CN102295698A - Cyclosporine A immunogen, cyclosporine A specific antibody, detection reagent, and detection kit - Google Patents
Cyclosporine A immunogen, cyclosporine A specific antibody, detection reagent, and detection kit Download PDFInfo
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- CN102295698A CN102295698A CN2011101303440A CN201110130344A CN102295698A CN 102295698 A CN102295698 A CN 102295698A CN 2011101303440 A CN2011101303440 A CN 2011101303440A CN 201110130344 A CN201110130344 A CN 201110130344A CN 102295698 A CN102295698 A CN 102295698A
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Abstract
The invention discloses a cyclosporine A immunogen, and a cyclosporine A specific antibody, a detection reagent and a detection kit obtained therefrom. A specific cyclosporine A derivative is used to prepare a cyclosporine A enzyme-labeled conjugate and the cyclosporine A immunogen through a chemosynthesis method, the cyclosporine A specific antibody is prepared from the cyclosporine A immunogen, and the homogeneous enzyme immune detection reagent of cyclosporine A is prepared from above substances. The detection reagent of the invention which has the advantages of high sensitivity and strong specificity can realize the high flux, and rapid and automatic detection of cyclosporine A by means of a fully-automatic biochemical analyzer.
Description
Technical field
The present invention relates to Ciclosporin A immunogen, anti-Ciclosporin A specific antibody, detection reagent and detection kit.
Background technology
Ciclosporin A (Cyclosporine A) structural formula is shown in (II):
Ciclosporin A is a kind of ring-type undecapeptide, is mainly used in the immunological rejection that suppresses in kidney, heart and the liver transplantation process, also can be used for treating diabetes, malaria and autoimmune disorder.But since its effectively treatment concentration range is narrower, concentration can not suppress the immunological rejection of transplant organ when low and can cause a series of severe side effect as renal tubal dysfunction, hypertension after the overdose, cardiovascular spasm, headache, diarrhoea, lymphoma etc.Therefore, carrying out monitor drug concentration in therapeutic process is very important.
At present, the method for Ciclosporin A being carried out monitor drug concentration mainly is a high performance liquid chromatography, puts the method for exempting from and fluorescence polarization method.The high performance liquid chromatography consumption time is long, and sample pre-treatments and complicated operating process require height to personnel; The radioactive ray of putting the method for exempting from has produced great harm to operator's health; Main dependence on import of reagent that fluorescence polarization method needs and expense are extremely expensive.
The homogeneous enzyme immunoassay check is a kind of competitive reaction, the free Ciclosporin A can combine the Ciclosporin A specific antibody with Ciclosporin A enzyme mark conjugate competitiveness in the reaction system, entire reaction betides in the liquid phase homogeneous system, need not to separate by solid phase.The free Ciclosporin A is many more in the sample, and competition bonded antibody is many more, and the Ciclosporin A enzyme mark conjugate that antibody discharges is also just many more, and the signal that obtains by enzyme mark conjugate and substrate reactions is also just strong more.In the mensuration process, behind the Ciclosporin A and antibody response in the sample, further add enzyme mark conjugate again, can calculate the content of sample by the variation of OD340nm light absorption value.
Homogeneous enzyme immunoassay detection method speed is fast, simple to operate, highly sensitive, high specificity and can on automatic clinical chemistry analyzer, realize to the monitoring medicine the rapid detection of high-throughput.Micromolecular high throughput testing such as illegal drug have been widely used in the world, because Ciclosporin A is bigger than general small molecules, it is bigger that its specific antibody and involved enzyme mark conjugate prepare difficulty, and the Ciclosporin A content that adopts the homogeneous enzyme immunoassay detection reagent to measure among the human sample has great importance.
Summary of the invention
One object of the present invention is to provide a kind of Ciclosporin A immunogen.
Another object of the present invention is to provide the anti-Ciclosporin A specific antibody that uses Ciclosporin A immunogen preparing of the present invention to obtain.
