CN106390115A - Stable preparation of humanized monoclonal antibody - Google Patents
Stable preparation of humanized monoclonal antibody Download PDFInfo
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- CN106390115A CN106390115A CN201610628048.6A CN201610628048A CN106390115A CN 106390115 A CN106390115 A CN 106390115A CN 201610628048 A CN201610628048 A CN 201610628048A CN 106390115 A CN106390115 A CN 106390115A
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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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Abstract
The invention relates to a stable preparation of a humanized monoclonal antibody. The stable preparation consists of the humanized anti-human PD-1 monoclonal antibody, a buffer solution, an isoosmotic adjusting agent and a surfactant. The composition (the stable preparation) disclosed by the invention has the effects of being stable and convenient to use and capable of prolonging the validity period of the antibody.
Description
Technical field
The present invention relates to a kind of hydro-acupuncture preparation of the anti-PD-1 monoclonal antibody of humanization.
Background technology
PD-1 is CD28 family member, participates in the immunomodulating of T cell.Part PD-L1/L2, be often expressed as in antigen be in
On delivery cell (APC), and PD-1 combines rear downward T cell effect.Most of solid tumor (such as nonsmall-cell lung cancer, hepatocarcinoma, stomaches
Cancer, George Hodgson lymphoma, renal cell carcinoma and melanoma) cell surface expression PD-L1, thus suppressing T cell activity.
Humanization anti-PD-1 monoclonal antibody JS001 product is by our company's independent research (patent：201310258289.2),
JS001 specificity can be combined with PD-1 and block the interaction of itself and receptor, thus cutting off tumor cell surface expression
PD-L1 is suppressed with the combination of T cell PD-1, and enhancing human body immunity power reaches anticancer purpose.
Antibody preparation must be previously prepared before for experimenter, and the process through storage and transport.And antibody exists
It may happen that the change such as poly or modify changes, activity reduces in storage and transportation, these changes can make experimenter go out
Existing immunotoxicity or effectiveness reduce it is therefore desirable to a kind of stable preparation reaches and front in subject still has it ensureing antibody
The required biological activity for the treatment of.This preparation is suitable for the stability in the long-term storage of medicine and transport.There is no in the market
The preparation being suitable for our antibody stabilization exists.
Content of the invention
The present invention provides a kind of process is simple rationally, with low cost, the strong preparation of stability.
The technical solution adopted for the present invention to solve the technical problems is：A kind of stable anti-PD-1 monoclonal anti system
Agent, preparation is made up of humanization anti-PD-1 monoclonal antibody JS001, buffer, isoosmotic adjusting agent and surfactant.
Preparation disclosed by the invention is hydro-acupuncture preparation.
Invention formulation formula is simple, albumen stable system.It is easy to large-scale production, storage and transport.Citron acid buffering
Liquid, histidine buffering liquid and acetate buffer have very strong buffer capacity and the protective capability to albumen.Buffer pH scope 5.0
～6.5, more preferably 5.5～6.5.
Anti- PD-1 monoclonal antibody hydro-acupuncture preparation protein content is 10-60mg/mL, more preferably 25-50mg/mL.
One or a combination set of isoosmotic adjusting agent selective chlorination sodium of the present invention, sucrose, Mannitol, Sorbitol, trehalose, more excellent
Turn to 125mM NaCl, 250mM sucrose, 250mM Mannitol, 250mM Sorbitol, 250mM trehalose, 200mM sucrose and chlorination
Sodium (both ratios are in the range of 1: 1 to 3: 1), 200mM Mannitol and sodium chloride (both ratios are in the range of 1: 1 to 3: 1),
(both ratios are 1 for 200mM Sorbitol and sodium chloride (both ratios are in the range of 1: 1 to 3: 1), 200mM trehalose and sodium chloride
One of: in the range of 1 to 3: 1).
