CN108144052A - Streptococcus pneumoniae polysaccharides-protein conjugate and its preparation method and purposes - Google Patents
Streptococcus pneumoniae polysaccharides-protein conjugate and its preparation method and purposes Download PDFInfo
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- CN108144052A CN108144052A CN201611099458.2A CN201611099458A CN108144052A CN 108144052 A CN108144052 A CN 108144052A CN 201611099458 A CN201611099458 A CN 201611099458A CN 108144052 A CN108144052 A CN 108144052A
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
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Abstract
A kind of proteinpolysaccharide conjugate with immunogenicity, the conjugate being made of high-pressure homogeneous processed streptococcus pneumoniae capsular polysaccharide and protein have immunogenicity, the preparation available for streptococcus pneumonia combined vaccine.The method provided by the invention for preparing the proteinpolysaccharide conjugate with immunogenicity, it is degraded using physical degradation methods to the capsular polysaccharide of purifying, so that participating in covalently bound polysaccharide reactant solubility increases, solution viscosity reduces, avoid the generation of gelatin phenomenon in reaction, conducive to the progress of reaction, convenient for being purified to proteinpolysaccharide conjugate.
Description
Technical field
The present invention relates to a kind of covalent conjugates more particularly to a kind of polysaccharide and protein by sewing obtained by covalent bond
Close object and the method for producing this kind of conjugate and the application in Streptococcus pneumoniae vaccine is produced.
Background technology
Streptococcus pneumonia (Streptococcus pneumoniae) is a kind of spherical gram sun under streptococcus
Property bacterium, have d hemolytics.By the pneumonia that streptococcus pneumonia is led to most frequently occurred in young or old people.Pneumonia chain
Coccus is also a kind of germ for generally leading to adult's bacterial infection meningitis.In addition, streptococcus pneumonia can also cause it is not of the same race
The disease of class, such as：Acute sinusitis, tympanitis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis and bee
Nest tissue inflammation etc..
Treatment can use B lactam antibiotics mostly by pneumococcal disease.In early days, almost all pneumonia streptococcus
The bacterial strain of bacterium is all to penicillin-susceptible, and with the raising of antibiotic utilization rate, germ also rises the resistance of antibiotic
Trend.
From 2000, a kind of streptococcus pneumonia combined vaccine of septivalency was proposed use in the U.S., is mainly suitable for 2 months
~23 months big babies or the child of 2 years old~5 years old can protect child from the deep seated infections of streptococcus pneumonia, such as：Sepsis
Disease and meningitis.
Streptococcus pneumonia can generate pod membrane in humans and animals body.According to the difference of polysaccharide antigen in pod membrane by pneumonia
Coccus is divided into 91 serotypes.
Chinese invention patent application 200680017776.8 discloses a kind of multivalent pneumococcal polysaccharide-protein conjugate
Composition, it includes 13 kinds of different polysaccharide-protein conjugates and physiologically acceptable carrier, wherein each is sewed
Close the Capsular polysaccharides that object includes the streptococcus pneumonia from different serotypes for being conjugated to carrier protein, and the Capsular polysaccharides
It is prepared from serotype 1,3,4,5,6A, 6B, 7F, 9V, 14,18C, 19A, 19F and 23F, wherein the carrier protein is CRM197.
The relative molecular mass of streptococcus pneumoniae capsular polysaccharide is larger, usually in 1,000KD~3,000KD.For containing
The immunogenic substance of polysaccharide, the numerical value of the relative molecular mass of polysaccharide are to ensure an antigenic important indicator.Opposite point
Protonatomic mass is bigger, and antigenicity is stronger, and the reduction of relative molecular mass may be along with antigenic loss.But for polysaccharide-egg
The conjugate of white matter, huge polysaccharide molecule during being combined with protein carrier there are many technical problems, such as：It is more
The solubility of sugar is too low, polysaccharide solution viscosity is excessively high, easily generation is cross-linked to form gel and combines during association reaction
Object complexity and purification difficult etc., the residual quantity for thus leading to reactant in conjugate is larger, and dissociation amylase content is higher, and reaction is received
Rate is relatively low, and the best immunogenicity of conjugate and the molecular size of polysaccharide fragment in conjugate have substantial connection.
Invention content
It is an object of the present invention to provide a kind of polysaccharide-protein conjugate with immunogenicity, convenient for conjugated
Object being produced and detaching, and immunogenicity is also retained.
