CN1485342A - Method for preparing specific Immunoglobulin of cystvirus and adenovirus in respiratory tract - Google Patents
Method for preparing specific Immunoglobulin of cystvirus and adenovirus in respiratory tract Download PDFInfo
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- CN1485342A CN1485342A CNA031344429A CN03134442A CN1485342A CN 1485342 A CN1485342 A CN 1485342A CN A031344429 A CNA031344429 A CN A031344429A CN 03134442 A CN03134442 A CN 03134442A CN 1485342 A CN1485342 A CN 1485342A
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Abstract
A method of preparing immunoglobins with high valence and high specialty against respiratory syncytial virus and adenovirus. It comprises culturing respiratory syncytial virus and adenovirus with Hep-2 cell strain, Hala Strain, preparing virus antigen, or preparing protective antigens according to sequences of respiratory syncytial virus and adenovirus by the genetic engineering technology; then, centrifuging the prepared virus antigens and getting purified antigens, or concentrating antigens by 20% sucrose, or purifying antigens by chromatographic absorbing columns, screening high-valent immunoglobins against respiratory syncytial virus and adenovirus, and neutralizing virus in viro; finally extracting immunoglobins from bloods containing high-valent immunoglobins against respiratory syncytial virus and adenovirus by a low-temperature alcohol method or ion exchanging chromatography and so on.
Description
One, affiliated technical field
The invention belongs to virusology and field of immunology, relate to a kind of process for preparing medicine, particularly a kind of respiratory syncytial virus and adenovirus specific immunoglobulin preparation method of preventing and treating of being used to.
Two, background technology
Breathing syncytial virus (Respiratory virus RSV) and adenovirus (Adenovirus Adv) is to cause the modal two kinds of viruses of respiratory tract infection.Especially children's upper respiratory tract infection, surpassing that 50% virus type infects is that annual winter-spring season is popular by due to these two kinds of viruses, has the whole year Sporadic cases to exist.The adult generally has anti-these two kinds of virus immunity power, but it is low in some immunologic functions, as prolonged application put, the chemotherapy patients, surgical patient, organ transplantation patient etc., also can cause infection, anti-virus infection medicine commonly used is generally chemical synthetic drug, herbal medicine at present, and biotechnological formulation such as Interferon, rabbit, in these medicines, still do not have a kind of at virus and the sure medicine of curative effect.Antiviral immunoglobulin is by behind the virus infection, in vivo the main specific antiviral substance of Chan Shenging.Because being widely current of respiratory syncytial virus and adenovirus, will some people be to obtain anti-virus ability by inapparent infection and produce anti respiratory syncytial virus and the adenovirus specific immunoglobulin that height is tired.The screening height is tired and is resisted these two kinds of virus immunity sphaeroprotein from the blood source, can obtain extensive blood supply source, can effectively satisfy clinical needs.
Three, summary of the invention
The object of the invention is, the preparation method of a kind of anti respiratory syncytial virus and adenovirus specific immunoglobulin is proposed, adopt the anti respiratory syncytial virus and the adenovirus specific immunoglobulin of the preparation of this method, have and not only can prevent, but also can treat the characteristics for the treatment of both principal and secondary aspect of disease.
Technical thought of the present invention is, behind virus infection, human body can produce antiviral immunoglobulin, and normal population is because the ubiquity inapparent infection of respiratory syncytial virus and adenovirus, and wherein some crowd has the tire immunology principle of anti-above-mentioned virus immunity sphaeroprotein of height.The antigen that adopts respiratory syncytial virus and adenovirus to extract, set up ELISA method immunofluorescence method and biochip method, tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) of screening height in health is donated blood the source, through haematogenous transmissible diseases such as hepatitis virus, virus of AIDS, syphilis after the assay was approved, extract immunoglobulin (Ig) with the cold ethanol method, be prepared into medicinal application in clinical in order to prevention and treatment.
