CA2080971C - Storable protein solution - Google Patents
Storable protein solutionInfo
- Publication number
- CA2080971C CA2080971C CA002080971A CA2080971A CA2080971C CA 2080971 C CA2080971 C CA 2080971C CA 002080971 A CA002080971 A CA 002080971A CA 2080971 A CA2080971 A CA 2080971A CA 2080971 C CA2080971 C CA 2080971C
- Authority
- CA
- Canada
- Prior art keywords
- pod
- buffer
- solution according
- solution
- storable
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
-
- 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
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/535—Production of labelled immunochemicals with enzyme label or co-enzymes, co-factors, enzyme inhibitors or enzyme substrates
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Urology & Nephrology (AREA)
- General Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Enzymes And Modification Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Detergent Compositions (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The present invention provides a storable POD
conjugate solution, characterised by a pH value of 5,0 to 6.5, adjusted by means of an organic buffer substance with aconcentration of 40 to 100 mmol/l, and 0.05 to 1.0 mol/l magnesium aspartate.
conjugate solution, characterised by a pH value of 5,0 to 6.5, adjusted by means of an organic buffer substance with aconcentration of 40 to 100 mmol/l, and 0.05 to 1.0 mol/l magnesium aspartate.
Description
-The present invention is concerned with storable con-jugates of protein and horseradish peroxidase (POD
conjugates).
In DD 237327 are described proteins, heterocyclic azines and polyalcohols in a medium with a pH value of from 6.0 to 7.5 for the stabilisation of POD(HRP) con-jugates. In EP-A 0,303,062, hydrolysed chicken albumin and/or calf serum, polyvinylpyrrolidone and/or calcium propionate, ANS (anilinoaphthysulphonic acid) in tris buffer of pH 7.2 are described for the stabilization of POD conjugates; EP-A 0,197,447 describes aminopyrine, for example, in phosphate, citrate or borate buffer; from DE-A 31 00 076 is known a medium containing ANS and serum protein; EP-A
0,070,992 describes a medium containing 4-aminoanti-pyrine, ANS and serum protein; and US-A 4,169,012 describes the use of polyvalent ions of Groups 2 and 3 of the Periodic System. However, POD conjugates in solution can only be stabilised for a limited period of time with these additives. Even after a few days, a distinct decrease of the POD activity or of the stability is observed in immunological tests.
The present invention seeks to provide a POD con-jugate solution with improved stability which can be stored at ambient temperature for a comparatively long period of time and which can be produced in a simple and reproducable way.
Thus, according to the present invention, there is provided a storable POD conjugate solution, ~.~
.. ~
2û80971 characterised by a pH value of 5.0 to 6 5, adjusted b~ means of an organic buffer substance with a concent-ration of 40 to 100 mmol/l, and 0.05lto 1~0 mol/l magnesium aspartate.
As POD conaugates, there are preferably used the conau~ates of PoD as label and of a binder and especiaIl~- immunological binder substsnce employ~d for immunological determination processes. As binder conjugate partners of POD, there are especially preferabl~ used antibodies,.fragments thereof, anti-gens-,~ haptens,~biotin and streptavidin.
~ ccording to the present invention, as~ organic buffer substance,. it is especisll~ preferred to use Good buffer,.
citrate buffer and/or 2-(N-morpholino)-ethanesulphonic acid (M~S.),. ~ES being preferabl~ u$ed.
n the basis of the pH values to be adjusted to one another,. of the concentration of the buffer substances and of the pres~nce of magnesium aspartate,. outstand~ng stability results are achieved with the POD conjugate~
solutions according to the present invention.
In adaition, the solutions according to the present invention preferablg contain stsbilisers, p~e~erving agents and/or inert proteins, namel~ especiall~ O to 0.4 g/l of stabiliser~, O to 1 g/l of preserving 2.5 agents and/or O to 20 g/l of inert protein..
Inert proteins (supporting proteins) include, for example, albumins, casein and immunoglobulins Stabi.-lis~rs which can be used according to the present 2~
invention include, for example, ANS, phenol and dimethylaminoantipyrine. Preserving agents which can be used according to the present invention include, for example, Kathon (Trade Mark), oxipyrion and methyl isothiazolone.
