JP2013508387A - プロテインaアフィニティークロマトグラフィーを利用した抗il−13抗体の単離精製 - Google Patents
プロテインaアフィニティークロマトグラフィーを利用した抗il−13抗体の単離精製 Download PDFInfo
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Abstract
Description
1.定義;
2.抗体作製;
3.抗体産生;
4.抗体精製;
5.サンプル純度の検定方法;
6.付加的修飾;
7.医薬組成物;及び
8.抗体使用。
本発明を理解し易くするために、先ず所定の用語を定義する。
本セクションで使用する「抗体」なる用語は、無傷抗体又はその抗原結合フラグメントを意味する。
3.1 一般産生ストラテジー
本発明の抗体を発現させるためには、遺伝子を転写及び翻訳制御配列と機能的に連結するように、部分又は全長軽鎖及び重鎖をコードするDNAを1以上の発現ベクターに挿入する(例えばその教示内容全体を本願に援用する米国特許第6,914,128号参照)。この関連で「機能的に連結」なる用語はベクター内の転写及び翻訳制御配列が抗体遺伝子の転写と翻訳を制御するというその所期機能を発揮するように抗体遺伝子をベクターにライゲーションすることを意味する。発現ベクターと発現制御配列は、使用される発現宿主細胞と適合可能となるように選択される。抗体軽鎖遺伝子と抗体重鎖遺伝子は、別々のベクターに挿入してもよいが、より典型的には、両方の遺伝子を同一発現ベクターに挿入する。抗体遺伝子は、標準方法(例えば抗体遺伝子フラグメントとベクター上の相補的制限部位のライゲーション又は制限部位が存在しない場合には平滑末端ライゲーション)により発現ベクターに挿入される。抗体又は抗体関連軽鎖及び重鎖配列を挿入する前に、発現ベクターに予め定常領域配列を保持させてもよい。例えば、抗IL−13抗体又は抗IL−13抗体関連VH及びVL配列から全長抗体遺伝子を作製する1つのアプローチはVHセグメントをベクター内のCHセグメントと機能的に連結し、VLセグメントをベクター内のCLセグメントと機能的に連結するように、夫々重鎖定常領域と軽鎖定常領域を予めコードする発現ベクターにこれらの配列を挿入する方法である。上記に加え、又は上記の代わりに、組換え発現ベクターは宿主細胞からの抗体鎖の分泌を助長するシグナルペプチドをコードすることができる。シグナルペプチドを抗体鎖遺伝子のアミノ末端にインフレームで連結するように抗体鎖遺伝子をベクターにクローニングすることができる。シグナルペプチドは免疫グロブリンシグナルペプチド又は異種シグナルペプチド(即ち、非免疫グロブリン蛋白質に由来するシグナルペプチド)とすることができる。
ある実施形態において、抗IL−13抗体産生の初期工程は、スピナーフラスコとバイオウェーブバッグの操作を使用し、抗IL−13抗体を発現するCHO細胞を凍結バイアル1本から110Lシードバイオリアクターの接種に望ましいバイオマスまで増殖させる。マスターセルバンクCHO細胞の凍結バイアルを解凍し、増殖培地(SR−512)に加え、遠心する。細胞を増殖培地に再懸濁し、容積を増加させながら使い捨てスピナーフラスコ、振盪フラスコ及び/又はバイオウェーブバッグで37℃及び5% CO2にて増殖させる。シードバイオリアクターに接種する前に20Lウェーブバッグ2個を使用して最終細胞塊増殖を最大にする。両方の20Lウェーブバッグからの細胞密度が約15〜17日目に生存細胞≧2.0×106個/mLに達したら、更に増殖させるために、増殖培地SR−520を充填した110シードバイオリアクターに培養液を移す。接種後、目標温度を37℃とし、pHを7.1の目標値に設定し、NaOHの添加とCO2スパージングにより制御する。空気と酸素のスパージングによりバイオリアクター内の溶存酸素(DO)を40%の目標値に制御する。約2〜4日後に細胞密度が生存細胞≧2.6×106個/mLに達したら、培養液を3000L産生用バイオリアクターに移す。
4.1 抗体精製概論
本発明は、抗体と少なくとも1種のHCPを含有する混合物から精製(ないし「HCP低減」)抗体調製物を生成する方法を提供する。本発明は、最終精製調製物の浸出プロテインAを低減する方法も提供する。本発明の精製工程は、上記方法及び当分野の慣用方法を使用して抗体が産生された時点で分離工程から開始する。表1は精製スキームの1態様を要約する。このスキームの変形も考えられ、限定されないが、プロテインAアフィニティークロマトグラフィー工程を省略したり、イオン交換工程の順序を逆にした変形が考えられ、本発明の範囲に含まれる。
本発明の精製方法の初期工程は、サンプルマトリックスからの抗体の第1段階の清澄化及び一次回収を含む。更に、一次回収工程はサンプルマトリックスに存在する可能性のあるウイルスを低減又は不活性化する点でもあり得る。例えば、熱不活性化(低温殺菌)、pH不活性化、溶媒/デタージェント処理、UV及びγ線照射、並びに所定の化学不活性化剤(例えばβ−プロピオラクトン又は例えばその教示内容全体を本願に援用する米国特許第4,534,972号におけるように銅フェナントロリン)の添加を含む各種ウイルス低減/不活性化方法の任意の1種以上を精製の一次回収段階中に使用することができる。本発明のある実施形態では、一次回収段階中にサンプルマトリックスをpHウイルス低減/不活性化に供する。
ある実施形態では、一次回収サンプルをアフィニティークロマトグラフィーに供し、更に目的抗体をHCPから精製する。ある実施形態において、クロマトグラフィー材料は目的抗体と選択的又は特異的に結合することが可能である。このようなクロマトグラフィー材料の非限定的な例としては、プロテインA、プロテインG、目的抗体と結合する抗原を含むクロマトグラフィー材料、及びFc結合蛋白質を含むクロマトグラフィー材料が挙げられる。特定態様において、アフィニティークロマトグラフィー工程は適切なプロテインA樹脂を充填したカラムに一次回収サンプルを供する段階を含む。プロテインA樹脂は各種抗体、特にIgG1、IgG2及びIgG4のアフィニティー精製・単離に有用である。プロテインAは主にそのFc領域を介して哺乳動物IgGと結合する細菌細胞壁蛋白質である。その天然状態において、プロテインAは5個のIgG結合ドメインと機能の不明な他のドメインをもつ。
ある実施形態においては、本発明は抗体を含有する溶出液が得られるように、抗体と少なくとも1種のHCPを含有する混合物を少なくとも1種のイオン交換分離工程に供することにより、前記混合物からHCP低減抗体調製物を生成する方法を提供する。イオン交換分離としては、2種類の物質を夫々のイオン電荷の差に基づいて分離する任意方法が挙げられ、カチオン交換材料又はアニオン交換材料を利用することができる。