The technical solution adopted in the present invention is, anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires is characterized in that, may further comprise the steps:
1) preparation respiratory syncytial virus adenovirus antigen
Respiratory syncytial virus and adenovirus are inoculated in Hep-2 cell or the hala cell or the HEKC of the individual layer of having grown up respectively, hatch for 37 ℃, every day observation of cell pathology situation, when cytopathogenic effect (CPE) occurs +++when above or detect positive through virus antigen, collecting cell and supernatant, inactivation of virus after ultrasonicly smash, stored frozen; Or the gene order of pressing respiratory syncytial virus and adenovirus is expressed the preparation protective antigen with gene engineering method;
2) purified virus antigen
Form sediment that layer concentrates or with discontinuous gradient density centrifugation purified virus antigen with sucrose, or chromatography adsorption column method purified virus antigen; With the ultrasonic respiratory syncytial virus of smashing and adenovirus antigen 5000 * 9 centrifugal 20 minutes, discard sediment and stay supernatant, pack into the discontinuous gradient density centrifugation pipe of 15%, 30%, 45%, 60% sucrose preparation, ultracentrifugation, 165000 * 9g, centrifugal 2 hours, determine this centrifuge tube position, virus place, sucking-off stored frozen according to the molecular weight of virus;
3) setting up high specificity anti respiratory syncytial virus and the adenovirus immune globulin whitening method of tiring of screening wraps by the enzyme plate with the respiratory syncytial virus and the adenovirus antigen 10 μ g/ml～20 μ g/ml that extract, set up the ELISA method or set up immunofluorescence method or set up biochip method, in order to screening normal population donate blood in the source height tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) with virus antigen with the cell of virus infection; And determine tire effective initial concentration of specific immunoglobulin of height with methods such as neutralization tests;
Above-mentioned immunofluorescence technique is, with respiratory syncytial virus and adenovirus inoculation Hep-2 or Hela cell, after pathology appears in cell, scrape cell, with PH7.2,0.01M PBS damping fluid is washed 3 times, preparation antigen sheet, after cold acetone is fixing, stored frozen, get serum to be checked or blood plasma, after dilution, be added on the antigen sheet and hatch, after washing, add goat-anti people fluorescence antibody, under fluorescent microscope, observe.Normal Hep-2 or Hela cell antigen sheet are done negative control, result of determination.
Above-mentioned biochip method is: antigen curing → antigen antibody reaction → marker colour developing → reading apparatus reading → result judges.
With millipore filtration is carrier, solidify and go into respiratory syncytial virus and adenovirus antigen, utilize the diafiltration of millipore filtration, concentrate, agglutination, make the antigen on serum from blood donors to be checked or blood plasma and the carrier carry out rapid reaction, again with the direct reaction solution on film of anti-human IgG marker, reacted chip is put into the chip reading system, under the support of the software of special use, gray-scale value to different dot matrix is analyzed, thereby realizes the rapid screening to respiratory syncytial virus and adenovirus specific IgG antibodies.This method is fit to the screening of large sample amount.
4) with the raw material of aforesaid method screening with cold ethanol method or ion exchange chromatography method or affinity chromatography extraction height tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig);
5) anti respiratory syncytial virus after purifying and adenovirus immunoglobulin (Ig) be through 60 ± 1 ℃, 10 hours inactivation of viruses and/or in pH value 4.1 ± 0.3, and 21 days inactivation of viruses of placement again through Sterile Filtration, are distributed into antiviral immunoglobulin under 24 ± 1 ℃ of conditions.
Anti respiratory syncytial virus of the present invention and the adenovirus specific immunoglobulin medicine virus that can neutralize is in vivo and in vitro transferred immunocyte kill virus specifically, both has and can prevent, and can treat the characteristics for the treatment of both principal and secondary aspect of disease again.
Four, embodiment
The present invention is described in further detail below in conjunction with embodiment that the contriver provides.
According to technique scheme, height tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) process for preparing medicine may further comprise the steps:
At first, preparation respiratory syncytial virus and adenovirus antigen; Respiratory syncytial virus and adenovirus, be inoculated in the Hep-2 cell, Hala cell or the HEKC that have grown up to individual layer respectively, hatch for 37 ℃, every day observation of cell pathology situation, when cytopathy (CPE) occurs +++time or positive through the virus antigen detection, collecting cell and supernatant, ultrasonic smashing behind inactivation of virus put the refrigerator stored frozen; Or, express the antigen of preparation with gene engineering method by respiratory syncytial virus and adenovirus and gene order.
Secondly, with 20% sucrose shallow lake layer concentrated antigen or with discontinuous gradient density centrifugation purified virus antigen or by chromatography adsorption column purifying antigen.
