JP2014501118A - 生物学的製剤の個別生成および体細胞を再プログラム化するための方法 - Google Patents
生物学的製剤の個別生成および体細胞を再プログラム化するための方法 Download PDFInfo
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Abstract
【選択図】図1
Description
本願は、2011年1月3日に出願された米国仮特許出願第61/429,409号、2011年1月10日に出願された米国仮特許出願第61/431,376号に対して優先権を主張する。前述の全出願は、参照によりその全体が本明細書に組み込まれる。
本発明は、合成により生成された多能性幹細胞(spPSC)または内因性多能性幹細胞(ePSC)を遺伝子導入または形質転換することにより、ポリペプチドまたはタンパク質、核酸、ウイルス、およびワクチン等の生物学的製剤を生成するための方法を提供することによりこの必要性を満たす。これらの細胞は、治療される種に由来し、所望の生物学的製剤を発現し、遺伝子導入された、または形質転換されたspPSCまたはePSCによる生物学的生成物の発現を誘発するベクターを遺伝子導入される。
本発明の個別生物学的製剤を生成するために、あらゆる種類の合成により生成された多能性幹細胞を使用することができる。2つの主なカテゴリーは、誘発または再プログラム化した多能性幹細胞(iPSC)と、核移植(SCNT)、ANT−OAR、および単為生殖によって生成された幹細胞である。
誘発した多能性幹細胞は、特定の幹細胞遺伝子およびタンパク質の発現、クロマチンメチル化パターン、倍加時間、胚様体形成、奇形腫形成、実行可能なキメラ形成、ならびに発生能および分化能(differentiability)等の多くの点で、胚幹(ES)細胞等の天然の多能性幹細胞に類似する。
生成したspPSCは、以下の点において、天然に単離された多能性幹細胞(マウスおよびヒトの胚性幹細胞(ESC)、それぞれmESCおよびhESCなど)と非常に類似しており、よって、天然に単離された多能性幹細胞に対するspPSCの同一性、確実性、および多能性を裏付ける。
○ 形態学:iPSCは、形態学的にESCに類似する。それぞれの細胞は、形状が丸く、大型の核小体、およびわずかな細胞質を有する。iPSCのコロニーも、ESCに類似する。ヒトiPSCはhESCに類似し、縁が鋭利で平らな密集したコロニーを形成し、マウスiPSCはmESCに類似し、hESCよりあまり平らではなく、より凝集したコロニーを形成する。
内因性多能性幹細胞(ePSC)を含む幹細胞は、その表面上に発現する特定の抗原を特徴とし、それによって単離され得る。多能性幹細胞は、他の方法の中でも、段階特異的胚抗原(SSEA)、転写因子Oct4およびNanogならびに他のマーカーの発現を特徴とし得る。今まで単離されてきた内因性多能性幹細胞の主な型は、非常に小さい胚様(VSEL)幹細胞である。
<不死化spPSCおよびePSCの生成>
本発明の好ましい実施形態では、spPSCおよびePSCは、典型的にはポリオーマサルウイルス40(SV40)を使用して、好ましくは大型T抗原の非ウイルス誘発を通して不死化される。Rose,M.R.et al.,(1983).“Expression of the Large T Protein of Polyoma Virus Promotes the Establishment in Culture of “Normal” Rodent Fibroblast Cell Lines”.PNAS 80:4354−4358(1983)およびHofmann,M.C.et al.“Immortalization of germ cells and somatic testicular cells using the SV40 large T antigen”Experimental Cell Research,201:417−435(1992)を参照。
好ましい実施形態において、
1.内因性多能性幹細胞が単離される。
1.体細胞が単離される。
1.内因性多能性幹細胞が単離される。
は、腫瘍壊死因子(TNF)分子、成長因子受容体、血管内皮成長因子(VEGF)分子、インターロイキン1、インターロイキン4、インターロイキン6、インターロイキン11、インターロイキン12、γインターフェロン、核因子カッパB活性化受容体リガンド(RANKL)、およびBlysからなる群から選択される。
目的のタンパク質の生成を最適化するために、遺伝子導入されたePSCまたはspPSC細胞は、体細胞に分化するように誘発されるべきである。
本発明は、奇形腫を形成することなく、幹細胞療法を促進するための方法も含む。本発明は、本明細書において、より大きな治療利益のために、上記に定義される合成により生成された多能性幹細胞(spPSC)と呼ばれる、観察された「記憶」または再プログラム化体細胞をどのように有利に利用するかを教示する。再プログラム化の前に起始細胞型に再分化する選好を付与するspPSCの記憶は、再生医療においてspPSCの安全かつ治療的有用性を強化するための手段を提供する。
