JP2021500367A - 操作された細胞外小胞の親和性精製 - Google Patents
操作された細胞外小胞の親和性精製 Download PDFInfo
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Abstract
Description
エキソソームポリペプチド−Fc結合ポリペプチド−Fc結合ポリペプチド
エキソソームポリペプチドドメイン−Fc結合ポリペプチド−エキソソームポリペプチドドメイン−Fc結合ポリペプチド
エキソソームポリペプチドドメイン−Fc結合ポリペプチドA−エキソソームポリペプチドドメイン−Fc結合ポリペプチドB
−EV産生細胞によるEVの細胞培養培地への分泌
−本発明のプロセス及び方法を用いたEVの親和性精製
−薬物負荷(例えば、EVの表面への抗体の負荷)
−本発明のプロセス及び方法を用いたEVの親和性精製
構築物設計及びクローニング:少なくとも1つのエキソソームポリペプチド及び少なくとも1つのFc結合ポリペプチドを含む種々の融合タンパク質が構築され、ベクターにクローニングされ、いくつかの異なるEV産生細胞供給源において産生されている。ORFは、典型的には、合成によって生成され、哺乳動物発現ベクターpSF−CAG−Ampにクローニングされた。簡単に述べると、合成したDNA及びベクタープラスミドを、製造業者の説明書(NEB)に従って、酵素Notl及びSailで消化した。制限され、精製されたDNA断片を、製造業者の説明書(NEB)に従って、T4リガーゼを用いて一緒に連結した。成功したライゲーション事象を、アンピシリン補充プレート上での細菌形質転換によって選択した。
実験設計及びアッセイに依存して、ある場合には、非ウイルス一過性トランスフェクション及びエキソソーム産生を、従来の2D細胞培養において実施し、一方、他の場合には、ウイルス媒介形質導入を使用して、安定な細胞株を作製し、これは典型的には、異なるタイプのバイオリアクター中で培養した。簡潔にするために、ここでは、いくつかの例のみを挙げる。
ウエスタンブロットは、EVにおける融合タンパク質の富化を評価するための非常に便利な分析方法である。簡単に述べると、SDS−PAGEを製造業者の説明書(インビトロジェン、Novex PAGE 4〜12%ゲル)に従って実施し、これにより、1ウェルあたり1×1010エキソソーム及び20ug細胞溶解物をロードした。SDS−PAGEゲルからのタンパク質を、製造業者の説明書((Immobilon、インビトロジェン)に従ってPVDF膜に移した。膜をOdysseyブロッキング緩衝液(Licor)中でブロックし、供給者の説明書に従ってFc結合ポリペプチド及び/又はエキソソームタンパク質に対する抗体でプローブした(一次抗体−Abeam、二次抗体−Licor)。分子プローブを680及び800nmの波長で可視化した。
操作されたHEK293T細胞(タンパク質Aに融合されたTNF受容体由来の膜貫通ドメインに結合したシンテニンを安定に発現する対照対Fc結合構築物)から、300kd中空繊維カラムを用いた接線流濾過、続いて濃縮のための10kdスピンフィルターを用いた限外濾過を用いて、条件培地からEVを単離した。次いで、Fc結合EVによるIgGの結合能力を、電子顕微鏡及びフローサイトメトリーを用いて評価した。
中空繊維バイオリアクター中で増殖させた遺伝子操作されたMSCからEV含有培地を収集した。MSCは、CD63とZドメインとの間に融合ポリペプチドを含むエキソソームを分泌し、ここで、Zドメインは、CD63タンパク質の第1及び第2のループに挿入された。
限外濾過及びサイズ排除クロマトグラフィー(UF−SEC)又はIgGベースの親和性液体クロマトグラフィーを使用して、MSC(CD81−GFP又はCD81−zドメインのいずれかを安定に発現する)の条件培地からEVを単離した。Abの細胞内送達の差異を調べるために、1e10EVを2μgの抗NFkB抗体(抗NFkB−Ab)と共に室温で2時間インキュベートし、過剰のmAbを同じIgGベースの親和性精製工程を用いて洗浄除去した。EV精製ランとEV‐Ab精製ランの両者の溶出条件は、0.5M HAc、pH3〜6であったが、0.1Mグリシン−HCl、pH3.0も評価した。ZZドメインを用いた競合溶出も別々に試験した。
Claims (21)
- 少なくとも1つのFc結合ポリペプチドを含む細胞外小胞(EV)を捕捉するためのプロセスであって:
(i)前記EVを含む培地を、Fcドメインを含むクロマトグラフィーマトリックスと接触させることと、
(ii)前記EVを前記Fcドメインに吸着させることと、
