WO2021249373A1 - Préparation liquide stable à haute concentration d'anticorps monoclonal anti-humain il-5 - Google Patents

Préparation liquide stable à haute concentration d'anticorps monoclonal anti-humain il-5 Download PDF

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WO2021249373A1
WO2021249373A1 PCT/CN2021/098803 CN2021098803W WO2021249373A1 WO 2021249373 A1 WO2021249373 A1 WO 2021249373A1 CN 2021098803 W CN2021098803 W CN 2021098803W WO 2021249373 A1 WO2021249373 A1 WO 2021249373A1
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concentration
liquid preparation
monoclonal antibody
human
polysorbate
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PCT/CN2021/098803
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English (en)
Chinese (zh)
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杨泗兴
杨芳
黄浩旻
朱祯平
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三生国健药业（上海）股份有限公司
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Priority to CN202180040146.7A priority Critical patent/CN115666613A/zh
Publication of WO2021249373A1 publication Critical patent/WO2021249373A1/fr

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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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • 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
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • 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

Definitions

  • the invention relates to the field of biopharmaceuticals, in particular to a stable high-concentration liquid preparation of anti-human IL-5 monoclonal antibody.
  • Interleukin-5 is a lymphokine secreted by activated T cells. It has biological activity on B cells and eosinophils. Studies have shown that anti-human IL-5 antibodies By specifically binding to human IL-5, it can prevent or reduce eosinophils related to certain allergic diseases (such as asthma), thereby achieving the purpose of treating allergic diseases.
  • Nucala (mepolizumab, mepolizumab, Bosatria) developed by GSK and Cinqair (reslizumab, Cinqaero) developed by TEVA, purchased from Schering ).
  • Nucala is a lyophilized preparation, which is reconstituted with 1.2ml of water for injection before administration to make 100mg/ml injection for subcutaneous administration.
  • Cinqair is a liquid preparation. A 10ml vial is used to fill 10ml of protein solution with a concentration of 10mg/ml. The method of administration is infusion.
  • the purpose of the present invention is to provide a stable high-concentration liquid anti-human IL-5 monoclonal antibody preparation.
  • the liquid preparation is composed of anti-human IL-5 monoclonal antibody, buffer, protein protective agent, and surfactant, which can stabilize the protein, so that the target protein can be stored at 2-8°C for at least 36 months, and at least at 25°C. Stored for 6 months, it has excellent long-term stability, and can be directly administered by subcutaneous injection during clinical use. Compared with the cumbersome reconstitution of freeze-dried preparations or intravenous infusion, the clinical accessibility is greatly expanded.
  • the first aspect of the present invention provides a stable high-concentration liquid preparation of anti-human IL-5 monoclonal antibody.
  • the liquid preparation includes anti-human IL-5 monoclonal antibody, buffer, protein protectant, and surface activity.
  • concentration of the anti-human IL-5 monoclonal antibody is 50-150 mg/ml
  • the anti-human IL-5 monoclonal antibody comprises the heavy chain shown in SEQ ID NO:1 and the heavy chain shown in SEQ ID NO:1.
  • the concentration of the anti-human IL-5 monoclonal antibody can be any of the following concentration ranges: 60-70 mg/ml, 70-80 mg/ml, 80-90 mg/ml, 90-100 mg/ml, 100-110 mg/ml , 110-120mg/ml, 120-130mg/ml, 130-135mg/ml.
  • the concentration of the anti-human IL-5 monoclonal antibody is 60-135 mg/ml. More preferably, the concentration of the anti-human IL-5 monoclonal antibody is 100 mg/ml.
  • the buffer is histidine-histidine hydrochloride buffer.
  • the histidine hydrochloride is histidine hydrochloride.
  • the concentration of the buffer is 10-30 mM.
  • the concentration of the buffer solution can be any of the following concentration ranges: 10-15 mM, 15-20 mM, 20-25 mM, 25-30 mM or 30-35 mM.
  • the concentration of the buffer is 20-30 mM. More preferably, the concentration of the buffer is 20 mM.
  • the concentration of the buffer refers to the concentration of histidine contained in the buffer.
  • the protein protective agent is trehalose or sucrose.
  • concentration of the trehalose or sucrose is 60-90 mg/ml.
  • concentration of said trehalose or sucrose can be any of the following concentration ranges: 60-65 mg/ml, 65-70 mg/ml, 70-75 mg/ml, 75-80 mg/ml, 80-85 mg/ml or 85 -90mg/ml.
  • the protein protective agent is trehalose.
  • the concentration of the trehalose is 80 mg/ml.
  • the surfactant is polysorbate 80 or polysorbate 20.
  • the concentration of the polysorbate 80 or polysorbate 20 is 0.2-1.0 mg/ml.
  • the concentration of the polysorbate 80 or polysorbate 20 can be any of the following concentration ranges: 0.2-0.4 mg/ml, 0.4-0.6 mg/ml, 0.6-0.8 mg/ml or 0.8-1.0 mg/ml ml.
  • the surfactant is polysorbate 80.
  • the concentration of the polysorbate 80 is 0.4 mg/ml.
  • the pH range of the liquid preparation is 5.2-7.0.
  • the pH range of the liquid formulation is any of the following ranges: 5.2-5.4, 5.4-5.6, 5.6-5.8, 5.8-6.0, 6.0-6.2, 6.2-6.4, 6.4-6.6, 6.6-6.8 or 6.8-7.0.
  • the pH of the liquid formulation is 5.8.
  • liquid preparation is used for subcutaneous injection administration.
  • the stable liquid anti-human IL-5 monoclonal antibody preparation means that the finished product of the liquid anti-human IL-5 monoclonal antibody preparation is stored at 2-8°C for at least 36 months, and at 25°C for at least 6 months.
  • the second aspect of the present invention provides the use of the stable high-concentration liquid anti-human IL-5 monoclonal antibody preparation for preparing a medicine for treating diseases mediated by eosinophil overexpression.
  • the diseases mediated by overexpression of eosinophils include asthma, granulomatosis with polyvasculitis, chronic obstructive pulmonary disease, nasal polyps, allergic dermatitis or hypereosinophilia syndrome.
  • the disease mediated by overexpression of eosinophils is asthma.
  • the dosage will vary depending on the age and weight of the patient, the characteristics and severity of the disease, and the route of administration. Please refer to As a result of animal experiments and various circumstances, the total dose should not exceed a certain range.
