JP2007535658A - 免疫グロブリンの精製 - Google Patents
免疫グロブリンの精製 Download PDFInfo
- Publication number
- JP2007535658A JP2007535658A JP2006546922A JP2006546922A JP2007535658A JP 2007535658 A JP2007535658 A JP 2007535658A JP 2006546922 A JP2006546922 A JP 2006546922A JP 2006546922 A JP2006546922 A JP 2006546922A JP 2007535658 A JP2007535658 A JP 2007535658A
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- JP
- Japan
- Prior art keywords
- matrix
- ligand
- antibody
- buffer
- sulfonamide
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
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- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- ADWNFGORSPBALY-UHFFFAOYSA-M sodium;2-[dodecyl(methyl)amino]acetate Chemical compound [Na+].CCCCCCCCCCCCN(C)CC([O-])=O ADWNFGORSPBALY-UHFFFAOYSA-M 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- UZZYXUGECOQHPU-UHFFFAOYSA-N sulfuric acid monooctyl ester Natural products CCCCCCCCOS(O)(=O)=O UZZYXUGECOQHPU-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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Abstract
【選択図】 なし
Description
NH2(CH2)nNH2
によって表される。式中、nは3〜9の値を有する整数である。この化合物はシランカップリング剤又はその誘導体を介して結合し、複素環式化合物が2官能性試薬を介してジアミンと結合する。したがって、R基は芳香族構造である。
「抗体」及び「免疫グロブリン」という用語は、本明細書では同義に用いられる。
(a)1種以上の抗体を含む液体を供給する段階と、
(b)前記液体を、1以上のスルホンアミド基を含む分離マトリックスに接触させて、これにより1種以上の抗体を前記マトリックスに吸着させる段階と、適宜、
(c)溶出液を、前記マトリックス中を通過させて1種以上の抗体を放出させる段階と、
(d)1種以上の抗体を溶出液の画分から回収する段階と
を含む。
図1は、担体に結合可能な点を有するスルホニル化アミンのいくつかの選択された例を示す図である。より具体的には、図1は、左から右へ、システアミンとアンモニア(上のライン);並びにジエチレントリアミンとトリエチレンテトラミン(下のライン)を示す。
スルホンアミド分離マトリックスの調製
以下に示すのは、スルホニルのR基を脂肪族基とした、本発明による分離マトリックスの調製法である。
マトリックスの容積とは沈殿層の容積のことをいう。
Sepharose(商標)を、アリルグリシジルエーテルを用いて以下の如く活性化した:100g量のSepharose 6FFを78gまで真空乾燥し、NaBH40.4g、Na2SO411g並びに50%NaOH水溶液60mlと混ぜた。この混合物を50℃で1時間攪拌した。アリルグリシジルエーテル80mlを添加した後、この懸濁液を更に20時間激しく攪拌しつつ50℃に保持した。この混合物を濾過した後、ゲルを、蒸留水500ml、エタノール500ml、蒸留水200ml、0.2M酢酸200ml並びに蒸留水500mlで連続的に洗浄した。滴定により、置換度はアリル0.4mmol/ゲル1mlであることが分かった。
