WO1991004489A1 - Systeme d'immuno-analyse interferometrique homogene - Google Patents
Systeme d'immuno-analyse interferometrique homogene Download PDFInfo
- Publication number
- WO1991004489A1 WO1991004489A1 PCT/CA1990/000309 CA9000309W WO9104489A1 WO 1991004489 A1 WO1991004489 A1 WO 1991004489A1 CA 9000309 W CA9000309 W CA 9000309W WO 9104489 A1 WO9104489 A1 WO 9104489A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antigen
- waveguide
- antibody
- bsa
- homogeneous immunoassay
- Prior art date
Links
- 238000003018 immunoassay Methods 0.000 title claims abstract description 43
- 239000000427 antigen Substances 0.000 claims abstract description 56
- 102000036639 antigens Human genes 0.000 claims abstract description 53
- 108091007433 antigens Proteins 0.000 claims abstract description 53
- 238000010521 absorption reaction Methods 0.000 claims abstract description 17
- 230000003287 optical effect Effects 0.000 claims abstract description 10
- 239000013307 optical fiber Substances 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 230000009918 complex formation Effects 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 3
- 238000012360 testing method Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 32
- 238000001228 spectrum Methods 0.000 description 23
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 19
- 229940098773 bovine serum albumin Drugs 0.000 description 19
- 238000005102 attenuated total reflection Methods 0.000 description 18
- 230000009102 absorption Effects 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- 230000008901 benefit Effects 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 7
- 230000035515 penetration Effects 0.000 description 7
- 230000003595 spectral effect Effects 0.000 description 7
- 238000005253 cladding Methods 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000027455 binding Effects 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 3
- 238000007654 immersion Methods 0.000 description 3
- 239000004816 latex Substances 0.000 description 3
- 229920000126 latex Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- 108010032595 Antibody Binding Sites Proteins 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920006254 polymer film Polymers 0.000 description 2
- 230000001902 propagating effect Effects 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012911 assay medium Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000005305 interferometry Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- SBIBMFFZSBJNJF-UHFFFAOYSA-N selenium;zinc Chemical compound [Se]=[Zn] SBIBMFFZSBJNJF-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000427 thin-film deposition Methods 0.000 description 1
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
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
-
- 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
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/28—Investigating the spectrum
- G01J3/45—Interferometric spectrometry
- G01J3/453—Interferometric spectrometry by correlation of the amplitudes
-
- 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
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N2021/7769—Measurement method of reaction-produced change in sensor
- G01N2021/7779—Measurement method of reaction-produced change in sensor interferometric
-
- 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
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
Definitions
- Fellgett's or the multiplex, advantage, which gives rise to improvements in signal-to- noise ratio (S/N) and reduction in measurement time for FT spectral acquisition, compared to the time required to obtain spectra with a grating instrument.
- Fellgett's advantage originates in the fact that information for all wavelengths emitted from the source reaches the detector at the same time in FTOS measurements, whereas in a grating instrument each spectral element ( ⁇ cm -1 -, corresponding to the resolution) is detected separately. This results in a dramatic decrease in measurement time if information from a large spectral region is required. This is an important consideration if multiple components absorbing in different regions of the spectrum are to be detected.
- an homogeneous immunoassay system for the determination of the presence of an antibody or an antigen in a sample which comprises of:
- Figure 1 shows an interferometrically coded signal
- FIG. 2 shows a schematic representation of the homogeneous immunoassay system made in accordance with the present invention
- Figure 5 shows a homogeneous immunoassay system according to the present invention for the detection of an antibody (ab) in which antigens are bound onto the waveguide, and a known amount of labeled antibodies (ab*) competes for the antigen with the unlabeled antibody;
- Figure 8 shows 2 curves representing intensities of the ⁇ (CO) absorptions of the X(CO) 3 label in the ATR spectrum measured from the surface of a waveguide immersed in a solution containing anti- BSA-X(CO) 3 (0.3 mg/ml), (a) with a bare waveguide and (b) with a
- Figure 9 shows superposition of ATR spectra recorded from the surface of a waveguide coated with (a) BSA-Z(CO)g and (b) BSA- X(CO) 3 .
- FIG. 2 An embodiment of the homogeneous immunoassay system according to the present invention is shown in Figure 2 and is generally denoted 1. It mainly consists in coupling of an optical fiber waveguide-based measurement cell to an optoelectronic detector assembly in which there are: a lens or beam condenser 3, an optical fiber waveguide 5, an aluminum sample boat 7, a stainless steel optical fiber coupler 9, a detector element 11, and a detector housing 13.
