WO2019214551A1 - 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂 - Google Patents

一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂 Download PDF

Info

Publication number
WO2019214551A1
WO2019214551A1 PCT/CN2019/085560 CN2019085560W WO2019214551A1 WO 2019214551 A1 WO2019214551 A1 WO 2019214551A1 CN 2019085560 W CN2019085560 W CN 2019085560W WO 2019214551 A1 WO2019214551 A1 WO 2019214551A1
Authority
WO
WIPO (PCT)
Prior art keywords
fusion protein
preparation
vascular endothelial
factor receptor
formulation
Prior art date
Application number
PCT/CN2019/085560
Other languages
English (en)
French (fr)
Inventor
贾慧峰
朱向阳
崔小培
张凤雪
Original Assignee
华博生物医药技术（上海）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 华博生物医药技术（上海）有限公司 filed Critical 华博生物医药技术（上海）有限公司
Publication of WO2019214551A1 publication Critical patent/WO2019214551A1/zh

Links

Classifications

    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the field of biotechnology pharmaceutical preparations, in particular to a stable recombinant human vascular endothelial factor receptor-antibody fusion protein pharmaceutical combination preparation and a preparation method thereof.
  • Age-related macular degeneration belongs to the aging structural lesions of the macular area of the retina. It is divided into two types: dry AMD and wet AMD (wAMD), of which wAMD accounts for about 20% of the total AMD.
  • the main pathogenesis of wAMD is abnormal expression of vascular endothelial growth factor (VEGF), which leads to choroidal neovascularization, which leads to vascular leakage, causing macular edema, exudation and hemorrhage, which leads to retinopathy of the corresponding area, eventually resulting in visual damage and even blindness.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • the VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PLGF, of which VEGF-A is the major vascular permeability inducer.
  • the vascular endothelial growth factor receptor family includes VEGFR1, VEGFR2 and VEGFR3, and the affinity activity of VEGFR1 is more than 10 times higher than that of VEGFR2. Therefore, blocking the binding of VEGF to its receptor VEGFR can effectively inhibit the proliferation and angiogenesis of endothelial cells, thereby achieving the purpose of treating wAMD.
  • VEGF vascular endothelial growth factor
  • ranibizumab a humanized anti-VEGF recombinant mouse monoclonal antibody
  • Many doctors abroad use it for labeling.
  • Ranibizumab marketed under the trade name Lucentis
  • Lucentis is a Fab segment of a humanized anti-VEGF recombinant murine monoclonal antibody expressed in Escherichia coli.
  • Abcecept under the trade name Eylea, is a soluble VEGF decoy receptor fusion protein.
  • Compaqip also known as Langmu, is a soluble VEGF decoy receptor fusion protein.
  • CN201310283328.4 discloses a novel soluble target VEFG decoy receptor (human recombinant vascular endothelial growth factor receptor-antibody fusion protein), which is a class I new drug independently designed by the applicant with completely independent intellectual property rights, and has low toxicity. It has the characteristics of high efficacy, low heterogeneity and simple CMC process.
  • VEFG decoy receptor human recombinant vascular endothelial growth factor receptor-antibody fusion protein
  • Recombinant fusion proteins are biological macromolecular drugs with complex structures. During the production and storage of drugs, various physical and chemical factors may affect the aggregation, precipitation, hydrolysis, oxidation and deamidation. The by-products produced can affect the safety and effectiveness of the final product, so it is important to develop a stable formulation of the formulation.
  • the object of the present invention is to provide a stable recombinant human vascular endothelial factor receptor-antibody fusion protein pharmaceutical combination preparation, which can maintain the stability of the recombinant fusion protein.
  • the pharmaceutical combination preparation can effectively inhibit side reactions such as aggregation, precipitation, hydrolysis, oxidation and deamidation of the recombinant fusion protein drug, thereby improving the safety of clinical use.
  • a recombinant fusion protein pharmaceutical combination preparation comprising: the recombinant fusion protein pharmaceutical combination preparation comprises:
  • a carrier comprising: a buffer, a stabilizer, sterile water for injection, and optionally a surfactant.
  • the human recombinant vascular endothelial growth factor receptor-antibody fusion protein has the sequence shown as SEQ ID NO.: 1.
  • the human recombinant vascular endothelial growth factor receptor-antibody fusion protein concentration is from 5 to 100 mg/mL; preferably from 10 to 60 mg/mL.
  • the buffering agent is selected from the group consisting of a histidine-acetate buffer system, an acetate buffer system, a citrate buffer system, a phosphate buffer system, or a combination thereof; An acetate buffer system, a histidine-acetate system, or a combination thereof; and/or
  • the stabilizer is selected from the group consisting of sodium chloride, amino acids, sugar alcohols, or combinations thereof.
  • the buffering agent is selected from the group consisting of an acetate buffer system, a citrate buffer system, or a combination thereof.
  • the amino acid is selected from the group consisting of arginine, Glycine, Histidine, or a combination thereof; and/or
  • the sugar alcohol is selected from the group consisting of sucrose, Mannitol, trehalose, maltose, sorbitol, or a combination thereof; preferably sucrose, mannitol, seaweed Sugar, or a combination thereof.
  • the amino acid is glycine.
  • the buffer has a concentration of 5-50 mM, preferably 5-20 mM; and/or
  • the stabilizer concentration is from 5 to 10% by weight, based on the total weight of the liquid formulation.
  • the sodium chloride (NaCl) concentration is 10-200 mM, preferably 30-200 mM, based on the total weight of the liquid formulation.
  • the amino acid concentration is 10-400 mM, based on the total weight of the liquid formulation.
  • the sugar alcohol concentration is from 1 to 15% by weight based on the total weight of the liquid formulation.
  • the surfactant is selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, or combinations thereof; preferably, said The surfactant is selected from the group consisting of sorbitol ester 20 (PS-20), sorbitan ester 40 (PS-40), sorbitan ester 60 (PS-60), sorbitan ester 80 (PS-80), and Pollock.
  • PS-20 sorbitan ester 40
  • PS-60 sorbitan ester 60
  • PS-80 sorbitan ester 80
  • Pollock Pollock.
