JP2017525344A - ベクター生産 - Google Patents
ベクター生産 Download PDFInfo
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- JP2017525344A JP2017525344A JP2017502253A JP2017502253A JP2017525344A JP 2017525344 A JP2017525344 A JP 2017525344A JP 2017502253 A JP2017502253 A JP 2017502253A JP 2017502253 A JP2017502253 A JP 2017502253A JP 2017525344 A JP2017525344 A JP 2017525344A
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Abstract
Description
a)本発明によるエンベロープウイルス粒子プロデューサー細胞を準備するステップ;および
b)エンベロープウイルスベクター粒子の生産に適した条件下で細胞を培養するステップ
を含む、エンベロープウイルス粒子を生産する方法を提供する。
主要組織適合複合体クラスI(MHC−I)は、細胞膜の外葉上に提示されるヘテロダイマー膜タンパク質である(Penn,D.J.(2002) Major Histocompatibility Complex(MHC) eLS,John Wiley & Sons,http://www.els.net/[DOI:10.1038/npg.els.0000919])。MHC−Iは、タンパク質のペプチド断片に結合して、それらを、それらがCD8+細胞傷害性T細胞により認識され得る細胞外環境に提示するように機能する。正常な細胞タンパク質から作成されるペプチド断片は、中枢および末梢の寛容メカニズムのために細胞傷害性T細胞を活性化しない。一方、外来ペプチド(例としてウイルスのタンパク質から生じるもの)は、その細胞を壊すために免疫応答の活性化を引き起こす。
本発明のエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞は、細胞表面上のMHC−Iの発現を減少させるように遺伝子操作されている。
ベクターは、1の環境から別の環境へと物を移行できるようにする、またはこれを容易にするツールである。本発明のウイルス粒子は、ベクターであり得る。
レトロウイルスベクターは、任意の好適なレトロウイルスに由来するもの、または由来することができるものであり得る。数多くの異なるレトロウイルスが同定されている。例としては、マウス白血病ウイルス(MLV)、ヒトT細胞白血病ウイルス(HTLV)、マウス乳房腫瘍ウイルス(MMTV)、ラウス肉腫ウイルス(RSV)、フジナミ肉腫ウイルス(FuSV)、モロニーマウス白血病ウイルス(Mo−MLV)、FBRマウス骨肉腫ウイルス(FBR MSV)、モロニーマウス肉腫ウイルス(Mo−MSV)、エーベルソンマウス白血病ウイルス(A−MLV)、トリ骨髄球しゅ症ウイルス−29(MC29)およびトリ赤芽球症ウイルス(AEV)が挙げられる。レトロウイルスの詳細なリストは、Coffin,J.M. et al.(1997) Retroviruses,Cold Spring Harbour Laboratory Press,758−63中に見出され得る。
本発明における使用のためのHIV由来ベクターは、HIV株に関してとりわけ限定されるものではない。HIV株の配列の多数の例は、HIV Sequence Database(http://www.hiv.lanl.gov/content/index)において見出され得る。
単純ヘルペスウイルス(HSV)は、天然で神経細胞に感染するエンベロープ二本鎖DNAウイルスである。HSVは外来DNAの大きな断片を収容することができ、このことはHSVをベクター系として魅力的なものとしており、HSVは神経細胞への遺伝子送達のためのベクターとして使用されている。
ワクシニアウイルスは、約190kbの直鎖状の二本鎖DNAゲノムを持つ大きなエンベロープウイルスである。ワクシニアウイルスは最大で約25kbの外来DNAを収容することができ、このこともまたワクシニアウイルスを大きな遺伝子の送達に有用なものとしている。
1の態様において、、本発明は、エンベロープウイルス粒子の生産のための、本発明のエンベロープウイルス粒子プロデューサー細胞の使用を提供する。
