CN111500563A - Method for purifying human coagulation factor VII from human plasma - Google Patents
Method for purifying human coagulation factor VII from human plasma Download PDFInfo
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- CN111500563A CN111500563A CN202010383496.0A CN202010383496A CN111500563A CN 111500563 A CN111500563 A CN 111500563A CN 202010383496 A CN202010383496 A CN 202010383496A CN 111500563 A CN111500563 A CN 111500563A
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- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6451—Coagulation factor XIIa (3.4.21.38)
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- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21021—Coagulation factor VIIa (3.4.21.21)
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Abstract
The invention discloses a method for purifying human coagulation factor VII from human plasma, which comprises the following steps: (1) removing cold glue plasma; (2) a first anion exchange chromatography; (3) filtering the eluent, and adjusting the conductivity and pH value of the product; (4) second ion exchange chromatography. The method can separate the human coagulation factor VII from the plasma without cold glue by adopting sodium glutamate as eluent through the first ion exchange chromatography, can further purify the human coagulation factor VII through the two times of chromatography, greatly improves the utilization rate of the plasma and ensures that the human coagulation factor VII can achieve higher specific activity.
Description
Technical Field
The invention relates to the technical field of bioengineering, in particular to a method for purifying human coagulation factor VII from human plasma.
Background
The blood coagulation factors are protein components involved in the blood coagulation process, and the blood coagulation factors involved in blood coagulation in plasma are more than ten, wherein the human blood coagulation factor VII is an initiation factor for initiating a coagulation cascade reaction in an extrinsic coagulation pathway, and is a vitamin K-dependent zymogen with serine protease hydrolysis synthesized by liver cells. Human factor vii is also widely studied for use in the treatment of hemophilia patients in addition to factor vii deficiency, and currently hemophilia patients face severe challenges due to the production of factor inhibitors on factor viii or factor ix in up to 20% of patients on chronic infusion of factor products. From clinical studies in the last century, it was found that human prothrombin complex (PCC) using plasma as a raw material is effective in treating patients who produce inhibitors; activated recombinant factor VII was introduced in Europe in 1996 by NOVO Nordisk A/B for the treatment of hemophilia patients producing inhibitors of factor VII or factor IX and of bleeding disorders, both of which have good therapeutic effects in clinical application and extremely low side effects.
The human coagulation factor VII is commonly used for hemophiliacs and traumatic bleeding patients clinically, the dosage of the coagulation factor VII is increased along with the gradual expansion of the medical insurance scope, the human coagulation factor VII is stable, but the titer of the coagulation factor VII is reduced by a virus inactivation or removal method in the preparation process. Therefore, how to provide a preparation process of human coagulation factor VII, which can improve the specific activity of the human coagulation factor VII, improve the utilization rate of plasma and reduce pollution, becomes a technical problem which is mainly solved by the technical personnel in the field.
Disclosure of Invention
The invention aims to provide a preparation process of human blood coagulation factor VII, which can improve the specific activity of the human blood coagulation factor VII, improve the utilization rate of blood plasma and reduce pollution so as to better solve the problems pointed out by the background technology.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for purifying human factor vii from human plasma comprising the steps of:
(1) cold glue removing blood plasma
Thawing fresh frozen plasma, continuously centrifuging at 0-3 deg.C to remove cold gel, collecting supernatant as cold gel-removed plasma, and filtering to obtain clarified cold gel-removed plasma;
(2) first anion exchange chromatography
Carrying out first anion exchange chromatography on the cold glue-removed plasma obtained after filtration to enable target protein containing the VII factor to be adsorbed in an anion gel packed column, desorbing the target protein containing the VII factor adsorbed in the gel packing by using sodium glutamate eluent to obtain a crude product containing the human coagulation factor VII, and then washing with salt to remove non-target VII factor protein combined on the packing to obtain elution collection liquid;
(3) filtering the eluent, regulating the conductivity and pH value of the product
Adjusting the pH value of the human coagulation factor VII-containing eluent obtained by the first anion exchange chromatography to 6.50-7.50, adjusting the conductivity value to 12-17 mS/cm, filtering, and obtaining a second anion exchange chromatography sample after filtering;
(4) second ion exchange chromatography
And (3) carrying out TMAE gel chromatography on the second anion exchange chromatography sample to ensure that the protein containing the VII factor is adsorbed in a TMAE gel packed column and is eluted by solutions with different ionic strengths.
In conclusion, the invention has the following beneficial effects:
1. the method can separate the human coagulation factor VII from the plasma by two times of ion exchange chromatography, greatly improves the utilization rate of the plasma, and can achieve higher specific activity.
2. The method adopts column chromatography, changes the traditional fixed bed mode, reduces the exposure of the sample in the air and reduces the pollution.
