JP2012506385A - 抗体精製中におけるウイルスの不活性化 - Google Patents
抗体精製中におけるウイルスの不活性化 Download PDFInfo
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Abstract
Description
1.定義、
2.抗体の生成、
3.抗体の産生、
4.抗体の精製、
5.試料純度をアッセイする方法、
6.さらなる修飾、
7.医薬組成物および
8.抗体の使用
1.定義
本発明をより容易に理解するために、ある種の用語を最初に定義する。
「抗体」という用語は、このセクションで使用するとき、インタクトな抗体またはこの抗原結合フラグメントをいう。
本発明の抗体を発現させるために、遺伝子が、転写および翻訳調節配列に操作的に連結されるように、部分的または完全長軽鎖および重鎖をコードするDNAは、1つまたは複数の発現ベクターに挿入される(例えば、その全体の教示が参照により本明細書に組み込まれる、米国特許第6,914,128号明細書を参照されたい)。この文脈では、「操作的に連結される」という用語は、ベクター内の転写および翻訳調節配列が、それらが目的とする抗体遺伝子の転写および翻訳の制御機能を果たすように、抗体遺伝子がベクター中にライゲートされることを意味すると意図する。発現ベクターおよび発現調節配列は、使用される発現宿主細胞と適合するように選択される。抗体の軽鎖遺伝子および抗体の重鎖遺伝子は、別々のベクター中に挿入でき、またはより典型的には、両遺伝子は、同じ発現ベクター中に挿入される。抗体遺伝子は、標準的な方法(例えば、抗体遺伝子フラグメントおよびベクター上の相補的制限部位のライゲーション、または制限部位がなければ平滑末端のライゲーション)によって発現ベクターに挿入される。抗体または抗体関連軽鎖または重鎖配列の挿入の前に、発現ベクターは、抗体の定常領域配列を既に保有することができる。例えば、抗IL−12、抗TNFα、もしくは抗IL−18抗体または抗IL−12、抗TNFα、もしくは抗IL−18抗体関連VHおよびVL配列を、完全長抗体遺伝子に転換する1つのアプローチは、VHセグメントが、ベクター内のCHセグメント(複数可)に操作的に連結し、VLセグメントが、ベクター内のCLセグメントに操作的に連結するように、重鎖の定常および軽鎖の定常領域をそれぞれ既にコードする発現ベクター中にそれらを挿入することである。追加的または代替的には、組換え発現ベクターは、宿主細胞からの抗体鎖の分泌を促進させるシグナルペプチドをコードすることができる。シグナルペプチドが、抗体鎖遺伝子のアミノ末端にインフレームで連結されるように、抗体鎖遺伝子をベクター中にクローニングさせることができる。シグナルペプチドは、免疫グロブリンのシグナルペプチドまたは異種のシグナルペプチド(すなわち、非免疫グロブリンタンパク質由来のシグナルペプチド)であってよい。
4.1 一般的な抗体の精製
本発明は、抗体および少なくとも1つのHCPを含む混合物から精製された(または「HCP減少型」)抗体調製物を生成するための方法を提供する。本発明の精製工程は、上記の方法および当技術分野の従来の方法を用いて抗体を生成する場合、分離のステップで始まる。表1に、精製計画の1つの実施形態をまとめる。プロテインAアフィニティークロマトグラフィーステップの省略、またはイオン交換ステップの順序の逆転を含め、ただしこれらに限定されないこのスキームの諸変更は予定されており、本発明の範囲内である。
本発明の精製方法の最初のステップは、清澄化の第1相および試料マトリックスからの抗体の一次回収に関連する。さらに、一次回収工程は、試料マトリックス中に存在し得るウイルスを不活性化する時点であってもよい。例えば、その全体の教示が参照により本明細書に組み込まれる、米国特許第4,534,972号明細書のような、熱不活性化(低温殺菌)、pH不活性化、溶媒/洗剤処理、UVおよびγ線照射ならびにβ−プロピオラクトンまたは例えば銅フェナントリンなどの追加のある種の化学的不活性剤が挙げられる、任意の1つまたは複数の様々なウイルス不活性化方法を、精製の一次回収相の間に使用することができる。本発明のある種の実施形態では、試料マトリックスは、一次回収相の間にpHウイルス不活性化に供する。
