CN113797331A - Stable anti-IL-4R alpha monoclonal antibody liquid preparation - Google Patents
Stable anti-IL-4R alpha monoclonal antibody liquid preparation Download PDFInfo
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- CN113797331A CN113797331A CN202010546188.5A CN202010546188A CN113797331A CN 113797331 A CN113797331 A CN 113797331A CN 202010546188 A CN202010546188 A CN 202010546188A CN 113797331 A CN113797331 A CN 113797331A
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Abstract
The invention provides a stable anti-IL-4R alpha monoclonal antibody liquid preparation. The invention greatly improves the defect of poor stability of the existing anti-IL-4R alpha monoclonal antibody preparation by optimizing the formula. The finished product of the liquid preparation medicine can be stored for at least 24 months at 2-8 ℃ and at least 6 months at 25 ℃, and has excellent stability. Therefore, the liquid preparation can provide the preparation stability of the anti-IL-4R alpha monoclonal antibody, and has wide industrial application prospect.
Description
Technical Field
The invention belongs to the field of biological pharmacy, and particularly relates to a stable anti-IL-4R alpha monoclonal antibody liquid preparation.
Background
Atopic Dermatitis (AD) is a common chronic inflammatory recurrent disease of the skin. The condition is the most common inflammatory skin disease worldwide, with about 15% -30% of children and 2% -10% of adults all over the world. According to statistics, more than 230 ten thousand teenagers suffer from atopic dermatitis (eczema) in China, and the number of children patients reaches 200-300 ten thousand.
Us FDA approved dupixent (dupilumab) for the treatment of adult patients with moderate to severe eczema (atopic dermatitis) in 2017. Dupixent is intended for patients who have inadequate control of eczema after topical application, or who are not advised to use topical application. Dupixent is administered by subcutaneous injection and the active ingredient is an antibody that binds to interleukin-4 receptor alpha subunit (IL-4 ra), a protein that causes inflammation. By binding to this protein, Dupixent is able to suppress the inflammatory response that plays a role in the development of atopic dermatitis.
The Dupixent preparation is 150mg/ml injection, and is known to have poor stability when stored at 2-8 ℃ for 15 months and at 25 ℃ for 14 days at most, as determined by EMA Association report Dupixent (European Medicines Agency, Science Medicines Health, EMA/512262/2017, p16, https:// www.ema.europa.eu/en/documents/association-report/Dupixent-ear-public-asset-report _ report.
PCT patent application WO2020/048312 discloses a self-developed recombinant anti-IL-4R alpha humanized monoclonal antibody, which is a recombinant humanized monoclonal antibody expressed in CHO cells by adopting a DNA recombination technology and is formed by humanizing a heavy chain variable region and a light chain variable region of an anti-IL-4R alpha murine antibody. There is a need for intensive research on such novel recombinant anti-IL-4R α humanized monoclonal antibodies to develop stable formulations suitable for clinical use.
Disclosure of Invention
In order to solve the problem of poor stability of the existing anti-IL-4R alpha antibody preparation, the invention aims to provide a stable anti-IL-4R alpha monoclonal antibody liquid preparation with high concentration. The liquid preparation consists of an anti-IL-4R alpha monoclonal antibody, histidine, arginine hydrochloride, trehalose, glacial acetic acid and polysorbate 80. Can stabilize protein, and has excellent stability, such as 24 months storage at 2-8 deg.C and 6 months storage at 25 deg.C.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a stable liquid preparation of anti-IL-4R alpha monoclonal antibody, wherein the liquid preparation comprises anti-IL-4R alpha monoclonal antibody, histidine, arginine hydrochloride, trehalose, glacial acetic acid and polysorbate 80, wherein the concentration of the anti-IL-4R alpha monoclonal antibody is 100-200mg/ml, and the anti-IL-4R alpha monoclonal antibody comprises the amino acid sequence shown in SEQ ID NO: 1-3 and a heavy chain as set forth in any one of SEQ ID NOs: 4, or a light chain as shown in figure 4.
Wherein the concentration of the anti-IL-4R alpha monoclonal antibody is 150mg/ml, and the anti-IL-4R alpha monoclonal antibody comprises the amino acid sequence shown in SEQ ID NO: 1 and the heavy chain as set forth in SEQ ID NO: 4, or a light chain as shown in figure 4.
Wherein the histidine concentration is 20-30mM, preferably 20 mM.