  • the third aspect of the present invention provides the use of the stable high-concentration liquid anti-human IL-5 monoclonal antibody preparation for the treatment of diseases mediated by eosinophil overexpression.
  • the diseases mediated by overexpression of eosinophils include asthma, granulomatosis with polyvasculitis, chronic obstructive pulmonary disease, nasal polyps, allergic dermatitis or hypereosinophilia syndrome.
  • the disease mediated by overexpression of eosinophils is asthma.
  • the fourth aspect of the present invention provides a method for treating a disease mediated by eosinophil overexpression, the method comprising administering the liquid formulation to a subject in need.
  • the diseases mediated by overexpression of eosinophils include asthma, granulomatosis with polyvasculitis, chronic obstructive pulmonary disease, nasal polyps, allergic dermatitis or hypereosinophilia syndrome.
  • the disease mediated by overexpression of eosinophils is asthma.
  • the administered dose When the liquid formulation is administered to a subject, the administered dose must be a therapeutically effective amount.
  • the therapeutically effective amount refers to an amount effective in treating cancer.
  • the dosage will vary depending on the age and weight of the patient, the characteristics and severity of the disease, and the route of administration. The results of animal experiments and various conditions can be referred to. The dose cannot exceed a certain range.
  • the present invention greatly improves the defect that the existing anti-human IL-5 monoclonal antibody cannot be prepared into a high-concentration liquid preparation by optimizing the formula.
  • the finished liquid drug product of the present invention can be stored for at least 36 months at 2-8°C and at least 6 months at 25°C. It has excellent long-term stability and can be directly administered by subcutaneous injection during clinical use, which is relatively cumbersome.
  • the reconstitution of lyophilized preparations or intravenous infusion administration greatly expands clinical accessibility. Therefore, the liquid preparation of the present invention can provide high-concentration preparation stability of anti-human IL-5 monoclonal antibody, and has a wide range of industrial application prospects.
  • Figure 1 shows the results of polysorbate 80 and pH DOE.
  • FIG. 2 shows the results analysis of buffer and protein protectant concentration.
  • Figure 3 shows the estimated validity period of SEC purity.
  • Figure 4 shows the estimated validity period of IEC purity.
  • the protein samples used in the following examples are derived from the humanized anti-human IL-5 monoclonal antibody 4-6-Humanized disclosed in WO2019/120060, and the heavy chain and light chain amino acid sequences are shown below.
  • Mobile phase 200mM phosphate buffer, pH 6.8 ⁇ 0.1. Use after filtering with 0.22 ⁇ m filter membrane and ultrasonic degassing.
  • Chromatographic column TSK G3000SWxl, 7.8 ⁇ 300mm 5 ⁇ m, TOSOH 08541.
  • High performance liquid chromatograph Waters Alliance e2695 2489 ultraviolet/visible light detector, Dionex Ultimate 3000 VWD-3400 (RS) Detector or other suitable HPLC systems equipped with ultraviolet detectors.
  • Chromatography software is used for integration, and the peak area normalization method is used to calculate the peak area percentage of each peak.
  • Acceptability criteria for system suitability 6-pin system suitability samples, the resolution of aggregates and monomers are both ⁇ 1.5, the retention time of the main peak is RSD ⁇ 1.0%, the peak area of the main peak is RSD ⁇ 2.0%, and the asymmetry of the main peak is all ⁇ 2.0, the number of theoretical plates is ⁇ 4000.
  • Test product report result The SEC purity report of the sample is the peak area percentage of the monomer main peak, and the aggregate content is the peak area percentage of the aggregate peak.
  • Mobile phase A 20mM phosphate buffer, pH 6.5 ⁇ 0.05. Use after filtering with 0.22 ⁇ m filter membrane and ultrasonic degassing.
  • Mobile phase B 20mM phosphate buffer + 200mM sodium chloride, pH 6.5 ⁇ 0.05. Use after filtering with 0.22 ⁇ m filter membrane and ultrasonic degassing.
  • Chromatographic column Propac WCX-10, 4 ⁇ 250mm, Thermo Dionex 054993.
  • High performance liquid chromatograph Waters Alliance e2695, Dionex Ultimate 3000 series or other suitable HPLC systems equipped with UV detectors.
  • System suitability sample Dilute the reference product with mobile phase to a concentration of 1.0mg/ml, centrifuge at 13000rpm for 10min, take the supernatant and transfer it to the sample bottle, and put it into the HPLC sample tray.
  • Test product Dilute the test product concentration to 1.0 mg/ml with mobile phase, centrifuge at 13000 rpm for 10 min, take the supernatant and transfer it to the sample bottle, and put it into the HPLC sample tray.
  • Chromatographic conditions column temperature 30 ⁇ 2°C; sample temperature 10 ⁇ 2°C; detection wavelength UV 214nm; injection volume 20 ⁇ l; flow rate 1.0ml/min.
  • the mobile phase gradient is as follows:
  • Purity analysis Use the peak area normalization method to calculate the peak area percentages of the main peak, acid peak area and alkali peak area on the sample spectrum. The IEC purity result is reported as the area percentage of the main peak.
  • this example uses DOE to investigate the polysorbate 80 and pH, the protein concentration is 100 mg/ml, the polysorbate 80 concentration range is 0-1 mg/ml, the pH range is 4-7, and trehalose The concentration is 80 mg/ml, and the histidine concentration is 20 mM.
  • the inspection indicators are SEC purity, IEC purity, and insoluble particles. The inspection conditions are 40°C high temperature for 5 weeks.
  • the protein concentration is 100 mg/ml
  • the histidine buffer and protein protectant trehalose concentration is shown in Table 3
  • the concentration of polysorbate 80 is 0.4 mg/ml.
  • pH is 5.8.
  • the inspection indicators were SEC purity, IEC purity, and insoluble particles.
  • Example 5 The long-term stability of the finished product of the liquid formulation
  • the insoluble particles did not change significantly during the protective long-term stability of the preparation.
  • the SEC purity and IEC purity are shown in Figure 3 and Figure 4, respectively. It can be seen from the analysis that according to the ICH guidelines, the SEC purity support preparation has a validity period of 91 months, and the IEC purity support preparation has a validity period of 71 months. Therefore, the liquid preparation of the present invention can support a drug with a validity period of at least 36 months.