ある種の実施形態では、一次回収試料は、HCPを取り除いて対象とする抗体の純度をさらに高めるためにアフィニティークロマトグラフィーに供される。ある種の実施形態では、クロマトグラフィー材料は、対象とする抗体と選択的に、または特異的に結合する能力を有する。かかるクロマトグラフィー材料の非限定的な例として、下記事項が挙げられる:プロテインA、プロテインG、対象とする抗体が結合する抗原を含むクロマトグラフィー材料およびFc結合タンパク質を含むクロマトグラフィー材料。具体的な実施形態では、アフィニティークロマトグラフィーステップは、一次回収試料を適当なプロテインA樹脂を含むカラムで処理するステップを含む。プロテインA樹脂は、様々な抗体アイソタイプ、特にIgG1、IgG2およびIgG4のアフィニティー精製および単離に有用である。プロテインAは、哺乳動物のIgGに、主にそのFc領域を介して結合するバクテリアの細胞壁タンパク質である。天然の状態では、プロテインAは、5つのIgG結合ドメインの他、未知の機能を担うその他のドメインを有する。
ある種の実施形態では、本発明は、抗体を含む溶出液が得られるように、少なくとも1つのイオン交換分離ステップに混合物を供することによって、抗体および少なくとも1つのHCPを含む混合物からHCP減少型抗体調製物を生成するための方法を提供する。イオン交換分離は、2つの基質を、それらのそれぞれのイオン電荷の差に基づいて分離する任意の方法を含み、陽イオン交換物質または陰イオン交換物質のいずれかを採用することができる。
本発明のある種の実施形態は、抗体試料をさらに精製および濃縮するために、限界濾過および/または透析濾過ステップを採用する。限界濾過は、「Microfiltration and Ultrafiltration:Principles and Applications」、L.ZemanおよびA.Zydney(Marcel Dekker社、New York、N.Y.、1996)および「Ultrafiltration Handbook」、Munir Cheryan(Technomic Publishing、1986;ISBN No.87762−456−9)に詳細に記載されている。好ましい濾過方法は、Milliporeカタログの表題「Pharmaceutical Process Filtration Catalogue」、177−202頁(ベッドフォード、Mass.、1995/96)に記載のような接線流濾過である。限界濾過とは、一般的に0.1μmより小さい孔径を有するフィルターを用いる濾過を意味すると考えられる。かかる小さい孔径を有するフィルターを採用することによって、抗体はフィルターの後に保持される一方で試料の体積が、フィルターを通る試料バッファーの透過により減少できる。
本発明は、疎水性相互作用分離ステップをさらに含み、抗体および少なくとも1つのHCPを含む混合物からHCP減少型抗体調製物を生成するための方法も特徴とする。例えば、減少したレベルのHCPを有する第2溶出液が得られるように、イオン交換カラムから得た最初の溶出液を、疎水性相互作用物質に供することができる。本明細書に記載されているものなどの疎水性相互作用クロマトグラフィーステップは、一般的に抗体凝集体などのタンパク質凝集体および工程関連不純物を除去するために行う。
ある種の実施形態では、一次回収は、産生バイオリアクターの収集物から細胞および細胞残骸(HCPを含む)を除去するために、pHの低下、遠心分離および濾過のステップを連続的に採用することによって進行することができる。例えば、限定するものではないが、抗体、培地および細胞を含む培養物は、およそ1時間、約3.5の酸性pHを用いてpH媒介ウイルス不活性化に供することができる。pHの低下は、クエン酸、例えば3Mのクエン酸などの既知の酸調製を用いて促進することができる。pH感受性ウイルス混入物を完全に排除しない場合、酸性pHへの曝露により、この混入物を減少させ、いくらかの培地/細胞混入物を沈殿させる。このウイルス減少/不活性化ステップに続いて、水酸化ナトリウム、例えば3Mの水酸化ナトリウムなどの塩基を用いて、約20から約40分間、pHを約4.9または5.0に調整する。この調整は、およそ20℃で行うことができる。ある種の実施形態では、pH調製した培養物を、次いでおよそ7000×gからおよそ11,000×gで遠心分離する。ある種の実施形態では、結果として生じる試料浮遊物を、多数の深層フィルターを含むフィルタートレインに通す。ある種の実施形態では、フィルタートレインは、およそ12個の16インチのCuno(商標)モデル30/60ZA深層フィルター(3M社)および3つの30インチの0.45/2μmのSartopore(商標)2フィルターカートリッジ(Sartorius)を装着したおよそ3回転のフィルターハウジングを含む。清澄化した浮遊物は、事前に滅菌した収集容器などの容器中に収集し、およそ8℃で維持する。この温度は次いで、捕獲クロマトグラフィーステップまたは以下に概説するステップの前に、およそ20℃に調整する。当業者は、上述の条件を変えることができ、これも本発明の範囲内であることに注目されたい。
