CN114210310B - Preparation method and application of hepatitis B virus and HBsAg immunoadsorption material - Google Patents
Preparation method and application of hepatitis B virus and HBsAg immunoadsorption material Download PDFInfo
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Abstract
The invention provides a preparation method and application of a hepatitis B virus and HBsAg immunoadsorption material. In the method, in the process of carrying out coupling reaction between the aldehyde crosslinked agarose microsphere and the hepatitis B virus antibody solution, a proper amount of triethylamine is added as a catalyst to improve the coupling efficiency, and a small amount of acid is added to protect the activity of the antibody, so that the adsorption rate of the finally prepared immunoadsorption material on the hepatitis B virus and the HBsAg in positive serum of a patient with hepatitis B can reach more than 97%, and the adsorption effect is obvious. The immunoadsorption material prepared by the invention can directly, efficiently and selectively adsorb the hepatitis B virus and the HBsAg from the blood plasma, can effectively reduce the hepatitis B virus and the HBsAg in the blood of a patient by one perfusion, and has higher practical value.
Description
Technical Field
The invention relates to the technical field of immunoadsorption material preparation, in particular to a preparation method and application of a hepatitis B virus and HBsAg immunoadsorption material.
Background
Hepatitis B (HB) is a major liver disease facing the world, mainly caused by infection of hepatitis B virus (hepatitis B virus, HBV), including acute and chronic hepatitis, and some chronic hepatitis patients develop cirrhosis or liver cancer.
At present, two common means for preventing and treating hepatitis B are available, namely, the prevention is carried out by injecting hepatitis B vaccine; and secondly, drug therapy. However, both control methods have obvious drawbacks: 1. the injection of hepatitis B vaccine is the most effective method at present for preventing and treating hepatitis B, but the effectiveness of the hepatitis B vaccine is only 45% due to the escape phenomenon of viruses on the vaccine, so that the majority of people are directly exposed to the risk of being infected by the hepatitis B virus. 2. For the infected person, the current method for effectively controlling the course of disease is antiviral drug therapy, however, these drugs mainly act by inhibiting viral activity and reducing viral load, and cannot effectively clear HBsAg (hepatitis b surface antigen). Studies have shown that a large amount of HBsAg in patient serum is a significant cause of immune tolerance in chronic HBV patients. And the patients can generate drug resistance after taking antiviral drugs for a long time, so that the treatment effect is reduced.
The immunoadsorption therapy is a new therapeutic technology, mainly used for treating diseases which are difficult to treat by using traditional methods, and the principle is that a certain antibody and antigen or certain ligand with specific adsorption performance are fixed on a carrier, and the adsorption performance of the ligand is utilized to selectively or specifically remove toxic proteins or other endogenous pathogenic factors in the blood of a patient, so that the purposes of purifying the blood, relieving the symptoms and treating the diseases are achieved. The therapy has better effect in clinical treatment of immune diseases, such as systemic lupus erythematosus, myasthenia gravis, rheumatic diseases and the like.
The patent with publication number CN111659355A provides an alkylation modified hepatitis B virus immunoadsorbent and a preparation method thereof, wherein the method takes an antibody as a ligand, and requires alkylation modification, so that the preparation process is complex and the cost is high. The patent with publication number CN112844331A provides a hepatitis B virus adsorbent based on a nano structure, a preparation method and application thereof, and DNA nano material is used as an intermediate structure for connecting an aptamer and an adsorption carrier. The patent with publication number of CN112717902A provides a hepatitis B virus adsorbent, a preparation method and application thereof, and uses nucleic acid aptamer to replace antibody as adsorption ligand, which can reduce cost, but the adsorption efficiency of the aptamer is far lower than that of monoclonal antibody, thus being unfavorable for clinical patients.
Therefore, the hepatitis B virus adsorbent prepared by the prior art has the problems of complicated preparation steps and unfavorable mass production, and the prepared adsorbing material has low adsorption rate on positive serum of hepatitis B patients due to the complexity of positive serum components of the hepatitis B patients.
