WO1989006792A1 - Procede et appareil de determination d'un analyte - Google Patents

Procede et appareil de determination d'un analyte Download PDF

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Publication number
WO1989006792A1
WO1989006792A1 PCT/US1988/004702 US8804702W WO8906792A1 WO 1989006792 A1 WO1989006792 A1 WO 1989006792A1 US 8804702 W US8804702 W US 8804702W WO 8906792 A1 WO8906792 A1 WO 8906792A1
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WO
WIPO (PCT)
Prior art keywords
analyte
zone
labeled
reaction
regulating means
Prior art date
Application number
PCT/US1988/004702
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English (en)
Inventor
Fern De-La-Croix
Original Assignee
Boehringer Mannheim 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 Boehringer Mannheim Corporation filed Critical Boehringer Mannheim Corporation
Publication of WO1989006792A1 publication Critical patent/WO1989006792A1/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
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/581—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with enzyme label (including co-enzymes, co-factors, enzyme inhibitors or substrates)
    • 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

Definitions

  • This invention relates to apparatus useful for determining one or more components in a sample, as well as methods for determining said components.
  • Dry chemistry refers to the apparatus used in the determinations, because the apparatus is dry to the touch. Generally, these apparatus take the form of monolayer and multilayer test strips and analytical test elements. These analytical devices have excellent storage and handling properties, and are convenient to use.
  • the determination of an analyte in a sample typically involves reacting the analyte with a reaction partner which undergoes some type of change following reaction, leading to a detectable signal. While the change may be caused directly by the reaction with the analyte, frequently this is not the case, as the change usually results from some property produced by the interaction between analyte and reaction product which does not exist in unreacted components.
  • a reaction partner which carries a label.
  • reaction, partner i's contained in a test strip or other apparatus in such a way that it is non-reactive unless and until its partner analyte contacts the test strip, in the form of a fluid sample.
  • the analyte and reaction partner bind to each other to form a complex, which must then be determined.
  • This is accomplished by reacting the label carried by the reaction partner with another substance so as to form a detectable signal.
  • the label is an enzyme, as it frequently is, the sub,stance used is a substrate for the enzyme which, upon reaction with the enzyme, either forms a visible color or changes color. Measuring the change or amount of color gives a measure of complex, and hence of analyte.
  • An immuno- enzymometric assay has an additional feature in that after the sample has contacted the labeled reaction partner and some of the latter has been bound, the mixture of complex and unreacted labeled reaction partner is contacted to a sample of analyte or an analyte analogue which also binds to the labeled moiety, but which is in solid phase form. This solid phase bound reactant binds to uncomplexed reaction partner, and removes it from the solution mixture. One then has a clean division of labeled partner bound to analyte, and excess labeled reaction partner bound to solid phase. Addition of substrate to either of these gives a color. If the amount of the labeled moiety with which one began is known, one measures the amount of signal either in the liquid phase, which gives a direct relationship to the amount of analyte, or in the solid phase, which provides an indirect relationship.
  • This type of assay involves two phases, and is thus called a heterogeneous assay.
  • a heterogeneous assay When performed using a test strip, one has the advantage of having labeled moiety, immobilized component, and reactive substance for the label all in one device. Fluid samples will diffuse through test strips, and thus the reactions will occur quickly and without the need for intervention by the investigator.
  • the immunoenzymometric assay is not the only type of assay used for these analytical systems.
  • a competitive assay uses, rather than labeled binding partner, a sample' of labeled analyte corresponding to the analyte being determined.
  • the solid phase bound reactant in these cases, is the reaction partner for the analyte and labeled analyte. If any of the analyte is in the sample, competition for the binding sites ensues.