5.1 宿主細胞タンパク質のアッセイ
本発明は、単離/精製した抗体組成物中の宿主細胞タンパク質(HCP)の残留レベルを決定するための方法も提供する。上記のように、HCPは、望ましくは最終標的物質産物、例えば抗IL−12、抗TNFα、または抗IL−18抗体から排除される。典型的なHCPは、抗体産生の源から生じるタンパク質を含む。標的抗体からHCPを同定し、十分に除去できなければ、低下した有効性および/または被験者の有害な反応を引き起こし得る。
ある種の実施形態では、本発明は、単離/精製された抗体組成物中に存在するアフィニティークロマトグラフィー材料の残留レベルを求めるための方法も提供する。特定の状況では、かかる材料は精製工程中に抗体組成物内に滲出する。ある種の実施形態では、単離/精製された抗体組成物中に存在するプロテインAの濃度を特定するためのアッセイ法が利用される。本明細書で用いる場合、用語「プロテインA ELISA」とは、当該アッセイ法で用いられる第2抗体が、対象とする抗体、例えば抗IL−12抗体、抗TNFα抗体または抗IL−18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を指す。第2抗体は当業者に既知の従来法により製造可能である。例えば、第2抗体は、抗体を産生および製造するための従来法に関連して、天然または組換えプロテインAを用いて製造可能である。
本発明の抗体は、修飾することができる。いくつかの実施形態では、抗体またはこの抗原結合フラグメントを化学的に修飾し、所望の効果をもたらす。例えば、本発明の抗体または抗体フラグメントのペグ化は、例えば、それぞれが参照によりその全体が本明細書に組み込まれる次の文献:Focus on Growth Factors3:4−10頁(1992);EP0154316およびEP0401384に記載のような、当技術分野で既知の任意のペグ化反応によって行うことができる。1つの態様では、ペグ化は、ポリエチレングリコール分子(または類似の反応性水溶性ポリマー)とのアシル化反応またはアルキル化反応によって行う。本発明の抗体および抗体フラグメントのペグ化のための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。本明細書で使用するとき、「ポリエチレングリコール」は、モノ(Cl−ClO)アルコキシまたはアリールオキシポリエチレングリコールなどの他のタンパク質を誘導体化するために使用されるPEGの任意の形態を包含することを意味する。
本発明の抗体および抗体部分は、患者への投与に適した医薬組成物中に組み込むことができる。典型的に、医薬組成物は、本発明の抗体または抗体部分および薬学的に許容される担体を含む。本明細書で使用するとき、「薬学的に許容される担体」は、生理的に適合性のある任意および全ての溶媒、分散媒、コーティング、抗菌剤および抗真菌剤、等張剤および吸収遅延剤などを含む。薬学的に許容される担体の例には、1つまたは複数の水、生理食塩水、リン酸緩衝生理食塩水、ブドウ糖、グリセロール、エタノールなどおよびこれらの組合せが挙げられる。多くの場合、組成物中に、等張剤、例えばマンニトール、ソルビトールなどの糖、多価アルコールまたは塩化ナトリウムを含むことが望ましい。薬学的に許容される担体は、抗体または抗体部分の有効期間または効果を増強させる、少量の湿潤剤または乳化剤などの補助物質、保存剤またはバッファーをさらに含むことができる。
8.1 抗IL−12抗体の一般的な使用
IL−12に結合するそれらの能力を所与とし、本発明の抗IL−12抗体またはこの部分は、酵素結合免疫吸着測定法(ELISA)、ラジオイムノアッセイ(RIA)または組織の免疫組織化学などの従来のイムノアッセイを用いて、(例えば、試料マトリックス、1つの態様では血清または血漿などの生物試料中の)IL−12、1つの態様ではhIL−12を検出するために使用することができる。本発明は、本発明の抗体または抗体部分と試料を接触させるステップおよびIL−12に結合した抗体(もしくはは抗体部分)または結合していない抗体(もしくは抗体部分)のいずれかを検出し、それによって試料中のIL−12を検出するステップを含む、生物試料中のIL−12を検出するための方法を提供する。