JP5064225B2 - 抗体精製法 - Google Patents
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Description
用語「抗体」及び「免疫グロブリン」は、本明細書中で互換的に使用される。
図1において、a)はプロトタイプマルチモーダルリガンドである2−アミノベンズイミダゾールを示し、b)はプロトタイプマルチモーダルリガンドであるチオミカミンを示し、c)はビーズ形態の担体に固定されたプロトタイプマルチモーダルリガンドであるN−ベンジル−N−メチルエタノールアミンを示し、d)はプロトタイプマルチモーダルリガンドであるN,N−ジメチルベンジルアミンを示す。実験の部で、プロトタイプリガンドを6%アガロースマトリックスであるSepharose(商標)6FFにカップリングする。
非結合条件下で、約50mgのmAb1を含む試料を、プロトタイプ901035A(N−ベンジル−N−メチルエタノールアミン)及び901035B(N,N−ジメチルベンジルアミン)上に約5及び12mS/cmで注入した。5、10及び15カラム体積(CV)時に通過液画分(FT)を集めた。溶出ピークからの画分をプールした。FT画分を、HCP及びプロテインAの含有量について分析した。
カラム及びゲルは、スウェーデン、Uppsala、GE Healthcareから入手した。
使用する化学薬品は全て分析級とした。水はMilliQで濾過した。
対照マトリックスは、Q Sepharose(商標)Fast Flow(FF)(スウェーデン、Uppsala、GE Healthcare)とした。マルチモーダル分離マトリックスのプロトタイプは、下表1に記載した通りのリガンドを所持した。
A.マトリックスへのアリル基の導入
Sepharose(商標)6 Fast Flow(スウェーデン、Uppsala、GE Healthcare)をアリルグリシジルエーテルで次のように活性化した。即ち、100mlのSepharose(商標)6 Fast Flowを吸引乾燥し、0.3gのNaBH4、12gのNa2SO4及び35mlの50%NaOH水溶液と混合した。混合物を50℃で1時間撹拌した。100mlのアリルグリシジルエーテルを添加した後、懸濁液を激しく撹拌しながら更に16時間50℃に保持した。混合物を濾過した後、ゲルを500mlの蒸留水、500mlのエタノール、200mlの蒸留水、200mlの0.2M酢酸及び500mlの蒸留水で順次洗浄した。
50mlのアリル活性化Sepharose(商標)6 Fast Flow(アリル基0.22ミリモル/ml排水ゲル)、1gの酢酸ナトリウム及び15mlの蒸留水からなる撹拌懸濁液に、臭素を黄色が持続するまで添加した。次いで、ギ酸ナトリウムを懸濁液が完全に脱色されるまで添加した。反応混合物を濾過し、ゲルを500mlの蒸留水で洗浄した。次いで、活性化ゲルを反応容器に直ちに移送し、N−ベンジル−N−メチルエタノールアミンと更に反応させた。
アミン基の窒素原子を経由してマトリックスにアミン基を直接導入した。典型的な手順において、マトリックスへのカップリングは、アリル基の臭素化及び塩基性条件下での求核置換により実現された。25mlの臭素活性化ゲル(アリル基0.22ミリモル/ml排水ゲル)を、N−ベンジル−N−メチルエタノールアミン(16.0ml)の溶液を含む反応ガラス瓶に移した。5mlの水を添加し、反応溶液のpHを水酸化ナトリウム溶液で12.0に調整した。反応物を撹拌下に16時間50℃で保持した。反応混合物を濾過した後、ゲルを、10mlの蒸留水で3回、10mlの0.5HCl水で3回、最後に10mlの蒸留水で3回、順次洗浄した。BMEA Sepharose(商標)Fast Flowゲルが、アミン0.15ミリモル/mlゲルの置換度で得られた。
MAb1及びMAb2と表示され、それぞれ1.46及び1.50の吸光係数を有する2つの異なるヒト化IgG抗体、サブクラス1を使用した。双方の抗体とも、CHO培養で発現させ、続いて本発明の実験に先立って従来からのプロテインAアフィニティークロマトグラフィーを使用して精製した。
式中、
A280は280nmでの吸光度であり、
ε(mL・mg−1・cm−1)は特定のタンパク質に対する吸光係数であり、
C(mg/mL)はタンパク質の濃度であり、
l(cm)は光路長である。
緩衝液は、25mM Bis−Tris、pH6.0又は6.5とした。所望される導電率、約5又は12mS/cmに応じて、35又は100mMのNaClを含めた。プロトタイプ901035A及び901035Bの場合、溶出緩衝液(B−緩衝液)は、25mM Bis−Tris、0.5M NaCl、pH6.5とした。リガンドとしてチオミカミン及びABIを用いるプロトタイプの場合、溶出緩衝液(B−緩衝液)は、0.5M酢酸ナトリウム、pH4.0とした。流速は0.5mL/分(150cm/時間)とした。
