WO1986001900A1 - Vat for immunoenzymologic dosing - Google Patents

Vat for immunoenzymologic dosing Download PDF

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Publication number
WO1986001900A1
WO1986001900A1 PCT/FR1985/000238 FR8500238W WO8601900A1 WO 1986001900 A1 WO1986001900 A1 WO 1986001900A1 FR 8500238 W FR8500238 W FR 8500238W WO 8601900 A1 WO8601900 A1 WO 8601900A1
Authority
WO
WIPO (PCT)
Prior art keywords
antigen
antibody
vat
immunoenzymologic
dosing
Prior art date
Application number
PCT/FR1985/000238
Other languages
French (fr)
Inventor
Dominique Bon
Michel Delaage
Paul Prince
Original Assignee
Immunotech
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 Immunotech filed Critical Immunotech
Publication of WO1986001900A1 publication Critical patent/WO1986001900A1/en
Priority to FI861997A priority Critical patent/FI861997A0/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • 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

Definitions

  • a good method of separating the free conjugate from that linked to the antibody consists in fixing the antibody in advance on a solid support.
  • a variant of this process consists in having an antigen fixed to a solid support (Agf) and an antibody-enzyme conjugate (AcE) ' .
  • the antigen to be assayed competes with the fixed antigen for binding to the labeled antibody.
  • the enzymatic activity associated with the solid phase (CfE) is measured at the end of the incubation. Again, this activity is a decreasing function of the amount of antigen:
  • the enzymatic activity associated with the solid support CfE is measured, which then presents itself as an increasing function of the quantity of antigen to be assayed.
  • the most used enzymes are:
  • the revelation of the enzymatic activity is generally a colored reaction which develops on contact with the solid phase. and diffuses into the solution.
  • the enzymatic activity 5 can also be revealed using a substrate forming a product which is deposited on a surface by modifying the optical properties, in particular, the reflectivity or the refractive index ( see for example European Patent No. 0112721). This situation has so far remained difficult to reconcile with the direct measurement of an optical density.
  • the solutions adapted to this problem are:
  • Io (x) intensity of incident light
  • l (x) optical path.
  • the invention overcomes the above-mentioned drawbacks and targets a cell for the immunoenzymological assay by direct measurement of the optical density of a solution contained in this cell which is characterized in that it comprises at least two transparent planar faces which are parallel to each other and that at least part of its internal face carries a coating based on antigen or antibody 15 fixed by any suitable means such as, for example, that described in the application for French patent n ° 83 05618.
  • planar and parallel faces are spaced one centimeter apart.
  • a tank according to the invention is used in the following manner:
  • a sample of the solution to be analyzed is introduced; upon contact with the coated surface, a specific immunological reaction occurs, which reaction can be detected by means of an enzyme conjugate which either competes or sandwiches with the substance to be assayed. After an appropriate incubation time, the solution is eliminated and replaced by a specific substrate solution of the enzyme used, providing a coloration, the intensity of which is measured directly between the two parallel faces of the tank 30 with a light ray of suitable wavelength.

Abstract

Vat for the immunoenzymologic dosing by directly measuring the optical density of a solution contained in said vat which is characterized in that it comprises at least two transparent planar faces parallel to each other, at least a portion of its inner surface carrying an antigen or antibody coating fixed by any appropriate means.

