CN115300623A - Compositions of anti-EGFR fusion proteins or antigen binding fragments thereof and uses thereof - Google Patents
Compositions of anti-EGFR fusion proteins or antigen binding fragments thereof and uses thereof Download PDFInfo
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- CN115300623A CN115300623A CN202110497420.5A CN202110497420A CN115300623A CN 115300623 A CN115300623 A CN 115300623A CN 202110497420 A CN202110497420 A CN 202110497420A CN 115300623 A CN115300623 A CN 115300623A
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Abstract
The invention relates to a pharmaceutical composition of an anti-EGFR fusion protein or an antigen binding fragment thereof. Specifically, the invention provides a pharmaceutical composition containing an anti-EGFR fusion protein or an antigen-binding fragment thereof, which is more favorable for production and administration and has more stable performance. The technical problem that the antibody drug is easy to degrade, polymerize or undergo undesirable chemical modification and the like to become unstable due to the large molecular weight and the complex structure of the antibody drug is solved, so that the antibody is suitable for administration and can exert better treatment effect.
Description
Technical Field
The invention relates to a pharmaceutical composition of an anti-EGFR fusion protein or an antigen binding fragment thereof, and a preparation and application thereof.
Background
Based on the results of various in vitro and in vivo studies with anti-EGFR antibodies, anti-EGFR antibodies can inhibit cancer cell proliferation, reduce tumor-mediated angiogenesis, induce cancer cell apoptosis, and enhance the toxic effects of radiation therapy and traditional chemotherapy. Thus, anti-EGFR antibodies can inhibit tumors at various levels.
However, liquid formulations comprising anti-EGFR antibodies or fusion proteins or antigen-binding fragments for therapeutic purposes may suffer from problems with protein multimer formation due to the aggregation properties of the antibodies or fusion proteins or antigen-binding fragments, and also may undergo deamination due to proteolytic reactions. Such denaturation reactions can be caused, for example, by storage at elevated temperatures during transport or by shear stress. If a liquid formulation comprising an anti-EGFR antibody or fusion protein or antigen-binding fragment aggregates due to a denaturing reaction, precipitation and particle formation may occur, causing embolism.
In this regard, the liquid formulation may be filtered (e.g., injected via a syringe) prior to administration to a patient to prevent aggregation. However, such additional steps may complicate the administration method and are not suitable for clinical trials. Furthermore, after filtration, particles may continue to form, resulting in reduced stability.
Therefore, there is still a need to develop a stable pharmaceutical formulation comprising an anti-EGFR antibody or fusion protein or antigen binding fragment, which has low turbidity and also no aggregation or particle formation under stress conditions.
To achieve the clinical potential of an antibody or fusion protein or antigen-binding fragment, it is necessary to maintain the biological activity of the antibody or fusion protein or antigen-binding fragment during storage and administration. Chemical and physical instability can contribute to a reduction in biological activity. Due to changes in water and temperature, the antibody or fusion protein or antigen-binding fragment may undergo aggregation, oxidation, deamidation or hydrolysis. One method of maintaining the biological activity of an antibody or fusion protein or antigen-binding fragment is to stabilize the antibody formulation by lyophilization. Particularly useful lyophilized formulations can provide high antibody concentrations once reconstituted, and therefore, there is a need for stable lyophilized formulations of anti-EGFR antibodies or fusion proteins or antigen binding fragments.
Disclosure of Invention
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a pharmaceutical composition comprising an anti-EGFR fusion protein or antigen-binding fragment thereof, wherein the anti-EGFR fusion protein or antigen-binding fragment thereof is a fusion protein or antigen-binding fragment thereof that specifically binds EGFR; and a buffer that is a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer; the buffer has a pH of 5.5 to 6.5, preferably 6.0.
In alternative embodiments, the buffer concentration is 5mM to 30mM, preferably 5mM to 25mM, and most preferably 10mM.
In alternative embodiments, the concentration of the fusion protein or antigen-binding fragment thereof that specifically binds EGFR is from 1mg/ml to 20mg/ml, preferably 5mg/ml.
In an alternative embodiment, the pharmaceutical composition, which further comprises a sugar, preferably trehalose or sucrose or mannitol, most preferably trehalose.
In alternative embodiments, the sugar concentration is 50mM to 250mM, preferably 50mM to 150mM, most preferably 135mM.
In an alternative embodiment, the pharmaceutical composition, which further comprises a surfactant, preferably the surfactant is polysorbate, more preferably polysorbate 80.
In an alternative embodiment, wherein the concentration of surfactant is from 0.1mg/mL to 0.4mg/mL, preferably 0.2mg/mL.
