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WO1987006345A1 - Immuno-annalyse de mesure colorimetrique de proportionnalite - Google Patents

Immuno-annalyse de mesure colorimetrique de proportionnalite Download PDF

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Publication number
WO1987006345A1
WO1987006345A1 PCT/US1987/000569 US8700569W WO8706345A1 WO 1987006345 A1 WO1987006345 A1 WO 1987006345A1 US 8700569 W US8700569 W US 8700569W WO 8706345 A1 WO8706345 A1 WO 8706345A1
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WO
WIPO (PCT)
Prior art keywords
component
antibody
reaction zone
analyte
specimen
Prior art date
Application number
PCT/US1987/000569
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English (en)
Inventor
Miles G. Hossom
Original Assignee
Murex Corporation
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 Murex Corporation filed Critical Murex Corporation
Publication of WO1987006345A1 publication Critical patent/WO1987006345A1/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
    • G01N33/54386—Analytical elements
    • 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
    • G01N33/72—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood pigments, e.g. haemoglobin, bilirubin or other porphyrins; involving occult blood
    • G01N33/721—Haemoglobin
    • G01N33/723—Glycosylated haemoglobin
    • 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
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors

Definitions

  • the present invention relates to an immunological method of determining the relative amount of a component of an analyte of interest present in a specimen.
  • PRIOR ART Immunodetection has been used in the field of electophoresis to measure the amount and location of separated protein bands on a nitrocellulose sheet (Blangarin, et al . , Clinical Chemistry, vol. 30, No. 12, 1984, p.2021-2025).
  • a first antibody directed against the different fragments or classes of proteins (e.g., human im unoglobulins)
  • a second antibody directed against the first antibody and labelled with a signal generating material, is allowed to react, thus forming a protein:first antibody: labelled second antibody-label complex.
  • the label such as an enzyme, is contacted with an amount of an appropriate substrate and a color appears at the given bands where protein is present.
  • the quantity of color formed is measured photometrical ly.
  • a labelled antibody directed against the antigens of interest, is added to the separated bands.
  • the color indicates the presence of the band, which is compared to a sample mixture run simultaneously which has been developed with a dye or stain, such as Coomasie blue, which will stain all the protein bands in the sample.
  • a dye or stain such as Coomasie blue
  • glycosylated hemoglobin is an important substance of interest. Its proportion to the total hemoglobin in a blood sample is a useful indicator for maintenance of a diabetic patient where diet and insulin therapy must be carefully balanced to maintain the patient in reasonable health. In these, as well as healthy individuals, total hemoglobin content in the blood may vary due to nondiabetic related influences. A healthy individual will normally have a glycosylated hemoglobin level of about 4-5% of the total hemoglobin in the blood, whereas a poorly controlled diabetic may demonstrate glycosylated hemoglobin levels which are as much as 15% of the total hemoglobin.
  • the present invention provides a method for colorimetrical ly quantifying the relative amount of a component as a part of a total sample within a single test format.
  • the present invention comprises a method for the semi-quantitation of a component of an analyte of interest, present in a specimen, where the analyte is composed of at least two components.
  • the method consists of (a) immobilizing an antibody directed against the component on a solid support material in a delimited area defining a reaction zone; (b) contacting with the immobilized antibody a specimen containing the analyte such that substantially all of the component binds to the antibody while the specimen is retained on or within the reaction zone; (c) reading the reaction zone to determine the relative amount of analyte present; (d) washing the reaction zone to remove substantially all material not bound to the antibody; (e) reading the reaction zone to determine the relative amount of component remaining bound to the antibody; and (f) calculating from the readings the ratio of the said component to the analyte.
  • An immunoassay method which can provide in a single test format an quantitative ratio measurement of a specimen and a constituent thereof can be highly useful where current testing procedures require two or more separate tests to be performed.
  • the amount of a component part as a percentage of the total amount of substance can provide an indication of the presence or progression of a disease state, such as diabetes, sickle cell anemia, heart disease, or the like.
  • the assay can be performed in a three dimensional inert porous filter matrix means such as glass fiber, scintered glass, paper, or the like.
