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WO2013003898A1 - Procédé pour de détection d'un cancer chez un patient - Google Patents

Procédé pour de détection d'un cancer chez un patient Download PDF

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Publication number
WO2013003898A1
WO2013003898A1 PCT/AU2012/000798 AU2012000798W WO2013003898A1 WO 2013003898 A1 WO2013003898 A1 WO 2013003898A1 AU 2012000798 W AU2012000798 W AU 2012000798W WO 2013003898 A1 WO2013003898 A1 WO 2013003898A1
Authority
WO
WIPO (PCT)
Prior art keywords
epcam
blood sample
cancer
patient
detection
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/AU2012/000798
Other languages
English (en)
Inventor
Howard Milne Chandler
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.)
Clinical Genomics Pty Ltd
Original Assignee
Clinical Genomics Pty Ltd
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 Clinical Genomics Pty Ltd filed Critical Clinical Genomics Pty Ltd
Publication of WO2013003898A1 publication Critical patent/WO2013003898A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • 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
    • G01N33/57415—Specifically defined cancers of breast
    • 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
    • G01N33/57419—Specifically defined cancers of colon
    • 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
    • G01N33/57423—Specifically defined cancers of lung
    • 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
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • 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
    • G01N33/57449—Specifically defined cancers of ovaries
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705