  • the surfactant in the formulation, is present in an amount of from 0.005 to 0.1% by weight based on the total weight of the liquid formulation.
  • the surfactant is PS-20 and the concentration is from 0.005 to 0.1% by weight.
  • the buffer is an acetate buffer system.
  • the formulation is an injectable preparation.
  • the sugar alcohol is sucrose.
  • the formulation has a pH in the range of 5.0 to 7.5, preferably 5.2 to 6.2.
  • the formulation comprises: a human recombinant vascular endothelial growth factor receptor-antibody fusion protein, an acetate buffer system, a stabilizer, and the balance of sterile water for injection.
  • the formulation comprises:
  • the formulation has a pH in the range of preferably 5.2-6.2.
  • the acetate buffer system is a buffer system of glacial acetic acid and sodium acetate.
  • kits comprising the liquid preparation of the first aspect of the invention, and a container containing the pharmaceutical combination preparation.
  • kit further contains instructions.
  • a third aspect of the invention provides a recombinant fusion protein pharmaceutical combination preparation according to the first aspect of the invention and a kit of the second aspect of the invention for use in the preparation of a prophylactic or therapeutic wet age correlation Macular degeneration drugs.
  • the antibody pharmaceutical combination preparation of the invention can effectively inhibit the side reaction such as aggregation, precipitation, hydrolysis, oxidation and deamidation of the recombinant fusion protein, and can effectively improve the product under pressure (high temperature, strong light irradiation, freeze-thaw, etc.), acceleration and long-term. Stability under refrigeration conditions.
  • the present inventors have unexpectedly developed a recombinant fusion protein pharmaceutical preparation for the first time, which can effectively improve the stability of the product under pressure, acceleration and long-term refrigeration conditions, and can improve the safety of clinical use.
  • the recombinant fusion protein to which the present invention is applicable also includes recombinant fusion proteins obtained by other genetic engineering techniques. On the basis of this, the present invention has been completed.
  • a preferred recombinant fusion protein of the present invention is a recombinant human vascular endothelial growth factor receptor-antibody fusion protein (see CN201310283328.4); patent name: novel recombinant fusion protein, its preparation method and use, amino acid as SEQ ID NO.: 1 Show.
  • the single-chain theoretical amino acid sequence of recombinant human angiogenic growth factor is as follows:
  • the recombinant fusion protein pharmaceutical combination preparation of the present invention comprises: a human recombinant vascular endothelial growth factor receptor-antibody fusion protein, a buffer, a stabilizer, a surfactant, and a sterile water for injection.
  • the recombinant fusion protein pharmaceutical combination preparation comprises: a human recombinant vascular endothelial growth factor receptor-antibody fusion protein, a buffer, and sterile water for injection.
  • the recombinant fusion protein pharmaceutical combination preparation comprises: a human recombinant vascular endothelial growth factor receptor-antibody fusion protein, a buffer, a sugar alcohol, and sterile water for injection.
  • the recombinant fusion protein pharmaceutical combination preparation comprises: a human recombinant vascular endothelial growth factor receptor-antibody fusion protein, a buffer, sodium chloride, and sterile water for injection.
  • the recombinant fusion protein pharmaceutical combination preparation comprises: a human recombinant vascular endothelial growth factor receptor-antibody fusion protein, a buffer, an amino acid, and sterile water for injection.
  • the recombinant fusion protein pharmaceutical combination preparation comprises: a human recombinant vascular endothelial growth factor receptor-antibody fusion protein, a buffer, a sugar alcohol, a surfactant, and sterile water for injection.
  • the recombinant fusion protein concentration is between 5 and 100 mg/mL, preferably between 10 and 60 mg/mL.
  • the buffering agent is one or a combination of two or more of histidine-acetate, acetate, citrate and phosphate, and the concentration of the buffer is 5-50 mM, preferably 5 -20 mM.
  • the stabilizer is one or a combination of two or more of sodium chloride, an amino acid, and a sugar alcohol.
  • the amino acid is one or a combination of two or more of arginine, glycine, and histidine.
  • the amino acid concentration is from 10 to 400 mM, preferably from 50 to 200 mM.
  • the sugar alcohol is one or a combination of two or more of sucrose, mannitol, trehalose, maltose, and sorbitol.
  • the concentration is from 1 to 15% by weight, preferably from 5 to 10% by weight, based on the total weight of the liquid formulation.
  • the sodium chloride concentration is 10-200 mM.
  • the surfactant is polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, preferably PS-20, PS-40, PS-60, PS-80 and poloxamer 188, more preferably PS-20 and PS-80, in an amount of from 0.005 to 0.1% by weight, based on the total weight of the liquid formulation.
  • a kit for a recombinant fusion protein pharmaceutical combination preparation of the present invention for use in the preparation of a prophylactic or therapeutic wet age-related macular degeneration.
  • the fusion protein maintains stability under accelerated and long-term refrigeration conditions and improves the safety of clinical use.
  • the present invention provides a novel preparation having a long shelf life, which can stabilize a recombinant fusion protein such as a recombinant human vascular factor receptor-antibody fusion protein under pressure (high temperature, strong light irradiation, freeze-thaw, etc.) It maintains its stability under accelerated and long-term refrigeration conditions.
  • a recombinant fusion protein such as a recombinant human vascular factor receptor-antibody fusion protein under pressure (high temperature, strong light irradiation, freeze-thaw, etc.) It maintains its stability under accelerated and long-term refrigeration conditions.
  • the novel preparation of the invention can improve the physical and chemical stability of the antibody preparation, so that the recombinant fusion protein can be stably preserved in the novel preparation, and the product shelf life is prolonged while the product quality is improved, and the clinical application is improved. safety.