本発明のある実施形態では抗体サンプルを更に精製・濃縮するために限外濾過及び/又は透析濾過工程を利用する。限外濾過はMicrofiltration and Ultrafiltration:Principles and Applications,L.Zeman and A.Zydney(Marcel Dekker,Inc.,New York,N.Y.,1996)及びUltrafiltration Handbook,Munir Cheryan(Technomic Publishing,1986;ISBN No.87762−456−9)に詳細に記載されている。濾過工程の1例は表題“Pharmaceutical Process Filtration Catalogue”
のMilliporeカタログ177〜202頁(Bedford,Mass.,1995/96)に記載されているようなタンジェンシャルフロー濾過である。限外濾過は一般に0.1μm未満の細孔サイズのフィルターを使用する濾過を意味するとみなされる。このような細孔サイズの小さいフィルターを利用することにより、抗体をフィルターに保持しながら、サンプルバッファーをフィルターに透過させることによりサンプルの体積を減少させることができる。
本発明は、抗体と少なくとも1種のHCPを含有する混合物からHCP低減抗体調製物を生成する方法であって、更に疎水性相互作用分離工程を含む方法にも関する。例えば、HCP濃度の低下した第2の溶出液が得られるように、イオン交換カラムから得られた第1の溶出液を疎水性相互作用材料に供することができる。本願に記載する工程等の疎水性相互作用クロマトグラフィー工程を一般に実施し、抗体凝集物等の蛋白質凝集物と工程関連不純物を除去する。
ある実施形態では、一次回収の前に先ず遠心及び濾過工程を利用して産生用バイオリアクター回収液から細胞及び細胞破片(HCPを含む)を除去する。例えば、非限定的な例として、抗体と培地と細胞を含む培養液を約7000×g〜約11,000×gで遠心することができる。ある実施形態では、得られたサンプル上清を次に複数のデプスフィルターを含むフィルター列に通す。ある実施形態においては、フィルター列は、12個前後の16インチCuno(登録商標)モデル30/60ZAデプスフィルター(3M Corp.)と、3個の30インチ0.45/0.2μm Sartopore(登録商標)2フィルターカートリッジ(Sartorius)を装着した3個前後のフィルターハウジングから構成される。清澄化した上清を予め滅菌した回収液容器等の容器に採取し、約8℃に維持する。この温度を次に、以下に概説する1以上の捕集クロマトグラフィー工程の前に約20℃に調整する。当然のことながら、当業者は上記条件を変更することができ、このような変更も本発明の範囲内に含まれる。
5.1 宿主細胞蛋白質の検定
本発明は、単離/精製抗体組成物中の残留レベルの宿主細胞蛋白質(HCP)濃度の測定方法も提供する。上記のように、最終目的物質(例えば抗IL−13抗体)からHCPを排除することが望ましい。典型的なHCPとしては、抗体産生源に由来する蛋白質が挙げられる。目的抗体からHCPを同定し、十分に除去することができないと、効力低下及び/又は有害な対象反応に繋がる恐れがある。
ある実施形態においては、本発明は、単離/精製抗体組成物中のアフィニティークロマトグラフィー材料の残留濃度の測定方法も提供する。所定状況において、このような材料は精製工程中に抗体組成物中に浸出する。ある実施形態では、単離/精製抗体組成物中のプロテインA濃度を測定するアッセイを利用する。本願で使用する「プロテインA ELISA」なる用語はアッセイで使用される第2の抗体が目的抗体(例えば抗IL−13抗体)を精製するために利用されるプロテインAに特異的であるELISAを意味する。第2の抗体は、当業者に公知の従来方法に従って産生させることができる。例えば、第2の抗体は従来の抗体作製及び産生方法のコンテキストで天然又は組換えプロテインAを使用して産生させることができる。
本発明の抗体は、修飾することができる。ある実施形態では、所望効果を提供するために抗体又はその抗原結合フラグメントを化学的に修飾する。例えば、本発明の抗体又は抗体フラグメントのペグ化は例えば各々その開示内容全体を本願に援用するFocus on Growth Factors 3:4−10(1992);EP0 154 316;及びEP0 401 384に記載されているような当分野で公知のペグ化反応のいずれかにより実施することができる。ある態様において、ペグ化は反応性ポリエチレングリコール分子(又は同様の反応性水溶性ポリマー)とのアシル化反応又はアルキル化反応により実施される。本発明の抗体及び抗体フラグメントのペグ化に適した水溶性ポリマーはポリエチレングリコール(PEG)である。本願で使用する「ポリエチレングリコール」とは、モノ(C1−C10)アルコキシ−又はアリールオキシ−ポリエチレングリコール等の他の蛋白質を誘導体化するために従来から使用されている型のPEGの任意のものを包含する。
本発明の抗体及び抗体部分は、対象に投与するのに適した医薬組成物に配合することができる。典型的には、医薬組成物は本発明の抗体又は抗体部分と、医薬的に許容可能な担体を含有する。本願で使用する「医薬的に許容可能な担体」とは、生理的に適合可能な全溶媒、分散媒、コーティング、抗細菌剤及び抗真菌剤、等張剤及び吸収遅延剤等を包含する。医薬的に許容可能な担体の例としては水、生理食塩水、リン酸緩衝生理食塩水、デキストロース、グリセロール、エタノール等の1種以上とその組み合わせが挙げられる。多くの場合には、例えば糖、多価アルコール(例えばマンニトール、ソルビトール)、又は塩化ナトリウム等の等張剤を組成物に加えることが望ましい。医薬的に許容可能な担体としては更に抗体又は抗体部分の保存期間又は効力を増す微量の助剤(例えば湿潤剤、乳化剤、防腐剤又は緩衝剤)も挙げられる。
8.1 抗IL−13抗体の使用概論
本発明の抗IL−13抗体又はその抗原結合部分は、IL−13と結合することができるため、酵素免疫測定法(ELISA)、放射免疫測定法(RIA)又は組織免疫組織化学等の従来のイムノアッセイを使用して(例えばサンプルマトリックス中、ある態様では血清や血漿等の生体サンプル中で)IL−13、ある態様ではhIL−13を検出するために使用することができる。本発明は生体サンプル中のIL−13の検出方法として、サンプルを本発明の抗体又は抗体部分と接触させる段階と、IL−13と結合した抗体又は未結合抗体を検出することにより、サンプル中のIL−13を検出する段階を含む方法を提供する。結合した抗体又は未結合抗体の検出を容易にするために検出可能な物質で抗体を直接又は間接的に標識する。適切な検出可能な物質としては各種酵素、補欠分子族、蛍光材料、発光材料及び放射性材料が挙げられる。適切な酵素の例としては西洋ワサビペルオキシダーゼ、アルカリホスファターゼ、β−ガラクトシダーゼ又はアセチルコリンエステラーゼが挙げられ、適切な補欠分子族複合体の例としてはストレプトアビジン/ビオチンとアビジン/ビオチンが挙げられ、適切な蛍光材料の例としてはウンベリフェロン、フルオレセイン、イソチオシアン酸フルオレセイン、ローダミン、ジクロロトリアジニルアミンフルオレセイン、ダンシルクロリド又はフィコエリスリンが挙げられ、発光材料の1例としてはルミノールが挙げられ、適切な放射性材料の例としては、125I、131I、35S又は3Hが挙げられる。診断関連、例えばIL−13の上昇を伴う病態の診断にはサンプル中のIL−13の検出が有用であると思われ、及び/又は抗IL−13抗体による治療が有効であり得る対象を同定するのに有用であると思われる。
