CN106474470B - Composition of anti-IL-17A antibody - Google Patents

Composition of anti-IL-17A antibody Download PDF

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CN106474470B
CN106474470B CN201610739134.4A CN201610739134A CN106474470B CN 106474470 B CN106474470 B CN 106474470B CN 201610739134 A CN201610739134 A CN 201610739134A CN 106474470 B CN106474470 B CN 106474470B
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颜贞
李�杰
常海明
杨婷婷
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Shanghai Hengrui Pharmaceutical Co Ltd
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

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Abstract

The present invention relates to a composition of anti-IL-17A antibodies. Specifically, the invention relates to a pharmaceutical composition, which comprises an anti-IL-17A antibody, a buffering agent, disaccharide and optionally a surfactant. The pharmaceutical composition of the invention can effectively inhibit the aggregation and deamidation of the antibody, thereby preventing the degradation of the antibody product therein and obtaining a stable injection composition.

Description

Composition of anti-IL-17A antibody
Technical Field
The present invention relates to a composition of stable anti-IL-17A antibodies.
Background
IL-17A (like IL-17) is involved in the production of proinflammatory responses and induces and mediates the expression of a variety of cytokines including alpha tumor necrosis factor (TNF- α), IL-6, IL-8, IL-1 β, GRO- α, granulocyte-colony stimulating factor (G-CSF), prostaglandin E2(PGE 2), IL-10, IL-12, IL-1R antagonists, leukemia inhibitory factor, etc. IL-17 also induces the production of nitric oxide outside chondrocytes and human bone joints.
The SHR-1314 injection is an autonomously developed humanized monoclonal antibody medicament, takes IL-17A as a target, specifically binds IL-17A to inhibit the generation of cytokines such as GRO α and the like, achieves the effect of blocking a signal conduction pathway, is mainly used for treating psoriasis, and is clinically confirmed for other autoimmune diseases.
WO2015070697 discloses a novel class of anti-IL-17A antibodies with high affinity and long half-life, which are expected to have better therapeutic effects on the above mentioned diseases. However, these new anti-IL-17A antibodies are extremely unstable and difficult to formulate into clinically useful formulations, and WO2015070697 does not describe anything about how they can be formulated. Therefore, it is necessary to intensively study these antibodies to obtain a stable and clinically convenient preparation.
Disclosure of Invention
The invention aims to provide a stable anti-IL-17A antibody composition.
The composition of the present invention comprises an anti-IL-17A antibody, a buffer, a disaccharide, and optionally a surfactant.
In the composition of the present invention, the anti-IL-17A antibody preferably has the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively, and the amino acid sequences of HCDR1, HCDR2 and HCDR3 of SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively, as shown in the following table:
Figure BDA0001093885410000011
Figure BDA0001093885410000021
further preferred anti-IL-17A antibodies have the light chain of SEQ ID NO. 7 and the heavy chain amino acid sequence of SEQ ID NO. 8:
SEQ ID NO:7
EIVLTQSPDFQSVTPKEKVTITCSASSSVNYMHWFQQKPDQSPKLWIYRTSNLASGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQRSSYPWTFGQGTKLEIKR
SEQ ID NO:8
EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEVHWVRQAPGQGLEWMGVIDPGTGGVAYNQKFEGRVTMTADTSTSTAYMELRSLRSDDTAVYYCTRYSLFYGSSPYAMDYWGQGTLVTVSS
the concentration of the anti-IL-17A antibody may be 50-150mg/ml, preferably 70-100mg/ml, most preferably 80 mg/ml.
Preferred buffers of the present invention are histidine-hydrochloride systems, preferably histidine-histidine hydrochloride buffers, in an amount which is not particularly limited, and in embodiments of the present invention, for example, from 1 to 50mM, preferably from 5 to 20mM, most preferably 10 mM.
The disaccharide can be selected from sucrose, lactic acid, trehalose, maltose, preferably sucrose. The amount of the disaccharide used is not particularly limited, and in an embodiment of the present invention, for example, is 10 to 500mg/ml, preferably 50 to 200mg/ml, more preferably 50 to 100mg/ml, most preferably 76 mg/ml.
The surfactant may be selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and the polyoxyethylene sorbitan fatty acid ester may be selected from polysorbate 20, 40, 60, or 80. The amount of the surfactant to be used is not particularly limited, and in an embodiment of the present invention, for example, is 0.1 to 10mg/ml, preferably 0.2 to 5mg/ml, more preferably 0.3 to 0.9mg/ml, most preferably 0.6 mg/ml.
The composition is an injectable pharmaceutical composition.
The pH of the composition may range from 5.0 to 7.0, preferably from 5.4 to 6.2, most preferably from 5.8 to 6.0.
In one embodiment of the invention, the composition consists of an anti-IL-17A antibody, a buffer, a disaccharide, a surfactant, optionally including water.
The injectable pharmaceutical composition may be an injection or further prepared in the form of lyophilized powder. The lyophilized powder can be prepared by conventional methods in the art.
The invention also provides an injection which is reconstructed after the freeze-dried powder is redissolved and can be directly used for injection.
