CN118203658A - Recombinant Claudin18.2 fully human monoclonal antibody injection preparation and preparation method thereof - Google Patents
Recombinant Claudin18.2 fully human monoclonal antibody injection preparation and preparation method thereof Download PDFInfo
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- CN118203658A CN118203658A CN202211620044.5A CN202211620044A CN118203658A CN 118203658 A CN118203658 A CN 118203658A CN 202211620044 A CN202211620044 A CN 202211620044A CN 118203658 A CN118203658 A CN 118203658A
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
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- Proteomics, Peptides & Aminoacids (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention provides a recombinant Claudin18.2 fully human monoclonal antibody injection preparation and a preparation method thereof. The injection preparation comprises 50-80 mg/mL of recombinant anti-Claudin 18.2 fully human monoclonal antibody, 0.01-0.03% (w/v) of surfactant, 40-200 mmol/L, pH of stabilizer, regulator and solvent, wherein the pH of the injection preparation is 6.0-7.5. The recombinant Claudin18.2 fully human monoclonal antibody injection preparation is preservative-free, colorless to pale yellow, clear to micro-opalescent liquid, can still maintain the physical and chemical stability of the monoclonal antibody for a long time, and effectively prolongs the storage period.
Description
Technical Field
The invention belongs to the technical field of antibody medicines, and in particular relates to a recombinant Claudin18.2 fully humanized monoclonal antibody injection preparation and a preparation method thereof.
Background
Stomach cancer is one of the common cancers worldwide, and among the death factors associated with cancer in developed countries, stomach cancer accounts for the fourth (male) and fifth (female). Most gastric cancer patients are already in an advanced stage after diagnosis. Early gastric cancer may be cured by gastric resection, and the recurrence rate still reaches 50%. So far, advanced gastric cancer is incurable, and the survival time in chemotherapy is 8-10 months. Multiple chemotherapy regimens were studied to increase response rate and tolerability, however 5-year survival remains elusive.
Immunotherapy and targeted drugs, such as trastuzumab (trastuzumab), ramucirumab (Ramucirumab), and kinase inhibitors, have been used in the treatment of various cancers including gastric cancer. With the advent of targeted therapies, various molecules targeting different pathways were used in gastric cancer treatment, claudin18.2 as a highly specific cell surface molecule, expressed in normal tissues only on differentiated gastric mucosal epithelial cells and not on gastric stem cells. Claudin18.2 molecules are expressed for the most part in primary gastric cancer and its postmetastatic cancer types, and in addition, activation of Claudin18.2 expression is often observed in pancreatic cancer, esophageal cancer, ovarian cancer, lung cancer. Claudin18.2 acts as a cell membrane surface protein, and the exposed extracellular structure allows binding of antibodies, which characteristics suggest that Claudin18.2 is an ideal target for therapeutic monoclonal antibody development.
Disclosure of Invention
Biopharmaceuticals can experience various damaging conditions during production, transportation, storage and use, such as high temperatures, light and freeze thawing. To ensure the safety and effectiveness of the drug, the structural integrity of the drug, particularly the integrity of the higher-level structure, must be maintained. The polymers and insoluble particles of biopharmaceuticals are key factors in eliciting biopharmaceutical immune responses. The appearance of biopharmaceuticals is also a very important indicator. The pharmacopoeia of various countries prescribes that the biopharmaceuticals must be free of visible foreign matter, since the presence or absence of visible foreign matter in the biopharmaceuticals and the amount of insoluble particulate content are directly related to the safety of the biopharmaceuticals, they are considered to be one of the most important factors responsible for the immune response of the biopharmaceuticals. SEC-HPLC is an analytical method that uses the relative relationship of the pore size of the gel pores to the size of the sample being analyzed for separation. The molecules of larger molecular weight in the sample are completely excluded from entering the gel pores and can only pass through the chromatographic column along the interstices between the porous gel particles, and are therefore eluted from the column by the mobile phase first. And the molecules with smaller molecular weight can enter the gel cavity, are more strongly retained in the column and are not easy to elute, so that the separation of solute molecules with different sizes is achieved. Analysis of biopharmaceuticals is mainly used to measure the content of multimers, mainly in terms of a decrease in monomer content and an increase in multimers. DSF is a more advanced differential fluorescence scanning technique. This technique conducts a study of protein stability by detecting small changes in tryptophan autofluorescence. The tryptophan fluorescence intensity in proteins is closely related to their surrounding environment, and therefore, assessment of the chemical and thermal stability of proteins without labelling can be achieved by detecting changes in tryptophan fluorescence. The cIEF can focus and separate the heterobody with different charges according to the isoelectric points of the heterobody, and the focusing band is detected at 280nm to obtain a charge distribution map. The isoelectric point of the sample to be measured is calibrated using two markers of known isoelectric point (pI markers) added to the sample. The CE-SDS uses high-voltage DC electric field as driving force and capillary as separation channel. Gel is filled in the capillary, at the moment, the gel can form a molecular sieve in the capillary, and the sample is separated according to different moving speeds in the capillary according to the molecular weight, so that the component diffusion can be effectively reduced, the obtained peak is sharp, and the separation efficiency is high.