The solutions according to the present invention possess outstanding stabilities. For different POD
conjugates, for example, MAB-POD or hepten-POD, after storage for 3 weeks at 35C, the peroxidase activity is still 80 to 99% of the initial value.
The following Examples are given for the purpose of illustrating the present invention, without limit-ing it thereto. If nothing otherwise is stated, the percentages and parts are by weight.
ExamPle 1 CarrY out of an immunoloqical determination Process.
The test was carried out according to the ELISA
test principle as a one-step sandwich test by means of solid phase-bound streptavidin, a biotinylated, mono-clonal antibody (MAB-Bi) and a peroxidase-labelled second monoclonal antibody (MAB-POD).
100 ~1 of sample and 1000 ~1 of working solution were introduced into a polystyrene test tube coated with streptavidin (production according to EP-A
0 269 092).
comPosition of the POD storaqe solution.
.~ , MAB-PO~ (POD activity: 20 U/ml) 40 mmol/l buffer (4-morpholinoethanesulphonic acid, phosphate buffer or citrate buffer)(pH value according to the following ~able 1 0.1 mol/l magnesium aspartate 0~2 g/l 4-dimeth~laminoantipgrine O.I g~l oxip~rion 10 g/~ bovine immunoglobulin.
Composition of the working solution.
1.5 ~ g/ml MAB-Bi l/lOOth POD storage solution Incubation was carried out for 1 hour at ambient temperature~, followed b~ washing twice with 0.9~
aqueous sodium chloride solution, whereafter IOOO k~l of substrate solution were added thereto.
Sl~bst~ate solution;
100 mmol/l phosphate-citrate buffer (pH 5.0) 1.47 mmol/l sodium perborate 9.1 mmol/l 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt (ABTS ~ ) After incubation for ~0 minutes, the colour formed was determined photometricall~ at 420 nm.
Example 2.
Determination of a Pero~idase acti~it~ in MAB-POD
conaugates~.
2.9 ml of substrate solution and 0 1 ml of dilute sample (M~B-~OD) were mixed in a cuvette with 1 cm path length - an~, after mixing, the absorption change was moni.tored at smbient temperature for 5 minutes at 405 nm.
An average value of the extinction change per minute was determined. The ~OD activit~ was determined according to the following equation:
activity = 0.8152 x A~min (U/ml of æsmple solution) ~xampIe 3.
Stabilit.~ of anti-~SH antibod~-POD con~ugate in various buffer solutions.
Anti-~S~:antibody-POD conjugate was stored in PQD stora~e solution (without the addition of MAB-Bi) at different pH values in different buffer substances for 3 weeks at 4C and 35C.
The function. of the conjugate was tested according to the process described in ~ample 1 in the presence of buffer and magnesium aspartate~- The POD activity was also tested according to Example 2~
The following Table 1 shows the results obtained:
--7~
Tsble activïtg sfter'storage for buffer ion,. pH
conjugates).
In DD 237327 are described proteins, heterocyclic azines and polyalcohols in a medium with a pH value of from 6.0 to 7.5 for the stabilisation of POD(HRP) con-jugates. In EP-A 0,303,062, hydrolysed chicken albumin and/or calf serum, polyvinylpyrrolidone and/or calcium propionate, ANS (anilinoaphthysulphonic acid) in tris buffer of pH 7.2 are described for the stabilization of POD conjugates; EP-A 0,197,447 describes aminopyrine, for example, in phosphate, citrate or borate buffer; from DE-A 31 00 076 is known a medium containing ANS and serum protein; EP-A
0,070,992 describes a medium containing 4-aminoanti-pyrine, ANS and serum protein; and US-A 4,169,012 describes the use of polyvalent ions of Groups 2 and 3 of the Periodic System. However, POD conjugates in solution can only be stabilised for a limited period of time with these additives. Even after a few days, a distinct decrease of the POD activity or of the stability is observed in immunological tests.