Wherein, the concentration of the arginine hydrochloride is 25-75mM, and preferably, the concentration of the arginine hydrochloride is 25 mM.
Wherein the trehalose concentration is 50-80mg/ml, preferably, the trehalose concentration is 70 mg/ml.
Wherein the concentration of the glacial acetic acid is 0.4-1.7mg/ml, and preferably, the concentration of the glacial acetic acid is 0.89 mg/ml.
Wherein the concentration of the polysorbate 80 is 0.3-1.5mg/ml, and preferably, the concentration of the polysorbate 80 is 0.3 mg/ml.
Wherein, the pH range of the liquid preparation is 5.0-6.3, and preferably, the pH of the liquid preparation is 5.8.
In a second aspect, the invention provides the use of said liquid formulation for the manufacture of a medicament for the treatment of a disease associated with overexpression of IL-4R α.
Wherein, the diseases related to IL-4R alpha overexpression comprise atopic dermatitis, asthma, anaphylaxis, eosinophilic esophagitis, skin infection, nasal polyp and the like.
Has the advantages that: the invention provides a stable anti-IL-4R alpha monoclonal antibody liquid preparation. The invention greatly improves the defect of poor stability of the existing anti-IL-4R alpha monoclonal antibody preparation by optimizing the formula. The finished product of the liquid formulation medicine can be stored for at least 24 months at 2-8 ℃ and at least 6 months at 25 ℃, and has excellent stability. Therefore, the liquid formula preparation can provide the preparation stability of the anti-IL-4R alpha monoclonal antibody, and has wide industrial application prospect.
Drawings
FIG. 1 shows the results of DOE pH test and polysorbate 80 concentration analysis.
Figure 2 is an analysis of insoluble microparticle results for different concentrations of polysorbate 80.
FIG. 3 is an analysis of the SEC purity long term stability results.
FIG. 4 is an analysis of IEC purity long-term stability results.
Detailed Description
The anti-human IL-4 Ra monoclonal antibodies used in the present invention are derived from the Humanized anti-human IL-4 Ra monoclonal antibodies 4-2-Humanized-IgG4, 4-2-Humanized-IgG1, 4-2-Humanized-IgG1-SELF disclosed in WO2020/048312, comprising identical heavy chain variable regions, different heavy chain constant regions and identical light chains, the heavy and light chain amino acid sequences being as follows.
4-2-Humanized-IgG4 heavy chain amino acid sequence (SEQ ID NO: 1)
QVQLVQSGAEVKKPGASVKVSCKASGSTLTDDYINWVRQAPGQRLEWVGWIFPGNGNSYYNEKFKDRATLTVDKSASTAYMELSSLRSEDTAVYFCARGLVRYRALFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
4-2-Humanized-IgG1 heavy chain amino acid sequence (SEQ ID NO: 2)
QVQLVQSGAEVKKPGASVKVSCKASGSTLTDDYINWVRQAPGQRLEWVGWIFPGNGNSYYNEKFKDRATLTVDKSASTAYMELSSLRSEDTAVYFCARGLVRYRALFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
4-2-Humanized-IgG1-SELF heavy chain amino acid sequence (SEQ ID NO: 3)
QVQLVQSGAEVKKPGASVKVSCKASGSTLTDDYINWVRQAPGQRLEWVGWIFPGNGNSYYNEKFKDRATLTVDKSASTAYMELSSLRSEDTAVYFCARGLVRYRALFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Amino acid sequences of 4-2-Humanized-IgG4, 4-2-Humanized-IgG1, 4-2-Humanized-IgG1-SELF light chain (SEQ ID NO: 4)
DIQMTQSPSSLSASVGDRVTITCRASSSINYMHWYQQKPGKAPKPWIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWSSYPITFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
For exemplary purposes, the protein sample used in the following examples is 4-2-Humanized-IgG4, comprising the amino acid sequence set forth in SEQ ID NO: 1 and the heavy chain as set forth in SEQ ID NO: 4, or a light chain as shown in figure 4.
The detection method used in the following examples is illustrated below:
SEC purity, Polymer detection method:
mobile phase: 200mM phosphate buffer, pH 6.8. + -. 0.1. Filtering with 0.22 μm filter membrane, and ultrasonic degassing. A chromatographic column: TSK G3000SWxl, 7.8X 300mm 5 μm, TOSOH 08541. High performance liquid chromatograph: waters Alliance e 26952489 UV/visible light Detector, Dionex Ultimate3000VWD-3400(RS) Detector or other suitable HPLC system equipped with a UV Detector.
