CN101199483B - Stable anti-HER2 humanized antibody preparation - Google Patents
Stable anti-HER2 humanized antibody preparation Download PDFInfo
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- CN101199483B CN101199483B CN2006101472804A CN200610147280A CN101199483B CN 101199483 B CN101199483 B CN 101199483B CN 2006101472804 A CN2006101472804 A CN 2006101472804A CN 200610147280 A CN200610147280 A CN 200610147280A CN 101199483 B CN101199483 B CN 101199483B
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Abstract
The invention discloses a humanized anti-HER2 antibody preparation, which contains humanized anti-HER2 antibody, protective agent, buffering agent, surfactant and isotonic regulator. The invention has the advantages of stability and low price.
Description
Technical field
The invention belongs to biological technical field, more specifically, the invention discloses a kind of stable biological preparation.
Background technology
Humanized Anti-HER 2 is the deutero-Humanized monoclonal antibodies of a kind of recombinant DNA, optionally acts on the position, extracellular of human epidermal growth factor acceptor-2 (HER2).This antibody belongs to the IgG1 type, contain the people framework region and can with the complementary determining region of the bonded mouse-anti of HER2-p185HER2 antibody, in external and zoopery, all show the propagation of the tumor cell can suppress the HER2 overexpression.In addition, this antibody is the potential medium of the cell-mediated cytotoxic reaction (ADCC) of antibody dependence, and in vitro study, this antibody-mediated ADCC is proved to be in the cancerous cell of HER2 overexpression than more preferably producing in the cancerous cell of the non-overexpression of HER2.Gone on the market by drugs approved by FDA at present, as the metastatic breast cancer of single therapy HER2 overexpression.
The preparation that is applied to clinical humanized Anti-HER 2 is a lyophilized formulations, its excipient is the L-histidine monohydrochloride, the L-histidine, α, α-two carboxylic trehaloses, Polyoxyethylene Sorbitol Fatty Acid Esters 20, this preparation is not only not really stable, should not place for a long time, and the α of its use, α-two carboxylic trehaloses cost an arm and a leg, and have increased patient's drug cost.
Summary of the invention
In order to address the above problem, applicant of the present invention has carried out a large amount of experiments, has obtained a kind of preparation of stable, inexpensive anti-HER 2 humanized antibody.
Particularly:
The invention discloses a kind of anti-HER 2 humanized antibody preparation, form by anti-HER 2 humanized antibody, protective agent, buffer agent, surfactant and isoosmotic adjusting agent.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention is lyophilized formulations.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention; wherein each components contents is anti-HER 2 humanized antibody 10～40mg/ml, protective agent 10～100mg/ml, buffer agent 3～10mmol; surfactant 0.05～0.2mg/ml, isoosmotic adjusting agent 2～9mg/ml.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention, wherein protective agent is one of nonreducing sugar, monosodium glutamate, histidine, trihydroxylic alcohol or its combination.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention, wherein nonreducing sugar is sucrose or trehalose.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention, wherein buffer agent is histidine or succinic acid buffer.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention, wherein buffer agent is a histidine buffering liquid.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention, wherein surfactant is a tween 20.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention, wherein isoosmotic adjusting agent is a sodium chloride.
Above-mentioned anti-HER 2 humanized antibody preparation disclosed by the invention; wherein the content of anti-HER 2 humanized antibody is 20mg/ml, and protectant content is 38mg/ml, and the content of buffer agent is 4.44mmol; the content of surfactant is 0.09mg/ml, and the content of isoosmotic adjusting agent is 4mg/ml.
Above-mentioned preparation disclosed by the invention, preferred lyophilized formulations, these lyophilized formulations are according to Pharmacopoeia of the People's Republic of China version in 2005, two appendix XIX C crude drug and pharmaceutical preparation stability test guideline have been carried out stability experiment, experimental result shows, preparation disclosed by the invention 4 ℃ preserve more than 3 years or 30 ℃ preserve that biological activity remains on more than 95% more than 1 year, lyophilized formulations disclosed by the invention is rebuild with 0.9% or 1.1% benzyl alcohol, preparation after the reconstruction was preserved 3 months at 2～8 ℃, biological activity remains on more than 93%, has reached purpose of the present invention.
The specific embodiment
Further specify the present invention below in conjunction with embodiment, experimental example, following embodiment, experimental example should not be construed as limitation of the present invention.
Anti-HER 2 humanized antibody: it prepares with reference to Carter P, Presta L, Gorman CM, RidgwayJB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM.ProcNatl Acad Sci U S is May 15 A.1992; 89 (10): 4285-9.Humanization of ananti-p185HER2 antibody for human cancer therapy.Anti-HER 2 humanized antibody of the present invention is not limited only to that this is a kind of, and those skilled in the art utilizes anti-HER 2 humanized antibody that general technique for gene engineering obtains also at the row of anti-HER 2 humanized antibody of the present invention.
Unless stated otherwise, other supplementary material is commercially available pharmaceutic adjuvant rank.