特定のラジカル付加条件で固定化したシステアミンは別にして、アミン基は、アミン基の窒素原子を介してマトリックスへ直接導入された。典型的な方法では、塩基性条件下でのアリル基の臭素化と求核置換を介して、マトリックスへのカップリングが優先して行われた。
10g量のアリル活性化ゲル(0.4mmolアリル基/mlゲル)をジオキサンで洗浄し、システアミンHCl(1g)をジオキサン12mlに溶かした溶液を入れた反応容器に移した。反応物を70℃に加熱し、AIBN(0.9g)を加えた。70℃で攪拌下に17時間反応させた。反応混合物を濾過した後、ゲルを、ジオキサン10mlで3回、エタノール10mlで3回、蒸留水10mlで3回、0.5HCl水溶液10mlで3回、最後に蒸留水10mlで3回、連続的に洗浄した。置換度がアミン0.34mmol/ゲル1mlのシステアミンSepharose(商標)ゲルが得られた。
攪拌下、アリル活性化Sepharose(商標)6FF(0.4mmolアリル基/mlゲル)100ml、AcONa4g、及び蒸留水100mlの懸濁液に、黄色が消えなくなるまで臭素を加えた。次いで、ギ酸ナトリウムを、懸濁液の色が完全に消えるまで加えた。この反応混合物を濾過し、ゲルを蒸留水5000mlで洗った。次いで、活性化ゲルを反応容器に直接移し、しかるべきリガンドと更に反応させた。
10g量の臭素活性化ゲル(0.4mmolアリル基/mlゲル)を、ジエチレントリアミン溶液(12.5ml)を含む反応バイアルに移した。50℃で攪拌下に17時間反応させた。反応混合物を濾過した後、ゲルを、蒸留水10mlで3回、0.5HCl水溶液10mlで3回、最後に蒸留水10mlで3回、連続的に洗浄した。置換度がアミン0.56mmol/ゲル1mlのジエチレントリアミンSepharose(商標)ゲルが得られた。
10g量の臭素活性化ゲル(0.4mmolアリル基/mlゲル)を、トリエチレンテトラミン溶液(12.5ml)を含む反応バイアルに移した。50℃で攪拌下に17時間反応させた。反応混合物を濾過した後、ゲルを、蒸留水10mlで3回、0.5HCl水溶液10mlで3回、最後に蒸留水10mlで3回、連続的に洗浄した。置換度がアミン0.62mmol/ゲル1mlのトリチレンテトラミンSepharose(商標)ゲルが得られた。
10g量の臭素活性化ゲル(0.4mmolアリル基/mlゲル)を、ペンタエチレンヘキサミン溶液(12.5ml)を含む反応バイアルに移した。50℃で攪拌下に17時間反応させた。反応混合物を濾過した後、ゲルを、蒸留水10mlで3回、0.5HCl水溶液10mlで3回、最後に蒸留水10mlで3回、連続的に洗浄した。置換度がアミン0.61mmol/ゲル1mlのペンタエチレンヘキサミンSepharose(商標)ゲルが得られた。
10g量の臭素活性化ゲル(0.4mmolアリル基/mlゲル)を、ポリエチレンイミン溶液12.5ml(50%水溶液)を含む反応バイアルに移した。50℃で攪拌下に17時間反応させた。反応混合物を濾過した後、ゲルを、蒸留水10mlで3回、0.5HCl水溶液10mlで3回、最後に蒸留水10mlで3回、連続的に洗浄した。置換度がアミン0.45mmol/ゲル1mlのポリエチレンイミンSepharose(商標)ゲルが得られた。
1)10g量の臭素活性化ゲル(0.32mmolアリル基/mlゲル)を、アジ化ナトリウム(1g)を水(3ml)に溶解し、50%NaOH水溶液を加えてpH12に調整した溶液を含む反応バイアルに移した。50℃で攪拌下に17時間反応させた。反応混合物を濾過した後、ゲルを、蒸留水20mlで3回、DMF10mlで3回、連続的に洗浄した。乾燥ゲルは、DTE(1.5g)とDBU(1.2ml)のDMF(7.5ml)溶液中で室温において18時間攪拌し更に還元した。反応混合物を濾過した後、ゲルを、DMF10mlで3回、エタノール10mlで3回、最後に蒸留水10mlで3回、連続的に洗浄した。置換度がアミン基0.21mmol/ゲル1mlのアミンSepharose(商標)ゲルが得られた。
基本方法