A−緩衝液は25mM Bis−Tris、pH6.0とした。導電率は、50mM NaClを添加して約7mS/cmとし、B−緩衝液は、0.5M酢酸ナトリウム、pH4.0とした。流速は0.5mL/分(150cm/時間)とした。試料濃度は、MAbを4mg/mL、rPrAを0.04mg/mL(1%(w/w)に相当)とした。
選択した画分を、800μLのSPA試料希釈液+200μL試料の比率でSPA試料希釈液と混合した。混合後、画分を加熱ブロック上、99℃で10分間加熱し、次いで、再混合した。次いで、試料を組換えプロテインAについて分析した。
試料(最小で600μL)をHCP含有量について分析した。検出下限は10ng/mLである。
プロトタイプリガンドN−ベンジル−N−メチルエタノールアミン(901035A)及びN,N−ジメチルベンジルアミン(901035B)で精製したMAb−1含有試料
実施例1では、50mgのMAb1を含む試料を、Sepharose(商標)6FFに固定化したN−ベンジル−N−メチルエタノールアミン(901035A)、Sepharose(商標)6FFに固定化したN,N−ジメチルベンジルアミン(901035B)及び対照マトリックスQ Sepharose(商標)FFに、25mM Bis−Tris、100mM NaCl(〜12mS/cm)、pH6.5で適用した。溶出は、25mM Bis−Tris、0.5M NaCl、pH6.5で実施した。
プロトタイプリガンド、チオミカミン及び2−アミノベンズイミダゾールで精製したMAb−1含有試料
この実施例では、20mgのMAb1を含む試料を、プロトタイプ及び対照分離マトリックスに注入した。緩衝液は、平衡化及び注入の場合、25mM Bis−Tris、35mM NaCl(〜5mS/cm)、pH6.5とした。溶出緩衝液は、0.5M 酢酸ナトリウム、pH4.0とした。a)チオミカミン、65μモル/mL(1282004)、b)チオミカミン128μモル/mL(1282002)、c)Q Sepharose(商標)FF、d)2−アミノベンズイミダゾール(ABI)、65μモル/mL(1282045)及びe)2−アミノベンズイミダゾール(ABI)、146μモル/mL(1282032)である。HCP及びプロテインA分析の結果を下表4及び5に示す。
プロトタイプリガンド、チオミカミン及び2−アミノベンズイミダゾールで精製したMAb−2含有試料
20mgのMAb2を含む試料をプロトタイプ及び対照に適用した。緩衝液は、25mM Bis−Tris、100mM NaCl(〜12mS/cm)、pH6.0とした。溶出は、0.5M酢酸ナトリウム、pH4.0で実施した。得られたクロマトグラムを図3に示す。図3a)は、チオミカミン65μモル/mL(1282004、緑)、チオミカミン128μモル/mL(1282002、青)及びQ Sepharose(商標)FF(黒)。図3b)は、2−アミノベンズイミダゾール65μモル/mL(1282045、青)、2−アミノベンズイミダゾール146μモル/mL(1282032、緑)及びQ Sepharose(商標)FF(黒)である。分析SECを使用して、下表6及び7に示すようなHCP及びプロテインA分析のための画分を選択した。
プロトタイプリガンド、N−ベンジル−N−メチルエタノールアミン、N,N−ジメチルベンジルアミン、チオミカミン及び2−アミノベンズイミダゾールでの、MAb1及び組換えプロテインA(rPrA)を含む試料からのMAb1の精製
この実施例では、Ab1−rプロテインAを含む試料についてのプロトタイプでのクロマトグラフィーを実施した。A−緩衝液は、25mM Bis−Tris、50mM NaCl、pH6.0とした。導電率は約7mS/cmであった。B−緩衝液は、0.5M酢酸ナトリウム、pH4.0とした。流速は0.5mL/分(150cm/時間)であった。試料は、mAb1が4mg/mL、rプロテインAが1%(w/w)の濃度の、10mgのmAb1、0.10mgのrPrAとした。結果を図4に示す。
Q Phenyl Sepharose 6 Fast Flow配置での抗体精製
非結合条件下で、約50mgのmAbを含む試料をプロトタイプQ Phenyl Sepharose(商標)6 Fast Flowに注入した。5、10及び15カラム容積(CV)時に通過液画分(FT)を採取した。溶出ピークからの画分を分析した。
カラム及びPhenyl Sepharose(商標)6 Fast Flowは、スウェーデン、Uppsala、GE Healthcareから入手した。
HR 5/5(商標) カタログ番号18−0338−01 CV=1mL。
クロマトグラフィー装置 AKTAExplorer(商標)10
分光計 Spectra MAX plus。
使用する化学薬品は、全て分析級とした。水はMiLLiQで濾過した。
架橋アガロースゲル(Phenyl Sepharose(商標)6 Fast Flow(高置換)、スウェーデン、Uppsala、GE Healthcare)から出発する、本発明による分離マトリックスを調製するための1つの方法を次に例示する。
