JP2013514073A - 洗浄溶液及びアフィニティークロマトグラフィーの方法 - Google Patents
洗浄溶液及びアフィニティークロマトグラフィーの方法 Download PDFInfo
- Publication number
- JP2013514073A JP2013514073A JP2012543787A JP2012543787A JP2013514073A JP 2013514073 A JP2013514073 A JP 2013514073A JP 2012543787 A JP2012543787 A JP 2012543787A JP 2012543787 A JP2012543787 A JP 2012543787A JP 2013514073 A JP2013514073 A JP 2013514073A
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- Prior art keywords
- protein
- arginine
- wash
- column
- washing
- Prior art date
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- Granted
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- 238000005406 washing Methods 0.000 title claims abstract description 68
- 238000000034 method Methods 0.000 title claims abstract description 67
- 238000001042 affinity chromatography Methods 0.000 title claims abstract description 66
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 153
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 153
- 150000003839 salts Chemical class 0.000 claims abstract description 89
- 239000004475 Arginine Substances 0.000 claims abstract description 83
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 79
- 239000012535 impurity Substances 0.000 claims abstract description 38
- 150000001483 arginine derivatives Chemical class 0.000 claims abstract description 30
- 229960003121 arginine Drugs 0.000 claims description 82
- 238000004140 cleaning Methods 0.000 claims description 54
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 51
- 239000011780 sodium chloride Substances 0.000 claims description 26
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 229960003589 arginine hydrochloride Drugs 0.000 claims description 11
- 239000011159 matrix material Substances 0.000 claims description 8
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- 235000009697 arginine Nutrition 0.000 description 74
- 239000000758 substrate Substances 0.000 description 63
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 10
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- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 2
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical compound NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- 235000014852 L-arginine Nutrition 0.000 description 2
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
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- SNEIUMQYRCDYCH-UHFFFAOYSA-N acetylarginine Chemical compound CC(=O)NC(C(O)=O)CCCN=C(N)N SNEIUMQYRCDYCH-UHFFFAOYSA-N 0.000 description 2
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- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
- B01D15/3804—Affinity chromatography
- B01D15/3809—Affinity chromatography of the antigen-antibody type, e.g. protein A, G, L chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
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Abstract
【選択図】なし
Description
アフィニティークロマトグラフィーにより、ゲル基質のような固相中の標的に対象のタンパク質が選択的に結合することに基づき、細胞採取のように分子混合物から対象のタンパク質を精製できる。この固相成分は通常はカラムに形成され、対象のタンパク質を含む混合物をそれに通す。この最初の手順である捕捉手順において、対象のタンパク質は固相中の標的に特異的に結合し、混合物中の他の成分はカラムを通って流れる。しかし、高分子量種(HMWs)、低分子量種(LMWs)及びホスト細胞タンパク質(HCPs)を含む混合物内のある成分は、不純物として対象のタンパク質と共にカラム内に保持される。そのため通常は1回以上の洗浄手順を行い、対象のタンパク質を固相に結合させたまま、洗浄溶液を1回以上カラムに用いてこれらの不純物を除去する。最後に、洗浄手順により不純物を除去した後、溶離手順によりカラムから対象のタンパク質を回収し、ここでは固相標的への対象のタンパク質の結合を分裂させる溶離溶液をカラムに用いて対象のタンパク質を溶離液中に回収する。従って、対象のタンパク質の精製におけるアフィニティークロマトグラフィーの有効性の大部分は、固相標的への対象のタンパク質の結合を分裂させずにまたは不要な影響を与えずに、不純物(例えばHMWs、LMWs、HCPs)を有効に除去できる洗浄条件を識別することにかかっている。