Definitions

  • This invention relates to a method for the detection of cancer in a patient, and in particular to the determination or assessment of the total Epithelial Cell Adhesion
  • EpCAM Molecule
  • CTCs circulating tumor cells
  • CTCs may be removed from blood samples by anti-EpCAM antibody immobilized on a solid surface in a flow cell 1 , or by antirEpC AM labeled magnetic particles 2 that are magnetically removed from the blood sample.
  • CTCs are detected either by microscopy or molecular techniques. Both detection methods provide important information about the cancer, but both are time consuming and expensive. This restricts their use for routine patient monitoring and renders them unsuitable for point-of-care monitoring and for screening the asymptomatic, but at-risk population, for example, those over 60 years of age.
  • EpCAM is a known cancer marker that is overexpressed in a wide range of cancers including breast, lung, colorectal, ovarian, pancreatic, and hepatocellular carcinomas. That EpCAM is overexpressed in ovarian and pancreatic cancers is of particular interest as these cancers are currently lethal since they are usually only detected late in their development.
  • the present invention provides a method for detection of cancer in a patient, which comprises the step of determining the amount of Epithelial Cell Adhesion Molecule (EpCAM) in a blood sample taken from the patient.
  • EpCAM Epithelial Cell Adhesion Molecule
  • the blood sample is a whole blood sample.
  • the total amount of EpCAM in the blood sample is determined using a binding entity, for example an antibody or aptamer, which specifically binds EpCAM, such as anti-EpCAM.
  • the binding entity may be labelled with a disclosing agent, such as magnetic beads, a fluorescent label, a radioisotope label or an enzyme label.
  • the method of the invention includes a further step of determining the amount of an additional marker in the blood sample, such as the cytokeratin (C ) marker of epithelial-derived cancer cells.
  • an additional marker in the blood sample such as the cytokeratin (C ) marker of epithelial-derived cancer cells.
  • the method of the present invention may be used for the detection of an epithelial- derived cancer in a patient, particularly breast, lung, colorectal, ovarian, pancreatic and/or hepatocellular carcinomas.
  • EpCAM concentration in the blood is proposed as a method for assessing total CTC burden, and means are disclosed for its rapid purification and quantitative detection in blood samples, particularly whole blood samples.
  • the EpCAM which is detected represents that of intact CTCs,_ CTC fragments, EpCAM- bearing microvesicles (exosomes) and any soluble EpCAM in the blood (which Abe et al 3 suggests may be present in elevated amounts in a proportion of cancer patients).
  • the method of the invention is unaffected by contaminating white blood cells, which may complicate microscopic enumeration and can interfere with PCR detection.
  • the present invention provides a method for detection of cancer in a patient which comprises the step of determining the amount of Epithelial Cell Adhesion Molecule (EpCAM) in a blood sample taken from the patient.
  • EpCAM Epithelial Cell Adhesion Molecule
  • the blood sample is a whole blood sample.
  • the present invention provides a method for determination of the total EpCAM concentration in the blood sample, not just an indication of the number of CTCs which are isolated from the blood sample. Determination of the total EpCAM
  • concentration in the blood is an indicator of both total CTC burden and other EpC AM (such as soluble EpCAM) in the blood, and is accordingly of diagnostic significance in the detection of cancer, particularly epithelial-derived cancer.
  • the total EpCAM amount measured or determined in the blood sample from the patient may be compared with standard or normal total EpCAM levels from the blood of patients without cancer. An elevated total EpCAM level determined in the blood sample from the patient in this comparison is indicative of cancer in the patient.
  • the method of the present invention determines the total EpCAM level in a blood sample from the patient. Since EpCAM is overexpressed in epithelial-derived cancers such as breast, lung, colorectal, ovarian, pancreatic and hepatocellular carcinomas, the method of the present invention has application in the determination and diagnosis of these cancers.
  • the EpCAM is determined in the blood sample from the patient using a binding entity, such as an antibody or aptamer, specifically binding to EpCAM (anti- EpCAM).
  • a binding entity such as an antibody or aptamer, specifically binding to EpCAM (anti- EpCAM).
  • the anti-EpCAM is provided as disclosing agent-labelled anti-
  • the disclosing agent may be magnetic beads or particles.
  • the use of magnetic beads or particles as a disclosing agent is well known to persons skilled in the art.
  • the disclosing agent may be a fluorescent, radioisotope or enzyme label of the type which is also well known to persons skilled in the art.
  • suitable fluorescent labels include fluorescein, rhodamine and associated derivatives, and Quantum Dots
  • suitable enzyme labels include alkaline phosphatase, horse radish peroxidase, urease and penicillinase.
  • the method of the invention comprises the further step of determining the amount of an additional marker, such as the cytokeratin (CK) marker of epithelial-derived cancer cells, in the blood sample.
  • an additional marker such as the cytokeratin (CK) marker of epithelial-derived cancer cells
  • this additional marker may be determined in moieties such as CTCs captured from the blood sample using anti- EpCAM.
  • the total amount of EpCAM in a blood sample is measured or determined.
  • anti-EpCAM which has been immobilized on a solid surface such as a microtitre well or tube may be used to capture total EpCAM in the blood sample (including intact CTCs, CTC fragments, EpCAM-bearing exosomes and soluble EpCAM) as in traditional ELISA testing, however in order to overcome the limitations of restricted blood sample volume and diffusion-limited reaction kinetics which arise from the use of such microtitre wells or tubes, in an alternative embodiment the blood sample may be flowed through a flow-cell past surfaces of the flow-cell which have anti-EpCAM immobilized thereon, for example, as described by Stott et at '.