The present invention seeks to provide a POD con-jugate solution with improved stability which can be stored at ambient temperature for a comparatively long period of time and which can be produced in a simple and reproducable way.
Thus, according to the present invention, there is provided a storable POD conjugate solution, ~.~
.. ~
2û80971 characterised by a pH value of 5.0 to 6 5, adjusted b~ means of an organic buffer substance with a concent-ration of 40 to 100 mmol/l, and 0.05lto 1~0 mol/l magnesium aspartate.
As POD conaugates, there are preferably used the conau~ates of PoD as label and of a binder and especiaIl~- immunological binder substsnce employ~d for immunological determination processes. As binder conjugate partners of POD, there are especially preferabl~ used antibodies,.fragments thereof, anti-gens-,~ haptens,~biotin and streptavidin.
~ ccording to the present invention, as~ organic buffer substance,. it is especisll~ preferred to use Good buffer,.
citrate buffer and/or 2-(N-morpholino)-ethanesulphonic acid (M~S.),. ~ES being preferabl~ u$ed.
n the basis of the pH values to be adjusted to one another,. of the concentration of the buffer substances and of the pres~nce of magnesium aspartate,. outstand~ng stability results are achieved with the POD conjugate~
solutions according to the present invention.
In adaition, the solutions according to the present invention preferablg contain stsbilisers, p~e~erving agents and/or inert proteins, namel~ especiall~ O to 0.4 g/l of stabiliser~, O to 1 g/l of preserving 2.5 agents and/or O to 20 g/l of inert protein..
Inert proteins (supporting proteins) include, for example, albumins, casein and immunoglobulins Stabi.-lis~rs which can be used according to the present 2~
invention include, for example, ANS, phenol and dimethylaminoantipyrine. Preserving agents which can be used according to the present invention include, for example, Kathon (Trade Mark), oxipyrion and methyl isothiazolone.
The solutions according to the present invention possess outstanding stabilities. For different POD
conjugates, for example, MAB-POD or hepten-POD, after storage for 3 weeks at 35C, the peroxidase activity is still 80 to 99% of the initial value.
The following Examples are given for the purpose of illustrating the present invention, without limit-ing it thereto. If nothing otherwise is stated, the percentages and parts are by weight.
ExamPle 1 CarrY out of an immunoloqical determination Process.
The test was carried out according to the ELISA
test principle as a one-step sandwich test by means of solid phase-bound streptavidin, a biotinylated, mono-clonal antibody (MAB-Bi) and a peroxidase-labelled second monoclonal antibody (MAB-POD).
100 ~1 of sample and 1000 ~1 of working solution were introduced into a polystyrene test tube coated with streptavidin (production according to EP-A
0 269 092).
comPosition of the POD storaqe solution.
.~ , MAB-PO~ (POD activity: 20 U/ml) 40 mmol/l buffer (4-morpholinoethanesulphonic acid, phosphate buffer or citrate buffer)(pH value according to the following ~able 1 0.1 mol/l magnesium aspartate 0~2 g/l 4-dimeth~laminoantipgrine O.I g~l oxip~rion 10 g/~ bovine immunoglobulin.
Composition of the working solution.
1.5 ~ g/ml MAB-Bi l/lOOth POD storage solution Incubation was carried out for 1 hour at ambient temperature~, followed b~ washing twice with 0.9~
aqueous sodium chloride solution, whereafter IOOO k~l of substrate solution were added thereto.
Sl~bst~ate solution;
100 mmol/l phosphate-citrate buffer (pH 5.0) 1.47 mmol/l sodium perborate 9.1 mmol/l 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt (ABTS ~ ) After incubation for ~0 minutes, the colour formed was determined photometricall~ at 420 nm.
Example 2.
Determination of a Pero~idase acti~it~ in MAB-POD
conaugates~.
2.9 ml of substrate solution and 0 1 ml of dilute sample (M~B-~OD) were mixed in a cuvette with 1 cm path length - an~, after mixing, the absorption change was moni.tored at smbient temperature for 5 minutes at 405 nm.
An average value of the extinction change per minute was determined. The ~OD activit~ was determined according to the following equation:
activity = 0.8152 x A~min (U/ml of æsmple solution) ~xampIe 3.