本発明のある実施形態において、抗IL−13抗体又はその抗原結合部分は1種以上のIL−13関連障害の治療に利用され、このような障害としては、限定されないが、呼吸器障害(例えば喘息(例えばアレルギー性及び非アレルギー性喘息(例えば、例えば幼児における例えば呼吸器合胞体ウイルス(RSV)感染に起因する喘息))、慢性閉塞性肺疾患(COPD)、並びに気道炎症、好酸球増加、線維化及び粘液過剰産生を伴う他の病態(例えば嚢胞性線維症及び肺線維症))が挙げられる。
原薬の産生バッチは産生用リアクターの1サイクルに由来する原薬のシード継代培養、産生、一次回収・捕集、及び精密精製から得られたABT−308モノクローナル抗体の溶液である。
USP/EP/JP標準に準拠する精製水を使用し、GMP Solution Recordsに従って溶液を調製する。調合培地溶液を0.1μmフィルターで濾過し、予め滅菌した適当な寸法の容器、バッグ又はバイオリアクターに捕集する。使用後に0.1μnmフィルターの完全性を試験する。増殖培地と産生培地の組成を表2に示す。
スピナーフラスコとバイオウェーブバッグの操作を利用してCHO細胞をMCBの凍結バイアル1本から110Lシードバイオリアクターの接種に望ましいバイオマスまで増殖させる。マスターセルバンクの凍結バイアルを解凍し、増殖培地(SR−512)に加え、遠心する。細胞を増殖培地に再懸濁し、容積を増加させながら使い捨てスピナーフラスコ又はバイオウェーブバッグで37℃、5% CO2にて増殖させる。20Lウェーブバッグ2個を使用し、シードバイオリアクターに接種する前に20Lウェーブバッグ2個を使用して最終細胞塊増殖を最大にする。両方の20Lウェーブバッグからの細胞密度が約15〜17日目に生存細胞≧2.0×106個/mLに達したら、更に増殖させるために、増殖培地SR−520を充填した110シードバイオリアクターに培養液を移す。接種後、目標温度を37℃とし、pHを7.1の目標値に設定し、NaOH添加とCO2スパージングにより制御する。空気と酸素のスパージングによりバイオリアクター内の溶存酸素(DO)を40%の目標値に制御する。約2〜4日後に細胞密度が生存細胞≧2.6×106個/mLに達したら、培養液を3000L産生用バイオリアクターに移す。
3000L産生用バイオリアクターの部分フィルを使用して細胞培養液を更に増殖させる。先ず、リアクターに増殖培地(SR−520)を仕込み、110Lシードバイオリアクターからのバッチを接種する。
産生培地SR−521(1950L)を3000Lバイオリアクター内の細胞培養液に加え、産生段階を開始する。消泡剤Cを加えて発泡を抑える。CO2スパージングとNaOH添加のオンオフにより培養pHを6.9の目標値に制御する。温度と溶存酸素を夫々35℃と40%の目標値に制御する。バイオリアクター内のDOは先ず空気スパージングにより所望値に制御した後、必要に応じて純水素を補充する。生存細胞密度が≧3.0×106個/mLに達したら、温度を33℃の目標値まで下げ、pHとDOを夫々6.9と40%の目標値に維持する。必要に応じてグルコース(SR−334)を加える。細胞生存率が≦50%まで低下したら、培養液を回収する。
工程性能及びインプロセス試験結果を表3及び表4に示す。
一次回収・捕集操作は、濾過による回収液の清澄化、プロテインAアフィニティークロマトグラフィーによる抗体の捕集、及び低pHウイルス不活性化と、その後の深層濾過を含む。精密精製操作はアニオン交換クロマトグラフィー、疎水性相互作用クロマトグラフィー、ウイルス濾過、限外濾過/透析濾過、並びに最終濾過、ボトリング及び凍結を含む。
USP精製水(USP−PW)又は注射用水(WFI)を使用し、GMP Solution Recordsに従って溶液を調製する。大半の溶液を0.2μmフィルターで濾過し、放射線照射済みバッグ、オートクレーブ滅菌済み又は現場蒸気処理済み容器に捕集する。
濾過による一次回収の目的は、産生用バイオリアクター回収液から細胞及び細胞破片を除去することである。未処理回収液をデプスフィルター、デリピッドデプスフィルター及びメンブレンフィルターから構成されるフィルター列に通す。清澄化上清を回収液槽に捕集し、2〜8℃に維持する。清澄化した回収液のインプロセス制御はPoros AクロマトグラフィーによるABT−308濃縮、バイオバーデン及び内毒素試験を含む。
プロテインAアフィニティークロマトグラフィーの目的は、清澄化した回収液からABT−308を捕集し、工程関連不純物を低減することである。回収液全体を処理するために典型的には3クロマトグラフィーサイクルを実施する。後続処理のために3サイクルからの生成物プールを集める。
低pHインキュベーションは、プロテインA溶出液中に存在する可能性のある外来エンベロープウイルスの不活性化によりウイルス安全性を更に確実にする専用ウイルス低減工程である。低pHインキュベーション後の濾過の目的は低pH処理中に形成される可能性のある沈殿を除去することである。
一次回収・捕集操作の工程性能を表5に示し、インプロセス制御の結果を表6に示す。
強アニオン交換クロマトグラフィー工程の目的は、宿主細胞蛋白質、DNA及び内毒素等の工程関連不純物を低減することである。この工程は、ウイルス除去工程も兼用できる。ある実施形態では、抗体がカラムを通過し、不純物が樹脂に保持されるフロースルーモードでQ Sepharose(登録商標)FF樹脂カラムを操作し、代替態様では、Q Sepharose FF樹脂カラムの代わりにMustang Q(登録商標)メンブレン(Pall Corp.)を利用する。操作は10〜14℃で実施する。
Phenyl Sepharose(登録商標)工程の目的は、ABT−308凝集物、フラグメント及び工程関連不純物を除去することである。操作は10〜14℃で実施する。
ナノ濾過は、Phenyl Sepharose(登録商標)HPカラム溶出液中に存在する可能性のある直径≧20nmの外来ウイルスの物理的除去によりウイルス安全性を更に確実にする専用ウイルス除去工程である。操作は10〜14℃で実施する。
