WO2002034786A1 - Procede d"elimination de polymeres d"albumine serique humaine - Google Patents
Procede d"elimination de polymeres d"albumine serique humaine Download PDFInfo
- Publication number
- WO2002034786A1 WO2002034786A1 PCT/JP2001/009335 JP0109335W WO0234786A1 WO 2002034786 A1 WO2002034786 A1 WO 2002034786A1 JP 0109335 W JP0109335 W JP 0109335W WO 0234786 A1 WO0234786 A1 WO 0234786A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- serum albumin
- human serum
- multimer
- buffer
- anion exchanger
- Prior art date
Links
Classifications
-
- 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
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/18—Ion-exchange chromatography
Definitions
- the present invention relates to a method for removing multimers of human serum albumin. More specifically, the present invention relates to a method for removing a multimer of human serum albumin by contacting a human serum albumin solution containing the multimer with an anion exchanger under specific conditions.
- HSA Human serum albumin
- HSA Human serum albumin
- the purified HSA is used, for example, in the treatment of hypoalbuminemia due to albumin loss such as surgery, hemorrhagic shock or burns or nephrotic syndrome.
- purification methods usually used in protein diagnosing such as salting out method, ultrafiltration method, isoelectric point precipitation method, electrophoresis method, ion exchange chromatography, and the like.
- One method, gel filtration method, affinity chromatography, and the like can be used.
- an object of the present invention is to provide a method for efficiently removing a multimer of human serum albumin produced in a process for producing human serum albumin by performing only one step.
- Another object of the present invention is to provide human serum albumin which is highly safe as a pharmaceutical.
- the present invention is characterized in that a human serum albumin solution containing a multimer of human serum albumin is brought into contact with an anion exchanger equilibrated with a buffer having a salt concentration of 10 to 150 mM and a pH of 5 to 9.5. And a method for removing a human serum albumin multimer.
- the present invention also provides a human serum albumin produced by a production process including the method. Includes high purity human serum albumin with reduced multimer content.
- FIG. 1 shows that the sample after dialyzing against 50 mM phosphate buffer (pH 6.5) containing 75 mM NaCl (before treatment) and the sample after dialyzing were subjected to strong anion exchange chromatography equilibrated with the same buffer and passed through.
- FIG. 4 is a drawing showing the results when the fraction (after treatment) was analyzed by gel filtration HPLC.
- the method of the present invention comprises the steps of: preparing a human serum albumin solution containing a human serum albumin multimer to a buffer composition having an appropriate salt concentration, and then equilibrating the human serum albumin solution with the same buffer solution for anion exchange. It is characterized by contacting the body with a human body, removing the multimer by adsorbing it to an anion exchanger, and recovering high-purity human serum albumin. By performing this method, high-purity human serum albumin substantially free of human serum albumin multimers can be efficiently obtained.
- multimers are expected to be produced at each production step, but multimer-containing aqueous solutions produced at any step can be used.
- examples thereof include an aqueous solution of Fraction V of the low-temperature alcohol fractionation, and an aqueous solution containing the multimer in each purification step generated when Fraction V is subjected to further purification steps (chromatography, heat treatment, etc.).
- the multimer-containing aqueous solution of each production step generated in the production of HSA can also be used.
- a culture of an rHSA-producing host an aqueous solution containing a multimer in each purification step generated when the culture is subjected to a further production step (chromatography, heat treatment, etc.) and the like can be mentioned.
- the culture includes a culture solution in which the host is cultured and a host crushed liquid obtained by crushing the host by a commonly used method.
- the host producing rHSA is not particularly limited, and includes yeast, Escherichia coli, Bacillus subtilis, and animal cells.
- yeast for example, Saccharomyces or Pichia
- Saccharomyces cerevisiae AH22 or a mutant thereof is used.
- the method of the present invention comprises a human serum albumin solution containing contaminants derived from plasma or a recombinant host, which is subjected to treatment steps such as ultrafiltration, heat treatment, ion exchange chromatography, B and B chromatographies, gel filtration and salting out. It is desirable to use it at a stage where purification has progressed to some extent (purity of HSA or rHSA is about 85% or more).