In an alternative embodiment, a pharmaceutical composition comprises:
(a) 1mg/ml to 20mg/ml of a fusion protein or an antigen-binding fragment thereof that specifically binds EGFR,
(b) 5mM to 30mM disodium hydrogen phosphate/sodium dihydrogen phosphate buffer, pH 5.5 to 6.5,
(c) 50mM to 200mM trehalose, and
(d) 0.1mg/mL to 0.4mg/mL polysorbate 80.
In an alternative embodiment, a pharmaceutical composition comprises:
(a) 5mg/ml of a fusion protein or antigen-binding fragment thereof that specifically binds EGFR,
(b) 10mM disodium hydrogen phosphate/sodium dihydrogen phosphate buffer, pH6.0,
(c) 135mM trehalose, and
(d) 0.2mg/mL polysorbate 80.
In an alternative embodiment, a pharmaceutical composition, wherein said anti-EGFR fusion protein or antigen-binding fragment thereof comprises heavy chains HCDR1, HCDR2 and HCDR3 as represented by the amino acid sequences of SEQ ID No. 2, SEQ ID No. 3 and SEQ ID No. 4; and light chains LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences shown as SEQ ID NO 6, SEQ ID NO 7 and SEQ ID NO 8, and/or heavy chains comprising the amino acid sequences shown as SEQ ID NO 9.
In an alternative embodiment, the anti-EGFR fusion protein or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof of murine, chimeric, humanized, or fully human origin.
In an alternative embodiment, a lyophilized formulation comprising an anti-EGFR fusion protein or antigen-binding fragment thereof, wherein said formulation is obtained by freeze-drying the aforementioned pharmaceutical composition.
In an alternative embodiment, a liquid formulation comprising an anti-EGFR fusion protein or antigen-binding fragment thereof, wherein said liquid formulation is obtained by aseptic filling of the aforementioned pharmaceutical composition.
In an alternative embodiment, the above-mentioned lyophilized formulation or liquid formulation of the pharmaceutical composition can be used for preparing a medicament for treating, inhibiting tumor cell proliferation or metastasis of a disease or condition, preferably, the disease or condition is cancer, more preferably, the cancer is selected from: kidney, pancreas, head and neck, breast, prostate, colon, stomach and ovary, lung and skin tumors.
The amino acid sequences of two heavy chains of the antibody are shown as SEQ ID NO. 1 and SEQ ID NO. 9, and the amino acid sequence of a light chain is shown as SEQ ID NO. 5.
The invention provides a pharmaceutical composition containing anti-EGFR fusion protein or antigen binding fragment thereof, which is more beneficial to production and administration and has more stable performance. The technical problem that antibody drugs are easy to degrade, polymerize or undergo undesirable chemical modification and the like to become unstable due to the fact that the antibody drugs are large in molecular weight and complex in structure is solved, and the drugs are suitable for administration and can exert better treatment effects.
Detailed description of the terms
In order that the invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless otherwise defined herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
"buffering agent" refers to a buffering agent that is resistant to pH changes by the action of its acid-base conjugated components.
"pharmaceutical composition" means a mixture containing one or more of the anti-EGFR fusion proteins or antigen-binding fragments thereof described herein and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to maintain the stability of the active ingredient of the fusion protein or antigen-binding fragment, to facilitate administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
Herein, "pharmaceutical composition" and "formulation" are not mutually exclusive.
In the solution form of the pharmaceutical composition of the present invention, if not specifically mentioned, the solvent is water.
"lyophilized formulation" means a pharmaceutical composition in the form of a liquid or solution or a formulation or pharmaceutical composition obtained after a vacuum freeze-drying step of a liquid or solution formulation.
The term "about" as used herein means that a numerical value is within an acceptable error range for the particular value determined by one of ordinary skill in the art, which numerical value depends in part on how the value is measured or determined (i.e., the limits of the measurement system). For example, "about" in each practice in the art may mean within 1 or a standard deviation of more than 1. Alternatively, "about" or "substantially comprising" may mean a range of up to 20%. Furthermore, particularly for biological systems or processes, the term may mean at most an order of magnitude or at most 5 times the value. Unless otherwise indicated, when a particular value appears in the application and claims, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for that particular value.
The pharmaceutical composition of the invention can achieve a stable effect: a pharmaceutical composition wherein the antibody substantially retains its physical and/or chemical stability and/or biological activity upon storage, preferably the pharmaceutical composition substantially retains its physical and chemical stability and its biological activity upon storage. The shelf life is generally selected based on a predetermined shelf life of the pharmaceutical composition. There are a number of analytical techniques currently available for measuring protein stability, which can measure stability after storage at a selected temperature for a selected period of time.