The preparation of the preparation of embodiment anti-HER 2 humanized antibody
Embodiment 1
Prescription:
Amounts of components
Anti-HER 2 humanized antibody 20mg/ml
Sucrose 38mg/ml
L-histidine 0.32mg/ml
L-histidine hydrochloride monohydrate 0.5mg/ml
Tween 20 0.09mg/ml
Sodium chloride 4mg/ml
Preparation process:
Molecular exclusion chromatography is adopted in the anti-HER 2 humanized monoclonal antibody purification final step of recombinating, and mobile phase is:
L-histidine 0.32mg/ml
L-histidine hydrochloride monohydrate 0.5mg/ml
Sodium chloride 4mg/ml
Through the stock solution of the anti-HER 2 humanized monoclonal antibody of this step purification acquisition reorganization, the concentration of the anti-HER 2 humanized monoclonal antibody of reorganization should be greater than 20mg/ml in the stock solution.
The preparation of preparation:
According to the required sucrose of the volume calculation of stock solution and the consumption (final concentration is respectively 38mg/ml and 0.09mg/ml) of tween 20, and add in the stock solution.
Adjust the concentration of all components in the solution, make each constituent content as follows:
Amounts of components
Anti-HER 2 humanized antibody 20mg/ml
Sucrose 38mg/ml
L-histidine 0.32mg/ml
L-histidine hydrochloride monohydrate 0.5mg/ml
Tween 20 0.09mg/ml
Sodium chloride 4mg/ml
Obtain semi-finished product, go in the cillin bottle semi-finished product are aseptic subpackaged, add a cover rubber stopper, aluminium-plastic cap is added a cover in lyophilization, obtains finished product.
Embodiment 2
Prescription:
Amounts of components
Anti-HER 2 humanized antibody 10mg/ml
Sucrose 10mg/ml
L-histidine 0.16mg/ml
L-histidine hydrochloride monohydrate 0.25mg/ml
Tween 20 0.05mg/ml
Preparation method is with embodiment 1.
Embodiment 3:
Prescription
Constituent content
Anti-HER 2 humanized antibody 20mg/ml,
Sucrose 50mg/ml
L-histidine 0.32mg/ml
L-histidine monohydrate 0.5mg/ml
Tween 80 0.09mg/ml
Sodium chloride 4mg/ml
Preparation method is with embodiment 1.
Experimental example 4
Anti-HER 2 humanized antibody 40mg/ml,
Trehalose 100mg/ml
L-histidine 0.48mg/ml
L-histidine monohydrate 0.75mg/ml
Tween 80 0.2mg/ml
Sodium chloride 9mg/ml
Preparation method is with embodiment 1
The experimental example stability experiment
Each three batches in the resulting sample of embodiment 1-4 carries out stability experiment, and experimental result is as shown in table 1, and wherein respectively three batch samples of obtaining for embodiment 1-4 of NO1-4 are carried out the meansigma methods of result behind the stability experiment.
The external biological activity test method is with reference to Synergistic Interactions between Tamoxifen andTrastuzumab (Herceptin) .Athanassios Argiris, Chun-Xia Wang, Steve G.Whalenand Michael P.DiGiovanna, Clin Cancer Res.2004 Feb 15; 10 (4): 1409-20, carry out.
Table 1: the active result of external biological
| Preservation condition | ?No.1 | NO.2 | NO.3 | NO.4 |
| 4 ℃, lucifuge, 3 years | ?102％ | 94％ | 97％ | 96％ |
| 30 ℃, lucifuge, 1 year | ?97％ | 91％ | 96％ | 95％ |
| Reconstituted formulation, 2-8 ℃, 3 months | ?98％ | 85％ | 95％ | 93％ |
Claims (4)
1. preparation that contains anti-HER 2 humanized antibody; by anti-HER 2 humanized antibody; protective agent; buffer agent; surfactant and isoosmotic adjusting agent are formed; wherein protective agent is sucrose or trehalose; buffer agent is the histidine buffering liquid of being made up of L-histidine and L-histidine hydrochloride monohydrate or L-histidine monohydrate; isoosmotic adjusting agent is a sodium chloride; surfactant is tween 20 or tween 80; wherein each components contents is anti-HER 2 humanized antibody 10～40mg/ml; protective agent 10～100mg/ml; L-histidine 0.16-0.48mg/ml; L-histidine hydrochloride monohydrate or L-histidine monohydrate are 0.25-0.75mg/ml; surfactant 0.05～0.2mg/ml; isoosmotic adjusting agent 2～9mg/ml, described preparation are lyophilized formulations.
2. the described preparation of claim 1, wherein each components contents is anti-HER 2 humanized antibody 20mg/ml, sucrose 38mg/ml, L-histidine 0.32mg/ml, L-histidine hydrochloride monohydrate 0.5mg/ml, tween 20 0.09mg/ml, sodium chloride 4mg/ml.