  • Size exclusion high performance liquid chromatography (SEC-HPLC): TSKgel G3000SWXL analytical column (TOSOH, 5 ⁇ m, 7.8mm ⁇ 300mm), by high performance liquid chromatography instrument (Waters, e2695), refer to the Pharmacopoeia of the People's Republic of China (2015) Version, three parts) 0514 General Principles were determined by high performance liquid chromatography, and the purity was calculated by the area normalization method.
  • RP-HPLC RP-HPLC: with a XBridge TM BEH300 C4 analytical column (Waters, 3.5 ⁇ m, 4.6mm ⁇ 250mm ), Water by high performance liquid chromatography instrument (Waters, e2695), reference to "Pharmacopoeia of People's Republic of China (2015 edition, three parts) General rules for high performance liquid chromatography, the purity is calculated by the area normalization method.
  • SDS-polyacrylamide gel electrophoresis SDS-PAGE: According to the Chinese Pharmacopoeia (2015 edition) three general rules 0541 electrophoresis fifth method, concentrated gel concentration of 4.5%, separation gel concentration of 10%, by scanner Purity is calculated based on the gray scale of the target column strip after scanning.
  • Binding specific activity rabbits labeled with horseradish peroxidase (HRP) were bound to different concentrations of the analyte (recombinant fusion protein) and recombinant human VEGF-165 (rhVEGF-165) coated on the surface of the ELISA plate well.
  • the amount of recombinant fusion protein anti-human IgG-Fc antibody bound was determined by a four parameter curve fitting S-shaped curve, and calculating the concentration of half-maximal effect (EC 50).
  • the relative activity (%) is obtained by comparing the EC 50 values of the analyte and the reference.
  • Biological specific activity After mixing different concentrations of the analyte (recombinant fusion protein) with a certain amount of rhVEGF-165, add primary human umbilical vein endothelial cells HUVEC (Aussie Bio, Cat#:HEVEC-00F) After incubation for 5 days, the growth level of the cells was determined by CCK-8 (Tongren Chemical, Cat#: CK04), and a sigmoidal curve was obtained by four-parameter fitting, and the half-inhibitory concentration (IC 50 ) was calculated. Finally, the relative activity (%) is obtained by comparing the IC 50 values of the analyte and the reference product.
  • High-concentration human recombinant vascular endothelial growth factor receptor-antibody fusion protein was separately desalted by G-25 to the buffered salt system to be screened (as shown in Table 1), and the protein concentration was adjusted to about 10 mg// with each buffer system. mL, sterilized and filtered for use.
  • the prepared sample to be studied was stored under high temperature pressure (40 ° C ⁇ 2 ° C), and samples were taken for SEC-HPLC after 2 weeks.
  • the test results are shown in Table 1.
  • each stabilizer was compared under a buffer system of 5 mM acetate (pH 5.7), and the stabilizers selected included sugar alcohol, sodium chloride and amino acids.
  • a high concentration of human recombinant vascular endothelial growth factor receptor-antibody fusion protein was pre-swipped into a 5 mM acetate buffer system, prepared by adding a high concentration mother liquor of each stabilizer, and the protein concentration was adjusted to about 10 mg/mL.
  • the prepared samples to be studied were stored under high temperature pressure (40 ° C ⁇ 2 ° C), and samples were taken for SEC-HPLC after 4 weeks.
  • the test results are shown in Table 2 and Table 3.
  • w/v is the mass to volume ratio.
  • Example 3 Recombinant human vascular endothelial growth factor receptor-antibody fusion protein pharmaceutical combination preparation
  • the preparation was formulated in the following formula, and the amino acid sequence of the recombinant fusion protein is shown in SEQ ID NO.: 1.
  • Recombinant human vascular endothelial growth factor receptor-antibody fusion protein 10mg/mL Acetate buffer system (glacial acetic acid + sodium acetate) 5mM sucrose 85g/L pH 5.7
  • the solvent is sterile water for injection.
  • the semi-finished product was aseptically dispensed into a vial (0.2 mL/bottle), and a bromobutyl rubber stopper and an aluminum cap were attached to obtain a finished product.
  • Pressurization conditions include: high temperature (40 ° C ⁇ 2 ° C), strong light irradiation (4500Lx ⁇ 500Lx, 5 ° C ⁇ 3 ° C) and repeated freezing and thawing (5 cycles, ⁇ -70/5 ° C ⁇ 3 ° C temperature repeatedly frozen Save and melt) and so on.
  • the items include: SDS-PAGE purity, SEC-HPLC purity, RP-HPLC purity and biological activity. Table 4.
  • the pharmaceutical combination preparation of the present invention has high stability and can effectively protect the recombinant fusion protein of the main drug component, thereby effectively resisting the destructive action of each pressurized condition.
  • the inspection items include: SDS-PAGE purity, SEC-HPLC purity, RP. - HPLC purity, binding activity, biological activity, etc., and partial test results are shown in Table 5.
  • the pharmaceutical combination preparation of the present invention is highly stable, and the pharmaceutical combination preparation can be preserved for at least 6 months under accelerated conditions at 25 °C.
  • the inspection items include: SDS-PAGE purity, SEC-HPLC purity, RP-HPLC purity and biological activity. The whole time period point sample completes the full inspection of the release project.
  • the new formulation of the present invention is very stable, and the purity, binding activity and biological activity of the two-year sample are almost unchanged, and other items such as appearance and protein are examined. Concentration, pH, and insoluble particles, etc., are almost unchanged.
  • the results show that the pharmaceutical combination preparation of the present invention can be stably stored for at least two years under long-term refrigerating conditions.
  • the recombinant fusion protein can maintain good stability under various pressure conditions (high temperature, strong light irradiation and repeated freezing and thawing), and can be stably stored for at least 6 months under accelerated conditions (25 ° C), while in long-term refrigeration conditions ( It can be stored stably for at least two years at 2-8 ° C), and the physical and chemical properties of each test are almost unchanged, showing high stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Microbiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mycology (AREA)
  • Vascular Medicine (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cardiology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明提供了一种重组人血管内皮因子受体-抗体融合蛋白制剂及其制备。具体而言，本发明药物组合制剂包含重组融合蛋白、缓冲剂、稳定剂、表面活性剂及无菌注射用水。本发明药物组合制剂可抑制融合蛋白的聚集沉淀、水解、氧化及脱酰胺等副反应，同时能提高产品在加压（高温、强光照射及冻融等）、加速及长期冷藏条件下的稳定性。