A further object of the present invention is to provide the anti-Ciclosporin A detection of antibodies of a kind of the present invention of containing reagent.
Another purpose of the present invention is to provide a kind of Ciclosporin A detection kit.
The technical solution used in the present invention is:
The Ciclosporin A immunogen, its structural formula is suc as formula shown in (I):
In the formula, R is a linking group, and carrier has immunogenicity.
Preferably, carrier is for having immunogenic protein.
R is preferably-O-(CH
2)
n-COO-, n are the integers between the 1-20, and special, R is-O-(CH
2)
4-COO-.
A kind of anti-Ciclosporin A specific antibody obtains by producing behind the above-mentioned Ciclosporin A immunogen immune animal.
A kind of Ciclosporin A detection reagent contains the substrate of above-mentioned anti-Ciclosporin A specific antibody, Ciclosporin A enzyme mark conjugate and enzyme.
The Ciclosporin A detection kit, the indicator that contains above-mentioned anti-Ciclosporin A specific antibody and detect anti-Ciclosporin A specific antibody and Ciclosporin A mixture.
Ciclosporin A immunogen of the present invention, the immunogenicity height can be prepared specific Ciclosporin A antibody.
Anti-Ciclosporin A specific antibody high specificity of the present invention does not have any cross reaction with common medicine, and is highly sensitive, can reach 12.5 ng/ml, far below clinical application scope 100 ng/ml～450 ng/ml of Ciclosporin A.
Ciclosporin A detection reagent of the present invention and detection kit can be determined the Ciclosporin A content in the sample easily and fast, exactly.
Ciclosporin A detection reagent of the present invention and detection kit can be measured a plurality of samples simultaneously on automatic clinical chemistry analyzer, realize the rapid mensuration of high-throughput of Ciclosporin A, highly sensitive, high specificity, tolerance range all is enhanced before comparing with detection efficiency, has realized the full-automation of testing process simultaneously.
Description of drawings
Fig. 1 is a Ciclosporin A homogeneous enzyme immunoassay reaction normal graphic representation.
Embodiment
The technical solution used in the present invention is:
The Ciclosporin A immunogen, its structural formula is suc as formula shown in (I):
In the formula, R is a linking group, and carrier has immunogenicity.Preferably, carrier is for having immunogenic protein.Though the immunogenic material that possesses that other are enough big also can be used as carrier, generally selects for use protein as carrier.The most frequently used immunogenic carrier comprises serum protein, hemocyanin (KLH) and thyroglobulin.The selection of carrier is those skilled in the art's a basic general knowledge.
R is preferably-O-(CH
2)
n-COO-, n are the integers between the 1-20, and special, R is-O-(CH
2)
4-COO-.
A kind of anti-Ciclosporin A specific antibody is obtained by above-mentioned Ciclosporin A immunogen immune animal.
" antibody " of indication not only refers to complete antibody molecule among the present invention, also comprises the antibody fragment or the derivative that keep the complete antibody specific binding capacity.Antibody of the present invention can be that polyclonal antibody can be a monoclonal antibody also, is preferably polyclonal antibody.
Antibody of the present invention can obtain by prior art for preparing.The typical method that obtains polyclonal antibody is to use single immunogen, after adding or not adding adjuvant, carries out immunity at one or more position of animal, and host animal comprises: rabbit, goat, mouse, sheep, cavy or horse.Lasting immunity is carried out always, reaches the highest until antibody titer.Animal is regularly taken a blood sample and obtains an amount of specific corrosioning anteserum, and antiserum(antisera) can purifying.Monoclonal antibody can be made by somatocyte hybriding technology.
A kind of Ciclosporin A detection reagent contains the substrate of above-mentioned anti-Ciclosporin A specific antibody, Ciclosporin A enzyme mark conjugate and enzyme.Wherein, Ciclosporin A enzyme mark conjugate can obtain by chemical synthesis process.
