CN114893956A - Freeze-drying method of Claudin18.2VLP product - Google Patents
Freeze-drying method of Claudin18.2VLP product Download PDFInfo
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- CN114893956A CN114893956A CN202210623229.5A CN202210623229A CN114893956A CN 114893956 A CN114893956 A CN 114893956A CN 202210623229 A CN202210623229 A CN 202210623229A CN 114893956 A CN114893956 A CN 114893956A
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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Abstract
The invention provides a freeze-drying method of Claudin18.2VLP products, which is characterized by comprising the following steps: comprises a freeze-drying process; the freeze-drying process comprises a sublimation drying stage; wherein the sublimation drying stage: after the vacuum degree of the product after the pre-freezing stage is reduced to 0-10 pascal within 1-10 minutes, carrying out step sublimation drying at five temperature nodes; the temperature difference between the five temperature nodes is 10-30 ℃; the temperature ranges of the five temperature nodes are selected from-60 ℃ to 35 ℃. The product prepared by the method has the appearance qualification rate of more than 95 percent, the protein content of 100ug, the protein purity of more than 95 percent and the protein activity detection consistent with the protein stock solution.
Description
Technical Field
The invention provides a freeze-drying method, and particularly relates to a freeze-drying method of a Claudin18.2VLP product.
Background
Claudins is a family of proteins that function to maintain tight junctions that control the exchange of molecules between cells. Widely distributed in stomach, pancreas and lung tissues, and can be used for diagnosis and treatment.
The CLDN18.2 subtype is a stomach-specific subtype that has become an ideal target since Sahin found CLDN18.2 to be a highly selective molecule and to be expressed only extensively in cancer cells.
CLDN18.2 is usually buried in the gastric mucosa and is essentially inaccessible to monoclonal antibodies in normal tissues, and the development of malignant tumors results in the destruction of tight junctions, exposing the CLDN18.2 epitope on the surface of tumor cells as a specific target. Thus, CLDN18.2 confers specificity to targeted therapies. Expression recently found in pancreatic (50%), esophageal and lung cancers also shows potential for diagnosis and treatment of other tumors.
VLPs (Virus-like particles) are nanoscale protein particles that are self-assembled from single or multiple structural proteins (e.g., capsid proteins) to form structures similar to native viral particles, are highly repetitive and ordered, do not have viral genetic material, do not self-replicate, and are susceptible to infection into cells. The well-defined structure, stability, noninfectiveness of VLPs, and the ability to encapsulate molecules, have wide applications in biotechnology, chemistry, and therapeutics.
CLDN18.2 is a promising target spot in HER-2 negative gastric cancer patients, has high selectivity and potential in the aspect of human morbidity, and is an ideal supplement for targeted therapy of gastric cancer. The (envelope) VLP technique is to assemble conformationally intact membrane proteins, which aggregate on the surface of cell membranes, onto the surface of viroid particles, thereby obtaining soluble, high-concentration, correctly folded intact multi-transmembrane proteins.
And Claudin18.2 is a four-time transmembrane protein, and the whole-field transmembrane protein is difficult to obtain by performing in vitro expression and purification by a conventional method, so the full-length transmembrane protein of Claudin18.2 obtained by using a VLP technology has an integral epitope, and is favorable for screening a functional antibody for identifying a target natural conformation. However, Claudin18.2VLP has poor thermal stability and is not easy to store for a long time. The ideal solution is to freeze-dry and store the product, thus prolonging the storage life, facilitating transportation and production.
Disclosure of Invention
The invention aims to overcome the defects, and the Claudin18.2VLP protein product with poor thermal stability is prepared into dry powder by using a freeze drying technology, so that the product is convenient to store and transport.
The freeze drying technology is that the product is frozen into solid state, and the water vapor is sublimated from the solid directly under vacuum condition to leave the matter in the frozen ice shelf, so that the dried product has no loss of solid skeleton structure, maintained material form and excellent water re-hydrating performance.