5g量のアミン結合ゲルを、エタノール10mlで3回、その後DCM(ジクロロメタン)10mlで3回洗った。ゲルをバイアルに移し、DCM(2ml)とDIPEA3.3当量を加えた。この混合物を5分間攪拌した。DCM(3ml)に溶解したメチルスルホニルクロリド3当量を滴下した後、反応混合物を室温で18時間攪拌した。反応混合物を濾過した後、ゲルを、DCM10mlで3回、エタノール10mlで3回、蒸留水10mlで3回、0.5MHCl10mlで3回、最後に蒸留水10mlで3回、連続的に洗浄した。
IgGの選択的吸着
本発明による新しい非芳香族スルホンアミドリガンドが、ヒト免疫グロブリン(IgG)を選択的に吸着するかどうかを試験するために、種々の条件において、IgGと3種の異なるモデルタンパク質の吸着性を試験した。試験方法の原理としては、タンパク質を、緩衝液A(塩及び緩衝成分を含む)で平衡化したHR5/5カラム(Sepharose(商標)Fast Flow(Amersham Biosciences、Uppsala、Sweden)に固定化したスルホンアミドリガンドを含む)に注入(15μl)した。次いで、15mlの緩衝液Aを、カラムを通してポンプで送液し、その後緩衝液Aから緩衝液B(緩衝液Bは緩衝成分を含むが塩を含まない)へ5mlの直線的濃度勾配を施した(以下のUNICORN(商標)メソッドを参照されたい)。次いで、280、254及び215nmにおいてクロマトグラフィーの形状を監視した。
吸着用緩衝液(緩衝液A#)と溶出緩衝液(緩衝液B#)の6種類の組合せを用いた。
緩衝液B1:20mMリン酸緩衝液(pH7.4)
2.緩衝液A2:0.25MNa2SO4を含む20mMリン酸緩衝液(pH7.4)
緩衝液B1:20mMリン酸緩衝液(pH7.4)
3.緩衝液A3:0.50MNa2SO4を含む20mM酢酸緩衝液(pH4.0)
緩衝液B2:20mM酢酸緩衝液(pH4.0)
4.緩衝液A4:0.25MNa2SO4を含む20mM酢酸緩衝液(pH4.0)
緩衝液B2:20mM酢酸緩衝液(pH4.0)
5.緩衝液A2:0.25MNa2SO4を含む20mMリン酸緩衝液(pH7.4)
緩衝液B3:100mM酢酸緩衝液(pH4.0)
6.緩衝液A5:0.50MNa2SO4を含む20mMグリシン緩衝液(pH10.0)
緩衝液B4:20mMグリシン緩衝液
試料
用いた試料は、ウシ血清アルブミン(BSA)、リボヌクレアーゼA(RIB A)、トランスフェリン(TRANSF)及びヒト免疫グロブリン(IgG、Gammanorm)であった。これらのタンパク質は、濃度15mg/mlで緩衝液Aに溶解し、一度に1種のタンパク質のみをカラムに通した。
装置
液体クロマトグラフィー
(LC)システム:AKTA(商標)Explorer(Amersham Biosciences、Uppsala、Sweden)10XT又は同等品
ソフトウェア: UNICORN(商標)
注入ループ: Superloop(商標)15μl
カラム: HR5/5
機器パラメータ
流量: 0.5ml/分
検出セル:10mm
波長: 280、254及び215nm
UNICORN(商標)法
1(a)スルホンアミドリガンド:pH7.4における吸着及び脱着条件
非芳香族スルホンアミドリガンドが免疫グロブリンを選択的に吸着するかどうかを記録するために、ヒトIgGを、本発明による新規マトリックスを充填した1mlカラム(HR5/5)に通した。更に、ウシ血清アルブミン(BSA)、リボヌクレアーゼA(RIB A)、トランスフェリン(TRANSF)などのタンパク質もカラムに通した。異なるpHと異なる塩(Na2SO4)含有量の異なる5種類の緩衝液を吸着用緩衝液として用いた。表1及び2に、pH7.4(緩衝液A1及びA2)の結果を示した。以下に示す表1から分かるように、0.25MのNa2SO4を移動相に加えた場合は、BSA、RIB A及びTRANSFは、検討したリガンドに吸着されなかった。しかし、IgGは、ポリアミンをベースとする4種のリガンドのうち3種に定量的に吸着し、カラムに通したIgGの90%は第4のリガンド、即ちトリエチレンテトラミンをベースとするリガンドに吸着した。更に、アンモニア(モノアミン)の1種のみ、即ちシステアミンをベースとするリガンドがIgGを吸着した。