  • Sandwich assays encompass a broad range of types of assays.
  • a sandwich assay refers to formation of a complex between the analyte being determined, a labeled, epitopically active fragment of a monoclonal antibody,
  • Baier, et al., U.S. Patent No. 4,670,383 teaches an immunoenzymometric assay system.
  • the assay involves adding an antibody (or fragment) which carries a label to a sample, and then addition of solid phase bound antigen to pick up excess labeled antibody. This first solid phase is removed. The liquid phase is left, and to this is added an antibody which binds either the first antibody, or to the antibody-antigen complex. It is this second step which allows for measurement of the amount of antigen in the sample.
  • Deutsch, et al. U.S. Patent No. 4,477,576 also involves a system similar to the Baier system.
  • the patent discloses a method whereby labeled antibody is added to an antigen containing system. Following this the sample is combined with solid phase bound antigen. Some labeled antibody binds in solution, and some to solid phase antigen. ⁇ The solid is then removed, and is immersed in a solution containing enzyme substrate. This results in a product forming which can be measured, and hence the amount of antigen may be determined.
  • Liotta U.S. Patent No. 4,446,232 teaches a device which can be used in competitive displacement or immuno ⁇ enzymometric assays.
  • the first part (or zone) of the device one has immobilized antigens, and labeled antibodies.
  • the antigen in the sample competes with the immobilized antigen for labeled antibody.
  • Those labeled antibodies which do not bind to the solid phase bound antigen diffuse into a second zone, where a means is present to form a detectable signal with the labeled antibodies.
  • test strips including one where a solid phase bound binding partner is used.
  • an immobilized form When an immobilized form is used, however, no provision is made for measuring anything in this system but the immobilized form. This is also the case in the disclosed "rate of flow" type of system, where an immobilized form is not used.
  • the '537 patent is directed to products.
  • Deutsch, et al. rely on differential rate of diffusion between complex and uncomplexed materials. Column 16, lines 7-13 of Deutsch, et al. (either one) show this in particular.
  • Deutsch, et al. require a retarding element (which can be the test paper itself) , which slows capillary transport of • a "moving element".
  • the "moving element” is one of either the reaction product (i.e., the complex), or the first reagent (i.e., the label).
  • “Slowing" of one to separate two implies that both are moving.
  • Deutsch, et al. lacks a solid phase bound partner which removed substances from solution phase.
  • Mochida, et al. U.S. Patent No. 4,200,436 describes an assay using a Fab or Fab' fragment which carries a label and then binds to an analyte in a sample. The complexes are separated from uncomplexed Fab, e.g., using a solid phase. Mochida, et al. does disclose the possibility of measuring non-solid phase bound material. This is done by adding a substrate which reacts with the label. There is no teaching or suggestion of a separation means or of a flow regulator.
  • U.S. Patent No. 4,144,306 teaches an analytical device which contains a "reagent layer” containing a "non-diffusable material” which is a “detectable moiety” and which reacts with an analyte.
  • a "reagent layer” containing a "non-diffusable material” which is a “detectable moiety” and which reacts with an analyte.
  • This can be, e.g., a labeled antibody.
  • the non-diffusable material reacts with the sample, it becomes diffusible and moves to a second layer where it can be detected (the "registration layer”).
  • Measurement can be made of material in either layer.
  • Behringwerke European Patent Application 186 799 teaches various test strips which can be used in different types of assays, including IEMAs ' , competitive, and sandwich assays. Its broadest claim sets forth an apparatus which contains a “mobile phase application zone” (“MPAZ”) an “adsorptive zone” (“AZ”) a “labeled reactant zone” (“RZ”), and a “solid phase z.one” (“SPZ”). The claims require a specific physical relationship among these four zones.
  • MPAZ mobile phase application zone
  • AZ an "adsorptive zone”
  • RZ labeleled reactant zone
  • SPZ solid phase z.one
