, it would be desirable to have a tumorous event in the gastrointestinal tract as early as possible, particularly in a growth phase in which the tumor has not yet made any contact with the body's vascular system (in the "polyp cancer sequence", before the infiltration of the submucosa) ) to be able to prove.
  • Polyps (polyposis coli) are tried according to the prior art by means of various determination methods, occult blood in the stool demonstrated. For this, non-immunological tests (e.g. pseudoperoxidase activity, porphyrin detection) and immunological tests are used (Favenne L. et al. (1,992) Ann. Biol. Clin. 50: 31 1 -31 3).
  • non-immunological tests e.g. pseudoperoxidase activity, porphyrin detection
  • immunological tests are used (Favenne L. et al. (1,992) Ann. Biol. Clin. 50: 31 1 -31 3).
  • test principles are not very specific, since they can be disturbed by a large number of influencing factors (false positive / false negative, e.g. due to non-compliance with urgently necessary dietary requirements on the part of the patient and from a number of medicinal products, as well as through excessive vitamin C administration ( e.g. in vegetables, fruit juices etc.), Thomas L., Labor und Diagnose, 5th edition, 1 998).
  • a positive test for occult blood in the stool must be clarified until the source of the bleeding is located or the cause of the bleeding has been found.
  • the clinical finding justifies further diagnostics to be carried out quickly, e.g. by endoscopy, sonography, x-ray.
  • the aim of the invention is, in particular, to meet the continuing need for specific, easy-to-carry out procedures, so that a neoplastic event, particularly with regard to the problem of the so-called adenoma-carcinoma sequence in polyps (polyposis coli) in the gastrointestinal tract, is particularly early and can be proven beyond any doubt.
  • CEA, CA1 9.9, CA72.4 or parts thereof are evident as a result of the considerable proteolytic activity and the extreme physiological conditions (e.g. pH, acid in the stomach, alkaline in the intestine) of the gastrointestinal tract is not permanently impaired. This also applies to the detection of CEA, CA1 9.9 or CA72.4 using immunological methods.
  • CEA, CA1 9.9 or CA72.4 have only been quantified in native, undigested patient samples (e.g. body fluids, sera, blood plasma) and used in clinical tumor diagnostics for a variety of tumor diseases.
  • the tumor markers CEA, CA1 9.9 and CA72.4 are detected in the stool can.
  • the determination can be made using commercially available test systems.
  • a tumor in the gastrointestinal tract i.e. in particular in the esophagus, in the stomach, in the small intestine, in the biliary tract, in the pancreas or / and in the large intestine, is thus indicated, and thus a localization of the tumorous events in the GIT allows.
  • GIT gastrointestinal tract
  • the determination of a neoplastic event in the GIT has so far not been possible with the methods of the prior art or has been possible only with great effort.
  • a stool sample cannot be considered a "body fluid" sample because the entire GIT is biologically outside the body.
  • the method according to the invention to detect the tumor markers CEA, CA1 9.9 or / and CA72.4 as free proteins in the stool using conventional test systems according to the prior art, for example using commercially available test systems. It is therefore not necessary to isolate cells from the stool and to analyze the proteins contained in the cells. It was surprisingly found that solid tumors release the tumor markers mentioned as soluble proteins into the lumen of the GIT and that these markers are not found in exfoliated gastrointestinal epithelial cells. The tumor markers described are released by tumor cells, pass through the GIT as a protein and can finally be detected as a protein in the stool. This possibility, namely that these proteins remain detectable in the stool after, for example, gastric or intestinal passage, is surprising and is not described in the literature.
  • the qualitative and / or quantitative determination according to the invention of the tumor markers CEA, CA1 9.9 or / and CA72.4 in stool in combination with a simultaneous qualitative and / or quantitative detection of the same tumor markers in blood or plasma gives the treating physician previously unavailable information as to whether the tumor is "only" in the GIT, especially in the intestinal lumen, or whether it has broken through the submucosa and has already contacted the vascular system or is already in the metastatic stage (the information results from the quotient formation of the blood or stool measurements obtained ).