It is another object of the present invention to provide a kind of sides for producing the polysaccharide-protein conjugate with immunogenicity
Method optimizes the combined process of capsular polysaccharide and carrier protein, improves joint efficiency and conjugate yield rate, improves conjugate stoste
Stability and immunogenicity, convenient for subsequent purifying and application.
It is yet a further object of the present invention to provide a kind of polysaccharide-protein conjugates with immunogenicity to prepare lung
Application in scorching streptococcus combined vaccine.
A kind of polysaccharide-protein conjugate with immunogenicity, by coming from streptococcus pneumonia, (serotype is such as：1、2、
3、4、5、6A、6B、7F、8、9N、9V、10A、11A、12F、14、15B、16F、17F、18C、19A、19F、20、20F、23A、23F
And 33F) capsular polysaccharide, the molecular weight of capsular polysaccharide is 150,000Da~400,000Da (especially 200,000Da~300,
000Da) the conjugate formed with protein.
Another kind has the polysaccharide-protein conjugate of immunogenicity, by coming from 18C serotype S. pneumoniae capsulars
Conjugate of the molecular weight of polysaccharide for 150,000Da~400,000Da and CRM197 protein composition.
Another kind has the polysaccharide-protein conjugate of immunogenicity, by coming from 18C serotype S. pneumoniae capsulars
Conjugate of the molecular weight of polysaccharide for 200,000Da~300,000Da and CRM197 protein composition.
A kind of method for producing the polysaccharide-protein conjugate with immunogenicity, first using physical shear by pneumonia chain
Coccus capsular polysaccharide is degraded, then ultrafiltration enrichment, obtains the capsular polysaccharide of degradation, then more to the pod membrane of degradation by activator
Sugar is activated, and is adjusted pH value, then the capsular polysaccharide of the degradation of activation and CRM197 albumen are mixed, in room temperature, is made degradation
Capsular polysaccharide and CRM197 protein-interactings 30 minutes~add in after sixty minutes terminator, reaction system in low temperature (such as：2
DEG C~8 DEG C) under overnight (such as：16 hours~24 hours) after, it is filtered with clarification filter, ultrafiltration membrane concentration dialysis, so as to obtain lung
Scorching Streptococcus polysaccharides and protein conjugate unit price stoste.
Physical shear method is such as：Emulsification and homogeneous are (such as：It is high-pressure homogeneous).Under physical shear effect, big point in solution
Son is crushed chain rupture under strong shearing, shock and cavitation, degrades so as to cause it, but its structural unit is substantially not
Become.
The effect of homogeneous is the heterogeneity in homodisperse same system, breaks up or refine the insoluble phase in liquid
Grain forms the solution of stable uniform.
Material enters homogenizing valve under the impetus of plunger, is pressurized and discharges in homogenizing valve.In the process, object
Material is by a variety of effects：Cavitation, the high-frequency vibration effect of great turbulence level, the shear action with homogenizing valve edge, with homogeneous
The effect of impact of valve guard ring.
Homogeneous can be divided into：Bead mill method (belong to solid shear effect, up to higher percentage of damage, fairly large can operate, big point
Sub- purpose product easy in inactivation, slurries separation are difficult), high pressure homogenization method (belong to liquid shear effect, can up to higher percentage of damage
Large-scale operation, for a small amount of material ＜ 100ml, hardly possible operation), sonioation method (belongs to liquid shear effect, saccharomycete imitated
Fruit is poor, and shattering process heating is violent, is not suitable for large-scale operation) and X-press methods (belong to solid shear effect, it is broken
Rate is high, and activity preservation rate is high, and to freezing, sensitive purpose product is not suitable for).
Activator is such as：1- cyano -4- Dimethylamino-pyridines tetrafluoro boric acid, cyanogen bromide and sodium metaperiodate etc..These compounds
Individually and combination application is in the present invention.Dosage is the 50w/w%~100w/w% of polysaccharide (capsular polysaccharide degraded) weight,
Such as：But be not limited only to 50w/w%, 55w/w%, 60w/w%, 65w/w%, 70w/w%, 75w/w%, 80w/w%, 85w/w%,
90w/w%, 95w/w% and 100w/w% etc., especially 65w/w%~80w/w%.
