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WO2025129039A1 - Détection par biocapteur de la stadification du cancer du sein dans des biomarqueurs salivaires - Google Patents

Détection par biocapteur de la stadification du cancer du sein dans des biomarqueurs salivaires Download PDF

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Publication number
WO2025129039A1
WO2025129039A1 PCT/US2024/060095 US2024060095W WO2025129039A1 WO 2025129039 A1 WO2025129039 A1 WO 2025129039A1 US 2024060095 W US2024060095 W US 2024060095W WO 2025129039 A1 WO2025129039 A1 WO 2025129039A1
Authority
WO
WIPO (PCT)
Prior art keywords
her2
functionalized
sensing area
transistor
concentration
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.)
Pending
Application number
PCT/US2024/060095
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English (en)
Inventor
Josephine F. Esquivel-Upshaw
Yu-Te Liao
Fan Ren
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.)
University of Florida
University of Florida Research Foundation Inc
Original Assignee
University of Florida
University of Florida Research Foundation Inc
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Publication of WO2025129039A1 publication Critical patent/WO2025129039A1/fr
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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
    • 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
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes
    • 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

Definitions

  • a method comprises providing a bio fluid sample to a functionalized sensing area disposed between two electrodes of a disposable test strip, the functionalized sensing area configured to detect a concentration of HER2, CA15-3 or CA 125 in a range from 5 x 10 4 g/mL to 5 x w 15 g/mL in the bio fluid sample; and generating two synchronized voltage pulses, a first voltage pulse applied to a first functionalized electrode of the disposable test strip thereby inducing charges to appear on a second electrode of the disposable test strip, which is connected to a gate of a transistor, and a second voltage pulse applied to a load resistor which is connected to a drain of the transistor, where a drain voltage output of the transistor is a function of the concentration of HER2, CA15-3 or CA 125 in the bio fluid sample and provides an indication of HER2, CA15-3 or CA 125 concentration in
  • the bio fluid sample can comprise saliva, blood, serum, sweat, urine, or tear fluid.
  • the sensing area can be functionalized with an anti-HER2/ERBB2, CA 15-3 or CA 125 monoclonal antibody.
  • the sensing area can be functionalized with a CA15-3 monoclonal antibody.
  • the sensing area can be functionalized with a recombinant anti-MUC16 antibody.
  • the sensing area is functionalized with a monoclonal mouse anti-human SP1 antibody.
  • the sensing area can be functionalized with a CEA Monoclonal antibody.
  • the sensing area is functionalized with an anti-CA 27-29 monoclonal antibody.
  • the functionalized sensing area can be configured to detect a concentration of HER2, CA15-3 or CA 125 of less than 10 11 g/mL in the bio fluid sample and the drain voltage output of the transistor provides indications of HER2 CA15-3 or CA 125 concentrations of less than 10 11 g/mL.
  • the functionalized sensing area can be configured to detect a concentration of HER2, CA15-3 or CA 125 of less than 10' 12 g/mL in the bio fluid sample and the drain voltage output of the transistor provides indications of HER2 CA15-3 or CA 125 concentrations of less than 10 12 g/mL.
  • the bio fluid sample can be provided to the functionalized sensing area via an opening in the disposable test strip.
  • the disposable test strip can be configured for single-use, and the transistor can be electrically coupled to the two electrodes through a detachable connection.
  • the indication of the HER2, CA15-3 or CA 125 concentrations can be an average of a plurality of synchronized gate and drain pulse measurements.
  • the plurality of synchronized gate and drain pulse measurements can comprise 10 consecutive pulse measurements.
  • the indication of the HER2, CA15-3 or CA 125 concentrations can be provided in 15 msec or less.
  • FIGS. 2A and 2B illustrate examples of output drain voltage waveforms for pure artificial saliva and HER2 protein diluted in saliva from 10 7 g/mL to 10 15 g/mL and output digital readings from PCB under different HER2 protein concentrations, respectively, in accordance with various embodiments of the present disclosure.
  • the limit of detection is 1 O’ 15 g/mL while the sensitivity is 70/dec.
  • FIGS. 3A and 3B illustrate examples of output digital reading results from the human sample test with strips functionalized by HER2 antibody and conversion of the output reading from human samples into exact HER2 protein concentration, respectively, in accordance with various embodiments of the present disclosure.
  • FIG. 4 illustrates an example of average output digital reading from PCB with different CA15-3 protein concentrations, in accordance with various embodiments of the present disclosure.
  • the limit of detection is 10’ 15 g/mL while the sensitivity is 30/dec.
  • FIGS. 5A and 5B illustrate examples of output digital reading results from the human sample test with strips functionalized by CA15-3 antibody and conversion of the output reading from human samples into exact CA15-3 protein concentration, respectively, in accordance with various embodiments of the present disclosure.
  • HER2 HER2
  • HER-2/neu HER2
  • CA15-3 is a tumor-associated antigen that can be detected in the blood of some breast cancer patients.