を含むプロセス。 - 少なくとも1つのFc結合ポリペプチドを含むEVを単離するためのプロセスであって:
(i)前記EVを含む培地を、Fcドメインを含むクロマトグラフィーマトリックスと接触させることと、
(ii)前記EVを前記Fcドメインに吸着させることと、
(iii)前記Fcドメインから前記EVを放出する培地を前記クロマトグラフィーマトリックス全体に通過させることによって前記EVを溶出することと、
を含むプロセス。 - 前記Fcドメインが、前記クロマトグラフィーマトリックスに付着した抗体の一部である、請求項1又は2に記載のプロセス。
- 前記抗体がIgG抗体である、請求項3に記載のプロセス。
- 前記抗体が、ヒト、動物、又は合成起源のものである、請求項3又は4に記載のプロセス。
- 前記Fcドメインからの前記EVの放出が、適切なpHを有する培地の曝露によって誘発される、請求項2〜5のいずれか1項に記載のプロセス。
- 前記pHが8未満、好ましくは6未満、好ましくは4未満である、請求項6に記載のプロセス。
- 前記EVの前記少なくとも1つのFc結合ポリペプチドが融合タンパク質であり、前記融合タンパク質が少なくとも1つのエキソソームポリペプチドに融合された少なくとも1つのFc結合ポリペプチドを含み、場合により、前記少なくとも1つのエキソソームポリペプチドが、CD9、CD53、CD63、CD81、CD54、CD50、FLOT1、FLOT2、CD49d、CD71、CD133、CD138、CD235a、ALIX、ARRDC1、シンテニン−1、シンテニン−2、Lamp2b、TSPAN8、TSPAN14、CD37、CD82、CD151、CD231、CD102、NOTCH1、NOTCH2、NOTCH3、NOTCH4、DLL1、DLL4、JAG1、JAG2、CD49d/ITGA4、ITGB5、ITGB6、ITGB7、CD11a、CD11b、CD11c、CD18/ITGB2、CD41、CD49b、CD49c、CD49e、CD51、CD61、CD104、Fc受容体、インターロイキン受容体、免疫グロブリン、CD2、CD3ε、CD3ζ、CD13、CD18、CD19、CD30、CD34、CD36、CD40、CD40L、CD44、CD45、CD45RA、CD47、CD86、CD110、CD111、CD115、CD117、CD125、CD135、CD184、CD200、CD279、CD273、CD274、CD362、COL6A1、AGRN、EGFR、GAPDH、GLUR2、GLUR3、HLA−DM、HSPG2、L1CAM、LAMB1、LAMC1、LFA−1、LGALS3BP、Mac−1α、Mac−1β、MFGE8、SLIT2、STX3、TCRA、TCRB、TCRD、TCRG、VTI1A、VTI1B、他のエキソソームポリペプチド、及びそれらの任意の組み合わせを含む群から選択される、請求項1〜7のいずれか1項に記載のプロセス。
- 前記クロマトグラフィーマトリックスが、アガロース、デキストラン、レクチン、ヘパリン、セルロース、デンプン、デキストラン、寒天、アガロース、ポリ(メタ)アクリレート、ポリアクリルアミド、ポリスルホン、ポリビニルポリマー、ポリスチレン、シリカ、アルミナ、酸化ジルコニウム、酸化チタン、多糖−ミネラル構造、多糖−合成ポリマー、合成ポリマー−ミネラル構造、又はそれらの任意の組み合わせのうちの1つ以上からなる、請求項1〜8のいずれか1項に記載のプロセス。
- 前記クロマトグラフィーマトリックスが、ビーズ、繊維、不規則な形状の粒子、膜、平坦な構造又は多孔質ミネラル材料の形態である、請求項1〜9のいずれか1項に記載のプロセス。
- 前記プロセスが、前記クロマトグラフィーマトリックスを含むクロマトグラフィーカラム中で実施される、請求項1〜10のいずれか1項に記載のプロセス。
- EVに結合するためのクロマトグラフィーマトリックスの使用であって、前記クロマトグラフィーマトリックスがFcドメインを含み、前記EVが少なくとも1つのFc結合ポリペプチドを含む使用。
- 前記Fcドメインが抗体に含まれる、請求項12に記載の使用。
- 前記抗体が、ヒト、動物、又は合成起源のものである、請求項12又は13に記載の使用。
- 前記クロマトグラフィーマトリックスが、アガロース、デキストラン、レクチン、ヘパリン、セルロース、デンプン、デキストラン、寒天、アガロース、ポリ(メタ)アクリレート、ポリアクリルアミド、ポリスルホン、ポリビニルポリマー、ポリスチレン、シリカ、アルミナ、酸化ジルコニウム、酸化チタン、多糖−ミネラル構造、多糖−合成ポリマー、合成ポリマー−ミネラル構造、又はそれらの任意の組み合わせのうちの1つ以上からなる、請求項12〜14のいずれか1項に記載の使用。