In view of the foregoing, there is a need for an improved method of preparing hepatitis B virus and HBsAg immunoadsorption materials that addresses the above-described problems.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a preparation method and application of an hepatitis B virus and HBsAg immunoadsorption material. According to the method, triethylamine is added as a catalyst during coupling of the hepatitis B antibody to improve the coupling efficiency, and acid is added to protect the activity of the antibody, so that the coupling rate is improved, the dosage of monoclonal antibodies is reduced, the cost is reduced, and the adsorption performance of the immunoadsorption material is indirectly improved.
In order to achieve the aim of the invention, the invention provides a preparation method of an immunoadsorption material for hepatitis B virus and HBsAg, which comprises the following steps:
s1, hydroformylation of crosslinked agarose microspheres: washing and draining the crosslinked agarose microspheres by using purified water, mixing the crosslinked agarose microspheres with an oxidant solution, carrying out an oscillating reaction, and fully washing and draining the crosslinked agarose microspheres by using purified water after the reaction is finished to obtain the aldehyde crosslinked agarose microspheres;
s2, antibody coupling: mixing the aldehyde-based cross-linked agarose microsphere obtained in the step S1 with triethylamine, then adding acid, then adding a hepatitis B virus antibody solution, and oscillating to perform a coupling reaction; after the reaction is finished, adding sodium borohydride solution to terminate the reaction; and (3) alternately washing and pumping the adsorption material by ethanol and purified water to obtain the hepatitis B virus and HBsAg immunoadsorption material.
As a further improvement of the present invention, in step S2, the acid is acetic acid or dilute hydrochloric acid.
As a further improvement of the invention, the concentration of acetic acid in the solution of the coupling reaction is 0.2-0.8 mol/L, and the concentration of dilute hydrochloric acid is 0.001-0.01 mol/L.
As a further improvement of the invention, the mass volume ratio of the aldehyde group cross-linked agarose microsphere to the triethylamine is 1 g:0.005-0.05 mL, and the mass volume ratio of the aldehyde group cross-linked agarose microsphere to the hepatitis B virus antibody solution is 1 g:0.5-4 mL.
As a further improvement of the present invention, the antibody concentration of the hepatitis B virus antibody solution is 1 to 4mg/mL.
As a further improvement of the invention, in the step S2, the temperature of the oscillation reaction is 4-25 ℃, the time is 8-18 h, and the shaking speed is 120rpm.
As a further improvement of the present invention, in step S2, the hepatitis b virus antibody is a murine or human monoclonal antibody.
The invention also improves the application of the hepatitis B virus and HBsAg immunoadsorption material prepared by any one of the preparation methods, and the hepatitis B virus and HBsAg immunoadsorption material is used in the blood adsorption field.
The beneficial effects of the invention are as follows:
1. according to the preparation method of the hepatitis B virus and HBsAg immunoadsorption material, provided by the invention, the immunoadsorption material is obtained by coupling the cross-linked agarose microspheres with the hepatitis B virus antibody, wherein the hepatitis B virus antibody is a murine or human monoclonal antibody, the specificity is strong, and the adsorption efficiency is high. The immunoadsorption material is prepared through two steps of activation of cross-linked agarose microsphere and coupling of antibody, and the reaction principle of the immunoadsorption material is shown in figure 1: the activated agarose microsphere with aldehyde group is coupled with the antibody with amino group, and after the coupling is finished, the reaction is stopped under the action of sodium borohydride, so that the antibody can be stably fixed on the agarose microsphere. The immunoadsorption material has simple and efficient production process and is suitable for large-scale production.
2. According to the invention, triethylamine is added as a catalyst during antibody coupling to improve coupling efficiency, so that the dosage of monoclonal antibodies is saved, the cost is reduced, and the adsorption performance of the immunoadsorption material is indirectly improved. Triethylamine is an organic compound, has the chemical property of tertiary amine, has N atom nucleophilicity stronger than that of an amino group of an antibody, and the N atom of the triethylamine attacks a C atom with positive charge on an aldehyde group of an agarose microsphere, so that the coupling reaction is easier to occur, and the fixing efficiency of the antibody is higher. Monoclonal antibodies, although having high affinity, are expensive, and can be lost during the preparation of the adsorbent material and difficult to recover. Therefore, the triethylamine is added as the catalyst in the preparation process of the adsorbent, so that the fixing efficiency of the antibody can be improved, the feeding amount of the antibody is reduced, the preparation cost of the adsorbent material can be effectively reduced, and the adsorption efficiency of the adsorbent material is indirectly improved.