- a beam condenser 3 to focus the interferometric signal onto the waveguide 5 aids in increasing the throughput of the signal reaching the detector 11.
- a variety of beam condensers are commercially available, and simple lens systems can be assembled.
- a detector design based on optical fiber technology has been implemented to enhance signal detection from optical fiber waveguides.
- the homogeneous immunoassay system of the present invention is an immunoassay where no separation step is required.
- an optical waveguide coated with an antigen (or antibody) is immersed in a solution containing the corresponding antibody (or antigen).
- Introduction of the interferometrically coded signal ( Figure 1) to the waveguide at such an angle that it is internally reflected through the waveguide establishes an evanescent wave at the waveguide- solution interface.
- the evanescent wave a the waveguide-solution interface has a depth of penetration proportional to the wavelength of the radiation propagating through the waveguide:
- An homogeneous interferometric immunoassay system for the detection of an antigen (ag) has the antibodies bound onto the waveguide, and a known amount of labeled antigen (ag*) in the surrounding solution competes for the antibody binding sites with the unlabeled antigen ( Figure 4).
- An homogeneous interferometric immunoassay system for the detection of an antibody (ab) has the antigen molecules bound onto the waveguide and a known amount of labeled antibody (ab*) in the surrounding solution competes for the antigen with the unlabeleld antibody ( Figure 5).
- a sandwich-type homogeneous interferometric immunoassay for total antibody content is also possible using the system of the present invention.
- Antigens are coated onto the surface of the waveguide, and antibodies specific to these antigens are introduced in the solution surrounding the waveguide. Following an incubation period, the solution is replaced with a solution containing labeled protein A molecules.
- Protein A is a substance that binds to the Fc fragment of antibodies. Accordingly, the amount of labeled protein
- a bound at the surface of the waveguide provides a measure of the total antibody content of the initial solution.
- This invention also deals with the first application of a waveguide transmitting radiation in the mid-infrared region of the electromagnetic spectrum for the development of a homogeneous "mid-infrared" immunoassay.
- the waveguide utilized was a ZnSe rod (8 X 0.5 X 0.5 cm) transmitting radiation in the frequency range between 5000 and 650 c ⁇ r
- the coated waveguide was washed 3 times with distilled water and then immersed in 4 ml of a phosphate buffer (0.01 M, pH 7.4) solution containing bovine serum albumin (BSA) (1 mg/ml) and water-soluble carbodiimide [WSC; l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride] (1 mg/ml).
- BSA bovine serum albumin
- WSC water-soluble carbodiimide
- HOOCC 6 H 5 Cr(CO) 3 (100 mg) in 20 ml of phosphate buffer in the presence of WSC (100 mg) at 4°C.
- the solution was dialyzed (molecular weight cutoff, 20,000) twice against phosphate buffer and once against water, and the dialysate was evaporated under reduced pressure to yield a yellow solid, anti-BSA-[Lys- ⁇ -NHCOC 6 H 5 Cr(CO) 3 l n ' henceforth denoted as anti-BSA-X(CO) 3 .
- IR in KBr: ⁇ (CO) 1975, 1910 cm -1 .
- Protein A-[Lys- ⁇ -NHCOC 6 H 5 Cr(CO) 3 ] n ' henceforth denoted as Protein A-X(CO) 3 was synthesized by the above procedure.
- a waveguide coated with CML to which BSA had been covalently bound was immersed in phosphate buffer (0.01 M, pH 7.4).
- the ATR spectrum from the surface of the waveguide was recorded as the reference spectrum.
- the buffer was then decanted, and 4 ml of a buffer solution containing labeled anti-BSA-X(CO) 3 (0.05 mg/ml) was introduced.
- Spectral acquisition was commenced immediately upon addition of the antibody solution.
- the formation of the BSA-[anti- BSA-X(CO) 3 ] complex with time was monitored by the growth of the peaks in the ATR spectrum due to the v(CO) absorptions of the X(CO) 3 label ( Figure 7, curve 1).
- BSA-X(CO) 3 not bound to the BSA on the surface of the waveguide.
- the background signal can arise in two ways: (1) penetration of the evanescent wave beyond the bound fraction into the solution surrounding the waveguide, and (2) nonspecific binding of anti-BSA-
- BSA was complexed to two different labels having distinct absorptions.
- a phosphate buffer solution containing BSA-X(CO) 3 and BSA-Z(CO)g was deposited onto the surface of an anti-BSA/CML-coated waveguide.