本発明のベクター、例としてウイルス粒子は、目的ヌクレオチド(NOI)を含み得る。
本発明のエンベロープウイルス粒子または形質導入細胞は、薬学的に許容される担体、希釈剤または賦形剤と共に、対象への投与のために製剤化され得る。好適な担体および希釈剤としては、等張食塩水溶液、例えばリン酸緩衝生理食塩水が挙げられ、潜在的にヒト血清アルブミンを含有する。
1の態様において、本発明は、治療における使用のための、例えば遺伝子治療における使用のためのエンベロープウイルス粒子および形質導入細胞を提供する。エンベロープウイルス粒子は、エンベロープウイルスベクター粒子と呼ばれることがある。
本発明との関連における予防への言及はより通例的には予防的処置に関連するものであるが、本明細書中の全ての処置への言及は、治療的、緩和的および予防的な処置を包含すると理解されるものである。哺乳類、とりわけヒトの処置が好ましい。ヒトの処置および動物の処置の両方が本発明の範囲内にある。
1の態様において、本発明は、ワクチンとしての使用のための本発明のエンベロープウイルス粒子を提供する。好ましくは、エンベロープウイルス粒子は感染性でなく、例えば細胞に感染する能力がない。
材料と方法
β2M遺伝子破壊
Cas9をコードする真核生物発現プラスミドを作成するため、ストレプトコッカス・ピオゲネス(Streptococcus pyogenes)Cas9配列のヒトコドン最適化バージョンを、XbaIおよびPmeIを用いてhCas9プラスミド(Addgene、プラスミドno.41815)から切り取った。この断片を次いで、予めXbaIおよびEcoRVで消化したpcDNA3.1プラスミド(Invitrogen)にクローニングした。
全細胞懸濁液を、FcR Blocking Reagent(Miltenyi)と共に、PEコンジュゲート抗ヒトβ2M(BioLegend、クローン2M2)およびAPCコンジュゲート汎抗ヒトMHC−I(Santa Cruz Biotechnology)を伴って、リン酸緩衝生理食塩水、0.5%ウシ血清アルブミン、エチレンジアミン四酢酸(2mM)(染色溶液)中で、4℃で20分間インキュベートした。抗体染色後、細胞を洗浄し、染色溶液中に再懸濁し、フローサイトメトリー(FACSCanto、BD Biosciences)により解析した。
ミスマッチ選択的エンドヌクレアーゼアッセイを用いて、Cas9標的部位における非相同性末端結合(NHEJ)の結果として生じる変異の程度を測定した。簡潔には、β2M遺伝子内のcrRNA部位に隣接するプライマー(Fw:5’−TACAGACAGCAAACTCACCCAGTC−3’;Rv:5’−AGAACTTGGAGAAGGGAAGTCACG−3’)を用いてPCRを行った。PCR産物を変性させ、再アニーリングさせて、Surveyorヌクレアーゼアッセイ(Transgenomic)を使用して消化した。この酵素は2本鎖の歪みの部位においてDNAを切るため、野生型と変異アレル(ヌクレアーゼ活性の結果として生じる変異または欠失を保有するもの)との間の再アニーリングの生成物が特異的に消化される。反応生成物をSpreadex EL1200 Wide Miniゲル(Elchrom Scientific)上で分離し、エチジウムブロミドにより染色し、バンドの強度をImageQuant TLソフトウェアにより定量した。2つの移動度の低い切断産物に対する未切断の親断片の比を、式(1−(親画分)1/2)×100を用いて算出した(Lombardo,A. et al.(2011) Nat.Methods 8:861−9)。
第三世代レンチウイルスベクター(LV)は、pCCLsin.cPPT.PGK.GFP.preトランスファーベクター、パッケージングプラスミドpMDLg/p.RRE、pCMV.REV、VSV−GエンベローププラスミドpMD2.Gを使用した293T細胞のリン酸カルシウム一過性トランスフェクションにより、先に記載されているように生産した(Follenzi,A. et al.(2002) Methods Mol.Med. 69:259−74)。293T細胞は、トランスフェクションの24時間前に15cmディッシュ内に播種した。トランスフェクションの2時間前、培養培地を新しい培地で置き換えた。各ディッシュについて、LVゲノムプラスミド、パッケージングプラスミドpMDLg/pRREおよびpCMV.REV、ならびにpMD2.Gの混合物を含有する溶液を、それぞれ35μg、12.5μg、6.25μgおよび9μgのプラスミドDNAを用いて調製した。