A stable pharmaceutical antibody formulation is one in which no significant change is observed under the following conditions: stored at refrigeration temperatures (2-8 ℃) for at least 3 months, preferably 6 months, more preferably 1 year, and even more preferably up to 2 years. In addition, stable liquid formulations include liquid formulations that: which exhibits desirable characteristics after storage at temperatures including 25 ℃ for periods of time including 1 month, 3 months, 6 months. Typical acceptable criteria for stability are as follows: typically no more than about 10%, preferably no more than about 5%, of the antibody monomer is degraded as measured by SEC-HPLC. By visual analysis, the antibody drug formulation was a pale yellow near colorless clear liquid or colorless, or clear to slightly opalescent. The concentration, pH and osmolality of the formulation have no more than ± 10% variation. Typically, no more than about 10%, preferably no more than about 5% reduction is observed. Typically no more than about 10%, preferably no more than about 5% aggregates are formed.
The approximately 110 amino acid sequence of the heavy and light chains of antibodies near the N-terminus varies widely, as the variable region (Fv region); the remaining amino acid sequence near the C-terminus is relatively stable and is a constant region. The variable regions include 3 hypervariable regions (HVRs) and 4 Framework Regions (FRs) which are relatively sequence-conserved. The 3 hypervariable regions determine the specificity of the antibody, and are also known as Complementarity Determining Regions (CDRs). Each of the light chain variable region (LCVR or VL) and heavy chain variable region (HCVR or VH) consists of 3 CDR regions and 4 FR regions, arranged sequentially from amino terminus to carboxy terminus in the order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2 and HCDR3. The CDR amino acid residues in the LCVR and HCVR regions of the antibody or antigen-binding fragment of the invention are in number and position according to the known Kabat numbering convention (LCDR 1-3, HCDR1-3).
The "fusion protein" as used herein refers to a protein comprising one, two or more polypeptides derived from different naturally occurring proteins or engineered proteins artificially combined to form one protein. Including but not limited to the following exemplified forms, 1, fusion proteins consisting of one polypeptide chain, fused to each other by the same or different polypeptides, to form one polypeptide chain comprising said different polypeptides; 2. for fusion proteins consisting of two or more polypeptide chains, wherein optionally one or more polypeptide chains are fused to each other by the same or different polypeptides to form polypeptide chains comprising said same or different polypeptides, these polypeptide chains are combined with each other in a covalent or non-covalent fashion to form the protein.
The term "antibody or antigen-binding" or "functional fragment" thereof as used herein refers to Fab fragments, fab 'fragments, F (ab') 2 fragments, and scFv fragments which bind to antibodies and have antigen-binding activity. The Fv fragment contains the variable regions of the antibody heavy and light chains, but lacks the constant region, and has the smallest antibody fragment with the entire antigen-binding site. Generally, fv antibodies also comprise a polypeptide linker between the VH and VL domains, and are capable of forming the structure required for antigen binding. Two antibody variable regions can also be joined into a single polypeptide chain using different linkers, called single chain antibodies (scFv) or single chain Fv (scFv).
Detailed Description
The development process of the fusion protein preparation formula comprises screening of a buffer system, screening of additives, screening of a surfactant, and preliminary compatibility and stability research of raw materials and auxiliary materials. SEC-HPLC (size exclusion-high Performance liquid chromatography) below represents size exclusion-high performance liquid chromatography, in which HMW and LMW represent high molecular weight and low molecular weight, respectively. CEX-HPLC (cation exchange-high performance liquid chromatography) represents high performance liquid ion exchange chromatography. The following reference standards for insoluble particulates and visible foreign matter are in accordance with relevant pharmacopoeia regulations.
Example 1: nucleotide sequence
Converting the target amino acid sequence into nucleotide sequences, wherein the obtained nucleotide sequences are respectively as follows: SEQ ID NO 10 (EGFR heavy chain), SEQ ID NO 11 (EGFR light chain), SEQ ID NO 12 ((IL 10) 2-Fc).
Example 2: gene synthesis and construction of expression vector
The pcDNA3.4-G418 and pcDNA3.1-G418 vectors are respectively adopted as special vectors for expressing the light chain and the heavy chain of the multifunctional antibody. pcDNA3.4-G418 contains the promoter CMVPromotor used for the light chain, the eukaryotic selection marker G418 tag and the prokaryotic selection tag Ampicilline. The pcDNA3.1-G418 vector contains a promoter CMVPromoter used by a heavy chain, a eukaryotic selection marker G418 tag and a prokaryotic selection tag Ampicilline. Obtaining nucleotide sequences of antibody expression light chains and heavy chains by gene synthesis, carrying out double enzyme digestion on a vector and a target fragment by HindIII and XhoI, carrying out enzyme ligation by DNA ligase after recovery, transforming an escherichia coli competent cell DH5 alpha, selecting positive clones, carrying out plasmid extraction and enzyme digestion verification, and obtaining recombinant plasmids containing the first heavy chain, the second heavy chain and the first light chain of the antibody, namely pcDNA3.1-G418-1, pcDNA3.1-G418-2 and pcDNA3.4-G418-3 respectively.
