JP6141524B2 - 活性炭を用いた標的タンパク質含有サンプルからのフラグメントの除去 - Google Patents
活性炭を用いた標的タンパク質含有サンプルからのフラグメントの除去 Download PDFInfo
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- JP6141524B2 JP6141524B2 JP2016519501A JP2016519501A JP6141524B2 JP 6141524 B2 JP6141524 B2 JP 6141524B2 JP 2016519501 A JP2016519501 A JP 2016519501A JP 2016519501 A JP2016519501 A JP 2016519501A JP 6141524 B2 JP6141524 B2 JP 6141524B2
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Description
本発明は、精製される標的タンパク質(例えばモノクローナル抗体)を含有するサンプルからのフラグメントの除去に活性炭を用いることができるという驚くべき予想外の発見に、少なくとも一部は基づく。
本明細書において互換的に用いられる用語「活性炭素」または「活性炭」とは、その細孔構造を増強する処理が施された炭素質材料を指す。活性炭は、場合により、活性チャコールとも呼ばれる。活性炭は非常に大きな表面積を有する多孔質固体である。活性炭は、石炭、木材、ヤシ殻、堅果殻および泥炭を含む種々の原料源に由来し得る。活性炭は、制御雰囲気下での加熱を含む物理的活性化、または強酸、塩基もしくは酸化剤を使用した化学的活性化を用いて、上記材料から製造することができる。活性化プロセスは、不純物除去のための高い能力を活性炭に付与する表面積の大きな多孔質構造をもたらす。活性化プロセスを変更して表面の酸性度を制御することができる。
本発明の方法では、活性炭などの特定の炭素質材料が、フラグメントの選択的除去に使用される。活性炭は、表面積の非常に大きな多孔質固体として説明できる。いくつかの実施形態において、活性炭は活性チャコールを含む。活性炭は、石炭、木材、ヤシ殻、堅果殻および泥炭を含むが、これらに限定されない種々の原料源に由来し得る。活性炭は、制御雰囲気下での加熱を含む物理的活性化により、または強酸、塩基もしくは酸化剤を用いる化学的活性化により、上記材料から製造することができる。活性化プロセスは、不純物除去のための高い能力を活性炭に付与する表面積の大きな多孔質構造をもたらす。活性化プロセスを変更して表面の酸性度を制御することができる。
サンプルにおける標的タンパク質のフラグメントの量を測定する一般的技術として、いくつかの異なる分析クロマトグラフィープロセスが挙げられる。サイズ排除またはゲル透過クロマトグラフィーは、フラグメントの流体力学的容積の差に基づいて、フラグメントを標的タンパク質から分離する。逆相HPLCおよび疎水性相互作用クロマトグラフィー(HIC)は、疎水性の差に基づいて標的タンパク質からフラグメントを分離する。陰イオン交換(AEX)および陽イオン交換(CEX)クロマトグラフィーは、電荷量の差に基づいて、フラグメントを標的タンパク質から分離する。混合モードクロマトグラフィーは、電荷量および疎水性両方の差に基づいて、標的タンパク質からフラグメントを分離する。
標的タンパク質を含有するサンプルからフラグメントを選択的に除去するために用いてよい1つの基本手順が以下で説明される。
本代表的実施例は、モノクローナル抗体フラグメントが、活性炭を用いた静的処理により、モノクローナル抗体を含有するサンプルから選択的に除去され得ることを実証する。
本代表的実施例は、モノクローナル抗体フラグメントが、活性炭を充填したクロマトグラフィーカラムにサンプルを通すことにより、モノクローナル抗体を含有するサンプルから選択的に除去され得ることを実証する。
本代表的実施例は、プロテインAと結合するモノクローナル抗体フラグメントが、活性炭を充填したクロマトグラフィーカラムに通すことにより、モノクローナル抗体を含有するサンプルから選択的に除去され得ることを実証する。
本代表的実施例は、プロテインAと結合しないモノクローナル抗体フラグメントもまた、活性炭を充填したクロマトグラフィーカラムに通すことにより、モノクローナル抗体を含有するサンプルから選択的に除去され得ることを実証する。
本代表的実施例は、モノクローナル抗体フラグメントが、各種活性炭を用いた静的処理により、モノクローナル抗体を含有するサンプルから選択的に除去され得ることを実証する。