3. In the invention, triethylamine is added as a catalyst, and acid is also added to protect the activity of the antibody. The hepatitis B virus monoclonal antibody used in the invention has an alkaline isoelectric point, and the triethylamine aqueous solution is alkaline, so that the antibody is easy to aggregate or inactivate. Meanwhile, triethylamine is an organic compound, is harmful to human bodies, is difficult to remove in a reaction system, and increases production cost if an organic solvent is added for extraction. After the acid is added, the acid reacts with triethylamine to form salt which can be removed by washing with ethanol. Therefore, the addition of the acid ensures the activity of the hepatitis B virus monoclonal antibody, and simultaneously ensures that the adsorbent can be conveniently and rapidly cleaned without increasing the production cost.
Drawings
Fig. 1 is a schematic diagram of the preparation principle of the hepatitis b virus and HBsAg immunoadsorption material provided by the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail with reference to specific embodiments.
It should be further noted that, in order to avoid obscuring the present invention due to unnecessary details, only structures and/or processing steps closely related to aspects of the present invention are shown in the specific embodiments, and other details not greatly related to the present invention are omitted.
In addition, it should be further noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Referring to fig. 1, the preparation method of the hepatitis b virus and HBsAg immunoadsorption material provided by the invention comprises the following steps:
s1, hydroformylation of crosslinked agarose microspheres: washing and draining the crosslinked agarose microsphere with purified water, mixing with an oxidant solution, carrying out oscillation reaction, and fully washing and draining the crosslinked agarose microsphere with purified water after the reaction is finished to obtain the aldehyde crosslinked agarose microsphere.
S2, antibody coupling: mixing the aldehyde-based cross-linked agarose microsphere obtained in the step S1 with triethylamine, then adding acid, then adding a hepatitis B virus antibody solution, and oscillating to perform a coupling reaction; after the reaction is finished, adding sodium borohydride solution to terminate the reaction; and (3) alternately washing and pumping the adsorption material by ethanol and purified water to obtain the hepatitis B virus and HBsAg immunoadsorption material. In the operation, triethylamine and the aldehyde-based cross-linked agarose microsphere are uniformly mixed, and then acid is added, so that a good reaction environment is constructed for the subsequent coupling of the antibody, the inactivation of the antibody can be effectively prevented, and the coupling efficiency is improved.
Among them, the acid is preferably acetic acid or dilute hydrochloric acid. The concentration of acetic acid in the solution of the coupling reaction is 0.2-0.8 mol/L, and the concentration of dilute hydrochloric acid is 0.001-0.01 mol/L. The pH value of the coupling reaction is neutral, such as 6.5-7.5. The experimental result shows that the triethylamine is added in the coupling reaction process of the hepatitis B virus antibody and the aldehyde crosslinking agarose microsphere, the triethylamine is an organic compound, the chemical property of tertiary amine is achieved, the nucleophilicity of N atoms of the triethylamine is stronger than that of N atoms on amino groups of the antibody, and the N atoms of the triethylamine attack C atoms with positive charges on aldehyde groups of the agarose microsphere, so that the coupling reaction is easier to occur, and the fixing efficiency of the antibody is higher. The method can reduce the dosage of the antibody in production, reduce the cost and indirectly improve the adsorption performance of the immunoadsorption material. The hepatitis b virus monoclonal antibody used in the present invention has an alkaline isoelectric point, and triethylamine aqueous solution is alkaline, so that the antibody is easily aggregated or inactivated. Meanwhile, triethylamine is an organic compound, is harmful to human bodies, is difficult to remove in a reaction system, and increases production cost if an organic solvent is added for extraction. After the acid is added, the acid reacts with triethylamine to form salt which can be removed by washing with ethanol. Therefore, the addition of the acid ensures the activity of the hepatitis B virus monoclonal antibody, and simultaneously ensures that the adsorbent can be conveniently and rapidly cleaned without increasing the production cost.
The mass volume ratio of the aldehyde-based crosslinked agarose microsphere to the triethylamine is 1 g:0.005-0.05 mL, and the mass volume ratio of the aldehyde-based crosslinked agarose microsphere to the hepatitis B virus antibody solution is 1 g:0.5-4 mL.
