JP2013516194A - B細胞を形質導入するためのベクターおよび方法 - Google Patents
B細胞を形質導入するためのベクターおよび方法 Download PDFInfo
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Abstract
【選択図】図1
Description
本出願は、35 U.S.C.(米国特許法)第119条(e)の下、2010年1月8日に出願され、「B細胞を形質導入するためのベクターおよび方法(VECTORS AND METHODS FOR TRANSDUCING B CELLS)」と題する米国仮特許出願第61/293,522号の利益を主張し、ここで、この米国特許出願は、参照によりその全体が本明細書に組み込まれる。
本開示は、特異的抗体などの目的のタンパク質を発現させるために、一般的に、形質導入に非常に抵抗性のある細胞集団であるB細胞の遺伝子改変、およびその細胞の分化または活性化に関する。
骨髄をそのままにしておくと、B細胞は抗原提示細胞(APC)として機能し、抗原を内在化させる。抗原は、受容体を介したエンドサイトーシスによりB細胞によって取り込まれ、プロセシングされる。抗原は抗原ペプチドにプロセシングされ、MHCII分子上にロードされ、B細胞の細胞外表面上でCD4+ヘルパーT細胞に提示される。これらのT細胞は、MHCII/抗原分子に結合し、このB細胞の活性化をもたらす。T細胞による刺激により、活性化B細胞はより特殊化した細胞に分化し始める。胚中心B細胞は、記憶B細胞または形質細胞に分化し得る。これらのB細胞の多くは形質芽細胞になり、最終的に形質細胞になり、大量の抗体を産生し始める(例えば、Trends
Immunol.2009 June;30(6):277−285;Nature Reviews,2005,5:231−242参照)。
Reviews,2005,5:231−242;Nature Med.2010,16:123−129;Neuberger,M.S.;Honjo,T.;Alt,Frederick
W.(2004).Molecular biology of B
cells.Amsterdam:Elsevier,pp.189−191;Bertil Glader;Greer,John G.;John Foerster;Rodgers,George G.;Paraskevas,Frixos(2008).Wintrobe’s Clinical Hematology,2−Vol.Set.Hagerstwon,MD:Lippincott
Williams&Wilkins.pp.347;Walport,Mark;Murphy,Kenneth;Janeway,Charles;Travers,Paul J.(2008).Janeway’s immunobiology.New York:Garland Science,pp.387−388;Rawstron AC(May 2006).“Immunophenotyping
of plasma cells”.Curr Protoc Cytomも参照されたい)。
RANKLおよびTRAIL)などの様々なサイトカインのいずれかをコードしてもよい。別の実施形態において、目的の核酸は、抗体タンパク質、またはその抗原結合断片をコードする。さらなる実施形態において、CD40Lを細胞または細胞株上に提供するか、または組織培養プレートもしくはビーズに結合させてもよい。特定の一実施形態において、このプロモーターは、B細胞特異的プロモーターである。特定の実施形態において、このB細胞は活性化され、目的のタンパク質を発現する形質細胞に分化する。
本開示の形質導入法で使用するための細胞の原型の例として、B細胞が挙げられる。
tetrameric complex system)(StemCell Technologies社、バンクーバー、カナダ)などの当該技術分野で公知の様々な抗体のいずれかを用いる負の選択または正の選択によって精製することができる。R&D Systems社のMagCellectヒトB細胞単離キット(ミネアポリス、ミネソタ州)などの他の単離キットが市販されている。
2009,113:1422−1431;Blood 2009 Oct 8;114(15):3173−80;Blood.2003;101(6):2167−2174;Current Protocols in Molecular Biology