本発明は、
1.目的の体細胞、特に再生したい体細胞の単離、
2.体細胞の、合成により生成された多能性幹細胞(spPSC)、特に上述のように誘発した多能性幹細胞(iPSC)への体細胞の形質転換、
3.spPSCが体細胞の固有の後成的記憶を維持する、spPSCの集団の増殖、
4.培養物中のspPSCの、元の体細胞型を有する再分化した体細胞への再分化、および
5.細胞型が望まれる身体の領域内への再分化した体細胞の投与または送達、を伴う。
好ましくは、最低500個の治療用細胞が投与され、一般的には、細胞療法は1500万〜5憶個の細胞を利用する。より好ましくは、1500万〜1憶個の細胞が最適効果のために投与される。
組み換えタンパク質生成のための合成により生成された患者特異的多能性幹細胞の遺伝子修飾
患者からのSCNTもしくはPGAもしくはANT−OARもしくはiPSC等の合成により生成された多能性幹細胞(spPSC)は、生物学的製剤の生成を誘発するための遺伝子修飾に使用される。SCNT由来幹細胞は、患者の細胞の核を調製した除核卵母細胞内に移植することにより調製される。ANT−OAR由来細胞は、修飾した核を、除核し、調製した卵母細胞内に移植する前に患者の核DNAを遺伝的に修飾することにより調製される。iPSC由来幹細胞は、遺伝子修飾、多能性転写因子の活性化因子、後成的修飾、または上述の当該技術分野に公知の他の方法を使用して、患者の細胞を再プログラム化することにより調製される。得られた合成により生成された患者特異的幹細胞系は、生物学的製剤の生成における後の遺伝的修飾のために、マスターセルバンク(master cell bank)およびワーキングバンク(working bank)として「保存される」。
組み換えインスリン生成のための合成により生成された患者特異的多能性幹細胞の遺伝子修飾
患者からのSCNTもしくはPGAもしくはANT−OARもしくはiPSC由来幹細胞等の合成により生成された多能性幹細胞(spPSC)は、生物学的製剤の生成を誘発するための遺伝子修飾に使用される。SCNT由来幹細胞は、患者の細胞の核を調製した除核卵母細胞内に移植することにより調製される。ANT−OAR由来細胞は、修飾した核を、除核し、調製した卵母細胞内に移植する前に患者の核DNAを遺伝的に修飾することにより調製される。iPSC由来幹細胞は、遺伝子修飾、多能性転写因子の活性化因子、後成的修飾、または上述の当該技術分野に公知の他の方法を使用して、患者の細胞を再プログラム化することにより調製される。得られた合成により生成された患者特異的幹細胞系は、生物学的製剤の生成における後の遺伝的修飾のために、マスターセルバンクおよびワーキングバンクとして「保存される」。
合成により生成された患者特異的多能性幹細胞の遺伝的修飾を使用したインスリン生成のためのβ細胞の生成
インスリンを生成するために、患者からの体細胞をspPSCを生成するための遺伝的修飾に使用し、これらは生物学的製剤の生成を誘発するために使用される。spPSC由来幹細胞は、遺伝的修飾、多能性転写因子の活性化因子、後成的修飾、または当該技術分野に公知の他の方法を使用して、患者の細胞を再プログラム化することにより調製される。得られた患者特異的幹細胞系は、生物学的製剤の生成における後の遺伝的修飾のために、マスターセルバンクおよびワーキングバンクとして「保存される」。あるいは、内因性多能性幹細胞(ePSC)は、上述の技法により単離されて、保存され得る。
再プログラム化および遺伝子導入して生物抗体治療薬を生成するための成体(体細胞)抗体生成細胞の単離
抗体生成B細胞は、患者特異的製造細胞系を生成し、治療用抗体生物学的製剤を生成する目的のために末梢血、骨髄、および他の容易に利用可能な造血細胞源から単離される。B細胞は、CD19発現に基づき利用可能なキット(StemCell Technologies)を利用して単離される。最高レベルの免疫グロブリン(Ig)を生成する細胞を選択するために、限界希釈法または細胞選別法が利用され得る。簡単な増殖の後、高Ig生成クローナル細胞は、標準的な再プログラム化法を使用して、多能性または前駆体状態に再プログラム化される。得られた患者特異的幹細胞は、標準的な分子生物学技法および方法を使用して、所望の抗体遺伝子構築物を形質導入される。得られた発現抗体治療薬は、公的に入手可能であるか、抗体治療薬の事項の組成物の所有者により内密に維持されるかどうかに関わらず、現状技術のバイオテクノロジー法により処理され、精製される。所望の精製された抗体生成物を得るための方法は、イオン交換クロマトグラフィーを含む。
体細胞抗体生成細胞への再分化を伴う再プログラム化および遺伝子導入して生物学的抗体治療薬を生成するための成体(体細胞)抗体生成細胞の単離