In the present invention anti-PD-1 monoclonal antibody formulation, isoosmotic adjusting agent more preferably 150mM sucrose+50mM sodium chloride,
150mM Mannitol+50mM sodium chloride, 150mM Sorbitol+50mM sodium chloride, 150mM trehalose+50mM sodium chloride.
Surfactant of the present invention select 0.01%-0.2% polysorbate 20,0.01-0.2% polyoxyethylene sorbitan monoleate or both
Combination.
In the present invention anti-PD-1 monoclonal antibody formulation, surfactant is more preferably 0.01%～0.02% poly- Pyrusussuriensiss
Ester 20 or 0.01%～0.02% polyoxyethylene sorbitan monoleate.
Specific embodiment
With reference to embodiment, the present invention is further described.
Embodiment one：Antibody preparation screening experiment
Antibody preparation preparation method：By Dialysis, antibody is changed liquid in purpose buffer, sample is three step purification
Monoclonal antibody afterwards.Being placed in 4 DEG C of refrigerators dialysis and changing liquid 3 times.Sample after dialysis takes a sample frozen after carrying out subpackage
In -80 DEG C of refrigerators, the sample being simultaneously positioned over 4 DEG C and 40 DEG C is analyzed detection, detection in taking-up in the 2nd week the 4th week respectively
Project includes activity, SEC-HPLC and CEX-HPLC.
Buffer forms：
Citrate buffer：
| Citrate buffer | 0.5M citric acid | 0.5M sodium citrate |
| pH 5.0 | 36.5% | 63.4% |
| pH 5.5 | 26.5% | 73.5% |
| pH 6.0 | 15.0% | 85.0% |
Histidine buffering liquid：
| Histidine buffering liquid | 0.5M histidine | 0.5M histidine hydrochloric acid |
| pH 5.5 | 22.5% | 77.5% |
| pH 6.0 | 50.0% | 50.0% |
| pH 6.5 | 70.0% | 30.0% |
Acetate buffer：
| Acetate buffer | 0.5M acetic acid | 0.5M sodium acetate |
| pH 5.0 | 29.6% | 70.4% |
| pH 5.5 | 13.6% | 86.4% |
| pH 6.0 | 2.4% | 97.6% |
Analyzing detecting method：
Concentration Testing：Measured with ultraviolet absorption method.
Purity detecting：Molecular dimension Exclusion High Performance liquid chromatography analysis.
Activity determination：Antibody is combined ELISA experiment and is tested with PD-L1 Competitive assays ELISA with PD-1
Charge isomer：Electric charge heteroplasmon main peak content is measured using cation-exchange chromatography.
PH of cushioning fluid selection gist：
Content of monomer after JS001 places 2 weeks and 4 weeks under the conditions of 40 DEG C is investigated by SEC-HPLC method, thus really
Determine the Optimal pH of antibody stabilization.
To test initial (0W), the content of monomer placed two weeks (2W) and place surrounding (4W), fitting a straight line simultaneously calculates down
Drop angle rate (%/week)；Average descending slope is JS001 in two kinds of different antibodies concentration (10mg/mL and 60mg/mL) descending slopes
Meansigma methodss；Screening criteria is average fall off rate≤0.25% of monomer/week under two concentration；The isotonic condition of preliminary examinations simultaneously
The impact of lower different auxiliary material (7.3g/L sodium chloride, 25.0g/L sucrose or 45.5g/L Mannitol) antagonist stability.Citric acid
In buffer, content of monomer collects and is shown in Table shown in 1-1 JS001 at various ph values；In histidine buffering liquid, JS001 is in different pH
Under value, content of monomer collects and is shown in Table shown in 1-2；In acetate buffer, content of monomer collects and is shown in Table 1-3 JS001 at various ph values
Shown.
Content of monomer (SEC-HPLC) under table 1-1 JS001 different pH value in citrate buffer
Content of monomer (SEC-HPLC) under table 1-2 JS001 different pH value in histidine buffering liquid
Content of monomer (SEC-HPLC) under table 1-3 JS001 different pH value in acetate buffer
Can be seen that either in citrate buffer, acetate buffer still in histidine from table 1-1,1-2 and 1-3
In buffer, antibody preparation all can keep relative stability in the range of pH 5.0～6.5, and optimal pH condition is 5.5～6.5.