Stabilit.~ of anti-~SH antibod~-POD con~ugate in various buffer solutions.
Anti-~S~:antibody-POD conjugate was stored in PQD stora~e solution (without the addition of MAB-Bi) at different pH values in different buffer substances for 3 weeks at 4C and 35C.
The function. of the conjugate was tested according to the process described in ~ample 1 in the presence of buffer and magnesium aspartate~- The POD activity was also tested according to Example 2~
The following Table 1 shows the results obtained:
--7~
Tsble activïtg sfter'storage for buffer ion,. pH
-3 weeks at 4G ~ weeks at 35C
immune~ POD immune POD
sctivi,ty activit~ activit~ activit~
ace.tate, pH 6.0 I.OQ% 100~ 87~ 90 phosphate,. pX 6.0 lOQ~ lOQ~' 78~ lOQ%
MES,~ pH 6.5 lOQ% 100~ 87~ 10~%
~ES, pH 6.. 0 100~ lOo~ 87% 1 W~
10 MES, pH 5.0 1 W ~ 100% 82~' 100%
~E~,!pH 4.0 100~ lOOX 43~ n.d.
~hosphate,l pH 8.0 100~ lOC~ 62~ lOa%
n..d. = not determine~
Table 1 shows tha,t admittedl~ the POD activitg is still present after-storage for 3 weeks at 35C but small losses in the activity are onlg seen . when the pH value of the buffer is from 5 to 6.5, E~smpIe 4 Influence of msgnesium aspartate~
As described in E~ample 3,. anti-~S~.antibody-POD
conjugate (ac~ivi.tg 20 U/ml in 40 mmol/ml 4-MES buffer at pH 6,0) was stored in the pre~ence of different magnesium aspartate concentrations, The stabilit~ of the solutions was tested after 3 weeks storage in a test according to Example- 1~ The following Table 2 show~ the results obtsined:
Table 2 .
magnesium ~spsrtate activitg after storage for concentrstion 3 weeks at 4C 3 week~ a1t 35C
0.00 mol/l 100~ 64%
0.05 mol/l 100~ 84 0.10 mol/l 100% 77 0,25 mol/l 100~ 81~
Table 2 sh~ws that magne~ium sspartate has a--positive influence on the performance of the anti-TSH antibodg conjugates.
Example 5, Influence of buffer solutions with a pH value of from 5.5 to 6.0 on the stabilit~ of different POD con~ugates.
The POD-hapten and antibodg conjugates mentioned in Table 3, with an average enzgmatic activitg of 0..4 to 20 U/ml, were stor~ed for 3 weeks st 4C and 35C in 8 solution of 40 mmol/l 4-MES (pH 5.0 to 6.0),.
0~1 g/l oxip~rion snd 10 g/l bovine immunoglobulin.
20 SubsequentlY t 8n appropriate function test for the antigen was carried out analogouslg to Example 1.
The following Table 3 shows the results obtained:
_9_ Table 3 .
POD conjugate with act~vit~ after storsge for O,l mol/l aspsrtate O
~ w-eeks 4 C ~~weeks 35C
anti-TSH.MAB-POD 100~ 85 5 snti-~S~-PAB-~OD 100~ 89 anti-~H MAB-POD 100~ 86 anti-FSH MAB-POD lQO~ 84%
anti-HCG M~B-POD 100~ 79 anti-CE~ MAB-POD IOO~ 77
immune~ POD immune POD
sctivi,ty activit~ activit~ activit~
ace.tate, pH 6.0 I.OQ% 100~ 87~ 90 phosphate,. pX 6.0 lOQ~ lOQ~' 78~ lOQ%
MES,~ pH 6.5 lOQ% 100~ 87~ 10~%
~ES, pH 6.. 0 100~ lOo~ 87% 1 W~
10 MES, pH 5.0 1 W ~ 100% 82~' 100%
~E~,!pH 4.0 100~ lOOX 43~ n.d.