or Current Protocols in Immunology,John Wiley&Sons,New York,N.Y.(2009)参照)。例えば、ドナーのPBMC、Bリンパ球もしくはTリンパ球およびB−CLLなどの他のB細胞癌細胞を単離し、無血清か、または10%FCSを補充するかのいずれかで、かつペニシリン/ストレプトマイシンおよび/または他の適切な補助剤を補充したRPMI 1640(GibcoBRL Invitrogen社、オークランド、ニュージーランド)または他の適切な培地で培養してもよい。特定の実施形態において、細胞を48ウェルプレートに1E5細胞で播種し、濃縮ベクターを、所定の方法を用いて、当該技術者によって日常的に最適化され得る様々な用量で加える。特定の実施形態において、B細胞を、10%AB血清、5%FCS、50ng/mlのrhSCF、10ng/mlのrhlL−15および5ng/mlのrhlL−2を補充したRPMIならびに必要であれば定期的に新しくした培地中のMS5細胞単層に移してもよい。当該技術者に認識されるように、他の適切な培地および補助剤を必要に応じて用いてもよい。
1998 92:4509−4520;Luo,et al.,Blood
2009 113:1422−1431参照)。かかる因子は、限定されないがIL−1、IL−2、IL−3、IL−4、IL−5、IL−6、IL−7、IL−8、IL−9、IL−10、IL−11、IL−12、IL−13、IL−14、IL−15、IL−16、IL−17、IL−18、IL−19、IL−20、IL−21、IL−22、IL−23、IL−24、IL−25、IL−26、IL−27、IL−28、IL−29、IL−30、IL−31、IL−32、IL−33、IL−34、IL−35、IFN−γ、IFN−α、IFN−β、IFN−ω、C型ケモカインXCL1およびXCL2、(現在までに、CCL−1〜CCL28を含む)C−C型ケモカインおよび(現在までに、CXCL1〜CXCL17を含む)CXC型ケモカイン、ならびにTNFスーパーファミリーのメンバー(例えば、TNF−α、4−1BBリガンド、B細胞活性化因子(BLyS)、FASリガンド、リンホトキシン、OX40L
RANKLおよびTRAIL)からなる群から選択されてもよい。特に、形質導入B細胞(または形質導入前のB細胞)を、支持細胞と接触させるか、または支持細胞上で培養してもよい。特定の実施形態において、これらの支持細胞は間質細胞株、例えば、マウスの間質細胞株S17またはMS5である。さらなる実施形態において、精製したCD19+細胞を、CD40−リガンドを発現する繊維芽細胞の存在下で、IL−10およびIL−4などのB細胞活性化因子サイトカインの存在下で培養してもよい。組織培養プレートまたはビーズなどの表面に結合させたCD40Lも提供してもよい。別の実施形態において、精製したCD19+細胞を、CD40Lを発現する支持細胞の存在下で、IL−10、IL−4、IL−7、CpG
DNA、IL−2、IL−15、IL6、およびIFN−αから選択される1種以上のサイトカインまたは因子の存在下で培養してもよい。
Protocols in Cell Culture,2000−2009参照)。一実施形態において、本明細書に記載の方法で使用する培地には、(ウシ胎仔血清または他の適切な血清を含むか、または含まない)イスコフ改変ダルベッコ培地が含まれるが、これに限定されない。例示的な培地には、RPMI 1640、AIM−V、DMEM、MEM、α−MEM、F−12、X−Vivo15、およびX−Vivo20も含まれるが、これらに限定されない。さらなる実施形態において、培地は、界面活性剤、抗体、プラスマネートもしくは還元剤(例えば、N−アセチルシステイン、2−メルカプトエタノール)、または1種以上の抗生物質を含んでもよい。いくつかの実施形態において、IL−6、可溶性CD40L、および架橋促進剤も用いてもよい。
J.Cell Cloning 1987;5:1−16;Loken,MR,et al.,Flow Cytometry Characterization
of Erythroid,Lymphoid and Monomyeloid Lineages in Normal
Human Bone Marrow,in Flow Cytometry in Hematology,Laerum OD,Bjerksnes R.eds.,Academic Press,New
York 1992;pp.31−42;およびLeBein TW,et
al.,Leukemia 1990;4:354−358を参照されたい。