Description

一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂 技术领域
本发明涉及生物技术药物制剂领域，具体涉及稳定的重组人血管内皮因子受体-抗体融合蛋白药物组合制剂及其制备方法。
背景技术
年龄相关性黄斑变性(AMD)属于视视网膜黄斑区的衰老性结构病变，在临床上又分为干性AMD和湿性AMD(wAMD)两种，其中wAMD约占总AMD人数的20％。wAMD的主要致病机理位血管内皮生长因子(VEGF)异常表达，导致脉络膜新生血管生成，进而导致血管渗漏，引发黄斑水肿、渗出和出血，从而引起相应区域视网膜病变，最终出现视觉损伤甚至失明。
不同的血管内皮生长因子(VEGF)可与各自受体(VEFGR)亚型结合，导致VEGFR的磷酸化，进而发挥相应的生物学作用。VEGF家族包括VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E和PLGF，其中VEGF-A是主要的血管渗透机制诱导因子。血管内皮生长因子受体家族包括VEGFR1、VEGFR2和VEGFR3，VEGFR1的亲和活性比VEGFR2高10倍以上。因此阻断VEGF与其受体VEGFR的结合，能有效抑制内皮细胞的增生及血管再生，进而达到治疗wAMD的目的。
目前已获批准的针对VEGF的生物抗体类靶向治疗药物包括贝伐珠单抗、雷珠单抗、康柏西普和阿柏西普。贝伐珠单抗，商品名为阿瓦斯汀(Avastin)，是一种人源化抗VEGF的重组鼠单克隆抗体，主要用于治疗结直肠癌及肺癌，国外有很多医生进行标签外使用，用于治疗wAMD。雷珠单抗，商品名为诺适得(Lucentis)，是在大肠埃希菌中表达的人源化抗VEGF重组鼠单克隆抗体的Fab段。阿柏西普，商品名为Eylea，是一种可溶性VEGF诱骗受体融合蛋白。康柏西普，商品名朗沐，也是一种可溶性VEGF诱骗受体融合蛋白。
CN201310283328.4公开了一种新型的可溶性靶向VEFG诱骗受体(人重组血管内皮生长因子受体-抗体融合蛋白)，它是申请人自主设计具有完全自主知识产权的I类新药，具有毒性低、药效高、异质性低、CMC工艺简单等特点。
重组融合蛋白属于生物大分子药物，其结构较为复杂。药物在生产及储存过程中，受各种物理及化学因素的影响，会发生聚集沉淀、水解、氧化及脱酰胺等变化。产生的副产物会影响最终产品的安全性及有效性，因此开发稳定性好的制剂处方非常重要。
发明内容
本发明目的在于提供一种稳定的重组人血管内皮因子受体-抗体融合蛋白药物组合制剂，可以使重组融合蛋白保持很好的稳定性。药物组合制剂可有效抑制重组融合蛋白药物发生聚集沉淀、水解、氧化及脱酰胺等副反应，提高临床使用的安全性。
本发明的第一方面，提供了一种重组融合蛋白药物组合制剂，其特征在于，所述的重组融合蛋白药物组合制剂包括：
(a)人重组血管内皮生长因子受体-抗体融合蛋白，和
(b)载体，所述的载体包括：缓冲剂、稳定剂、无菌注射用水，和任选的表面活性剂。
在另一优选例中，在所述的制剂中，所述人重组血管内皮生长因子受体-抗体融合蛋白具有如SEQ ID NO.：1所示的序列。
在另一优选例中，所述的制剂中，所述的人重组血管内皮生长因子受体-抗体融合蛋白浓度为5-100mg/mL；优选为10-60mg/mL。
在另一优选例中，所述的缓冲剂选自下组：组氨酸-醋酸盐缓冲体系、醋酸盐缓冲体系、枸橼酸盐缓冲体系、磷酸盐缓冲体系，或其组合；优选醋酸盐缓冲体系、组氨酸-醋酸盐体系，或其组合；和/或
所述的稳定剂选自下组：氯化钠、氨基酸、糖醇，或其组合。
在另一优选例中，所述的缓冲剂选自下组：醋酸盐缓冲体系、枸橼酸盐缓冲体系，或其组合。
在另一优选例中，所述的氨基酸选自下组：精氨酸(Arginine)、甘氨酸(Glycine)、组氨酸(Histidine)，或其组合；和/或
所述的糖醇选自下组：蔗糖(Sucrose)、甘露醇(Mannitol)、海藻糖(Trehalose)、麦芽糖(Maltose)、山梨醇(Sorbitol)，或其组合；优选为蔗糖、甘露醇、海藻糖，或其组合。
在另一优选例中，所述的氨基酸为甘氨酸。
在另一优选例中，所述的缓冲剂的浓度为5-50mM，较佳地为5-20mM；和/或
所述的稳定剂浓度为5-10重量％，以所述液体制剂的总重量计。
在另一优选例中，在所述的制剂中，所述的氯化钠(NaCl)浓度为10-200mM，优选为30-200mM，以所述液体制剂的总重量计。
在另一优选例中，在所述的制剂中，所述的氨基酸浓度为10-400mM，以所述液体制剂的总重量计。
在另一优选例中，在所述的制剂中，所述的糖醇浓度为1-15重量％，以所述液体制剂的总重量计。
在另一优选例中，所述的表面活性剂选自下组：聚氧乙烯山梨醇酐脂肪酸酯、聚氧乙烯氢化蓖麻油、甘油脂肪酸酯，或其组合；优选地，所述的表面活性剂选自下组：山梨醇酯20(PS-20)、山梨醇酯40(PS-40)、山梨醇酯60(PS-60)、山梨醇酯80(PS-80)、泊洛沙姆188，或其组合；更优选地，所述的表面活性剂选自下组：PS-20、PS-80，或其组合。
在另一优选例中，在所述的制剂中，所述的表面活性剂含量为0.005-0.1wt％，以所述液体制剂的总重量计。
在另一优选例中，所述表面活性剂为PS-20，所述浓度为0.005-0.1重量％。
在另一优选例中，所述的缓冲剂为醋酸盐缓冲体系。
在另一优选例中，所述的制剂为注射制剂。
在另一优选例中，所述糖醇为蔗糖。