以下に示す表3及び4から分かるように、酸性条件におけるIgGの吸着は、明らかにpH7.4における吸着ほど選択的ではない。緩衝液として0.25MNa2SO4を加えた20mM酢酸緩衝液(pH4.0)(緩衝液A4)を用いることにより、システアミン、トリエチレンテトラミン及びジエチレントリアミンをベースとしたリガンドは、それぞれ、IgG注入量の40、40及び60%を吸着する(表3)。同じ条件において、リボヌクレアーゼA及びトランスフェリンは吸着されない。しかし、カラムに通したウシ血清アルブミンの90、10及び100%が、それぞれ、システアミン、トリエチレンテトラミン及びジエチレントリアミンをベースとしたリガンドに吸着される。
いくつかの実験がpH10.0において行われた。表5から、吸着用緩衝液A5(0.50MNa2SO4を含む20mMグリシン緩衝液(pH10.0))を用いることにより、IgGは、システアミン及びトリエチレンテトラミンをベースとしたリガンドに定量的に吸着することが分かる。しかし、溶出緩衝液B4(20mMグリシン緩衝液)によって、IgGの吸着量の10%しか溶出させることができなかった。IgGの定量的脱着を実現するには、例えば溶出緩衝液B3(100mM酢酸緩衝液、pH4.0)を用いることにより、pHを酸性条件に変えなければならない。
CH3SO2Cl変性アミンリガンドとCH3SO2Cl変性アミンリガンドの比較(メチルスルホンアミドリガンドとアセトアミドリガンド)
本発明によるスルホンアミド構造が、アセトアミドリガンドより強く抗体と相互作用することを確かめるために、2種のアミンリガンドであるトリエチレンテトラミン及びシステアミンをベースとして、それぞれのタイプの2種のリガンドを調製した(上記の実施例2、実験の部に従って)。以下に示す表6において、4種類の緩衝液系(緩衝液B1〜3及びB5)についてのIgG吸着の結果が提示されている。表6から明らかに分かるように、本発明によるスルホンアミド構造は、検討したすべての条件においてアセトアミドリガンドより効果的にIgGを吸着する。システアミンをベースにしたアセトアミドリガンドは、緩衝液A1とA5を吸着用緩衝液として用いた場合に、IgG(注入量の50%)を吸着することができた唯一のリガンドであった。しかし、このリガンドは、20mMリン酸緩衝液(pH7.4)において塩濃度を0.5MNa2SO4から0.25MNa2SO4に低下させた場合は、IgGを吸着することができなかった。メチルスルホンアミドリガンドは両方ともすべての検討条件でIgGを吸着する。これらの結果は、本発明によるメチルスルホンアミドリガンドがアセトアミドリガンドより優れたIgG吸着剤であることを示している。
Claims (28)
- 適宜スペーサーアームを介してリガンドが固定化された多孔質担体からなる分離マトリックスであって、前記リガンドが、スルホニルのR基が脂肪族化合物である1以上のスルホンアミドを含む分離マトリックス。
- 前記スルホンアミドがその窒素を介して前記多孔質担体に結合している、請求項1記載のマトリックス。
- 前記スルホンアミドがその硫黄を介して前記多孔質担体に結合している、請求項1記載のマトリックス。
- 前記R基がメチル基である、請求項1乃至請求項3のいずれか1項記載のマトリックス。
- 前記1以上のスルホンアミドの窒素が第一級又は第二級アミンである、請求項1乃至請求項4のいずれか1項記載のマトリックス。
- 前記リガンドがモノアミンである、請求項1乃至請求項5のいずれか1項記載のマトリックス。
- 前記リガンドがポリアミンである、請求項1乃至請求項5のいずれか1項記載のマトリックス。
- 各ポリアミンが2〜6個のアミンを含む、請求項7記載のマトリックス。
- 前記リガンドが、前記担体に固定化されたポリマーの繰返し単位として存在する、請求項1乃至請求項8のいずれか1項記載のマトリックス。
- 前記ポリマーがポリエチレンイミンである、請求項9記載のマトリックス。
- 前記ポリマーが2種以上の異なるリガンド基を有する、請求項9又は請求項10記載のマトリックス。
- 前記リガンドが脂肪族化合物である、請求項1乃至請求項11のいずれか1項記載のマトリックス。
- 前記担体が架橋多糖である、請求項1乃至請求項12のいずれか1項記載のマトリックス。
- 請求項1乃至請求項13のいずれか1項記載の分離マトリックスを充填したクロマトグラフィーカラム。
- 実質的に無菌である、請求項14記載のクロマトグラフィーカラム。
- 使い捨て用品である、請求項14又は請求項15記載のクロマトグラフィーカラム。