  • Immobilized or insolubilized on or within a delimited area of the filter defining a reaction zone is an antibody directed against the component part of the total sample.
  • the component part When fluid specimen is added to the filter the component part will immunofogically bind to the antibody, thereby becoming bound to the filter.
  • a first absorbence reading of the filter area containing the specimen composed of the component part of interest and the-total sample, which correlates with the amount of total sample present in the specimen, is taken. Subsequently, the reaction area is washed with an appropriate buffer or other solution to remove the unbound sample.
  • a second absorbence reading is taken of the reaction zone, which yields a measurement of the quantity of component part that is bound to the antibody retained on or within the filter.
  • the ratio of the two measurements gives the percentage of component part to the total sample.
  • Sensitive dyes such as fluorescein, Sudan Black B, Oil Red 0, or the like can be employed; the particular staining or coloring material is chosen on an individual basis and optimized depending on the analyte. While the method of this invention is suitable for coio ⁇ ' metric or spectrophotometric measurement of material absorption, other measurement techniques that produce a detectable signal are suitable. Coio ⁇ ' metric measurement presents certain advantages over other methods in that no second antibody is required, as compared to a sandwich immunoassay which uses a capture antibody and an antibody-label conjugate which binds to the analyte, thereby "tagging" the analyte with a measurable signal.
  • HbAlC 5 glycosylated hemoglobin
  • HbAlC measurements reflect the level of control present over the proceeding 100-120 days, and is especially helpful when renal
  • HbAlC levels 15 thresholds are high or low.
  • a healthy individual will normally have an HbAlC level of about 4-5% of the total hemoglobin in the blood, whereas a poorly controlled diabetic may demonstrate HbAlC levels which are as much as 15% of the total hemoglobin.
  • hemoglobin is a molecule inherently colored with the he e moiety, it lends itself well to colorimet ⁇ ' c measurement.
  • the sample solution is added to the matrix in a volume sufficient to saturate an area of the matrix.
  • the total sample is then colorimetrically read by measuring the absorbence of the light passed through the filter matrix area containing the reactants. The measurement is recorded.
  • the matrix is incubated for a sufficient length of time to permit the HbAlC to bind to the antibody on or in the matrix. Preferentially, the incubation period should be of adequate duration to permit the antibody to bind substantially all of the HbAlC on or in the matrix; however, a controlled incubation time which permits binding a representative portion of the HbAlC is also satisfactory.
  • the filter matrix is subsequently washed with an appropriate solution to remove substantially all unbound hemoglobin and other unbound material.
  • a second absorbence reading is then taken of the HbAlC remaining in the filter matrix.
  • the ratio of the absorbence readings is proportional to the ratio of glycosylated hemoglobin to total hemoglobin in the sample.
  • concentration of HbAlC can, if necessary, be determined by applying the absorbence ratio to a separately determined measurement, employing a standard method.
  • HbS hemoglobin S
  • This inherited disease is caused by a defect of a single amino acid in the hemoglobin molecule.
  • Individuals who inherit this abnormal gene from only one parent are called heterozygous individuals possessing the sickle cell trait, and have erythrocytes (red blood cells) that contain only 25% - 45% HbS, exhibiting no abnormal health patterns.
  • Individuals who inherit the abnormal gene from both parents are ho ozygous, and have the sickle cell anemia disease.
  • Their erythrocyte population contains 75% or more of HbS.
  • the amount of HbS which is present is a prominent factor in determining the severity of the disease.
  • the amount of other abnormal hemoglobins or abnormal concentrations of normal hemoglobins can be determined as a fraction of total hemoglobin.
  • a noncolored nonabsorptive protein can be measured using a sensitive protein stain.
  • Lipoproteins are complexes or compounds containing lipid and protein. Almost all lipids in plasma are present as lipoproteins, are characterized by their densities, and can broadly categorized as high density lipoproteins (“HDL”) or low density liproproteins (“LDL”). Their presence in plasma is normal, but the ratio of LDL to total lipoproteins (“TLP”) has been shown to be an indication of the relative risk of coronary arterial disease, particularly coronary atherosclerosis. High LDL is a direct risk factor for such disease, because LDL is the major transport protein for cholesterol in plasma. The LDL:TLP ratio provides a better indication of increased risk than either measurement alone.
  • the present invention can determine the ratio of LDLrTLP by combining a serum sample and a mixture of at least two of monoclonal antibodies, one directed against LDL and another directed against HDL.