3. the described preparation of claim 1, wherein each components contents is anti-HER 2 humanized antibody 20mg/ml, sucrose 50mg/ml, L-histidine 0.32mg/ml, L-histidine monohydrate 0.5mg/ml, tween 80 0.09mg/ml, sodium chloride 4mg/ml.
4. the described preparation of claim 1, wherein each components contents is anti-HER 2 humanized antibody 40mg/ml, trehalose 100mg/ml, L-histidine 0.48mg/ml, L-histidine monohydrate 0.75mg/ml, tween 80 0.2mg/ml, sodium chloride 9mg/ml.
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| CN2006101472804A CN101199483B (en) | 2006-12-14 | 2006-12-14 | Stable anti-HER2 humanized antibody preparation |
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| CN101199483B true CN101199483B (en) | 2011-01-26 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10000573B2 (en) | 2008-03-14 | 2018-06-19 | Centro De Immunologia Molecular | Monoclonal antibody and a method thereof |
| US10189899B2 (en) | 2013-07-23 | 2019-01-29 | Biocon Limited | Use of a CD6 binding partner and method based thereon |
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| CN102770157B (en) * | 2009-11-20 | 2017-05-17 | 拜康有限公司 | Formulations of antibody |
| CN107787331B (en) * | 2015-06-17 | 2022-01-11 | 豪夫迈·罗氏有限公司 | anti-HER 2 antibodies and methods of use |
| KR102514528B1 (en) | 2016-10-21 | 2023-03-27 | 바이오콘 리미티드 | Monoclonal antibody for the treatment of lupus and its treatment method |
| CN111375057B (en) * | 2018-12-28 | 2024-06-21 | 上海复宏汉霖生物技术股份有限公司 | Pharmaceutical formulation comprising anti-Her 2 monoclonal antibody |
| CN113827717A (en) * | 2020-06-23 | 2021-12-24 | 三生国健药业（上海）股份有限公司 | anti-HER 2 monoclonal antibody freeze-dried preparation and preparation method thereof |
| WO2022261716A1 (en) * | 2021-06-16 | 2022-12-22 | Exopharm Limited | Aqueous formulations for preservation of extracellular vesicles |
| CN113480657B (en) * | 2021-08-06 | 2023-01-20 | 南京融捷康生物科技有限公司 | Single-domain antibody aiming at HER2, and derivative protein and application thereof |
| WO2023165142A1 (en) * | 2022-03-01 | 2023-09-07 | 苏州智核生物医药科技有限公司 | Her2 binding polypeptide and use thereof |
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| US6267958B1 (en) * | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
| US6685940B2 (en) * | 1995-07-27 | 2004-02-03 | Genentech, Inc. | Protein formulation |
| CN1539505A (en) * | 1995-07-27 | 2004-10-27 | �����ɷ� | Stable isotonic lyophilized protein formulation |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6267958B1 (en) * | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
| US6685940B2 (en) * | 1995-07-27 | 2004-02-03 | Genentech, Inc. | Protein formulation |
| CN1539505A (en) * | 1995-07-27 | 2004-10-27 | �����ɷ� | Stable isotonic lyophilized protein formulation |
| US7060268B2 (en) * | 1995-07-27 | 2006-06-13 | Genentech, Inc. | Protein formulation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10000573B2 (en) | 2008-03-14 | 2018-06-19 | Centro De Immunologia Molecular | Monoclonal antibody and a method thereof |
| US10189899B2 (en) | 2013-07-23 | 2019-01-29 | Biocon Limited | Use of a CD6 binding partner and method based thereon |
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| Publication number | Publication date |
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| CN101199483A (en) | 2008-06-18 |
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Effective date of registration: 20080801 Address after: Bing Shanghai Road, Pudong New Area Zhangjiang hi tech Park No. 399 Applicant after: Zhongxin Guojian Pharmaceutical Co., Ltd., Shanghai Address before: Shanghai Zhangjiang hi tech park, Bing Road No. 399 Applicant before: Shanghai Zhongjian Biotechnology Institute |
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Owner name: ANTIBODIES NATIONAL ENGINEERING RESEARCH CENTER Free format text: FORMER OWNER: SHANGHAI CP GUOJIAN PHARMACEUTICAL CO., LTD. Effective date: 20110401 |
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Free format text: CORRECT: ADDRESS; FROM: 201203 NO. 399, LIBING ROAD, ZHANGJIANG HIGH-TECH. PARK, PUDONG NEW DISTRICT, SHANGHAI TO: 201203 BUILDING 3, NO. 399, LIBING ROAD, ZHANGJIANG HIGH-TECH. PARK, PUDONG NEW DISTRICT, SHANGHAI |
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Effective date of registration: 20110401 Address after: Shanghai city 201203 libing road Zhangjiang High Tech Park of Pudong New Area No. 399 building 3 Patentee after: Antibodies National Engineering Research Center Address before: Shanghai city 201203 libing road Pudong New Area Zhangjiang hi tech Park No. 399 Patentee before: Shanghai CP Guojian Pharmaceutical Co., Ltd. |