MAB IIフラグメント混入溶液の調製は、モノクローナル抗体の一部をパパイン酵素で消化し抗体フラグメントを産生することから開始した。消化後、前記酵素は、0.3Mヨードアセテートの溶液の添加により不活性化される。パパイン消化モノクローナル抗体溶液は、透析用チューブ(標準RC透析トライアルキット、Spectra/Por1−3、3.5K MWCO、54mm平面幅、品番:132725、Spectrum Laboratories,Inc.Rancho Dominguez、CA、90220 USA)により水に透析され、緩衝塩が除去された。前記透析用チューブに、約0.15Lのパパイン消化モノクローナル抗体溶液が添加され、4.0Lの水中に24時間浸される。透析用チューブは、次に、4.0Lの新鮮な水を入れた新しい容器に移され、さらに24時間浸されたままにされる。
本代表的実施例は、モノクローナル抗体フラグメントが、活性炭を用いた酸性および中性pH溶液条件での静的処理により、モノクローナル抗体を含有するサンプルから選択的に除去され得ることを実証する。
本代表的実施例は、モノクローナル抗体フラグメントが、低溶液伝導率および高溶液伝導率両方で、4.0から9.0のpH範囲にて活性炭を用いた静的処理により、モノクローナル抗体溶液から選択的に除去され得ることを実証する。
Claims (19)
- 精製される標的タンパク質を含むサンプル中のフラグメントの量を低減する方法であって、
(a)標的タンパク質および標的タンパク質のフラグメントを含むサンプルを用意するステップであって、フラグメントが標的タンパク質の量の少なくとも0.2%以上の量である、ステップ、
(b)サンプルを活性炭に接触させるステップであって、活性炭がフラグメントと結合する、ステップ、
(c)サンプルから活性炭を除去し、それによりサンプル中のフラグメントの量を低減するステップ
を含み、
前記標的タンパク質が抗体である、方法。 - 抗体がモノクローナル抗体である、請求項1に記載の方法。
- 抗体がポリクローナル抗体である、請求項1に記載の方法。
- 活性炭がデバイス内に充填される、請求項1に記載の方法。
- デバイスがカラム、ポッド、カートリッジまたはカプセルである、請求項4に記載の方法。
- フラグメントが標的タンパク質の量の少なくとも0.5%以上の量で存在する、請求項1に記載の方法。
- フラグメントが標的タンパク質の量の少なくとも1%以上の量で存在する、請求項1に記載の方法。
- フラグメントが標的タンパク質の量の少なくとも2%以上の量で存在する、請求項1に記載の方法。
- ステップ(c)が、サンプルから活性炭を除去するために、ろ過もしくは遠心分離またはこれらの組合せを用いることを含む、請求項1に記載の方法。
- フラグメントがプロテインAと結合する、請求項1に記載の方法。
- フラグメントがプロテインAと結合しない、請求項1に記載の方法。
- サンプルがプロテインAアフィニティークロマトグラフィーカラムから収集された溶出液である、請求項1に記載の方法。
- 活性炭がカラム、ポッド、カートリッジまたはカプセルに充填される、請求項1に記載の方法。
- フラグメントが抗体の量の少なくとも0.5%以上の量である、請求項1に記載の方法。
- フラグメントが抗体の量の少なくとも1%以上の量である、請求項1に記載の方法。
- フラグメントが抗体の量の少なくとも2%以上の量である、請求項1に記載の方法。
- 活性炭が、ろ過もしくは遠心分離またはこれらの組合せを用いて除去される、請求項1に記載の方法。
- フラグメントの量の低減後、サンプル中の標的タンパク質の純度が高められる、請求項1に記載の方法。
- 標的タンパク質の純度が、少なくとも10%の割合だけ高められる、請求項18に記載の方法。
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- 2014-04-04 US US14/891,724 patent/US10519194B2/en active Active
- 2014-04-04 CN CN201480035275.7A patent/CN105324166B/zh active Active
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JP2016527201A (ja) | 2016-09-08 |
SG11201508835YA (en) | 2015-11-27 |
KR20160005703A (ko) | 2016-01-15 |
US10519194B2 (en) | 2019-12-31 |
CA2910770A1 (en) | 2015-01-15 |
CN105324166A (zh) | 2016-02-10 |
WO2015005960A1 (en) | 2015-01-15 |
CN105324166B (zh) | 2018-01-19 |
CA2910770C (en) | 2018-02-27 |
KR101847004B1 (ko) | 2018-04-10 |
EP3019262A1 (en) | 2016-05-18 |
US20160090399A1 (en) | 2016-03-31 |
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