在另一优选例中，所述的制剂pH范围为5.0-7.5，较佳地为5.2-6.2。
在另一优选例中，所述的制剂包括：人重组血管内皮生长因子受体-抗体融合蛋白、醋酸盐缓冲体系、稳定剂，和余量的无菌注射用水。
在另一优选例中，所述的制剂包括：
人重组血管内皮生长因子受体-抗体融合蛋白  10-60mg/mL；
醋酸盐缓冲体系                           5–20mM
蔗糖                                     5-10重量％
以及作为余量的无菌注射用水，且所述的制剂pH范围为优选5.2-6.2。
在另一优选例中，所述的醋酸盐缓冲体系为冰醋酸和醋酸钠的缓冲体系。
本发明的第二方面，提供了一种试剂盒，所述的试剂盒含有本发明第一方面所述的液体制剂，以及盛装所述药物组合制剂的容器。
进一步地，所述的试剂盒中还含有说明书。
本发明的第三方面，提供了一种如本发明第一方面所述的重组融合蛋白药物组合制剂及本发明第二方面所述的试剂盒的用途，用于制备预防或治疗湿性年龄相关性黄斑变性的药物。
本发明的抗体药物组合制剂可有效抑制重组融合蛋白的聚集沉淀、水解、氧化及脱酰胺等副反应，同时能有效提高产品在加压(高温、强光照射及冻融等)、加速及长期冷藏条件下的稳定性。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地研发出一种重组融合蛋白药物组合制剂，能有效提高产品在加压、加速及长期冷藏条件下的稳定性，可提高临床使用的安全性。本发明可应用的重组融合蛋白还包括其它基因工程技术获得的重组融合蛋白。在此基础上，完成了本发明。
重组人血管内皮生长因子受体-抗体融合蛋白
本发明优选的重组融合蛋白是重组人血管内皮生长因子受体-抗体融合蛋白(参见CN201310283328.4)；专利名称：新型重组融合蛋白及其制法和用途，氨基酸如SEQ ID NO.： 1所示。
重组人血管内生长因子单链理论氨基酸序列如下：
Figure PCTCN2019085560-appb-000001
融合蛋白药物组合制剂
本发明的重组融合蛋白药物组合制剂，包含：人重组血管内皮生长因子受体-抗体融合蛋白、缓冲剂、稳定剂、表面活性剂和无菌注射用水。
在另一优选例中，所述的重组融合蛋白药物组合制剂，包含：人重组血管内皮生长因子受体-抗体融合蛋白、缓冲剂和无菌注射用水。
在另一优选例中，所述的重组融合蛋白药物组合制剂，包含：人重组血管内皮生长因子受体-抗体融合蛋白、缓冲剂、糖醇和无菌注射用水。
在另一优选例中，所述的重组融合蛋白药物组合制剂，包含：人重组血管内皮生长因子受体-抗体融合蛋白、缓冲剂、氯化钠和无菌注射用水。
在另一优选例中，所述的重组融合蛋白药物组合制剂，包含：人重组血管内皮生长因子受体-抗体融合蛋白、缓冲剂、氨基酸和无菌注射用水。
在另一优选例中，所述的重组融合蛋白药物组合制剂，包含：人重组血管内皮生长因子受体-抗体融合蛋白、缓冲剂、糖醇、表面活性剂和无菌注射用水。
所述的重组融合蛋白浓度在5-100mg/mL之间，较佳地为10-60mg/mL。
所述的缓冲剂为组氨酸-醋酸盐、醋酸盐、枸橼酸盐和磷酸盐中的一种或两种以上组合体系，所述的缓冲剂的浓度为5-50mM，优选5-20mM。
所述的稳定剂为氯化钠、氨基酸及糖醇中的一种或两种以上组合。
所述的氨基酸为精氨酸、甘氨酸、组氨酸中的一种或两种以上的组合。所述的氨基酸浓度为10-400mM，较佳地为50–200mM。
所述的糖醇为蔗糖、甘露醇、海藻糖、麦芽糖、山梨醇中的一种或两种以上的组合。所述浓度为1-15重量％，较佳地为5-10重量％，以所述液体制剂的总重量计。
所述的氯化钠浓度为10-200mM。
所述的表面活性剂为聚氧乙烯山梨醇酐脂肪酸酯、聚氧乙烯氢化蓖麻油、甘油脂肪酸酯，优选PS-20、PS-40、PS-60、PS-80及泊洛沙姆188，更优选PS-20及PS-80，所述含量为0.005-0.1重量％，以所述液体制剂的总重量计。
本发明的重组融合蛋白药物组合制剂的试剂盒，用于制备预防或治疗湿性年龄相关性黄 斑变性。融合蛋白可以保持加速及长期冷藏条件下的稳定性，可提高临床使用的安全性。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
本发明的有益之处在于：
(a)本发明提供具有较长保质期的的新型制剂，可使重组融合蛋白，如重组人血管因子受体-抗体融合蛋白保持稳定，在加压(高温、强光照射及冻融等)、加速及长期冷藏条件下均能保持其稳定性。
(b)本发明的新型制剂，能提高抗体制剂的物理学及化学稳定性，使得该重组融合蛋白在新型制剂中稳定保存，在提升产品质量的同时，延长产品的货架期，提高临床实用的安全性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。下述各实施例中，缓冲对体系浓度指总缓冲离子浓度。
除非另行定义，文中所使用的专业与科学术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法或材料皆可应用于发明文献中。文中所述的较佳实施方法与材料仅作示范之用。
通用实施方式
体积排阻高效液相色谱(SEC-HPLC)：用TSKgel G3000SWXL分析柱(TOSOH，5μm，7.8mm×300mm)，通过高效液相色谱仪器(Waters，e2695)，参照《中华人民共和国药典》(2015版，三部)0514通则高效液相色谱法进行测定，以面积归一法计算纯度。