~hosphate,l pH 8.0 100~ lOC~ 62~ lOa%
n..d. = not determine~
Table 1 shows tha,t admittedl~ the POD activitg is still present after-storage for 3 weeks at 35C but small losses in the activity are onlg seen . when the pH value of the buffer is from 5 to 6.5, E~smpIe 4 Influence of msgnesium aspartate~
As described in E~ample 3,. anti-~S~.antibody-POD
conjugate (ac~ivi.tg 20 U/ml in 40 mmol/ml 4-MES buffer at pH 6,0) was stored in the pre~ence of different magnesium aspartate concentrations, The stabilit~ of the solutions was tested after 3 weeks storage in a test according to Example- 1~ The following Table 2 show~ the results obtsined:
Table 2 .
magnesium ~spsrtate activitg after storage for concentrstion 3 weeks at 4C 3 week~ a1t 35C
0.00 mol/l 100~ 64%
0.05 mol/l 100~ 84 0.10 mol/l 100% 77 0,25 mol/l 100~ 81~
Table 2 sh~ws that magne~ium sspartate has a--positive influence on the performance of the anti-TSH antibodg conjugates.
Example 5, Influence of buffer solutions with a pH value of from 5.5 to 6.0 on the stabilit~ of different POD con~ugates.
The POD-hapten and antibodg conjugates mentioned in Table 3, with an average enzgmatic activitg of 0..4 to 20 U/ml, were stor~ed for 3 weeks st 4C and 35C in 8 solution of 40 mmol/l 4-MES (pH 5.0 to 6.0),.
0~1 g/l oxip~rion snd 10 g/l bovine immunoglobulin.
20 SubsequentlY t 8n appropriate function test for the antigen was carried out analogouslg to Example 1.
The following Table 3 shows the results obtained:
_9_ Table 3 .
POD conjugate with act~vit~ after storsge for O,l mol/l aspsrtate O
~ w-eeks 4 C ~~weeks 35C
anti-TSH.MAB-POD 100~ 85 5 snti-~S~-PAB-~OD 100~ 89 anti-~H MAB-POD 100~ 86 anti-FSH MAB-POD lQO~ 84%
anti-HCG M~B-POD 100~ 79 anti-CE~ MAB-POD IOO~ 77
Claims (9)
1. A storable peroxidase conjugate solution, having a pH value of 5.0 to 6.5, adjusted by means of an organic buffer substance with a concentration of 40 to 100 mmol/l, and comprising 0.05 to 1.0 mol/l magnesium aspartate.
2. A solution according to claim 1, wherein said buffer substance is at least one of Good buffer, citrate buffer and 2-(N-morpholino)-ethanesulphonic acid.
3. A solution according to claim 1, wherein said buffer substance comprises 2-(N-morpholino)-ethanesulphonic acid.
4. A solution according to claim 1, 2 or 3, additionally containing at least one of a stabiliser, a preserving agent and an inert protein.