The pH of capsular polysaccharide and CRM197 protein-interactings is 8.90~9.60, and temperature is room temperature, the time for 3 minutes~
5 minutes.
Empirical tests, the polysaccharide-protein conjugate produced have immunogenicity, add excipient and use is made in auxiliary agent
In the vaccine that streptococcus pneumonia prevents.
The advantageous effect that technical solution of the present invention is realized：
The present invention degrades to the capsular polysaccharide of purifying using physical degradation methods, have easy to operate, degradation efficient and
The characteristics of controllability is good.Clipped polysaccharide relative molecular mass distribution is concentrated, and can be suitble to large-scale production with Linear Amplifer.
The present invention degrades to the capsular polysaccharide of purifying using physical degradation methods so that it is anti-to participate in covalently bound polysaccharide
Object solubility is answered to increase, solution viscosity reduces, and avoids the generation of gelatin phenomenon in reaction, conducive to the progress of reaction, convenient for pair
Polysaccharide-protein conjugate is purified.
Description of the drawings
Fig. 1 is the ELISA testing results of polysaccharide-protein conjugate after present invention degradation；
Fig. 2 is the ELISA testing results of the undegradable 18C polysaccharide-protein conjugates of the present invention.
Specific embodiment
Below in conjunction with attached drawing detailed description of the present invention technical solution.The embodiment of the present invention is only to illustrate the skill of the present invention
Art scheme and it is unrestricted, although the present invention is described in detail with reference to preferred embodiment, those of ordinary skill in the art
It should be appreciated that the technical solution of invention can be modified or replaced equivalently, without departing from the essence of technical solution of the present invention
God and range, should all cover in scope of the presently claimed invention.
Embodiment 1
The present embodiment is by comparing the pneumococcal capsular polysaccharide of control standard items and test sample to a kind or more serotype
Carry out it is qualitative, such as：Table 1 lists the discriminating reference information of several serotype capsular polysaccharide, passes through nuclear magnetic resonance spectroscopy spy
It levies region to confirm, obtained collection of illustrative plates is integrated, and by comparison reference standards and test sample with qualitative.
The reagent used：1) heavy water：Sigma heavy water, purity 99%；2) standard polysaccharide：Purchased from serum research institute of Denmark
(SSI)。
Measuring method：The standard polysaccharide 5mg of test serum type is taken, adds in heavy water 1ml, abundant mixing after redissolution, freeze-drying is overnight.
Fully mixing is to get 5mg/ml standard polysaccharide solutions after rejoining the redissolution of 1ml heavy water.600 μ l of sample are measured in nuclear magnetic tube
Put 600M nuclear magnetic resonance measurings.Test sample separately is taken, is measured in the same method.
Table 1
Embodiment 2
The popular highest serotype 18C pneumococcus of selection China, by physical shear 18C capsular polysaccharides, is dropped
The capsular polysaccharide of solution.
The present embodiment uses ATS homogenizers, has that crushing efficiency is high, treating capacity is big, moment crushes, and residence time of material is few
In 1 second and the features such as cooling in place (ensureing that drop temperature is less than 10 degree).
Through Sephacry1S-300 (XK-50) column separating purification, Fractional Collections, it is 200,000Da to obtain between molecular weight area
Several polysaccharide chains of~300,000Da.Molecular weight is measured using high pressure liquid technology, so as to the physical shear to macromolecular polysaccharide
Technique optimizes.
Embodiment 3
Polysaccharide activator is used as by 1- cyano -4- Dimethylamino-pyridines tetrafluoro boric acids (CDAP), activates the pod membrane of purifying
Polysaccharide (undegraded) and the capsular polysaccharide degraded through physical shear, and carry out coupling with CRM197 and combine (referring to FEBS
Letters, 1983,154,209~210), polysaccharide-CRM197 protein conjugates are made.
Specific method is：Capsular polysaccharide solution (5mg/ml~10mg/ml) after undegradable 18C capsular polysaccharides and degradation
It is mixed with CDAP solution (CDAP dosages are 50w/w%~100w/w% of polysaccharide total amount), with adjustment pH to 8.90~9.60, room
Temperature activation 1 minute~5 minutes.Then CRM197 albumen is added in, room temperature acts on 30 minutes~60 minutes；Add excessive glycine
Terminate reaction system, room temperature 30 minutes.Reactant finally is placed in 2 DEG C~8 DEG C to react 16 hours~24 hours.