反相高效液相色谱(RP-HPLC)：用XBridge TMBEH300 C4分析柱(Waters，3.5μm，4.6mm×250mm)，通过Water高效液相色谱仪器(Waters，e2695)，参照《中华人民共和国药典》(2015版，三部)通则高效液相色谱法进行测定，以面积归一法计算纯度。
SDS-聚丙烯酰胺凝胶电泳(SDS-PAGE)：依照《中国药典》(2015年版)三部通则0541电泳法第五法，浓缩胶浓度为4.5％，分离胶浓度为10％，经扫描仪扫描后根据目标柱条带灰度计算纯度。
结合比活性：以不同浓度的待测物(重组融合蛋白)与包被在ELISA板孔表面的重组人VEGF-165(rhVEGF-165)结合，用辣根过氧化物酶(HRP)标记的兔抗人IgG-Fc抗体来测定结合的重组融合蛋白的量，经四参数拟合得到S形曲线，并计算半最大效应浓度 (EC 50)。最后，通过比较待测物及参比品的EC 50值，得出相对比活性(％)。
生物学比活性：以不同浓度的待测物(重组融合蛋白)与一定量的rhVEGF-165混合后，加入原代人脐静脉内皮细胞HUVEC(澳赛尔斯生物，Cat#：HEVEC-00F)孵育5天，通过CCK-8(同仁化学，Cat#：CK04)测定细胞的生长水平，经四参数拟合得到S形曲线，并计算半抑制浓度(IC 50)。最后，通过比较待测物及参比品的IC 50值，得出相对比活性(％)。
通过以下实施例进一步详细说明本发明。这些实施例仅用于说明性目的，而并不限于本发明的范围。
实施例1不同缓冲体系稳定性比较
将高浓度人重组血管内皮生长因子受体-抗体融合蛋白，通过G-25脱盐分别换液到的待筛选缓冲盐体系下(如表一)，并用各自的缓冲体系调整蛋白浓度至约10mg/mL，除菌过滤后备用。
将制备好的待研究样品，置于高温加压(40℃±2℃)条件下储存，2周后取样送检SEC-HPLC检测项，检测结果见表一。
表1不同缓冲体系的稳定性比较(SEC-HPLC高分子杂质含量)
Figure PCTCN2019085560-appb-000002
结果显示，在枸橼酸酸盐缓冲体系中(pH 5.0-6.0)，pH值越高越稳定；在缓冲体系浓度5-20mM区间内，重组融合蛋白稳定性随缓冲剂浓度升高而降低。我们惊喜地发现，醋酸盐缓冲体系的稳定性显著优于枸橼酸盐，并表现出极优异的稳定性。在pH5.0-5.5下，缓冲体系浓度在5-20mM区间内，未表现出稳定性上的差异。
实施例2不同稳定剂保护效果对比
在缓冲体系5mM醋酸盐(pH 5.7)下，比较各稳定剂的保护效果，筛选的稳定剂包括糖醇、氯化钠及氨基酸。
高浓度人重组血管内皮生长因子受体-抗体融合蛋白，预换液到5mM醋酸盐缓冲体系下，通过添加各稳定剂的高浓度母液制备各处方，并调整蛋白浓度至约10mg/mL。
制备好的待研究样品，置于高温加压(40℃±2℃)条件下储存，4周后取样送检SEC-HPLC检测项，检测结果见表2及表3。
表2不同稳定剂保护效果比较(SEC-HPLC高分子杂质含量)
Figure PCTCN2019085560-appb-000003
表3不同稳定剂保护效果比较(SEC-HPLC高分子杂质含量)
Figure PCTCN2019085560-appb-000004
备注：w/v为质量体积比。
结果显示(表二)，在缓冲体系5mM醋酸盐(pH 5.7)下，保护剂(蔗糖、海藻糖、甘露醇和甘氨酸)的加入，在一定程度上，均能提高重组融合蛋白在高温下的稳定性。在蔗糖稳定剂组，随着加入量的提升，保护效果愈加显著。同时发现(表三)，在蔗糖保护剂存在的基础上，氯化钠的表现出一定程度的负作用。
实施例3重组人血管内皮生长因子受体-抗体融合蛋白药物组合制剂
按以下配方配制制剂，重组融合蛋白氨基酸序列如SEQ ID NO.：1所示。
处方
重组人血管内皮生长因子受体-抗体融合蛋白 10mg/mL
醋酸盐缓冲体系(冰醋酸+醋酸钠) 5mM
蔗糖 85g/L
pH 5.7
溶剂为无菌注射用水。
将半成品无菌分装至西林瓶中(0.2mL/瓶)，加盖溴化丁基橡胶塞和铝盖，获得成品。
实施例4加压条件稳定性试验
加压条件包括：高温(40℃±2℃)、强光照射(4500Lx±500Lx，5℃±3℃)和反复冻融(5个循环，≤-70/5℃±3℃温度下反复冻存及融化)等。
成品制备后置于各压力条件下储存，在设定时间点或处理次数后取样送检，检项包括：SDS-PAGE纯度、SEC-HPLC纯度、RP-HPLC纯度及生物学活性，检测结果见表4。
表4各加压条件下的稳定性试验检测结果
Figure PCTCN2019085560-appb-000005
结果显示，高温及强光照射的加压条件，会导致三项纯度不同程度下降1-3％，但均满足产品的放行质量标准，同时生物学活性未发生明显变化；冻融加压条件对产品的纯度及活性无明显影响。总之，本发明的药物组合制剂稳定性很高，能有效保护主药成分重组融合蛋白，从而有效抵抗各加压条件的破坏作用。
实施例5加速条件稳定性试验
成品制备后置于加速条件下储存(温度25℃±2℃，湿度60％RH±10％RH)，在各取样时间点送检，检项包括：SDS-PAGE纯度、SEC-HPLC纯度、RP-HPLC纯度、结合活性及生物学活性等，部分检测结果见表5。
表5加速条件的稳定性试验检测结果
Figure PCTCN2019085560-appb-000006