System applicability sample: the reference substance is diluted to the concentration of 5.0mg/ml by a mobile phase, centrifuged at 13000rpm for 10min, and the supernatant is taken and transferred to a sample bottle and placed in an HPLC sample tray. And (3) testing the sample: diluting the sample concentration to 5.0mg/ml with mobile phase, centrifuging at 13000rpm for 10min, taking supernatant, transferring to a sample bottle, and placing into HPLC sample plate. Chromatographic conditions are as follows: the column temperature is 25 +/-2 ℃; the sample temperature is 10 +/-2 ℃; detecting the wavelength UV 280 nm; the injection volume is 20 mu L; the flow rate was 0.5 ml/min.
Integration was performed using chromatography software and peak area normalization was used to calculate the peak area percentage of each peak. Acceptance criteria for system suitability: the separation degree of polymers and monomers of 6-needle system applicability samples is more than or equal to 1.5, the retention time RSD of a main peak is less than or equal to 1.0%, the peak area RSD of the main peak is less than or equal to 2.0%, the asymmetry of the main peak is less than or equal to 2.0, and the number of theoretical plates is more than or equal to 4000. The test article reports the results: the SEC purity of the sample is reported as the peak area percentage of the monomer main peak and the polymer content as the peak area percentage of the polymer peak.
The IEC purity detection method comprises the following steps:
mobile phase A: 20mM phosphate buffer, pH 6.5. + -. 0.05. Filtering with 0.22 μm filter membrane, and ultrasonic degassing. Mobile phase B: 20mM phosphate buffer +200mM sodium chloride, pH 6.5. + -. 0.05. Filtering with 0.22 μm filter membrane, and ultrasonic degassing. A chromatographic column: propac WCX-10, 4X 250mm, Thermo Dionex 054993. High performance liquid chromatograph: waters Alliance e2695, Dionex Ultimate series 3000 or other suitable HPLC system equipped with an ultraviolet detector.
System applicability sample: the reference substance is diluted to 1.0mg/ml by mobile phase, centrifuged for 10min at 13000rpm, and the supernatant is transferred to a sample bottle and placed in an HPLC sample tray. And (3) testing the sample: diluting the sample concentration to 1.0mg/ml with mobile phase, centrifuging at 13000rpm for 10min, taking supernatant, transferring to a sample bottle, and placing into an HPLC sample tray. Chromatographic conditions are as follows: the column temperature is 30 +/-2 ℃; the sample temperature is 10 +/-2 ℃; the detection wavelength is UV 214 nm; the injection volume is 20 mu L; the flow rate was 1.0 ml/min. The mobile phase gradient was as follows:
purity analysis: and calculating the peak area percentages of a main peak, an acid peak area and an alkali peak area on the sample map by using a peak area normalization method. The IEC purity results are reported as peak area percentages of the main peak.
The starting components used in the following examples are commercially available, unless otherwise noted.
The following examples and experimental examples are intended to further illustrate the present invention, but are not intended to limit the present invention in any way.
Example 1 Effect of buffer systems on formulation stability
As shown in Table 1, 10mM citric acid system, 20mM histidine-histidine hydrochloride system, and 20mM histidine-acetic acid system were prepared, respectively, and the pH was 5.5. The stability of 150mg/ml protein in different systems was investigated. Three groups of solutions were left at 40 ℃ for 15 days and sampled at 0, 2, 5, 9, 15 days for SEC purity and IEC purity.
TABLE 1 buffer System examination results
As can be seen from the results in Table 1, the SEC purity and IEC purity results for both histidine-histidine hydrochloride buffer and histidine-acetic acid buffer systems are superior to those for the citric acid system.
Example 2 arginine/arginine hydrochloride on formulation viscosity
Arginine/arginine hydrochloride has the effect of reducing the viscosity of a high-concentration protein solution and protecting the protein, and in the embodiment, the concentration of the protein is 150mg/ml, and the viscosity is higher, so the arginine hydrochloride is added for testing to explore the effects of reducing and protecting the viscosity of the protein.