5. A solution according to claim 4, containing 0 to 0.4 g/l of stabiliser.
6. A solution according to claim 4, containing 0 to 1 g/l of preserving agent.
7. A solution according to claim 5, containing 0 to 1 g/l of preserving agent.
8. A solution according to claim 4, containing 0 to 20 g/l of inert protein.
9. A solution according to claim 6 or 7, containing 0 to 20 g/l of inert protein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4135542.3 | 1991-10-28 | ||
| DE4135542A DE4135542A1 (en) | 1991-10-28 | 1991-10-28 | STORAGE PROTEIN SOLUTIONS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2080971A1 CA2080971A1 (en) | 1993-04-29 |
| CA2080971C true CA2080971C (en) | 1996-07-09 |
Family
ID=6443602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002080971A Expired - Fee Related CA2080971C (en) | 1991-10-28 | 1992-10-20 | Storable protein solution |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0539923B1 (en) |
| JP (1) | JP2615325B2 (en) |
| KR (1) | KR930007973A (en) |
| AT (1) | ATE133262T1 (en) |
| AU (1) | AU640090B2 (en) |
| CA (1) | CA2080971C (en) |
| DE (2) | DE4135542A1 (en) |
| DK (1) | DK0539923T3 (en) |
| ES (1) | ES2082326T3 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4206932A1 (en) * | 1992-03-05 | 1993-09-09 | Boehringer Mannheim Gmbh | IMMUNOLOGICAL METHOD FOR DETERMINING A HAEMOGLOBIN DERIVATIVE |
| CN1055933C (en) * | 1995-05-09 | 2000-08-30 | 中国科学院上海有机化学研究所 | Polyclonal antibody, preparing process and use thereof |
| BRPI0110914B8 (en) | 2000-05-15 | 2021-05-25 | Hoffmann La Roche | 'liquid pharmaceutical composition, process for its preparation and use of a pharmaceutical composition' |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7610608A (en) * | 1976-09-24 | 1978-03-29 | Akzo Nv | PROCESS FOR STABILIZING PEROXIDASE-CONTAINING COMPOSITIONS. |
| DE3044454C2 (en) * | 1980-11-26 | 1982-12-09 | Boehringer Mannheim Gmbh, 6800 Mannheim | Stabilized enzyme preparation |
| JPS5886083A (en) * | 1981-11-12 | 1983-05-23 | Wako Pure Chem Ind Ltd | Stabilizing agent for glycerol-3-phosphoric acid oxidase |
| JPS6255081A (en) * | 1985-09-05 | 1987-03-10 | Toyobo Co Ltd | Stable xanthine oxidase composition |
| DE3726634A1 (en) * | 1987-08-11 | 1989-02-23 | Biotest Ag | STABILIZED PEROXIDASE PREPARATION |
| DE3829001A1 (en) * | 1988-08-26 | 1990-07-05 | Trigon Chemie Gmbh | ASPARAGINIC DERIVATIVES AND METHOD FOR THEIR PREPARATION |
| FR2653782B1 (en) * | 1989-10-30 | 1992-02-07 | Cis Bio Int | STABILIZED PEROXYDASE COMPOSITION FOR USE IN IMMUNO-ENZYMATICS. |
| US5231004A (en) * | 1990-05-11 | 1993-07-27 | Eastman Kodak Company | Use of heme-containing proteins as stabilizers for enzyme-labeled immunoreactants |
| ES2148144T3 (en) * | 1990-11-20 | 2000-10-16 | Dade Behring Marburg Gmbh | PROCEDURE FOR THE STABILIZATION OF ENZYME CONJUGATES. |
-
1991
- 1991-10-28 DE DE4135542A patent/DE4135542A1/en not_active Withdrawn
-
1992
- 1992-10-12 AU AU26334/92A patent/AU640090B2/en not_active Ceased
- 1992-10-20 CA CA002080971A patent/CA2080971C/en not_active Expired - Fee Related
- 1992-10-21 KR KR1019920019333A patent/KR930007973A/en not_active Withdrawn
- 1992-10-27 DE DE59205094T patent/DE59205094D1/en not_active Expired - Fee Related
- 1992-10-27 DK DK92118352.1T patent/DK0539923T3/en active
- 1992-10-27 EP EP92118352A patent/EP0539923B1/en not_active Expired - Lifetime
- 1992-10-27 AT AT92118352T patent/ATE133262T1/en not_active IP Right Cessation
- 1992-10-27 JP JP4288617A patent/JP2615325B2/en not_active Expired - Lifetime
- 1992-10-27 ES ES92118352T patent/ES2082326T3/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0539923A1 (en) | 1993-05-05 |
| EP0539923B1 (en) | 1996-01-17 |
| AU2633492A (en) | 1993-04-29 |
| DK0539923T3 (en) | 1996-06-03 |
| DE4135542A1 (en) | 1993-04-29 |
| AU640090B2 (en) | 1993-08-12 |
| ATE133262T1 (en) | 1996-02-15 |
| JP2615325B2 (en) | 1997-05-28 |
| JPH06141860A (en) | 1994-05-24 |
| CA2080971A1 (en) | 1993-04-29 |
| DE59205094D1 (en) | 1996-02-29 |
| ES2082326T3 (en) | 1996-03-16 |
| KR930007973A (en) | 1993-05-20 |
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