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WO2008085777A2 - Procédé de détection précoce d'un cancer - Google Patents

Procédé de détection précoce d'un cancer Download PDF

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Publication number
WO2008085777A2
WO2008085777A2 PCT/US2007/089096 US2007089096W WO2008085777A2 WO 2008085777 A2 WO2008085777 A2 WO 2008085777A2 US 2007089096 W US2007089096 W US 2007089096W WO 2008085777 A2 WO2008085777 A2 WO 2008085777A2
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WO
WIPO (PCT)
Prior art keywords
cancer
cell
cells
tumor
micro
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Ceased
Application number
PCT/US2007/089096
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English (en)
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WO2008085777A3 (fr
WO2008085777A9 (fr
Inventor
Ajay Singhal
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XGENETICS Inc
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XGENETICS Inc
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Publication of WO2008085777A2 publication Critical patent/WO2008085777A2/fr
Publication of WO2008085777A3 publication Critical patent/WO2008085777A3/fr
Publication of WO2008085777A9 publication Critical patent/WO2008085777A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development

Definitions

  • This invention relates to early detection of cancer
  • Automated blood counting machines include the Beckman Coulter LH series, Sysmex XE-2100, Bayer ADVIA 120, and the Abbott Cell-Dyn series
  • Typical methods for detecting CTC are immunohistocytochemistry (ICCS) or RT-PCR (Reverse Transcription Polymerase Cham Reaction) or flow cytometry, which ranges from $30,000 to $150,000
  • ICCS immunohistocytochemistry
  • RT-PCR reverse Transcription Polymerase Cham Reaction
  • flow cytometry which ranges from $30,000 to $150,000
  • ICCS is known to require several (up to 10 slides) to accurately detect cancer cells
  • Flow cytometry can take as long as 10 hours for analysis, which is not practical for rapid screening and diagnostic in a clinical setting
  • the present invention focuses on an in vitro (i) cancer cell enrichment and (n) a cancer cell separation process and device The present invention will enable large pharmaceutical companies by a offering companion diagnostic modality for therapeutics The solution will also provide a diagnostic modality to large diagnostic device companies and laboratories
  • the method is a nanotechnology or microchip device, apparatus, system or contrivance It preferentially identifies, enriches, purifies, separates, marks, detects, images and counts circulating tumor cells (CTC) or leukemic cells or other biological species, associated with prognostic markers, in a known volume of sample of human blood, bone marrow or other fluid
  • CTC circulating tumor cells
  • leukemic cells or other biological species associated with prognostic markers
  • FIG 1 is a flowchart of the nanotechnology chip in operation to detect circulating tumor cells (CTC) and other illnesses associated with the related biomarkers
  • FIG 2 is an array of micro-well and array of micro-structures fabricated by nanotechnology and chip fabrication methods The array carries micro-probes to mark and identify bio-markers, unique to cancer and the cancer cells to be diagnosed
  • FIG 3 is a schematic of apparatus for detection of epithelial and blood-based cancers and any other types of cancers, and of diagnostic and prognostic markers in a sample of blood or another fluid from a human or animal
  • FIG 4 is a schematic of apparatus for cancer cell enrichment, with example methods, to transfer to the chip, detection, imaging and analysis on the chip of the cells or circulating tumor cells (CTC) for epithelial cancers and other types of cancers, and of diagnostic and prognostic and therapeutic markers in a sample of blood or another fluid from a human or animal
  • CTC circulating tumor cells
  • FIG 5 is a schematic of apparatus for cancer cell enrichment, with removal of
  • CTC circulating tumor cells
  • FIG 6 is a schematic of Dynabeads, showing antibody tagging to protein expression sites on a T-cell
  • FIGS 1 THROUGH 6 PREFERRED EMBODIMENT
  • FIG 1 The figure shows taking a known volume (0 l ⁇ l to 20ml) of sample of human blood, bone marrow or other fluid such as saliva, sputum (4A) in a vacutamer tube As illustrated in Figure 4, the sample 4A is subjected to removal of red blood cells by lysis buffer step (4B), and removal of "debris" (4C) or of leukocytes or of white blood cells, which lack CD45 [0041]
  • a sample of 10ml blood contains about 5x108 red blood cells, 1x106 white blood cells (WBC or leukocytes) and 4x107 platelets Threshold concentration of the circulating tumor cells (CTC), for example, for metastatic breast cancer has been shown to be 5 cells per 7 5ml of blood
  • the sensitivity requirement for tumor cell detection is of the order of 1 in 108 to 1 in 109 (or a billion) cells, since 10ml of whole blood contains about a billion cells
  • the cell-enriched serum (4D) is overlaid and incubated on the chip, carrying primary antibodies
  • the tumor cells will bind to the microchip device (3E, 4F, 5D)
  • the kinetics of this binding will be determined by the number of binding sites (6B) per cell and the dissociation constant (kD)
  • secondary fluorescent antibodies (4G, 5C, 6A) are attached onto the cells bound to the microchip device (3E, 4F, 5D)
  • the microchip device is then analyzed for counting and imaging the cells and their simultaneous pathological examination (5E)
  • breast cancer genes BRCA-I, and BRCA-2, antigens CEA
  • the associated tumor cells can be separated by magnetic polymer beads either by positive or by negative enrichment and by applying a magnetic field to the container (4D) These species can be marked with anti-
  • DNA, mRNA, protein species or the tumor cells associated with the proteins or biomarkers characterizing the disease are preferentially extracted, enriched, transferred, marked and analyzed onto the nanotechnology chip or device (3E, 4F,
  • the species and its sequence are identified, marked and quantitatively analyzed (Fig 1, 3H, 4H, 5E) If the results are withm the desired range, the patient is not ill with one of the above epithelial cancers For example, the CA125 antigen expressed in epithelial ovarian cancer, at levels higher than 30U/ml of serum will indicate presence of ovarian cancer If the results are outside the range, the patient is diagnosed ill or needing attention
  • the static sample in the chip assembly (3C, 3D, 3E) is optically illuminated, and fluoresced
  • the species will be electro- magnetically excited
  • the output optical or fluorescence, or luminescent or spectrometer or electrical or electromagnetic signal is detected using a photomultipher, CCD camera, CMOS detector or other microscopy or spectroscopy or electronic or electromagnetic device
  • the detector is connected to a computer assembly (3G)
  • the system also has the software capability of statistical image acquisition, classification and analysis (3G and 31)
  • the micro-chip assembly (Fig 2) is fabricated by using the following steps as one of the preferred embodiment
  • the size of the micro-chip device will range from a stamp size (l"x 1") to a post-card-size (4"x5") While the stamp size chip device may be smgle-use, the larger device and its different sections may be used multiple times for diagnosing and monitoring the same patient
  • the geometry of the micro-array on the lithography mask is shown After the mask is laid out and created, micro-well structures and micro-array are fabricated
  • the process sequence will include photolithography (contact mask lithography, i-lme-365nm, h-lme-405nm, g-lme-436nm, 248nm, 193nm, another equivalent printing method or a conventional complementary metal-on-semiconductor- CMOS processing sequence of a technology generation between 5 ⁇ m to 22nanometer) Precise reactive ion etching (RIE) will control the critical dimensions (CDs) withm a reasonable dimensional tolerance (of 10 to 30%) such that the micro-volume of the sample can be controlled
  • the substrates of interest are sapphire (A12O3), silicon, quartz, Si3N4, SiO2/Si, Si3N4/SiO2/Si, or a combination of these film stacks and plastic such as PMMA or other such material