The Ciclosporin A detection kit, the indicator that contains above-mentioned anti-Ciclosporin A specific antibody and detect Ciclosporin A specific antibody and Ciclosporin A mixture.
Indicator is selected from enzyme reagent, radio isotope reagent, fluorescent reagent, luminescence reagent and chemical illuminating reagent.Preferably, indicator is made up of the substrate of Ciclosporin A enzyme mark conjugate and enzyme.
Sample to be tested is various physiology samples, and for example blood sample need carry out the pre-treatment of blood sample before measuring.
Below in conjunction with embodiment, further specify the present invention.
The Ciclosporin A derivatives chemical structure of using in following examples is suc as formula shown in (III).
N in this formula and the subsequent chemistry formula is the integer between the 1-20.
The synthetic route of this ciclosporin derivative is as follows:
Concrete synthesis step is as follows:
Synthesizing of compound 1
(1) accurately takes by weighing 1.0 g 4-pentenoic acid (10.0 mmol, 1.0 eq) with 1.6 g N-hydroxy-succinamide (14.0 mmol, 1.4 eq) join in the drying 100 mL round-bottomed flasks that contain 40 mL tetrahydrofuran (THF)s, and place on the magnetic stirring apparatus and stir.
(2) accurately take by weighing 2.5 g 1,3-dicyclohexylcarbodiimide (12.0 mmol, 1.2 eq) joins in the 20 mL tetrahydrofuran (THF)s, places fully mixing of magnetic stirring apparatus.
(3) under 23 ℃, the mixture in the step 2 is dropwise joined in the mixture of step 1, and constantly stir, all solid particulates dissolve fast, and produce a kind of white precipitate rapidly.
(4) the mixture stirring is spent the night, filter, vacuum concentration also uses flash chromatography on silica gel purification column purifying (elutriant: petrol ether/ethyl acetate=1/1), obtain 1.5 g white solid compound 1(productive rates: 75%).
Synthesizing of compound 2
(1) accurately takes by weighing following compound: 400 mg Ciclosporin A (0.332 mmol, 1.0 eq), 600 mg compound 1 (3.0 mmol, 9.0 eq) with 1 of 56 mg, 3-phorone-4,5-glyoxalidine-2-methene base-cyclohexyl phosphine-Ben Yajiaji dichloro ruthenium (0.0066 mmol, 0.2 mmol) is dissolved in 10 ml CH with it
2Cl
2In
(2) above-mentioned mixing solutions is joined 100 ml in flame-dried Schlenk pipe, finished reaction in 22 hours through vigorous stirring and reflux condensation mode, after the cooling, this mixed solution obtains a kind of solid crude extract behind vacuum concentration, with this crude extract through purification by flash chromatography (elutriant: 15% acetonitrile-ethyl acetate) obtain 400 mg yellow compound 2(productive rates: 85%).
Synthesizing of ciclosporin derivative
(1) take by weighing 1 g compound 2(0.739 mmol, 1 eq) and 166 mg lithium hydroxide (LiOHH
2O) (3.695 mmol 5eq), are dissolved in them in 5 ml distilled water and the 20 ml tetrahydrofuran (THF)s, after stirring is spent the night under the room temperature,
(2) this compound is concentrated and dilute with water through negative pressure, accurately regulate this pH value of solution to 5 with 1N hydrochloric acid, and use ethyl acetate extraction.
(3) after the extracting and demixing, with the organic layer separation and through Na
2SO
4Absorbent drying, after filtration, obtain 300 mg Ciclosporin A derivative white solid (productive rates: 32%) behind vacuum concentration and the high-efficient liquid phase chromatogram purification.