  • pages 6 and 7 of the Behringwerke disclosure require that the reagent required for detection (i.e., the enzyme substrate), be added "after the separation stage” and "after the solid phase has been adequately washed". All of the discussion at pages 6-7 require a washing step, most certainly to remove uncomplexed label from the system. As the device is characterized by fluid contact between the various zones, washing the solid phase will result in the washing liquid removing everything uncomplexed. There is no possibility of ion exchange, e.g., in the Behringwerke disclosure.
  • the ⁇ array (sic) of the present invention is described as a homo ⁇ geneous array, in that no separation of bound and free specific binding pair substance is required.
  • This patent application is also directed to immobilizing non-reacted labeled material.
  • the '603 application immobilizes the material before a detectable complex forms, after which a substrate is added.
  • Test strips are frequently, if not always, comprised almost entirely of white paper. Light colors are lost against the white background, particularly when the amount of reacted substrate is small.
  • an object of the invention to provide an apparatus for determining one or more analytes in a fluid sample, which also allows for separation of one of a product of a label and its reaction component and unreacted reaction component to provide for improved analyte analyses.
  • Still another object of the invention is to provide various methods for determining one or more analytes in solution, using the apparatus described herein.
  • Figure 1 shows an embodiment of the invention using a separating means in the second zone.
  • Figure 2 shows an embodiment of the invention using both a separating means and a regulating means.
  • Figure 3 depicts an embodiment of the invention using a regulating means, but no separating means.
  • Figure 1 shows an embodiment of the invention which uses a means for separating mobile detectable moiety from unreacted reaction component.
  • the apparatus 10 includes a carrier foil 11, which is a backing for the additional components. This is generally, although not necessarily, made of plastic. Other than providing physical support to the strip, it has no other function.
  • An optional sponge 13 is provided. This feature of the device can be impregnated, with a buffer, and may receive the sample being analyzed. It will be understood, however, that the sample may be introduced at other positions in the device.
  • the first zone is positioned so that it receives sample which diffuses from sponge 13 when the sponge is used. If it is not, sample may be added directly to the first zone.
  • This zone 14 contains portions 15 and 16, corresponding to a conjugate pad 15, and a matrix 16. While this figure shows these as separate parts of the first zone, it will be understood by the skilled artisan that they may be of one piece, especially when a displacement assay is being run.
  • conjugate pad 15 contains the removable labeled analyte, labeled analyte analogue, or labeled reaction partner.
  • matrix 16 contains an immobilized form of a reactant.
  • the immobilized reagent is identical, or epitopically equivalent to the analyte being determined.
  • the immobilized component must be present in an amount sufficient to bind essentially all of the labeled conjugate present in 15. This is necessary to provide for the situation where the sample contains none of the analyte being analyzed.
  • the immobilized reagent binds to both analyte and labeled analyte. Again, there must be sufficient solid phase bound reagent such that if there is no analyte present, essentially all of the labeled analyte is reacted. In a displacement assay, it will be understood that 15 and 16 will, of necessity, be of one piece because the immobilized reagent will already have bound to it the labeled analyte or analyte analogue.
  • the second zone 19 contains two parts, but this is not necessarily so.
  • substrate pad 18 contains a substrate which reacts with the"label on the labeled component to form a detectable signal. This may be, but need not be, an enzyme substrate.
  • Trapper pad 20, which is key to the invention, is in fluid contact with the substrate pad 18, or, if 18 and 20 constitute one piece, this one piece second zone is in fluid contact with the first zone.
  • the - trapper pad contains a means, such as ionic exchange paper, which traps either the reaction product of the label and substrate, or unreacted substrate.
  • the waste pad 22 which is adapted for receiving excess fluid. Further, it absorbs any materials which may be removed when the test strip is washed.