As shown in Table 2, 0-100mM arginine hydrochloride was added to 20mM histidine-histidine hydrochloride and 20mM histidine-acetic acid systems, respectively, the former adjusted to pH 5.5 with hydrochloric acid and the latter adjusted to pH 5.5 with acetic acid.
TABLE 2 influence of arginine hydrochloride
From the results in Table 2, it is clear that in the histidine-histidine hydrochloride system, the addition of arginine hydrochloride at a concentration of 50mM or more significantly reduced the viscosity; in a histidine-acetic acid system, arginine hydrochloride with the concentration of more than 25mM can be added to obviously reduce the viscosity. The histidine-acetic acid system has better buffering capacity than the histidine-histidine hydrochloride system, so the histidine-acetic acid is selected as the buffering system subsequently.
Example 3 pH and polysorbate 80 investigation
As shown in table 3, this example uses DOE design to examine the effect of pH and polysorbate 80 on the formulation. Glacial acetic acid is used for adjusting the pH value to be 5.0-6.6, and the dosage of polysorbate 80 is 0-3 mg/ml. The protein concentration of other components is 150mg/ml, histidine is 20mM, arginine hydrochloride is 25mM, and trehalose is 50 mg/ml. The prepared sample is placed at 40 ℃ for 30 days for inspection, samples are taken at 0, 7, 14, 21 and 30 days respectively, and SEC purity, IEC purity and insoluble particles (more than or equal to 10 mu m) are detected.
Table 3 pH and polysorbate 80 survey design table
Numbering | Mode(s) | | Polysorbate | 80 |
3-1 | A0 | 6.6 | 1.5 | |
3-2 | 0A | 5.8 | 3.0 | |
3-3 | -- | 5.0 | 0.0 | |
3-4 | -+ | 5.0 | 3.0 | |
3-5 | 0a | 5.8 | 0.0 | |
3-6 | 0 | 5.8 | 1.5 | |
3-7 | 0 | 5.8 | 1.5 | |
3-8 | a0 | 5.0 | 1.5 | |
3-9 | +- | 6.6 | 0.0 | |
3-10 | ++ | 6.6 | 3.0 |
TABLE 4 results of DOE examination
The results in table 4 were subjected to slope analysis and the slopes of each set were analyzed using the JMP DOE model as shown in fig. 1. As can be seen from the results in FIG. 1, the preferred pH range is pH5.0-6.3, and the preferred polysorbate 80 amount is 0-1.5 mg/ml.
Example 4 insoluble particle examination
This example examines the effect of polysorbate 80 on insoluble microparticles. As shown in Table 5, this example prepared 6 aliquots with a protein concentration of 150mg/ml, histidine 20mM, arginine hydrochloride 25mM, trehalose 50mg/ml, polysorbate 800-0.5 mg/ml, and adjusted to pH5.8 with glacial acetic acid. Insoluble particles were detected after formulation.
TABLE 5 insoluble microparticle results for different polysorbate 80 dosages
As can be seen from FIG. 2, the insoluble particles decreased with increasing polysorbate 80, and the insoluble particle data tended to stabilize above the concentration of 0.3 mg/ml. Therefore, the preferable concentration of polysorbate 80 is 0.3mg/ml or more.
Example 5 trehalose and histidine survey
This example examines the effect of trehalose and histidine levels on the formulation. 4 sets of formulations were prepared as in Table 6, protein concentration 150mg/ml, 25mM arginine hydrochloride, and 0.3mg/ml polysorbate 80 was added, and the pH was adjusted to 5.8 with glacial acetic acid. The samples were left at 40 ℃ for 14 days and sampled at 0, 7 and 14 days for SEC purity and IEC purity.
TABLE 6 trehalose and histidine survey
TABLE 7 trehalose and histidine observations
As can be seen from the results in Table 7, there was no significant difference between the SEC and IEC purity prescribed for each group, and therefore, the preferred concentration range of histidine was 20-30mM, and the preferred concentration range of trehalose was 50-80mg/ml, considering the principle that the injection was isotonic with the human body.
Example 6 glacial acetic acid investigation
As shown in Table 8, in this example, glacial acetic acid was added to 50ml of a histidine (20mM) and arginine hydrochloride (25mM) solution, and the pH was measured in each amount added in Table 8. The concentration of glacial acetic acid corresponding to each pH was calculated.
TABLE 8 glacial acetic acid investigation
As is clear from the results in Table 8, the concentration of glacial acetic acid at pH5.0-6.3 in 20mM histidine and 25mM arginine hydrochloride solution is about 0.4-1.7 mg/ml.