The antibody concentration of the hepatitis B virus antibody solution is 1-4 mg/mL. The hepatitis B virus antibody is a murine or human monoclonal antibody.
In the step S2, the temperature of the oscillation reaction is 4-25 ℃, the time is 8-18 h, and the shaking speed is 120rpm.
The invention also improves the application of the hepatitis B virus and HBsAg immunoadsorption material prepared by any one of the preparation methods, and the hepatitis B virus and HBsAg immunoadsorption material is used in the blood adsorption field, and the adsorption rate of the hepatitis B virus and HBsAg in positive serum of a hepatitis B patient can reach more than 97%.
Example 1
A preparation method of an immunoadsorption material for hepatitis B virus and HBsAg comprises the following steps:
activation of crosslinked agarose microspheres: washing 2g of microspheres with clear water, pumping, adding a proper amount of oxidant solution into the microspheres, oscillating for reaction, and fully cleaning with purified water.
Coupling of antibodies: adding 0.01mL of triethylamine into each 1g of microspheres, and then adding dilute hydrochloric acid to ensure that the concentration of the dilute hydrochloric acid in the reaction system is 0.002mol/L, or adding acetic acid to ensure that the concentration of the acetic acid in the reaction system is 0.4mol/L; then, a solution containing 2mg of antibody was added per 1g of the microspheres, and the reaction was carried out on a shaker at 25℃for 10 hours. After the reaction is finished, preparing 2mg/mL sodium borohydride solution, adding 15 mu L of sodium borohydride solution into each 1g microsphere, continuously reacting for 4 hours, and alternately cleaning and pumping the immunoadsorption material by using ethanol and purified water to obtain the hepatitis B virus and HBsAg immunoadsorption material.
6 batches of immunoadsorption materials were prepared according to the above method, the adsorption performance was detected by using positive serum of hepatitis B patients, and the content of hepatitis B antigen in serum before and after adsorption was tested, and the results are shown in Table 1.
TABLE 1 adsorption Performance of the adsorbent material of example 1
As can be seen from Table 1, the adsorption efficiency of the adsorption material prepared by the method on positive serum can reach more than 90%.
Examples 2 to 11 and comparative examples 1 to 4
The immunoadsorbents provided in examples 2 to 11 and comparative examples 1 to 4 are different from example 1 in the addition amount of triethylamine and the addition amount of acid, as shown in Table 2, and the remaining experimental procedures are substantially the same as in example 1, and are not repeated here. After the preparation of the adsorption material, the adsorption performance was tested by using positive serum of hepatitis B patient, and the results are shown in Table 2.
TABLE 2 adsorption Property of immunoadsorption materials of examples 2 to 11 and comparative examples 1 to 4
As can be seen from Table 2, compared with comparative examples 1 to 4, the adsorption performance of the immunoadsorbent material of the other examples except examples 5 and 10 can reach more than 80%, and the adsorption effect is much better than that of the adsorbent material of comparative examples 1 to 4. It can also be seen from examples 2, 5-7, 10-11 and comparative examples 1-3 that an excessive amount of acid or base has an effect on the activity of the antibody, resulting in a decrease in the adsorption performance of the adsorbent. The results of examples 5 and 10, and comparative example 1, however, show that when the concentration of the acid is too low, the adsorption performance is significantly reduced, indicating that the effect of the base on the antibody is greater than that of the acid. Because the isoelectric point of the hepatitis B virus monoclonal antibody is alkaline, the antibody can be aggregated in alkaline solution, so that the coupling amount to the microsphere is reduced, and the performance of the adsorption material is seriously reduced.
Examples 12 to 14 and comparative examples 5 to 7
Examples 12-14 comparative examples 5-7 provide immunoadsorbents prepared by the same method as in example 1, except that triethylamine and antibody were added in the same amounts as in example 1. After the preparation of the adsorbing material, the adsorbing performance of the adsorbing material was detected by using positive serum of hepatitis B patient, and the result is shown in Table 3.