Utilize Bruker Avance III plus 400 MHz that the ciclosporin derivative is carried out NMR (Nuclear Magnetic Resonance) spectrum scanning, interior mark adopts TMS.The result is as follows:
1H NMR (CDCl3,400MHz): 0.69-2.40 (72H, m), 2.48-2.60 (5H, m), and 2.67-3.10 (12H, m), 3.25-3.48 (5H, m), and 3.79-3.81 (1H, m), 4.43-4.46 (1H, m), and 4.70-5.40 (13H, m), 5.58-5.67 (1H, m), 7.29-7.41 (1H, m), and 7.80-7.82 (1H, m); Be characterized by the ciclosporin derivative shown in the formula III.
Utilize chromatogram/mass-spectrometric technique (LCMS) that the derivative that obtains is carried out Analysis and Identification, instrument is the series connection level Four bar mass spectrograph LC/MSD1200 series of Agilent company, and ion source adopts positive ion or negative ionization pattern.The chromatographic column specification is: Welchrom XB-C18 (50 * 4.6 mm, 5 μ m), and column temperature is 30 ℃, and flow velocity is 1.5 mL/min, and moving phase is 30%-95% for the acetonitrile-water ratio.
LCMS result shows: purity 99.7%; Retention time 2.713 min; Molecular weight 1259; Molecule is from being: 1260 (M+1).
The BSA-Ciclosporin A is immunogenic synthetic
The Ciclosporin A immunogen is passed through-O-(CH by bovine serum albumin and Ciclosporin A derivative
2)
4-COO-group is formed by connecting, and concrete synthetic method is as follows:
1) with BSA(200 mg) be dissolved in 50 ml, 0.2 M, the phosphoric acid buffer of pH 8.5 (Phosphate buffer solution, PBS) in;
2) following chemical is joined stirring and dissolving in the small beaker: 200 mg Ciclosporin A derivatives, 3.5 ml dimethylformamide (dimethylformamide, DMF), 3.5 ml ethanol, 7.0 ml, 10 mM, the potassium phosphate buffer of pH 5.0,400 mg 1-ethyl-3-(3-dimethylaminopropyl) carbodiimides, 50 mg N-hydroxy thiosuccinimide (N-hydroxysuccinimide, Sulfo-NHS), stirring and dissolving was reacted 30 minutes under room temperature;
3) will dissolve good drips of solution and add in the BSA solution, and under 2～8 ℃, stir and spend the night, obtain antigen; (4 * 4L) purifying obtain the Ciclosporin A immunogen, are stored in-20 ℃ with the dialysis of synthetic good antigen process neutral phosphonic phthalate buffer.
The preparation of anti-Ciclosporin A specific antibody
Resulting Ciclosporin A immunogen is adopted ordinary method inoculation experiments animal rabbit, get antiserum(antisera) behind the booster immunization, concrete steps are as follows:
With PBS synthetic Ciclosporin A immunogen is diluted to 1.0 mg/ml, the antigenic solution with 1.0 ml mixes with Freund's complete adjuvant then, and rabbit is injected;
After 2～3 weeks, again to the rabbit injection once with the identical antigenic solution of 1.0 ml and Freund's incomplete adjuvant, afterwards every around once, totally twice, the antibody titer of acquisition is about 1:30000.
The preparation of glucose-6-phosphate dehydrogenase (G6PD)-Ciclosporin A conjugate
1. the preparation of glucose-6-phosphate dehydrogenase (G6PD) (G6PDH) solution:
A) take by weighing 37.5 mg G6PDH(100KU).Room temperature is dissolved in 6 mL, 0.05 M tirs, 3.3 mM MgCl
2, 0.85% NaCl, pH=9.0.G6PDH（100KU）:~0.04?μM；
B) in enzyme solution, add 112.5 mg NADH, 67.5 mg G-6-P and 0.375 mL Trivalin SF (Carbitol);
C) dropwise add 1.125 mL dimethyl sulfoxide (DMSO) (dimethy sulfoxide, DMSO).