  • Elevated levels of CA15-3 may indicate the presence of cancer cells and can be used as a complementary tool alongside other diagnostic tests and imaging techniques.
  • concentrations of HER2 and CA15-3 in saliva can be correlated to their concentrations in serum, thus saliva samples can also be employed for breast cancer detection.
  • the ELISA based detections of HER2 and CA15-3 require trained technicians and one to two weeks to obtain results.
  • the limit of detection of ELISA is only around 10 8 to about IO 10 g/mL.
  • a more efficient and cost-effective alternative is the utilization of biosensors for the detection of breast cancer tumor markers.
  • FETs Field-effect transistors
  • SiNW-FET silicon nanowire FET
  • gFET graphene FET
  • MOSFETs Si metal-oxide-semiconductor field-effect transistors
  • TFET tunneling FET
  • a system with a reusable printed circuit board (PCB) containing a MOSFET and disposable test strips can be employed.
  • PCB printed circuit board
  • synchronized double-pulses can be applied at the gate and drain terminals of the transistor to ensure that the channel charge does not accumulate. Additionally, there is no need to reset the drain and gate paths to mitigate the charge accumulation at the gate and drain of the sensing transistor for sequential testing. With the double-pulse approach, it only takes a few seconds to show the result of the test, due to the rapid response of the functionalized test strips and the resulting electrical signal output.
  • LOD limits of detection
  • a double-pulse measurement approach is used to detect HER2 and CA15-3 in saliva samples collected from healthy volunteers and breast cancer patients.
  • the voltage output responses of the transistor correlated to the HER2 and CA15-3 concentrations, detection limits and sensing sensitivity were determined.
  • the sensing platform can be separated from the detection platform.
  • the detected signal is the average of 10 digital output readings corresponding to the 10 voltage pulses.
  • the sensor sensitivities achieved were approximately 70/dec for HER2 and 30/dec for CA15-3.
  • the test time takes less than 15 msec and only needs 3 pL of saliva to complete. The technique is easy to operate and has the potential for widespread public use.
  • test strips used for glucose tests were functionalized and used for the testing of the breast cancer biomarkers.
  • the strips were made by Luvnshare Biomedical Inc. in Hsinchu, Taiwan.
  • the method of functionalizing the test strips is described in detail in “Fast SARS-CoV-2 virus detection using disposable cartridge strips and a semiconductor-based biosensor platform” by M. Xian et al. (J. Vac. Sci. Technol. B:Nanotechnol. Microelectron. 2021 , 39 (3), 033202) and “Digital biosensor for human cerebrospinal fluid detection with single-use sensing strips” by M. Xian et al. (J. Vac. Sci.
  • the first step is to plate the carbon electrodes with gold by connecting to the gate pulse source on the PCB board.
  • the strips can then be immersed into 10mM thioglycolic acid (TGA) solution for 4 hours to form strong Au-S bonds on the gold plated electrode.
  • TGA thioglycolic acid
  • the strips can be soaked in N, N’-dicyclohexylcarbodi-imide (0.1 mM) and N-hydroxysuccinimide (0.1 mM) in acetonitrile for 2 hours.
  • An antigen is any molecule or part of a molecule that can be recognized by the immune system.
  • An antibody is a Y-shaped protein produced by the immune system to specifically recognize and bind to a corresponding antigen.
  • Each antibody has a unique region, known as the variable region, that is structurally adapted to bind to a specific epitope (a small, unique portion of the antigen).
  • the specificity of the antigen-antibody interaction depends on the epitope of the antigen and the paratope of the antibody.
  • the epitope is the specific part of the antigen that is recognized by the antibody.
  • the antibody will recognize specific amino acid sequences or structural features of the corresponding protein that are unique to the molecule. These epitopes may be located on the protein’s extracellular domain or glycosylated regions.
  • the paratope is the region of the antibody that binds to the epitope. It is typically located within the variable region of the antibody and is made up of specific amino acid residues that create a complementary binding pocket for the epitope.
  • the complementarity between the paratope (antibody) and the epitope (antigen) results in a highly specific interaction, often described as a "lock and key” model.
  • the antibody's paratope has a shape and charge distribution that matches the epitope on the antigen.
  • the antigen-antibody binding interaction is a precise and specific molecular event, involving the recognition of epitopes on, e.g., the anti-HER2/ERBB2, CA 15-3 or CA 125 monoclonal antigen by the paratope of the antibody. This interaction is driven by a range of non-covalent forces and leads to various immune responses that can target and kill tumor cells.
  • the use of anti-HER2/ERBB2, CA 15-3 or CA 125 monoclonal antibodies harnesses this precise binding to improve cancer detection. This also applies to recombinant anti- MUC16 antibodies, monoclonal mouse anti-human SP1 antibodies, CEA Monoclonal antibodies, anti-CA 27-29 monoclonal antibody, and others.
  • a printed circuit board as illustrated in FIG. 1 B, was designed to convert the detected voltage signals related to the strips into digital readings.
  • a MOSFET STMicroelectronics STP200N3LL
  • Synchronous voltage pulses can be sent to both the electrode of the strip connecting to the gate and drain electrodes of the MOSFET.
  • the drain pulse can be applied, e.g., for around 1.1 msec at a constant voltage.