The ultrasonic antigen of smashing is centrifugal, discard sediment and stay supernatant, pack into the discontinuous gradient density centrifugation pipe of 15%, 30%, 5%, 60% sucrose preparation, ultracentrifugation, 165000 * g, time 2h determines according to the molecular weight of virus, the position of virus place centrifuge tube, the sucking-off stored frozen is standby.
Then, set up screening height tire specificity anti respiratory syncytial virus and adenovirus immune globulin whitening method.
Wrap by the enzyme plate with extraction and respiratory syncytial virus and adenovirus antigen 10 μ g/ml～20 μ g/ml, set up the ELISA method or set up immunofluorescence method with the cell of virus infection, or set up biochip method with virus antigen, in order to height in the screening normal population blood source tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig).Determine the initial concentration that the height of specificity preventing respiratory viruses and adenovirus immunoglobulin (Ig) is tired with methods such as neutralization tests.After the former detection of sexually transmitted disease of menses source is qualified, with blood source stored frozen, in order to the preparation of immunoglobulin (Ig).
At last, extract height tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) with cold ethanol method or ion exchange chromatography.
1, with the isolating Cohn ' s of cold ethanol partition method component I I+III (FII+III) or Cohn ' s component I+II+III (FI+II+III) is raw material, utilize ethanol regulator solution specific inductivity, under alcohol concn 15%-25% condition, regulating pH is 5.1～7.2, controlled temperature is isolated precipitation or the supernatant that contains the specificity antivirus immunoglobulin (Ig) at-3～-7 ℃, through the ultrafiltration and concentration dealcoholysis, be lower than 97% as purity, improve purity with ion exchange chromatography, especially use and contain the ion exchange resin of DEAE-or S-group (as DEAE-sepharose, DEAE-sepharose FF, S-sepharose, S-sepharose FF and DEAE-sephadx A-50) the direct impurity of absorption except that the specificity antivirus immunoglobulin (Ig), thereby directly wear the antiviral immunoglobulin that liquid obtains purifying from stream, wherein condition is that pH is 5.0～6.8, immunoglobulin (Ig) after the purification is through 60 ± 1 ℃, 10h inactivation of viruses and/or accent pH4.1 ± 0.3, place 21 days inactivation of viruses at 24 ± 1 ℃, through Sterile Filtration, be distributed into antiviral immunoglobulin again.
2, the raw material of specificity antivirus immunoglobulin (Ig) is introduced into equilibrated DEAE-sepharose CL-6B or DEAE-sepharose FF post, condition is pH5.0～6.0, ionic strength is 0.01～0.03, antiviral immunoglobulin stream passes post, stream passes the antiviral immunoglobulin of post again by Lysine-Sepharose 4B, to penetrate liquid also merges with washing, and after adjust pH is 6.0～5.4, adding SP-Sephadex C50 or CM-sepharose FF uses the glycine of pH11 to parse the specificity antivirus immunoglobulin (Ig), the isolating antiviral immunoglobulin purity nearly 100% of this separation method, polymer content is low, through 60 ± 1 ℃, 21 days inactivation of viruses are placed at 24 ± 1 ℃ in 10h inactivation of viruses and/or accent pH4.1 ± 0.3, through Sterile Filtration, be distributed into antiviral immunoglobulin again.
When 3, adopting affinity chromatography to extract height to tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig), raw material is carried out after damping fluid handles, the salt concn of damping fluid is 0.004～0.04; PH is 4.8～9.2.Pass through affinity column, the specificity antivirus immunoglobulin (Ig) passes affinity column, the specificity antivirus immunoglobulin (Ig) carries out ion exchange chromatography, use contains the ion exchange resin of DEAE-or S-group, directly adsorb the impurity except that the specificity antivirus immunoglobulin (Ig), thereby directly wear the antiviral immunoglobulin that liquid obtains purifying from stream, wherein condition is that pH is 5.0～6.8.Thereby obtain the specificity antivirus immunoglobulin (Ig) of purifying.
Below be the embodiment that the contriver finishes.
Embodiment 1: anti respiratory syncytial virus and adenovirus specific immunoglobulin sprays
Zhi Bei antiviral specific immunoglobulin as stated above, adding can office use III its water-soluble in activity stabilized antibiotic, suck by upper respiratory tract spraying, can in upper respiratory tract mucosa, play the effect of local neutralization virus and antibacterium secondary infection.Stored frozen used up in 1 week of back of freezing.
