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WO1996015453A1 - Procede et dispositif de dosage de proteines au moyen de reactions antigene/anticorps - Google Patents

Procede et dispositif de dosage de proteines au moyen de reactions antigene/anticorps Download PDF

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Publication number
WO1996015453A1
WO1996015453A1 PCT/IB1995/000999 IB9500999W WO9615453A1 WO 1996015453 A1 WO1996015453 A1 WO 1996015453A1 IB 9500999 W IB9500999 W IB 9500999W WO 9615453 A1 WO9615453 A1 WO 9615453A1
Authority
WO
WIPO (PCT)
Prior art keywords
membrane
protein
collector
body fluid
reactor
Prior art date
Application number
PCT/IB1995/000999
Other languages
English (en)
Inventor
Nisar A. Shaikh
Johan Jan Scharstuhl
Original Assignee
Spectral Diagnostics Inc.
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 Spectral Diagnostics Inc. filed Critical Spectral Diagnostics Inc.
Priority to AU37525/95A priority Critical patent/AU3752595A/en
Publication of WO1996015453A1 publication Critical patent/WO1996015453A1/fr

Links

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
    • G01N33/54387—Immunochromatographic test strips
    • G01N33/54388—Immunochromatographic test strips based on lateral flow
    • 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

  • This invention relates to a methods and devices for the separation of selected proteins from body fluids employing antigen/antibody reactions.
  • the devices of the present invention ar used for the separation of low density lipoproteins from whole blood.
  • Elevated plasma cholesterol and triglycerides levels are associated with increased risk for coronary disease.
  • elevated levels of low density lipoproteins (LDL) and decreased levels of high density lipoproteins (HDL) are described to be independent risk factors for premature coronary heart disease (CHD).
  • LDL refers to a group of heterogeneous particles (buoyant density greater than 1.019 Kg/L but less than or equal to 1.063 Kg/L) comprised of LDL+IDL (intermediate density lipoprotein or VLDL remmants) + Lp(a) fractions.
  • LDL cholesterol is effected as follows:
  • LDL Choi plasma or serum Choi, (after removal of VLDL & HDL fractions).
  • the only other technique that provides measurement of LDL directly is based upon specific removal of lipoprotein other than LDL from serum/plasma by affinity purified goat polyclonal antisera coated to latex particles.
  • serum or plasma is obtained by routine laboratory techniques and added to a small cup containing immunoseparation reagents. After brief incubation followed by cent ⁇ fugation, LDL is recovered and quantitated in the filtrate.
  • the methods and devices of this invention will be principally of interest in identifying and quantifying protein in blood and blood components such as plasma and serum. It is recognized however, that the invention is also applicable to other body fluids such as lymph, spinal fluid, synovial fluid, urine and saliva and to body fluid components other then proteins. For convenience, the invention will be described principally as applied to the analysis of blood
  • This invention provides a processes for identifying and quantitatively determining the amount of a selected protein in a sample of body fluid containing the protein together with contaminating products such as proteins.
  • the process is applicable, for example, and is particularly useful, for determining the presence and amount of LDL in blood in the presence of contaminants such as very low density lipoproteins (VLDL) intermediate density lipoproteins (IDL), HDL, and others
  • the body sample to be analyzed is passed through a series of laminated membranes which may be considered as two separate membrane units. Initially the units are not in contact with each other, but at the appropriate time they are brought into contact This arrangement permits control of the flow of the body fluid through the laminate for reasons which will be discussed in detail below.
  • the first unit comprises a separator membrane superimposed in capillary contact with a reactor membrane.
  • the second unit comprises a collector membrane superimposed on a capture membrane or as an extension of the capture membrane. Selected antibodies are appropriately distributed throughout the membrane structure for reasons hereinafter explained.
  • a number of structures can be designed to conduct the process of this invention.
  • the structure will include support means for the separate membrane units and means for bringing the units into contact when necessary to carry out the procedure of the invention.
  • Fig. 1 is a sketch showing the arrangement of the membranes of this invention.
  • Fig. 2 is a perspective view of a presently preferred test medical kit of the present invention, prior to assembly.
  • Fig. 3 is a perspective view of the test kit of Figure 2, after assembly.
  • Fig. 4 is a top plan view of the test kit of Figure 1 , after assembly.
  • Fig. 5 is an exploded view of the test kit of Figure 1 showing the arrangement of its parts.
  • Fig. 1 is a sketch showing the arrangement of the membranes as they are employed to carry out the process of this invention.
  • the membranes will always be in this or an equivalent configuration no matter how they are supported in a specific device.
  • 1 is an optional, coarse, filter membrane constructed of glass or other equivalent material. Its function is to assist in the removal of large particles such as red blood cells. It is not essential to the invention since in most instances the coarse particles can be removed by filtering the body fluid through the separator membrane 2.
  • the separator membrane 2 is a microporous, hydrophilic, asymmetric membrane the average pore size of which decreases from top to bottom.