- the type of the buffer used for preparing the albumin solution is not particularly limited, but a phosphate buffer, a tris-monohydrochloride buffer, and the like used for ordinary anion exchange chromatography are preferable.
- the concentration of the buffer component in the buffer is generally set to the conditions under which anion exchange chromatography is performed. That is, preferably 5 to 200 mM, more preferably 10 to 100 mM is used.
- the pH of the buffer may be set within a range in which a multimer of human serum albumin is adsorbed to the anion exchanger under the condition that the buffer does not contain a salt. That is, it is used in the range of pH 5 to 9.5, preferably in the range of pH 5.5 to 7.5, and more preferably in the range of pH 6 to 7.
- sodium chloride, alkaline chloride metal chloride such as chloride chloride, etc. can be used, but preferably sodium chloride is preferably used.
- the concentration of the salt is preferably in a concentration range in which a polymer is adsorbed but a monomer is not adsorbed, and is appropriately adjusted depending on a combination of a type, a concentration, and a pH of a buffer solution to be used. And preferably ranges from 25 to 100 mM, more preferably from 50 to 75 m.
- a method of replacing by dialyzing against a buffer solution of mM, pH 5 to 9.5, a gel filtration method, a method of once concentrating a human serum albumin solution, and then diluting with a buffer solution repeatedly are used. Can be used.
- the concentration of human serum albumin in the human serum albumin solution is not particularly limited as long as it is within the range where the albumin can be dissolved, but is preferably 1 to 30%, and more preferably 5 to 25%.
- the base carrier for the anion exchanger is not particularly limited, but it is preferable to select a carrier that does not nonspecifically adsorb human serum albumin.
- a strong anion exchange group any of a strong anion exchange group and a weak anion exchange group can be used, but a strong anion exchange group is preferably used.
- the strong anion exchanger having such a strong anion exchange group include Q-Sepharose FF (manufactured by Amersham-Pharmacia Biotech) and Cellfine Q (manufactured by Millipore). There is no particular limitation.
- an albumin solution containing the albumin multimer is subjected to column chromatography, and the albumin multimer is selectively adsorbed to the anion exchanger.
- the albumin solution is brought into contact with an anion exchanger according to the Ricki method to selectively adsorb the multimer to the anion exchanger, and then the solution is allowed to stand or centrifuged. To separate the anion exchanger and collect the resulting supernatant.
- either method may be used.
- chromatography conditions such as column size and flow rate are appropriately adjusted depending on the concentration and volume of the sample. For example, for 10 L of 10% human serum albumin, an anion exchanger volume of 25 L, a column size (700 cm 2 x 35 cm), and a flow rate of 1200 ml / min are set.
- the extent to which the multimers of human serum albumin have been removed can be determined by analyzing a part of the recovered solution by gel filtration high performance liquid chromatography (HPLC). For example, using a column of TSKgel G300SW (Tosoh Ltd. one company), eluting with 0.1MKH 2 P0 4 / 0.3M aCl buffer, it is carried out by measuring the absorbance of the 2 8 0 nm.
- HPLC gel filtration high performance liquid chromatography
- yeast According to the method described in Tokuhei 1 1—5 0 9 5 25, yeast (
- Saccharomyces cerevisiae produced rHSA.
- the culture solution containing rHSA was diluted with purified water to about twice the volume, and then adjusted to pH 4.5 with an acetic acid aqueous solution.
- the solution was applied to a streamline SP column (manufactured by Amersham Pharmacia Biotech) (diameter: 60 cm ⁇ 16 cm), which was equilibrated with a 50 mM sodium acetate buffer (pH 4.5) containing 50 mM sodium chloride.
- a human serum albumin solution containing 6.1% of human serum albumin multimer prepared by the method of Preparation Example (quantified by gel filtration HPLC analysis) was added to 50 mM, 75 mM, or Q-cephalo was dialyzed at room temperature for 8 hours in 50m sodium phosphate buffer (pH 6.5) containing lOOmM sodium chloride, and the human serum albumin solution was previously balanced with the same buffer.