- the absorptions of the X(CO) 3 and Z(CO)g labels can be distinguished and their intensities measured independently.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Plasma & Fusion (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
Abstract
L'invention se rapporte à un système d'immuno-analyse homogène qui permet de déterminer la présence d'un anticorps ou d'un antigène dans un échantillon et qui utilise un signal interférométrique provenant d'une source optique, un guide d'ondes recouvert d'un anticorps ou d'un antigène et comportant au moins une région immergée dans une solution contenant un échantillon, de sorte que l'antigène ou l'anticorps correspondant puisse être amené à former un complexe sur le guide d'ondes, un capteur destiné à mesurer le signal interférométrique après sa propagation à travers le guide d'ondes, ainsi qu'un dispositif de mesure permettant d'obtenir la transformée de Fourier du signal interférométrique en vue de déterminer le degré d'atténuation du signal interférométrique à une longueur d'onde correspondant à une caractéristique d'absorption du complexe antigène/anticorps ou d'une marque incorporée dans le complexe antigène/anticorps, ce qui permet de déterminer la quantité d'antigènes ou d'anticorps contenue dans l'échantillon.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40978889A | 1989-09-20 | 1989-09-20 | |
| US409,788 | 1989-09-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1991004489A1 true WO1991004489A1 (fr) | 1991-04-04 |
Family
ID=23621972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA1990/000309 WO1991004489A1 (fr) | 1989-09-20 | 1990-09-20 | Systeme d'immuno-analyse interferometrique homogene |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU6426490A (fr) |
| WO (1) | WO1991004489A1 (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5413939A (en) * | 1993-06-29 | 1995-05-09 | First Medical, Inc. | Solid-phase binding assay system for interferometrically measuring analytes bound to an active receptor |
| EP1496361A1 (fr) * | 2003-07-07 | 2005-01-12 | Matsushita Electric Industrial Co., Ltd. | Assay et système immunologique, utilisant une transformation Fourier, pour évaluer la survenue des phénomènes zonales. |
| WO2008118934A1 (fr) * | 2007-03-26 | 2008-10-02 | Purdue Research Foundation | Procédé et dispositif pour conjuguer la détection interférométrique en quadrature d'un immuno-essai |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61173138A (ja) * | 1985-01-28 | 1986-08-04 | Olympus Optical Co Ltd | 光強度ゆらぎによる免疫反応測定方法 |
| DE3623265A1 (de) * | 1986-07-10 | 1988-01-21 | Siemens Ag | Verfahren und anordnung zur faseroptischen messung einer weglaenge oder einer weglaengenaenderung |
| WO1989007756A1 (fr) * | 1988-02-14 | 1989-08-24 | Walter Lukosz | Procede optique integre d'interference |
-
1990
- 1990-09-20 WO PCT/CA1990/000309 patent/WO1991004489A1/fr unknown
- 1990-09-20 AU AU64264/90A patent/AU6426490A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61173138A (ja) * | 1985-01-28 | 1986-08-04 | Olympus Optical Co Ltd | 光強度ゆらぎによる免疫反応測定方法 |
| DE3623265A1 (de) * | 1986-07-10 | 1988-01-21 | Siemens Ag | Verfahren und anordnung zur faseroptischen messung einer weglaenge oder einer weglaengenaenderung |
| WO1989007756A1 (fr) * | 1988-02-14 | 1989-08-24 | Walter Lukosz | Procede optique integre d'interference |
Non-Patent Citations (1)
| Title |
|---|
| Dialog Informational Services, File 351: WPI, Acc No: 4239549, WPI Acc No: 86-242938/37 & JP, A, 61173138 (OLYMPUS OPTICAL KK) 4 August 1986, abstract * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5413939A (en) * | 1993-06-29 | 1995-05-09 | First Medical, Inc. | Solid-phase binding assay system for interferometrically measuring analytes bound to an active receptor |
| EP1496361A1 (fr) * | 2003-07-07 | 2005-01-12 | Matsushita Electric Industrial Co., Ltd. | Assay et système immunologique, utilisant une transformation Fourier, pour évaluer la survenue des phénomènes zonales. |
| WO2008118934A1 (fr) * | 2007-03-26 | 2008-10-02 | Purdue Research Foundation | Procédé et dispositif pour conjuguer la détection interférométrique en quadrature d'un immuno-essai |
Also Published As
| Publication number | Publication date |
|---|---|
| AU6426490A (en) | 1991-04-18 |
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