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WO1997035201A1 - Diagnostic serologique au moyen d'antigenes multiples - Google Patents

Diagnostic serologique au moyen d'antigenes multiples Download PDF

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Publication number
WO1997035201A1
WO1997035201A1 PCT/IL1997/000105 IL9700105W WO9735201A1 WO 1997035201 A1 WO1997035201 A1 WO 1997035201A1 IL 9700105 W IL9700105 W IL 9700105W WO 9735201 A1 WO9735201 A1 WO 9735201A1
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WIPO (PCT)
Prior art keywords
beads
accordance
antibodies
types
bead
Prior art date
Application number
PCT/IL1997/000105
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English (en)
Inventor
Ofer Markman
Ilan Paleyov
Original Assignee
Ofer Markman
Ilan Paleyov
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 Ofer Markman, Ilan Paleyov filed Critical Ofer Markman
Priority to EP97907257A priority Critical patent/EP0888544A1/fr
Priority to AU19381/97A priority patent/AU1938197A/en
Publication of WO1997035201A1 publication Critical patent/WO1997035201A1/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
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • 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
    • 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
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/585—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with a particulate label, e.g. coloured latex

Definitions

  • the present invention relates generally to medical diagnostic testing, and specifically to apparatus and methods for detection of antibodies in serum samples
  • immunoassay diagnostic tests are well known in the art, for example in diagnosing viral infections, auto-immune disorders and other pathologies and conditions, such as pregnancy These tests are based on antibody- antigen interactions, wherein a serum sample taken from a subject is applied to an antigen, such as a particular protein, which reacts with a specific type of antibody in the serum that recognizes and responds to the antigen The reacted antibody is typically bound to a labeling substance, whose concentration is then detected in order to measure the level of the specific antibody in the serum sample to be assayed Labeling substances known in the art include, inter alia, radioisotopes (for radioimmunoassay), conjugated enzymes (for ELISA - enzyme-linked immunoassay), and fluorescent labels
  • Immunoassay tests must frequently be performed on a serum sample for more than one type of antigen Generally in these cases the test is performed separately for each specific antigen-antibody reaction, for example, for a single strain of influenza virus The test must then be repeated for each different antigen of interest
  • Double antigen testing wherein a different label is used for each antigen, is also known in the art Such testing is useful for direct detection of antigens, but is not practical for antibody detection
  • antibodies of two different types, each type labeled with a different, respective fluorescent, isotopic or other marker are added to a sample containing antigens
  • concentrations of the two types of antigens are detected, for example by observing fluorescence in two different respective colors using a spectrometer
  • This method is practically impossible to implement when more than two antigens are to be detected
  • a number of methods have been developed for performing multiple single- antigen assays together on a given serum sample.
  • the antigens in these assays are preferably bound to solid-phase substrates, for more convenient handling.
  • test kits using these instruments typically include a test substrate having multiple plastic wells, wherein a different antigen to be tested for is bound to each of the wells. Up to 96 wells, each with a different antigen, may be used on a single substrate.
  • plastic or magnetic beads may be used to bind the antigens, as described, for example, by D. Leahy, et al.. in Transfusion 32 (1992), pages 548-553, which is incorporated herein by reference. As described in this article, the beads are of uniform size, and all the beads in a given test tube or test cell are bound to antigens of a single type.
  • Petts, et al.. in Eur. J. Clin. Microbiol. Infect. Pis. 7 (1988), pages 34-39, and Hadfield, et al.. in Journal of Immunological Methods 97 (1987), pages 153-158, describe other diagnostic techniques, in which two or more different antigens are bound to beads of respective, different colors.
  • the beads to which these antigens are bound form a dense precipitate. The color of the precipitate is thus indicative of the type of antibodies in the sample.
  • This type of test is useful in qualitative assays, for example, in identifying which single type of a group of types of antibodies is present in the sample, but it is not generally practical for multiple-antibody diagnosis or for quantitative determinations.