Example 7 accelerated stability test
In this example, 3 batches of drugs were prepared, specifically formulated with anti-IL-4R α monoclonal antibody 150mg/ml, histidine 20mM, arginine hydrochloride 25mM, trehalose 70mg/ml, glacial acetic acid 0.89mg/ml, polysorbate 800.3 mg/ml, pH 5.8. Three batches of the drug are placed at 25 ℃ for accelerated stability investigation for 6 months, samples are taken at 0, 1, 2, 3 and 6 months respectively, and SEC purity, IEC purity and insoluble particles are detected.
TABLE 9 accelerated stability results
From the results in Table 9, it is clear that after 6 months of accelerated stability, the insoluble particles, SEC purity, and IEC purity all meet the quality standards. Therefore, the liquid preparation formula of the invention has good protection effect on target protein at 25 ℃.
Example 8 Long term stability Studies
In this example, 3 batches of drugs were prepared, specifically formulated with anti-IL-4R α monoclonal antibody 150mg/ml, histidine 20mM, arginine hydrochloride 25mM, trehalose 70mg/ml, glacial acetic acid 0.89mg/ml, polysorbate 800.3 mg/ml, pH 5.8. Three batches of the drug were placed at 2-8 ℃ for long-term stability studies, and each point was sampled to detect SEC purity, IEC purity and insoluble particles.
TABLE 10 Long term stability results
From the results in Table 10, it is clear that the insoluble fine particles, SEC purity and IEC purity all meet the standards. As can be seen from the analysis of the results in FIGS. 3 and 4, the drug expiration date indicated by SEC purity is 33 months, and the drug expiration date indicated by IEC purity is 24 months, so that the anti-IL-4R α monoclonal antibody injection can be stored at 2-8 ℃ for at least 24 months under the protection of the formulation of the present invention.
Sequence listing
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<120> a stable anti-IL-4R alpha monoclonal antibody liquid preparation
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Claims (10)
1. A stable anti-IL-4R alpha monoclonal antibody liquid preparation, wherein the liquid preparation comprises an anti-IL-4R alpha monoclonal antibody, histidine, arginine hydrochloride, trehalose, glacial acetic acid and polysorbate 80, wherein the concentration of the anti-IL-4R alpha monoclonal antibody is 100-200mg/ml, and the anti-IL-4R alpha monoclonal antibody comprises the amino acid sequence shown in SEQ ID NO: 1-3 and a heavy chain as set forth in any one of SEQ ID NOs: 4, or a light chain as shown in figure 4.
2. The liquid formulation of claim 1, wherein the anti-IL-4 ra monoclonal antibody is present at a concentration of 150mg/ml, and wherein the anti-IL-4 ra monoclonal antibody comprises the amino acid sequence set forth in SEQ ID NO: 1 and the heavy chain as set forth in SEQ ID NO: 4, or a light chain as shown in figure 4.
3. The liquid formulation of claim 1, wherein the histidine concentration is 20-30mM, preferably wherein the histidine concentration is 20 mM.
4. The liquid formulation of claim 1, wherein the arginine hydrochloride concentration is 25 to 75mM, preferably wherein the arginine hydrochloride concentration is 25 mM.
5. The liquid formulation of claim 1, wherein said trehalose is at a concentration of 50-80mg/ml, preferably wherein said trehalose is at a concentration of 70 mg/ml.
6. The liquid formulation of claim 1, wherein said glacial acetic acid concentration is 0.4-1.7mg/ml, preferably said glacial acetic acid concentration is 0.89 mg/ml.
7. The liquid formulation of claim 1, wherein polysorbate 80 is present at a concentration of 0.3-1.5mg/ml, preferably polysorbate 80 is present at a concentration of 0.3 mg/ml.
8. The liquid formulation of claim 1, wherein the liquid formulation has a pH in the range of 5.0 to 6.3, preferably wherein the liquid formulation has a pH of 5.8.
9. Use of a liquid formulation according to any one of claims 1-8 for the manufacture of a medicament for the treatment of a disease associated with overexpression of IL-4 ra.
10. The use according to claim 9, wherein the diseases associated with overexpression of IL-4 ra comprise atopic dermatitis, asthma, allergic reactions, eosinophilic esophagitis, skin infections, nasal polyps.
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