结果显示加速6个月后，会引起主药成分重组融合蛋白的纯度发生不同程度的下降，反相及体积排阻纯度降低2-3％，SDS-PAGE纯度降低约5％，但均满足产品的放行质量标准，同时结合活性及生物学活性均未发生明显变化，其它检验项目如外观、蛋白浓度、pH值及不溶性微粒等均未发生显著变化。总之，本发明的药物组合制剂稳定性很高，在25℃加速条件下，本药物组合制剂能至少保存6个月。
实施例6长期稳定性试验
成品制备后置于长期冷藏条件下储存(5℃±3℃)，在各取样时间点送检，检项包括：SDS-PAGE纯度、SEC-HPLC纯度、RP-HPLC纯度及生物学活性等，整年期时间点样品完成放行项目的全检。
表6长期冷藏条件的稳定性试验检测结果
Figure PCTCN2019085560-appb-000007
在长期冷藏条件下(5℃±3℃)，本发明的新制剂稳定性很好，两年期样品的纯度、结合活性及生物学活性近乎无变化，其它各项全检项目如外观、蛋白浓度、pH值及不溶性微粒等，同样均近乎无变化。结果表明，本发明的药物组合制剂在长期冷藏条件下，能至少稳定储存两年以上。
以上研究结果表明，采用本发明的血管内皮因子受体-抗体融合蛋白药物组合制剂，具有很好的稳定性。可使重组融合蛋白在各压力条件(高温、强光照射和反复冻融)下保持较好的稳定性，在加速条件(25℃)下能至少稳定储存6个月，同时在长期冷藏条件(2-8℃)下能稳定储存至少两年，且各项理化及活性各检项上近乎无变化，表现出很高的稳定性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种重组融合蛋白药物组合制剂，其特征在于，所述的重组融合蛋白药物组合制剂包括：
    (a)人重组血管内皮生长因子受体-抗体融合蛋白，和
    (b)载体，所述的载体包括：缓冲剂、稳定剂、无菌注射用水，和任选的表面活性剂。
  2. 如权利要求1所述的制剂，其特征在于，在所述的制剂中，所述人重组血管内皮生长因子受体-抗体融合蛋白具有如SEQ ID NO.：1所示的序列。
  3. 如权利要求1所述的制剂，其特征在于，所述的制剂中，所述的人重组血管内皮生长因子受体-抗体融合蛋白浓度为5-100mg/mL；优选为10-60mg/mL。
  4. 如权利要求1所述的制剂，其特征在于，所述的缓冲剂选自下组：组氨酸-醋酸盐缓冲体系、醋酸盐缓冲体系、枸橼酸盐缓冲体系、磷酸盐缓冲体系，或其组合；优选醋酸盐缓冲体系、组氨酸-醋酸盐体系，或其组合；和/或
    所述的稳定剂选自下组：氯化钠、氨基酸、糖醇，或其组合。
  5. 如权利要求4所述的制剂，其特征在于，所述的氨基酸选自下组：精氨酸(Arginine)、甘氨酸(Glycine)、组氨酸(Histidine)，或其组合；和/或
    所述的糖醇选自下组：蔗糖(Sucrose)、甘露醇(Mannitol)、海藻糖(Trehalose)、麦芽糖(Maltose)、山梨醇(Sorbitol)，或其组合；优选为蔗糖、甘露醇、海藻糖，或其组合。
  6. 如权利要求1所述的制剂，其特征在于，所述的缓冲剂的浓度为5-50mM，较佳地为5-20mM；和/或
    所述的稳定剂浓度为5-10重量％，以所述液体制剂的总重量计。
  7. 如权利要求1所述的制剂，其特征在于，所述的表面活性剂选自下组：聚氧乙烯山梨醇酐脂肪酸酯、聚氧乙烯氢化蓖麻油、甘油脂肪酸酯，或其组合；优选地，所述的表面活性剂选自下组：山梨醇酯20(PS-20)、山梨醇酯40(PS-40)、山梨醇酯60(PS-60)、山梨醇酯80(PS-80)、泊洛沙姆188，或其组合；更优选地，所述的表面活性剂选自下组：PS-20、PS-80，或其组合。
  8. 如权利要求1所述的制剂，其特征在于，所述的制剂pH范围为5.0-7.5，较佳地为5.2-6.2。
  9. 如权利要求1所述的制剂，其特征在于，所述的制剂包括：人重组血管内皮生长因子受体-抗体融合蛋白、醋酸盐缓冲体系、稳定剂，和余量的无菌注射用水。
  10. 如权利要求1所述的制剂，其特征在于，所述的制剂包括：
    人重组血管内皮生长因子受体-抗体融合蛋白   10-60mg/mL；
    醋酸盐缓冲体系                             5–20mM
    蔗糖                                     5-10重量％
    以及作为余量的无菌注射用水，且所述的制剂pH范围为优选5.2-6.2。
  11. 一种试剂盒，其特征在于，所述的试剂盒含有权利要求1-10任一项所述的液体制剂，以及盛装所述药物组合制剂的容器。
  12. 如权利要求1-10任一项所述的重组融合蛋白药物组合制剂及权利要求11所述的试剂盒的用途，其特征在于，用于制备预防或治疗湿性年龄相关性黄斑变性的药物。
PCT/CN2019/085560 2018-05-08 2019-05-05 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂 WO2019214551A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810433564.2A CN108671229B (zh) 2018-05-08 2018-05-08 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂
CN201810433564.2 2018-05-08