UF/DF工程の目的は、原薬を最終製剤化バッファーである15mMヒスチジン,pH5.6で透析濾過し、ABT−308を濃縮することである。これらの操作は10〜14℃で実施する。
濾過・ボトリング操作は、クラス100層流フード下にクラス100領域で2〜8℃にて実施する。製剤化したABT−308を0.2μmフィルターで濾過し、予め滅菌したパイロジェンフリーPETGボトルに捕集する。ラベルを付けたボトルを凍結するまで空の−80℃(公称値)冷凍庫に入れた後、−80℃(公称値)に維持した保存用冷凍庫に移す。最終濾過・ボトリング工程のインプロセス制御はA280、バイオバーデン及び内毒素試験(原薬試験結果)を含む。
一次回収・捕集操作の工程性能を表7に示し、インプロセス制御結果を表8に示す。
この工程は、抗体サンプル中の残留宿主細胞蛋白質濃度の測定試験方法に関する。酵素免疫測定法(ELISA)を使用して宿主細胞蛋白質(抗原)を2層の特異的抗体の間にサンドイッチする。その後、非特異的部位をカゼインでブロックする。次に宿主細胞蛋白質をインキュベートすると、この間に抗原分子は第1の抗体(コーティング抗体)により捕集される。次に抗原(宿主細胞蛋白質)と結合する第2の抗体(ビオチン化抗宿主細胞蛋白質)を加える。ビオチン化抗宿主細胞蛋白質と結合するニュートラアビジンHRP−コンジュゲートを加える。次にK−Blue基質を加える。発色基質は結合した酵素共役抗体により加水分解され、青色を発色する。2M H3PO4で反応を停止すると、黄色に変色する。色強度はウェル内で結合した抗原の量に正比例する。
このELISAでは、プレートをニワトリ抗プロテインAでコーティングし、インキュベートする。非特異的部位をPBS中カゼインでブロックする。プレートを1×PBS+0.1%トリトンX−100で洗浄し、未結合材料を除去する。サンプルとCys−プロテインA標準を1×PBS+4.1%トリトンX+10%カゼインで希釈する。95℃±2℃に加熱することにより溶液を変性させ、プロテインAを抗体から分離する。ある実施形態において、例えば(GE Healthcare)を使用する場合には、溶液をプレートに加え、インキュベートする。代替態様において、例えば、プロテインAアフィニティー工程がProSep Ultra Plus(登録商標)(Milipore)を使用する場合には、溶液を冷却し、0.85% NaCl+12.5% 1N酢酸+0.1% Tween 20を各チューブに加え(1:1)、サンプル蛋白質からプロテインAを更に分離し易くする。チューブを激しくボルテックスし、インキュベートし、遠心する。上清を取り出し、更に処理する。未結合材料を1×PBS+0.1%トリトンX−I00で洗い流す。ビオチン化ニワトリ抗プロテインAをマイクロタイタープレートに加え、インキュベートする。プレートを洗浄して未結合材料を除去し、ニュートラアビジン−ペルオキシダーゼコンジュゲートを加える。
Claims (23)
- 抗IL−13抗体又はその抗原結合フラグメントと少なくとも1種の宿主細胞蛋白質(HCP)を含有するサンプル混合物からHCP低減抗IL−13抗体又はその抗原結合フラグメント調製物を生成する方法であって、前記方法が、
(a)前記サンプル混合物をアフィニティークロマトグラフィー樹脂と接触させ、アフィニティークロマトグラフィーサンプルを捕集する工程と;
(c)前記アフィニティークロマトグラフィーサンプルをpH低下に供し、pHを約3〜約4低下させ、pH低下サンプルを形成する工程と;
(d)前記pH低下サンプルを約4.5〜約6.5のpHに調整し、前記pH調整サンプルをイオン交換樹脂と接触させ、イオン交換サンプルを捕集する工程と;
(e)前記イオン交換サンプルを疎水性相互作用クロマトグラフィー(HIC)樹脂と接触させ、前記HCP低減抗体調製物を含有するHICサンプルを捕集する工程
を含む、前記方法。 - 前記pH低下が適切な酸を前記サンプル混合物と混合することにより実施され、前記適切な酸がクエン酸、酢酸、カプリル酸等から構成される群から選択される、請求項1に記載の方法。
- 前記アフィニティークロマトグラフィー樹脂が、プロテインA樹脂である、請求項1に記載の方法。
- 前記プロテインA樹脂が、MabSelect(登録商標)樹脂である、請求項3に記載の方法。
- 前記イオン交換樹脂が、アニオン交換樹脂又はカチオン交換樹脂である、請求項1に記載の方法。
- 前記イオン交換樹脂が、カチオン交換樹脂である、請求項5に記載の方法。
- 前記カチオン交換樹脂が、Fractogel、カルボキシメチル(CM)、スルホエチル(SE)、スルホプロピル(SP)、リン酸(P)及びスルホン酸(S)から構成される群から選択される、請求項6に記載の方法。
- 前記カチオン交換樹脂が、Fractogel(登録商標)SO3 −である、請求項7に記載の方法。
- 前記イオン交換樹脂が、アニオン交換樹脂である、請求項5に記載の方法。
- 前記アニオン交換樹脂が、Qセファロース、ジエチルアミノエチル(DEAE)、第四級アミノエチル(QAE)及び第四級アミン(Q)基から構成される群から選択される、請求項9に記載の方法。
- 前記アニオン交換樹脂が、Qセファロースである、請求項11に記載の方法。
- 前記イオン交換工程が、第1イオン交換工程と第2イオン交換工程を含む、請求項1に記載の方法。
- 前記HICが、1種以上の疎水基を含むカラムを使用して実施される、請求項1に記載の方法。
- 前記1種以上の疎水基が、アルキル基、アリール基及びその組合せから構成される群から選択される、請求項13に記載の方法。
- 前記カラムが、フェニルセファロース(例えばPhenyl Sepharose(登録商標)6ファストフローカラム、Phenyl Sepharose(登録商標)高性能カラム)、Octyl Sepharose(登録商標)高性能カラム、Fractogel(登録商標)EMDプロピル、Fractogel(登録商標)EMDフェニルカラム、Macro−Prep(登録商標)メチル、Macro−Prep(登録商標)t−ブチル担体、WP HI−Propyl(C3)(登録商標)カラム、及びToyopearl(登録商標)エーテル、フェニル又はブチルカラムから構成される群から選択される、請求項14に記載の方法。
- 前記カラムが、フェニルセファロースを含む、請求項15に記載の方法。
- 更に濾過工程を含み、前記HICサンプルを濾過に供してウイルス粒子を除去し、バッファー交換を容易にする、請求項1に記載の方法。
- 前記抗IL−13抗体又はその抗原結合部分が、ヒト化抗体、キメラ抗体又は多価抗体である、請求項11に記載の方法。
- 前記抗IL−13抗体又はその抗原結合部分が、ヒト化抗体である、請求項18に記載の方法。