0.1×TE溶液(dH2O中10mM Tris−HCl、1mM EDTA、pH8.0)および水(1:2)をDNA混合物に加えて1250μLの最終液量とした。溶液をスピニングホイール(spinning wheel)上に20〜30分間置き、次いで125μLの2.5M CaCl2を加えた。トランスフェクションの直前に、溶液をボルテックス上で撹拌し続けながら、1250μLの2×HBS(281mM NaCl、100mM HEPES、1.5mM Na2HPO4、pH7.12)を加えることにより沈殿を形成させた。沈殿をすぐに培養培地に加えて細胞上に14〜16時間置き、続いて培養培地を交換した。培地交換から30時間後に上清を回収し、0.22μmフィルター(Millipore)を通してろ過した。
10万個の293T細胞に、ポリブレン(8μg/mL)の存在下で連続的なベクター希釈物を形質導入した。GFP陽性(GFP+)細胞のパーセンテージは、フローサイトメトリーにより、形質導入の7日後に測定した。力価は形質導入単位293T(TU)/mLとして表し、以下の式を用いて算出した:
TU/mL=[(%GFP+細胞/100)×105×1/希釈係数]
ベクター粒子は、製造業者のプロトコール(NEN Life Science Products)に従って、HIV−1 Gag p24抗原の免疫捕獲により測定した。ベクターの感染力は、力価と粒子との間の比(TU/ng p24)として算出した。
統計解析は、p<0.05の有意レベルで、マン・ホイットニー検定を用いて行った。
表面に露出したMHC−I分子を欠いたレンチウイルスベクター(LV)の生産のための表面に露出したMHC−I分子を欠いた細胞株を作成するため、本発明者らは、ベータ−2−ミクログロブリン(β2M)をコードする遺伝子を恒久的に破壊することに着手した。β2Mは細胞膜上でのMHC−Iの発現のために必要とされるMHC−Iの普遍的構成成分であるため、本発明者らは、β2M遺伝子を遺伝的に不活性化することにより、MHC−Iを構成する遺伝子の各々を個別に破壊する必要なく、高度に多型である全てのMHC−I分子の表面発現を減じることを目的とした(Shiina,T. et al.(2009) J.Hum.Genet. 54:15−39;Adams,E.J. et al.(2013) Annu.Rev.Immunol. 31:529−6)。この目的のため、本発明者らはCRISPR/Cas9システム(Hsu,P.D.(2014) Cell 157:1262−78)を用いた。Cas9は、所望の位置に結合するように設計された適当なRNAガイドが提供された場合にゲノム中の予め決められた位置においてDNA二本鎖切断(DSB)を行うことができるRNAガイドヌクレアーゼである。結果として、DSBが起こる細胞は、ランダムなヌクレオチドを挿入するエラーを生じがちなメカニズムである非相同性末端結合(NHEJ)経路によりDNAを修復し、標的遺伝子のリーディングフレームをしばしば破壊する(Lombardo,A. et al.(2011) Nat.Methods 8:861−9)。本発明者らは、Cas9ヌクレアーゼをコードする1のプラスミドとβ2M遺伝子の第一エクソン中の配列と塩基対となるように設計されたガイドRNAを発現する他のプラスミドの2つのプラスミドを、一過性トランスフェクションにより、LV粒子を生産するように予め遺伝子操作されたHEK−293ベースの誘導性細胞株とLVパッケージングコンストラクトおよびゲノムコンストラクトを使用した一過性トランスフェクションによりLVを生産するために通例的に用いられるHEK−293T細胞の両方に送達した。本発明者らは、フローサイトメトリー解析により、未処理の細胞はβ2MおよびMHC−Iについて100%陽性である一方(図1Aおよび1E)、Cas9および適当なガイドRNAで処理した細胞のうち最大で44%までがβ2Mの発現を、結果として、それらの膜上のMHC−Iの発現を失う(図1Bおよび1F)ことを示した。本発明者らは次いで、蛍光活性化細胞分取(FACS)により、β2M陰性(β2M−)細胞をほぼ完全に純粋(95%)になるまで濃縮した。本発明者らは、これらの細胞は培養中に安定であり、β2MおよびMHC−Iのいずれについても陰性のままであることを示した(図1Dおよび1H)。HEK−293T細胞におけるβ2M破壊効率は最初はより低かったが(6%、図1F)、本発明者らはFACSソーティングによりβ2M−のHEK−293T細胞を容易に濃縮することができた(図1Gおよび1H)。