抗体生成B細胞は、患者特異的製造細胞系を生成し、治療用抗体生物学的製剤を生成する目的のために、末梢血、骨髄、および他の容易に利用可能な造血細胞源から単離される。最高レベルの免疫グロブリン(Ig)を生成する細胞を選択するために、限界希釈法または細胞選別法が利用され得る。簡単な増殖の後、高Ig生成クローナル細胞は、標準的な再プログラム化法を使用して、多能性または前駆体状態に再プログラム化される。得られた患者特異的幹細胞は、標準的な技法および方法を使用して、所望の抗体遺伝子構築物を形質導入される。遺伝子修飾後、多能性患者特異的細胞系は、CD40L、BAFF、toll様受容体活性化(TLR)の存在下での培養[Hayashi E.A.,et al.“TLR4 promotes B cell maturation: independence and cooperation with B lymphocyte−activating factor”.,J Immunol.,184:4662−4672(2010)、またはB細胞受容体(BCR)活性化およびノッチ受容体リガンドファミリー活性化等の当該技術分野に公知の他のB細胞成熟因子[Palanichamy A.et al.“Novel human transitional B cell populations revealed by B cell depletion therapy”.10,May 2009,J Immunol.,Vol.182,pp.5982−5993(2009)、Thomas M.D.et al.,“Regulation of peripheral B cell maturation”.,Cell Immunol.,239:92−102(2006)により成熟抗体生成B細胞に分化される。
高活性ADCC抗体生成のための患者特異的細胞系の生成
免疫グロブリンのN−アセチルグルコサミン(GlcNac)翻訳後修飾は抗体依存細胞媒介毒性(ADCC)において重要であり、フコシル化されないGlcNac残基はFcγ受容体に対して最高の親和性を有する。Mori K.,et al.,“Non−fucosylated therapeutic antibodies:the next generation of therapeutic antibodies”.,Cytotechnology.,55:109−114(2007)。
以下に、当初の特許請求の範囲に記載していた発明を付記する。
[1]
組み換えポリペプチドまたはタンパク質を生成するための方法であって、合成により生成した多能性幹細胞(spPSC)または内因性多能性幹細胞(ePSC)を、前記ポリペプチドまたはタンパク質が前記幹細胞によって発現する条件下で、前記ポリペプチドまたはタンパク質をコードする核酸で遺伝子導入することを含み、前記spPSCまたはePSCが動物の細胞から生成される、または単離される、方法。
[2]
前記ポリペプチドまたはタンパク質は、エリスロポエチン、第VIII因子、第IX因子、トロンビン、抗体もしくは抗体断片、αインターフェロン、インターフェロンα−2Aおよび2B、βインターフェロン、成長ホルモン、抗血友病因子、G−CSF、GM−CSF、可溶性受容体、TGF−β、骨形態形成タンパク質(BMP)、TGFα、インターロイキン2、β−グルコセレブロシダーゼもしくはその類似体、α1−プロテイナーゼ阻害剤、フィブリン、フィブリノーゲン、フォンビルブランド因子、イミグルセラーゼ、アガルシダーゼβ、ラロニダーゼ、グルコシダーゼα、サイロトロピンα、ならびにチモシンαからなる群から選択される、[1]に記載の方法。
[3]
前記抗体または抗体断片は、ターゲットに結合し、前記ターゲットは、腫瘍壊死因子(TNF)分子、腫瘍壊死因子受容体(TNFR)、成長因子受容体、血管内皮成長因子(VEGF)分子、インターロイキン1、インターロイキン4、インターロイキン6、インターロイキン11、インターロイキン12、γインターフェロン、核因子カッパB活性化受容体リガンド(RANKL)、およびBlysからなる群から選択される、[1]に記載の方法。
[4]
前記可溶性受容体は、TNFα、TNFβ、およびBlysからなる群から選択されるターゲットに結合される、[1]に記載の方法。
[5]
前記遺伝子導入したspPSCの不死化をさらに含む、[1]に記載の方法。
[7]
前記遺伝子導入し、不死化したspPSCの分化を誘発することをさらに含む、[5]に記載の方法。
[8]
前記遺伝子導入したspPSCまたはePSCの分化を誘発することをさらに含む、[1]に記載の方法。
[9]
前記遺伝子導入し、分化した細胞を不死化することをさらに含む、[7]に記載の方法。
[10]
前記spPSCは、誘発された多能性幹細胞、体細胞核移植により生成された多能性幹細胞(SCNT多能性幹細胞)、改変核移植卵母細胞補助再プログラム化により生成された多能性幹細胞(ANT−OAR多能性幹細胞)、および単為生殖により生成された多能性幹細胞(PGA多能性)からなる群から選択される、[1]に記載の方法。