抗体は、検出可能な物質で直接または間接的にラベル化し、結合したまたは結合していない抗体の検出を促進する。適した検出可能な物質には、様々な酵素、補欠分子族、蛍光物質、発光物質および放射性物質が挙げられる。適した酵素の例には、西洋ワサビペルオキシダーゼ、アルカリンホスファターゼ、βガラクトシダーゼまたはアセチルコリンエステラーゼが挙げられ、適した補欠分子族複合体の例には、ストレプトアビジン/ビオチンおよびアビジン/ビオチンが挙げられ、適した蛍光物質の例には、ウンベリフェロン、フルオレセン、フルオレセンイソチオシアネート、ローダミン、ジクロロトリアジニルアミンフルオレセン、ダンシルクロリドまたはフィコエリトリンが挙げられ、発光物質の例には、ルミノールが挙げられ、適した放射性物質の例には、125I、131I、35Sまたは3Hが挙げられる。試料中のIL−12の検出は、診断状況、例えば、増加したIL−12に関連する状態の診断に有用であり得、および/または抗IL−12抗体での治療から恩恵を受け得る患者を同定するのに有用であり得る。
インターロイキン12は、関節リウマチなどの炎症性疾患に役割を果たすことが関連付けられた。誘発性IL−12p40のメッセージは、関節リウマチ患者由来の滑液中に検出され、IL−12は、関節リウマチを有する患者由来の滑液中に存在することが示された(例えば、その全体の教示が参照により本明細書に組み込まれる、Moritaら(1998)Arthritis and Rheumatism 41:306−314頁を参照されたい)。IL−12陽性細胞は、関節リウマチの滑膜の下内層中に存在することが見出された。本発明のヒト抗体および抗体部分は、例えば、関節リウマチ、若年性関節リウマチ、ライム関節炎、リウマチ性脊椎炎、骨関節炎および痛風性関節炎を治療するために使用することができる。典型的に、抗体または抗体部分は、全身的に投与されるが、ある種の障害については、抗体または抗体部分の局所投与が有益であり得る。本発明の抗体または抗体部分は、自己免疫疾患の治療に有用な1つまたは複数の追加の治療剤とともに投与することもできる。
インターロイキン12は、炎症性腸疾患、すなわちクローン病にも役割を果たす。IFN−γおよびIL−12の増加した発現が、クローン病を有する患者の腸粘膜において起こる(例えば、その全体の教示が参照により本明細書に組み込まれる、Faisら(1994)J.Interferon Res.14:235−238頁;Pyrronchiら(1997)Amer.J.Pathol.150:823−832頁;Monteleoneら(1997)Gastroenterology 112:1169−1178頁;Berrebiら(1998)Amer.J.Pathol.152:667−672頁を参照されたい)。抗IL−12抗体は、大腸炎のマウスモデル、例えば、TNBS誘導型大腸炎IL−2ノックアウトマウスおよび最近ではIL−10ノックアウトマウスにおいて、疾患を抑制することが示された。したがって、本発明の抗体および抗体部分は、炎症性腸疾患の治療に使用することができる。
インターロイキン12は、多発性硬化症の主要なメディエーターとして関連付けられた。誘導性IL−12p40のメッセージまたはIL−12自体の発現は、多発性硬化症を有する患者の病変において実際に示すことができる(その全体の教示が参照により本明細書に組み込まれる、Windhagenら(1995)J.Exp.Med 182:1985−1996頁、Drulovicら(1997)J.Neurol.Sci.147:145−150頁)。多発性硬化症を有する慢性進行性の患者は、IL−12の上昇した血中濃度を有する。多発性硬化症を有する患者由来のT細胞および抗原提示細胞(APC)を用いる研究により、Th1型免疫応答を引き起こす進行性多発性硬化症の基礎として、免疫相互作用の自己永続的な一連が明らかになった。T細胞からのIFN−γの増加した分泌により、APCによるIL−12の増加した産生が引き起こされ、Th1型免疫活性化および疾患の慢性状態を引き起こす循環が永続化した(その全体の教示が参照により本明細書に組み込まれる、Balashovら(1997)Proc.Natl.Acad.Sci.94:599−603頁)。多発性硬化症におけるIL−12の役割は、マウスおよびラットの多発性硬化症の実験的アレルギー性脳脊髄炎(EAE)モデルを用いて研究した。マウスにおける多発性硬化症の再発寛解型EAEモデルにおいて、抗IL−12mAbを用いて前処理することにより、麻痺が遅延され、臨床スコアが減少した。麻痺のピークで、または続く寛解期間の間に、抗IL−12mAbで処理することにより、臨床スコアが減少した。したがって、本発明の抗体またはこの抗原結合部分は、ヒトにおいて多発性硬化症に関連する症状を緩和させる働きをし得る。