The pharmaceutical composition can effectively inhibit the aggregation and deamidation of the antibody, thereby preventing the degradation of the antibody product, obtaining a stable injection composition, and can be stably stored for 6 months at 25 ℃ and 12 months at 2-8 ℃. In addition, the pharmaceutical composition has a protective effect on protein oxidative degradation, can be compatible with glass and stainless steel containers, and can be stably stored in the containers.
Drawings
FIG. 1 shows the degradation curve of the formulation of example 5 under strong oxidative conditions, with blanks and 0.005% H2O2The degradation curves of the groups overlap.
Figure 2 shows the degradation curve of the formulation of example 5 under strong oxidizing conditions.
Detailed Description
The present invention is further illustrated in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
The anti-IL-17A antibody was formulated in a pH 5.5-6.5 formulation containing 10mM histidine hydrochloride, 76mg/mL sucrose, 0.6mg/mL polysorbate 80, respectively, at a protein concentration of 80 mg/mL. Each formulation was filtered and filled into 2mL neutral borosilicate glass tubular injection vials sealed with polytetrafluoroethylene/hexafluoropropylene coated copolymer films chlorinated butyl rubber stoppers for the injections. The samples were stored at 40 ℃ for stability analysis. The results show that anti-IL-17A antibodies are most stable at pH 5.8-6.0.
TABLE 1 Effect of pH on degradation of anti-IL-17A antibodies stored at 40 ℃
Figure BDA0001093885410000031
Example 2
An anti-IL-17A antibody preparation was prepared at a protein concentration of 80mg/mL in the following buffer:
1)15mM phosphate, 76mg/mL sucrose, pH5.8
2)10mM histidine hydrochloride, 76mg/mL sucrose, pH5.8
Each formulation was aliquoted into 2mL vials and stored at 40 ℃. Stability analysis of the drug product shows that the stability of the anti-IL-17A antibody in a histidine buffer salt system is obviously superior to that of a phosphate buffer system.
TABLE 2 Effect of buffer systems on degradation of anti-IL-17A antibodies stored at 40 deg.C
Figure BDA0001093885410000032
Figure BDA0001093885410000041
Example 3
Prescription screening is carried out by designing prescriptions containing different sucrose concentrations by adopting DSC technology:
the experimental result shows that the T of the SHR-1314 monoclonal antibody is the T when the sucrose concentration reaches 76mg/mlmThe value has larger increase, which indicates that the stability of the protein is better under the concentration
TABLE 3 recipe compositions and recipe screening test results for different sucrose concentrations
Figure BDA0001093885410000042
Example 4
An anti-IL-17A antibody preparation with a protein concentration of 80mg/mL was prepared in buffers containing the following surfactants at different concentrations:
1)10mM histidine hydrochloride, 76mg/mL sucrose, pH5.8
2)10mM histidine hydrochloride, 76mg/mL sucrose, 0.6mg/mL polysorbate 20, pH5.8
3)10mM histidine hydrochloride, 76mg/mL sucrose, 0.3mg/mL polysorbate 80, pH5.8
4)10mM histidine hydrochloride, 76mg/mL sucrose, 0.6mg/mL polysorbate 80, pH5.8
5)10mM histidine hydrochloride, 76mg/mL sucrose, 0.9mg/mL polysorbate 80, pH5.8
Each formulation was filled into 2mL vials and sealed with a film-coated plug. The drug was placed on a constant temperature shaker at 25 ℃ and shaken at 500 rpm. The stability results show that 0.6-0.9 mg/mL of polysorbate 80 and 20 effectively prevent the formation of large particle aggregates of the anti-IL-17A antibody.
TABLE 4 Effect of surfactants on aggregation of anti-IL-17A antibodies shaken at 25 ℃ and 500rpm
Figure BDA0001093885410000051
Example 5
The anti-IL-17A antibody was formulated at 80mg/mL in 10mM histidine hydrochloride, 76mg/mL sucrose, 0.6mg/mL polysorbate 80, pH 5.8. The antibody was filled into 2mL vials and sealed with a coated rubber plug. The sample is placed in a low temperature of-20 ℃ to 40 ℃ for 3 times of circulation, or in a freeze-thaw cycle of 4 ℃ to 40 ℃ for 3 times. The stability of the drug is evaluated by detecting the protein content, the purity and the activity, and the result proves that the anti-IL-17A antibody is relatively stable in the prescription and can still meet the quality standard after low temperature and freeze-thaw circulation.
TABLE 5 stability of anti-IL-17A antibody formulations during low temperature cycling and freeze-thaw cycling
Figure BDA0001093885410000052
Example 6
To an anti-IL-17A antibody preparation containing 80mg/mL of a protein, 10mM of histidine hydrochloride, 76mg/mL of sucrose, 0.6mg/mL of polysorbate 80, and pH5.8, 0.005% of hydrogen peroxide, or 0.005% of hydrogen peroxide + 0.005% of ferric iron was added, respectively. Standing at 37 deg.C for 48 h. The results show that the formulation has a certain protective effect against oxidative degradation of proteins, see fig. 1 and 2.
Example 7
The anti-IL-17A antibody was formulated at 80mg/mL in 10mM histidine hydrochloride, 76mg/mL sucrose, 0.6mg/mL polysorbate 80, pH 5.8. The formulations were filled in glass bottles and 316L stainless steel jars, respectively, and left at room temperature for 48 hours. Protein content and purity analysis showed that anti-IL-17A antibody was stable within 48 hours. The formulation is compatible with 316L stainless steel cans.
TABLE 6 stability of anti-IL-17A antibodies in stainless Steel jars
Figure BDA0001093885410000061
Figure IDA0001093885460000011
Figure IDA0001093885460000021
Figure IDA0001093885460000031