Claims (9)
- 組み換えポリペプチドまたはタンパク質を生成するための方法であって、合成により生成した多能性幹細胞(spPSC)または内因性多能性幹細胞(ePSC)を、前記ポリペプチドまたはタンパク質が前記幹細胞によって発現する条件下で、前記ポリペプチドまたはタンパク質をコードする核酸で遺伝子導入することを含み、前記spPSCまたはePSCが動物の細胞から生成される、または単離される、方法。
- 前記ポリペプチドまたはタンパク質は、エリスロポエチン、第VIII因子、第IX因子、トロンビン、抗体もしくは抗体断片、αインターフェロン、インターフェロンα−2Aおよび2B、βインターフェロン、成長ホルモン、抗血友病因子、G−CSF、GM−CSF、可溶性受容体、TGF−β、骨形態形成タンパク質(BMP)、TGFα、インターロイキン2、β−グルコセレブロシダーゼもしくはその類似体、α1−プロテイナーゼ阻害剤、フィブリン、フィブリノーゲン、フォンビルブランド因子、イミグルセラーゼ、アガルシダーゼβ、ラロニダーゼ、グルコシダーゼα、サイロトロピンα、ならびにチモシンαからなる群から選択される、請求項1に記載の方法。
- 前記抗体または抗体断片は、ターゲットに結合し、前記ターゲットは、腫瘍壊死因子(TNF)分子、腫瘍壊死因子受容体(TNFR)、成長因子受容体、血管内皮成長因子(VEGF)分子、インターロイキン1、インターロイキン4、インターロイキン6、インターロイキン11、インターロイキン12、γインターフェロン、核因子カッパB活性化受容体リガンド(RANKL)、およびBlysからなる群から選択される、請求項1に記載の方法。
- 前記可溶性受容体は、TNFα、TNFβ、およびBlysからなる群から選択されるターゲットに結合される、請求項1に記載の方法。
- 前記遺伝子導入したspPSCの不死化をさらに含む、請求項1に記載の方法。
- 前記遺伝子導入し、不死化したspPSCの分化を誘発することをさらに含む、請求項5に記載の方法。
- 前記遺伝子導入したspPSCまたはePSCの分化を誘発することをさらに含む、請求項1に記載の方法。
- 前記遺伝子導入し、分化した細胞を不死化することをさらに含む、請求項7に記載の方法。
- 前記spPSCは、誘発された多能性幹細胞、体細胞核移植により生成された多能性幹細胞(SCNT多能性幹細胞)、改変核移植卵母細胞補助再プログラム化により生成された多能性幹細胞(ANT−OAR多能性幹細胞)、および単為生殖により生成された多能性幹細胞(PGA多能性)からなる群から選択される、請求項1に記載の方法。
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KR20140037036A (ko) | 2014-03-26 |
RU2013136357A (ru) | 2015-02-10 |
RU2595390C2 (ru) | 2016-08-27 |
JP6373459B2 (ja) | 2018-08-15 |
NZ613888A (en) | 2015-07-31 |
SG191836A1 (en) | 2013-08-30 |
JP2018007660A (ja) | 2018-01-18 |
KR20170120726A (ko) | 2017-10-31 |
MX348776B (es) | 2017-06-28 |
CN108017692A (zh) | 2018-05-11 |
JP6223829B2 (ja) | 2017-11-01 |
BR112013018744A2 (pt) | 2016-09-20 |
IL227299A0 (en) | 2013-09-30 |
WO2012094321A1 (en) | 2012-07-12 |
IL227299B (en) | 2020-06-30 |
MX2013007633A (es) | 2015-07-14 |
US20170081641A1 (en) | 2017-03-23 |
US20120171722A1 (en) | 2012-07-05 |
ZA201305849B (en) | 2014-10-29 |
BR112013018744B1 (pt) | 2022-03-29 |
AU2012204501B2 (en) | 2016-05-19 |
WO2012094321A4 (en) | 2012-09-20 |
EP2661491A1 (en) | 2013-11-13 |
US9512200B2 (en) | 2016-12-06 |
US10030230B2 (en) | 2018-07-24 |
CN103403152A (zh) | 2013-11-20 |
AU2012204501A1 (en) | 2013-08-22 |
MY161859A (en) | 2017-05-15 |
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