- 前記調製物が、HCPを実質的に含まない、請求項1に記載の方法。
- 更に深層濾過工程を含む、請求項1に記載の方法。
- 請求項1に記載の方法により生成されたHCP低減抗体調製物と医薬的に許容可能な担体を含有する、医薬組成物。
- 前記組成物が、HCPを実質的に含まない、請求項22に記載の医薬組成物。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20160052724A (ko) * | 2013-09-13 | 2016-05-12 | 제넨테크, 인크. | 정제된 재조합 폴리펩티드를 포함하는 방법 및 조성물 |
JP2016519145A (ja) * | 2013-05-15 | 2016-06-30 | メディミューン リミテッド | 組換え産生ポリペプチドの精製 |
JP2016531304A (ja) * | 2013-09-13 | 2016-10-06 | ジェネンテック, インコーポレイテッド | 細胞株中の宿主細胞タンパク質及び組換えポリペプチド産物を検出及び定量化するための組成物並びに方法 |
JP2018533355A (ja) * | 2015-08-20 | 2018-11-15 | ジェネンテック, インコーポレイテッド | Fkpaの精製、及び組換えポリペプチドの産生のためのその使用 |
WO2020022363A1 (ja) * | 2018-07-25 | 2020-01-30 | 第一三共株式会社 | 抗体-薬物コンジュゲートの効果的な製造方法 |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200944231A (en) * | 2007-11-30 | 2009-11-01 | Glaxo Group Ltd | Antigen-binding constructs |
CA2932207A1 (en) * | 2008-10-20 | 2010-12-09 | Abbvie Inc. | Isolation and purification of antibodies using protein a affinity chromatography |
JP5856845B2 (ja) | 2008-10-20 | 2016-02-10 | アッヴィ・インコーポレイテッド | 抗体精製中におけるウイルスの不活性化 |
RS60577B1 (sr) | 2009-10-20 | 2020-08-31 | Abbvie Inc | Izolacija i prečišćavanje anti-il-13 antitela upotrebom protein a afinitetne hromatografije |
JP2013535683A (ja) | 2010-07-30 | 2013-09-12 | イー・エム・デイー・ミリポア・コーポレイシヨン | クロマトグラフィー媒体及び方法 |
EP3235508B1 (en) | 2011-03-16 | 2020-12-30 | Sanofi | Compositions comprising a dual v region antibody-like protein |
EP2820149A1 (en) * | 2012-02-27 | 2015-01-07 | Biogen Idec MA Inc. | High-throughput method for sialic acid quantitation |
EP2970378B1 (en) | 2013-03-15 | 2021-05-26 | Biogen MA Inc. | Hydrophobic interaction protein chromatography under no-salt conditions |
TWI596107B (zh) | 2013-06-25 | 2017-08-21 | 卡地拉保健有限公司 | 單株抗體之新穎純化方法 |
EP3019262A1 (en) | 2013-07-12 | 2016-05-18 | Merck Patent GmbH | Removal of fragments from a sample containing a target protein using activated carbon |
EP3048109A4 (en) * | 2013-09-17 | 2017-04-19 | Kaneka Corporation | Novel antibody purification method and antibody obtained therefrom, and novel antibody purification method using cation exchanger and antibody obtained therefrom |
CN105017418B (zh) * | 2014-03-27 | 2021-02-23 | 上海药明康德新药开发有限公司 | 单克隆抗体纯化工艺方法 |
FR3025515B1 (fr) | 2014-09-05 | 2016-09-09 | Lab Francais Du Fractionnement | Procede de purification d'un anticorps monoclonal |
TW201628649A (zh) | 2014-10-09 | 2016-08-16 | 再生元醫藥公司 | 減少醫藥調配物中微可見顆粒之方法 |
JP6665184B2 (ja) * | 2014-12-08 | 2020-03-13 | イー・エム・デイー・ミリポア・コーポレイシヨン | 混床イオン交換吸着剤 |
SG10202101105XA (en) | 2015-08-13 | 2021-03-30 | Amgen Inc | Charged depth filtration of antigen-binding proteins |
EP3448391A4 (en) | 2016-04-27 | 2019-12-18 | AbbVie Inc. | METHODS OF TREATING DISEASES IN WHICH IL-13 ACTIVITY IS HARMFUL WITH ANTI-IL-13 ANTIBODIES |
KR102369014B1 (ko) | 2016-08-16 | 2022-03-02 | 리제너론 파아마슈티컬스, 인크. | 혼합물로부터 개별 항체들을 정량하는 방법 |
PL3532838T3 (pl) | 2016-10-25 | 2022-10-03 | Regeneron Pharmaceuticals, Inc. | Metody i systemy analizy danych chromatograficznych |
