JP7303743B2 - 細胞を樹状細胞または抗原提示細胞にリプログラムするための組成物、その方法および使用 - Google Patents
細胞を樹状細胞または抗原提示細胞にリプログラムするための組成物、その方法および使用 Download PDFInfo
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Description
本開示は、単離された転写因子を導入および発現することにより、分化細胞、複能性または多能性幹細胞から、抗原提示能を有する樹状細胞または抗原提示細胞を作製する方法の開発に関する。より詳細には本開示は、転写因子の組み合わせの驚くべき使用による直接的な細胞リプログラミングにより、分化細胞、複能性または多能性幹細胞を樹状細胞または抗原提示細胞の状態にリダイレクトするための方法を提供する。
細胞リプログラミングは、1つの細胞状態のエピジェネティックかつ転写性のネットワークを異なる細胞型のネットワークに再接続することに依存する。転写因子(TF)形質導入実験により、成体体細胞または分化細胞の可塑化が強調され、任意の望ましい細胞型を生成する新規な技術が提供された。TFの強制的発現により、体細胞または分化細胞を、胚性幹細胞と著しく類似した誘導多能性幹細胞(iPSC)にリプログラミングすることが可能である(1、2)。あるいは体細胞は、別の特別な細胞型に変換することも可能である(3)。TFを用いて標的細胞の同一性を特定することで、直接的な系譜変換が、マウスおよびヒト線維芽細胞を神経細胞、心筋細胞および肝細胞などの複数の細胞型にリプログラミングするのに有効であることが立証された(4)。系譜変換は、造血系でも実証されており、TFの強制的発現はB細胞および線維芽細胞におけるマクロファージの運命を誘導し(5)、クローン原性造血前駆体へのマウス線維芽細胞の直接的リプログラミングはGata2、Gfi1b、cFosおよびEtv6で実現される(6)。これらの4種のTFは、内皮様の中間体を通して進む動的多段階血液生成工程を誘導し、インビトロで発達的な造血を再現する(7)。
インビトロ、エクスビボまたはインビボでの樹状細胞または抗原提示細胞への、幹細胞もしくは分化細胞、またはそれらの混合物からなるリストから選択される細胞のリプログラミングまたは誘導因子として、
BATF3(配列番号1または配列番号2)、IRF8(配列番号5、配列番号6)、PU.1(配列番号7、配列番号8)、TCF4(配列番号13、配列番号14)、
からなるリストの配列と90%同一の配列によりコードされた少なくとも2種の単離された転写因子の組み合わせを含む組成物に関する。
BATF3(配列番号1または配列番号2)およびIRF8(配列番号5、配列番号6);またはBATF3(配列番号1、配列番号2)およびPU.1(配列番号7、配列番号8);またはIRF8(配列番号5、配列番号6)およびPU.1(配列番号7、配列番号8);またはTCF4(配列番号13、配列番号14)およびBATF3(配列番号1、配列番号2);またはTCF4(配列番号13、配列番号14)およびIRF8(配列番号5、配列番号6);またはTCF4(配列番号13、配列番号14)およびPU.1(配列番号7、配列番号8);またはBATF3(配列番号1、配列番号2)、IRF8(配列番号5、配列番号6)およびPU.1(配列番号7、配列番号8);またはTCF4(配列番号13、配列番号14)、BATF3(配列番号1、配列番号2)およびIRF8(配列番号5、配列番号6);またはTCF4(配列番号13、配列番号14)、IRF8(配列番号5、配列番号6)およびPU.1(配列番号7、配列番号8);またはTCF4(配列番号13、配列番号14)、BATF3(配列番号1、配列番号2)、IRF8(配列番号5、配列番号6)およびPU.1(配列番号7、配列番号8)
であってもよい。
インビトロ、エクスビボまたはインビボでの樹状細胞または抗原提示細胞への、幹細胞もしくは分化細胞、またはそれらの混合物からなるリストから選択される細胞のリプログラミングまたは誘導因子として、
BATF3(配列番号1または配列番号2)、IRF8(配列番号5、配列番号6)、PU.1(配列番号7、配列番号8)、TCF4(配列番号13、配列番号14)、およびそれらの混合物からなるリストの配列と少なくとも90%同一、好ましくは少なくとも91%、92%、93%、94%、95%、96%、97%、98%、99%、または同一である少なくとも2種の配列の組み合わせの使用である。
幹細胞または分化細胞、およびそれらの混合物からなるリストから選択される細胞に、BATF3(配列番号1または配列番号2)、IRF8(配列番号5、配列番号6)、PU.1(配列番号7、配列番号8)、TCF4(配列番号13、配列番号14)、およびそれらの混合物からなるリストの配列と少なくとも90%同一である、好ましくは少なくとも91%、92%、93%、94%、95%、96%、97%、98%、99%、または同一である配列をコードする少なくとも2つの核酸配列を含む1つまたは複数のベクターを形質導入するステップと、