  • the waste pad 22 can, alternatively, be used as a measuring point. When separation of detectable moiety and unreacted reaction component takes place in the second zone, the element which is not trapped can be washed into the waste pad. This element, rather than the trapped element, can be measured as well as, or in preference to, the trapped element.
  • FIG. 2 Another embodiment is shown in Figure 2. This embodiment is identical to that shown in Figure 1, except that it adds regulating means 22 to the device 21.
  • the regulating means may contain substances, such as a buffer, which help to regulate flow of the analyte containing sample.
  • Component 22 may be placed at various points in the apparatus. For example, it may be positioned in the first zone itself, such as between 15 and 16 of Figure 2; it may be between 16 and 18 in this figure, in the second zone, for example, by being positioned between Figures 18 and 20, or even at the end of the second zone and before the waste pad.
  • the regulating means can be made of various substances, such as paper which possesses capillarity properties which differs from at least one of its neighbors.
  • Figure 3 shows yet another of the various embodiments encompassed by this invention.
  • the embodied device 31 is identical to that of Figure 2, but it lacks the trapper zone 20.
  • the device depicted here regulates flow of sample therethrough, with concentration of detectable moiety or unreacted reaction component.
  • the apparatus shown in Figures 1-3 are all usable for determining one or more analytes in any sample to be analyzed. For example, if the analysis being undertaken is to determine the presence of illicit drugs, a urine sample is taken from the subject and either sponge 13 is dipped therein, or an amount.of urine is added directly to the conjugate pad 15. The dose is small. When urine, e.g., is added directly to the first zone, 50 1 is sufficient. When the sponge is used, this generally holds about 1 ml.
  • additional material such as a "run buffer” or a washing solution may be used.
  • this material may be added at the same point as the sample or at some different point or points in the apparatus.
  • the sample diffuses through 13 and 17, as provided in the device, until it reaches first zone component 15.
  • first zone component 15 the sample encounters enzyme labeled antibodies against the drug or drugs to be identified. If more than one drug is being assayed, each type of antibody may carry a different label but need not. Reactions occur between whatever drugs are present in the sample and the labeled antibodies. These complexes, plus any uncomplexed labeled antibody flows to that portion of the first zone 16 which contains immobilized reagents, in this case, immobilized drug or drugs which correspond to those being assayed.
  • the immobilized drugs react with the uncomplexed antibodies, removing these from solution.
  • the complex of drugs and labeled antibodies flow into the second zone, where substrate reacts with any label carried therein. If a separating means is employed, as in Figures 1 and 2, this acts either to separate * the reaction product of label and substrate from unreacted substrate, or unreacted substrate from the reaction product.
  • additional systems of substrate and enzyme are provided, each of which can be reacted and separated differentially.
  • One determines either reaction product or unreacted substrate in either the waste pad or the second zone. The determination step can be preceded by a washing step, if appropriate.
  • test strips can be used to determine substances like glucose, various enzymes such as alpha amylase, and so forth.
  • a test strip is prepared for analysis of thyroxin (T4) in a fluid.
  • the test strip is configured as is the device of Figure 2.
  • the first zone contains antibodies to T4 labeled with the enzyme beta-galactosidase (4U/ml) , and T4-succinimide ester which is immobilized onto CnBr activated paper (3512, Schleicher and Schuell) .
  • the regulating means contains phosphate buffered saline (PBS) on Whatman 54 paper, and chlorophenol-red-beta-D-galacto- pyranoside (CPRG) , a substrate for beta galactosidase, is impregnated into the second zone, together with an ion exchange trap (DE81, Whatman paper) .
  • CPRG when unreacted, is yellow.
  • the reaction product is purple; however, when a separating means such as the ion exchange paper is not used, the resulting mixture of reaction product and unreacted CPRG is a muddy brown color. Neither the purple color indicative of the reaction nor the yellow color showing unreacted substrate is easily discernable.