Buffer system selection gist：
Under the conditions of Optimal pH, we carry out research to buffer system selection further and compare, thus select to make antibody
The buffer components of stability and concentration the most.
Prepare citrate buffer and histidine buffering liquid respectively, detect that charge isomer main peak contains by CEX-HPLC
Measure, and the impact to charge isomer main peak basic value is analyzed.The results are shown in Table shown in 1-4：
Antibody charge isomer main peak content (0W) in table 1-4 citrate buffer and histidine buffering liquid
Can be seen that antibody charge isomer main peak content three kinds of Formulation Buffer from table 1-4 all relatively stable, and
No significant difference under variable concentrations.Because citrate buffer is more excellent, we select citrate buffer to carry out adjuvant further
Additive screens.
Adjuvant selection gist：
After Optimal pH and buffer composition determination condition, we carry out research to interpolation adjuvant further and compare, thus
Select the adjuvant additive that can make antibody stability the most, investigate simultaneously and have or not synergism between different auxiliary material.
Add 125mM sodium chloride, 250mM sucrose, 250mM Mannitol, 250mM Pyrusussuriensiss respectively in citrate buffer
Alcohol, 250mM trehalose, 100mM sucrose+100mM sodium chloride, 100mM Mannitol+100mM sodium chloride, 100mM Sorbitol+
100mM sodium chloride, 100mM trehalose+100mM sodium chloride, 150mM sucrose+50mM sodium chloride, 150mM Mannitol+50mM chlorination
Sodium, 150mM Sorbitol+50mM sodium chloride, 150mM trehalose+50mM sodium chloride, 40 DEG C place 4 weeks after carry out activity and purity
Detection.
From table 1-5, SEC-HPLC purity data can be seen that and adds various adjuvants in citrate buffer to adjust
Osmotic pressure has significant Stabilization to JS001, the average fall off rate of monomer all≤0.3%/week.
Table 1-5 adjuvant impact to content of monomer (SEC-HPLC) under citrate buffer pH6.0
Test us further to utilize PD-1 antigen binding Elisa method detection initial (0W), place two weeks (2W) and put
Put the biological activity of surrounding (4W) JS001 afterwards.With initial value as reference, JS001
Biologic activity computing formula is：
After table 1-6 activity data can be seen that 4 weeks, JS001 is under two variable concentrations (10mg/mL and 60mg/mL)
The decline of activity is respectively less than 30%.The requirement of study on the stability is met under conditions of citrate buffer pH 6.0.
The impact of table 1-6 adjuvant antagonist activity (in conjunction with Elisa method) under citrate buffer pH6.0
The content of our charge isomer main peaks after CEX-HPLC detects JS001 study on the stability, screening criteria is
40 DEG C place 4 weeks after JS001 charge isomer main peak content value：Content is higher, and stability is better.Result as shown in table 1-7,
In citrate buffer, (pH 6.0) adds different adjuvants, the main peak content of JS001 charge isomer all higher it is shown that
Good stability.
Table 1-7 is in the impact of 6.0 times adjuvant antagonist charge isomer main peak contents of citrate buffer pH
Comprehensive SEC-HPLC, the result with reference to Elisa activity and CEX-HPLC, (pH under the conditions of citrate buffer
6.0), 125mM sodium chloride, 250mM sucrose, 250mM Mannitol, 250mM Sorbitol, 250mM trehalose, 200mM sucrose are added
With sodium chloride (both ratios 1: 1 or 3: 1), 200mM Mannitol and sodium chloride (both ratios 1: 1 or 3: 1), 200mM Sorbitol
With sodium chloride (both ratios 1: 1 or 3: 1), 200mM trehalose and sodium chloride (both ratios 1: 1 or 3: 1), in different preparations
Antibody is all relatively stable.We select content of monomer, biological activity and charge isomer main peak content to be optimal adjuvant to add
Plus thing：50mM sodium chloride+150mM Mannitol carries out surfactant research.