  • monoclonal antibodies are designed so that one of them is acid-switchable or acid-labile; i.e., the antibody dissociates from the antigen at a particular pH, while being associated to the antigen at a different pH.
  • monoclonal antibodies are designed for this purpose by screening hybridoma cell populations to isolate those clones which are acid sensitive at a certain pH. After incubating to facilitate immunological binding of LDL & HDL to their appropriate monoclonal antibody, the mixture is added to a filter matrix, which traps and immobilizes the immune complexes.
  • the monoclonal antibodies can be pre-immobilized on or within the filter in a delimited reaction area, to which is added the serum sample.
  • the reaction area washed with a neutral solution, e.g., pH 7.4, to remove unbound material from the reaction area.
  • the complexes are contacted with a sensitive specific stain which will color only the lipoprotein molecules.
  • a suitable stain or dye but not a limitation, is Sudan Black B, which is a diazo dye specific for fats and lipids.
  • Oil Red 0 is a weakly acidic diazo dye used to identify neutral fats. Neither stain will color the antibody.
  • a stain the need for a second antibody conjugated to a label is obviated.
  • an absorbence reading is taken of the reaction zone to determine the total amount of lipoprotein present (LDL plus HDL).
  • the reaction zone is subsequently washed again, this time with an appropriate solution having a lower pH, such as pH 4.0, which causes the acid switchable monoclonal antibody to dissociate from its bound component, either LDL or HDL. In this manner either LDL or HDL will remain not both, depending on which is bound to the acid sensitive monoclonal antibody.
  • Staphylococcus Protein A can be used to bind to the complexes formed of LDL and an appropriate labelled monoclonal antibody, and, HDL and an appropriate labelled monoclonal antibody.
  • one of the antibodies can be IgG2a and the other could be IgG2b .
  • Protein A is an unique property of Protein A is that at a pH greater than 4.5 it forms a stable con.plex with IgG2a and IgG2b, but at a pH less than 3.5 IgG2a dissociates from Protein A, thereby permitting its removal from the reaction area with the correlative decrease of label present, a means for detecting the amount of LDL or HDL present as the remaining monoclonal antibody complex still bound to the, Protein A is provided.
  • the analyte can be any substance that is inherently colored or capable of being colored. By colored it is meant that the analyte, or molecule attached thereto, is capable of being quantified by colorimetric means.
  • Naturally colored materials which exist in the body include hemoglobin, ferritin, cytochrome C, and the like. Hemoglobin is perhaps the most commonly analyzed fluid in the body, and the hemoglobin molecule can provide the basis for a quantitative absorbence measurement.
  • the analyte is a protein, or of a proteinaceous structure. The amino acid structure of noncolored proteins has been well researched, and many methods have been developed to stain, dye or otherwise color proteins. Generally, these methods involve the covalent or ionic bonding of a dye or staining molecule, such as bromocresol green or Biuret's reagent, where the intensity of the color is proportional to the amount of compound it is bound to.
  • Other substances include drugs, hormones, vitamins, enzymes, antibodies, polysaccharides, bacteria, protozoa, parasites, fungi, viruses, cell and tissue antigens, and the like.
  • Samples can be obtained from any of the biological fluids commonly used for analysis such as but not limited to, whole blood, serum or plasma, saliva, feces, sputum, mucus, cerebral spinal fluid, urine, pus, wound exudate, cell or tissue extracts, and the like. It is preferable that the sample not contain extraneous undesirable colored matter which might interfere with an accurate absorbence measurement of the colored analyte.
  • Colorimetry is a convenient and accurate means of measuring the optical density, also called the absorbence, of a solution. If light is passed through a solution containing a colored compound, certain wavelengths are selectively absorbed. The resultant color observed is due to the transmitted light. Measuring light absorption aids scientists in both the identification and quantification of substances. The amount of absorption of a compound at a given wavelength is a function of compound concentration.
  • the assay of the present invention is conducted using a solid phase medium that will lend itself to colorimetry.
  • a preferred embodiment employs a filter matrix material that is inert, porous and light transmitting.
  • Glass fiber filter paper is convenient, inexpensive and reliable, but other materials such as nitrocellulose, paper, polymeric or other plastics, and the like, as well as other structures such as beads or particles, wells, tubes, and the like, are usable so long as they are inert, porous and light transmitting.
  • a filter matrix will be described as an illustration of a solid support surface.
  • the matrix is three-dimensional wherein the interstitial voids therein define and can hold a volume.