a)抗体または抗体切片から成る混合物をプロテインAカラムに負荷し
b)(i)0.05〜2.0Mの範囲(より好ましくは0.05〜0.85Mの範囲、最も好ましくは0.1〜0.5Mの範囲)にある濃度のアルギニン−HCl及び(ii)0.1〜2.0Mの範囲にある濃度の塩化ナトリウムから成る洗浄溶液でプロテインAカラムを洗浄し、ここで洗浄溶液はプロテインAカラムから不純物を除去し
c)抗体または抗体切片をプロテインAカラムから溶離させる
ことから成る。好ましくは、洗浄溶液は8.0より高いpHにある。アルギニン−HClの好ましい濃度及び濃度範囲は前述の通りである。例として、好ましい実施形態では、アルギニン−HClは約0.25Mの濃度または0.25Mの濃度にある。塩化ナトリウムの好ましい濃度及び濃度範囲は上述の通りである。例として、好ましい実施形態では、塩化ナトリウムは約1Mの濃度または1Mの濃度にある。好ましいpH及びpH範囲は上述の通りである。例として、一実施形態では、洗浄溶液のpHは8.1〜9.5の範囲にある。別の実施形態では、洗浄溶液のpHは8.5またはそれより高い。別の実施形態では、洗浄溶液のpHは9.0である。
実施例1:アルギニン/非緩衝塩洗浄液と他の洗浄液との比較
本実施例では、アフィニティークロマトグラフィー中に抗体含有液から不純物を除去するための様々な洗浄液の有効性を比較する。より詳細には、3種の洗浄液(1種目はpH5.0でアルギニンおよび非緩衝塩を含まず、2種目はpH7.0で非緩衝塩を含むがアルギニンを含まず、3種目はpH9.0で非緩衝塩とアルギニンの両方を含む)を比較する。
本実施例では、アフィニティー液体クロマトグラフィー(ALC)中に不純物を除去するための、異なったpH値で異なった量の非緩衝塩および/またはアルギニンを含むさらなる洗浄液の有効性を比較する。本実施例で使用するクロマトグラフィーの条件は、以下の表8に記載の通りである。
本実施例では、HCPおよびHMWの除去に対する洗浄液のパラメータとしてのpHの分析を行い、塩基性pH条件の優位性を示す。実施例2の表8に記載の条件を使用したアフィニティー液体クロマトグラフィー(ALC)を、わずかに異なるレベルのHMWおよびHCPを用いて、mAb−Vaの細胞回収物に対して行う。
本実施例では、Tween80、アルギニン以外のアミノ酸または高濃度のトリスを含む他の洗浄液を、アルギニン/非緩衝塩洗浄液と比較する。本実施例では、HCPおよびHMWの除去に対する洗浄液のパラメータとしてのpHの分析を行い、塩基性pH条件が優位であること示す。実施例1の表1に記載の条件を使用したアフィニティー液体クロマトグラフィー(ALC)を、わずかに異なるレベルのHMWおよびHCPを用いて、mAb−Vaの細胞回収物に対して行う。
本実施例では、高pHのアルギニン/非緩衝塩洗浄液の有効性を、高pHおよび低pHの非緩衝塩液と比較する。詳細に述べると、以下の条件、つまり(1)低pH(すなわち7.0)の非緩衝塩洗浄液、(2)高pH(すなわち9.0)の非緩衝塩洗浄液および(3)高pH(すなわち9.0)でアルギニンと組合せた非緩衝塩洗浄液を評価および比較する。さらに、HMW、LMWおよびHCPの除去に対するアルギニンの効果を分析し、塩基性pH条件でアルギニンと組合せた非緩衝塩液の使用が特に有効で有益であることを示す。本実施例で比較する洗浄液を以下の表15に記載する。
本実施例では、さらなるアルギニンおよび非緩衝塩の濃度ならびにpH洗浄条件について、アフィニティー液体クロマトグラフィー(ALC)中に不純物を除去することに対するそれらの有効性を決定づけるために検討する。本実施例で比較する洗浄液を以下の表18に記載する。
Claims (15)
- 目的タンパク質が結合するアフィニティークロマトグラフィー(AC)マトリックスを使用して、精製された目的タンパク質を産生する方法であって、前記ACマトリックスから前記目的タンパク質を溶出する前に、(i)アルギニンまたはアルギニン誘導体および(ii)非緩衝塩を含む1種または複数の洗浄液で前記ACマトリックスを洗浄することを含む方法。
- (i)アルギニンまたはアルギニン誘導体および(ii)非緩衝塩の両方を含む1種の洗浄液で前記ACマトリックスが洗浄される、請求項1に記載の方法。
- 前記洗浄液がアルギニン−HClを含む、請求項2に記載の方法。
- 前記非緩衝塩が塩化ナトリウム(NaCl)である、請求項2に記載の方法。
- 前記ACマトリックスが一次洗浄液および二次洗浄液の2種の洗浄液で洗浄され、ここで、
(a)一次洗浄液がアルギニンまたはアルギニン誘導体を含み、二次洗浄液が非緩衝塩を含む、または
(b)一次洗浄液が非緩衝塩を含み、二次洗浄液がアルギニンまたはアルギニン誘導体を含む、
請求項1に記載の方法。 - 前記目的タンパク質が前記プロテインAカラムに結合する抗体または抗体断片である、請求項1から5のいずれか一項に記載の方法。
- 前記1種または複数の洗浄液が前記ACマトリックスから不純物を除去する、請求項1から6のいずれか一項に記載の方法。
- プロテインAカラムを使用して、精製された抗体または抗体断片を産生する方法であって、
a)抗体または抗体断片を含む混合物を前記プロテインAカラムに負荷すること、
b)(i)0.05〜0.85Mの範囲の濃度のアルギニン−HClおよび(ii)0.1〜2.0Mの範囲の濃度の塩化ナトリウムを含む洗浄液で前記プロテインAカラムを洗浄し、前記洗浄液が、前記プロテインAカラムから不純物を除去すること、および
c)前記プロテインAカラムから前記抗体または抗体断片を溶出すること
を含む方法。 - 前記アルギニン−HClが0.25Mまたは約0.25Mの濃度である、請求項1から8のいずれか一項に記載の方法。
- 前記塩化ナトリウムが1Mまたは約1Mの濃度である、請求項1から9のいずれか一項に記載の方法。
- 前記1種または複数の洗浄液のpHが8.0より高い、請求項1から10のいずれか一項に記載の方法。
- 前記1種または複数の洗浄液のpHが約8.5〜9.5の範囲である、請求項1から11のいずれか一項に記載の方法。
- もう1つの洗浄液のpHが9.0である、請求項12に記載の方法。
- 前記不純物が高分子(HMW)種を含む、請求項7から13のいずれか一項に記載の方法。
- 前記不純物が宿主細胞タンパク質(HCP)を含む、請求項7から13のいずれか一項に記載の方法。
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JP2016530533A (ja) * | 2013-09-05 | 2016-09-29 | ジェネンテック, インコーポレイテッド | クロマトグラフィー再使用のための方法 |
JP2019094334A (ja) * | 2013-09-05 | 2019-06-20 | ジェネンテック, インコーポレイテッド | クロマトグラフィー再使用のための方法 |
US10940401B2 (en) | 2013-09-05 | 2021-03-09 | Genentech, Inc. | Method for chromatography reuse |
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