Embodiment 2: anti respiratory syncytial virus and the adenovirus height specific immunoglobulin injection liquid of tiring
Zhi Bei antiviral immunoglobulin after safety experiment is qualified, can be used for urgent patient's rescue through aseptic experiment in the heavy dose of input body of vein as stated above, and patients such as immunologic hypofunction use.
Claims (9)
1, anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires is characterized in that, may further comprise the steps:
1) preparation respiratory syncytial virus adenovirus antigen
Respiratory syncytial virus and adenovirus are inoculated in Hep-2 cell or the hala cell or the HEKC of the individual layer of having grown up respectively, hatch for 37 ℃, every day observation of cell pathology situation, when cytopathogenic effect (CPE) occurs +++when above or detect positive through virus antigen, collecting cell and supernatant, inactivation of virus after ultrasonicly smash, stored frozen; Or the gene order of pressing respiratory syncytial virus and adenovirus is expressed the preparation protective antigen with gene engineering method;
2) purified virus antigen
Form sediment that layer concentrates or with discontinuous gradient density centrifugation purified virus antigen with sucrose, or chromatography adsorption column method purified virus antigen; With the ultrasonic respiratory syncytial virus of smashing and adenovirus antigen 5000 * 9 centrifugal 20 minutes, discard sediment and stay supernatant, pack into the discontinuous gradient density centrifugation pipe of 15%, 30%, 45%, 60% sucrose preparation, ultracentrifugation, 165000 * 9g, centrifugal 2 hours, determine this centrifuge tube position, virus place, sucking-off stored frozen according to the molecular weight of virus;
3) set up screening height tire specificity anti respiratory syncytial virus and adenovirus immune globulin whitening method
Wrap by the enzyme plate with the respiratory syncytial virus and the adenovirus antigen 10 μ g/ml～20 μ g/ml that extract, set up the ELISA method or set up immunofluorescence method or set up biochip method, in order to screening normal population donate blood in the source height tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) with virus antigen with the cell of virus infection; And determine tire effective initial concentration of specific immunoglobulin of height with methods such as neutralization tests;
4) with the raw material of aforesaid method screening with cold ethanol method or ion exchange chromatography method or affinity chromatography extraction height tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig);
5) anti respiratory syncytial virus after purifying and adenovirus immunoglobulin (Ig) be through 60 ± 1 ℃, 10 hours inactivation of viruses and/or in pH value 4.1 ± 0.3, and 21 days inactivation of viruses of placement again through Sterile Filtration, are distributed into antiviral immunoglobulin under 24 ± 1 ℃ of conditions.
2. as right 1 described anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that: the tire raw material of specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) of height that contains with cold ethanol partition method or ion exchange chromatography method or affinity chromatography screening extracts height tire specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig), and raw material is selected from down group: the intermediate product that contains specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) of human plasma, human serum, cold ethanol partition method.
3. as right 2 described anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that: the alcohol concn that separates specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) with the cold ethanol partition method is 15%～25%; PH is 5.1～7.2; Temperature is-3 ℃～-7 ℃.
4. as right 1 described anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that, if respiratory syncytial virus and the adenovirus antigen purity extracted are lower than 97%, improve purity with ion exchange chromatography, use contains the ion exchange resin of DEAE-or S-group, directly adsorb the impurity except that the specificity antivirus immunoglobulin (Ig), thereby directly wear the antiviral immunoglobulin that liquid obtains purifying from stream, wherein condition is that pH is 5.0～6.8;
Described ion exchange resin is selected from down group: DEAE-Sepharose, DEAE-Sepharose FF, S-Sepharose, S-Sepharose FF and DEAE-SepHadx A-50.
5. anti respiratory syncytial virus as claimed in claim 4 and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that: when tiring specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) with ion exchange chromatography extraction height, raw material is through DEAE-Sepharose CL-6B or DEAE-Sepharose FF post, and anti respiratory syncytial virus and adenovirus immunoglobulin (Ig) stream pass post; Equilibrium conditions is pH5.0～6.0, and ionic strength is 0.01～0.03.