3. Sodium glutamate is used as eluent to desorb the human coagulation factor VII from the first ion exchange chromatography packing to obtain a crude product containing the human coagulation factor VII, and the sodium glutamate has the function of a protein protective agent and is beneficial to the activity protection of protein.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, which are not specified under specific conditions, are generally performed under conventional conditions. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The first embodiment is as follows:
a method for purifying human factor vii from human plasma comprising the steps of:
s1-plasma with cold glue removed:
thawing fresh frozen plasma, continuously centrifuging at 0-3 deg.C to remove cold glue, collecting supernatant as cold glue-removed plasma, and filtering with filter element with pore diameter of 0.22um to obtain clarified cold glue-removed plasma;
s2-preparation before first chromatography:
preparing a UniGel-80Q ion exchange filler chromatographic column, balancing a UniGel-80Q gel filler by using a buffer solution containing 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L-0.15 mol/L sodium chloride, wherein the pH of the buffer solution is 6.80-7.80, and treating and then loading the sample.
S3-first anion exchange chromatography:
adjusting the conductivity of plasma to 10-13 mS/cm, the pH value to 7.00-8.00 and the protein content to 45 g/L +/-5 g/L, loading the adjusted cold gel-removed plasma to a Unigel-80Q gel chromatographic column, adsorbing a target protein containing the blood coagulation factor VII in a Unigel-80Q gel filler, allowing the non-target protein to flow through and discard, collecting a flow-through liquid at a linear flow rate of 1-3cm/min, balancing the gel filler 5CV with a buffer solution containing 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L-0.15 mol/L sodium chloride, adsorbing the target protein containing the VII in the gel filler with a 0.3-0.5 mol/L sodium glutamate eluent to obtain a crude product containing the human blood coagulation factor VII, and washing with salt to remove the non-target factor protein bound on the filler to obtain an elution collected liquid;
s4-preparation before second chromatography:
preparing a TMAE ion exchange filler chromatographic column, balancing TMAE gel filler by using a buffer solution containing 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L-0.15 mol/L sodium chloride, wherein the pH of the buffer solution is 6.80-7.80, and treating the buffer solution to be subjected to sample loading;
s5-second ion exchange chromatography:
adjusting the pH value of the human coagulation factor VII-containing eluent obtained by the first anion exchange chromatography to 6.50-7.50, adjusting the conductivity value to 12-17 mS/cm, filtering, loading the filtered and adjusted elution collecting solution to a TMAE gel chromatographic column, adsorbing target protein in TMAE gel filler, allowing non-target protein to flow through and discard, collecting the flow through solution at a linear flow rate of 1-3cm/min, balancing the gel filler with a buffer solution containing 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L0-0.15 mol/L1 sodium chloride to obtain 5CV, washing the non-target protein with weaker binding capacity with a solution containing 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L-0.15 mol/364 sodium chloride, discarding, adsorbing the elution with a solution containing 0.01 mol/3635-0.02 mol/L mol/4835 mol/6 mol/4835 mol sodium chloride in the gel filler containing weak binding capacity, and collecting the elution solution containing 0.01 mol/L-0.5 mol/5 mol sodium citrate/4835 sodium chloride.
The factor VII eluate obtained from the two chromatographies of this example has the following data:
and (4) conclusion:
and (3) delivering the collected plasma sample, flow-through liquid, washing liquid and eluent to detect the titer and the protein content of the blood coagulation factor VII, and finally calculating the specific activity of the factor VII. The method can separate the human coagulation factor VII from the plasma through two-step ion exchange chromatography, greatly improves the utilization rate of the plasma, and the human coagulation factor VII can reach higher specific activity which is not less than 2IU/mg protein higher than the specific activity of the factor VII specified in European pharmacopoeia.
The method adopts column chromatography (no report is found at present when the human coagulation factor VII is purified by the column chromatography from the blood plasma), changes the traditional fixed bed mode, reduces the exposure of the sample in the air and reduces the pollution; sodium glutamate is used as eluent to desorb the human coagulation factor VII from the first ion exchange chromatography packing to obtain the product containing the human coagulation factor VII, and meanwhile, the sodium glutamate also has the function of a protein protective agent and is beneficial to the protection of protein activity.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. A method for purifying human factor vii from human plasma, comprising the steps of:
(1) cold glue removing blood plasma
Thawing fresh frozen plasma, continuously centrifuging at 0-3 deg.C to remove cold gel, collecting supernatant as cold gel-removed plasma, and filtering to obtain clarified cold gel-removed plasma;
(2) first anion exchange chromatography
Carrying out first anion exchange chromatography on the cold glue-removed plasma obtained after filtration to enable target protein containing the VII factor to be adsorbed in an anion gel packed column, desorbing the target protein containing the VII factor adsorbed in the gel packing by using sodium glutamate eluent to obtain a crude product containing the human coagulation factor VII, and then washing with salt to remove non-target VII factor protein combined on the packing to obtain elution collection liquid;
(3) filtering the eluent, regulating the conductivity and pH value of the product
Adjusting the pH value of the human coagulation factor VII-containing eluent obtained by the first anion exchange chromatography to 6.50-7.50, adjusting the conductivity value to 12-17 mS/cm, filtering, and obtaining a second anion exchange chromatography sample after filtering;
(4) second ion exchange chromatography
And (3) carrying out TMAE gel chromatography on the second anion exchange chromatography sample to ensure that the protein containing the VII factor is adsorbed in a TMAE gel packed column and is eluted by solutions with different ionic strengths.