特定の実施形態では、ウイルスベクターを用いて、本明細書に記載の発現系を有するB細胞などの形質細胞に形質導入する。ウイルスベクターの例として、アデノウイルスベースのベクター、アデノ随伴ウイルス(AAV)ベースのベクター、レトロウイルスベクター、レトロウイルス−アデノウイルスベクター、およびアンプリコンベクターを含む単純ヘルペスウイルス(HSV)由来のベクター、複製欠陥HSVおよび弱毒化HSVが挙げられるが、これらに限定されない(例えば、Krisky,Gene Ther.5:1517−30,1998;Pfeifer,Annu.Rev.Genomics Hum.Genet.2:177−211,2001参照。これらの各々は参照によりその全体が組み込まれる)。
al.,PNAS USA 95:11939−11944,1998;Miyoshi
et al.,Science 283:682−686,1999;Sutton
et al.,J Virol 72:5781−5788,1998;およびFrecha
et al.,Blood.112:4843−52,2008参照。これらの各々は参照によりその全体が組み込まれる)。
et al.,2010 Mol.Therapy 18:1748参照)。しかし、かかるアクセサリータンパク質を含むことは安全上懸念される。本明細書に記載のベクターの1つの利点は、アクセサリータンパク質を必要としないことである。したがって、特定の実施形態において、レトロウイルスベクターは、HIVゲノムまたはSIVゲノムなどのレンチウイルスゲノム由来の特定の最小配列を含む。レンチウイルスのゲノムは、一般的に、5’末端反復配列(LTR)領域、gag遺伝子、pol遺伝子、env遺伝子、アクセサリー遺伝子(例えば、nef、vif、vpr、vpu、tat、rev)、および3’LTR領域で構成されている。ウイルスのLTRは、U3、R(反復)およびU5と呼ばれる3つの領域に分けられる。U3領域はエンハンサーおよびプロモーターのエレメントを含み、U5領域はポリアデニル化シグナルを含み、R領域はU3およびU5領域を分離する。R領域の転写配列は、ウイルスRNAの5’および3’末端の両方に見られる(例えば、“RNA Viruses:A Practical Approach”(Alan J.Cann,Ed.,Oxford University Press,2000);O Narayan,J.Gen.Virology.70:1617−1639,1989;Fields et al.,Fundamental Virology
Raven Press.,1990;Miyoshi et al.,J
Virol.72:8150−7,1998;ならびに米国特許第6,013,516号参照。これらの各々は参照によりその全体が組み込まれる)。レンチウイルスベクターは、必要に応じて、ベクターの活性を調節するために、レンチウイルスゲノムのこれらのエレメントのうちの任意の1つ以上を含み得るか、またはレンチウイルスベクターは、レンチウイルス複製の病理学的作用を減少させるか、またはレンチウイルスベクターを1ラウンドだけの感染に制限するために、これらのエレメントのうちの1つ以上に欠失、挿入、置換、もしくは変異を含み得る。
Research,Vol.29,pp1672−1682,2001に提供されるテトラサイクリン応答性プロモーターが含まれ、これらの文献の各々は参照によりその全体が組み込まれる。
et al.,PNAS USA 84:4831−4835,1987参照)、pgkプロモーター(例えば、Adra
et al.,Gene 60:65−74,1987;Singer−Sam
et al.,Gene 32:409−417,1984;およびDobson
et al.,Nucleic Acids Res.10:2635−2637,1982参照。これらの各々は参照により組み込まれる)が挙げられる。組織特異的プロモーターの限定されない例として、lckプロモーター(例えば、Garvin et al.,Mol.Cell Biol.8:3058−3064,1988;およびTakadera et al.,Mol.Cell Biol.9:2173−2180,1989参照)、ミオゲニンプロモーター(Yee et al.,Genes
and Development 7:1277−1289.1993)、ならびにthy1(例えば、Gundersen et al.,Gene 113:207−214,1992参照)が挙げられる。
Spring Harbor Laboratory Press,N.Y.(1989))、Coffinら(Retroviruses.Cold Spring