In view of this, the present invention aims at studying the stability of samples under different conditions by SEC-HPLC, DSF, cIEF and CE-SDS, and screening out recombinant anti-Claudin 18.2 fully human monoclonal antibody injection preparation and its preparation method, so as to solve the problem that the pharmaceutical composition of recombinant anti-Claudin 18.2 fully human monoclonal antibody is easy to form aggregates and insoluble particles in long-term storage.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
The injection preparation of the recombinant anti-Claudin 18.2 fully human monoclonal antibody comprises 50-80 mg/mL of the recombinant anti-Claudin 18.2 fully human monoclonal antibody, 0.01-0.03% (w/v) of surfactant, 40-200 mmol/L, pH of stabilizer, regulator and solvent; the pH of the injection preparation is 6.0-7.5.
Further, the pH regulator can be any one of sodium citrate-citric acid buffer solution and disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution; preferably, the pH regulator is disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution, and the pH value of the preparation is kept to be 6.0-7.5. The concentration of the disodium hydrogen phosphate-sodium dihydrogen phosphate buffer may be 20mmol/L.
Further, the pH of the injection preparation is 6.0 to 6.5, for example, 6.0, 6.3, 6.5, etc.
Still further, the pH regulator does not interact with the recombinant anti-Claudin 18.2 fully human monoclonal antibody itself, and can provide a stable environment, so that the pH value of the preparation is always maintained at 6.0-6.3. The pH regulator has good physiological compatibility with blood, small vascular irritation caused by injection and good compliance of patient administration.
Further, the surfactant is selected from at least one or a combination of two of polysorbate 20 and polysorbate 80. The surfactant can increase the solubility of the recombinant anti-Claudin 18.2 fully human monoclonal antibody, and can improve the stability of the preparation by reducing the surface tension and the free energy of the system between proteins and penicillin bottles.
Further, the surfactant is polysorbate 20, and the concentration of polysorbate 20 is 0.02% -0.03% (w/v, g/100 ml), preferably 0.03%.
Further, the stabilizer is at least one or a combination of more of sodium chloride, trehalose, mannitol and proline. The concentration range of the stabilizer is 40 mmol/L-200 mmol/L.
Further, the stabilizer is at least one or a combination of two of sodium chloride and mannitol, and the concentration range of the stabilizer component is 40 mmol/L-120 mmol/L.
Still further, the stabilizer consists of sodium chloride with a concentration of 100mmol/L and mannitol with a concentration of 40mmol/L.
The stabilizer can be matched with the pH regulator, so that the injection preparation has osmotic pressure equivalent to that of blood plasma, reduces injection pain and/or relieves gastrointestinal adverse reaction caused by the administration of partial patients; meanwhile, the stability of the spatial structure of the recombinant anti-Claudin 18.2 fully human monoclonal antibody is maintained, the shelf life of the recombinant anti-Claudin 18.2 fully human monoclonal antibody is obviously prolonged, and the drug effect is maintained stable.
Further, the concentration of the active substance recombinant anti-Claudin 18.2 fully human monoclonal antibody is 50mg/mL. The protein concentration can ensure that the injection preparation of the invention has better stability and obviously prolongs the storage period of the recombinant anti-Claudin 18.2 fully human monoclonal antibody.
Further, the solvent is selected from at least one of the following: water for injection, purified water and physiological saline. When physiological saline is used instead of water for injection or purified water, the influence of physiological saline on osmotic pressure should be considered, and the dosage of osmotic pressure regulator such as sodium chloride and mannitol should be appropriately reduced.