  • Fluorescence-activated cell sorting (FACS) devices and methods are well known in the art. FACS is performed using flow cytometry methods and apparatus, such as the FACStar PLUSTM family of instruments, manufactured by Becton Dickinson Immunocyto etry Systems, of San Jose, California. In flow cytometry, cells in a stream of fluid are made to pass through a laser beam, which causes them to fluorescently emit and/or scatter light. The intensity of this emitted or scattered light signal from each individual cell is analyzed. In FACS, this signal is then used to cause an electrical charge, dependent on the signal, to be applied to a droplet of fluid containing the cell. A system of electrical deflection plates downstream causes the droplets to be sorted and collected according to the signals they produced.
  • FACS Fluorescence-activated cell sorting
  • FACS Fluorescence Activated Cell Sorting
  • beads of substantially the same size as cells are inserted into the apparatus for processing, as described by Dulling and Waldschmidt in ISAC XVI Cytometry Supplement 6 (1993), page 47; by Bell and Shenton, in ISAC XVII Cvtometrv Supplement 7 (1994), page 38; and by Mathai, et al.. in ISAC XVII Cvtometrv Supplement 7 (1994), page 38, which are inco ⁇ orated herein by reference.
  • the multiple antibody assay is performed using methods of flow cytometry.
  • this apparatus operates in conjunction with a flow cytometry system.
  • Yet another object of the present invention is to provide a test kit for preparation of a sample for assaying antibodies for multiple antigens simultaneously.
  • a multi-antigen test kit comprises a multiplicity of beads, having a plurality of sizes and/or shapes and/or colors, wherein the sizes and/or shapes and/or colors are chosen so that the beads may be sorted according to their respective shapes, sizes and/or colors.
  • the sizes of the beads are on the order of the size of cells, and they are sorted by fluorescence-activated cell sorting (FACS).
  • beads in the context of the present invention is taken to mean miniature pellets or particles, which may be of any desired shape. In one preferred embodiment of the present invention, the beads are substantially spherical.
  • color refers to the broader meaning of wavelength, the intensity of spectral emissions, absorbances and excitations.
  • the test kit includes a plurality of different types of antigens, wherein each antigen type is associated with a respective size, shape and/or color, and wherein the specific antigen is bound to all beads in the kit having substantially the same size, shape and/or color.
  • the beads are many times larger than the antigens and the antibodies reacting therewith, so that the sizes and shapes of the beads remain substantially unchanged during use of the test kit.
  • the multiplicity of antigen-bound beads are mixed with a serum sample, causing specific antibodies present in the sample to bond to corresponding specific antigens.
  • the multiplicity of beads to which the sample has been applied are then developed, using methods known in the art, so that a fluorescent-labeled molecule is conjugated or bound to each of the bonded antibodies.
  • the developed beads are passed through flow cytometry apparatus, which sorts the beads according to their sizes and/or shapes and/or color and analyzes the fluorescent light signal received from each of the beads. It will be appreciated that in this manner, the beads are sorted into groups, each group corresponding to a different antigen, whereby the fluorescent light signals received from each group are indicative of the presence and concentration level of the specific antibody in the sample associated with the single specific antigen.
  • the flow cytometry apparatus is adapted to provide a data readout that includes simultaneous assays of the levels of all the specific antibodies in the sample for which specific antigens were provided.
  • the flow cytometry apparatus preferably applies calibration standards and thresholds, as are known in the art, to the analysis of the data.
  • the data output includes a list of pathologies, disorders and/or other medical conditions, wherein each of the listed pathologies, disorders and conditions is followed by an indication of its presence or absence, and/or by a measure of the concentration of antibodies in the sample associated with the pathology, disorder or condition.
  • the data output may include a histogram or other statistical analysis.
  • test kit, flow cytometry apparatus and method are suitable for assaying viral agents, such as HIV, hepatitis, herpes, influenza and other agents known in the art.
  • test kit, flow cytometry apparatus and method are suitable for diagnosing autoimmune disorders, such as systemic lupus erythematosus, or myasthenia gravis, or, in still other preferred embodiments, for analyzing physiological conditions, such as pregnancy, cancer, respiratory virologies, infections endangering pregnant women, kidney disorders, liver disorders, as well as pathology, epidemiology
  • a test kit for multi-antigen serological diagnosis including a plurality of bead groups, each group including at least one bead; and a plurality of types of antigens, wherein each bead group has at least one common identifying physical characteristic, and herein each type of antigen is bound to the at least one bead of one, respective, bead group.