  • the ion exchange paper is used, however, the purple color of the reaction product is concentrated and discernable from the yellow CPRG. If desired, unreacted yellow can be removed in a washing step.
  • a test device is prepared to determine phenobarbital in a biological fluid.
  • the first zone contains antibodies to phenobarbital conjugated to horseradish peroxidase, and immobilized phenobarbital-succinimide ester, on CnBr activated paper as in Example 1.
  • the second zone contains the horseradish peroxidase substrate vanillin azine (0.5 mg/ml) which, in unreacted form, is yellow.
  • the trap is designed to pick up unreacted vanillin azine, but to pass the reaction product of horseradish peroxidase and vanillin azine, which is purple, into the waste zone.
  • This example uses the device shown in Figure 3, and is designed for the determination of human chorionic gonadotropin (hCG) , a pregnancy hormone.
  • hCG human chorionic gonadotropin
  • a conjugate of hCG specific antibody and beta galactosidase is incorporated into the first zone, together with hCG immobilized onto CnBr activated paper.
  • the flow regulating means contains PBS, and the second zone contains resorufin-beta-D-galactopyranoside. Those complexes of hCG and conjugate which flow to the second zone react with the resorufin substrate forming an observable fuschia color.
  • the particular materials used for the flow regulating means or the separating means can and will vary. Different factors, such as the substrate used, the analyte being assayed, and the label determine what materials are used. Similarly, the substrate must be chosen so as to give some observable or detectable result when reacted with the label. Typically, the reaction is between an enzyme label and a substrate, but this is not the only, possibility.
  • the label can be a fluorescent substance, and the reactive component a substance which caps or quenches the fluorescence.
  • the label may itself be a-'cleavable -substance and the the reactive component a substance which performs the cleavage, leading to color formation.
  • the apparatus described supra comprises a plurality of zones, the first of which contains the reactive components for the analyte to be determined.- Depending on the test system being used, some facets of the zone may vary. Typically, this zone will contain at least one immobilized reagent which binds to the analyte or analyte being determined. Typically, this immobilized reagent is a member of an antigen-antibody complex. This need not always be the case, however, as this immobilized reagent may be, e,g., protein A, a streptavidin-bictin complex, or any of the materials familiar to the skilled artisan.
  • This zone also contains at least one of a labeled analyte, labeled analyte analogue, or labeled reaction partner for the analyte being determined.
  • a labeled moiety typically, is an enzyme, but this is not essential.
  • the label is, e.g., a fluorescent or radioactive substance, a portion of an enzyme which later binds to a complement to form a whole, operational enzyme, and other materials which will be recognized by the skilled artisan.
  • the label itself can be the same or different for the plurality of labeled moieties. This is so because, even if the reaction between label and reactive component is the same with formation of the same detectable moiety, the difference in the analyte means that the different substances may separate differently.
  • a flow regulating means is incorporated here, this means may be any substance which has flow properties which differ from any part of the device.
  • the flow regulating means may also have incorporated therein any of the various reagents described supra.
  • the second zone contains the reaction component which reacts with the label to form the detectable moiety.
  • this reaction component is an enzyme substrate, but it need not be, and attention is drawn to the foregoing discussion for other materials which may be used.
  • the separation means is preferably an ionic exchange means, such as ionic exchange paper, which has particular attraction for one of the detectable moiety or unreacted reaction component as compared to the other.
  • Different types of separation means can be used as well, such as materials which, in connection with the detectable moiety and unreacted reaction component, have different degrees of hydrophobic interaction with the two. It is important to recognize that the interaction between separating means and the substance which separates out need not be a "chemical reaction" in the classic sense, i.e., that the separated substance undergoes chemical reaction which somehow alters the substance.

