JP2018512416A - クロマトグラフィーのための方法 - Google Patents
クロマトグラフィーのための方法 Download PDFInfo
- Publication number
- JP2018512416A JP2018512416A JP2017550147A JP2017550147A JP2018512416A JP 2018512416 A JP2018512416 A JP 2018512416A JP 2017550147 A JP2017550147 A JP 2017550147A JP 2017550147 A JP2017550147 A JP 2017550147A JP 2018512416 A JP2018512416 A JP 2018512416A
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- JP
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- Prior art keywords
- ligand
- core
- lid
- plasma
- fix
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- Granted
Links
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Classifications
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- B01J41/00—Anion exchange; Use of material as anion exchangers; Treatment of material for improving the anion exchange properties
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/472—Complement proteins, e.g. anaphylatoxin, C3a, C5a
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- 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
- C07K14/745—Blood coagulation or fibrinolysis factors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
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- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
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- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/644—Coagulation factor IXa (3.4.21.22)
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Abstract
Description
一般
マトリックスの容積は確定されたベッドボリュームを示し、グラムで示されたマトリックスの重量は吸入乾燥重量を示す。大規模な反応では、マグネットバースターラーを使用するとビーズの損傷を引き起こすため、撹拌とは、懸架式のモーター駆動の撹拌機を指している。従来の方法を使用して、機能性を分析し、アリル化の程度またはビーズ上のリガンド含量を決定した。
使用した担体粒子は、米国特許第6,602,990号に記載の方法に従って調製された高架橋アガロースビーズであった。米国特許第6,602,990号はその全体が参照により本明細書に組み込まれる。ビーズは、88マイクロメーターの体積加重平均直径(D50、v)および細孔容積の69%がMw110kDaのデキストラン分子に利用可能であるような細孔サイズ分布を有していた。これは、「Handbook of Process Chromatography,A Guide to Optimization,Scale−Up and validation」(1997)Academic Press,San Diego.Gail Sofer&Lars Hagel編、ISBN 0−12−654266−X、p.368に記載の方法に従って測定した場合、ビーズ上のデキストラン110kDaのKdが0.69であるとも表現することができる。
6xゲル容積(GV)の蒸留水を用いて250mL(g)の担体粒子を洗浄し、次いで3xGVの50%NaOHを用いて洗浄した。次いで、ゲルを吸引乾燥させ、2Lの丸底フラスコに移した。485mLの50%NaOHを添加し、機械的プロペラ撹拌を適用し、フラスコを50℃の水浴に浸漬した。30分後、80mLのアリルグリシジルエーテル(AGE)を添加した。18.5時間反応を進行させた。1xGVの蒸留水、3xGVのエタノール、次いで8xGVの蒸留水を用いてゲルを洗浄した。
部分臭素化およびシェル不活性化
アリル化ゲルスラリー(プロトタイプ76)171.8gをガラスフィルター(por.2)に移し、吸引乾燥させた。乾燥したゲルを、機械的撹拌機を備えた1000mLの丸底フラスコに移す。571gの蒸留水を添加し、懸濁液を300rpmで撹拌する。83.7gの1.6%臭素溶液を1.5分かけて添加する。添加後、懸濁液は依然として白色である。室温で15分間反応を進行させた。丸底フラスコを浴中に浸漬し、温度が50℃に達した時点で52gの50%NaOHを添加した。17時間反応を放置した。反応物をガラスフィルター(por.2)に移し、10×1GVの蒸留水を用いて洗浄する。滴定により、残りのアリル含量、216μmol/mLを測定した。これは、理論上3.5μmのシェルの厚さに相当する。
機械的撹拌機を備えた250mLの丸底フラスコに、41.5mL(g)の部分的にアリル化された塩基性マトリックスを上から流した。10.37gの蒸留水および1.66gの酢酸ナトリウムを添加した。数分間撹拌した後、0.66mLの臭素をピペットで添加し、反応物を300rpmでさらに20分間撹拌する。過剰の臭素は、4.15mLの40%蟻酸ナトリウム溶液を添加することによって消費される。反応物は無色である。15分後、8.30mLの塩化トリメチルアンモニウム(TMAC)を添加し、50%NaOHを添加することによってpHを11〜11.5に調整する。反応物を250rpm、30℃で18時間撹拌する。ガラスフィルター(por.3)に移す前に、60%酢酸を添加することにより反応物をpH5〜7に中和する。10×1GVの蒸留水、続いて2×1GVの20%EtOHを用いてゲルを洗浄した。イオン交換基の滴定により125μmol/mLのQリガンド密度を得た。
サンプル
サンプルはヒト血漿であった。凍結したヒト血漿を解凍し、綿で濾過し、カラムに適用した。
カラム:プロトタイプ99、ベッド高さ28.6cm、カラム体積(CV)22.5mLのTricorn10/300。
SDS PAGEおよび液体クロマトグラフィー質量分析法(LC−MS)により、FVIII活性(Chromogenix Coamatic Factor VIIIキット)、vWF(Technozym vWF:Ag ELISAキット)、FIX(ROX Factor IXキット)について選択された画分を分析した。
Claims (14)
- 血漿から治療用タンパク質を精製するためのクロマトグラフィー法であって、内部多孔質コアと外部多孔質リッドとを有する多孔質リッドビーズを含む樹脂を充填したクロマトグラフィーカラムに血漿を充填する工程であって、前記内部コアはアニオン交換リガンドを備え、前記リッドおよびコアの多孔度により500kDよりも大きい分子の進入を許容しない工程と、前記コアの前記アニオン交換リガンド上に第IX因子(FIX)を吸着する工程と、フロースルー中で分離された血漿タンパク質を収集する工程と、前記コアの前記リガンドからFIXを溶出させる工程とを含むクロマトグラフィー法。