  • the substrates of the microchip device (Fig 2, 3E, 4F, 5E) will be a composite consisting of micro-spheres of magnetic particles (for example, of permanent magnets- Nd2Fel4B, Sm2Col7) embedded and dispersed throughout the substrate for preferential paramagnetic enrichment of the cell species
  • This variation of the preferred embodiment will help the tumor cell enrichment and separation process Cell enrichment, separation and adhesion of cells to the antibodies on the micro-chip substrate can, therefore, be carried out in a single step
  • the plastic or polymer or composite polymer substrate [0053] In another variation, the plastic or polymer or composite polymer substrate,
  • the substrate thickness may be larger, for ease of fabrication and sample handling
  • CDs critical dimensions
  • the holes sizes, shapes, depths and array sizes may be modified
  • the volume of these micro-wells is such that they structures can handle varying volumes of the raw or enriched sample carrying the cellular or biological species of interest THEORY OF OPERATION
  • the preferred embodiment is the platform illustrated in Fig 1 , which is a combination of device and chemistry (assay) that preferentially enriches, isolates by filtering unwanted cells based on their size ( ⁇ 6-7 ⁇ m) and surface treatment and by binding the desired cells to the device substrate, images and analyzes circulating tumor cells (CTC) associated with one or more bio-markers
  • CTC circulating tumor cells
  • bio-markers are molecules or proteins that characterize the surface of
  • cancer cells for a certain cancer type
  • these proteins or bio-markers may be more highly or less highly expressed It is desirable that the cancer cells equally and highly expressive such that they can be isolated and imaged with high signal-to-noise ratio or high mean fluorescence intensity (MFI)
  • epithelial cancer cells for breast cancer unlike leukocytes (or white blood cells), consist of cytokeratm, CK+, namely CK8, CK9, CK19, and CD45- (a marker for leukocytes)
  • cytokeratm CK+
  • CK8 CK9
  • CK19 CK19
  • CD45- a marker for leukocytes
  • bio-markers are FDA approved in 2004 (CellSearchTM and Cell SpotterTM) for monitoring treatment response to therapy for breast cancer patients
  • cellular debris, i e cellular debris, i e , leukocytes, red-blood cells, and platelets will be preferentially separated
  • the present invention for cancer cell detection and imaging utilizes preferential separation labelling, and purification of CD3, CD4 and CD8 with appropriate antibodies Typical volumes of the antibodies requirements are whole blood to the antibody reagent in the ratio of 10 1 Work-flow for another application of HIV testing, by CD4- T cell lymphocyte detection and imaging, which uses much smaller whole blood volume (
  • red-blood cells may be separated by lysis
  • enriched sample (l-200 ⁇ l) is transferred to the microchip device (3E, 4F, 5E) with microwell or micro-pillar or micro-posts structures
  • the microwell structures are loaded with bead-based assay carrying the fluorescent-conjugated antibody tagging agent, e g , Alexafluor-488 (A21335, clone 289-14120, Molecular Probes, Eugene, Oregon, United States )
  • the preferred embodiment includes optimizing the cell capture and binding affinity to the device cartridge first with cell lines with known surface density and expression These samples are readily available and can be easily engineered in a laboratory environment to optimize the expression rate, which determines their detectability
  • the known cell lines which will serve as internal controls, are the CD3 and CD4 cell lines
  • the concentration of these cells relative to circulating tumor cells (CTC) in peripheral blood is 10,000 to 100,000x more abundant
  • CD34 are about 1000 times more abundant compared to CTC in blood and can also serve as internal reference and calibration species
  • Another important aspect of the present invention is the performance of a prevalence study Initially, one will use known cell samples and dilute them to certain concentrations such that they can be treated as standards With these pre-determined concentrations, one will be able to demonstrate the higher efficacy of our method over that of the benchmark, namely flow cytometry Flow cytometry, however, takes up to 10 hours for analysis, and therefore, while it can be a good calibration tool, it is slow for clinical application
  • Surface chemistry optimization namely, hydrophobicity and protem-protem interactions between the surface molecule proteins and the surface of the device, will be optimized, first with the cell lines for highly abundant, well characterized cells for example, with CD3, CD4 and CD34 Subsequently, one can carry out this optimization specific for the desired species of rare cancer cells
  • the device will consist of one or more table-top instruments for sample preparation and cell quantification
  • cancer cell enrichment will be carried out by positive or negative immunomagnetic enrichment, e g by using Dynal Beads CD45-, in combination with magnetic particle separation, for negative separation While positive enrichment tags the specific CTC species, negative enrichment method leaves the cell character prime and untouched
  • sample handling and processing will be performed using a disposable, cartridge-based micro-chip device, a consumable containing an array of microwells or micro-pillars
  • the unique structure of the micro-well device and its surface treatment with primary antibodies will promote tight trapping and binding of the CTCs (6B)
  • the fabrication of the device and novel structures will use proven methods
  • the trapped cells will be sandwiched by subsequently treating them with secondary antibodies, for fluorescent imaging and enhanced mean fluorescence intensity (MFI)
  • MFI mean fluorescence intensity
  • Tumor-cell recovery is known to be in the range of 50% to 90% (as published by Ve ⁇ dex, LLC) However, in other reports,by quadrapole magnetic flow sorter, cancer cell recovery is shown to be 89%, [Nakamura M, Decker K, Chosy J, Cornelia K, Melmk K, Moore L, Lasky LC, Zborowski M, Chalmers JJ The separation of a breast cancer cell line from human blood using a quadrupole magnetic flow sorter Biotechnol Prog 2001, 17 1145- 1155]
  • reagents are available, for example, immunofluorescence staining of the enriched cancer cell sample can be carried out with anticytokeratm (CK3- 6H5)-FITC CD45-MACS (Cat No 130-045-801, Miltenyi Biotec, Auburn, CA), for example for breast cancer, biomarkers for epithelial cancer cells are CK8+, CK9+, CK19+, CD45-, or Her2 Positive or negative cell-labelmg can be applied Positive labeling has been reported to limit further labeling, for analysis if specific sites are already bound with antibodies
  • Dynabeads used in magnetic cell separation technology, are commercially available from Invitrogen Corporation (Carlsbad, CA) and are shown in Fig 6
  • the present invention contrasts, with the liquid phase approach used by Ve ⁇ dex, LLC, which uses ferro-fluids
  • the figure 6 shows Dynabeads (6A) signaling to T cells (6B) and the mechanism of binding of to the cell specific sites
  • our method is based on single cancer cell detection Because of the ability for single-cell detection, the method is expected to assist in the early detection of cancer or metastatic cancer With an X-ray or a mammogram, however, detection requires a tumor comprising at least 1,000,000 cells, below which the sensitivity of the test decays dramatically ( 0 5mm to 5mm tumor size will have 100,000 to 100,000,000 cells, with an average size of about 10mm) Further, the present invention is non-mvasive, avoids painful biopsy, and can be used as a screening method and to increase diagnostic validation, in combination with other methods such as X-ray, and ⁇ n-v ⁇ vo biological imaging
  • the present invention offers the ability to test multiple (3 or 4 ) biomarkers simultaneously
  • the method offers the ability to format and detect these markers in a single test compared to multiple tests, as well as an ability to carry out pathological examination of the cells
  • the method also offers a tool to test the efficacy of novel drugs or drug combination in the treatment of specific cancer
  • the method can help surgeons improve decision- making whether or not to perform surgery, depending upon the benign or malignant nature of the cells
  • the results will be in on a solid-phase substrate, will be objective and operator independent, and will reduce use of expensive chemicals and reagents