  • the mixture will generally fill the void volume of the matrix and the volume of the mixture in unit area of the matrix will be defined by the void volume. In this manner, an absorbence reading can be taken of a constant volume retained by the matrix, thereby affording reproducible results.
  • the analyte being measured is preferentially immobilized and retained within the matrix by trapping or binding to the matrix a capture antibody directed against the analyte of interest prior to or concurrent with the addition of sample containing the analyte.
  • a capture antibody directed against the analyte of interest prior to or concurrent with the addition of sample containing the analyte.
  • the antibody recognizes the particular spatial and polar configuration on the analyte molecule, called an idiotypic determinant or an epitope.
  • the antibody is useful in an assay for quantifying one component contained in a solution of any components.
  • Monoclonal antibodies provide even greater selectivity and specificity because of their unique structure and properties. Moreover, monoclonal antibodies can be designed to recognize only one specific protein whereas a polyclonal antibody will cross-react with proteins that are similar yet not identical in structure. Monoclonal antibodies are prepared according to the method described by Milstein and Kohler in Nature 256:495-497, 1975. The method is well known and need not be reviewed here. The filter matrix is washed with a relatively colorless solution such as but not limited to water, salt solution, buffer, detergent and the like, and the material not bound to the immobilized antibody is removed and replaced by the colorless wash solution. During this process the volume of liquid contained in the matrix remains relatively constant and equal to the matrix void volume.
  • a relatively colorless solution such as but not limited to water, salt solution, buffer, detergent and the like
  • a blocking agent such as gelatin, serum, B.S.A., skim milk, egg albumin, Tween-20, or the like, can be added to the solid support surface.
  • ratioing method be applicable to a broad range Of analytes and systems where a measurement of the proportion of component to total sample is required.
  • HbAlC glycosylated hemoglobin
  • glass fiber filter paper Micro Filtration Systems D
  • a second reading of the absorption of the reaction area is taken as an indication of the amount of HbAlC present that has bound to the immobilized monoclonal antibody.
  • the ratio of absorbencies of HbAlC to total hemoglobin is calculated and the per cent of HbAlC present in the patient is thereby obtained.
  • Staphylococcus Protein A is first immobilized on a filter matrix.
  • a specimen containing HbF is mixed at neutral pH with fluorescin-labeled mouse IgG2b monoclonal antibody directed against HbF and fluorescein-labeled mouse IgG2a monoclonal antibody cross-reacti e with all hemoglobin antibody.
  • the mixture is allowed to incubate to permit binding of antibody to hemoglobin until equilibrium is reached.
  • the reaction mixture is then added to a delimited area of the filter matrix containing the immobilized Protein A and incubated so as to permit binding of Protein A to the Fc portion of IgG2a and IgG2b.
  • the reaction zone is then washed with a 0.05M Tris buffered saline solution ("TBS") at pH 7 to remove unbound material.
  • TBS Tris buffered saline solution
  • the reaction zone is read for the amount of fluorescent signal generated.
  • the reaction zone is washed with TBS at pH 4.0 to elute out IgG2a:total hemoglobin complex.
  • the reaction zone is again read for the remaining amount of fluorescent signal associated with the IgG b: HbF remaining bound to immobilized Protein A. From these two measurements the ratio of the second measurement correlative with the amount of Hb ) to the first measurement (correlative with total hemoglobin) produces the relative amount of HbF present in the specimen.
  • a specimen containing LDL is combined at neutral pH with a mixture of a monoclonal antibody directed against LDL and a monoclonal antibody cross-reactive with all lipoprotein.
  • the latter monoclonal antibody is selected so as to be acid switchable; i.e., the antibody binds with the analyte in a neutral pH range, while it will dissociate from the analyte within, an acidic pH range.
  • the mixture is incubated to permit immunological binding to occur.
  • the resultant reaction mixture is added to glass fiber filter paper (Micro Filtration Systems, Dublin, California) in a delimited area. Subsequently, an effective amount of Sudan Black B stain is added to the reaction zone so as to stain the lipoprotein present.
  • the area is washed with neutral pH buffer solution to remove unbound material. Colorimetric reading is taken of the reaction area to measure the absorbence of the material immobilized therein. Then, a buffer solution at about pH 4.5 is added to facilitate the dissociation and elutin of the acid switchable monoclonal antibody and the lipoprotein bound thereto. A second absorbence reading is taken of the reaction zone to measure the remaining stained LDL bound to the immobilized monoclonal antibody. From the two readings the amount of LDL to total lipoprotein (or LDL:HDL) can then be calculated.