- 少なくとも1つのFc結合ポリペプチドを含むEVであって、前記EVが、請求項1〜15のいずれか1項に記載のプロセスを用いた捕捉又は単離によって得ることができるEV。
- 少なくとも1つの融合タンパク質を含むEVであって、前記少なくとも1つの融合タンパク質が、少なくとも1つのエキソソームポリペプチドに融合された少なくとも1つのFc結合ポリペプチドを含むEV。
- 前記少なくとも1つのFc結合ポリペプチドが、タンパク質A、タンパク質G、タンパク質A/G、タンパク質L、タンパク質LG、Zドメイン、ZZドメイン、ヒトFCGRI、ヒトFCGR2A、ヒトFCGR2B、ヒトFCGR2C、ヒトFCGR3A、ヒトFCGR3B、ヒトFCGRB、ヒトFCAMR、ヒトFCERA、ヒトFCAR、マウスFCGRI、マウスFCGRIIB、マウスFCGRIII、マウスFCGRIV、マウスFCGRn、SPHペプチド、SPAペプチド、SPG2、SpA模倣物1、SpA模倣物2、SpA模倣物3、SpA模倣物4、SpA模倣物5、SpA模倣物6、SpA模倣物7、SpA模倣物8、SpA模倣物9、SpA模倣物10、Fey模倣物1、Fey模倣物2、及びそれらの任意の組み合わせを含む群から選択される、請求項16又は17に記載のEV。
- 前記少なくとも1つのFc結合ポリペプチド及び前記エキソソームポリペプチドを含む前記融合ポリペプチドが、pH感受性切断部位を含むリンカーをさらに含む、請求項17又は18に記載のEV。
- 前記少なくとも1つのエキソソームポリペプチドが、CD9、CD53、CD63、CD81、CD54、CD50、FLOT1、FLOT2、CD49d、CD71、CD133、CD138、CD235a、ALIX、シンテニン−1、シンテニン−2、Lamp2b、TSPAN8、TSPAN14、CD37、CD82、CD151、CD231、CD102、NOTCH1、NOTCH2、NOTCH3、NOTCH4、DLL1、DLL4、JAG1、JAG2、CD49d/ITGA4、ITGB5、ITGB6、ITGB7、CD11a、CD11b、CD11c、CD18/ITGB2、CD41、CD49b、CD49c、CD49e、CD51、CD61、CD104、Fc受容体、インターロイキン受容体、免疫グロブリン、CD2、CD3ε、CD3ζ、CD13、CD18、CD19、CD30、CD34、CD36、CD40、CD40L、CD44、CD45、CD45RA、CD47、CD86、CD110、CD111、CD115、CD117、CD125、CD135、CD184、CD200、CD279、CD273、CD274、CD362、COL6A1、AGRN、EGFR、GAPDH、GLUR2、GLUR3、HLA−DM、HSPG2、L1CAM、LAMB1、LAMC1、LFA−1、LGALS3BP、Mac−1α、Mac−1β、MFGE8、SLIT2、STX3、TCRA、TCRB、TCRD、TCRG、VTI1A、VTI1B、他のエキソソームポリペプチド、及びそれらの任意の組み合わせを含む群から選択される、請求項17〜19のいずれか1項に記載のEV。
- 前記少なくとも1つのFc結合ポリペプチドが、前記EVの外表面上に提示される、請求項16〜20のいずれか1項に記載のEV。
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PCT/EP2018/078976 WO2019081474A1 (en) | 2017-10-24 | 2018-10-23 | AFFINITY PURIFICATION OF MODIFIED EXTRACELLULAR VESICLES |
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CN108715834B (zh) * | 2018-06-01 | 2021-09-14 | 天晴干细胞股份有限公司 | 一种富含cd41+、cd81+微囊的血小板裂解液制备方法 |
JP7315243B2 (ja) * | 2018-07-31 | 2023-07-26 | 国立大学法人三重大学 | エクソソームの製造方法 |
EP3986429A4 (en) * | 2019-06-21 | 2023-07-19 | Entelexo Biotherapeutics Inc. | PLATFORMS, COMPOSITIONS AND METHODS OF DELIVERING THERAPEUTIC COMPOUNDS |