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Le procédé faisant l'objet de la présente invention est un dispositif ou un appareil de conception unique, un matériau, ou une combinaison de ces éléments, qui identifie, sépare, permet l'imagerie et établit la classification de cellules et de biomarqueurs de pronostic associés à un cancer de nature épithéliale. L'invention utilise une puce constituée de verre, de silicium, de quartz, d'une combinaison de ces matériaux, ou d'une matière plastique, fabriquée grâce à la nanotechnologie. Le procédé peut être utilisé pour le diagnostic et la surveillance de la pathologie, de la progression de la maladie, de l'efficacité des médicaments et de la réponse du patient au traitement.
PCT/US2007/089096 2007-01-03 2007-12-28 Procédé de détection précoce d'un cancer Ceased WO2008085777A2 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US88323607P 2007-01-03 2007-01-03
US60/883,236 2007-01-03
US89286307P 2007-03-04 2007-03-04
US60/892,863 2007-03-04
US89686907P 2007-03-23 2007-03-23
US60/896,869 2007-03-23
US91117307P 2007-04-11 2007-04-11
US60/911,173 2007-04-11
US93841907P 2007-05-16 2007-05-16
US60,938,419 2007-05-16
US98048307P 2007-10-17 2007-10-17
US60,980,483 2007-10-17