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Abstract

Procédé permettant de déterminer la quantité relative d'un constituant d'un analyte donné présente dans un échantillon, ledit analyte étant composé d'au moins deux constituants. Le procédé comporte les étapes suivantes: (a) insolubilisation d'un anticorps dirigé contre ledit constituant sur un matériau support solide dans une zone délimitée qui définit une zone de réaction; (b) mise en contact avec ledit anticorps insolubilisé d'un échantillon contenant ledit analyte de manière que sensiblement la totalité dudit constituant adhère audit anticorps, alors que l'échantillon est retenu sur ou à l'intérieur de ladite zone de réaction; (c) lecture de la zone de réaction afin de déterminer la quantité relative présente; (d) lavage de ladite zone de réaction pour éliminer seulement l'essentiel du matériau non lié audit anticorps; (e) lecture de ladite zone de réaction afin de déterminer la quantité relative de constituants restants liés audit anticorps; (f) calcul, à l'aide desdites lectures, du rapport quantitatif entre ledit constituant et ledit analyte.
PCT/US1987/000569 1986-04-11 1987-03-19 Immuno-annalyse de mesure colorimetrique de proportionnalite WO1987006345A1 (fr)

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US850,966 1986-04-11

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008485A1 (fr) * 1989-12-01 1991-06-13 Pb Diagnostic Systems, Inc. Immunoanalyse pour la detection des anticorps aux agents de maladies infectieuses
WO1992004961A1 (fr) * 1990-09-26 1992-04-02 Immunicon Corporation Appareil et procedes de separation magnetique
US6013532A (en) * 1990-09-26 2000-01-11 Immunivest Corporation Methods for magnetic immobilization and manipulation of cells
WO2008106021A1 (fr) * 2007-02-26 2008-09-04 Response Biomedical Corporation Dosage comparatif de multiples analytes
CN119804871A (zh) * 2025-03-13 2025-04-11 北京众驰伟业科技发展有限公司 一种基于常规凝血试剂的狼疮抗凝物检测系统及方法