インターロイキン12は、インスリン依存性糖尿病(IDDM)の重要なメディエーターとして関連付けられた。IDDMは、IL−12の投与によってNODマウスにおいて誘発され、抗IL−12抗体は、IDDMの養子伝達モデルにおいて保護的であった。早期発症のIDDM患者は、いくつかの残りの島細胞機能が維持される、いわゆる「ハネムーン期間」をしばしば経験する。これらの残りの島細胞は、インスリンを産生し、インスリン投与より優れた血中グルコース濃度を制御する。抗IL−12抗体でこれらの早期発症患者を治療することにより、島細胞のさらなる破壊を防ぐことができ、それによってインスリンの内在性供給源が維持できる。
インターロイキン12は、乾癬における主要なメディエーターとして関連付けられた。乾癬は、TH1型サイトカイン発現プロファイルに関連する急性および慢性皮膚病変に関わる(その全体の教示が参照により本明細書に組み込まれる、Hamidら(1996)J.Allergy Clin.Immunol.1:225−231頁;Turkaら(1995)Mol.Med.1:690−699頁)。IL−12p35およびp40のmRNAは、罹患したヒトの皮膚試料中に検出された。したがって、本発明の抗体またはこの抗原結合部分は、慢性皮膚障害であるかかる乾癬を緩和させる働きをし得る。
IL−18に結合する能力を前提とし、本発明の抗IL−18抗体またはその一部は、IL−18、1つの態様ではhIL−18(例えば、試料マトリックス中の、1つの態様では血清または血漿などの生物試料)を、酵素免疫測定法(ELISA)、ラジオイムノアッセイ(RIA)または組織免疫組織化学(tissue immunohistochemistry)などの従来型の免疫測定法を用いながら検出するのに利用可能である。本発明は生物試料中のIL−18を検出する方法を提供し、この方法は、試料を本発明の抗体または抗体部分と接触させるステップ、およびIL−18に結合した抗体(もしくは抗体部分)または非結合抗体(もしくは抗体部分)のいずれかを検出するステップを含み、これにより試料中のIL−18を検出する。抗体は、結合抗体または非結合抗体の検出に役立つ検出可能物質により直接的または間接的にラベル化される。適する検出可能物質として、様々の酵素、補欠分子族、蛍光物質、発光物質および放射性物質が挙げられる。適する酵素の例として、西洋ワサビペルオキシダーゼ、アルカリンホスファターゼ、βガラクトシダーゼまたはアセチルコリンエステラーゼが挙げられ、適した補欠分子族複合体の例として、ストレプトアビジン/ビオチンおよびアビジン/ビオチンが挙げられ、適した蛍光物質の例として、ウンベリフェロン、フルオレセン、フルオレセンイソチオシアネート、ローダミン、ジクロロトリアジニルアミンフルオレセン、ダンシルクロリドまたはフィコエリトリンが挙げられ、発光物質の例として、ルミノールが挙げられ、適する放射性物質の例として、125I、131I、35Sまたは3Hが挙げられる。試料中のIL−18を検出すれば、それは診断状況、例えばIL−18の増加に関連する症状の診断に有用であり得、および/または抗IL−18抗体を用いた治療から利益を得ることができる患者を識別するのに有用であり得る。
本発明の1つの態様は、肝損傷を治療および/または予防するための新規手段を提供することである。IL−18阻害剤は、肝損傷の予防および治療に有効であることが見出された。したがって、本発明は、肝損傷の治療用および/または予防用薬剤を製造するために、IL−18阻害剤を使用することにも関連する。より具体的には、本発明は、アルコール性肝炎、ウイルス性肝炎、免疫性肝炎、劇症肝炎、肝硬変および原発性胆汁性肝硬変の治療および/または予防に関連する。
IL−18の阻害剤は関節炎の治療に有効であることも、本発明に基づき見出された。治療効果として、疾患の重症度の低減、ならびに疾患の拡大阻止が挙げられる。したがって、本発明は関節炎を治療および/または予防するためにIL−18の阻害剤を使用することに関連する。これまでに概説した最新技術からは、関節炎に関与する1つの特定因子、すなわちインターロイキンIL−18を遮断すれば、関節炎の緩和または関節炎に罹患した関節の治癒さえも引き起こすと結論付けることはできなかったので、この新知見は予想外であった。