Centre sampling detection KD values (constant of characterization polysaccharide and protein binding rate), treat that conjugate will be reacted after reaction
It clarified, concentrated and ultrafiltration dialysis, to remove floating preteins and reaction reagent.
For the capsular polysaccharide after undegradable 18C capsular polysaccharides and degradation, with protein combining ratio referring to table 2.
Analyze the ratio (0.3~3.0) of sugar/albumen in conjugate, association reaction yield (being more than 20%) and antigenicity (in detail
See embodiment 4 and 5).
Table 2
Using the KD values of HPLC detection conjugates, the total starches content in stoste is detected using anthrone method for data in table 2
And dissociation amylase content, Lowry methods detect total protein content and HPLC in stoste and measure Free protein content and remaining reagent
Deng.
Embodiment 4
The different size of polysaccharide fragment of ELISA method detection is to 18C type streptococcus pneumoniae polysaccharides protein conjugate immunogenics
Influence, test method is as follows：
(1) standard polysaccharide coating elisa plate per 100 μ l of hole, is placed in 4 DEG C of coatings overnight.(2) it after being coated with, takes out
Elisa plate, discards coating buffer, and PBST board-washings 3 times add in the closing of 150 μ l confining liquids, 37 DEG C of incubation 60min.(3) closing terminates
Afterwards, elisa plate is taken out, discards confining liquid.(4) immune serum is added in, per hole 100 μ l, 37 DEG C of incubation 90min.(5) board-washing, side
The same step of method (3).(6) sheep anti mouse HRP-IgG is added in, per hole 100 μ l, 37 DEG C of incubation 1h.(7) board-washing, the same step of method (3).
(8) TMB is added in, per 100 μ l of hole, 4.5min is placed in dark place.(9) terminate liquid stopped reaction is added in.(10) in 450nm~620nm
Carry out enzyme mark reading.
Result of the test is referring to table 3 and its corresponding Fig. 1.
The ELISA testing results of polysaccharide-protein conjugate after table 3 is degraded
Embodiment 5
The polysaccharide protein conjugate immunization experiment mouse of purifying, and be sampled, experimentation is as follows：
18C polysaccharide-CRM conjugates stoste carries out intraperitoneal injection NIH mouse (females the 0th week, 2 weeks and 4 weeks respectively：10g
~12g, 30), each every injection dosage 0.5ml (about 2.2 μ g conjugates) respectively took 10 respectively at the 2nd week, 4 weeks and 6 weeks
Mouse, eyeball blood sampling, centrifuges serum, not higher than -20 DEG C preservations.
Result of the test is referring to its corresponding Fig. 2 of table 4.
The ELISA testing results of 4 undegradable 18C polysaccharide-protein conjugates of table
By 5 the data obtained of embodiment 4 and embodiment (table 3 and table 4 and corresponding Fig. 1 and Fig. 2) as it can be seen that exempting from every time
Sample antibody dramatically increases after epidemic disease, is improved to the 6th week antibody titer the most apparent.
Claims (14)
1. a kind of polysaccharide-protein conjugate with immunogenicity, it is characterised in that by molecular weight be 150,000Da~400,
The conjugate of the polysaccharide of 000Da and protein composition, the polysaccharide come from streptococcus pneumoniae capsular polysaccharide.
2. the polysaccharide-protein conjugate according to claim 1 with immunogenicity, it is characterised in that the polysaccharide
By the streptococcus pneumoniae capsular polysaccharide being emulsified or high-pressure homogeneous method is produced.
3. the polysaccharide-protein conjugate according to claim 1 with immunogenicity, it is characterised in that the albumen
Matter is CRM197 albumen.
4. the polysaccharide-protein conjugate according to claim 1 with immunogenicity, it is characterised in that the polysaccharide
Molecular weight be 200,000Da~300,000Da.
5. the polysaccharide-protein conjugate according to claim 1 with immunogenicity, it is characterised in that the pneumonia chain
The capsular polysaccharide of coccus be taken from serotype for 1,2,3,4,5,6A, 6B, 7F, 8,9N, 9V, 10A, 11A, 12F, 14,15B,
16F, 17F, 18C, 19A, 19F, 20, the streptococcus pneumonias of the one or more of 20F, 23A, 23F and 33F.