Example 3: plasmid extraction
Recombinant plasmids containing the above-mentioned respective target genes were transformed into E.coli competent cells DH 5. Alpha. According to the method described in molecular cloning protocols (2002, scientific Press), transformed bacteria were plated on LB plates containing 100. Mu.g/ml ampicillin and cultured, plasmid clones were selected and cultured in liquid LB medium and shaken at 260rpm for 14 hours, and plasmids were extracted from endotoxin-free plasmid macroextraction kits, dissolved in sterile water and subjected to concentration measurement with a nucleic acid protein meter.
Example 4: plasmid transfection, transient expression and antibody purification
At 37 ℃ C, 8% CO 2 Culturing ExpicCHO at 100rpm to a cell density of 6X 10 6 cells/ml. The constructed vectors PCDNA3.1-G418-6-1, PCDNA3.1-G418-6-2 and PCDNA3.4-G418-6-3 were transfected into the above cells using liposomes at a plasmid concentration of 1. Mu.g/ml and a liposome concentration referred to ExpicHO TM Expression System kit determination of 5% CO at 32 ℃% 2 Culturing at 100rpm for 7-10 days. The feed was fed once between 18-22h and 5-8 days after transfection. The above culture product was centrifuged at 4000rpm, filtered through a 0.22 μm filter and the culture supernatant was collected, and the resulting antibody protein was purified by protein A, ion column and the eluate was collected.
The concrete operation steps of the ProteinA and the ion column purification are as follows: the cell culture fluid is centrifuged at high speed, and the supernatant is taken out and subjected to affinity chromatography by using a GE protein A chromatographic column. The chromatography was performed using an equilibration buffer of 1 XPBS (pH 7.4), the cell supernatant was combined and washed with PBS until the UV light returned to the baseline, and then the target protein was eluted with 0.1M glycine (pH 3.0) as an elution buffer, and the pH was adjusted to neutral with Tris. The pH of the product obtained by affinity chromatography is adjusted to be 1-2 pH units lower or higher than the pI, and the product is diluted appropriately to control the sample conductance to be below 5 ms/cm. Performing NaCl gradient elution under corresponding pH conditions by using appropriate buffer solution with corresponding pH such as phosphate buffer solution, acetic acid buffer solution, etc., and ion exchange chromatography such as anion exchange or cation exchange, and selecting collection tube containing target protein according to SDS-PAGE and SEC-HPLC, and storing.
Example 5: buffer system screening
2 sets of buffer solutions at different pH values were designed with buffer salts commonly used for antibody preparations. And (3) carrying out ultrafiltration on the antibody stock solution to obtain buffer solutions with different pH values, carrying out sterilization filtration, and carrying out aseptic subpackaging. And (3) carrying out an accelerated stability experiment at 40 ℃ by using the subpackaged samples, periodically sampling, and carrying out detection on characters, size exclusion high performance liquid chromatography (SEC-HPLC) and the like. The data obtained for stability were compared, and the correlation between the data was summarized, and a buffer solution at a pH value favorable for stability of the antibody was selected.
TABLE 1 buffer system screening study protocol
The 7 groups of buffer systems were sampled, detected and analyzed at different sampling points under two different investigation conditions, and the results are shown in table 2.
TABLE 2 buffer system screening test results
Note that 40 is the investigation condition of 40 plus or minus 2 ℃; w is a study period, 1w =1 week.
The SEC-HPLC evaluation result in the purity investigation item shows that after the samples of F1-F4 corresponding to the disodium hydrogen phosphate/sodium dihydrogen phosphate buffer system are placed at 40 ℃ for 3 weeks, the main peak proportion can still be maintained above 97%, and the stability is better than that of the samples of F5-F7. Indicating that the antibody sample can be kept in a stable state over a wide pH range under the buffer system. Considering that the pH of the antibody sample should not be too close to the isoelectric point, a 10mM disodium hydrogen phosphate/sodium dihydrogen phosphate buffer system with a pH of 6.0 was chosen as the buffer system for the antibody formulation recipe.