  • the cells are indicated in the figure as 3.
  • the pore size at the top will generally be larger than the most coarse particle which is to be removed from the sample. Accordingly, the separator membrane will separate coarse particles by filtration. If the body fluid under analysis is blood, the body fluid passing into the reactor membrane 4 will be plasma containing all lipoproteins such as LDL and HDL and dissolved contaminants including carbohydrates such as glucose and proteins such as protein C.
  • the separator membrane 2 and the reactor membrane 4 comprise the first membrane unit.
  • the membranes are in capillary contact, more specifically the bottom surface of the separator membrane is in capillary contact with the top surface of the reactor membrane.
  • “Capillary contact” means that the membranes are in sufficient contact, usually complete, laminar surface contact, so that the fluid in one membrane flows into the adjacent membrane because of the influence of capillary forces induced by the hydrophillic properties of the membrane. In most instances, there will be complete contact throughout the total surface areas of the adjacent membranes maintained by the use of spot adhesives and contact pressure.
  • the function of the reactor membrane is to remove contaminating substances such as proteins which will interfere with the measurement to be performed. This is accomplished by immobilizing on the reaction membrane a sufficient number of selected antibodies so that substantially all of the contaminating materials react with them and thereby become immobilized or irreversibly bound to the reactor membrane.
  • the reactor membrane may carry any of a number of known antibodies to HDL, VLDL, IDL, cholesterol and the like. Many of types of these antibodies are known and readily available, some from commercial sources. These include, for example, anti APOAI, A2, E, C, anti HDL and the like. There will be no antibody to LDL in the reactor membrane with the result that the plasma containing LDL is free to flow into the collector membrane.
  • the second membrane unit as shown comprises a collector membrane 5 superimposed and in capillary contact with a capture membrane 6.
  • the second membrane unit is not initially in contact with the bottom surface of the reactor membrane. This is to allow sufficient incubation time for the antibodies in the reactor membrane to react with and bind the contaminating substances. This is normally from about 5 to 15 minutes, preferably 8 to 12 minutes. A 10 minute incubation period is usually selected.
  • the top surface of the collector membrane 5 is brought into capillary contact with the bottom surface of the reactor membrane 4, thus bringing them into position so that the fluid for analysis can flow by capillary attraction into the collector membrane 5 and from there into the capture membrane 6.
  • the fluid which passes from the reactor membrane 4 to the membrane 5 will be substantially free of contaminants and, if it is present, will contain the protein to be determined.
  • the collector membrane 4 will contain an antibody, preferably monoclonal, to the protein to be determined, suitably in excess, so that all of the said protein will react with the antibody to form a reaction product.
  • useful membranes are prepared from a mixture of hydrophilic and hydrophobic polymers.
  • Polysulfones, polyether sulfones and polyetheramides are useful as hydrophobic polymers.
  • Polyvinyl pyrolidones are useful as hydrophilic polymers.
  • Nitrocellulose polymers are also suitable.
  • the pore size in the separator membrane varies from about 20-30 ⁇ m at the upper surface to from about 1.8 to 3.0 ⁇ m at the lower surface.
  • the average pore size in the other membranes is from about 3 to 10 ⁇ m.
  • the LDL or other analyte to be determined will react with an epitope on the reversibly bound antibody to form a complex.
  • the antibody will be labelled so that the product formed will be a protein/labelled antibody complex. Suitable labels are well known and include, for example, gold or carbon particles or any of a variety of fluorescent or luminescent enzymes.
  • the capture membrane 6 contains immobilized bound antibodies at spaced segments 7, 8 and 9. These antibodies which are normally identical are selected to react with a second epitope on the analyte or protein to be determined.
  • a detectable product is formed in accordance with known art.
  • the detectable product is one which is visible to the naked eye.
  • the label may be selected so that the product is fluorescent, luminescent or is made visible by other means under light ranging from ultraviolet to infra red light.
  • concentration of bound antibodies in each of the segments 7 through 9 will, in the case of LDL be selected to indicate the amount of LDL in the sample.
  • concentrations of LDL conform to the following norms:
  • the capture membrane may contain a control segment 10. However, it is not necessary that it do so.
  • the control segment will contain an antibody which reacts with an antigen normally present in the sample to be analyzed but one which will not interfere with the principal reactions of the invention.
  • the reaction product should become detectable under the conditions of the invention. Hence, the bound antibody will normally be labelled.
  • Other control reagents are possible.
  • the control reaction is not necessarily an antigen/antibody reaction.
  • the process of this invention is applicable to very low volumes of body fluid. Only a few drops of blood or other body fluid, e.g. about 100 ul are necessary for the practice of this invention.