US20180164221A1 (en) | 2016-12-07 | 2018-06-14 | Progenity Inc. | Gastrointestinal tract detection methods, devices and systems |
WO2018183932A1 (en) | 2017-03-30 | 2018-10-04 | Progenity Inc. | Treatment of a disease of the gastrointestinal tract with a il-13 inhibitor |
TWI679209B (zh) * | 2017-04-14 | 2019-12-11 | 南韓商Cj醫藥健康股份有限公司 | 使用陽離子交換層析法純化同功抗體之方法 |
DK3668985T3 (da) * | 2017-08-17 | 2021-09-20 | Just Evotec Biologics Inc | Fremgangsmåde til rensning af glycosyleret protein fra værtscellegalectiner og andre urenheder |
TW202005694A (zh) | 2018-07-02 | 2020-02-01 | 美商里珍納龍藥品有限公司 | 自混合物製備多肽之系統及方法 |
CN110818789B (zh) * | 2018-08-07 | 2023-02-28 | 三生国健药业(上海)股份有限公司 | 一种高纯度食蟹猴白细胞介素17a的纯化方法 |
CN116726361A (zh) | 2018-11-19 | 2023-09-12 | 比奥拉治疗股份有限公司 | 用生物治疗剂治疗疾病的方法和装置 |
US20220306727A1 (en) * | 2019-06-05 | 2022-09-29 | Seagen Inc. | Methods of Purifying Masked Antibodies |
BR112022000847A2 (pt) * | 2019-08-01 | 2022-05-31 | Regeneron Pharma | Método para inativação viral |
BR112021025769A2 (pt) | 2019-12-06 | 2022-04-12 | Regeneron Pharma | Composições de proteína anti-vegf e métodos para a produção das mesmas |
WO2021119482A1 (en) | 2019-12-13 | 2021-06-17 | Progenity, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
BR112022013624A2 (pt) * | 2020-01-17 | 2022-09-13 | Regeneron Pharma | Cromatografia de interação hidrofóbica para depuração viral |
CN112326966A (zh) * | 2020-11-02 | 2021-02-05 | 杭州昱鼎生物科技有限公司 | 一种新型冠状病毒抗原的快速检测试剂盒及其制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09509658A (ja) * | 1994-02-22 | 1997-09-30 | スミスクライン・ビーチャム・コーポレイション | 抗体の精製 |
WO2009017491A1 (en) * | 2006-06-14 | 2009-02-05 | Smithkline Beecham Corporation | Methods for purifying antibodies using ceramic hydroxyapatite |
JP2009523154A (ja) * | 2006-01-11 | 2009-06-18 | グラクソ グループ リミテッド | キメラおよびヒト化抗ヒトil−13抗体 |
JP2009532474A (ja) * | 2006-04-05 | 2009-09-10 | アボツト・バイオテクノロジー・リミテツド | 抗体精製 |
Family Cites Families (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE266710C (ja) | ||||
USRE30985E (en) | 1978-01-01 | 1982-06-29 | Serum-free cell culture media | |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4510245A (en) | 1982-11-18 | 1985-04-09 | Chiron Corporation | Adenovirus promoter system |
US4560655A (en) | 1982-12-16 | 1985-12-24 | Immunex Corporation | Serum-free cell culture medium and process for making same |
US4657866A (en) | 1982-12-21 | 1987-04-14 | Sudhir Kumar | Serum-free, synthetic, completely chemically defined tissue culture media |
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4534972A (en) | 1983-03-29 | 1985-08-13 | Miles Laboratories, Inc. | Protein compositions substantially free from infectious agents |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
DD266710A3 (de) | 1983-06-06 | 1989-04-12 | Ve Forschungszentrum Biotechnologie | Verfahren zur biotechnischen Herstellung van alkalischer Phosphatase |