Example 6: screening of auxiliary materials (sugar)
Adding 20mM histidine/histidine hydrochloride buffer solution with pH of 6.0, adding different adjuvants such as trehalose, arginine, sodium chloride, etc. to obtain samples with different prescriptions, changing antibody protein solution to corresponding prescription, sterilizing, filtering, and packaging. The high temperature stability test at 40 ℃ is carried out by using the subpackaged samples, and the samples are taken at 1 week, 3 weeks and 4 weeks for appearance, protein content, pH value, molecular exclusion high performance liquid chromatography (SEC-HPLC) and the like. Comparing the stability test data, selecting the prescription which is favorable for antibody stability and has the best economic cost.
The formulation screening protocol and 7 formulation evaluation data statistics are shown in tables 3 and 4.
Table 3 formulation screening protocol
Table 4 summary table of prescription screening test results
Note: 25. the investigation conditions for 40 were 25 ℃ and 40 ℃; w is a study period, 1w =1 week.
The SEC-HPLC evaluation result in the purity investigation item shows that the contents of the polymer and the small molecular fragment of the samples of F10 and F11 show a gradual increase trend along with the increase of time after the samples are placed at 40 ℃ for 4 weeks, and the proportion of the main peak is obviously reduced, which indicates that the samples are unstable in the buffer solution added with arginine; the sodium chloride addition amount of the samples of F12, F13 and F14 is different, the contents of the polymer and the small molecular fragment are not obviously changed, and the result shows that the sodium chloride has no influence on the samples; the samples were kept at 40 ℃ for 3 weeks, the stability of the samples of F8 and F9 was close, and the lower trehalose content protocol was better from an economic point of view.
Example 7: surfactant screening
Preparing samples of different prescriptions with 10mM disodium hydrogen phosphate-sodium dihydrogen phosphate, 135mM trehalose, buffer solution with pH6.0, and different types of surfactants (polysorbate 80 and polysorbate 20), changing the antibody protein solution to the corresponding prescription, sterilizing, filtering, and packaging. The dispensed samples were subjected to repeated freeze-thawing (cycle temperature: -80-4 ℃) and shaking for 7 days (250rpm, 25 ℃) to conduct appearance, size exclusion high performance liquid chromatography (SEC-HPLC), and the like. Comparing the stability detection data, and selecting the active agent which is beneficial to the stability of the antibody and the content thereof.
The surfactant screening protocol and the statistical data for the 6 surfactant evaluation groups are shown in tables 5 and 6 below.
Table 5 surfactant screening protocol
Note: the antibody concentration was 5mg/ml.
TABLE 6 surfactant screening results
The evaluation results of SEC-HPLC in the purity examination item show that the increase in the polymer content of the samples in F1, F5 and F6 is slower after 2 and 5 freeze thawing cycles. Therefore, polysorbate 80 at 0.2g/L is preferred as a surfactant for the formulation of the item in general.
From the above results, it was confirmed that the optimal formulation of the antibody was formulated at pH6.0, 10mM disodium hydrogen phosphate/sodium dihydrogen phosphate buffer system, 135mM trehalose, and 0.2g/L polysorbate 80.
Example 8: light damage test for stock solution stability test
The compatibility of the raw materials and the auxiliary materials of the candidate preparation prescription is evaluated through a long-term stability test and an accelerated stability test, and whether the stability of the stock solution can be maintained under different environmental conditions or not is judged.
And (3) performing ultrafiltration on the purified antibody to a preparation buffer solution of 10mM disodium hydrogen phosphate/sodium dihydrogen phosphate buffer, 135mM trehalose and 0.02% polysorbate 80 (pH 6.0), wherein the antibody solubility is 5mg/ml, performing sterile filtration and sterile subpackaging, performing stability study on the subpackaged samples under the irradiation of sunlight and ultraviolet for 5 days, and performing SEC-HPLC detection.
The test protocol and results are shown in tables 7 and 8, and the results show that: under the irradiation of sunlight and ultraviolet for 5 days, the purity of the sample is reduced, the number of polymers is increased, and the antibody is aggregated to a certain degree; the illumination test result shows that the sunlight has great influence on the antibody, the antibody is broken, and the stability is reduced.
TABLE 7 design of photo-destructive test
Time (sky) | 5 |
Condition | 5 (sunlight + ultraviolet) |
Note: 1. the sunlight illumination intensity is 4500Lx +/-500 Lx, and the ultraviolet illumination intensity is 250 mu W/cm <2 >.