2. the activation of Ciclosporin A derivative
A) taking by weighing 10 mg Ciclosporin A derivatives under anhydrous state is dissolved among 210 μ L DMSO and the 90 μ L DMF;
B) make whole solution temperature drop to 2-8 ℃;
C) add 6 μ L Tributylamines (tributylamine);
D) add 3.5 μ L isobutyl chlorocarbonates (isobutylchloroformate);
E) 2-8 ℃ was stirred 30 minutes.
3. enzyme and Ciclosporin A is connected
A) activated Ciclosporin A derivative solution is dropwise joined in the dissolved enzyme solution;
B) 2-8 ℃ of stirring spent the night;
4. obtain enzyme mark conjugate by G-25 gel chromatography column purification
5. in enzyme mark conjugate solution, add BSA to final concentration 0.5%, NaN
3To 0.1%.Be stored in 2-8 ℃.
The preparation of Ciclosporin A homogeneous enzyme immunoassay reagent
1. the preparation of reagent A: the Ciclosporin A specific antibody of preparation is added to (11.25 mM NAD are dissolved in the pH8.55 mM Tris damping fluid) in the homogeneous phase enzyme substrates, and the ratio of antibody and substrate is 1:100-1:10000.
2. the preparation of reagent B: the enzyme mark conjugate of preparation is added to (120 mM Tris, pH=8.2), the ratio of enzyme mark conjugate is 1:100-1:10000 in the damping fluid of enzyme.
The check of Ciclosporin A homogeneous enzyme immunoassay
By automatic clinical chemistry analyzer, add sample earlier, add reagent A(antibody and substrate mixed solution again), add reagent B(enzyme solution at last), the OD of mensuration different time points
340Light absorption value, the speed of reaction when calculating different sample concentration needs constantly to adjust the ratio of reagent A and reagent B in the actual mechanical process, optimize sample pretreatment process, draws comparatively ideal reaction normal graphic representation, as shown in Figure 1.
The typical curve that obtains by the homogeneous enzyme immunoassay detection reagent, the basic, normal, high concentration blood sample of replication (is dissolved in the Ciclosporin A standard substance in the blank whole blood matrix, is respectively 60.0,300.0 to concentration, 600.0 ng/ml) 5 times, the rate of recovery height (＞90%) of discovery sample.
Utilize test sample book (the Ciclosporin A standard substance are dissolved in the 50.0 mM Tris damping fluids) to carry out the sensitivity test of Ciclosporin A homogeneous enzyme immunoassay reagent, the sensitivity of reagent reached 12.5 ng/mL(degree of confidence be 99.73%, 12.5 ng/ml sample in 3 times of standard deviation scopes, do not have with 0 ng/ml sample intersect).
The medicine interference test
Choose 32 kinds of common compounds and medicine, adjusting its concentration is 10.0 μ g/ml, carries out interference test and measures, and test-results is as shown in the table:
Method by the check of Ciclosporin A homogeneous enzyme immunoassay is measured above-claimed cpd, and the result is all negative.As seen, antibody of the present invention is the specific antibody of anti-Ciclosporin A.
Use anti-Ciclosporin A specific antibody of the present invention, the substrate of marking conjugate and enzyme with the Ciclosporin A enzyme makes up, and can obtain Ciclosporin A detection reagent of the present invention or test kit.
Claims (13)
1. Ciclosporin A immunogen, its structural formula is suc as formula shown in (I):
In the formula, R is a linking group, and carrier has immunogenicity.
2. Ciclosporin A immunogen according to claim 1 is characterized in that: carrier is for having immunogenic protein.
3. Ciclosporin A immunogen according to claim 1 is characterized in that: carrier is a bovine serum albumin.
4. Ciclosporin A immunogen according to claim 1 is characterized in that: R is-O-(CH
2)
n-COO-, n are the integers between the 1-20.
5. Ciclosporin A immunogen according to claim 1 is characterized in that: R is-O-(CH
2)
4-COO-.
6. an anti-Ciclosporin A specific antibody obtains by producing behind any described Ciclosporin A immunogen immune animal of claim 1～5.