Surfactant selection gist：
After determining pH value, buffer system and the adjuvant additive of antibody-solutions, we study interpolation surface further and live
Property agent polysorbate 20 or the impact of polyoxyethylene sorbitan monoleate antagonist stability.In citrate buffer pH 6.0+ sodium chloride
(2.92g/L) under the conditions of+Mannitol (25.00g/L), compare polysorbate 20 (0.001%, 0.01%, 0.20%, 0.2%),
Polyoxyethylene sorbitan monoleate (0.001%, 0.01%, 0.20%, 0.2%), 0.001% polysorbate 20+0.20% polyoxyethylene sorbitan monoleate,
0.02% polysorbate 20+0.02% polyoxyethylene sorbitan monoleate, 0.20% polysorbate 20+0.001% polyoxyethylene sorbitan monoleate are to JS001
(40mg/mL) 40 DEG C place 4 weeks after Key Quality attribute impact, concrete outcome is shown in Table 1-8.
Table 1-8 adds the impact to JS001 stability for the surfactant
Can be seen that from table 1-8 and adding variable concentrations polysorbate 20, polyoxyethylene sorbitan monoleate, polysorbate 20 and poly- mountain
After pear ester 80 combination, antibody preparation content of monomer and charge isomer main peak content are respectively provided with good stability.
By antagonist activity (in conjunction with Elisa), monomer purity (SEC-HPLC) and charge isomer main peak purity (CEX-
HPLC) three Key Quality attributes are checked, our final choice antibody preparation prescriptions are in pH 6.0 citrate buffer
In, add 2.92g/L sodium chloride, 25.00g/L Mannitol and 0.20% polyoxyethylene sorbitan monoleate.But still need to further this preferably be located
Side is lower to design stability test, and the stability of checking antibody preparation, referring specifically to embodiment two.
Embodiment two：Prescription confirmatory experiment
Prescription checking test includes freeze-thaw stability test and 25 DEG C of shaking stability tests, investigates JS001 and is stored in
The stability of whole prescription.
Shaking stability experiment：
JS001 albumen source used by test, in working reference product, is concentrated into desired concn with preferred antibody preparation prescription,
Carry out shaking stability test, level shaking and circumference shake 3 days respectively.We are high spot reviews JS001 content of monomer (SEC-
HPLC), charge isomer main peak content (CEX-HPLC) and antibody activity (in conjunction with Elisa), result collects and is shown in Table 2-1.
Table 2-1 antibody preparation shaking stability result collects
Freeze-thaw stability is tested：
JS001 albumen source used by test, in working reference product, is concentrated into desired concn with preferred antibody preparation prescription,
Carry out freeze-thaw stability test, respectively freeze thawing 1,3,5,6 times.Our high spot reviews JS001 content of monomer (SEC-HPLC), electric charges
Isomer main peak content (CEX-HPLC) and antibody activity (in conjunction with Elisa), result collects and is shown in Table 2-2.
Table 2-2 antibody preparation freeze-thaw stability result collects
In sum, we are by different buffer systems, condition of different pH, different antibodies concentration and different isotonic tune
Section agent and surfactant composition are investigated, the stability of exploratory development recombinant humanized anti-PD-1 monoclonal antibody JS001,
And determine optimal hydro-acupuncture preparation formula.
The above some one exemplary embodiment only describing the present invention by way of explanation, undoubtedly, for ability
The those of ordinary skill in domain, in the case of without departing from the spirit and scope of the present invention, can by with various different in the way of to institute
The embodiment of description is modified.
Claims (20)
1. a kind of stabilization formulations containing Humanized monoclonal antibodies, by humanization anti-PD-1 monoclonal antibody JS001, buffering
Liquid, isoosmotic adjusting agent and surfactant etc. form.