6. as right 4 described anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that, described ion exchange chromatography stream passes the antiviral immunoglobulin of post again by Lysine-Sepharose 4B, after will penetrating liquid and washing also merging, add SP-SephadexC50 or CM-Sepharose FF absorption, use the glycine of pH11 to parse the specificity antivirus immunoglobulin (Ig); Equilibrium conditions is a pH value 6.0～5.4; Analysis condition is the glycine of pH11.
7. anti respiratory syncytial virus as claimed in claim 1 and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that, when described affinity chromatography extraction height is tired specificity anti respiratory syncytial virus and adenovirus immunoglobulin (Ig), raw material is carried out after damping fluid handles, pass through affinity column, the specificity antivirus immunoglobulin (Ig) passes affinity column, the specificity antivirus immunoglobulin (Ig) carries out ion exchange chromatography, thereby obtains the specificity antivirus immunoglobulin (Ig) of purifying;
The solid carrier of affinity chromatography is selected from: Sephadex, PDX, Sephacryl, Sepharose, Sepharose CL, Sepharose FF, Superdex, Superose, Trisaceyl, Trisacylplus, Ultrogel A, Ultrogel AcA, highly porous regenerated cellulose pearl; The salt concn of damping fluid is 0.004～0.04, and the pH value is 4.8～9.2.
8. as right 1 described anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that: described immunofluorescence technique is, with respiratory syncytial virus and adenovirus inoculation Hep-2 or Hela cell, after pathology appears in cell, scrape cell, with PH7.2,0.01M the PBS damping fluid is washed 3 times, preparation antigen sheet, after cold acetone is fixing, stored frozen, get serum to be checked or blood plasma, after dilution, be added on the antigen sheet and hatch, after washing, add goat-anti people fluorescence antibody, observe under fluorescent microscope, normal Hep-2 or Hela cell antigen sheet are done negative control, result of determination.
9. as right 1 described anti respiratory syncytial virus and the adenovirus height specific immunoglobulin preparation method that tires, it is characterized in that, described biochip method is: with millipore filtration is carrier, solidify and go into respiratory syncytial virus and adenovirus antigen, utilize the diafiltration of millipore filtration, concentrate, agglutination, make the antigen on serum from blood donors to be checked or blood plasma and the carrier carry out rapid reaction, again with the direct reaction solution on film of anti-human IgG marker, reacted chip is put into the chip reading system, under the support of the software of special use, gray-scale value to different dot matrix is analyzed, thereby realizes the rapid screening to respiratory syncytial virus and adenovirus specific IgG antibodies.
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| CN 03134442 CN100349918C (en) | 2003-07-30 | 2003-07-30 | Method for preparing specific Immunoglobulin of cystvirus and adenovirus in respiratory tract |
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| CN 03134442 CN100349918C (en) | 2003-07-30 | 2003-07-30 | Method for preparing specific Immunoglobulin of cystvirus and adenovirus in respiratory tract |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102507933A (en) * | 2011-10-27 | 2012-06-20 | 遵义医学院 | Detecting method for respiratory syncytial virus |
| CN105601736A (en) * | 2016-01-28 | 2016-05-25 | 哈尔滨派斯菲科生物制药股份有限公司 | Respiratory syncytial virus resistance human immune globulin and preparation method thereof |
| CN107064503A (en) * | 2017-05-16 | 2017-08-18 | 上海兰卫医学检验所股份有限公司 | The determination methods and device of a kind of syphilis helicoid antibody testing result |
-
2003
- 2003-07-30 CN CN 03134442 patent/CN100349918C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102507933A (en) * | 2011-10-27 | 2012-06-20 | 遵义医学院 | Detecting method for respiratory syncytial virus |
| CN102507933B (en) * | 2011-10-27 | 2013-10-02 | 遵义医学院 | Detecting method for respiratory syncytial virus |
| CN105601736A (en) * | 2016-01-28 | 2016-05-25 | 哈尔滨派斯菲科生物制药股份有限公司 | Respiratory syncytial virus resistance human immune globulin and preparation method thereof |
| CN105601736B (en) * | 2016-01-28 | 2019-04-23 | 哈尔滨派斯菲科生物制药股份有限公司 | A kind of anti respiratory syncytial virus human immunoglobulin(HIg) and preparation method thereof |
| CN107064503A (en) * | 2017-05-16 | 2017-08-18 | 上海兰卫医学检验所股份有限公司 | The determination methods and device of a kind of syphilis helicoid antibody testing result |
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| CN100349918C (en) | 2007-11-21 |
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