Publications (1)

Publication Number Publication Date
WO2019214551A1 true WO2019214551A1 (zh) 2019-11-14

Family

ID=63805180

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/085560 WO2019214551A1 (zh) 2018-05-08 2019-05-05 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂

Country Status (2)

Country Link
CN (1) CN108671229B (zh)
WO (1) WO2019214551A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112494658A (zh) * 2020-12-04 2021-03-16 苏桥生物(苏州)有限公司 一种稳定的Fc融合蛋白制剂
US11103552B2 (en) 2018-05-10 2021-08-31 Regeneron Pharmaceuticals, Inc. High concentration VEGF receptor fusion protein containing formulations
CN116392441A (zh) * 2023-04-21 2023-07-07 上海腾瑞制药股份有限公司 一种酸性成纤维细胞生长因子滴眼液制剂

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108671229B (zh) * 2018-05-08 2022-03-25 华博生物医药技术（上海）有限公司 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂
US11407832B2 (en) * 2018-12-03 2022-08-09 Immuneonco Biopharmaceuticals (Shanghai) Inc. Recombinant protein targeting PD-L1 and VEGF
CN109932444B (zh) * 2019-03-19 2022-03-11 北京泰德制药股份有限公司 一种糖蛋白多种电荷异构体翻译后修饰的评价方法
CN110585430B (zh) * 2019-09-29 2023-09-08 华博生物医药技术（上海）有限公司 一种人源化抗人il-17a单克隆抗体的药物组合物
JP7326500B2 (ja) * 2019-12-10 2023-08-15 レメゲン シーオー．，エルティーディー． ＴＡＣＩ－Ｆｃ融合タンパク質医薬品製剤

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101951925A (zh) * 2008-02-20 2011-01-19 建新公司 血管发生抑制
CN103319610A (zh) * 2013-07-05 2013-09-25 华博生物医药技术（上海）有限公司 新型重组融合蛋白及其制法和用途
CN103816115A (zh) * 2010-08-31 2014-05-28 成都康弘生物科技有限公司 一种含有抑制血管增生的融合蛋白的药物组合物及用途
CN104974262A (zh) * 2014-04-04 2015-10-14 华博生物医药技术（上海）有限公司 新型重组双功能融合蛋白及其制法和用途
CN107001457A (zh) * 2014-11-25 2017-08-01 瑞泽恩制药公司 用于治疗血管性眼病的方法和制剂
CN108671229A (zh) * 2018-05-08 2018-10-19 华博生物医药技术（上海）有限公司 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA200708845B (en) * 2005-03-25 2010-07-28 Regeneron Pharma Vegf antogonist formulations
CN101781370A (zh) * 2009-05-21 2010-07-21 浙江大学 可溶性血管内皮生长因子受体重组融合蛋白及用途
JP6032735B2 (ja) * 2012-08-30 2016-11-30 公立大学法人大阪府立大学 Ｖｅｇｆ結合性融合ペプチド
KR20240042200A (ko) * 2013-09-11 2024-04-01 이글 바이오로직스 인코퍼레이티드 점도저하제를 함유하는 액체 단백질 제형
EP3122783B1 (en) * 2014-03-24 2019-09-04 Immuneonco Biopharmaceuticals (Shanghai) Co., Ltd. Novel recombinant bi-functional fusion proteins, preparation and use thereof
CN104940926B (zh) * 2014-09-25 2017-09-22 信达生物制药(苏州)有限公司 重组融合蛋白制剂
CN105435222B (zh) * 2014-09-25 2018-05-29 信达生物制药(苏州)有限公司 重组融合蛋白制剂

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101951925A (zh) * 2008-02-20 2011-01-19 建新公司 血管发生抑制
CN103816115A (zh) * 2010-08-31 2014-05-28 成都康弘生物科技有限公司 一种含有抑制血管增生的融合蛋白的药物组合物及用途
CN103319610A (zh) * 2013-07-05 2013-09-25 华博生物医药技术（上海）有限公司 新型重组融合蛋白及其制法和用途
CN104974262A (zh) * 2014-04-04 2015-10-14 华博生物医药技术（上海）有限公司 新型重组双功能融合蛋白及其制法和用途
CN107001457A (zh) * 2014-11-25 2017-08-01 瑞泽恩制药公司 用于治疗血管性眼病的方法和制剂
CN108671229A (zh) * 2018-05-08 2018-10-19 华博生物医药技术（上海）有限公司 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11103552B2 (en) 2018-05-10 2021-08-31 Regeneron Pharmaceuticals, Inc. High concentration VEGF receptor fusion protein containing formulations
CN112494658A (zh) * 2020-12-04 2021-03-16 苏桥生物(苏州)有限公司 一种稳定的Fc融合蛋白制剂
CN116392441A (zh) * 2023-04-21 2023-07-07 上海腾瑞制药股份有限公司 一种酸性成纤维细胞生长因子滴眼液制剂
CN116392441B (zh) * 2023-04-21 2023-11-28 上海腾瑞制药股份有限公司 一种酸性成纤维细胞生长因子滴眼液制剂

Also Published As

Publication number Publication date
CN108671229A (zh) 2018-10-19
CN108671229B (zh) 2022-03-25

Similar Documents

Publication Publication Date Title
WO2019214551A1 (zh) 一种重组人血管内皮生长因子受体-抗体融合蛋白的药物组合制剂
JP7473603B2 (ja) 液体医薬組成物
KR20140084078A (ko) 항체 제제
EP3452075B1 (en) Ophthalmic pharmaceutical composition
KR102385802B1 (ko) Gm-csf 중화 화합물을 포함하는 액체 제제
KR20160034307A (ko) 안정화 항체 조성물
CA2962480C (en) Recombinant fusion protein formulation
RU2704611C2 (ru) Составы на основе антител
JP2005513110A (ja) Ｅｇｆ受容体に対する抗体を含む凍結乾燥製剤
JP2017515909A (ja) 抗体処方物
JP7357540B2 (ja) 液体医薬組成物
JP7465814B2 (ja) 高濃度タンパク質製剤の粘度低下
JP7220664B2 (ja) 液体医薬組成物
CN110585430B (zh) 一种人源化抗人il-17a单克隆抗体的药物组合物
JP2020534255A (ja) 治療用タンパク質の凍結乾燥医薬配合物のためのプロセス
KR20150075083A (ko) Gm-csf를 중화하는 화합물을 포함하는 액체 제제
TW202023603A (zh) 包含vegf拮抗物之液體組成物
JP2023139290A (ja) 安定的抗ｏｓｍｒ抗体製剤
JP2022105056A (ja) 高濃度の抗ｖｅｇｆ抗体を含有するタンパク質溶液製剤
WO2022132636A1 (en) High concentration formulations of anti-csf1 and anti-csf1r antibodies
CN116322764A (zh) 因子xii抗原结合蛋白的高浓度制剂
JP7467438B2 (ja) 抗ｒｓｖ抗体の製剤及びその使用方法
CN113289029B (zh) 一种单克隆抗体-细胞因子融合蛋白制剂
CN112717129A (zh) 抗vegf抗体制剂
WO2018184541A1 (zh) 英夫利西单抗冻干制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19798899

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19798899

Country of ref document: EP

Kind code of ref document: A1