TABLE 8 photo-destructive test results
Example 9: antibody freeze-thaw stability study of stock solution stability experiment
The mechanical shearing force generated by repeated freezing and thawing can damage antibody protein molecules, and the repeated freezing and thawing phenomenon is inevitable to occur more or less during production or other subsequent storage, so that the experiment is set to judge whether the antibody can be repeatedly frozen and thawed. The results are shown in Table 9, which shows that when the antibody concentration is about 5mg/ml, the antibody is frozen for 2 to 5 times at-80 ℃ and-20 ℃ and thawed at room temperature, the SEC-HPLC result of the antibody is not influenced, and the antibody can be stably frozen and thawed repeatedly.
TABLE 9 repeated Freeze/thaw test of antibodies
Note: DR0, DR2 and DR5 are frozen at-80 deg.C, and thawed at 25 deg.C for 0, 2 and 5 times, respectively.
Example 10: liquid formulation stability test
The samples were formulated into a formulation recipe: 5mg/ml sample, 10mM disodium hydrogen phosphate-sodium dihydrogen phosphate buffer, 135mM trehalose, 0.02% polysorbate 80, pH6.0; sterilizing, filtering, and packaging; the samples were tested for-80 deg.C stability, 4 deg.C stability and 25 deg.C stability, and 1M, 3M and 6M were set out for appearance, size exclusion high performance liquid chromatography (SEC-HPLC), etc.
As a result, as shown in tables 10, 11 and 12, under the condition of-80 ℃ (3 months), the antibody has no obvious change of the polymer and the small molecular fragment; under the condition of 4 ℃ (3 months), the polymer and the small molecular fragment are not obviously changed; under 25 deg.C (1 month) there was no significant change in the dimer, and under 25 deg.C (3 months) there was a slight increase in the dimer.
Long-term stability experimental data show that the antibody has better low-temperature storage effect in a formula of 10mM disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution, 135MM trehalose, 0.02% polysorbate 80 and pH6.0. It can also be seen that the long term stability of the composition of the present invention is superior to that of 202110141918.8.
TABLE 10 results of antibody-80 ℃ stability test
TABLE 11 results of the antibody stability test at 4 deg.C
TABLE 12 results of antibody stability test at 25 deg.C
Note: NA means no detection of the sample.
Example 11: preparation of lyophilized preparation
The pre-lyophilization solutions were prepared at the concentrations shown in table 13 and lyophilized to the final product.
TABLE 13 Pre-lyophilization solution Components
Composition (I) | Concentration of |
Antibodies | 5mg/ml |
Disodium hydrogen phosphate dodecahydrate | 0.44g/L |
Sodium dihydrogen phosphate dihydrate | 1.37g/L |
Trehalose | 51.35g/L |
Polysorbate-80 | 0.2g/L |
The purified antibody was ultrafiltered with an ultrafiltration membrane pack, concentrated by displacement, ultrafiltered into a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer, and mixed with a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer containing trehalose and polysorbate-80 at a certain ratio, ph6.0, so that the concentrations of the components after mixing were as shown in table 13. Mixing, packaging into lyophilized injection bottle, packaging at a ratio of 2 mL/bottle, and freeze drying. The freeze-drying procedure was as follows:
(1) Pre-freezing at 0 deg.C for 60min; pre-freezing at-45 ℃ for 2h;
(2) Sublimation stage, setting vacuum degree at 10Pa, heating to-10 deg.C for 30min, and maintaining for 1 hr; heating to-5 deg.C for 60min, and maintaining for 26 hr; heating to 0 deg.C for 30min, and maintaining for 5 hr; heating to 5 deg.C for 30min, and maintaining for 2 hr;
(3) Desorption drying, namely heating to 25 ℃ within 30min, keeping the temperature for 4h under the pressure of 10Pa, and keeping the temperature for 2h under the pressure of 5 Pa;
(4) After the freeze-drying is finished, the mixture is pressed and taken out of the box, and then the cover is manually rolled and stored at 4 ℃.
Example 12: stability test of lyophilized preparation
The results of the freeze-dried preparation stability experiments are shown in tables 14-18, and the antibody is stable under the condition of 4 ℃ (2 months), and the polymer is increased by about 0.5%; under 25 ℃ (2 months) conditions, the increase in mer is about 0.5%; at 40 deg.C (1 month), the increase in mer was about 0.6%. Are all in the mass standard range (SEC main peak content is more than 95 percent).
As described above, the lyophilized product of the antibody was stable in the formulation of 10mM disodium hydrogen phosphate-sodium dihydrogen phosphate buffer, 135mM trehalose, 0.02% polysorbate 80, pH 6.0.
TABLE 14 design of photo-destructive test
Note: 1. the sunlight illumination intensity is 4500Lx +/-500 Lx, and the ultraviolet illumination intensity is 250 mu W/cm <2 >.