The specific method comprises the following steps:
the invention provides a freeze-drying method of Claudin18.2VLP products, which is characterized by comprising the following steps: comprises a freeze-drying process;
the freeze-drying process comprises a sublimation drying stage;
wherein, the sublimation drying stage: after the vacuum degree of the product after the pre-freezing stage is reduced to 0-10 pascal within 1-10 minutes, carrying out step sublimation drying at five temperature nodes;
the temperature difference between the five temperature nodes is 10-30 ℃;
the temperature ranges of the five temperature nodes are selected from-60 ℃ to 35 ℃.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
the five temperature nodes comprise a first temperature node, a second temperature node, a third temperature node, a fourth temperature node and a fifth temperature node;
wherein the first temperature node is selected from-55 ℃ to-45 ℃;
the second temperature node is selected from-35 ℃ to-25 ℃;
the third temperature node is selected from-15 ℃ to-5 ℃;
the fourth temperature node is selected from 0-10 ℃;
the fifth temperature node is selected from 20 ℃ to 30 ℃.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
the first temperature node is selected to be-50 ℃;
the second temperature node is selected to be-30 ℃;
the third temperature node is selected from-10 ℃;
the fourth temperature node is selected to be 5 ℃;
the fifth temperature node was selected to be 25 ℃.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
the specific method for sublimation drying comprises the following steps:
s1, raising the temperature for 200 minutes at 150 ℃ below zero, and keeping the temperature for 9-16 hours at the final temperature of-30 ℃;
s2, heating for 1-10s, and keeping the temperature for 1-2 hours at the final temperature of-10 ℃;
s3, heating for 1-10s, keeping the temperature at 5 ℃ for 1-2 hours;
s4, heating for 1-10s, keeping the temperature at 25 ℃ for 3-8 hours.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
the pre-freezing stage comprises the following steps: keeping the temperature of the product at 4 ℃ for 1-2 hours, then cooling the product from 4 ℃ to-50 ℃ in 30-50 minutes, keeping the temperature at-50 ℃ for 1-3 hours, and completely freezing the product.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
also comprises a pretreatment procedure;
the pretreatment step is carried out before the freeze-drying step;
the pretreatment process comprises the following steps:
s0-1, adding a freeze-drying protective agent into the protein stock solution;
s0-2, subpackaging the mixed solution of S1 into containers.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
the final supplement concentration of the freeze-drying protective agent is 6-8%.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
the lyoprotectant is selected from trehalose and mannitol.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
after the sublimation drying stage is completed, the vacuum is released, the product is removed, and the product is stoppered and capped under sterile conditions, thus completing the lyophilized finished product of Claudin18.2 VLP.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
the protein content of the freeze-dried product is 100ug, and the protein purity is more than 95%.
Further, the invention provides a lyophilization method of the Claudin18.2VLP product, which is characterized in that:
replacing claudin18.2 VLPs with any other protein.
Drawings
FIG. 1. appearance results of the lyophilized product provided in example 1;
FIG. 2 Elisa test results of the lyophilized product provided in this example 1;
FIG. 3 shows the HPLC detection results of the lyophilized product provided in this example 1;
FIG. 4 shows the results of comparative experiments.
Detailed Description
In a particular embodiment, for use in the lyophilization process of the claudin18.2VLP product;
comprises a pre-freezing stage and a sublimation drying stage;
the pre-freezing stage: keeping the temperature of the product at 4 ℃ for 1-2 hours, then cooling the product from 4 ℃ to-50 ℃ at a cooling rate of 30-50 minutes, keeping the temperature at-50 ℃ for 1-3 hours, and completely freezing the product.
The sublimation drying stage: after the vacuum degree of the product after the pre-freezing stage is reduced to 0-10 pascal within 1-10 minutes, carrying out step sublimation drying at five temperature nodes;
the five temperature nodes comprise a first temperature node, a second temperature node, a third temperature node, a fourth temperature node and a fifth temperature node;
the first temperature node is selected from-55 ℃ to-45 ℃;
the second temperature node is selected from-35 ℃ to-25 ℃;
the third temperature node is selected from-15 ℃ to-5 ℃;
the fourth temperature node is selected from 0-10 ℃;
the fifth temperature node is selected from 20 ℃ to 30 ℃.
The specific method comprises the following steps:
and 4, keeping the temperature for 3-8 hours, wherein the temperature rise time is 1-10s, and the final temperature is a fifth temperature node.
Based on the method, the prepared freeze-dried product has the protein content of 100ug and the protein purity of more than 95 percent.
The most common scheme is as follows:
example 1 lyophilization of Claudin18.2VLP product
A method for lyophilizing a Claudin18.2VLP (product No.: CLD-HE1822, Human Claudin18.2 Protein VLP) product, comprising the steps of:
s1, supplementing trehalose with a final concentration of 8% (replacing with mannitol) into a protein stock solution;
s2, subpackaging the protein mixed solution into 2ml penicillin bottles, wherein the liquid level volume does not exceed 1/3 of each penicillin bottle;
s3, freeze-drying the packed Claudin18.2VLP product, wherein the freeze-drying mainly comprises 3 stages, namely a pre-freezing stage, a sublimation drying stage, a desorption drying stage and freeze-drying storage.