Description

CUVE POUR DOSAGE IMMUNOENZYMO OGIQUEIMMUNOENZYMO OGIQUE DOSAGE TANK
Les méthodes de dosage dites immunoenzy- ologiques représentent actuellement un des domaines les plus prometteurs de l'analyse biologique et du diagno-stic. Elles consistent, brièvement, à combiner les avantages de la réaction antigène-anticorps, très spécifique, et de la mesure des activités enzymatiques, très sensible et qui dispense du recours aux isotopes radioactifs. Ces méthodes relèvent de l'un ou l'autre des deux types suivants: 1. La compétition : - L'antigène à doser (Ag) est fixé à l'anticorps (Ac) et forme le complexe (C) . Il est mis en compétition avec un conjugué antigène-enzyme (Ag-E) . Après incubation, on procède à la séparation du conjugué libre et fixé à l'anticorps et l'on mesure l'activité enzymatique de l'une ou l'autre fraction. La quantité d'enzyme associé à l'anticorps (CE) est donc une fonction décroissante de la quantité d'antigène à doser :So-called immuno-enzymatic assay methods currently represent one of the most promising fields of biological analysis and diagnosis. They consist, briefly, in combining the advantages of the antigen-antibody reaction, very specific, and the measurement of enzymatic activities, very sensitive and which dispenses with the recourse to radioactive isotopes. These methods fall under one or the other of the following two types: 1. Competition: - The antigen to be assayed (Ag) is attached to the antibody (Ac) and forms the complex (C). It is put in competition with an antigen-enzyme conjugate (Ag-E). After incubation, the free conjugate fixed to the antibody is separated and the enzymatic activity of one or the other fraction is measured. The amount of enzyme associated with the antibody (CE) is therefore a decreasing function of the amount of antigen to be assayed:
Ac -+ Ag ( C Ac + Ag - E 1— * CEAc - + Ag ( C Ac + Ag - E 1— * CE
Une bonne méthode de séparation du conjugué libre de celui lié à l'anticorps consiste à fixer l'anticorps à l'avance sur un support solide. - Une variante de ce procédé consiste à disposer d'un antigène fixé à un support solide (Agf) et d'un conjugué anticorps-enzyme (AcE)'. L'antigène à doser entre en compétition avec l'antigène fixé pour la liaison à l'anticorps marqué. On mesure l'activité enzymatique associée à la phase solide (CfE) à la fin de l'incubation. A nouveau, cette activité est une fonction décroissante de la quantité d'antigène :A good method of separating the free conjugate from that linked to the antibody consists in fixing the antibody in advance on a solid support. - A variant of this process consists in having an antigen fixed to a solid support (Agf) and an antibody-enzyme conjugate (AcE) ' . The antigen to be assayed competes with the fixed antigen for binding to the labeled antibody. The enzymatic activity associated with the solid phase (CfE) is measured at the end of the incubation. Again, this activity is a decreasing function of the amount of antigen:
Agf + AcE 5 > CfE Ag + AcE * .» CE 2. Les techniques "sandwich" :Agf + AcE 5> CfE Ag + AcE *. " THIS 2. Sandwich techniques:
On dispose de 2 anticorps (au moins), l'un d'entre eux est fixé à un support'solide Ac.f, l'autre est conjugué à l'enzyme Ac-E. L'antigène réagit avec l'un et l'autre anticorps, réalisant un pont entre eux ; le complexe ternaire est appelé sandwich :It has 2 antibody (at least) one of them is attached to a carrier solid Ac.f, the other is conjugated to the enzyme Ac-E. The antigen reacts with both antibodies, bridging them; the ternary complex is called a sandwich:
ACjf + Ag + Ac2E ~~l cfEAC j f + Ag + Ac 2 E ~~ l cfE
On mesure l'activité enzymatique associée 0 au support solide CfE qui se présente alors comme fonction croissante de la quantité d'antigène à doser.The enzymatic activity associated with the solid support CfE is measured, which then presents itself as an increasing function of the quantity of antigen to be assayed.
Ces procédés sont bien connus et ont donné lieu à de nombreuses réalisations commerciales. L'état de 5 la question est bien résumé par de nombreux ouvrages tels que "Enzyme-Immunoassay, Edward T. Maggio, 1980, CRC Press, Inc. USA" et "Enzyme-Immunoassây,. Eiji Ishikawa, M.D.," Ph.D., Tadashi Kawai, M.D. , Ph.D., Kiyoshi Miyai, M.D. Ph.D., .198.1.., Igaku-Shoin, Tokyo-New-York". 0 Ces procédés, et notamment ceux qui ont donné lieu à une réalisation commerciale, sont caractérisés par le fait que l'un des partenaires de la réaction (soit antigène, soit anticorps) est fixé sur une phase solide, et qu'à la fin de l'incubation, une partie de l'activité 5 enzymatique se trouve associée à la phase solide sur laquelle elle est mesurée.These processes are well known and have given rise to numerous commercial achievements. The state of the question is well summarized by numerous works such as "Enzyme-Immunoassay, Edward T. Maggio, 1980, CRC Press, Inc. USA" and "Enzyme-Immunoassay, Eiji Ishikawa, MD, " Ph. D., Tadashi Kawai, MD, Ph.D., Kiyoshi Miyai, MD Ph.D., .198.1 .., Igaku-Shoin, Tokyo-New-York ". 0 These processes, and in particular those which gave rise to a commercial achievement, are characterized by the fact that one of the reaction partners (either antigen or antibody) is fixed on a solid phase, and that at the end of the incubation, part of the activity 5 enzymatic is associated with the solid phase on which it is measured.