  • the at least one identifying physical characteristic includes bead size or bead shape or bead color, and the largest dimension of each bead is between 0.5 and 10 micrometers.
  • the beads are substantially spherical.
  • the plurality of groups of beads includes at least three groups of beads, and the plurality of types of antigens includes at least three different, respective, types of antigens.
  • At least one of the plurality of types of antigens is adapted for assaying anti-viral antibodies. Additionally or alternatively, preferably at least one of the plurality of types of antigens is adapted for detecting autoimmune disorders, cancer markers, respiratory virologies, infections endangering pregnant women, pathology, epidemiology, kidney disorders, liver disorders.
  • apparatus for multi-antigen serological diagnosis of a serum sample including a test kit as described above; and a sorter, adapted to sort the beads according to their respective, identifying, physical characteristics.
  • the sorter sorts the beads according to their sizes and/or shapes and/or color.
  • the sorter includes fluorescence-activated cell sorting apparatus, which sorts the beads according to fluorescent light emission therefrom.
  • the sorter further sorts the beads according to a physical characteristic indicative of presence or substantial absence of predetermined antibodies on the beads.
  • the apparatus includes a processor, which provides an output responsive to the presence or substantial absence of predetermined types of antibodies in the sample; a display, which displays information relating to the sample based on said output; and a printer, which prints information relating to the sample based on said output.
  • the apparatus also includes a preparation unit, which prepares the test kit for sorting.
  • the preparation unit includes an applicator which applies the sample to the test kit, and a developer which develops a predetermined marker onto at least some of the beads that have antibodies reacted with the antigens thereon.
  • a method for assaying multiple types of antibodies in a serum sample including the following steps: providing a plurality of beads; binding a plurality of types of antigens to the beads; applying a serum sample to the beads; developing the beads with a marker; sorting the developed beads, so as to generate a bead count; classifying the levels of one or more types of antibodies in the sample using the bead count.
  • Preferably providing a plurality of beads includes providing a plurality of groups of beads, all beads in each group having a common identifying physical characteristic.
  • each type of antigen is bound to substantially all the beads in one, respective, group of beads.
  • beads from different groups are mixed according to the types of antibodies to be assayed, and beads from at least three different groups are mixed.
  • Preferably developing the beads includes conjugating a fluorescent marker to at least some of the antibodies that have reacted with antigens bound to the beads.
  • a plurality of different fluorescent markers, respectively, are conjugated to a plurality of different types of antibodies.
  • sorting the beads includes sorting the beads by size, shape and/or color.
  • Preferably sorting the developed beads further includes: irradiating the beads with laser radiation; receiving light signals from the beads; identifying the beads according to the light signals received therefrom; and counting beads from which substantially similar light signals were received.
  • Preferably receiving light signals from the beads includes receiving scattered light signals and/or receiving fluorescent emission light signals.
  • Preferably classifying the levels of one or more types of antibodies in the sample includes applying thresholds to the bead count.
  • Preferably classifying the levels of one or more types of antibodies in the sample further includes determining the presence or substantial absence of the one or more types of antibodies and/or determining the respective concentrations of the one or more types of antibodies.
  • classifying the levels of one or more types of antibodies in the sample includes classifying the levels of anti-viral antibodies and/or of antibodies indicative of autoimmune disorders, cancer markers, respiratory virologies, infections endangering pregnant women, pathology, epidemiology, kidney disorders, liver disorders.
  • FIG. 1 is schematic illustration of apparatus for analyzing antibody levels in a serum sample, in accordance with a preferred embodiment of the present invention
  • Fig. 2 is a schematic illustration of a test preparation unit for preparation of samples for analysis, in accordance with the preferred embodiment of the present invention shown in Fig. 1;
  • Fig. 3A is a schematic illustration of beads coated with specific antigens, in accordance with a preferred embodiment of the present invention.
  • Fig. 3B is a schematic illustration of the beads of Fig. 3 A, mixed together in a test kit, in accordance with a preferred embodiment of the present invention