Q−基(−N(CH3)3)は、次のように、グリシジルトリメチルアンモニウムクロリド(G−MAC)との反応によってPhenyl Sepharose(商標)6 Fast Flow(高置換)に導入した。即ち、15gの吸引乾燥Phenyl Sepharose(商標)6 Fast Flow(高置換)を、5mlの水、5mlの50%NaOH水溶液、0.02gのNaBH4及び40mlのG−MACと混合した。混合物を30℃で16時間撹拌した。混合物を濾過した後、ゲルを、100mlの蒸留水、100mlのエタノール及び100mlの蒸留水で順次洗浄した。
使用するモノクロナール抗体は、CHO培養で発現させ、続いて、当面の実験に先立って従来からのプロテインAアフィニティークロマトグラフィーを使用して精製した。
mAb試料を緩衝液で10倍に希釈した。試料溶液の2つの控えをA280で測定した。平均値を使用し、Lambert−Beerの法則に従って濃度を計算した。即ち、
C=A/(l×ε)
C=IgGの濃度
A=280nmでの吸光度
l=光路長
ε=mAbに対するモル吸光係数、mg−1ml=1.46。
宿主細胞タンパク質及びプロテインAからのmAbの分離を、非結合条件下で試験した。カラムに適用する試料はMabSelectで精製したmAbとした。流速は、0.5ml/分(150cm/時間)とした。ラン中は終始、280nmでの吸光度を検出した。2つの異なる緩衝液(下記参照)を試験した。各ランの前にA−緩衝液への緩衝液交換を実施した。試料体積に応じてHiPrep脱塩及びHiTrap脱塩カラムを使用した。
緩衝液 A−緩衝液:25mM Tris/HCl、pH8.0
B−緩衝液:25mM Tris/HCl、0.5M NaCl、pH8.0
A−緩衝液:25mMリン酸塩緩衝液、pH7.0
B−緩衝液:25mMリン酸緩衝液、0.5M NaCl、pH7.0
方法:出発材料として、MabSelectからのpHを調整した溶出液を使用した。
選択した画分を、800μlのSPA試料希釈液+200μlの試料の比率でSPA試料希釈剤と混合した。混合した後、画分を加熱ブロック上、99℃で10分間加熱し、次いで再混合した。次いで、試料を組換えプロテインAについて分析した。
試料(最小で600μl)をHCP含有量について分析した。検出下限は10ng/mLである。
非結合条件下で、約50mgのmAbを、Q Phenyl Sepharose(商標)6 Fast Flowを充填したHR5/5カラムに2つの異なるpH(pH7.0及び8.0)で注入した。通過液画分を図1に従って5、10、15カラム容積(CV)時に採取した。表8及び9は、通過液画分のプロテインA及びHCP分析の結果を示す。画分中にプロテインAの残余は検出できなかった。更に、8.0の試料pHを使用した場合に、FT1及びFT2中に宿主細胞タンパク質は検出できなかった。7.0の試料pHを使用した場合には、少量の宿主細胞タンパク質が観察されたが、HCPは、試料中のHCP含有量に比べて約50分の1に低下した。又、図6は、勾配溶出でのクロマトグラムで極めて小さなピークのみが観察されるので(図6)、モノクロナール抗体分子がQ Phenyl Sepharose(商標)6 Fast Flowに吸着されないことを示している。
Claims (9)
- 液体試料中の1種以上の抗体を1種以上の他の化合物から分離する方法であって、当該方法が、液体試料を含む移動相をマルチモーダル分離マトリックスと接触させ、抗体を移動相中に遊離させた状態で、1種以上の目標化合物を吸着することを含んでおり、上記マルチモーダル分離マトリックスが、目標化合物の負に荷電した部位と相互作用できる第1の基と目標化合物と電荷−電荷相互作用以外の1種以上の相互作用ができる芳香族基を含む第2の基とを含む、分離方法。
- 前記液体試料が粗供給液を含む、請求項1記載の方法。
- 前記目標化合物が宿主細胞タンパク質であり、80%以上のタンパク質がマルチモーダル分離マトリックスに吸着される、請求項2記載の方法。
- 前記液体試料が、分離マトリックスからの溶出液を含む、請求項1記載の方法。
- 溶出液が得られる分離マトリックスが、タンパク質リガンドを含む、請求項4記載の方法。
- 第1の基が第4級アミンである、請求項1乃至請求項5のいずれか1項記載の方法。
- 第2の基が、芳香族又はヘテロ芳香族の環構造を含む疎水性基である、請求項1乃至請求項6のいずれか1項記載の方法。
- 前記分離マトリックスが粒状であり、第1の基を含むリガンドが固定された第1粒子と第2の基を含むリガンドが固定された第2粒子との混合物を含む、請求項1乃至請求項7のいずれか1項記載の方法。
- 分離マトリックスが、第1の基を含む第1リガンドと第2の基を含む第2リガンドとの混合物が固定されたフィルターである、請求項1乃至請求項8のいずれか1項記載の方法。
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