Les enzymes les plus utilisées sont :The most used enzymes are:
- la phosphatase alcaline- alkaline phosphatase
- la β -galactosidase " 0 - la peroxyHase- β -galactosidase "0 - peroxyHase
- l'acetylcholin'estérase.- acetylcholinesterase.
Les phases solides les plus utilisées sontThe most used solid phases are
- poudres- powders
- billes c - tubes- balls c - tubes
- plaques. Dans une réaction immunoenzymatique, la révélation de l'activité enzymatique est généralement une réaction colorée qui se développe au contact de la phase solide. et diffuse dans la solution. L'activité enzymatique 5 peut également être révélée à l'aide d'un substrat formant un produit qui se dépose sur une surface en en modifiant- les propriétés optiques, en particulier, le pouvoir de ré- flection ou l'indice de réfraction (voir par exemple le Brevet Européen n° 0112721). Cette situation est restée jus- 10 qu'ici difficilement compatible.avec la mesure directe d'une densité optique. Les solutions adaptées à ce problème sont :- plates. In an immunoenzymatic reaction, the revelation of the enzymatic activity is generally a colored reaction which develops on contact with the solid phase. and diffuses into the solution. The enzymatic activity 5 can also be revealed using a substrate forming a product which is deposited on a surface by modifying the optical properties, in particular, the reflectivity or the refractive index ( see for example European Patent No. 0112721). This situation has so far remained difficult to reconcile with the direct measurement of an optical density. The solutions adapted to this problem are:
- ou bien, la séparation de la phase solide du milieu d'in¬ cubation par décantation, centrifugatioh ou transfert dans des cuves en vue d'une mesure ultérieure de la densité- Or, the separation of the solid phase from the in¬ cubation medium by decantation, centrifugation or transfer into tanks for a subsequent measurement of the density
15 optique,15 optical,
- ou bien, pour les phases solides non divisées (parois de tubes ou d'alvéoles), on a développé des spectrophotomètrè spéciaux acceptant des plaques de culture ou des tubes cy¬ lindriques. La mesure de densité optique sensiblement per-- Or, for the undivided solid phases (walls of tubes or cells), special spectrophotometers have been developed which accept culture plates or cylindrical tubes. The measurement of optical density substantially per-
20 pendiculairement à -la surface du liquide dans les alvéoles des plaques de culture est alors imprécise, même si les cuves sont à fond plat, à cause de la courbure du ménisque (voir Brevet U.S. n° 4.444.879). Elle l'est également dans les tubes de forme ronde. 25 En effet, il résulte de la loi de BEER-20 pendicularly to the surface of the liquid in the cells of the culture plates is then imprecise, even if the vessels are flat-bottomed, because of the curvature of the meniscus (see U.S. Patent No. 4,444,879). It is also in round tubes. 25 Indeed, it follows from BEER-
LAMBERT que la densité optique n'est plus proportionnelle à la concentration dès lors que le chemin optique n'est plus uniforme, comme le montrent les relations suivantes :LAMBERT that the optical density is no longer proportional to the concentration as soon as the optical path is no longer uniform, as the following relationships show:
• Çhemin_uniforme :• This_uniform path:
3030
DO = Log Io _ iDO = Log Io _ i
où :or :
DO ≈ densité optique,DO optique optical density,
J3c IO = intensité de lumière incidente,J3c IO = incident light intensity,
I = intensité de lumière transmise,I = intensity of transmitted light,
<---. = coefficient d'extinction caractéristique de la substance, 1 = chemin optique Chemin variable : mr- Iθ(x)dX<---. = characteristic extinction coefficient of the substance, 1 = optical path Variable path: mr- Iθ (x) dX
DO = Log y lo(x)/exp(< l(x)C)dx où : 5 x = paramètre arbitraire,DO = Log y lo (x) / exp (<l (x) C) dx where: 5 x = arbitrary parameter,
Io(x) = intensité de lumière incidente, l(x) = chemin optique.Io (x) = intensity of incident light, l (x) = optical path.
L'invention obvie aux inconvénients ci- dessus rappelés et vise une cuve pour le dosage immunoenzy- 10 mologique par la mesure directe de la densité optique d'une solution contenue dans cette cuve qui est caractérisée par le fait qu'elle comporte au moins deux faces transparentes plane et parallèles entre elles et qu'au moins une partie de sa sur face interne porte un revêtement à base d'antigène ou d'anti 15 corps fixé par tout moyen approprié tel que, par exemple, cel décrit dans la demande de brevet français n° 83 05618.The invention overcomes the above-mentioned drawbacks and targets a cell for the immunoenzymological assay by direct measurement of the optical density of a solution contained in this cell which is characterized in that it comprises at least two transparent planar faces which are parallel to each other and that at least part of its internal face carries a coating based on antigen or antibody 15 fixed by any suitable means such as, for example, that described in the application for French patent n ° 83 05618.