In one embodiment of the invention, the injection formulation comprises 50mg/mL of recombinant anti-Claudin 18.2 fully human monoclonal antibody, 20.03% (w/v) polysorbate, 100mmol/L sodium chloride, 40mmol/L, pH mannitol modulator (20 mmol/L sodium dihydrogen phosphate/disodium hydrogen phosphate), and vehicle; the pH of the injectable formulation was 6.0.
In one embodiment of the invention, the injection formulation comprises 50mg/mL of recombinant anti-Claudin 18.2 fully human monoclonal antibody, 20.02% (w/v) polysorbate, 100mmol/L sodium chloride, 40mmol/L, pH mannitol modulator (20 mmol/L sodium dihydrogen phosphate/disodium hydrogen phosphate), and vehicle; the pH of the injectable formulation was 6.3.
Compared with the prior art, the recombinant anti-Claudin 18.2 fully human monoclonal antibody injection preparation has the following advantages:
(1) Compared with the reported anti-Claudin 18.2 antibody analogue, the antibody has obvious advantages of binding affinity, ADCC (antibody-dependentcellular cytotoxicity, antibody-dependent cell-mediated cytotoxicity), CDC (complementdependent cytotoxicity, complement-dependent cytotoxicity), growth inhibition effect, endocytosis activity and the like, thereby having great potential for treating tumors.
Note that: the "anti-Claudin 18.2 antibody analog" in the tables is IMAB362 (Zolbetuximab, claudiximab) from Astellas/Ganymed.
(2) The recombinant Claudin18.2 fully humanized monoclonal antibody injection preparation provided by the invention is preservative-free, colorless to pale yellow, clear to micro-opalescent liquid, and can still maintain the physical and chemical stability of the monoclonal antibody for a long time, so that the storage period is effectively prolonged;
(3) The recombinant Claudin18.2 fully human monoclonal antibody injection preparation provided by the invention has the advantages of simple auxiliary material components and stable and controllable quality.
The invention also provides a preparation method of the recombinant Claudin18.2 fully human monoclonal antibody injection preparation.
The preparation method of the recombinant Claudin18.2 fully human monoclonal antibody injection preparation provided by the invention comprises the following steps:
1) Weighing surfactant, stabilizer, solvent and pH regulator in certain proportion;
2) Adding solvent and pH regulator into the preparation container to make pH value reach preset value, and using the solution as solution A;
3) Taking part of the solution A, adding a stabilizer 1 (sodium chloride), stirring and dissolving to obtain a solution B;
4) Taking part of the solution A, adding a stabilizer 2 (mannitol), stirring and dissolving to obtain a solution C;
5) Taking part of the solution A, adding the surfactant, stirring and dissolving to obtain a solution D;
6) Ultrafiltering and changing the recombinant Claudin18.2 fully human monoclonal antibody sample into a part of solution A by using an ultrafiltration method to obtain a solution E; the remaining solution A was mixed with the solution B, C, D, E, filtered through a 0.22 μm filter, and filled.
In the method steps 3), 4) and 5), the stirring time is 15-30min.
In the above method step 6), the ultrafiltration is performed by ultrafiltration of a recombinant anti-Claudin 18.2 fully human monoclonal antibody sample into a portion of solution A using a 30KD ultrafiltration tube.
The application of the recombinant Claudin18.2 fully human monoclonal antibody injection preparation in preparing medicaments for treating gastric cancer also belongs to the protection scope of the invention.