- アミン及び/又はポリアミンを多孔質担体に固定化する第1の段階と、前記アミンをスルホニル化して脂肪族スルホンアミドリガンドを形成する後続の段階とを含む抗体分離用マトリックスの調製方法。
- 多孔質担体を活性化する第1の段階と、スルホンアミドを、その硫黄を介して前記活性化部位に付着させて脂肪族スルホンアミドリガンドを形成する後続の段階とを含む抗体分離用マトリックスの調製方法。
- 液体から抗体を単離する方法であって、
(a)1種以上の抗体を含む液体を供給する段階と、
(b)前記液体を、1以上の脂肪族スルホンアミドリガンドを含む分離マトリックスに接触させて、1種以上の抗体を前記マトリックスに吸着させる段階と、適宜、
(c)溶出液を、前記マトリックス中を通過させて1種以上の抗体を放出させる段階と、
(d)1種以上の抗体を溶出液の画分から回収する段階と
を含む方法。 - 段階(a)で供給される前記液体が1種以上の他のタンパク質も含む、請求項19記載の方法。
- 段階(b)の前記分離マトリックスがクロマトグラフィーカラムに供給される、請求項19又は請求項20記載の方法。
- 段階(b)の前記分離マトリックスが請求項1乃至請求項13のいずれか1項記載のものである、請求項19乃至請求項21のいずれか1項記載の方法。
- 段階(b)が中性に近いpH、例えばpH7.2〜7.6、好ましくは約7.4で行われる、請求項21記載の方法。
- 段階(c)が、塩濃度を次第に低下させる溶出液を前記分離マトリックスに添加することによる濃度勾配溶出である、請求項19乃至請求項23のいずれか1項記載の方法。
- 段階(b)が中性以上のpHで行われ、段階(c)が、pHが次第に低下する溶出液の添加による濃度勾配溶出である、請求項19乃至請求項24のいずれか1項記載の方法。
- 段階(d)において回収される抗体がヒト抗体又はヒト化抗体である、請求項19乃至請求項25のいずれか1項記載の方法。
- 段階(d)において回収される抗体が免疫グロブリンG(IgG)である、請求項19乃至26のいずれか1項記載の方法。
- 抗体の量を測定する方法であって、請求項19乃至請求項27のいずれか1項記載の方法と、更に、分光光度的に抗体の量を測定する段階(e)とを含む方法。
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JP2014507649A (ja) * | 2011-01-18 | 2014-03-27 | バクスター・インターナショナル・インコーポレイテッド | ヒト血液中の抗βアミロイド抗体の測定 |
JP2017515099A (ja) * | 2014-03-14 | 2017-06-08 | ジーイー・ヘルスケア・バイオプロセス・アールアンドディ・アクチボラグ | 生物粒子の精製用分離マトリックス |
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CA2549923A1 (en) | 2005-07-07 |
WO2005061543A1 (en) | 2005-07-07 |
DE602004013040T2 (de) | 2009-07-02 |
CN100516086C (zh) | 2009-07-22 |
EP1697416B1 (en) | 2008-04-09 |
US20070151928A1 (en) | 2007-07-05 |
US8685248B2 (en) | 2014-04-01 |
CN1898265A (zh) | 2007-01-17 |
EP1697416A1 (en) | 2006-09-06 |
US20100151581A1 (en) | 2010-06-17 |
JP4739233B2 (ja) | 2011-08-03 |
AU2004303746B2 (en) | 2011-03-24 |
DE602004013040D1 (de) | 2008-05-21 |
SE0303532D0 (sv) | 2003-12-23 |
ATE391729T1 (de) | 2008-04-15 |
AU2004303746A1 (en) | 2005-07-07 |
ES2304638T3 (es) | 2008-10-16 |
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