The pre-freezing stage is that the freeze dryer is cooled to 4 ℃, then the product is put into the freeze dryer, the freeze dryer is kept at 4 ℃ for 1-2h, the temperature is reduced from 4 ℃ to-50 ℃ at the cooling rate of 30-50min (most preferably about 45 min), the temperature is kept at-50 ℃ for 1-3h (most preferably about 3h), and the product is completely frozen;
the sublimation stage is that the vacuum degree is reduced to 0-10 pascal within 1-10min, 5 temperature points are set, namely-50 ℃, minus 30 ℃, minus 10 ℃ and 5 ℃ 25 ℃, after the pre-freezing stage is finished, the partition plate is started to heat, the temperature of the partition plate is set to be-30 ℃, the temperature rise time is 150-; then the temperature of the clapboard is heated to-10 ℃ and maintained for about 2 hours, and the dried noodle basically reaches the bottom of the bottle; setting the temperature of the clapboard to 5 ℃, and maintaining for 2 hours; controlling the temperature of the partition board to be 25 ℃ until the temperature of the partition board reaches 25 ℃ and maintaining for 5 hours, and finishing freeze-drying;
and (4) removing the vacuum, taking out the product, and then performing corking and capping on the product in an aseptic environment, thereby completing the freeze-dried finished product of the Claudin18.2 VLP.
Example 2 detection of lyophilized finished product of Claudin18.2VLP
The freeze-dried products of different batches are randomly extracted and detected in the following aspects, and the results show that the qualification rate of the appearance of the finished product is more than 95%, the protein content is 100ug, the protein purity is more than 95%, and the protein activity detection is consistent with the protein stock solution.
The method comprises the following specific steps:
and (3) appearance detection: observing whether the freeze-dried finished product of the Claudin18.2VLP has the phenomena of bulging, sinking, defect, bottle spraying and the like, and if not, judging that the product is qualified. The product has an appearance as shown in FIG. 1, and has an appearance qualification rate of more than 95%.
And (3) purity detection: the results of the HPLC analysis are shown in FIG. 2.
And (3) protein activity detection: the results of Elisa testing are shown in FIG. 3.
Comparative experiment 1:
the activity data (4 # in FIG. 4) shows that the effect of the activity is not so great but the appearance is not good and there is a sink, only by reducing the amount of trehalose to 5% based on the experimental conditions of the examples.
Comparative experiment 2:
by adopting the existing process, namely freezing by adopting liquid nitrogen in the pre-freezing stage, the activity data (5 # in figure 4) shows that the influence of the activity is not great, but the appearance is not good, and the bulge exists
Comparative experiment 3:
the process conditions of the nodes are adjusted, and the following comparative experiments are carried out to find that the node conditions provided by the invention are the optimal combination, and the comparative experiments are as follows:
comparison 3-1: the subpackaged samples are completely pre-frozen by liquid nitrogen, and then the samples are put into a freeze dryer, and the freeze-drying procedure is as follows:
the first temperature node is selected from-55 ℃ to-45 ℃ and is kept for 2 h;
the second temperature node is selected from-30 ℃ and is kept for 15 hours;
the third temperature node is selected from 0 ℃ and is kept for 2 h;
the fourth temperature node is selected from the group consisting of heat preservation at 25 ℃ for 6 h;
the experimental results are as follows: bulging, collapse and atrophy
Comparison 3-2: the subpackaged samples are completely pre-frozen by liquid nitrogen, and then the samples are put into a freeze dryer, and the freeze-drying procedure is as follows:
the first temperature node is selected from-50 ℃ and is kept for 2.5 h;
the second temperature node is selected from-30 ℃ and is kept for 1h (the temperature rise rate is 30 min);
the third temperature node is selected from-50 ℃ and is kept for 1.5 h;
the fourth temperature node is selected from-30 ℃ and is kept for 15 hours;
the fifth temperature node is selected from 0 ℃ and is kept for 2 h;
the sixth temperature node is selected from 25 ℃ and is kept for 6 h;
the experimental results are as follows: bulging, collapse and atrophy
the first temperature node is selected from 4 ℃ and is kept for 1 h;
the second temperature node is selected from-50 ℃ and is kept for 3 h;
the third temperature node is selected from-30 ℃ and is kept for 10 hours;
the fourth temperature node is selected from-10 ℃ and is kept for 2 h;
the fifth temperature node is selected from 5 ℃ for heat preservation for 2h
The sixth temperature node is selected from 25 ℃ and is kept for 5 hours;
the experimental results are as follows: layering
the first temperature node is selected from-50 ℃ and is kept for 5 hours;
the second temperature node is selected from-30 ℃ and is kept for 15h (the heating rate is 3 h);
the third temperature node is selected from 5 ℃ and is kept for 2 h;
the fourth temperature node is selected from 25 ℃ and is kept for 6 h;
the experimental results are as follows: bulging and layering.