Suivant une caractéristique avantageuse,, le faces planes et parallèles sont distantes d'un centimètre.According to an advantageous characteristic, the planar and parallel faces are spaced one centimeter apart.
On utilise une cuve selon l'invention de la 20. façon suivante :A tank according to the invention is used in the following manner:
- on introduit un échantillon de la solution à analyser ; au contac _de la surface revêtue, il se produit une réaction immunologique spécifique, réaction pouvant être détectée au moyen d'un conjugué enzymatique faisant soit, compétition, 25 soit, sandwich, avec la substance à doser. Après un temps d'incubation approprié, la solution est éliminée et rempla¬ cée par une solution de substrat spécifique de l'enzyme utilisée fournissant une coloration dont on mesure directe¬ ment l'intensité entre les deux faces parallèles de la cuve 30 avec un rayon lumineux de ^longueur d'onde appropriée.- a sample of the solution to be analyzed is introduced; upon contact with the coated surface, a specific immunological reaction occurs, which reaction can be detected by means of an enzyme conjugate which either competes or sandwiches with the substance to be assayed. After an appropriate incubation time, the solution is eliminated and replaced by a specific substrate solution of the enzyme used, providing a coloration, the intensity of which is measured directly between the two parallel faces of the tank 30 with a light ray of suitable wavelength.
La cuve ainsi définie permet l'obtention de résultats précis et reproductibles par opposition à certaines mesures pouvant faire appel à des processus antérieurs du typ de ceux décrits dans la demande de brevet japonais n° 55-34269 5 (Patents Abstracts of Japan, vol.6-n°2 (P-96) (880) , 8 Janvier où l'échantillon à doser peut amener des interférences non sp cifiques. L'exemple nullement limitatif suivant est donné à titre illustratif de l'invention : - Dosage de la p1 icroglobuline :The tank thus defined makes it possible to obtain precise and reproducible results as opposed to certain measurements which may call on previous processes of the type of those described in Japanese patent application No. 55-34269 5 (Patents Abstracts of Japan, vol. 6-n ° 2 (P-96) (880), January 8 where the sample to be assayed can cause non-specific interference. The following nonlimiting example is given as an illustration of the invention: - Determination of p 1 icroglobulin:
a) Préparation des réactifs :a) Preparation of the reagents:
- Cuves revêtues par un premier anticorps monoclonal antiβ_ microglobuline (procédé selon demande de bre¬ vet rappelée ci-dessus)- Tanks coated with a first monoclonal antibody antiβ_ microglobulin (process according to patent request mentioned above)
- Conjugué : deuxième anticorps monoclonal antiβ2 microglobuline lié à la galactosidase selon- Conjugate: second monoclonal antiβ 2 microglobulin antibody linked to galactosidase according to
Ishikawa (référence rappelée plus haut) .Ishikawa (reference recalled above).
b) Mode opératoire :b) Procedure:
50 μl de solution standard de β~ microglobuline + 1 ml de conjugué (deuxième anticorps monoclonal anti 2-microg_Obuline lié à la /.galactosidase) dilué en tampon phosphate 10™ molaire, NaCl 0,15 M (pH 7, albumine (1 g/l)-Tween (1 g/1).50 μl of standard solution of β ~ microglobulin + 1 ml of conjugate (second anti- 2 monoclonal antibody-microg_Obuline linked to /.galactosidase) diluted in 10 ™ molar phosphate buffer, 0.15 M NaCl (pH 7, albumin (1 g / l) -Tween (1 g / 1).
Incubation 4 h. à température ambiante.4 h incubation. at room temperature.
_2_2
3 lavages en^tampon phosphate 10 molaire.3 washes in ^ 10 molar phosphate buffer.
NaCl 0,15 M (pH 7,2)-albumine (1 g/l)-Tween (1 g/1). Incubation du substrat de laAgalactosidase : orthonitrophenyl- -D-galactoside pour la révélation de la réaction = 1 ml par cuve, pendant 1 h à 20°C. Lecture de la D.0. à 410 nm.0.15 M NaCl (pH 7.2) -albumin (1 g / l) -Tween (1 g / 1). Incubation of the Agalactosidase substrate: orthonitrophenyl- -D-galactoside to reveal the reaction = 1 ml per cell, for 1 h at 20 ° C. Reading of D.0. at 410 nm.
On établit la courbe correspondante. Celle-ci figure au dessin annexé. On se sert de cette courbe dite courbe standard pour évaluer le titre de toute solu¬ tion de titre inconnu en $2-microglobuline suivant la valeur de la densité optiq.ue obtenue en se servan d'une cuve selon l'invention.We establish the corresponding curve. This is shown in the accompanying drawing. This so-called standard curve is used to evaluate the titer of any solution of unknown title in $ 2 -microglobulin according to the value of the optical density obtained by using a tank according to the invention.
Il va de soi que la présente invention n'a été décrite qu'à titre purement explicatif et nullement limi¬ tatif et que toutes modifications utiles pourront y être ap- portées sans sortir de son cadre. It goes without saying that the present invention has only been described for explanatory purposes and is in no way limitative and that any useful modifications may be made thereto without departing from its scope.