TABLE 15 photo-failure test results
TABLE 16 Freeze-dried product stability at 4 deg.C results
TABLE 17 Freeze-dried product stability at 25 deg.C results
Note: NA is no detection of the sample.
TABLE 18 Freeze-dried product stability results at 40 deg.C
Sequence listing
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tgcaacgtga atcacaagcc tagcaataca aaggtggaca agaaggtgga gccaaagtct 720
tgtgataaga cccatacatg ccccccttgt cctgctccag agctgctggg aggaccatcc 780
gtgttcctgt ttccacccaa gcccaaggac accctgatga tctctcgcac cccagaggtg 840
acatgcgtgg tggtggacgt gtcccacgag aaccccgagg tgaagttcaa ttggtacgtg 900
gatggcgtgg aggtgcataa cgctaagacc aagccaaggg aggagcagta caattccacc 960
tatcgggtgg tgagcgtgct gacagtgctg caccaggatt ggctgaacgg caaggagtat 1020
aagtgcaagg tgagcaataa ggccctgccc gctcctatcg agaagaccat ctctaaggcc 1080
aagggccagc ctagagagcc acaggtgtac acactgcctc catctcgcaa ggagatgacc 1140
aagaaccagg tgtccctgac atgtctggtg aagggctttt atccctccga catcgctgtg 1200
gagtgggaga gcaatggcca gcctgagaac aattacaaga ccacaccccc tgtgctggac 1260
agcgatggct ctttcaagct gtatagcaag ctgaccgtgg ataagtctag gtggcagcag 1320
ggcaacgtgt ttagctgttc tgtgatgcat gaggctctgc acaatcatta cacacagaag 1380
tccctgagcc tgtctcccgg caag 1404
<210> 11
<211> 642
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 11
gatatcctgc tgacccagag ccctgtgatt ttgtctgtga gccctggcga gcgcgtatcc 60
tttagctgca gggcttctca gtccatcggg accaacattc actggtatca gcagcgcacc 120
aacgggtctc caagactcct gatcaagtac gcaagcgagt ccatatctgg cattccaagc 180
aggttttccg gtagcggaag cggtacagac ttcacattgt ccatcaactc cgtcgagagt 240
gaagacatcg ccgattacta ctgtcagcag aacaataact ggcccacaac ctttggagct 300
ggcaccaagt tggagctgaa aaggaccgtg gccgcaccta gcgttttcat cttccccccc 360
agcgacgagc agctgaagag cggaactgct agcgtcgtgt gtctccttaa caatttttac 420
cccagagagg ccaaagtcca gtggaaggtc gacaacgccc tgcagtccgg caacagccag 480
gaatccgtca ccgagcagga ctccaaagac tccacatata gcctgagctc aacacttacg 540
ctgagcaagg ctgattatga gaaacacaag gtctacgcat gcgaagtgac ccaccagggg 600
ctgtcttctc ccgtgaccaa gtcctttaat cggggtgagt gc 642
<210> 12
<211> 1761
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 12
atgcactcca gcgccctgct gtgctgtctg gtgctgctga ccggcgtgag ggcttctcca 60
ggacagggca cccagtctga gaactcctgc acacatttcc caggcaacct gcccaatatg 120
ctgagggacc tgcgggatgc cttttcccgg gtgaagacat tctttcagat gaaggaccag 180
ctggataatc tgctgctgaa ggagagcctg ctggaggact tcaagggcta cctgggctgt 240
caggctctgt ctgagatgat ccagttttat ctggaggaag tgatgcccca ggccgagaac 300
caggaccctg atatcaaggc tcacgtgaac agcctgggcg agaatctgaa gaccctgagg 360
ctgaggctga ggcggtgcca taggttcctg ccttgtgaga ataagagcaa ggccgtggag 420
caggtgaaga acgcttttaa taagctgcag gagaagggca tctacaaggc catgtctgag 480
ttcgacatct ttatcaacta catcgaggct tatatgacaa tgaagatccg gaattcttcc 540
ggcggcggcg gctctggagg aggaggatcc ggaggaggag gcagctctcc aggccagggc 600
acccagagcg agaactcttg cacacacttc cctggcaacc tgccaaatat gctgagagac 660
ctgcgcgatg ccttttctag agtgaagacc ttctttcaga tgaaagatca gctggataac 720
ctgctgctga aggagtccct gctggaggat ttcaagggtt acctgggttg tcaggctctg 780
agcgaaatga ttcagtttta tctggaggaa gtgatgccgc aggctgaaaa ccaggacccc 840
gacatcaagg cccacgtgaa ctctctgggt gaaaatctga agaccctgag actgcgcctg 900
agacgctgcc atcgcttcct gccctgcgaa aataagtcta aagctgtcga acaggtcaaa 960
aatgctttta ataagctgca agagaagggc atctataaag ctatgtccga atttgatatc 1020
tttatcaatt atatcgaggc ttatatgacc atgaagatca gaaatggctc cggcggcggc 1080
gataagaccc acacatgccc accttgtcca gctccagagc tgctgggagg accttccgtg 1140