- the mixture was applied to a single FF column (2.5 cm x 10 cm in diameter), the same buffer (500 ml, elution rate 12 ml / min) was fed, and all the passed-through fractions were collected.
- Experimental example 1 Gel filtration HPLC analysis
- Example 1 The flow-through fraction 0.02ml of Example 1, gel filtration 0.1MK3 ⁇ 4P0 4 subjected to buffer equilibrated with TSKgel G300SW (Tosoh Ltd. one company) column (diameter 0.75Cmx30cm), detection wavelength 2 8 0 nm containing 0.3MNaCl HPLC analysis was performed.
- FIG. 1 and Table 1 show the analysis results of Example 1.
- Table 1 shows that a human serum albumin solution is dialyzed against a phosphate buffer containing sodium chloride at a concentration of 50 to 75 mM, and then the solution is passed through a strong anion exchange force column equilibrated with the same buffer. Shows that the multimers are selectively adsorbed on the strong anion exchanger, and that human serum albumin with reduced multimer concentration can be obtained with high recovery.
- a human serum albumin-containing solution containing a multiplicity of human serum albumin is prepared into a predetermined buffer composition, and this is brought into contact with an anion exchanger equilibrated with the same buffer, The multimer can be effectively removed, and the monomer can be recovered in high yield.
- the method of the present invention provides high-purity human serum albumin substantially free of human serum albumin multimers that may cause side effects such as shock and allergy when administered to humans.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Analytical Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT01978882T ATE535544T1 (de) | 2000-10-24 | 2001-10-24 | Verfahren zur verhinderung von polymeren des humanen serumalbumins |
DK01978882.7T DK1329461T3 (da) | 2000-10-24 | 2001-10-24 | Fremgangsmåde til fjernelse af humane serum-albumin-polymerer |
AU10935/02A AU783871B2 (en) | 2000-10-24 | 2001-10-24 | Method of eliminating human serum albumin polymers |
CN018056296A CN1406245B (zh) | 2000-10-24 | 2001-10-24 | 去除人血清白蛋白多聚体的方法 |
ES01978882T ES2373035T3 (es) | 2000-10-24 | 2001-10-24 | Método para eliminar polímeros de seroalbúmina humana. |
EP01978882A EP1329461B8 (en) | 2000-10-24 | 2001-10-24 | Method of eliminating human serum albumin polymers |
CA2395589A CA2395589C (en) | 2000-10-24 | 2001-10-24 | Method for removing multimers of human serum albumin |
US10/175,382 US7001885B2 (en) | 2000-10-24 | 2002-06-20 | Method for removing multimers of human serum albumin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000-324029 | 2000-10-24 | ||
JP2000324029A JP4798832B2 (ja) | 2000-10-24 | 2000-10-24 | ヒト血清アルブミン多量体の除去方法 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/175,382 Continuation US7001885B2 (en) | 2000-10-24 | 2002-06-20 | Method for removing multimers of human serum albumin |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002034786A1 true WO2002034786A1 (fr) | 2002-05-02 |
Family
ID=18801620
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2001/009335 WO2002034786A1 (fr) | 2000-10-24 | 2001-10-24 | Procede d"elimination de polymeres d"albumine serique humaine |
Country Status (11)
Country | Link |
---|---|
US (1) | US7001885B2 (ja) |
EP (1) | EP1329461B8 (ja) |
JP (1) | JP4798832B2 (ja) |