harbor Laboratory Press,N.Y.(1997))および“RNA Viruses:A Practical Approach”(Alan J.Cann,Ed.,Oxford
University Press,(2000))に記載の制限エンドヌクレアーゼ消化、ライゲーション、形質転換、プラスミド精製、PCR増幅、DNAシークエンシングの標準的な技術を含むが、これらに限定されない当該技術分野で公知の任意の適切な遺伝子工学技術を用いて達成することができる。
CCL−10)およびCf2Th(ATCC CRL 1430)細胞株が含まれる。
本明細書で使用する「目的の遺伝子」または「遺伝子」または「目的の核酸」とは、標的形質導入細胞において発現する目的のタンパク質をコードする目的の核酸を指す。「遺伝子」という用語を用いてもよいが、これは、これがゲノムDNAに存在し、「核酸」という用語と同義で用いられる遺伝子であることを意味しない。一般的に、目的の核酸は、目的のタンパク質をコードするのに適する核酸を提供し、cDNAまたはDNAを含み得、イントロンを含んでも含まなくてもよいが、一般的にはイントロンを含まない。他の場所で述べたように、目的の核酸は、発現制御配列に作動可能に連結され、標的細胞において目的のタンパク質を効果的に発現する。特定の実施形態において、本明細書に記載のベクターは2つ以上の目的の遺伝子を含んでもよく、例えば、本明細書に記載の内部プロモーターを用いて組織化され得る免疫グロブリンの重鎖および軽鎖などの2、3、または4つの目的の遺伝子を含んでもよい。
299737)および重鎖(AAB26315.1 Gl 299746)の例示的な配列を、GenBank登録番号で提供する参照)。さらなる実施形態において、目的の核酸がコードする抗体は、Fuzeon(商標)(T−20/エンフビルチド/ペンタフシド(pentafuside)/DP−178)を含む。DP−178は、HIV上のgp41由来のアミノ酸配列であり、その標的細胞と融合するHIVの能力を妨げる。Fuzeonは、当該技術者に知られる方法を用いて合成することができる(例えば、2001
J.Virol.75:3038−3042参照;この論文に記載の方法は、治療用量のDP−178ペプチドの分泌をもたらした可能性はほとんどないことに留意すべきである)。
−33、IL−34、IL−35が含まれる。インターフェロンには、IFN−γ、IFN−α、IFN−βおよびIFN−ωが含まれる。本明細書で使用することが企図されるケモカインには、C型ケモカインXCL1およびXCL2、(これまでにCCL1〜CCL28を含む)C−C型ケモカインおよび(これまでにCXCL1〜CXCL17を含む)CXC型ケモカインが含まれる。TNFスーパーファミリー(例えば、TNF−α、4−1BBリガンド、B細胞活性化因子、FASリガンド、リンホトキシン、OX40L RANKL、およびTRAIL)も目的の遺伝子として企図される。
12/ICA512、150kD、およびRIN極性)を含むが、これらに限定されない多発性硬化症またはI型糖尿病の発症と関連する。これらの自己抗原に対する抗体は当該技術分野で公知であり、配列決定を行い、通常の技術を用いて組換え技術で作製することができる(例えば、J.Clin.Invest.107(5):555−564(2001)参照)。
Chemother Pharmacol 2010,DOI 10.1007/s00280−010−1518−3;米国特許第7,084,105号参照)。さらなる実施形態において、目的の核酸は、食欲を促し、癌患者を治療するために用いることができるグレリンとして知られる因子をコードする(例えば、Obes
Facts.2010 3:285−92;FASEB J.18(3):439−56参照)。別の実施形態において、目的の核酸は、アンジオポエチン1およびアンジオポエチン2に結合し、阻害する結合ペプチドをコードする(例えば、AMG386、癌を治療するために用いられる抗体(ペプチボディ)のFc断片参照)。
et al.(1998)Proc.Nat’l.Acad.Sci.(USA)95:11804)、魚(Nguyen