  • Fig. 3C is a schematic illustration of the test kit of Fig. 3B, after application of the serum sample, in accordance with a preferred embodiment of the present invention
  • Fig. 3D is a schematic illustration of color development of the test kit and serum sample of Fig. 3C, in accordance with a preferred embodiment of the present invention
  • Fig. 4 is a schematic illustration of a sorter for sorting beads and receiving fluorescence signals from samples for analysis, in accordance with a preferred embodiment of the present invention shown in Fig. 1;
  • Fig. 5 is a table, representing schematically sample results of the operation of the reading unit
  • Fig. 6 is a schematic illustration of an analysis and display unit for analysis and presentation of data, in accordance with a preferred embodiment of the present invention shown in Fig. 1;
  • Fig. 7 is a schematic illustration of a Sample output of the Analysis and Display unit. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • Fig. 1 illustrates schematically apparatus 20 for multi-antigen serological diagnosis on a single sample, in accordance with a preferred embodiment of the present invention.
  • Apparatus 20 preferably comprises a test preparation unit 22, a sorter 24 and an analysis and display unit 26.
  • test preparation unit 22 receives a serum sample 28 and a suitably prepared test kit 30.
  • the test kit and serum combination is processed as illustrated in Fig. 1 and in subsequent figures, and outputs test results 32. These results preferably comprise data relating to the levels of specific antibodies detected in serum sample 28.
  • Fig. 2 schematically illustrates test preparation unit 22, which preferably comprises a mixer 40, for preparing test kit 30; applicator 42, for applying serum sample 28 to the prepared test kit; and developer 44, for color development of the test kit after application of the serum sample.
  • Mixer 40, applicator 42 and developer 44 are preferably automated laboratory devices of types known in the art, and preferably operate under the control of a robot 46, likewise of a type known in the art.
  • some or all of the operations of test preparation unit 22 may be performed manually by a laboratory technician. After these operations are completed, the test kit with serum sample is ready for transfer to sorter 24.
  • test kit 30 comprises a multiplicity of beads 50, 52, 54, having a plurality of different sizes, and grouped initially according to these sizes.
  • the beads Preferably have dimensions in the range 0.5 to 10 micrometers and are made of plastic, for example polypropylene, polystyrene, or latex, as described in the references cited above, or other polymers or particles known in the art.
  • plastic for example polypropylene, polystyrene, or latex, as described in the references cited above, or other polymers or particles known in the art.
  • beads 50, 52 and 54 shown in Figs. 3A-3D are spherical, in other preferred embodiments of the present invention, the beads may have different shapes and colors, and are grouped and sorted according to their shape or size or color or combination thereof.
  • test kit 30 can include tens or hundreds of different types of antigens, each type bound to beads of a different size and/or shape and/or color.
  • each of antigens 56, 58 and 60 of the serum sample 28 is adapted to react with a corresponding specific antibody 66, 68 or 70, respectively, which may be present in serum sample 28.
  • beads 50, 52 and 54 are selected and mixed together in preparation for analysis, based on the specific antibodies whose levels are to be analyzed.
  • test cell 64 may be prepared by the manufacturer with test kit 30 in pre-mixed form.
  • Fig. 3C it will be seen that when serum sample 28 is applied by applicator 42 (shown in Fig. 2) to the contents of test kit 30, antibodies 66 react with antigens 56 on beads 50, and antibodies 68 react with antigens 58 on beads 52. In this example, however, antibodies 70 are not present in the serum sample, and therefore, antigens 60 on beads 54 remain unreacted.
  • developer 44 (shown in Fig. 2) biochemically develops the kit to which serum sample 28 has been applied, using methods and materials known in the art, wherein reacted antibodies are conjugated to fluorescent dye markers, for example FITC (fluorescein) or rhodamine.
  • fluorescent dye markers for example FITC (fluorescein) or rhodamine.
  • beads of substantially the same size are distinguishable by color as to whether antibody 66 has reacted with an antigen 56 thereon. Distinguishing these beads 50 and 50A would otherwise be very difficult, because antigens 56, 58 and 60 and antibodies 66, 68 and 70 are typically smaller than the beads by several orders of magnitude. Antigens 56, 58 and 60 are shown to be comparable in size to the beads in Figs. 3A-3D for demonstrative simplicity only.
  • reacted antibodies are marked with the same color