腫瘍壊死因子−αは、脂質代謝、凝固、インスリン抵抗性および内皮機能に影響を及ぼす単球/マクロファージによって主に分泌される多機能性炎症促進性サイトカインである。TNFαは、17kDタンパク質サブユニットからなる可溶性の同種三量体である。TNFαの膜結合型26kD前駆体の形態も存在する。これは、滑膜細胞中および組織のマクロファージ中に見出される。単球またはマクロファージ以外の細胞も、TNFαを産生する。例えば、ヒト非単球腫瘍細胞系はTNFαの他、CD4+およびCD8+末梢血Tリンパ球を産生し、またいくつかの培養されたT細胞系およびB細胞系はTNFαを産生する。TNFαは関節リウマチに関与しているが、これに限定されないが、また多くの炎症性疾患において生じている。TNFαの受容体は、滑膜の他、末梢血および滑液中のいくつかの単核細胞上にある。TNFαは関節リウマチにおける重要な炎症メディエーターであり、したがって特異的免疫療法の有用な標的であり得る。
本試験の目的は、抗IL−18抗体の精製工程におけるウイルス除去の有効性を評価することであった。評価されたステップには、低pHによる不活性化、陽イオン交換捕獲クロマトグラフィー(Fractogel(商標)EMD S03−樹脂)、陰イオン交換クロマトグラフィー(Q−Sepharose(商標)FF樹脂)および疎水性相互作用クロマトグラフィー(Phenyl Sepharose(商標)HP樹脂)精密精製クロマトグラフィーが含まれる。本試験は、薬物製造期間中における直交法によるウイルス除去に関するICHガイドラインを満たしている。
本試験は図4に概説するプロトコールに従い実施された。各工程ステップは、供給流体中に濃縮されたウイルススパイクを添加実施された(ウイルススパイクボリューム1−7.1%v/v)。負荷物、生成物および保持コントロール流体は、ウイルス数について分析され、また各ステップについて対数減少係数を求めた。
ウイルス除去試験の一環として、試料およびバッファーのいずれかがアッセイで用いたウイルス細胞系に有毒であるかどうか判定するために、これらは試験された。試料とバッファーは、これらが選択したウイルスが指標細胞系に感染する能力に与える影響についても評価された。結果を関連する陽性対照と比較したときに、試験したいずれのバッファーについても、ウイルスの感染性が有意に低下するようなことは検出されなかった。この試験の結果から、精製工程で用いられたバッファーは、クロマトグラフィーおよびナノ濾過ステップのチャレンジ試験での使用を目的として、超遠心分離後のウイルス調製物の再懸濁用として承認された。
ウイルス力価を低減させる際の各工程ステップの有効性は、下記式により対数減少係数(LRF)を計算して求められた:
この手順では、抗IL−12抗体試料中の残留宿主細胞タンパク質濃度を決定するための試験方法論を記載する。酵素結合免疫吸着測定法(ELISA)を使用して、特異抗体の2つの層の間に宿主細胞タンパク質(抗原)をサンドイッチする。これに続いて、カゼインを用いて非特異的部位をブロックする。宿主細胞タンパク質を、次いで抗原分子が一次抗体に捕獲される間、インキュベートする(抗原のコーティング)。抗原(宿主細胞タンパク質)に固定する二次抗体(ビオチン化した抗宿主細胞タンパク質)を次いで添加する。ビオチン化抗宿主細胞タンパク質に結合するHRPコンジュゲート型ニュートラアビジンを添加する。これに続いてKブルーサブストレートを添加する。青色を生成する発色性基質を、結合した酵素コンジュゲート型抗体によって加水分解する。色を黄色に変える2MのH3PO4で反応を止める。色の強度は、ウェル中の結合した抗原の量に直接的に比例する。
このELISAでは、プレートはニワトリ抗プロテインAでコーティングされ、インキュベーションされた。非特異的部位は、PBS中のカゼインでブロックされる。プレートは、未結合物質を除去するために1×PBS+0.1%トリトンX−100内で洗浄される。試料およびCys−rプロテインA標準物質は1×PBS+4.1%トリトンX+10%カゼインで希釈される。当該溶液は、95℃±2℃で加熱することにより変性を受け、プロテインAをABT874から分離する。次に、溶液はプレートに添加され、インキュベーションされる。未結合物質は、1×PBS+0.1%トリトンX−100で洗浄除去される。ビオチン化されたニワトリ抗プロテインAはマイクロタイタープレートに添加され、インキュベーションされる。当該プレートは未結合物質を除去するために洗浄され、またニュートラアビジンペルオキシダーゼコンジュゲートが添加される。
Claims (31)