GB201917698D0 (en) * | 2019-12-04 | 2020-01-15 | Univ Ulster | A method of isolating exosomes |
US20240200141A1 (en) * | 2020-03-27 | 2024-06-20 | The Regents Of The University Of California | Covalent chemistry enables extracellular vesicle purification on nanosubstrates ? toward early detection of hepatocellular carcinoma |
KR20230172538A (ko) | 2021-04-14 | 2023-12-22 | 안자리움 바이오사이언시스 아게 | Fc-유래된 폴리펩티드 |
AU2022315530A1 (en) | 2021-07-20 | 2024-01-18 | Ags Therapeutics Sas | Extracellular vesicles from microalgae, their preparation, and uses |
CN114081960A (zh) * | 2021-11-17 | 2022-02-25 | 中国人民解放军空军军医大学 | 一种前列腺癌分子靶向系统及其构建方法和应用 |
WO2023102550A2 (en) | 2021-12-03 | 2023-06-08 | The Broad Institute, Inc. | Compositions and methods for efficient in vivo delivery |
CN114134109B (zh) * | 2021-12-10 | 2023-01-24 | 广州远想生物科技股份有限公司 | Egf间充质干细胞外泌体的纯化方法 |
WO2023144127A1 (en) | 2022-01-31 | 2023-08-03 | Ags Therapeutics Sas | Extracellular vesicles from microalgae, their biodistribution upon administration, and uses |
CN114807023B (zh) * | 2022-04-29 | 2024-03-15 | 中山大学·深圳 | 一种细胞膜囊泡及其制备方法与应用 |
WO2023232976A1 (en) | 2022-06-03 | 2023-12-07 | Ags Therapeutics Sas | Extracellular vesicles from genetically-modified microalgae containing endogenously-loaded cargo, their preparation, and uses |
WO2024088808A1 (en) | 2022-10-24 | 2024-05-02 | Ags Therapeutics Sas | Extracellular vesicles from microalgae, their biodistribution upon intranasal administration, and uses thereof |
EP4385618A1 (en) | 2022-12-16 | 2024-06-19 | Chiral Technologies Europe SAS | Composite material for bioseparations |
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CN111344012A (zh) | 2020-06-26 |
GB201717446D0 (en) | 2017-12-06 |
EP4112080A1 (en) | 2023-01-04 |
WO2019081474A1 (en) | 2019-05-02 |
EP3700566A1 (en) | 2020-09-02 |
JP7328217B2 (ja) | 2023-08-16 |
EP3700566B1 (en) | 2022-08-17 |
US11975070B2 (en) | 2024-05-07 |
CN111344012B (zh) | 2023-12-22 |
US20210188903A1 (en) | 2021-06-24 |
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