The components of the recombinant Claudin18.2 fully human monoclonal antibody injection preparation provided by the invention have mutual synergistic effect: alcohols (mannitol) and saccharides (trehalose) can not only form hydrogen bonds with proteins to increase protein stability, but also serve as a drug osmotic pressure regulator; salts (NaCl) can be combined with protein molecules through electrostatic action, so that the stability of protein colloid is improved, and NaCl is also a common osmotic pressure regulator; the surfactant (Tween 20 and Tween 80) can compete for replacing the protein of the adsorption layer, reduce the surface adsorption effect of the protein, increase the protein solubility and reduce the large particle amount of the protein. The recombinant Claudin18.2 fully human monoclonal antibody is used in combination, so that the physical and chemical stability of the monoclonal antibody can be maintained, and the storage period can be effectively prolonged.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. In the drawings:
FIG. 1 is a graph comparing the results of the 37℃stability test monomer (SEC-HPLC) in example 3, wherein each prescription group represents T0, 1W, 2W, and 4W from left to right, respectively;
FIG. 2 is a graph comparing the results of the main peak of the stability test (cIEF) at 37℃in example 3, wherein each prescription group represents T0, 1W, 2W, 4W from left to right;
FIG. 3 is a graph comparing the results of the 25℃stability test monomer (SEC-HPLC) in example 3, wherein each prescription group represents T0, 1M, 2M, 3M, and 6M from left to right, respectively;
FIG. 4 is a graph comparing the results of the main peak of stability test (cIEF) at 25℃in example 3, wherein each prescription group represents T0, 1M, 2M, 3M, 6M from left to right;
FIG. 5 is a graph comparing the results of the shock stability test monomer (SEC-HPLC) in example 5, wherein each prescription group represents T0, 5D, and 10D from left to right;
FIG. 6 is a graph comparing the results of the oscillation stability test main peak (cIEF) in example 5, wherein each prescription group represents T0, 5D, and 10D from left to right;
FIG. 7 is a graph comparing the results of the light stability test monomer (SEC-HPLC) in example 5, wherein each prescription group represents T0, 5D, and 10D from left to right;
FIG. 8 is a graph showing comparison of the results of the main peak of the light stability test (cIEF) in example 5, wherein each prescription group represents T0, 5D, and 10D from left to right;
FIG. 9 is a graph comparing the results of the freeze-thaw stability test monomer (SEC-HPLC) in example 5, wherein each prescription group represents T0, 1C, 2C, 3C, 4C, 5C from left to right, respectively;
FIG. 10 is a comparison of the results of the main peak of the freeze-thaw stability test (cIEF) in example 5, representing T0, 1C, 2C, 3C, 4C, 5C from left to right, respectively, in each prescription group.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified.
The recombinant anti-Claudin 18.2 fully human monoclonal antibody in the invention adopts the CLDN18.2 antibody (i.e. HBM1029 antibody) prepared in example 3 of Chinese patent publication No. CN 112707965A.
The remaining said starting materials are available from published commercial sources unless otherwise specified.
Example 1, pre-prescription study
Table 1 pre-prescription study experimental conditions
Note that: w represents weeks, D represents days, h represents hours, and C represents the number of freeze thawing.
The recombinant anti-Claudin 18.2 fully human monoclonal antibody is respectively stored at different temperatures, frozen thawing, oxidation and different pH conditions according to the table 1, and sampled at different sampling points for SEC-HPLC, CE-SDS (reduced, non-reduced) and cIEF detection, so as to observe the stability of the recombinant anti-Claudin 18.2 fully human monoclonal antibody. The experimental results are shown in Table 2.
Table 2 pre-prescription study results summary table
Note that: in the table "/" indicates that the item was not detected; "NR" means non-reduction, and "R" means reduction.
According to the SEC detection result of the forced degradation experiment, the protein has better monomer stability under different conditions, the protein degradation rate only increases under high temperature, and the cIEF detection result shows that the recombinant protein is easy to deamidate so as to greatly increase the acid peak content, so that the heat stability of the protein is expected to be increased by changing a buffer solution system (such as citrate buffer solution) or adding alcohols (mannitol) and saccharides (trehalose) to form hydrogen bonds with the protein, and the acid peak increasing rate is expected to be reduced by optimizing pH (pH 6.0-7.5).
Since the hydrophobic nature of the recombinant protein is not known, proline with a stronger hydrophobic nature was added in subsequent studies to investigate the behavior of the recombinant protein in hydrophobic additives.
Since NaCl can be combined with protein molecules through electrostatic action, the stability of protein colloid is improved, and meanwhile, the NaCl is a common osmotic pressure regulator, so that the NaCl is taken as an investigation object in the subsequent research.
Because polysorbate 20/polysorbate 80 can compete for protein in the substituted adsorption layer, the surface adsorption effect of the protein is reduced, the protein solubility is increased, and the large particle amount of the protein is reduced. Tween 20/tween 80 was therefore both listed as subjects in the subsequent study.
Example 2 preliminary screening experiments on formulation
TABLE 3 prescriptions design table for prescriptions
Note that: in the table "-" represents that the substance is not added; the vehicle used in the preparation of the samples in this table is water for injection or purified water.
The recombinant anti-Claudin 18.2 fully human monoclonal antibody is ultrafiltered and changed into a buffer system of Table 3 by a 30KD ultrafilter tube, a corresponding stabilizer is added, the final concentration of the monoclonal antibody is 50mg/mL, and after the preparation is completed, the sample is packaged into penicillin bottles. And placing the subpackaged sample in a 37 ℃ incubator for stability experiments. The experimental results are shown in Table 4.