2. The method for purifying human blood coagulation factor VII from human plasma according to claim 1, wherein in the step (1) and the step (3), the filtration is performed by using a filter element with a pore size of 0.22 um.
3. The method for purifying human factor VII from human plasma according to claim 1, wherein in the step (2), the exchange gel for the first anion exchange chromatography is Unigel-80Q.
4. The process according to claim 1, wherein the step (2) comprises a first preparation of anion exchange chromatography before the chromatography, wherein the gel filler is equilibrated with a buffer solution containing 0.01 mol/L-0.02 mol/L mol of sodium citrate and 0.1 mol/L-0.15 mol/L mol of sodium chloride, the pH of the buffer solution is 6.80-7.80, and the buffer solution is loaded after the treatment.
5. The method for purifying human blood coagulation factor VII from human plasma according to claim 1, wherein in the step (2), the filtered plasma is treated to adjust the plasma conductivity to 10-13 mS/cm, the pH value to 7.00-8.00, and the protein content to 45 g/L ± 5 g/L before chromatography.
6. The method for purifying human blood coagulation factor VII from human plasma according to claim 1, wherein in the step (2), the gel filler is loaded with the filtered and adjusted cryo-removed plasma, the target protein is adsorbed in the gel filler, the non-target protein is drained and discarded, the drainage fluid is collected at a linear flow rate of 1-3cm/min, and the gel filler is balanced by 5CV after using a buffer solution containing 0.01 mol/L-0.02 mol/L mol/sodium citrate and 0.1 mol/L-0.15 mol/L mol sodium chloride.
7. The method for purifying human blood coagulation factor VII from human plasma according to claim 1, wherein in the step (2), 0.3-0.5 mol/L mol of sodium glutamate solution is used as eluent.
8. The process of claim 1, wherein step (4) comprises a second pre-chromatographic preparation of ion exchange chromatography comprising equilibrating the gel packing with a buffer comprising 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L-0.15 mol/L sodium chloride, the buffer having a pH of 6.80-7.80, and loading the gel after treatment.
9. The method for purifying human blood coagulation factor VII from human plasma according to claim 1, wherein in the step (4), during chromatography, the elution collected liquid after filtration is loaded on TMAE gel filler, so that target protein is adsorbed in the TMAE gel filler, non-target protein is flowed through and discarded, the flow-through liquid is collected at a linear flow rate of 1-3cm/min, and then 5CV of gel filler is balanced by using buffer solution containing 0.01 mol/L-0.02 mol/L mol/L-0.15 mol/L mol/sodium chloride.
10. The method for purifying human blood coagulation factor VII from human plasma according to claim 1, wherein in the step (4), after the chromatography, the non-target protein with weak binding capacity of the gel filler is washed by using a solution containing 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L-0.15 mol/L sodium chloride as a washing solution, the washing solution is discarded, the target protein containing the factor VII adsorbed in the gel filler is desorbed by using a solution containing 0.01 mol/L-0.02 mol/L sodium citrate and 0.1 mol/L-0.5 mol/L sodium chloride as an eluent, and the eluent is collected.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111961130A (en) * | 2020-08-31 | 2020-11-20 | 华兰生物工程重庆有限公司 | Method for extracting and separating IgM and IgG from blood plasma |
| CN114438061A (en) * | 2020-10-30 | 2022-05-06 | 北京双鹭立生医药科技有限公司 | Method for purifying factor VII |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111961130A (en) * | 2020-08-31 | 2020-11-20 | 华兰生物工程重庆有限公司 | Method for extracting and separating IgM and IgG from blood plasma |
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| CN114438061A (en) * | 2020-10-30 | 2022-05-06 | 北京双鹭立生医药科技有限公司 | Method for purifying factor VII |
| CN114438061B (en) * | 2020-10-30 | 2023-10-20 | 北京双鹭立生医药科技有限公司 | Method for purifying factor VII |
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