  • different types of reacted antibodies are marked with different color dyes. These embodiments are useful when more than one type of antibody may react with a given antigen, for example antibodies IgG, IgM and IgE, as are known in the art. In this case the different colors associated respectively with the different antibodies are used to determine their respective concentrations in the sample.
  • sorter 24 includes a fluorescence-activated cell sorting (FACS) system, such as the FACStar PLUS system, manufactured by Becton Dickinson, or any other type of FACS system known in the art.
  • FACS fluorescence-activated cell sorting
  • beads 50, 52 and 54 are mixed with a sheath fluid 72 and expelled through a nozzle 74, which directs them through a laser beam 75, preferably in the 400-700 nm range of wavelength, produced by a laser 76.
  • the amount and pattern of light that the beads 50, 52, 54 scatter is measured by a scattering detector 77.
  • This measurement is used by processor 79 to determine the size and/or shape and/or color of the bead, using methods known in the art, and thus to sort the beads by size and/or shape and/or color. Since each different size or shape bead is bound to a different specific antigen, determining the beads' sizes allows sorting of the different types of antigens.
  • the FACS system is calibrated using beads of predetermined known sizes and shapes. Such calibration of FACS systems using beads is known in the art for the pu ⁇ oses of calibrating the systems to sort biological cells of comparable size and/or shape.
  • the identity of an antigen, bound to a bead of known size, shape, and color is determined in real time.
  • the method for controlling the identification of the antigen is performed in real time from the size, shape and intensity of the 5 out of 6 colors read by the FACS system.
  • the sixth color, FL1 of the antigen is used for determining the antibody binding.
  • a set of beads of known size, shape and color, and with various FL1 intensities, preferably different from the size, shape, and color of the antigens to be identified, are introduced into the apparatus.
  • the (0,0,0) coordinates of the matrix, which describes the parameters of the antigen are determined.
  • the brightness and intensity of the scattered laser signal received are dependent on the ratio of antigens/antibodies in the sample.
  • the parameters, namely size, shape, and color, of the antibody are determined from the fluorescent signal emitted by the fluorescent chemical marker. From these measured data, the size, shape, and color of the antigen are determined.
  • the calibration includes determining one or more threshold values of size and color.
  • the predetermined threshold values are applied to data received by processor 79, in order to produce an output indicative of the levels of antibodies in the sample.
  • This output may be in the form of a bargraph 80, as shown schematically in Fig. 5.
  • Fig. 5 shows only two values of color, (+) and (-), corresponding to whether the fluorescent signals received are greater or less than a given threshold value
  • multiple thresholds may be set, corresponding to multiple different levels of fluorescent emission.
  • Unit 26 preferably comprises output data processor 90, which receives data from processor 79 (shown in Fig. 4).
  • Processor 90 pools the data received regarding the sizes of the beads, the shapes of the beads, and the color of the beads, and matches the output data with corresponding specific antigen- antibody reactions.
  • the fluorescent signal data are then classified in accordance with predetermined standards for classifying antigen-antibody reactions, as are known in the art. These standards may be preset by the manufacturer of the apparatus, or, alternatively, they may be set by the user in accordance with specific test requirements.
  • Classification results 32 are output to display 92 and printer 94, for example, in the form of tables and/or graphs.
  • Fig. 7 shows a typical output table 100, in accordance with a preferred embodiment of the present invention, comprising classification results 32 for samples taken from five patients and tested for five different viruses.
  • the test kit, flow cytometry apparatus and diagnostic methods executed thereby are adapted for assaying viral agents, such as HIV, hepatitis, he ⁇ es, influenza and other agents known in the art.
  • test kit, flow cytometry apparatus and diagnostic methods executed thereby are adapted for diagnosing autoimmune disorders, such as systemic lupus erythematosus, or myasthenia gravis, or, in still other preferred embodiments, for analyzing physiological conditions, such as pregnancy such as pregnancy, cancer, respiratory virologies, infections endangering pregnant women, kidney disorders, liver disorders, as well as pathology, epidemiology.
  • autoimmune disorders such as systemic lupus erythematosus, or myasthenia gravis
  • physiological conditions such as pregnancy such as pregnancy, cancer, respiratory virologies, infections endangering pregnant women, kidney disorders, liver disorders, as well as pathology, epidemiology.
  • the diagnostic methods described here may be executed using any suitable circuitry and/or software inco ⁇ orated, inter alia, in processor 79 and processor 90.