2. the preparation described in claim 1, is hydro-acupuncture preparation.
3. preparation described in claim 1, the content of humanization anti-PD-1 monoclonal antibody is 10～60mg/mL.
4. preparation described in claim 1, the content of humanization anti-PD-1 monoclonal antibody is more optimized for 25～50mg/mL.
5. preparation described in claim 1, wherein buffer are one of citrate buffer, histidine buffering liquid, acetate buffer
Or a combination thereof.
6. the preparation described in claim 5, wherein buffer are citrate buffer.
7. the preparation described in claim 5, wherein buffer are histidine buffering liquid.
8. the preparation described in claim 5, wherein buffer are acetate buffer.
9. preparation described in claim 6, the wherein concentration of structure rafter acid buffer are about 10～20mM.
10. the preparation described in claim 7, the wherein concentration of histidine buffering liquid are about 10～20mM.
The concentration of the preparation described in 11. claim 8, wherein acetate buffer is about 10～20mM.
Preparation described in 12. claim 1, isoosmotic adjusting agent be one of sodium chloride, sucrose, Mannitol, Sorbitol, trehalose or
A combination thereof.
Preparation described in 13. claim 12, isoosmotic adjusting agent concentration is about 50mM～250mM.
Preparation described in 14. claim 12, isoosmotic adjusting agent is 125mM sodium chloride, 250mM sucrose, 250mM Mannitol, 250mM
One of Sorbitol, 250mM trehalose.
Preparation described in 15. claim 12, isoosmotic adjusting agent is that (both ratios are in 1: 1 to 3: 1 model for 200mM sucrose and sodium chloride
In enclosing), 200mM Mannitol and sodium chloride (both ratios are in the range of 1: 1 to 3: 1), 200mM Sorbitol and sodium chloride (both
Ratio is in the range of 1: 1 to 3: 1), one of 200mM trehalose and sodium chloride (both ratios are in the range of 1: 1 to 3: 1).
Preparation described in 16. claim 1, wherein surfactant are polysorbate 20, polyoxyethylene sorbitan monoleate or a combination thereof.
Preparation described in 17. claim 16, concentration range when polysorbate 20 and polyoxyethylene sorbitan monoleate are applied in combination is 0.01%
～0.02%.
Preparation described in 18. claim 16, polysorbate 20 concentration is 0.001%～0.2%, more preferably 0.01%～
0.02%.
Preparation described in 19. claim 16, polyoxyethylene sorbitan monoleate concentration is 0.001%～0.2%, more preferably 0.01%～
0.02%.
Preparation described in 20. claim 1, the buffer pH scope of its buffer is 5.0～6.5, more preferably pH5.5～6.5.
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109498565A (en) * | 2018-12-27 | 2019-03-22 | 兴盟生物医药(苏州)有限公司 | A kind of stable anti-PD-1 antibody preparation and application thereof |
| WO2019085982A1 (en) * | 2017-11-02 | 2019-05-09 | 正大天晴药业集团南京顺欣制药有限公司 | Pharmaceutical composition containing anti-pd-l1 humanized monoclonal antibody |
| CN109966487A (en) * | 2017-12-28 | 2019-07-05 | 上海复宏汉霖生物制药有限公司 | A kind of pharmaceutical formulation comprising anti-PD-L1 monoclonal antibody |
| CN110787292A (en) * | 2020-01-06 | 2020-02-14 | 上海复宏汉霖生物技术股份有限公司 | Programmed cell death receptor 1 antibody preparation and application thereof |
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| CN112274636A (en) * | 2020-10-02 | 2021-01-29 | 朱吉安 | Stable aqueous solution composition containing recombinant fully human anti-PD-1 monoclonal antibody |
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| WO2021083271A1 (en) * | 2019-10-31 | 2021-05-06 | 上海君实生物医药科技股份有限公司 | Stable preparation containing anti-pd-l1 antibody |
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