  • CEA, CA1 9.9 and CA72.4 remain quantitatively detectable even with intensely homogenized, longer-stored stool samples (for example when sending samples). A clear reaction is obtained even with severe thinning of the stool.
  • the malignancy in the gastrointestinal tract of a human or an animal is preferably determined. It is further preferred to detect the tumor marker immunochemically, in particular by means of anti-CEA, anti-CA1 9.9 or / and anti CA72.4 antibodies. Monoclonal or polyclonal antibodies, preferably monoclonal antibodies, can be used. Antibodies are advantageously used which do not cross-react with other constituents of the stool, in particular not with other stool proteins.
  • Antibodies which can be used according to the invention can be produced by methods known in the prior art. Methods for producing specific monoclonal antibodies are well known to those skilled in the art.
  • the antigen in this case CEA, CA1 9.9 or CA72.4 or parts thereof, is used to generate antibodies.
  • the method that was first described by Koehler and Milstein can be used for this purpose, modifications and further developments of these methods being known to the person skilled in the art.
  • the specificity can be determined by selection. The selection is made for specific antibodies that bind to CEA, CA1 9.9 or CA72.4, but not to other stool proteins.
  • the detection is based on the principle of the immunoassay.
  • An immunoassay which is preferred according to the invention is carried out by a) bringing the sample into contact with at least two different receptors, of which the first receptor R1 is in the solid phase and is bindable with CEA, CA1 9.9 or CA72.4 and the second
  • Receptor R2 is in the liquid phase and is also capable of binding with the same tumor marker, the receptor R2 bearing a label or mediating the binding to a detectable molecule, b) separating the solid from the liquid phase, and c) the label or the detectable molecule determined in one of the phases, preferably in the solid phase and accordingly the The amount of tumor markers present in the sample was quantified, using an antibody as at least one of the receptors R1 or R2 which is specifically bindable to CEA, CA1 9.9 or CA72.4 and in particular does not bind to any other stool protein.
  • an antibody against the respective tumor marker to be determined is used both as receptor R1 and as receptor R2.
  • detection technologies can also be used, e.g. the quartz crystal technology, microbalance technology, lateral flow technology, K a n d e l a b e r - T e c h n o l o g i e, T R A C E - T e c h n o I o g i e o d e r electrochemiluminescence technology.
  • another object of the present invention is a test kit for the detection and / or diagnosis of malignant tumor occurrence in the gastrointestinal tract in humans or animals, which is intended in particular for carrying out the method described above, by determining a tumor marker CEA, CA1 9.9 or / and CA72.4 or parts thereof, the test kit containing at least one monoclonal or polyclonal antibody against CEA, CA1 9.9 or CA72.4.
  • the test kit preferably contains an antibody for the corresponding tumor marker, which does not cross-react with any other stool protein.
  • the test kit can optionally contain further reagents necessary for carrying out an immunoassay or for carrying out the test method provided in each case.
  • the test kit preferably contains an antibody bound to a solid phase and specific for at least one of the tumor markers mentioned.
  • the invention further relates to the use of antibodies against CEA, CA1 9.9 or CA72.4 for the qualitative or quantitative determination of tumor markers in human or animal stool and a reagent for the selective quantitative determination of CEA, CA1 9.9 or / and CA72.4.
  • the invention furthermore relates to antibodies, in particular monoclonal antibodies, which specifically bind CEA, CA1 9.9 or CA72.4 and do not cross-react with any other stool protein.
  • the antibodies can be generated, for example, by the method of Koehler and Milstein (Nature 256, 495-497 (1 995)).