  • the invention Since the invention is designed for quantitative determinations, it is necessary that the volume of material in certain of the membranes be known. Accordingly, the dimensions of the reactor membrane 4 will be selected so that it will hold all of the sample delivered to it through the separator membrane 2. Since the reactor membrane 4 is, initially, separated from the collector membrane 5, the former may become saturated with the filtered body fluid under analysis, but the body fluid will not escape from the reactor membrane 4.
  • reaction inert washing fluid such as a buffer, for example a phosphate buffer.
  • the buffer is added in excess and, as a result, the fluid under analysis will flow through the elongated capture membrane 6 where the protein/labelled antibody complex, if present will react with the pre-spaced immobilized antibodies as explained above. Detection of the reaction provides a quantitative measure of the amount of analyte in the body fluid.
  • a number of devices are possible for the practice of this invention. All will comprise a unitary structure for initially retaining a first membrane unit in proximity to but out of contact with a second membrane unit and, after a selected time interval which will permit the contaminating substance to be bound to the reactor membrane, the first membrane unit is brought into contact with the second membrane unit. The first membrane unit is removed to permit a washing fluid to be passed through the collector membrane and the capture membrane to permit the flow of the body fluid to be analyzed through these membranes for the purposes described above.
  • the structures and function of the membranes comprising each membrane unit have also been described above.
  • FIGs 2 through 5 illustrate the presently preferred device for practicing the process of this invention.
  • the device includes a bottom member 11 which is rectangular in plan view.
  • the bottom member 1 1. and the other structural members may be produced from a number of commercially available materials, preferably "ADS" (acrylo-nitrile-butadiene-styrene trimer or polypropylene or polycarbonate.)
  • ADS acrylo-nitrile-butadiene-styrene trimer or polypropylene or polycarbonate.
  • the bottom member 11 has a flat base 12 and an upstanding flange 13 which runs along the edge of the base 12 on its four sides.
  • An elongated internal flange 14 forms an elongated rectangular cavity 15 for holding the second membrane unit 20 of the invention including the collector membrane 5 and the capture membrane 6.
  • a suitable size for the base is 0.5-inches high, 2.0 inches wide and 3.5 inches long.
  • a cover member 25 is adapted to fit over the second membrane unit 20 and is secured on the bottom member 11.
  • the cover member 25 has an arcuate end 26, an arcuate body portion 27, which may be rectangular, and two depressions 28A and 28B formed between the end 26 and the body portion 27.
  • the cover member 25 has a first elongated opening 29 adapted to receive a selected volume of the patients's blood or other sample to be analyzed. It has rounded ends.
  • a second elongated opening 30 (display window), which may be rectangular, within the cover member 25, permits the physician or other medical personnel, to view the detectable product formed by reaction between a protein/labelled antibody complex and a capture antibody.
  • a snap-in member 35 is adapted to be removably connected within the depressions 28 and 29.
  • the snap-in member 35 has an elongated opening 36 which is of the same size and shape as the opening 29 of the cover member 25.
  • An elongated funnel member 40 has a hollow nozzle portion 41 which fits through the opening 36.
  • An externally projecting rim 42 of the funnel member 40 mates with the top face 37 of the snap-in member 35 and prevents the funnel member from passing through the opening 36.
  • the first membrane unit 45 is positioned at the bottom of funnel 40 and is held by the tapered shape of the funnel nozzle portion 41 or is adhered thereto.
  • the taper of the funnel nozzle 41 is selected so that, initially, the funnel 41 sits loosely in the snap in member 35 so that the first member unit 45 is held in proximity to, but out of contact with the second membrane unit 20. At the end of the incubation period the funnel 41 is pushed further into the snap in member 35 so that the membrane units 20 and 45 are superimposed in capillary contact.
  • the snap in unit 35 containing the funnel 40 is removed and a sufficient quantity of washing liquid, suitably a phosphate or carbonate buffer is passed through the opening 29 onto the upper surface of the collector membrane 5 to wash all of the body sample into the capture membrane 6 wherein it moves by capillary action from the upstream end 42 towards the downstream end 43 so that the contained protein to be analyzed, if any is present as a protein/labelled antibody complex, will react with the capture antibody to form a detectable product.
  • the number of products formed will be a measure of the quantity of detectable protein in the sample.
  • the collector membrane is not necessarily separate from the capture membrane. It may be merely an extension thereof containing the labelled reversibly bound antibody to the protein to be determined. In that structure, the protein/labelled antibody complex forms upstream of the immobilized antibodies in the capture membrane and the second membrane unit of the invention in one element including a collector section and a capture section.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
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  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Investigating Or Analysing Biological Materials (AREA)