- 前記アニオン交換リガンドが、ジエチルアミノエチル(DEAE)、第四級アミノエチル(QAE)または第四級アンモニウム(Q)から選択される請求項1に記載の方法。
- 前記アニオン交換リガンドがQリガンドである請求項2に記載の方法。
- FIX以外の他の血漿タンパク質が、前記コアとシェルとのふるい分け効果によって互いに分離された前記フロースルーで収集され、第VIII因子(FVIII)およびフォン・ヴィレブランド因子(vWF)、IgG、ヒト血清アルブミン(HSA)および補体C3(C3)を含む請求項1、2または3に記載の方法。
- 前記血漿の充填を1〜20回、好ましくは5〜10回反復した後、前記FIXが前記コアの前記リガンドから溶出される前に、ランニングバッファーを用いて対応する数のフロースルー(FT)を得る請求項1乃至4の1項以上に記載の方法。
- それぞれのFTの特定の画分をプールして、それぞれFVIII/vWF、IgG/HSAおよびC3を得る請求項5に記載の方法。
- 前記リッドビーズの総厚さが直径40〜100μmであり、前記リッドの厚さが2〜10μmである請求項1乃至6の1項以上に記載の方法。
- 前記コアの前記リガンド濃度が50〜200μmol/mLである請求項1乃至7の1項以上に記載の方法。
- 前記リッドが、親和性リガンド、疎水性相互作用リガンド、IMACリガンド、カチオン交換リガンドまたはマルチモーダルリガンドを備え、FIX以外の他の血漿タンパク質、例えばFVIII/vWF、IgG、HSA、C3が、FIXが前記コアの前記リガンドに吸着されるのと同じ工程で前記リッドの前記リガンドに吸着され、血漿タンパク質が前記リッドの前記リガンドから順に溶出され、Fixが前記コアのリガンドから溶出される請求項1乃至8の1項以上に記載の方法。
- 前記リッドの前記リガンドが、免疫グロブリン親和性を有するリガンド、例えばタンパク質AもしくはGまたはそれらの変異体である請求項9に記載の方法。
- 前記リッドおよびコアが同じ多孔度のアガロースから製造されている請求項1乃至10の1項以上に記載の方法。
- 前記リッドの前記多孔度が前記コアの前記多孔度よりも大きい請求項1乃至10の1項以上に記載の方法。
- 前記リッドの前記多孔度が前記コアの前記多孔度よりも小さい請求項1乃至10の1項以上に記載の方法。
- 請求項1乃至13の1項以上の方法から得られた血漿タンパク質の治療のための使用。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005537479A (ja) * | 2002-08-27 | 2005-12-08 | アメルシャム・バイオサイエンシーズ・アクチボラグ | クロマトグラフィー用二層粒子 |
JP2010537960A (ja) * | 2007-08-30 | 2010-12-09 | エルエフベー ビオテクノロジーズ | 第viii因子およびフォンビルブラント因子の精製方法 |
JP2011525523A (ja) * | 2008-06-24 | 2011-09-22 | オクタファルマ アクチェン ゲゼルシャフト | 凝固第viii因子の精製方法 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4721572A (en) * | 1985-07-12 | 1988-01-26 | Miles Laboratories, Inc. | Purfication of blood clotting factors and other blood proteins on non-carbohydrate sulfated matrices |
ES2045167T5 (es) * | 1987-10-23 | 1996-07-01 | Centre Regional De Transfusion | Preparacion de concentrado de factor ix humano de elevada pureza y de otras proteinas plasmaticas. |
US5138034A (en) * | 1989-07-12 | 1992-08-11 | The Green Cross Corporation | Method of fractionating plasma proteins |
IT1256622B (it) | 1992-12-04 | 1995-12-12 | Sclavo Spa | Processo per l'estrazione del complesso fattore viii-fattore von willebrand (fviii:c-fvw) da plasma umano totale. |
FR2887883B1 (fr) | 2005-06-29 | 2007-08-31 | Lab Francais Du Fractionnement | Procede de separation des proteines fibrinogene, facteur xiii et colle biologique d'une fraction plasmatique solubilisee et de preparation de concentres lyophilises desdites proteines |
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AU2009238686B2 (en) | 2008-04-22 | 2014-08-28 | Cytiva Bioprocess R&D Ab | Chromatography medium |
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FR2942233B1 (fr) | 2009-02-19 | 2015-03-13 | Lfb Biotechnologies | Moyens pour la purification d'une proteine du plasma sanguin, et procedes pour sa mise en oeuvre |
US8574437B2 (en) * | 2010-02-19 | 2013-11-05 | Ge Healthcare Bio-Sciences Ab | Method for production of chromatography media |
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CN102584983B (zh) * | 2012-02-01 | 2014-11-05 | 中国科学院过程工程研究所 | 一种分离纯化凝血因子viii的方法 |
US20140154233A1 (en) | 2012-12-05 | 2014-06-05 | Csl Limited | Method of purifying therapeutic proteins |
CA2910119A1 (en) | 2013-05-20 | 2014-11-27 | Shantha Biotechnics Private Limited | Purification of polysaccharide protein conjugates |
US10626164B2 (en) * | 2014-07-25 | 2020-04-21 | Csl Limited | Purification of VWF |
GB201506113D0 (en) * | 2015-04-10 | 2015-05-27 | Ge Healthcare Bio Sciences Ab | Method for chromatography |
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