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WO2008085777A2 true WO2008085777A2 (fr) 2008-07-17
WO2008085777A3 WO2008085777A3 (fr) 2008-10-16
WO2008085777A9 WO2008085777A9 (fr) 2008-12-11

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012524909A (ja) * 2009-04-24 2012-10-18 ノースウェスターン ユニヴァーシティ ポリマーペンリソグラフィー製の多重生体分子アレイ
EP2543999A4 (fr) * 2010-03-05 2016-03-30 Konica Minolta Holdings Inc Procédé et système de détection de cellules
RU2676035C1 (ru) * 2018-07-20 2018-12-25 Федеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования "Российская медицинская академия непрерывного профессионального образования" Министерства здравоохранения Российской Федерации (ФГБОУ ДПО РМАНПО Минздрава России) Способ прогнозирования вероятности развития пролиферирующей миомы матки

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI71768C (fi) * 1984-02-17 1987-02-09 Orion Yhtymae Oy Foerbaettrade nykleinsyrareagenser och foerfarande foer deras framstaellning.
WO2005055804A2 (fr) * 2003-12-02 2005-06-23 Musc Foundation For Research Development Procedes et compositions de diagnostic du cancer des cellules epitheliales

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012524909A (ja) * 2009-04-24 2012-10-18 ノースウェスターン ユニヴァーシティ ポリマーペンリソグラフィー製の多重生体分子アレイ
EP2543999A4 (fr) * 2010-03-05 2016-03-30 Konica Minolta Holdings Inc Procédé et système de détection de cellules
US9448163B2 (en) 2010-03-05 2016-09-20 Konica Minolta Holdings, Inc. Method for detecting rare cell on observation region
RU2676035C1 (ru) * 2018-07-20 2018-12-25 Федеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования "Российская медицинская академия непрерывного профессионального образования" Министерства здравоохранения Российской Федерации (ФГБОУ ДПО РМАНПО Минздрава России) Способ прогнозирования вероятности развития пролиферирующей миомы матки

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WO2008085777A3 (fr) 2008-10-16
WO2008085777A9 (fr) 2008-12-11

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