et al.(2002)Immunogenetics,54:39)、げっ歯類、鳥類、ヒツジを含む(ファージライブラリーなどの中の抗体、sFvs、scFvまたはFabとしてフォーマットすることができる)様々な種由来の抗体遺伝子配列、ランダムペプチドライブラリーをコードする配列、またはフィブリノゲンドメイン(例えば、Weisel et al.(1985)Science 230:1388参照)、クニッツドメイン(例えば、米国特許第6,423,498号参照)、リポカリンドメイン(例えば、WO2006/095164参照)、V様ドメイン(例えば、米国特許出願公開第2007/0065431号参照)、C型レクチンドメイン(Zelensky and Gready(2005)FEBS J.272:6179)、mAb2またはFcab(商標)(例えば、PCT特許出願公開第WO2007/098934号;同第2006/072620号)などの代替の非抗体足場のループ領域にある遺伝子工学処理した多様なアミノ酸をコードする配列が含まれる。
Laboratory Manual,Chapter 14(Cold Spring Harbor Laboratory,Cold Spring Harbor,1988)に概説されている。組換え抗体技術の全ての態様についての大規模な紹介ならびに詳細な情報は、テキストブックの組換え抗体(John Wiley&Sons,NY,1999)の中で見つけることができる。詳細な抗体工学ラボマニュアルの包括的収集は、R.Kontermann and S.Dubel,Eds.,The Antibody Engineering Lab Manual(Springer
Verlag,Heidelberg/New York,2000)の中で見つけることができる。さらに関連するプロトコールは、John Wiley&Sons社、ボストン、マサチューセッツ州が発行する免疫学の現在のプロトコール(Current Protocols in Immunology)(2009年8月)でも入手可能である。
Manual,Second Edition,Cold Spring
Harbor,NY,(1989)に記載されている。例示的なクローニング/発現ベクターには、クローニングベクター、シャトルベクター、および発現コンストラクトが含まれ、それらの中に含まれるポリヌクレオチドの増幅、移行、および/または発現に適する、当該技術分野で公知のプラスミド、ファージミド、ファスミド、コスミド、ウイルス、人工染色体、または任意の核酸ビークルに基づいていてもよい。
et al.,1995;Sambrook et al.,上記参照。例えば、Invitrogen社、サンディエゴ、カリフォルニア州;Novagen社、マディソン、ウィスコンシン州;Pharmacia社、ピスカタウェイ、ニュージャージー州のカタログも参照されたい)。融合タンパク質の増強された生産レベルを促進するために、適切な調節制御下、ジヒドロ葉酸還元酵素(DHFR)をコードする配列を含む有用なコンストラクトを調製することができ、そのレベルは、適切な選択剤(例えば、メトトレキサート)の適用後の遺伝子増幅に起因する。
Publ.Assoc社&John Wiley&Sons社、ボストン、マサチューセッツ州、1993)、Sambrookら(Molecular Cloning,Second Ed.,Cold Spring Harbor Laboratory、プレーンビュー、ニューヨーク州、1989)、Maniatisら(Molecular Cloning,Cold Spring
Harbor Laboratory、プレーンビュー、ニューヨーク州、1982)、Glover(編)(DNA Cloning Vol.I and II,IRL Press、オックスフォード、イギリス、1985)、HamesおよびHiggins(編)(Nucleic Acid
Hybridization,IRL Press、オックスフォード、イギリス、1985)などに記載されている。
Manual,2nd Ed.,Cold Spring Harbor
Laboratory,Cold Spring Harbor,N.Y.,1989参照)。
frugiperda)細胞(例えば、Sf9細胞)、出芽酵母細胞、および本開示に係るタンパク質もしくはペプチドを発現させること、任意に、単離することに有用であると当該技術分野で公知の任意の他の真核生物の細胞が含まれる。大腸菌、枯草菌、サルモネラ菌、放線菌、または本開示に係るタンパク質もしくはペプチドを発現させること、任意に、単離することに適すると当該技術分野で公知の任意の原核細胞を含む原核細胞も企図される。原核細胞からタンパク質またはペプチドを単離する場合、特に、封入体からタンパク質を抽出するための当該技術分野で公知の技術を用いることができると企図される。適切な宿主の選択は、本明細書の教示から当該技術者の範囲内にある。本開示の融合タンパク質をグリコシル化する宿主細胞が企図される。