  • the present invention relates to aptamers which bind specifically to CEA, CA1 9.9 or CA72.4 and do not cross-react with any other stool protein.
  • Aptamers are oligonucleotide sequences that are specific
  • Such aptamers can, for example, according to those in US 5,270,163 or in Sumedha, Clin. Chem. 45 (1 999), 1 628-1 650 described methods can be produced or identified.
  • the immunochemical determination of the CEA was carried out according to the manufacturer's instructions with the Elecsys from Röche AG.
  • the Elecsys-CEA is a 1-step sandwich test based on the ECLIA principle.
  • ECLIA ElektroChemiLuminescenceImmunoAssay). Execution - Example 2
  • CA 1 9.9 was determined using ECLIA technology
  • the immunochemical determination of CA1 9.9 was carried out in accordance with the manufacturer's instructions using the Elecsys from Röche AG.
  • the Elecsys-CEA is a 1-step sandwich test based on the ECLIA principle.
  • ECLIA ElektroChemiLuminescenceImmunoAssay).
  • the immunochemical determination of the CA72.4 was carried out according to the manufacturer's instructions with the Elecsys from Röche AG.
  • the Elecsys-CEA is a 1-step sandwich test based on the ECLIA principle.
  • ECLIA ElektroChemiLuminescenceImmunoAssay).
  • the tumor markers CEA, CA1 9.9 and CA72.4 can also be determined using other commercially available immunochemical test systems.
  • biosensors such as, for example, amperometric sensors, potentiometric, ion-selective potentiometric or photometric sensors or else those using semiconductor electrodes such as field effect transistors (FET), chemosensitive field effect transistors (CHEMFET), suspended gate field effect transistors (SGFET) or ion sensitive field effect transistors.
  • FET field effect transistors
  • CHEMFET chemosensitive field effect transistors
  • SGFET suspended gate field effect transistors
  • ISFET ion-sensitive field effect transistors
  • optical detectors are described, among others, by F. Aberl and H.
  • the method according to the invention is also suitable for implementation by means of piezoelectric quartz crystals and surface wave elements which can be used as microbalances.
  • the primary antibody (the so-called catcher) is immobilized on a piezoelectric substrate and measured after binding with the CEA, CA1 9.9 or CA72.4 to be analyzed.
  • Such sensors are described, for example, by A. Leidl et al. in “Proceedings of the Second International Symposium on Minaturized Total Analyzes Systems ⁇ TAS", Basel 1 996. Quartz crystal microbalances as described by C. Köslinger et al., Fresenius J. Anal. Chem. (1 994), 349: 349-354, have been found to be particularly suitable or, for example, candelabrum technology from IBM, Inc.
  • analyte concentration by means of immunochromatographic methods, i.e. to be determined by means of so-called visual rapid tests (lateral flow tests).
  • Electrochemilluminescence is a process in which light is released. The light release is induced by applying an electrical potential to an electrode that mediates a cyclic oxidation / reaction of a ruthenium metal ion (Bruno, G. (1 997) Rec. Rp. S. 1 75-1 79; Williams R . (1 996), Amer. Biotech., P. 26).
  • a similar technology is the TRACE technology from CIS. example 1
  • An approximately 1 2 ml disposable tube and a microbiological inoculation loop (e.g. Sarstedt) are balanced to 0 using a sensitive digital laboratory balance.
  • the stool is then weighed in with the inoculation loop by pricking the stool sample with the eyelet and introducing the amount of stool remaining at the tip (approx. 100 mg) into the disposable tube.
  • a toothpick can also be used instead of the inoculation loop.
  • the volumes of the extraction buffer to be added are varied according to the weighed stool sample mass (e.g. 100 mg stool + 10 ml buffer or 75 m g stool + 7.5 ml buffer). Final concentration: 1 0 mg stool / ml extraction buffer.
  • the stool sample suspension is mixed vigorously at room temperature with a test tube shaker (e.g. VORTEX).
  • a test tube shaker e.g. VORTEX
  • the chairs must be well homogenized.
  • CHAPS 3 - [(3-cholamidopropyl) dimethylammonio] -1-propanesulfonate, 10 mM (Sigma) to the phosphate-buffered extraction buffer.
  • the stool test can be advantageously carried out using the ScheBo ® « Biotech AG stool dosing system (Quick-Prep).