ttcctgtttc cacccaagcc aaaggacacc ctgatgatct cccgcacccc agaggtgaca 1200
tgcgtggtgg tggacgtgag ccacgagaac cccgaggtga agttcaattg gtacgtggat 1260
ggcgtggagg tgcataacgc taagacaaag cctagggagg agcagtacaa tagcacctat 1320
cgggtggtgt ctgtgctgac agtgctgcat caggattggc tgaacggcaa ggagtataag 1380
tgcaaggtgt ctaataaggc cctgcctgct ccaatcgaga agaccatctc caaggccaag 1440
ggccagccca gagagcctca ggtgtacaca ctgcctccaa gccgcgagga gatgaccaag 1500
aaccaggtgt ctctgacatg tctggtgaag ggcttctatc cctctgatat cgctgtggag 1560
tgggagtcca atggccagcc tgagaacaat tacaagacca caccccctgt gctggactcc 1620
gatggcagct tctttctgta ttccaagctg accgtggaca agagcaggtg gcagcagggc 1680
aacgtgtttt cctgtagcgt gatgcatgag gccctgcaca atcattacac acaggattct 1740
ctgtccctga gccctggcaa g 1761
Claims (10)
1. A pharmaceutical composition comprising an anti-EGFR fusion protein or antigen-binding fragment thereof, wherein the anti-EGFR fusion protein or antigen-binding fragment thereof is a fusion protein or antigen-binding fragment thereof that specifically binds EGFR; and a buffer which is a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer, the buffer having a pH of 5.5 to 6.5, preferably 6.0.
2. The pharmaceutical composition according to claim 1, wherein the buffer concentration is 5mM to 30mM, preferably 5mM to 25mM, more preferably 10mM.
3. The pharmaceutical composition of claim 1, wherein the fusion protein or antigen-binding fragment thereof that specifically binds EGFR is at a concentration of 1mg/ml to 20mg/ml, preferably 5mg/ml.
4. The pharmaceutical composition according to claim 1, further comprising a sugar, preferably trehalose or sucrose or mannitol, most preferably trehalose.
5. The pharmaceutical composition according to claim 4, wherein the sugar concentration is 50mM to 250mM, preferably 50mM to 150mM, most preferably 135mM.
6. The pharmaceutical composition according to claim 1, further comprising a surfactant, preferably a polysorbate, more preferably polysorbate 80.
7. The pharmaceutical composition according to claim 6, wherein the concentration of the surfactant is from 0.1mg/mL to 0.4mg/mL, preferably 0.2mg/mL.
8. A pharmaceutical composition comprising:
(a) 1mg/ml to 20mg/ml of a fusion protein or antigen-binding fragment thereof that specifically binds EGFR,
(b) 5mM to 30mM disodium hydrogen phosphate/sodium dihydrogen phosphate buffer, pH 5.5 to 6.5,
(c) 50mM to 250mM trehalose, and
(d) 0.1mg/mL to 0.4mg/mL polysorbate 80.
9. A pharmaceutical composition comprising:
(a) 5mg/ml of a fusion protein or antigen-binding fragment thereof that specifically binds EGFR,
(b) 10mM disodium hydrogen phosphate/sodium dihydrogen phosphate buffer, pH6.0,
(c) 135mM trehalose, and
(d) 0.2mg/mL polysorbate 80.
10. The pharmaceutical composition of any one of claims 1 to 9, wherein the anti-EGFR fusion protein or antigen-binding fragment thereof comprises heavy chains HCDR1, HCDR2 and HCDR3 as set forth in the amino acid sequences of SEQ ID No. 2, SEQ ID No. 3 and SEQ ID No. 4; and/or comprises light chains LCDR1, LCDR2 and LCDR3 as represented by the amino acid sequences of SEQ ID NO 6, SEQ ID NO 7 and SEQ ID NO 8; and/or comprises the heavy chain as represented by the amino acid sequence of SEQ ID NO 9; preferably, the anti-EGFR fusion protein or antigen-binding fragment thereof comprises the amino acid heavy chain as set forth in SEQ ID NO 1, SEQ ID NO 9; and/or a light chain comprising amino acids as set forth in SEQ ID NO. 5.
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