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Abstract

L'invention concerne une trousse d'analyse servant à effectuer un diagnostic sérologique à base d'antigènes multiples et comprenant une pluralité de groupes de perles, chaque groupe étant composé d'au moins une perle, ainsi que d'une pluralité de types d'antigènes, chaque groupe de perles possédant au moins une caractéristique physique commune d'identification et chaque type d'antigène étant fixé à la perle au moins d'un groupe de perles respectif. Elle concerne également un procédé de détermination de types multiples d'anticorps dans un spécimen de sérum.
PCT/IL1997/000105 1996-03-21 1997-03-20 Diagnostic serologique au moyen d'antigenes multiples WO1997035201A1 (fr)

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EP97907257A EP0888544A1 (fr) 1996-03-21 1997-03-20 Diagnostic serologique au moyen d'antigenes multiples
AU19381/97A AU1938197A (en) 1996-03-21 1997-03-20 Multi-antigen serological diagnosis

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IL117605 1996-03-21
IL11760596A IL117605A0 (en) 1996-03-21 1996-03-21 Multi-antigen serological diagnosis

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US7253435B2 (en) 1999-04-15 2007-08-07 Millipore Corporation Particles with light-polarizing codes
US7407773B2 (en) 2000-11-03 2008-08-05 Procognia, Ltd. Method for characterizing a carbohydrate polymer
US7455979B2 (en) 1999-05-06 2008-11-25 Procognia Ltd. Polysaccharide structure and sequence determination
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US7557070B2 (en) 2000-10-18 2009-07-07 Millipore Corporation Multiplexed cell analysis system
US8119357B2 (en) 2003-12-18 2012-02-21 Procognia, Ltd. Method for analyzing a glycomolecule
CN108375572A (zh) * 2018-02-26 2018-08-07 深圳市生强科技有限公司 基于化学发光法的检测方法及装置
WO2021127424A1 (fr) * 2019-12-19 2021-06-24 Roche Diagnostics Hematology, Inc. Compositions et procédés d'étalonnage et de contrôle de qualité
CN115943309A (zh) * 2020-05-19 2023-04-07 艾迪泰克斯股份有限公司 用于多个免疫球蛋白同种型的双多重测定

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CA2249272A1 (fr) 1997-09-25
IL117605A0 (en) 1996-07-23
EP0888544A1 (fr) 1999-01-07

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