- (a)試料マトリックスをpHの低下に供し、そうして一次回収試料を形成するステップであり、前記pHの低下が約3から約5の間のpHであるステップ、
(b)前記一次回収試料を約4.5および6.5の間のpHに調整し、続いて前記一次回収試料をイオン交換樹脂にアプライし、イオン交換試料を収集するステップ、ならびに
(c)前記イオン交換試料を疎水性相互作用クロマトグラフィー(HIC)樹脂にアプライし、HIC試料を収集するステップであり、前記HIC試料が宿主細胞タンパク質(HCP)減少型抗体調製物を含むステップ
を含み、抗体、HCPおよびウイルス粒子を含む試料混合物から、前記試料混合物と比較して減少したウイルス粒子の数または減少したウイルス活性を含む前記HCP減少型抗体調製物を生成するための方法。 - 前記pHの減少が、適した酸と前記試料混合物とを混合することによって達成され、前記適した酸が、クエン酸、リン酸、酢酸、カプリル酸などから成る群から選択される、請求項1に記載の方法。
- 前記イオン交換樹脂が、陰イオン交換樹脂または陽イオン交換樹脂のいずれかである、請求項1に記載の方法。
- 前記イオン交換樹脂が陽イオン交換樹脂である、請求項3に記載の方法。
- 前記陽イオン交換樹脂が、カルボキシメチル(CM)、スルホエチル(SE)、スルホプロピル(SP)、Fractogel SO3 −、リン酸塩(P)およびスルホン酸塩(S)から成る群から選択される、請求項4に記載の方法。
- 前記陽イオン交換樹脂がFractogel SO3 −である、請求項5に記載の方法。
- 前記イオン交換樹脂が陰イオン交換樹脂である、請求項3に記載の方法。
- 前記陰イオン交換樹脂が、Qセファロース、ジエチルアミノエチル(DEAE)、4級アミノエチル(QAE)および4級アミン(Q)基から成る群から選択される、請求項7に記載の方法。
- 前記陰イオン交換樹脂がQセファロースである、請求項8に記載の方法。
- 前記イオン交換ステップが、第1のイオン交換ステップおよび第2のイオン交換ステップを含む、請求項1に記載の方法。
- 前記第1のイオン交換ステップが陽イオン交換ステップであり、第2の陰イオン交換ステップが続く、請求項10に記載の方法。
- 前記第1および前記第2のイオン交換ステップの間に起こる濾過ステップである中間ステップをさらに含む、請求項10に記載の方法。
- 前記濾過ステップが、捕獲限界濾過/透析濾過によって達成される、請求項12に記載の方法。
- 前記HICが、1つまたは複数の疎水基を含むカラムを用いて達成される、請求項1に記載の方法。
- 前記1つまたは複数の疎水基が、アルキル基、アリール基およびこれらの組合せから成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(商標)(Phenyl Sepharose(商標)6 Fast Flowカラム、Phenyl Sepharose(商標)High Performanceカラムなど)、Octyl Sepharose(商標)High Performanceカラム、Fractogel(商標)EMD Propyl、Fractogel(商標)EMD Phenylカラム、Macro−Prep(商標)Methyl、Macro−Prep(商標)t−Butyl Supports、WP HI−Propyl(C3)(商標)カラムおよびToyopearl(商標)エーテル、フェニルまたはブチルカラムから成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16に記載の方法。
- 前記HIC試料を濾過に供してウイルス粒子を除去し、バッファー交換を促進させる、濾過ステップをさらに含む、請求項1に記載の方法。
- 前記HCP減少型抗体調製物が、抗IL−12抗体もしくは抗IL−18抗体またはこれらの抗原結合部分を含む、請求項1に記載の方法。
- 前記抗IL−18抗体またはこの抗原結合部分が、ヒト化抗体、キメラ抗体または多価抗体である、請求項19に記載の方法。
- 前記抗IL−18抗体またはこの抗原結合部分がヒト化抗体である、請求項20に記載の方法。
- 前記抗IL−18抗体またはこの抗原結合部分が、約1×10−6から1×10−12M以下の範囲のKdでヒトIL−18から解離する単離されたヒト抗体である、請求項20に記載の方法。
- 前記抗IL−18抗体またはこの抗原結合部分が、インビボおよびインビトロの両方でIL−18を中和する、請求項19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。