US4767704A (en) | 1983-10-07 | 1988-08-30 | Columbia University In The City Of New York | Protein-free culture medium |
EP0154316B1 (en) | 1984-03-06 | 1989-09-13 | Takeda Chemical Industries, Ltd. | Chemically modified lymphokine and production thereof |
US4879231A (en) | 1984-10-30 | 1989-11-07 | Phillips Petroleum Company | Transformation of yeasts of the genus pichia |
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
GB8516415D0 (en) | 1985-06-28 | 1985-07-31 | Celltech Ltd | Culture of animal cells |
US4968615A (en) | 1985-12-18 | 1990-11-06 | Ciba-Geigy Corporation | Deoxyribonucleic acid segment from a virus |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4927762A (en) | 1986-04-01 | 1990-05-22 | Cell Enterprises, Inc. | Cell culture medium with antioxidant |
GB8610600D0 (en) | 1986-04-30 | 1986-06-04 | Novo Industri As | Transformation of trichoderma |
US5476996A (en) | 1988-06-14 | 1995-12-19 | Lidak Pharmaceuticals | Human immune system in non-human animal |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
DE68925971T2 (de) | 1988-09-23 | 1996-09-05 | Cetus Oncology Corp | Zellenzuchtmedium für erhöhtes zellenwachstum, zur erhöhung der langlebigkeit und expression der produkte |
DE68925966T2 (de) | 1988-12-22 | 1996-08-29 | Kirin Amgen Inc | Chemisch modifizierte granulocytenkolonie erregender faktor |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
EP0402226A1 (en) | 1989-06-06 | 1990-12-12 | Institut National De La Recherche Agronomique | Transformation vectors for yeast yarrowia |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
DK0585287T3 (da) | 1990-07-10 | 2000-04-17 | Cambridge Antibody Tech | Fremgangsmåde til fremstilling af specifikke bindingsparelementer |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
US5122469A (en) | 1990-10-03 | 1992-06-16 | Genentech, Inc. | Method for culturing Chinese hamster ovary cells to improve production of recombinant proteins |
ES2113940T3 (es) | 1990-12-03 | 1998-05-16 | Genentech Inc | Metodo de enriquecimiento para variantes de proteinas con propiedades de union alteradas. |
DE4041205A1 (de) | 1990-12-21 | 1992-06-25 | Schloemann Siemag Ag | Verfahren und anlage zum auswalzen von warmbreitband aus stranggegossenen duennbrammen |
DE69233697T2 (de) | 1991-03-01 | 2008-01-24 | Dyax Corp., Cambridge | Verfahren zur Entwicklung von bindenden Mikroproteinen |
DE69233750D1 (de) | 1991-04-10 | 2009-01-02 | Scripps Research Inst | Bibliotheken heterodimerer Rezeptoren mittels Phagemiden |
DE4122599C2 (de) | 1991-07-08 | 1993-11-11 | Deutsches Krebsforsch | Phagemid zum Screenen von Antikörpern |
US5457178A (en) * | 1993-07-07 | 1995-10-10 | Fmc Corporation | Insecticidally effective spider toxin |
WO1997002023A1 (en) * | 1995-06-30 | 1997-01-23 | Smithkline Beecham Corporation | USE OF Stat 6 SH2 DOMAIN SPECIFIC COMPOUNDS TO TREAT ALLERGIC REACTIONS |
US6090382A (en) | 1996-02-09 | 2000-07-18 | Basf Aktiengesellschaft | Human antibodies that bind human TNFα |