Abstract

On fait passer un échantillon biologique à analyser à travers une série de membranes stratifiées qui peuvent être considérées comme des unités membranaires séparées. La première unité comprend une membrane séparatrice placée sur une membrane de réaction en contact capillaire avec celle-ci. La seconde unité comprend une membrane collectrice placée sur une membrane de capture ou dans le prolongement de cette dernière. Initialement, les unités ne sont pas en contact les unes avec les autres, et sont mises en contact au moment opportun. Des anticorps sélectionnés sont répartis de manière appropriée dans la structure membranaire. Dans un mode de réalisation préféré, les dispositifs selon l'invention sont utilisés pour la séparation de lipoprotéines de faible densité du sang entier.
PCT/IB1995/000999 1994-11-14 1995-11-13 Procede et dispositif de dosage de proteines au moyen de reactions antigene/anticorps WO1996015453A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37525/95A AU3752595A (en) 1994-11-14 1995-11-13 Method and device for determination of proteins employing antigen/antibody reactions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33934694A 1994-11-14 1994-11-14
US08/339,346 1994-11-14

Publications (1)

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WO1996015453A1 true WO1996015453A1 (fr) 1996-05-23

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018439A1 (fr) * 1997-10-07 1999-04-15 Ucb Bioproducts, S.A. Dispositif d'essai pour la determination d'analytes dans un produit laitier liquide
BE1011487A3 (fr) * 1997-10-07 1999-10-05 Ucb Bioproducts Dispositif d'essai pour la determination d'analytes dans un produit laitier liquide.
WO2004090555A1 (fr) * 2003-04-02 2004-10-21 Cholestech Corporation Membranes adherentes conservant une porosite et une activite biologique dans un dispositif d'essai conçu pour mesurer le cholesterol serique associe a des lipoproteines haute densite
EP1482307A1 (fr) * 2002-03-01 2004-12-01 Matsushita Electric Industrial Co., Ltd. Biodetecteur
EP1530045A1 (fr) * 2003-11-04 2005-05-11 Cholestech Corporation Membranes et structures stratifiées contenant des réactifs et méthodes de leur préparation
US7582484B2 (en) 2002-01-18 2009-09-01 Cholestech Corporation High-density lipoprotein assay device and method
EP2112513A3 (fr) * 2008-03-27 2009-11-25 Sysmex Corporation Dispositif de test chromatographique
US7795038B2 (en) 2002-04-09 2010-09-14 Cholestech Corporation High-density lipoprotein assay device and method
US7824879B2 (en) 2007-01-09 2010-11-02 Cholestech Corporation Device and method for measuring LDL-associated cholesterol
EP2425247A1 (fr) * 2009-04-28 2012-03-07 Innovative Laboratory Technologies, Inc. Dispositifs de dosage immuno-chromatographique à écoulement latéral