  • Detection of arrested EpCAM may then be carried out using fluorescent, radioisotope or enzyme labeled anti-EpCAM and the label detected by methods well known to persons skilled in the art.
  • conversion of the enzyme substrate may be measured in situ or after displacement from the flow-cell.
  • One preferred embodiment of the method of the invention involves direct detection of EpCAM in a blood sample using anti-EpCAM magnetic beads.
  • the method includes:
  • these may include fluorescent, radioisotope or enzyme labeled anti- EpCAM, or anti-other CTC marker antibody such as cytokeratin (CK).
  • CK cytokeratin
  • detection of the disclosing agent may be carried out after the trapped particles have been released from the magnetic field and recovered, for example, in a cuvette or other collection vessel.
  • detection of the disclosing agent may be carried out with the trapped particles in situ.
  • the disclosing agent is enzyme-labeled anti-EpCAM
  • the enzyme substrate is added to the trapped particles in situ and then the converted substrate detected in situ or after displacement, for example into a cuvette for spectrophotomeric detection.
  • Another preferred embodiment of the method of the invention involves indirect detection via detection of the magnetic beads that are specifically bound to the EpCAM- bearing entities.
  • the method includes:
  • a particle counter e.g. Coulter counter
  • a particle counter e.g. Coulter counter
  • fluorescence of the filtrate, or the deposited particles from the filtrate or b) Use of fluorophore-labeled antibody directed against the magnetic particles (e.g. anti-mouse antibodies if the anti-EpCAM antibody is a mouse monoclonal antibody) and:
  • the method of this invention also encompasses the use of one or more additional disclosing agent-labeled antibodies against other markers, for example against the cytokeratin (CK) marker of epithelial-derived cancer cells.
  • the anti-marker may be added either to the blood sample, to arrested or separated CTCs, or to CTCs on the filter membrane. Where more than one fluorophore is used, their detection would be at different wavelengths, or where different enzymes are used, different substrates would be used successively.
  • EpCAM in a whole blood sample is detected using Enzyme Immuno-Assay (EIA).
  • EIA Enzyme Immuno-Assay
  • EpCAM-bearing cultured colorectal cancer cells (HTC1 16) are added to tubes of 5 ml of fresh human blood to a final estimated cell number of 0 (control), 50 and 500 cells per tube.
  • Five microliters of anti-EpCAM magnetic beads (Dynabeads® Epithelial Enrich, Invitrogen) are added to each blood sample, and after 5 minutes of mixing each is passed through a PTFE separation tube (100 mm, 1mm ID, 1.6mmOD) located in a magnetic field generated by rare-earth magnets.
  • the arrested magnetic particles in each separation tube are washed with PBS and anti-EpCAM antibody conjugated to horseradish peroxidase (HRP) introduced into the tube for 5 minutes.
  • HRP horseradish peroxidase
  • each separation tube is removed from the magnetic field and the particles displaced from the separation tube into a clear glass tube by 0.25 ml of HRP substrate (3, 3', 5, 5'-tetramethylbenzidine). After 5 minutes, the colour of the substrate in the tube is noted.
  • the control tube no added cells shows no colour (indicating that no EpCAM is detected by EIA), the substrate in the tube for the sample originally containing 50 cells becomes pale blue, while the substrate colour in the tube for the sample with 500 cells shows the greatest blue intensity, i.e. the colour development in the EIA is approximately proportional to the number of EpCAM-bearing cells added to . each blood sample.
  • EpCAM in a whole blood sample is detected using a fluorescent anti-EpCAM conjugate.
  • EpCAM-bearing cultured colorectal cancer cells (HTC1 16) are added to tubes of 5 ml of fresh human blood to a final estimated cell number of 0 (control), 20 and 200 cells per tube.
  • Anti-EpCAM magnetic beads (5 ⁇ 1) are added to each blood sample and after 5 minutes of mixing each is passed through a PTFE separation tube (100 mm, 1mm ID, 1.6mmOD) located in a magnetic field generated by an array rare-earth magnets. The arrested magnetic particles in each separation tube are washed with PBS and anti- EpCAM antibody conjugated fluorescein (FITC -Anti-human EpCAM Antibody, BioLegend) is introduced for 5 minutes.
  • FITC -Anti-human EpCAM Antibody BioLegend
  • each separation tube is removed from the magnetic field and the particles displaced by PBS through a filter selected to retain bead-labeled cells and beads aggregated by cellular fragments or soluble EpCAM (e.g. Whatmans Nuclepore 8 micron polycarbonate filter), while allowing unbound beads and conjugate to pass through.
  • a filter selected to retain bead-labeled cells and beads aggregated by cellular fragments or soluble EpCAM (e.g. Whatmans Nuclepore 8 micron polycarbonate filter), while allowing unbound beads and conjugate to pass through.
  • the fluorescence on the membrane is assessed by fluorescence microscopy or instrumental detection.
  • the control tube no added cells shows no fluorescence (i.e. no EpCAM detected), the sample originally containing 20 cells shows only a very small number of fluorescing particles, while the sample with 200 cells shows the greatest intensity, i.e. the fluorescent intensity is in approximate proportion to the number of EpC AM-bearing cells added to each blood sample.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • General Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un procédé de détection d'un cancer chez un patient, lequel procédé consiste à déterminer la quantité de molécules d'adhérence de cellules épithéliales (EpCAM) dans un échantillon de sang total prélevé à partir du patient.
PCT/AU2012/000798 2011-07-07 2012-07-03 Procédé pour de détection d'un cancer chez un patient Ceased WO2013003898A1 (fr)