US6955917B2 (en) * | 1997-06-20 | 2005-10-18 | Bayer Healthcare Llc | Chromatographic method for high yield purification and viral inactivation of antibodies |
US6914128B1 (en) | 1999-03-25 | 2005-07-05 | Abbott Gmbh & Co. Kg | Human antibodies that bind human IL-12 and methods for producing |
CA2508763C (en) | 2001-05-11 | 2012-01-24 | Kirin Beer Kabushiki Kaisha | Human antibody producing mouse and method for producing human antibody using the same |
US7646782B1 (en) | 2001-07-30 | 2010-01-12 | Primrose Donald R | Data link/physical layer packet buffering and flushing |
CN1856324A (zh) * | 2002-09-17 | 2006-11-01 | Gtc生物治疗学公司 | 缺乏重链间二硫键的免疫球蛋白分子的分离 |
GB0304576D0 (en) * | 2003-02-28 | 2003-04-02 | Lonza Biologics Plc | Protein a chromatography |
EP1601697B1 (en) * | 2003-02-28 | 2007-05-30 | Lonza Biologics plc | Antibody purification by Protein A and ion exchange chromatography |
EP1678208B1 (en) * | 2003-10-27 | 2013-05-15 | Wyeth LLC | Removal of high molecular weight aggregates using hydroxyapatite chromatography |
DE102004027816A1 (de) * | 2004-06-08 | 2006-01-05 | Bioceuticals Arzneimittel Ag | Verfahren zur Reinigung von Erythropoietin |
AR049390A1 (es) * | 2004-06-09 | 2006-07-26 | Wyeth Corp | Anticuerpos contra la interleuquina-13 humana y usos de los mismos |
TWI307630B (en) * | 2004-07-01 | 2009-03-21 | Glaxo Group Ltd | Immunoglobulins |
KR101363777B1 (ko) | 2005-09-30 | 2014-02-14 | 메디뮨 리미티드 | 인터루킨―13 항체 조성물 |
SI2007883T1 (sl) * | 2006-04-20 | 2012-02-29 | Wyeth Llc | Procesi äśiĺ äśenja za osamitev preäśiĺ äśenega virusa vezikularnega stomatitisa iz celiäśne kulture |
ES2902063T3 (es) * | 2006-09-08 | 2022-03-24 | Abbvie Bahamas Ltd | Proteínas de unión a interleucina-13 |
JP5856845B2 (ja) | 2008-10-20 | 2016-02-10 | アッヴィ・インコーポレイテッド | 抗体精製中におけるウイルスの不活性化 |
US20120141497A1 (en) * | 2009-03-11 | 2012-06-07 | Wyeth Llc | Methods of purifying small modular immunopharmaceutical proteins |
RS60577B1 (sr) | 2009-10-20 | 2020-08-31 | Abbvie Inc | Izolacija i prečišćavanje anti-il-13 antitela upotrebom protein a afinitetne hromatografije |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09509658A (ja) * | 1994-02-22 | 1997-09-30 | スミスクライン・ビーチャム・コーポレイション | 抗体の精製 |
JP2009523154A (ja) * | 2006-01-11 | 2009-06-18 | グラクソ グループ リミテッド | キメラおよびヒト化抗ヒトil−13抗体 |
JP2009532474A (ja) * | 2006-04-05 | 2009-09-10 | アボツト・バイオテクノロジー・リミテツド | 抗体精製 |
WO2009017491A1 (en) * | 2006-06-14 | 2009-02-05 | Smithkline Beecham Corporation | Methods for purifying antibodies using ceramic hydroxyapatite |
Non-Patent Citations (5)
Title |
---|
JPN6014013838; Journal of Chromatography A Vol.1176, 2007, pp.149-156 * |
JPN6015001469; Journal of Chromatography A Vol.661, 1994, pp.13-23 * |
JPN6015001471; Biotechnology and Bioengineering Vol.99, No.3, 2008, pp.599-613 * |
JPN6015001472; Journal of Chromatography B Vol.848, 2007, pp.151-158 * |
JPN6015001477; Journal of Immunological Methods Vol.124, 1989, pp.143-156 * |
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