  • the gate pulse can start, e.g., at 40 s after the drain pulse and end, e.g., at 40ps before the end of the drain pulse.
  • a variable resistor is connected to the drain as the load resistor.
  • FIG. 1C is a schematic diagram illustrates an example of circuitry of the PCB of FIG. 1 B. Additional details of sensor circuitry can be found in US Patent Application Pub. No. 2021/0003528, which is hereby incorporated by reference in its entirety.
  • FIG. 2A depicts dynamic drain output voltage waveforms at various concentrations ranging from 1 fg/ml to 10 pg/ml during each gate pulse.
  • VCO voltage-controlled oscillator
  • a sensitivity of 70/dec was achieved with a limit of detection (LOD) of 10 15 g/mL, which was six to seven orders lower than the gold standard ELISA test, which is around 10 8 to 10 9 g/mL, used to measure these biomarkers.
  • LOD limit of detection
  • the curve was refined by averaging ten consecutive identical pulse measurements. The total measurement time of 10 pulses is under 15 msec, hence, this technique holds promise for real-time point-of-service applications.
  • the antigen-antibody complexes undergo stretching and contracting, akin to double springs, in response to a pulsed gate electric field.
  • FIG. 3A shows output digital readings of 21 human saliva samples, where there are clear differences among healthy, in-situ and invasive breast cancer cases.
  • In-situ ductal carcinoma breast cancer is a type of cancer confined in a milk duct, which eventually grows into the rest of the breast tissue.
  • Invasive breast cancer is a type of cancer which has spread into the surrounding breast tissue.
  • Table 1 shows the median and the range of digital readings by disease status and overall p-value using Kruskal-Wallis test to examine if there exists statistically significant distinctions among two or more groups. The overall p-value is significant while the value for HER2 is 0.002, indicating that this sensor technology is an efficient way to detect HER2 biomarkers in saliva.
  • Immunohistochemistry which was the test used to determine HER2 status on the patients, is a special staining process performed on fresh or frozen breast cancer tissue removed during biopsy to show whether or not the cancer cells have too much HER2 receptors and/or hormone receptors on their surface.
  • IHC is a qualitative test based loosely off eye scored counting and gives a score of 0 to 3+ for the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample. For example 0 to 1 + is HER2 negative, 2+ is borderline and is confirmed positive using fluorescence in situ hybridization (FISH) and, 3+ is HER2 positive.
  • FISH fluorescence in situ hybridization
  • FIG. 3B shows the digital readings corresponding to the calibrated HER2 concentrations in the human samples, and the LOD of HER2 with gold standard ELISA kit is also labelled in the figure.
  • CA15-3 Another cancer antigen, CA15-3, is used as a surrogate marker to monitor metastatic breast cancer patients undergoing treatment and for the preclinical detection of tumor recurrence.
  • Levels of CA 15-3 have a significant relationship to outcome in patients with early breast cancer and is commonly used to detect breast cancer or monitor the effectiveness of cancer treatments. Detection of both CA15-3 and HER2 at the same time to ascertain breast cancer progression was strongly suggested.
  • FIG. 4 illustrates the calibration curve for the CA15-3 biomarker and a LOD of 10‘ 15 g/mL with a sensitivity of 30/dec was demonstrated. The sensitivity of detecting CA15-3 is less than half of the sensitivity for HER2, which is 70/dec.
  • CA15-3 protein 250 ⁇ 350 kDa, which is much larger than that of the HER2 protein, 185 kDa.
  • the disparity in size between the HER2 molecule and the CA15-3 molecule would produce a smaller spring constant for the CA15-3 molecule and diminish the detection sensitivity of CA15-3.
  • FIG. 5A the test results for detecting CA15-3 of the human samples are shown.
  • the digital reading decreases from the healthy group to the invasive breast cancer group, indicating an increase in CA15-3 concentration.
  • FIG. 5B depicts the conversion from the test results of the human samples to the actual CA15-3 protein concentration.
  • Similar DOL results as the HER2 detection showing the CA15-3 DOL concentration is around 5 x 10' 10 to 4 x 10' 9 g/mL, which is slightly higher than the DOL of ELISHA.
  • there was only invasive breast cancer sample (a star and located on the left side of CA15-3 DOL region in FIG. 5B) with the CA 15-3 concentration lower that the DOL.
  • CA15-3 is more sensitive to patients with early breast cancer, but ELISA based CA15-3 screening is not sensitive enough for in-situ breast cancer samples.
  • the median, the range by disease status and overall p-value analyzed with the Kruskal- Wallis test for CA15-3 test are listed in Table 1.
  • the overall p-value for CA15-3 is 0.005, indicating that this device provides an efficient way to detect the salivary biomarkers related to breast cancer.
  • HER2 sensitivity was determined to be 70/dec
  • CA15-3 sensitivity was 30/dec with diluted proteins.
  • ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • a concentration range of “about 0.1% to about 5%” should be interpreted to include not only the explicitly recited concentration of about 0.1 wt% to about 5 wt%, but also include individual concentrations (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within the indicated range.
  • the term “about” can include traditional rounding according to significant figures of numerical values.
  • the phrase “about ‘x’ to ‘y’” includes “about x’ to about ‘y’”.