TABLE 4 summary of stability test results at 37℃
In combination with the results of the test in Table 4, the sample polymers of buffers pH7.0 and pH7.5 were relatively high, the main peak content was reduced at a faster rate, the acid peak content was increased at a faster rate, and the product was unstable. The purity of the sample monomer with the pH value of 6.0 is relatively high, the main peak content is high, and the product stability is good. The comparison of the stabilizers shown in Table 3 shows that the stability of the sample with sodium chloride or mannitol as the stabilizer is better. The comparison of the surfactants described in Table 3 shows that the product with polysorbate 20 as surfactant has better stability. Subsequent studies were performed on this basis.
Example 3 formulation optimization experiments
The design of the experimental prescription performed in combination with the results of example 2 is shown in table 5.
Table 5 formulation recipe design table for formulation optimization experiment
Note that: in the table "-" represents that the substance is not added; the vehicle used in the preparation of the samples in this table is water for injection or purified water.
The recombinant anti-Claudin 18.2 fully human monoclonal antibody is ultrafiltered and changed into a buffer system of Table 5 by a 30KD ultrafilter tube, a corresponding stabilizer is added, the final concentration of the monoclonal antibody is 50mg/mL, and after the preparation is completed, the sample is packaged into penicillin bottles. And placing the packaged sample in a constant temperature box at 37 ℃/25 ℃ for stability experiments. The experimental results are shown in Table 6/Table 7, and the results are shown in FIGS. 1-4.
Table 6 formulation optimization experiment 37 ℃ stability experiment results summary table
TABLE 7 formulation optimization experiment 25 ℃ stability experiment results summary table
By combining the stability test results at 37 ℃ and 25 ℃, comparing the F12 sample with the F13 sample, and detecting by SEC-HPLC (SEC-high performance liquid chromatography) to show that the F12 prescription is better, and the purity of the two monomers is within 0.3 percent; cIEF detection (37 ℃ stability experiment) shows that the prescription of F13 is better, and the main peak content of the two is 2% different at 37 ℃ for 4 weeks; cIEF detection (stability experiment at 25 ℃) shows that the prescription of F12 is better, and the main peak content of the two is within 2 percent. Detection of data from insoluble particles showed that the difference between the F12 and F13 prescriptions was small and that the F12 prescriptions were slightly better. Namely, the stabilizer is sodium chloride and mannitol, and the stability of the preparation sample is better when the pH is 6.0-6.3.
Example 4 comparative experiments on protein concentration
And selecting an F12 preparation prescription of the preparation prescription optimization experiment, and carrying out a protein concentration comparison experiment. F12:50mg/mL; f12-1:70mg/mL; f12-2:80mg/mL. Ultrafiltering recombinant Claudin18.2 fully human monoclonal antibody with 30KD ultrafilter tube to F12 buffer system, adding stabilizer and surfactant in the final concentration of 70mg/mL and 80mg/mL, and packing the prepared sample into penicillin bottle. And placing the packaged sample in a constant temperature box at 25 ℃/2-8 ℃ for stability experiments. The experimental results are shown in Table 8/Table 9.
TABLE 8 protein concentration comparison experiment 25℃stability experiment results summary table
TABLE 9 protein concentration comparison experiment 2-8deg.C stability experiment results summary table
The results of the 25 ℃ stability experiment and the 2-8 ℃ stability experiment are combined, and the monomer stability and the charge heterosome stability of the F12 sample are superior to those of the F12-1 and F12-2 samples. Insoluble particle detection results show that at low protein concentrations, the number of sample particles is relatively small. The CE-SDS assay showed that the purity and activity stability of the three groups of samples were substantially unchanged. That is, the stability of the preparation sample with the protein concentration of 50mg/mL is better than that of the preparation sample with the protein concentration of 70mg/mL and 80 mg/mL.
Example 5 influence factor experiment
In combination with examples 3 and 4, protein concentrations of 50mg/mL were selected and factor experiments were performed on F12 and F13 to determine the final formulation recipe.
The recombinant anti-Claudin 18.2 fully human monoclonal antibody is ultrafiltered and changed into a buffer system of F12 and F13 by a 30KD ultrafilter tube, corresponding stabilizing agents and surfactants are added, the final concentration of the monoclonal antibodies is 50mg/mL respectively, and after preparation, the sample is packaged into penicillin bottles. And (5) respectively carrying out vibration, illumination and freeze thawing stability experiments on the samples after sub-packaging. The results are shown in Table 10, table 11 and Table 12, and the results are shown in FIGS. 5 to 10.