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0336483A1 (fr) * 1988-03-29 1989-10-11 Primecare B.V. Procédé et dispositif de séparation d'un liquide corporel des particules dans ce liquide et trousse d'essai pour ladite séparation et analyse du liquide corporel
WO1991017441A1 (fr) * 1990-04-27 1991-11-14 Genzyme Corporation Determination d'analytes dans des fluides biologiques en presence de substances perturbant les analyses
WO1992001226A1 (fr) * 1990-07-05 1992-01-23 Unilever Plc Dispositif de dosage analytique pour analyses de liaison specifique
EP0525829A2 (fr) * 1988-12-19 1993-02-03 Roche Diagnostics GmbH Bande d'essai pour l'analyse d'un échantillon fluid utilisant une réaction de liaision spécifique entre deux membres d'une réaction de liaison bioaffinité
EP0597268A1 (fr) * 1992-10-13 1994-05-18 Bayer Corporation Dispositif et procédé pour l'analyse du HDL cholestérol dans le sang entier
EP0627627A1 (fr) * 1993-06-01 1994-12-07 Bayer Corporation Dispositif de mesure de lipoprotéine-cholésterol à basse densité

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0336483A1 (fr) * 1988-03-29 1989-10-11 Primecare B.V. Procédé et dispositif de séparation d'un liquide corporel des particules dans ce liquide et trousse d'essai pour ladite séparation et analyse du liquide corporel
US5240862A (en) * 1988-03-29 1993-08-31 X-Flor B.V. Process and device for the separation of a body fluid from particulate materials
EP0525829A2 (fr) * 1988-12-19 1993-02-03 Roche Diagnostics GmbH Bande d'essai pour l'analyse d'un échantillon fluid utilisant une réaction de liaision spécifique entre deux membres d'une réaction de liaison bioaffinité
WO1991017441A1 (fr) * 1990-04-27 1991-11-14 Genzyme Corporation Determination d'analytes dans des fluides biologiques en presence de substances perturbant les analyses
WO1992001226A1 (fr) * 1990-07-05 1992-01-23 Unilever Plc Dispositif de dosage analytique pour analyses de liaison specifique
EP0597268A1 (fr) * 1992-10-13 1994-05-18 Bayer Corporation Dispositif et procédé pour l'analyse du HDL cholestérol dans le sang entier
EP0627627A1 (fr) * 1993-06-01 1994-12-07 Bayer Corporation Dispositif de mesure de lipoprotéine-cholésterol à basse densité

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE1011487A3 (fr) * 1997-10-07 1999-10-05 Ucb Bioproducts Dispositif d'essai pour la determination d'analytes dans un produit laitier liquide.
CZ301093B6 (cs) * 1997-10-07 2009-11-04 Neogen Corporation (Michigan Corporation) Zpusob detekce analytu v tekutém mlécném produktu a testovací zarízení k provádení zpusobu
WO1999018439A1 (fr) * 1997-10-07 1999-04-15 Ucb Bioproducts, S.A. Dispositif d'essai pour la determination d'analytes dans un produit laitier liquide
US7582484B2 (en) 2002-01-18 2009-09-01 Cholestech Corporation High-density lipoprotein assay device and method
EP1482307A1 (fr) * 2002-03-01 2004-12-01 Matsushita Electric Industrial Co., Ltd. Biodetecteur
EP1482307A4 (fr) * 2002-03-01 2006-05-03 Matsushita Electric Ind Co Ltd Biodetecteur
US7795038B2 (en) 2002-04-09 2010-09-14 Cholestech Corporation High-density lipoprotein assay device and method
US7195921B2 (en) 2003-04-02 2007-03-27 Cholestech Corporation Adhered membranes retaining porosity and biological activity
WO2004090555A1 (fr) * 2003-04-02 2004-10-21 Cholestech Corporation Membranes adherentes conservant une porosite et une activite biologique dans un dispositif d'essai conçu pour mesurer le cholesterol serique associe a des lipoproteines haute densite
EP1530045A1 (fr) * 2003-11-04 2005-05-11 Cholestech Corporation Membranes et structures stratifiées contenant des réactifs et méthodes de leur préparation
US7824879B2 (en) 2007-01-09 2010-11-02 Cholestech Corporation Device and method for measuring LDL-associated cholesterol
EP2112513A3 (fr) * 2008-03-27 2009-11-25 Sysmex Corporation Dispositif de test chromatographique
EP2425247A1 (fr) * 2009-04-28 2012-03-07 Innovative Laboratory Technologies, Inc. Dispositifs de dosage immuno-chromatographique à écoulement latéral
EP2425247A4 (fr) * 2009-04-28 2013-01-23 Innovative Lab Technologies Inc Dispositifs de dosage immuno-chromatographique à écoulement latéral

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