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  • Health & Medical Sciences (AREA)
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  • Investigating Or Analysing Biological Materials (AREA)
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  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)

Abstract

La présente invention concerne un procédé de détection qualitative et/ou quantitative de CEA, CA19.9, CA72.4 ou de parties de ceux-ci, qui servent de marqueurs tumoraux dans les selles humaines ou animales pour mettre en évidence une affection maligne dans le tube gastro-intestinal et dans la cavité abdominale (oesophage, estomac, intestin grêle, voies biliaires, pancréas et gros intestin).
PCT/EP2003/001504 2002-02-14 2003-02-14 Procede de detection dans les selles des marqueurs tumoraux cea, ca19.9 ou ca72.4 pour reconnaitre des tumeurs gastro-intestinales WO2003069343A2 (fr)

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AU2003210274A AU2003210274A1 (en) 2002-02-14 2003-02-14 Method for the detection of tumor markers cea, ca19.9, or ca72.4 in the stool, allowing diagnosis of gastrointestinal tumors

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DE10206056 2002-02-14
DE10206056.8 2002-02-14

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071366A1 (fr) * 2005-12-21 2007-06-28 Roche Diagnostics Gmbh Méthode d'évaluation du cancer colorectal par mesure de l'hémoglobine et de la pyruvate-kinase m2 dans un echantillon de selles
DE202012012084U1 (de) 2012-07-09 2013-04-15 Schebo Biotech Ag Testkit (Kombi-Schnelltest) zum synchronen Nachweis von Biomarkern im Stuhl zur Erkennung pathologischer Veränderungen im Gastrointestinaltrakt, insbesondere im Darm
WO2014008884A1 (fr) 2012-07-09 2014-01-16 Schebo Biotech Ag Trousse d'essai (essai combiné rapide) pour la détection synchrone de biomarqueurs dans les selles pour la reconnaissance de modifications pathologiques dans l'appareil gastro-intestinal, en particulier dans l'intestin
DE102016015060A1 (de) 2016-12-19 2018-03-29 Schebo Biotech Ag Verfahren zum Nachweis von Tumormarkern im Stuhl zur Erkennung gastrointestinaler Tumore
DE102018000815A1 (de) 2018-02-01 2019-08-01 Schebo Biotech Ag Verfahren zum Nachweis von Biomarkern im Stuhl zur Erkennung von Erkrankungen des Intestinaltraktes

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0072902B1 (fr) * 1981-08-21 1985-04-24 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé pour la détermination des antigènes carcinoembryonnaires (CEA) et pour la détermination appropriée de solution d'anticorps
US4818709A (en) * 1983-01-21 1989-04-04 Primus Frederick J CEA-family antigens, Anti-CEA antibodies and CEA immunoassay
CA2101943A1 (fr) * 1991-02-05 1992-08-06 Kamal Bahar Test simple pour le depistage d'un antigene carcino-embryonnaire
DE19828466A1 (de) * 1998-06-26 1999-12-30 Roche Diagnostics Gmbh Entstörung von Immunoassays durch Substanzen, die aus den Framework-Regionen von Antikörpern abgeleitet sind

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071366A1 (fr) * 2005-12-21 2007-06-28 Roche Diagnostics Gmbh Méthode d'évaluation du cancer colorectal par mesure de l'hémoglobine et de la pyruvate-kinase m2 dans un echantillon de selles
DE202012012084U1 (de) 2012-07-09 2013-04-15 Schebo Biotech Ag Testkit (Kombi-Schnelltest) zum synchronen Nachweis von Biomarkern im Stuhl zur Erkennung pathologischer Veränderungen im Gastrointestinaltrakt, insbesondere im Darm
WO2014008884A1 (fr) 2012-07-09 2014-01-16 Schebo Biotech Ag Trousse d'essai (essai combiné rapide) pour la détection synchrone de biomarqueurs dans les selles pour la reconnaissance de modifications pathologiques dans l'appareil gastro-intestinal, en particulier dans l'intestin
DE102012013888A1 (de) 2012-07-09 2014-05-22 Schebo Biotech Ag Testkit (Kombi-Schnelltest) zum synchronen Nachweis von Biomarkern im Stuhl zur Erkennung pathologischer Veränderungen im Gastrointestinaltrakt, insbesondere im Darm
US9766243B2 (en) 2012-07-09 2017-09-19 Schebo Biotech Ag Test kit (combined quick test) for the synchronous proof of biomarkers in faeces for detecting of pathological changes in the gastrointestinal tract, particularly in the intestine
DE102016015060A1 (de) 2016-12-19 2018-03-29 Schebo Biotech Ag Verfahren zum Nachweis von Tumormarkern im Stuhl zur Erkennung gastrointestinaler Tumore
DE102018000815A1 (de) 2018-02-01 2019-08-01 Schebo Biotech Ag Verfahren zum Nachweis von Biomarkern im Stuhl zur Erkennung von Erkrankungen des Intestinaltraktes

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AU2003210274A1 (en) 2003-09-04

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