KR (1) | KR100847883B1 (ja) |
CN (1) | CN1406245B (ja) |
AT (1) | ATE535544T1 (ja) |
AU (1) | AU783871B2 (ja) |
CA (1) | CA2395589C (ja) |
DK (1) | DK1329461T3 (ja) |
ES (1) | ES2373035T3 (ja) |
WO (1) | WO2002034786A1 (ja) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9902000D0 (en) | 1999-01-30 | 1999-03-17 | Delta Biotechnology Ltd | Process |
WO2002034785A1 (fr) * | 2000-10-24 | 2002-05-02 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Procede de monomerisation de polymeres d"albumine serique humaine |
SE526227C2 (sv) * | 2002-05-15 | 2005-08-02 | North China Pharmaceutical Group | Metod för rening av rekombinant humant serumalbumin |
WO2005004902A1 (ja) * | 2003-07-10 | 2005-01-20 | Nipro Corporation | プラスチック容器入り組換えヒト血清アルブミン製剤 |
FR2866890B1 (fr) * | 2004-02-27 | 2008-04-04 | Lab Francais Du Fractionnement | Procede de purification d'albumine comprenant une etape de nanofiltration, solution et composition a usage therapeutique la contenant |
CN102190722B (zh) * | 2010-03-16 | 2014-03-26 | 上海欣瑞特生物医药技术有限公司 | 一种纯化重组人血白蛋白的方法 |
KR101595151B1 (ko) * | 2012-01-31 | 2016-02-18 | 이화여자대학교 산학협력단 | 일산화질소에 의해 형성되는 알부민 다량체 및 알부민 구조변형체 |
US20140186447A1 (en) * | 2012-12-28 | 2014-07-03 | Abraxis Bioscience, Llc | Nanoparticle compositions of albumin and paclitaxel |
US10527604B1 (en) | 2015-03-05 | 2020-01-07 | Abraxis Bioscience, Llc | Methods of assessing suitability of use of pharmaceutical compositions of albumin and paclitaxel |
US10705070B1 (en) | 2015-03-05 | 2020-07-07 | Abraxis Bioscience, Llc | Methods of assessing suitability of use of pharmaceutical compositions of albumin and poorly water soluble drug |
ES2761854T3 (es) | 2016-10-04 | 2020-05-21 | Albumedix Ltd | Usos de albúmina de suero recombinante obtenida a partir de levadura |
CN107216383A (zh) * | 2017-07-13 | 2017-09-29 | 同路生物制药有限公司 | 一种人血白蛋白的制备方法及该人血白蛋白 |
CN115003284A (zh) | 2019-10-28 | 2022-09-02 | 阿布拉科斯生物科学有限公司 | 白蛋白和雷帕霉素的药物组合物 |
EP4069200A1 (en) | 2019-12-04 | 2022-10-12 | Albumedix Ltd | Methods and compositions produced thereby |
US11739166B2 (en) | 2020-07-02 | 2023-08-29 | Davol Inc. | Reactive polysaccharide-based hemostatic agent |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US4705848A (en) * | 1986-06-02 | 1987-11-10 | International Minerals & Chemical Corp. | Isolation of bioactive, monomeric growth hormone |
JPH0317023A (ja) * | 1989-06-15 | 1991-01-25 | Green Cross Corp:The | アルブミン製剤及びその製法 |
EP0570916A2 (en) * | 1992-05-20 | 1993-11-24 | The Green Cross Corporation | Recombinant human serum albumin, process for producing the same and pharmaceutical preparation containing the same |
WO1996037515A1 (en) | 1995-05-25 | 1996-11-28 | Delta Biotechnology Limited | Process of high purity albumin production |
JP2926722B2 (ja) | 1988-10-20 | 1999-07-28 | 吉富製薬株式会社 | アルブミン製剤及びその製造方法 |
JPH11509525A (ja) | 1995-05-25 | 1999-08-24 | デルタ、バイオテクノロジー、リミテッド | 高純度アルブミンの製造方法 |
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US4169829A (en) | 1972-07-05 | 1979-10-02 | Institut Merieux | Process for the preparation of purified albumin and albumin obtained by said process |
IL66614A (en) | 1981-08-28 | 1985-09-29 | Genentech Inc | Method of constructing a dna sequence encoding a polypeptide,microbial production of human serum albumin,and pharmaceutical compositions comprising it |