Claims (5)

1. A pharmaceutical composition comprising an anti-IL-17A antibody, a buffer, a disaccharide, and further comprising a surfactant, said anti-IL-17A antibody having the amino acid sequences LCDR1, LCDR2, and LCDR3 of SEQ ID NO 1, SEQ ID NO 2, and SEQ ID NO 3, respectively, and the amino acid sequences HCDR1, HCDR2, and HCDR3 of SEQ ID NO 4, SEQ ID NO 5, and SEQ ID NO 6, respectively; the concentration of the anti-IL-17A antibody is 80 mg/ml; the buffer is histidine-histidine hydrochloride buffer, and the concentration of the buffer is 10 mM; the disaccharide is sucrose, and the concentration is 76 mg/ml; the surfactant is polysorbate 80, and the concentration of the surfactant is 0.6 mg/ml; the pH value is 5.8-6.0.
2. The pharmaceutical composition of claim 1, wherein the anti-IL-17A antibody has the light chain of SEQ ID NO 7 and the heavy chain amino acid sequence of SEQ ID NO 8.
3. The pharmaceutical composition of claim 1, which is an injectable pharmaceutical composition further comprising water for injection.
4. A lyophilized powder prepared from the pharmaceutical composition of claim 3.
5. An injection obtained after reconstitution of a lyophilized powder according to claim 4.
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CN111303283A (en) * 2018-12-12 2020-06-19 上海君实生物医药科技股份有限公司 anti-IL-17A antibodies and uses thereof
EP3927729A4 (en) 2019-02-18 2023-10-11 Eli Lilly and Company Therapeutic antibody formulation
CN110124030A (en) * 2019-06-10 2019-08-16 通化东宝生物科技有限公司 A kind of Su Jin monoclonal antibody injection and preparation method thereof
CN114127108A (en) * 2019-07-30 2022-03-01 江苏恒瑞医药股份有限公司 Methods of treating autoimmune diseases with IL-17 antagonists
CN110585430B (en) * 2019-09-29 2023-09-08 华博生物医药技术（上海）有限公司 Pharmaceutical composition of humanized anti-human IL-17A monoclonal antibody
CN113769082A (en) * 2020-06-10 2021-12-10 上海君实生物医药科技股份有限公司 anti-IL-17A antibody pharmaceutical composition and application thereof
MX2023006596A (en) * 2020-12-03 2023-06-19 Jiangsu Hengrui Pharmaceuticals Co Ltd Anti-tslp antibody pharmaceutical composition and use thereof.
WO2022144023A1 (en) * 2021-01-04 2022-07-07 江苏恒瑞医药股份有限公司 Method for treating autoimmune diseases and inflammation by using anti-il-17 antibody
WO2022166918A1 (en) * 2021-02-05 2022-08-11 百奥泰生物制药股份有限公司 Anti-il-5 antibody formulation, preparation method therefor and use thereof
WO2022184114A1 (en) * 2021-03-03 2022-09-09 苏州盛迪亚生物医药有限公司 Method for treating autoimmune diseases and inflammations with anti-il-17 antibody
CN115746132B (en) * 2021-09-03 2023-09-08 三优生物医药(上海)有限公司 anti-IL-17A antibodies and uses thereof
CN114380906B (en) * 2022-03-25 2022-06-14 南京融捷康生物科技有限公司 anti-IL-17A single-domain antibody and application thereof

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WO2015070697A1 (en) * 2013-11-18 2015-05-21 上海恒瑞医药有限公司 Il-17a conjugate and uses thereof

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