Table 10 shock stability test results summary table
TABLE 11 summary of results of illumination stability experiments
TABLE 12 freeze-thaw stability test results summary table
Compared with the F12 and F13 prescriptions, the freeze thawing stability of the two prescriptions has no obvious difference. In the vibration stability experiment, SEC-HPLC detection shows that the prescription of F12 is better, and the prescriptions of cIEF and CE-SDS have no obvious difference. In the light stability experiment, SEC-HPLC, cIEF and CE-SDS detection all showed that the F12 prescription was better. By combining the results, the preparation method has better prescription stability of the F12 preparation when preparing the recombinant Claudin18.2 fully humanized monoclonal antibody injection preparation, and the injection preparation has the advantages of less auxiliary material consumption, reasonable collocation, improved stability, safety and reliability by creatively optimizing the prescription.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (10)
1. A recombinant anti-claudin 18.2 fully human monoclonal antibody injection preparation, which comprises a recombinant anti-claudin 18.2 fully human monoclonal antibody, a surfactant, a stabilizer, a pH regulator and a solvent;
Wherein the concentration of the recombinant anti-Claudin 18.2 fully human monoclonal antibody in the injection preparation is 50-80 g/L;
the mass volume percentage of the surfactant in the injection preparation is 0.01% -0.03% (w/v);
The stabilizer is selected from at least one or a combination of more of sodium chloride, trehalose, mannitol and proline; the concentration of each component in the stabilizer is 40-200 mmol/L;
The pH range of the injection preparation is 6.0-7.5.
2. The recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation according to claim 1, characterized in that: in the injection preparation, the concentration of the recombinant anti-Claudin 18.2 fully human monoclonal antibody is 50g/L.
3. The recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation according to claim 1 or 2, characterized in that: the pH value of the injection preparation ranges from 6.0 to 6.5, and the preferable pH value ranges from 6.0 to 6.3.
4. A recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation according to any one of claims 1-3, characterized in that: the pH regulator is any one of sodium citrate-citric acid buffer solution and disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution; preferably, the pH regulator is disodium hydrogen phosphate-sodium dihydrogen phosphate buffer.
5. The recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation according to any one of claims 1-4, characterized in that: the stabilizer is at least one of sodium chloride and mannitol, and the concentration of the stabilizer is 40-120 mmol/L;
more preferably, the stabilizer consists of sodium chloride and mannitol, wherein the concentration of the sodium chloride is 100mmol/L, and the concentration of the mannitol is 40mmol/L.
6. The recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation according to any one of claims 1-5, characterized in that: the surfactant is at least one of polysorbate 20 and polysorbate 80; preferably, the surfactant is polysorbate 20; more preferably, the mass volume percentage of polysorbate 20 in the injection preparation is 0.02% -0.03% (w/v).
7. The recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation according to any one of claims 1-6, characterized in that: the solvent is selected from at least one of the following: water for injection, purified water and physiological saline.
8. A method for preparing the recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation of any one of claims 1-7, comprising the steps of:
1) Weighing a prescribed amount of pH regulator, stabilizer, surfactant and solvent according to a proportion;
2) Adding solvent and pH regulator into the preparation container to make pH value reach preset value, and using the solution as solution A;
3) Taking part of the solution A, adding the stabilizer 1, stirring and dissolving to obtain a solution B; the stabilizer 1 is sodium chloride;
4) Taking part of the solution A, adding the stabilizer 2, stirring and dissolving to obtain a solution C; the stabilizer 2 is mannitol;
5) Taking part of the solution A, adding the surfactant, stirring and dissolving to obtain a solution D;
6) Ultrafiltering and changing the recombinant Claudin18.2 fully human monoclonal antibody sample into a part of solution A by using an ultrafiltration method to obtain a solution E; the remaining solution A was mixed with the solution B, C, D, E, filtered through a 0.22 μm filter, and filled.
9. The method of manufacturing according to claim 8, wherein:
in the steps 3), 4) and 5), the stirring time is 15-30min;
in the step 6), the ultrafiltration method uses a 30KD ultrafiltration tube to ultrafiltrate a recombinant anti-Claudin 18.2 fully human monoclonal antibody sample into a part of solution A.
10. Use of the recombinant anti-claudin 18.2 fully human monoclonal antibody injection formulation of any one of claims 1-7 in the preparation of a medicament for treating gastric cancer.
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