IL88326A (en) | 1987-11-18 | 1993-03-15 | Gist Brocades Nv | Purification of serum albumin |
JP3554796B2 (ja) * | 1988-10-31 | 2004-08-18 | 三菱ウェルファーマ株式会社 | アルブミン製剤及びその製造方法 |
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JPH07102148B2 (ja) * | 1992-05-20 | 1995-11-08 | 株式会社ミドリ十字 | 遺伝子操作により得られるヒト血清アルブミンの製造方法、およびそれにより得られるヒト血清アルブミン含有組成物 |
US5521287A (en) * | 1992-05-20 | 1996-05-28 | The Green Cross Corporation | Recombinant human serum albumin, process for producing the same and pharmaceutical preparation containing the same |
JPH07126182A (ja) | 1993-10-27 | 1995-05-16 | Green Cross Corp:The | 組換えヒト血清アルブミン製剤の滅菌方法 |
CA2138349A1 (en) * | 1993-12-17 | 1995-06-18 | Welfide Corporation | Method for decoloring human serum albumin |
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DK1084136T3 (da) * | 1998-06-01 | 2005-01-03 | Genentech Inc | Adskillelse af monomere af et antistof fra dets multimere ved anvendelse af ionbytterchromatografi |
-
2000
- 2000-10-24 JP JP2000324029A patent/JP4798832B2/ja not_active Expired - Fee Related
-
2001
- 2001-10-24 ES ES01978882T patent/ES2373035T3/es not_active Expired - Lifetime
- 2001-10-24 AU AU10935/02A patent/AU783871B2/en not_active Ceased
- 2001-10-24 CN CN018056296A patent/CN1406245B/zh not_active Expired - Fee Related
- 2001-10-24 CA CA2395589A patent/CA2395589C/en not_active Expired - Fee Related
- 2001-10-24 DK DK01978882.7T patent/DK1329461T3/da active
- 2001-10-24 WO PCT/JP2001/009335 patent/WO2002034786A1/ja active IP Right Grant
- 2001-10-24 EP EP01978882A patent/EP1329461B8/en not_active Expired - Lifetime
- 2001-10-24 AT AT01978882T patent/ATE535544T1/de active
- 2001-10-24 KR KR1020027008241A patent/KR100847883B1/ko active IP Right Grant
-
2002
- 2002-06-20 US US10/175,382 patent/US7001885B2/en not_active Expired - Lifetime
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US4705848A (en) * | 1986-06-02 | 1987-11-10 | International Minerals & Chemical Corp. | Isolation of bioactive, monomeric growth hormone |
JP2926722B2 (ja) | 1988-10-20 | 1999-07-28 | 吉富製薬株式会社 | アルブミン製剤及びその製造方法 |
JPH0317023A (ja) * | 1989-06-15 | 1991-01-25 | Green Cross Corp:The | アルブミン製剤及びその製法 |
EP0570916A2 (en) * | 1992-05-20 | 1993-11-24 | The Green Cross Corporation | Recombinant human serum albumin, process for producing the same and pharmaceutical preparation containing the same |
WO1996037515A1 (en) | 1995-05-25 | 1996-11-28 | Delta Biotechnology Limited | Process of high purity albumin production |
JPH11509525A (ja) | 1995-05-25 | 1999-08-24 | デルタ、バイオテクノロジー、リミテッド | 高純度アルブミンの製造方法 |
Also Published As
Publication number | Publication date |
---|---|
JP4798832B2 (ja) | 2011-10-19 |
CN1406245A (zh) | 2003-03-26 |
EP1329461B8 (en) | 2012-03-14 |
AU783871B2 (en) | 2005-12-15 |
EP1329461A1 (en) | 2003-07-23 |
AU1093502A (en) | 2002-05-06 |
US7001885B2 (en) | 2006-02-21 |
EP1329461B1 (en) | 2011-11-30 |
ES2373035T3 (es) | 2012-01-30 |
CA2395589C (en) | 2012-08-28 |
US20020183492A1 (en) | 2002-12-05 |
EP1329461A4 (en) | 2004-12-01 |
ATE535544T1 (de) | 2011-12-15 |
CA2395589A1 (en) | 2002-05-02 |
CN1406245B (zh) | 2010-05-26 |
DK1329461T3 (da) | 2012-01-30 |
KR20020065608A (ko) | 2002-08-13 |
KR100847883B1 (ko) | 2008-07-23 |
JP2002128795A (ja) | 2002-05-09 |
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