Applications Claiming Priority (2)

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US201161505158P 2011-07-07 2011-07-07
US61/505,158 2011-07-07

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WO2013003898A1 true WO2013003898A1 (fr) 2013-01-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014019025A1 (fr) * 2012-08-02 2014-02-06 Deakin University Aptamères epcam pour la détection de cellules souches cancéreuses
CN110004147A (zh) * 2019-03-05 2019-07-12 厦门大学 一种在人血浆中筛选的上皮细胞粘附分子EpCAM的核酸适体及其制备方法和应用
US10577610B2 (en) 2015-02-11 2020-03-03 Deakin University EpCAM aptamers and conjugates thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030017514A1 (en) * 2001-06-02 2003-01-23 Katharina Pachmann Method for quantitative detection of vital epithelial tumor cells in a body fluid
WO2010121315A1 (fr) * 2009-04-22 2010-10-28 Clinical Genomics Pty. Ltd. Procédé et appareil pour isoler une entité biologique cible à partir d'un échantillon biologique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030017514A1 (en) * 2001-06-02 2003-01-23 Katharina Pachmann Method for quantitative detection of vital epithelial tumor cells in a body fluid
WO2010121315A1 (fr) * 2009-04-22 2010-10-28 Clinical Genomics Pty. Ltd. Procédé et appareil pour isoler une entité biologique cible à partir d'un échantillon biologique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COUMANS ET AL.: "All circulating EpCAM+CK+CD45-objects predict overall survival in castration-resistant prostate cancer", ANNALS OF ONCOLOGY, vol. 21, no. 9, 10 February 2010 (2010-02-10), pages 1851 - 1857 *
MILTENYI BIOTECH: "CD326 (EpCAM) Tumour Cell Enrichment and Detection Kit", 7 August 2012 (2012-08-07), Retrieved from the Internet <URL:http://web.archive.org/web/20110103223618/http://www.miltenyibiotec.com/download/datasheets_en/149/MiltenyiBiotec_DataSheet_CD326-(EpCAM)-Tumor-CellEnrichment-and-Detection-Kit,-human_130-090-500.pdf> [retrieved on 20110103] *
RIETHODORF ET AL.: "Detection of Circulating Tumour Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System", CLINICAL CANCER RESEARCH., vol. 13, no. 3, 8 February 2007 (2007-02-08), pages 920 - 928 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014019025A1 (fr) * 2012-08-02 2014-02-06 Deakin University Aptamères epcam pour la détection de cellules souches cancéreuses
JP2015530081A (ja) * 2012-08-02 2015-10-15 ディーキン・ユニバーシティー 癌幹細胞を検出するためのＥｐＣＡＭアプタマー
US9567586B2 (en) 2012-08-02 2017-02-14 Deakin University EpCAM aptamer for detection of cancer stem cells
US10577610B2 (en) 2015-02-11 2020-03-03 Deakin University EpCAM aptamers and conjugates thereof
CN110004147A (zh) * 2019-03-05 2019-07-12 厦门大学 一种在人血浆中筛选的上皮细胞粘附分子EpCAM的核酸适体及其制备方法和应用

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