7. Ciclosporin A detection reagent contains the substrate of the described anti-Ciclosporin A specific antibody of claim 6, Ciclosporin A enzyme mark conjugate and enzyme.
8. Ciclosporin A detection reagent according to claim 7 is characterized in that: Ciclosporin A enzyme mark conjugate comprises glucose-6-phosphate dehydrogenase (G6PD)-Ciclosporin A enzyme mark conjugate.
9. Ciclosporin A detection kit, the indicator that contains the described anti-Ciclosporin A specific antibody of claim 6 and detect anti-Ciclosporin A specific antibody and Ciclosporin A mixture.
10. Ciclosporin A detection kit according to claim 9 is characterized in that: indicator is selected from enzyme reagent, radio isotope reagent, fluorescent reagent, luminescence reagent and chemical illuminating reagent.
11. Ciclosporin A detection kit according to claim 9 is characterized in that: indicator is made up of the substrate of Ciclosporin A enzyme mark conjugate and enzyme.
12. Ciclosporin A detection kit according to claim 11 is characterized in that: Ciclosporin A enzyme mark conjugate comprises glucose-6-phosphate dehydrogenase (G6PD)-Ciclosporin A enzyme mark conjugate.
13. Ciclosporin A detection kit according to claim 9 is characterized in that: anti-Ciclosporin A specific antibody is combined on the stable surface, and its indicator is made up of the substrate of Ciclosporin A enzyme mark conjugate and enzyme.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104764883A (en) * | 2015-03-31 | 2015-07-08 | 上海云泽生物科技有限公司 | Immunoassay method and kit for detecting concentration of cyclosporine A |
| CN104788560A (en) * | 2015-05-16 | 2015-07-22 | 苏州博源医疗科技有限公司 | Cyclosporin A immunogen, anti-cyclosporin A specific antibody and cyclosporin A detection reagent |
| CN108794621A (en) * | 2017-05-04 | 2018-11-13 | 南开大学 | Conjugate of cyclosporin and the preparation method and application thereof |
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| EP0487301A1 (en) * | 1990-11-20 | 1992-05-27 | BEHRINGWERKE Aktiengesellschaft | Method of stabilizing enzyme conjugates |
| US5239057A (en) * | 1987-03-27 | 1993-08-24 | Abbott Laboratories | Fluorescence polarization assay for cyclosporin a and metabolites and related immunogens and antibodies |
| CN101929998A (en) * | 2009-06-22 | 2010-12-29 | 常州赛德瑞尔生物科技有限公司 | Fast food safety homogeneous immunological detection reagent |
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| US5239057A (en) * | 1987-03-27 | 1993-08-24 | Abbott Laboratories | Fluorescence polarization assay for cyclosporin a and metabolites and related immunogens and antibodies |
| EP0487301A1 (en) * | 1990-11-20 | 1992-05-27 | BEHRINGWERKE Aktiengesellschaft | Method of stabilizing enzyme conjugates |
| CN101929998A (en) * | 2009-06-22 | 2010-12-29 | 常州赛德瑞尔生物科技有限公司 | Fast food safety homogeneous immunological detection reagent |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104764883A (en) * | 2015-03-31 | 2015-07-08 | 上海云泽生物科技有限公司 | Immunoassay method and kit for detecting concentration of cyclosporine A |
| CN104788560A (en) * | 2015-05-16 | 2015-07-22 | 苏州博源医疗科技有限公司 | Cyclosporin A immunogen, anti-cyclosporin A specific antibody and cyclosporin A detection reagent |
| CN104788560B (en) * | 2015-05-16 | 2018-06-19 | 苏州博源医疗科技有限公司 | Ciclosporin A immunogene, anti-Ciclosporin A specific antibody and Ciclosporin A detection reagent |
| CN108794621A (en) * | 2017-05-04 | 2018-11-13 | 南开大学 | Conjugate of cyclosporin and the preparation method and application thereof |
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