Examples 3,
Experiments were carried out as described in example 1, with the substitution of human CD40 protein (cat # CD4-HM140, happy bio-product).
The product results were as follows:
the result shows that the qualification rate of the appearance of the finished product is more than 95 percent, the protein content is 100ug, the protein purity is more than 95 percent, and the protein activity detection is consistent with the protein stock solution.
Experiments show that the method has good effect on the protein of which the buffer system is PBS, but has slightly poorer appearance effect than the protein of the PBS system on the complex buffer system.
Claims (10)
1. A method of lyophilizing a claudin18.2VLP product, comprising: comprises a freeze-drying process;
the freeze-drying process comprises a sublimation drying stage;
wherein the sublimation drying stage: after the vacuum degree of the product after the pre-freezing stage is reduced to 0-10 pascal within 1-10 minutes, carrying out step sublimation drying at five temperature nodes;
the temperature difference between the five temperature nodes is 10-30 ℃;
the temperature ranges of the five temperature nodes are selected from-60 ℃ to 35 ℃.
2. The method of claim 1 of lyophilizing a claudin18.2VLP product, wherein: the five temperature nodes comprise a first temperature node, a second temperature node, a third temperature node, a fourth temperature node and a fifth temperature node;
wherein the first temperature node is selected from-55 ℃ to-45 ℃;
the second temperature node is selected from-35 ℃ to-25 ℃;
the third temperature node is selected from-15 ℃ to-5 ℃;
the fourth temperature node is selected from 0-10 ℃;
the fifth temperature node is selected from 20 ℃ to 30 ℃.
3. The method of claim 1 of lyophilizing a claudin18.2VLP product, wherein:
the first temperature node is selected to be-50 ℃;
the second temperature node is selected to be-30 ℃;
the third temperature node is selected to be-10 ℃;
the fourth temperature node is selected to be 5 ℃;
the fifth temperature node is selected to be 25 ℃.
4. The method of claim 1 of lyophilizing a claudin18.2VLP product, wherein: the specific method for sublimation drying comprises the following steps:
s1, the temperature rise time is 150-;
s2, keeping the temperature for 1-2 hours, wherein the temperature rise time is 1-10s, and the final temperature is a third temperature node;
s3, keeping the temperature for 1-2 hours, wherein the temperature rise time is 1-10s, and the final temperature is a fourth temperature node;
s4, keeping the temperature for 3-8 hours, wherein the temperature rise time is 1-10s, and the final temperature is a fifth temperature node.
5. The method of claim 1 of lyophilizing a claudin18.2VLP product, wherein: the pre-freezing stage: and (3) after the product is kept at 4 ℃ for 1-2 hours, the temperature is reduced from 4 ℃ to a first temperature node within 30-50 minutes, the temperature is kept at the first temperature node for 1-3 hours, and the product is completely frozen.
6. The method of claim 1 of lyophilizing a claudin18.2VLP product, wherein: also comprises a pretreatment procedure;
the pretreatment process is carried out before the freeze-drying process;
the pretreatment process comprises the following steps:
s0-1, adding a freeze-drying protective agent into the protein stock solution;
s0-2, subpackaging the mixed solution of S1 into containers.
7. The method of claim 6, wherein said lyophilization of the claudin18.2VLP product is by: the supplement final concentration of the freeze-drying protective agent is 6-8%.
8. The method of claim 6, wherein said lyophilization of the claudin18.2VLP product is by: the lyoprotectant is selected from trehalose and mannitol.
9. The method of claim 1 of lyophilizing a claudin18.2VLP product, wherein: after the sublimation drying stage is completed, the vacuum is released, the product is removed, and the product is stoppered and capped under sterile conditions, thus completing the lyophilized finished product of Claudin18.2 VLP.
10. A process for lyophilizing a claudin18.2VLP product, as claimed in any one of claims 1-9, wherein:
replacing claudin18.2 VLPs with any other protein.
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2022
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