A kind of 6. method for producing the polysaccharide-protein conjugate described in claim 1 with immunogenicity, it is characterised in that
First streptococcus pneumoniae capsular polysaccharide is degraded using physical shear, then ultrafiltration enrichment, obtain the capsular polysaccharide of degradation, then lead to
It crosses activator to activate the capsular polysaccharide of degradation, adjusts pH value, then by the capsular polysaccharide of the degradation of activation and CRM197 eggs
It mixes in vain, in room temperature, makes the 30 minutes~addition termination after sixty minutes of capsular polysaccharide and CRM197 protein-interactings of degradation
Agent after reaction system is stayed overnight at low temperature, is filtered, ultrafiltration membrane concentration dialysis with clarification filter, so as to obtain pneumococal polysaccharide
With protein conjugate unit price stoste.
7. according to the method described in claim 6, it is characterized in that activator is selected from 1- cyano -4- Dimethylamino-pyridines four
The one or more of fluoboric acid, cyanogen bromide and sodium metaperiodate.
8. according to the method described in claim 6, it is characterized in that the activator dosage for polysaccharide total amount 50w/w%~
100w/w%.
9. according to the method described in claim 6, it is characterized in that the pH of the polysaccharide and CRM197 protein-interactings is
8.90~9.60.
10. the according to the method described in claim 6, it is characterized in that temperature of the polysaccharide and CRM197 protein-interactings
For room temperature.
11. the according to the method described in claim 6, it is characterized in that time of the polysaccharide and CRM197 protein-interactings
It is 1 minute~5 minutes.
12. according to the method described in claim 6, it is characterized in that the low temperature is 2 DEG C~8 DEG C.
13. according to the method described in claim 6, it is characterized in that described is 16 hours~24 hours overnight.
14. the polysaccharide-protein conjugate according to claim 1 with immunogenicity is preparing streptococcus pneumonia combination
Application in vaccine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981990A (en) * | 2019-12-20 | 2020-04-10 | 常州药物研究所有限公司 | Method for preparing sodium hyaluronate with controllable molecular weight |
| CN112741901A (en) * | 2019-10-31 | 2021-05-04 | 北京科兴中维生物技术有限公司 | Vaccine containing streptococcus pneumoniae capsular polysaccharide type 5 and preparation method thereof |
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| CN103830723A (en) * | 2012-11-26 | 2014-06-04 | 天士力制药集团股份有限公司 | Preparation method of streptococcus pneumoniae capsular polysaccharide protein conjugate vaccine |
| CN106102770A (en) * | 2014-01-21 | 2016-11-09 | 辉瑞公司 | Comprise immunogenic composition of conjugated capsular CA and application thereof |
| WO2016178123A1 (en) * | 2015-05-04 | 2016-11-10 | Pfizer Inc. | Group b streptococcus polysaccharide-protein conjugates, methods for producing conjugates, immunogenic compositions comprising conjugates, and uses thereof |
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2016
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| CN101378779A (en) * | 2005-12-22 | 2009-03-04 | 葛兰素史密丝克莱恩生物有限公司 | Vaccine |
| CN103830723A (en) * | 2012-11-26 | 2014-06-04 | 天士力制药集团股份有限公司 | Preparation method of streptococcus pneumoniae capsular polysaccharide protein conjugate vaccine |
| CN106102770A (en) * | 2014-01-21 | 2016-11-09 | 辉瑞公司 | Comprise immunogenic composition of conjugated capsular CA and application thereof |
| WO2016178123A1 (en) * | 2015-05-04 | 2016-11-10 | Pfizer Inc. | Group b streptococcus polysaccharide-protein conjugates, methods for producing conjugates, immunogenic compositions comprising conjugates, and uses thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112741901A (en) * | 2019-10-31 | 2021-05-04 | 北京科兴中维生物技术有限公司 | Vaccine containing streptococcus pneumoniae capsular polysaccharide type 5 and preparation method thereof |
| CN112741901B (en) * | 2019-10-31 | 2024-05-10 | 北京科兴中维生物技术有限公司 | Vaccine containing streptococcus pneumoniae capsular polysaccharide type 5 and preparation method thereof |
| CN110981990A (en) * | 2019-12-20 | 2020-04-10 | 常州药物研究所有限公司 | Method for preparing sodium hyaluronate with controllable molecular weight |
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Application publication date: 20180612 |