Biology)。
一実施形態において、本開示の細胞組成物には、本明細書に記載の目的のタンパク質を発現する形質導入され、かつ活性化/分化したB細胞集団が含まれる。一実施形態において、これらの組成物には、形質B細胞に分化し、目的の1つ以上のタンパク質を発現する形質導入B細胞が含まれる。形質導入され、かつ活性化された本開示のB細胞集団などの標的細胞集団は、単独で、または希釈剤および/またはサイトカインもしくは細胞集団などの他の成分と組み合わせて医薬組成物として投与することができる。簡単に説明すると、本開示の細胞組成物は、1種以上の薬学的もしくは生理学的に許容される担体、希釈剤または賦形剤と組み合わせて、本明細書に記載の目的のタンパク質を発現する形質導入され、かつ活性化/分化したB細胞集団を含み得る。かかる組成物には、中性緩衝生理食塩水、リン酸緩衝生理食塩水などの緩衝液、グルコース、マンノース、ショ糖もしくはデキストラン、マンニトールなどの炭水化物、タンパク質、ポリペプチドまたはグリシンなどのアミノ酸、酸化防止剤、EDTAもしくはグルタチオンなどのキレート剤、アジュバント(例えば、水酸化アルミニウム)、および防腐剤が含まれ得る。本開示の組成物を、好ましくは、静脈内投与用に製剤化する。
249:1527−1533;Sefton 1987,CRC Crit.Ref.Biomed.Eng.14:201;Buchwald
et al.,1980;Surgery 88:507;Saudek et al.,1989,N.Engl.J.Med.321:574参照)。別の実施形態において、ポリマー材料を用いることができる(Medical Applications of Controlled Release,1974,Langer and Wise(eds.),CRC Pres.,Boca Raton,Fla.;Controlled Drug Bioavailability,Drug Product Design and Performance,1984,Smolen and Ball(eds.),Wiley,New York;Ranger and Peppas,1983;J.Macromol.Sci.Rev.Macromol.Chem.23:61参照。Levy et al.,1985,Science 228:190;During et al.,1989,Ann.Neurol.25:351;Howard
et al.,1989,J.Neurosurg.71:105も参照されたい)。さらに別の実施形態において、放出制御システムを治療標的の近くに配置することができるので、全身用量のほんの一部しか必要としない(例えば、Medical Applications of Controlled Release,1984,Langer and Wise(eds.),CRC Pres.,Boca Raton,Fla.,vol.2,pp.115−138参照)。
実施例1
目的のタンパク質を産生するためのPBMC由来のB細胞の形質導入および培養
この実施例において、PBMC由来のB細胞を形質導入し、培養して、HIV中和抗体、b12、またはGFPを成功裏に産生した。
ヒトPBMCをRPMI培地で解凍し、血球計数器を用いて数をかぞえた。B細胞を、メーカーのプロトコールに従って、easy−SepB細胞陰性選択B細胞精製キット(easy−Sep B−cell negative selection
B−cell purification kit)を用いて、合計1.23×107個のPBMCから採取した。精製後、これらの細胞の数を数え、3.5×105個のB細胞を24ウェルプレートの2ウェルに加え、それぞれのウェルに培地を1.25ml入れた。この培地は、RPMI、IL−2(10ng/ml)、IL−10(100ng/ml)、CpG(2マイクロモル)からなり、PHA(4μg/ml)は含む場合と含まない場合があった。
これらの結果は、形質導入細胞が平均して1.05ng/mlのb12抗体を産生したことを示した(図1参照)。さらに、蛍光顕微鏡は、GFP形質導入B細胞が改変され、緑色に成長したことを示した。GFPおよびb12発現を促進するために用いたプロモーターは、分化したB細胞においてのみ有効であることに留意することが重要である。したがって、これらの細胞は、唯一、形質細胞になった後に蛍光を発する。それゆえに、この実験は、ウイルスが正確に細胞を改変すること、ならびに培養系が改変された静止B細胞を形質細胞に分化させることができることの両方を示した。
Claims (29)