材料と方法
地域倫理委員会の承認(プロトコールTIGET03)およびヘルシンキ宣言に従って、インフォームドコンセントに基づいて、健常ドナーからヒト末梢血を得た。Lymphoprep(Fresenius Kabi)に対する密度勾配遠心により末梢血単核細胞(PBMC)を分離した。
製造業者の説明書に従ったPan T cell IsolationキットII(Miltenyi Biotech)を用いたネガティブセレクションによってPBMCからCD3+T細胞を精製し、凍らせた。製造業者の説明書に従ったCD14 MicroBeads(Miltenyi Biotech)を用いたポジティブセレクションによって、同じドナーからのPBMCよりCD14+単球を単離した。細胞を、10%ウシ胎仔血清(FBS)(Euroclone)、100U/mLペニシリン/ストレプトマイシン(Lonza)、2mM L−グルタミン(Lonza)を補充したRPMI1640(Corning)中で、37℃において、10ng/mL rhIL−4(R&D Systems)および100ng/mL rhGM−CSF(Genzyme)の存在下で7日間培養することでDCを分化させた。2日目の細胞に、β2M+細胞またはβ2M−細胞により生産された1μg p24/mLのレンチウイルスベクター(LV)を形質導入した。6日目の細胞を1μg/mLのLPS(Sigma)を使用してさらに1日間成熟させることで成熟DCを作成した。7日目にDCを回収し、T細胞を刺激するために用いた。
CD3+T細胞を解凍し、10% FBS(Euroclone)、100U/mLペニシリン/ストレプトマイシン(Lonza)、2mM L−グルタミン(Lonza)および20U/mL rhIL−2(Chiron)を補充したRPMI1640(Corning)中で一晩培養した。T細胞を次いで、10% FBS(Euroclone)、100U/mL ペニシリン/ストレプトマイシン(Lonza)、2mM L−グルタミン(Lonza)を補充した最終液量200μLのIMDM(Sigma)中で3日間、未形質導入のDCまたはβ2M+細胞もしくはβ2M−細胞により生産されたLVを形質導入したDC(10:1および5:1のT細胞:DC比)で刺激し、次いで1μCi/ウェル 3H−チミジンで16時間パルスした。
LVバッチ中の全タンパク質は、PIC(Protease Inhibitor Cocktail;Roche)を補充した膜タンパク質溶解バッファー(150mM Tris−HCl、150mM NaCl、5mM EDTA、1%デオキシコレート、0.1% SDS、1% Triton−X100)で抽出した。試料を溶解液中に再懸濁し、4℃で10分間インキュベートした。溶解物のタンパク質濃度をBradfordアッセイ(BioRad)を用いてアッセイした。20μgのタンパク質を還元条件下でSDS−PAGEにより解析した。イムノブロッティングのため、iBlot Gel Transferスタック(Novex)を用いてポリビニリデンジフルオリド(PVDF)膜にタンパク質を転写し、特異抗体、その後にペルオキシダーゼコンジュゲート二次抗体(ECL MouseまたはRabbit IgG;GE Healthcare)と共にインキュベートし、化学発光試薬(ECL;GE Healthcare)を用いて検出し、オートラジオグラフィーフィルムに露光した。以下の抗体を用いた:ウサギモノクローナル抗ヒトMHC−I(OriGene Technologies、TBS、Tween−20 0.1%、スキムミルク粉末5%中で1:1000)、マウスモノクローナル抗Gag p24(NIH AIDS試薬プログラム#3537、TBS、Tween−20 0.1%、スキムミルク粉末 5%中で1:1000)。
LVプロデューサー細胞の細胞膜からのレンチウイルスベクター(LV)粒子中へのMHC−Iの取り込みを検出するため、本発明者らは、β2M+またはβ2M−のプロデューサー細胞の培養上清から超遠心により回収したLVから抽出したタンパク質に対してウエスタンブロット解析を行った。
Claims (25)