- (a)試料マトリックスをpHの低下に供し、そうして一次回収試料を形成するステップであり、前記pHの低下が約3.5までであるステップ、
(b)前記一次回収試料を約5.0のpHに調整し、続いて前記一次回収試料を陽イオン交換樹脂にアプライし、陽イオン交換試料を収集するステップ、
(c)前記陽イオン交換試料を陰イオン交換樹脂にアプライし、陰イオン交換試料を収集するステップ、ならびに
(d)前記陰イオン交換試料を疎水性相互作用クロマトグラフィー(HIC)樹脂にアプライし、HIC試料を収集するステップであり、前記HIC試料が、宿主細胞タンパク質(HCP)減少型抗体調製物を含むステップ
を含む、抗体および少なくとも1つのHCPを含む試料混合物から前記HCP減少型抗体調製物を生成するための方法。 - (a)試料マトリックスをpHの低下に供し、そうして一次回収試料を形成するステップであり、前記pHの低下が約3.5までであるステップ、
(b)前記一次回収試料を約5.0のpHに調整し、続いて前記一次回収試料を陽イオン交換樹脂にアプライし、陽イオン交換試料を収集するステップ、
(c)前記陽イオン交換試料を濾過に供し、濾過物を収集するステップ、
(d)(c)からの前記濾過物を陰イオン交換樹脂にアプライし、陰イオン交換試料を収集するステップ、ならびに
(e)前記陰イオン交換試料を疎水性相互作用クロマトグラフィー(HIC)樹脂にアプライし、HIC試料を収集するステップであり、前記HIC試料が、宿主細胞タンパク質(HCP)減少型抗体調製物を含むステップ
を含む、抗体および少なくとも1つのHCPを含む試料混合物から前記HCP減少型抗体調製物を生成するための方法。 - 陽イオン交換樹脂に前記一次回収試料をアプライする前記ステップの前に、プロテインAのアフィニティークロマトグラフィーステップをさらに含む、請求項26に記載の方法。
- 請求項1に記載の方法によって生成されるHCP減少型抗体調製物および薬学的に許容される担体を含む医薬組成物。
- 前記抗体が、抗IL−12抗体もしくは抗IL−18抗体またはこれらの抗原結合部分である、請求項28に記載の医薬組成物。
- 前記組成物がHCPを実質的に含まない、請求項28に記載の医薬組成物。
- IL−12またはIL−18によって促進される障害を中和するために使用される、請求項28に記載の医薬組成物。
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WO2010048192A2 (en) | 2010-04-29 |
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JP2016193900A (ja) | 2016-11-17 |
BRPI0920572A8 (pt) | 2015-10-27 |
BRPI0920572A2 (pt) | 2015-09-29 |
MX2011004201A (es) | 2011-05-24 |
WO2010048192A3 (en) | 2010-06-24 |
TW201028433A (en) | 2010-08-01 |
AU2009307737A1 (en) | 2010-04-29 |
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JP6023140B2 (ja) | 2016-11-09 |
US20150344564A1 (en) | 2015-12-03 |
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AU2009307737B2 (en) | 2015-07-23 |
NZ592097A (en) | 2013-01-25 |
KR101722423B1 (ko) | 2017-04-18 |
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RU2551237C2 (ru) | 2015-05-20 |
CA2738499A1 (en) | 2010-04-29 |
KR20110086069A (ko) | 2011-07-27 |
US20100136025A1 (en) | 2010-06-03 |
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US9109010B2 (en) | 2015-08-18 |
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