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US4168147A (en) * 1977-12-02 1979-09-18 Isolab, Inc. Method to determine a diagnostic indicator of blood sugar condition, and, a liquid chromatographic microcolumn therefor
US4189304A (en) * 1978-10-27 1980-02-19 Miles Laboratories, Inc. Device and method for detecting myoglobin
US4230685A (en) * 1979-02-28 1980-10-28 Northwestern University Method of magnetic separation of cells and the like, and microspheres for use therein
FR2455743A1 (fr) * 1979-05-02 1980-11-28 Goella Laboratoires Procede et dispositif pour le dosage des lipoproteines seriques
US4247533A (en) * 1978-05-01 1981-01-27 The Rockefeller University Hemoglobin A1c radioimmunoassay
US4407961A (en) * 1981-03-16 1983-10-04 Sanders James L Ion-exchange system and method for isolation and determination of glycosylated hemoglobin in human blood
US4474892A (en) * 1983-02-16 1984-10-02 Board Of Trustees Of The Leland Stanford Junior University Two-site immunoassays using monoclonal antibodies of different classes or subclasses and test kits for performing same
US4478744A (en) * 1982-01-25 1984-10-23 Sherwood Medical Company Method of obtaining antibodies
US4514505A (en) * 1982-05-21 1985-04-30 The Trustees Of Columbia University In The City Of New York Monoclonal antibody mixtures and use thereof for enhanced sensitivity immunoassays
US4544630A (en) * 1982-03-08 1985-10-01 Boehringer Mannheim Gmbh Process for specific determination of cholesterol in the presence of the HDL fraction in serum
US4619895A (en) * 1984-05-10 1986-10-28 The Regents Of The University Of California Lipoprotein marker for hypertriglyceridemia
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US4247533A (en) * 1978-05-01 1981-01-27 The Rockefeller University Hemoglobin A1c radioimmunoassay
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US4514505A (en) * 1982-05-21 1985-04-30 The Trustees Of Columbia University In The City Of New York Monoclonal antibody mixtures and use thereof for enhanced sensitivity immunoassays
US4474892A (en) * 1983-02-16 1984-10-02 Board Of Trustees Of The Leland Stanford Junior University Two-site immunoassays using monoclonal antibodies of different classes or subclasses and test kits for performing same
US4619895A (en) * 1984-05-10 1986-10-28 The Regents Of The University Of California Lipoprotein marker for hypertriglyceridemia

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Title
CHEMICAL ABSTRACTS, Vol. 97, No. 7, issued 16 August 1982 (Columbus, Ohio, USA), Laboratories Goella, S.A., "Device and Methods for Measuring Blood Lipoprotein", see page 317, column 1, the Abstract No. 97:52156c; & FR,A,2455743, 28 November 1980. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008485A1 (fr) * 1989-12-01 1991-06-13 Pb Diagnostic Systems, Inc. Immunoanalyse pour la detection des anticorps aux agents de maladies infectieuses
WO1992004961A1 (fr) * 1990-09-26 1992-04-02 Immunicon Corporation Appareil et procedes de separation magnetique
US5200084A (en) * 1990-09-26 1993-04-06 Immunicon Corporation Apparatus and methods for magnetic separation
US5876593A (en) * 1990-09-26 1999-03-02 Immunivest Corporation Magnetic immobilization and manipulation of biological entities
US6013532A (en) * 1990-09-26 2000-01-11 Immunivest Corporation Methods for magnetic immobilization and manipulation of cells
WO2008106021A1 (fr) * 2007-02-26 2008-09-04 Response Biomedical Corporation Dosage comparatif de multiples analytes
US7875433B2 (en) 2007-02-26 2011-01-25 Response Biomedical Corporation Comparative multiple analyte assay
CN119804871A (zh) * 2025-03-13 2025-04-11 北京众驰伟业科技发展有限公司 一种基于常规凝血试剂的狼疮抗凝物检测系统及方法

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