TABLE 3 adsorption Property of the immunoadsorption materials of examples 12 to 14 and comparative examples 5 to 7
As can be seen from table 3, the adsorption performance of the examples is much better than that of the comparative examples with the same amount of antibody added. The results of examples 13 and 14 demonstrate that the adsorption performance can be maintained at about 90% even when the amount of antibody added per g of microspheres is reduced to 1mg or even 0.5 mg. Meanwhile, the results of example 12 and comparative example 5 show that the adsorption performance of adding 4mg of antibody per g of microsphere is not as good as that of adding 2mg of antibody per g of microsphere after adding the catalyst. The results show that the utilization rate of the antibody in the coupling process is not high, and the addition of the catalyst can greatly increase the utilization rate of the antibody. Because of high cost of monoclonal antibody, the method can save the dosage of monoclonal antibody and reduce the production cost of adsorption material.
In summary, the immunoadsorption material for adsorbing hepatitis B virus and HBsAg provided by the invention adopts triethylamine as a catalyst. Because the triethylamine aqueous solution is alkaline, the monoclonal antibody in the invention can be aggregated and deactivated, and acid is added while the triethylamine is added, so that the coupling system is close to neutral, and the activity of the antibody is ensured and the catalytic efficiency is ensured. And the addition of acid can lead triethylamine to form salt, so that the reagent added in the reaction process can be cleaned and removed by ethanol and water, and the triethylamine is removed by extraction without using an organic reagent, thereby being convenient for production. The preparation method of the adsorption material is simple and efficient, and has lower cost compared with the traditional method, thus having higher practical value.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention.
Claims (2)
1. A method for preparing an immunoadsorption material for hepatitis b virus and HBsAg, which is characterized by comprising the following steps:
s1, hydroformylation of crosslinked agarose microspheres: washing and draining the crosslinked agarose microspheres by using purified water, mixing the crosslinked agarose microspheres with an oxidant solution, carrying out an oscillating reaction, and fully washing and draining the crosslinked agarose microspheres by using purified water after the reaction is finished to obtain the aldehyde crosslinked agarose microspheres;
s2, antibody coupling: mixing the aldehyde-based cross-linked agarose microsphere obtained in the step S1 with triethylamine, then adding acid, then adding a hepatitis B virus antibody solution, and oscillating to perform a coupling reaction; after the reaction is finished, adding sodium borohydride solution to terminate the reaction; alternatively washing and pumping the adsorption material by ethanol and purified water to obtain a hepatitis B virus and HBsAg immunoadsorption material; the acid is acetic acid or dilute hydrochloric acid; the concentration of acetic acid in the solution of the coupling reaction is 0.2-0.8 mol/L, and the concentration of dilute hydrochloric acid is 0.001-0.01 mol/L; the mass volume ratio of the aldehyde-based cross-linked agarose microspheres to the triethylamine is 1 g:0.005-0.05 mL, and the mass volume ratio of the aldehyde-based cross-linked agarose microspheres to the hepatitis B virus antibody solution is 1 g:0.5-4 mL; the antibody concentration of the hepatitis B virus antibody solution is 1-4 mg/mL; the temperature of the oscillation reaction is 4-25 ℃, the time is 8-18 h, and the shaking speed is 120 rpm; the hepatitis B virus antibody is a murine or human monoclonal antibody.
2. The use of the hepatitis b virus and HBsAg immunoadsorption material prepared by the preparation method of claim 1, wherein the hepatitis b virus and HBsAg immunoadsorption material is used in the blood adsorption field.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4138287A (en) * | 1976-03-18 | 1979-02-06 | Ab Kabi | Purifying and isolating method for hepatitis virus to use in preparing vaccine |
| CN111659355A (en) * | 2020-06-23 | 2020-09-15 | 武汉瑞法医疗器械有限公司 | Alkylation modified hepatitis B virus immunoadsorbent and preparation method thereof |
| CN112717902A (en) * | 2020-12-31 | 2021-04-30 | 武汉瑞法医疗器械有限公司 | Hepatitis B virus adsorbent and preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4138287A (en) * | 1976-03-18 | 1979-02-06 | Ab Kabi | Purifying and isolating method for hepatitis virus to use in preparing vaccine |
| CN111659355A (en) * | 2020-06-23 | 2020-09-15 | 武汉瑞法医疗器械有限公司 | Alkylation modified hepatitis B virus immunoadsorbent and preparation method thereof |
| CN112717902A (en) * | 2020-12-31 | 2021-04-30 | 武汉瑞法医疗器械有限公司 | Hepatitis B virus adsorbent and preparation method and application thereof |
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