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Abstract

Appareil de détermination d'un analyte dans un échantillon, et procédé de mise en oeuvre de cette détermination. L'appareil se caractérise par l'utilisation d'un dispositif (22) de régulation de l'écoulement qui permet de commander la progression normale d'une analyse dans la phase en solution.
PCT/US1988/004702 1988-01-21 1988-12-29 Procede et appareil de determination d'un analyte WO1989006792A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14631088A 1988-01-21 1988-01-21
US146,310 1988-01-21

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WO1989006792A1 true WO1989006792A1 (fr) 1989-07-27

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0397736A1 (fr) * 1988-01-21 1990-11-22 Boehringer Mannheim Corp Procede et appareil de determination d'un analyte.
EP0712495A1 (fr) * 1993-08-02 1996-05-22 Quidel Corporation Dispositif de titrage a flux lateral pour diagnostic medical et systeme d'extraction d'echantillons
EP1306673A1 (fr) * 2001-10-19 2003-05-02 Matsushita Electric Industrial Co., Ltd. Méthode d'essai de liaisons spécifiques et dispositif pour sa mise en oeuvre

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US4042335A (en) * 1975-07-23 1977-08-16 Eastman Kodak Company Integral element for analysis of liquids
US4094647A (en) * 1976-07-02 1978-06-13 Thyroid Diagnostics, Inc. Test device
US4189304A (en) * 1978-10-27 1980-02-19 Miles Laboratories, Inc. Device and method for detecting myoglobin
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US4446232A (en) * 1981-10-13 1984-05-01 Liotta Lance A Enzyme immunoassay with two-zoned device having bound antigens
US4459358A (en) * 1982-12-29 1984-07-10 Polaroid Corporation Multilayer element for analysis
US4615983A (en) * 1980-11-11 1986-10-07 Konishiroku Photo Industry Co., Ltd. Immunological measuring element
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USRE30267E (en) * 1975-06-20 1980-05-06 Eastman Kodak Company Multilayer analytical element
US4042335A (en) * 1975-07-23 1977-08-16 Eastman Kodak Company Integral element for analysis of liquids
US4094647A (en) * 1976-07-02 1978-06-13 Thyroid Diagnostics, Inc. Test device
US4248973A (en) * 1977-04-11 1981-02-03 Veb Arzneimittelwerk Dresden Capillary tube indicator for the determination of urea concentrations
US4233029A (en) * 1978-10-25 1980-11-11 Eastman Kodak Company Liquid transport device and method
US4189304A (en) * 1978-10-27 1980-02-19 Miles Laboratories, Inc. Device and method for detecting myoglobin
US4615983A (en) * 1980-11-11 1986-10-07 Konishiroku Photo Industry Co., Ltd. Immunological measuring element
US4446232A (en) * 1981-10-13 1984-05-01 Liotta Lance A Enzyme immunoassay with two-zoned device having bound antigens
US4459358A (en) * 1982-12-29 1984-07-10 Polaroid Corporation Multilayer element for analysis
US4744952A (en) * 1985-02-22 1988-05-17 Ogita Zen Ichi Test paper for determining the concentration of halogen ions by filter paper chromatography, and manufacturing process for and use of the same

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0397736A1 (fr) * 1988-01-21 1990-11-22 Boehringer Mannheim Corp Procede et appareil de determination d'un analyte.
EP0397736A4 (en) * 1988-01-21 1991-07-10 Boehringer Mannheim Corporation Apparatus for determining an analyte and method therefor
EP0712495A1 (fr) * 1993-08-02 1996-05-22 Quidel Corporation Dispositif de titrage a flux lateral pour diagnostic medical et systeme d'extraction d'echantillons
EP0712495A4 (fr) * 1993-08-02 1997-12-03 Quidel Corp Dispositif de titrage a flux lateral pour diagnostic medical et systeme d'extraction d'echantillons
EP1306673A1 (fr) * 2001-10-19 2003-05-02 Matsushita Electric Industrial Co., Ltd. Méthode d'essai de liaisons spécifiques et dispositif pour sa mise en oeuvre
CN100390542C (zh) * 2001-10-19 2008-05-28 松下电器产业株式会社 特异结合分析方法和使用该方法的装置
US7537731B2 (en) 2001-10-19 2009-05-26 Panasonic Corporation Specific binding analysis device
US8110147B2 (en) 2001-10-19 2012-02-07 Panasonic Corporation Method for analyzing an analyte qualitatively and quantitatively

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EP0389563A4 (en) 1991-01-23
EP0389563A1 (fr) 1990-10-03

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