- 麻疹ウイルスの糖タンパク質Hおよび糖タンパク質Fでシュードタイプ化したレトロウイルスベクターで休止B細胞を形質導入し、形質導入休止B細胞を得ることを含み、その際、前記レトロウイルスベクターは、形質B細胞に適合する異種プロモーターに作動可能に連結された目的の核酸を含み;かつ
分化した形質導入B細胞が前記目的の核酸を発現するように、前記形質導入B細胞を形質細胞に分化させるのに十分な条件下で、IL−2、IL−7、IL−10、およびCpGからなる群から選択される因子の1つ以上を含むB細胞活性化因子と組み合わせて、CD40Lを含む組成物と前記形質導入休止B細胞を接触させることを含む、B細胞において目的の核酸を発現させる方法。 - 前記レトロウイルスベクターがレンチウイルスベクターである、請求項1に記載の方法。
- 前記レンチウイルスベクターがレンチウイルスアクセサリー遺伝子を欠く、請求項2に記載の方法。
- 前記目的の核酸が、少なくとも免疫グロブリンのVL領域およびVH領域をコードする核酸を含む、請求項1〜3のいずれか1項に記載の方法。
- 前記目的の核酸が、抗体タンパク質もしくはその抗原結合断片、融合タンパク質またはDNAにコードされる小分子をコードする、請求項1〜3のいずれか1項に記載の方法。
- 前記抗体が、抗HIV抗体、抗RNA抗体、または免疫調節に関与するタンパク質に結合する抗体である、請求項5に記載の方法。
- 前記CD40Lが細胞または細胞株上に提供される、請求項1〜3のいずれか1項に記載の方法。
- 前記CD40Lが組織培養プレートまたはビーズに結合されている、請求項1〜3のいずれか1項に記載の方法。
- 前記プロモーターがB細胞特異的プロモーターである、請求項1〜3のいずれか1項に記載の方法。
- 前記プロモーターがEEKプロモーターである、請求項1〜3のいずれか1項に記載の方法。
- 麻疹ウイルスの糖タンパク質Hおよび糖タンパク質Fでシュードタイプ化したレトロウイルスベクターで多数のB細胞を形質導入し、多数の形質導入B細胞を得ることを含み、その際、前記レトロウイルスベクターは、前記B細胞の少なくとも20%を形質導入するのに十分な条件下で、形質B細胞に適合する異種プロモーターに作動可能に連結された目的の核酸を含み;かつ
前記形質導入B細胞の少なくとも20%が前記目的の核酸を発現するように、形質導入B細胞を形質細胞に分化させるのに十分な条件下で、IL−2、IL−7、IL−10、およびCpGからなる群から選択される因子の1つ以上を含むB細胞活性化因子と組み合わせて、CD40Lを含む組成物と前記多数の形質導入休止B細胞を接触させることを含む、B細胞において目的の核酸を発現させる方法。 - 形質導入のステップの前は、多数のB細胞が休止B細胞である、請求項11に記載の方法。
- 1つまたは多数の休止B細胞を血液から単離する、請求項1または請求項12のいずれかに記載の方法。
- 前記レトロウイルスベクターがレンチウイルスベクターである、請求項11〜13のいずれか1項に記載の方法。
- 前記レンチウイルスベクターがレンチウイルスアクセサリー遺伝子を欠く、請求項14に記載の方法。
- 前記形質細胞が、CD38、CD78、インターロイキン−6受容体、CD27高、およびCD138からなる群から選択される1つ以上のマーカーの細胞表面発現によって特徴づけられる、請求項11〜15のいずれか1項に記載の方法。
- 休止B細胞を、麻疹ウイルスの糖タンパク質Hおよび糖タンパク質Fでシュードタイプ化したレトロウイルスベクターと接触させ、形質導入B細胞を得ることを含み、その際、前記レトロウイルスベクターは、前記休止B細胞の少なくとも20%を形質導入するのに十分な条件下で、形質B細胞に適合する異種プロモーターに作動可能に連結された目的の核酸を含み;かつ
前記形質導入B細胞の少なくとも20%が前記目的の核酸を発現するように、前記形質導入B細胞を活性化するのに十分な条件下で、IL−2、IL−7、IL−10、およびCpGからなる群から選択される因子の1つ以上を含むB細胞活性化因子と組み合わせて、CD40Lを含む組成物と前記形質導入B細胞を接触させることを含む、休止B細胞を形質導入し、その活性化を促進する方法。 - 前記レトロウイルスベクターがレンチウイルスベクターである、請求項17に記載の方法。
- 前記レンチウイルスベクターがレンチウイルスアクセサリー遺伝子を欠く、請求項18に記載の方法。
- 前記目的の核酸が、少なくとも免疫グロブリンのVL領域およびVH領域をコードする核酸を含む、請求項17〜19のいずれか1項に記載の方法。