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Abstract

L'invention concerne divers exemples relatifs à la détection par biocapteur de la stadification du cancer du sein dans des biomarqueurs salivaires. Dans un exemple, un procédé consiste à fournir un échantillon de fluide biologique ou de tissu à une zone de détection fonctionnalisée disposée entre deux électrodes d'une bandelette réactive jetable. Le procédé consiste en outre à générer deux impulsions de tension synchronisées, une impulsion de tension étant appliquée à une électrode fonctionnalisée de la bandelette réactive jetable, induisant ainsi l'apparition de charges sur une autre électrode de la bandelette réactive jetable, qui est connectée à une grille d'un transistor, et une seconde impulsion de tension étant appliquée à une résistance de charge qui est connectée à un drain du transistor. La zone de détection fonctionnalisée détecte une concentration et une sortie de tension de drain du transistor fournit une indication de concentration de HER2, de CA15-3 ou de CA 125 dans une plage de 5 × 10-4 g/ml à 5 × 10-15 g/ml.
PCT/US2024/060095 2023-12-14 2024-12-13 Détection par biocapteur de la stadification du cancer du sein dans des biomarqueurs salivaires Pending WO2025129039A1 (fr)

Applications Claiming Priority (2)

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US202363609979P 2023-12-14 2023-12-14
US63/609,979 2023-12-14

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040142400A1 (en) * 2002-09-11 2004-07-22 Haiying Xia High affinity monoclonal antibody for recognizing the estrogen receptor (ER) and method for creating the antibody
WO2017066537A1 (fr) * 2015-10-16 2017-04-20 The Johns Hopkins University Détection multiplexée d'antigènes tumoraux en circulation et de marqueurs épigénétiques au moyen de dosages spectroscopiques raman améliorés par plasmon
US20180372678A1 (en) * 2015-12-09 2018-12-27 Ramot At Tel-Aviv University Ltd. Method and system for sensing by modified nanostructure
US20210003528A1 (en) * 2019-04-18 2021-01-07 University Of Florida Research Foundation, Inc. HANDHELD SENSOR FOR RAPID, SENSITIVE DETECTION AND QUANTIFICATION OF SARS-CoV-2 FROM SALIVA
US20210403597A1 (en) * 2018-11-16 2021-12-30 Memorial Sloan Kettering Cancer Center Antibodies to mucin-16 and methods of use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040142400A1 (en) * 2002-09-11 2004-07-22 Haiying Xia High affinity monoclonal antibody for recognizing the estrogen receptor (ER) and method for creating the antibody
WO2017066537A1 (fr) * 2015-10-16 2017-04-20 The Johns Hopkins University Détection multiplexée d'antigènes tumoraux en circulation et de marqueurs épigénétiques au moyen de dosages spectroscopiques raman améliorés par plasmon
US20180372678A1 (en) * 2015-12-09 2018-12-27 Ramot At Tel-Aviv University Ltd. Method and system for sensing by modified nanostructure
US20210403597A1 (en) * 2018-11-16 2021-12-30 Memorial Sloan Kettering Cancer Center Antibodies to mucin-16 and methods of use thereof
US20210003528A1 (en) * 2019-04-18 2021-01-07 University Of Florida Research Foundation, Inc. HANDHELD SENSOR FOR RAPID, SENSITIVE DETECTION AND QUANTIFICATION OF SARS-CoV-2 FROM SALIVA

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