- 細胞表面上のMHC−Iの発現を減少させるように遺伝子操作された、エンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- β2−ミクログロブリンをコードする遺伝子の遺伝子工学的破壊を含む、請求項1のエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- MHC−I α鎖をコードする1または複数の遺伝子の遺伝子工学的破壊を含む、請求項1または2のエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- HEK−293細胞またはその派生体である、請求項1〜3のいずれかのエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- HEK−293T細胞またはHEK−293 T−REx細胞である、請求項4のエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- エンベロープウイルス粒子が、レトロウイルス、単純ヘルペスウイルスもしくはワクシニアウイルス、ヘパドナウイルス、トガウイルス、フラビウイルス、アレナウイルス、コロナウイルス、オルソミクソウイルス、パラミクソウイルス、ブニヤウイルス、ボルナウイルス、ラブドウイルス、フィロウイルスである、またはそれらに由来する、請求項1〜5のいずれかのエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- エンベロープウイルス粒子が、レトロウイルスまたは単純ヘルペスウイルスまたはワクシニアウイルスに由来する、請求項1〜6のいずれかのエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- エンベロープウイルスベクターがレンチウイルスに由来する、請求項1〜6のいずれかのエンベロープウイルス粒子プロデューサー細胞またはパッケージング細胞。
- 請求項1から8のいずれか一項に記載のエンベロープウイルス粒子プロデューサー細胞株またはパッケージング細胞株の作製のための、細胞表面上のMHC−Iの発現を減少させるように遺伝子操作された親細胞。
- エンベロープウイルス粒子の生産のための、請求項1〜8のいずれかに記載のエンベロープウイルス粒子プロデューサー細胞の使用。
- エンベロープウイルス粒子が表面に露出したMHC−I分子を実質的に欠く、請求項10の使用。
- a)請求項1〜8のいずれかに記載のエンベロープウイルス粒子プロデューサー細胞を準備するステップ;および
b)エンベロープウイルス粒子の生産に適した条件下で細胞を培養するステップ
を含む、エンベロープウイルス粒子を生産する方法。 - 請求項12の方法により生産される、エンベロープウイルス粒子。
- 表面に露出したMHC−I分子を実質的に欠いた、エンベロープウイルス粒子。
- レトロウイルス、単純ヘルペスウイルスまたはワクシニアウイルスに由来する、請求項13または14のエンベロープウイルス粒子。
- 請求項13〜15のいずれかのエンベロープウイルス粒子が形質導入された細胞。
- 請求項13〜15のいずれかのエンベロープウイルス粒子または請求項15の細胞、および薬学的に許容される担体、希釈剤または賦形剤を含む医薬組成物。
- 治療における使用のための、請求項13〜15のいずれかのエンベロープウイルス粒子。
- ワクチン接種または遺伝子治療における使用のための、請求項18のエンベロープウイルス粒子。
- 治療における使用のための、請求項16の細胞。
- 請求項13〜15のいずれかのエンベロープウイルス粒子を細胞に形質導入することを含む、遺伝子治療の方法。
- 形質導入がエクスビボで実施される、請求項21の方法。
- 請求項13〜15のいずれかのエンベロープウイルス粒子または請求項16の細胞をその必要がある対象に投与することを含む、遺伝子治療の方法。
- ワクチンとしての使用のための、請求項13〜15のいずれかのエンベロープウイルス粒子。
- 請求項13〜15のいずれかのエンベロープウイルス粒子をその必要がある対象に投与することを含む、ワクチン接種の方法。
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US11957747B2 (en) | 2024-04-16 |
CN116218779A (zh) | 2023-06-06 |
EP3169788A1 (en) | 2017-05-24 |
CN106795500A (zh) | 2017-05-31 |
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