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Abstract

L'invention concerne une préparation liquide stable à haute concentration d'anticorps monoclonal IL-5 anti-humain, comprenant un anticorps monoclonal IL-5 anti-humain, une solution tampon, un protecteur de protéines et un agent tensioactif. La formulation est optimisée pour améliorer considérablement le défaut selon lequel l'anticorps monoclonal anti-IL-5 existant ne peut pas préparer une préparation liquide à haute concentration. Les produits pharmaceutiques liquides finis peuvent être conservés au moins pendant 36 mois entre 2 et 8 °C, et peuvent être conservés au moins pendant 6 mois à 25 °C. Par conséquent, la préparation liquide peut assurer la stabilité de la préparation liquide de l'anticorps monoclonal IL-5 anti-humain à haute concentration, et présente de larges perspectives d'application industrielle.
PCT/CN2021/098803 2020-06-10 2021-06-08 Préparation liquide stable à haute concentration d'anticorps monoclonal anti-humain il-5 WO2021249373A1 (fr)

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CN202180040146.7A CN115666613A (zh) 2020-06-10 2021-06-08 一种稳定的高浓度抗人il-5单克隆抗体液体制剂

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CN202010521390.2A CN113769081A (zh) 2020-06-10 2020-06-10 一种稳定的高浓度抗人il-5单克隆抗体液体制剂
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CN114137202A (zh) * 2022-01-12 2022-03-04 杭州隆基生物技术有限公司 单克隆抗体保存液
CN114306576A (zh) * 2022-01-11 2022-04-12 北京志道生物科技有限公司 一种防止il-2衍生物蛋白复合体聚集及非共价连接蛋白亚基脱落的制剂

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CN114306576A (zh) * 2022-01-11 2022-04-12 北京志道生物科技有限公司 一种防止il-2衍生物蛋白复合体聚集及非共价连接蛋白亚基脱落的制剂
CN114137202A (zh) * 2022-01-12 2022-03-04 杭州隆基生物技术有限公司 单克隆抗体保存液
CN114137202B (zh) * 2022-01-12 2023-12-01 杭州隆基生物技术有限公司 单克隆抗体保存液

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