Claims

REVENDICATIONS
1. Cuve pour le dosage immunoenzymologique par la mesure directe de la densité optique d'une .solution contenue dans cette cuve caractérisée par le fait qu'elle comporte au moins deux faces transparentes planes et paral- lèles entre elles, au moins une partie de sa surface interne portant un revêtement à base d'antigène ou d'anticorps fixé par tout moyen approprié.1. Cuvette for the immunoenzymological assay by direct measurement of the optical density of a .solution contained in this cuvette characterized by the fact that it comprises at least two transparent planar faces and parallel to each other, at least part of its internal surface carrying a coating based on antigen or antibody fixed by any appropriate means.
2. Cuve selon la revendication 1 caractéri¬ sée en ce que lesdites faces planes et parallèles sont dis- tantes de 1 cm. 2. A tank according to claim 1, characterized in that said planar and parallel faces are 1 cm apart.
PCT/FR1985/000238 1984-09-13 1985-09-09 Vat for immunoenzymologic dosing WO1986001900A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI861997A FI861997A0 (en) 1984-09-13 1986-05-13 KAERL FOER IMMUNIENZYMOLOGISK MAETNING.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8414168A FR2570189B1 (en) 1984-09-13 1984-09-13 IMMUNOENZYMOLOGICAL ASSAY PROCESS AND MEANS FOR IMPLEMENTING IT
FR84/14168 1984-09-13

Publications (1)

Publication Number Publication Date
WO1986001900A1 true WO1986001900A1 (en) 1986-03-27

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Application Number Title Priority Date Filing Date
PCT/FR1985/000238 WO1986001900A1 (en) 1984-09-13 1985-09-09 Vat for immunoenzymologic dosing

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EP (1) EP0192720A1 (en)
JP (1) JPS62500467A (en)
FI (1) FI861997A0 (en)
FR (1) FR2570189B1 (en)
WO (1) WO1986001900A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2223096A (en) * 1988-09-06 1990-03-28 Atomic Energy Authority Uk Detecting a selected species

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1019494A (en) * 1963-04-19 1966-02-09 Hellige & Co Gmbh F Improvements relating to equipment for measuring optical properties
FR2050482A1 (en) * 1969-07-03 1971-04-02 Merck Anlagen Gmbh
JPS56129841A (en) * 1980-03-17 1981-10-12 Kuraray Co Ltd Cell for measuring light absorption
US4444879A (en) * 1981-01-29 1984-04-24 Science Research Center, Inc. Immunoassay with article having support film and immunological counterpart of analyte

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3376685D1 (en) * 1982-12-21 1988-06-23 Ares Serono Nv Assay technique
JPS6429841A (en) * 1987-07-24 1989-01-31 Shimadzu Corp Film with holding battery

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1019494A (en) * 1963-04-19 1966-02-09 Hellige & Co Gmbh F Improvements relating to equipment for measuring optical properties
FR2050482A1 (en) * 1969-07-03 1971-04-02 Merck Anlagen Gmbh
JPS56129841A (en) * 1980-03-17 1981-10-12 Kuraray Co Ltd Cell for measuring light absorption
US4444879A (en) * 1981-01-29 1984-04-24 Science Research Center, Inc. Immunoassay with article having support film and immunological counterpart of analyte

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENTS ABSTRACTS Of JAPAN, Volume 6, No. 2, (P-96) (880), 8 January 1982 & JP - A - 56 129 841 (KURARAY K.K. et al.) (cited in the application) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2223096A (en) * 1988-09-06 1990-03-28 Atomic Energy Authority Uk Detecting a selected species

Also Published As

Publication number Publication date
FR2570189A1 (en) 1986-03-14
EP0192720A1 (en) 1986-09-03
JPS62500467A (en) 1987-02-26
FR2570189B1 (en) 1986-09-26
FI861997A (en) 1986-05-13
FI861997A0 (en) 1986-05-13

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