- 前記目的の核酸が、抗体タンパク質もしくはその抗原結合断片、融合タンパク質またはDNAにコードされる小分子をコードする、請求項17〜19のいずれか1項に記載の方法。
- 前記抗体が、抗HIV抗体、抗RNA抗体、または免疫調節に関与するタンパク質に結合する抗体である、請求項21に記載の方法。
- 前記CD40Lが細胞または細胞株上に提供される、請求項17〜19のいずれか1項に記載の方法。
- 前記CD40Lが組織培養プレートまたはビーズに結合されている、請求項17〜19のいずれか1項に記載の方法。
- 前記プロモーターがB細胞特異的プロモーターである、請求項17〜19のいずれか1項に記載の方法。
- 前記プロモーターがEEKプロモーターである、請求項17〜19のいずれか1項に記載の方法。
- B細胞活性化因子と組み合わせて、CD40Lを含む組成物と休止B細胞を接触させ、活性化B細胞を得ることを含み、その際、前記B細胞活性化因子は、IL−2、IL−7、IL−10、およびCpGからなる群から選択される因子の1つ以上を含み、前記接触のステップが前記B細胞を活性化するのに十分な条件下で行われ、その結果、それが形質細胞に分化し;かつ
前記活性化B細胞を、麻疹ウイルスの糖タンパク質Hおよび糖タンパク質Fでシュードタイプ化したレトロウイルスベクターで形質導入し、形質導入し、分化した形質細胞を得ることを含み、その際、前記レトロウイルスベクターは、前記形質導入し、分化した形質細胞が前記目的の核酸を発現するように、形質B細胞に適合する異種プロモーターに作動可能に連結された前記目的の核酸を含む、B細胞において目的の核酸を発現させる方法。 - 前記レトロウイルスベクターがレンチウイルスベクターである、請求項27に記載の方法。
- 前記レンチウイルスベクターがレンチウイルスアクセサリー遺伝子を欠く、請求項28に記載の方法。
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Cited By (5)
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JP2017516496A (ja) * | 2014-05-19 | 2017-06-22 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | ヒツジb細胞を用いて抗体を産生するための方法およびその使用 |
JP2022132351A (ja) * | 2015-04-03 | 2022-09-08 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | B細胞のゲノム編集のための組成物及び方法 |
JP7463442B2 (ja) | 2015-04-03 | 2024-04-08 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | B細胞のゲノム編集のための組成物及び方法 |
JP2019509729A (ja) * | 2016-02-16 | 2019-04-11 | デューク ユニバーシティ | 抗体産生のためにb細胞を拡張及び分化する方法 |
JP7018203B2 (ja) | 2016-02-16 | 2022-02-10 | デューク ユニバーシティ | 抗体産生のためにb細胞を拡張及び分化する方法 |
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EP2521789B1 (en) | 2016-12-14 |
EP2521789A2 (en) | 2012-11-14 |
CA2786664A1 (en) | 2011-07-14 |
US20130143267A1 (en) | 2013-06-06 |
US9074223B2 (en) | 2015-07-07 |
ES2617749T3 (es) | 2017-06-19 |
WO2011085247A2 (en) | 2011-07-14 |
WO2011085247A3 (en) | 2011-11-10 |
EP2521789A4 (en) | 2013-08-21 |
DK2521789T3 (en) | 2017-03-27 |
WO2011085247A4 (en) | 2011-12-29 |
JP5873807B2 (ja) | 2016-03-01 |
CA2786664C (en) | 2020-03-10 |
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