該形質導入された体細胞を、樹状細胞または抗原提示細胞の生育を支援する細胞培地中で培養するステップと、
を含む樹状細胞または抗原提示細胞に幹細胞または分化細胞をリプログラミングまたは誘導するための方法に関する。
該体細胞を、PU.1(配列番号7、配列番号8)をコードする核酸配列、IRF8(配列番号5、配列番号6)をコードする核酸配列、BATF3(配列番号1、配列番号2)をコードする核酸配列を含む1種または複数のベクターで形質導入し、各上記核酸配列が、プロモーターに動作可能に連結されていること;および
該形質導入された体細胞を、樹状細胞の生育を支援する細胞培地で培養し、それによりiDCを調製すること、
を含む、方法である。
本開示は、樹状細胞または抗原提示細胞への分化または未分化細胞の誘導またはリプログラミングを可能にする転写因子の新規な使用および組み合わせの本明細書に記載された驚くべき効果に一部基づく、樹状細胞状態または抗原提示細胞状態への細胞誘導または細胞リプログラミングのための組成物、核酸構築物、方法およびそれらのキットに関する。そのような組成物、核酸構築物、方法およびキットは、樹状細胞をインビトロ、エクスビボ、またはインビボで誘導するために用いることができ、これらの誘導樹状細胞または抗原提示細胞は、免疫療法の適用に用いることができる。
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Claims (14)
- BATF3、IRF8、およびPU.1である、3種の転写因子をコードする3つのポリヌクレオチド配列の組み合わせを含む、1つまたは複数の構築物またはベクター。
- 前記3種の転写因子は、
a)配列番号1または配列番号2(BATF3)、
b)配列番号5または配列番号6(IRF8)、および
c)配列番号7または配列番号8(PU.1)
からなる群から選択される配列と少なくとも90%同一である配列によりコードされる、
請求項1に記載の1つまたは複数の構築物またはベクター。 - 前記3種の転写因子の組み合わせが、5’から3’に向かって以下の順:
PU.1、IRF8、BATF3;または
IRF8、PU.1、BATF3
である、請求項1または2に記載の1つまたは複数の構築物またはベクター。 - 前記1つまたは複数のベクターが、ウイルスベクターである、請求項1~3のいずれか1項に記載の1つまたは複数のベクター。
- 前記1つまたは複数のベクターが、レンチウイルス、レトロウイルス、アデノウイルス、ヘルペスウイルス、ポックスウイルス、およびアデノ随伴ウイルスベクターからなる群から選択される、請求項4に記載の1つまたは複数のベクター。
- 医療において使用するための、BATF3、IRF8およびPU.1である3種の転写因子をコードする3つのポリヌクレオチド配列の組み合わせを含む構築物またはベクターを含む組成物。
- 癌、神経変性疾患、加齢疾患、および感染性疾患からなる群から選択される疾患の治療において使用するための、BATF3、IRF8およびPU.1である3種の転写因子をコードする3つのポリヌクレオチド配列の組み合わせを含む1つまたは複数の構築物またはベクターを含む組成物。
- 前記癌は、悪性腫瘍、早期癌、基底細胞癌、子宮頸部異形成、軟組織肉腫、生殖細胞腫瘍、網膜芽細胞腫、ホジキンリンパ腫、血液癌、前立腺癌、卵巣癌、子宮頸癌、子宮癌、膣癌、乳癌、上咽頭癌、気管癌、喉頭癌、気管支癌、細気管支癌、肺癌、食道癌、胃癌、胆管癌、腸癌、結腸癌、大腸癌、直腸癌、膀胱癌、尿管癌、腎臓癌、肝臓癌、胆嚢癌、脾臓癌、脳癌、リンパ系癌、骨癌、膵臓癌、白血病、皮膚癌、および骨髄腫からなる群から選択される、請求項7に記載の組成物。
- 薬物スクリーニングにおける使用のための、BATF3、IRF8およびPU.1である3種の転写因子をコードする3つのポリヌクレオチド配列の組み合わせを含む1つまたは複数の構築物またはベクターを含む組成物。
- 免疫療法における使用のための、BATF3、IRF8およびPU.1である3種の転写因子をコードする3つのポリヌクレオチド配列の組み合わせを含む1つまたは複数の構築物またはベクターを含む組成物。
- 樹状細胞に細胞をリプログラミングまたは誘導するための方法であって、
a)細胞に、BATF3、IRF8およびPU.1である3種の転写因子をコードする3つのポリヌクレオチド配列を含む1つまたは複数のベクターを形質導入するステップと、
b)前記形質導入された細胞を、樹状細胞の生育を支援する細胞培地中で培養するステップと
を含む、方法。 - 前記3種の転写因子の組み合わせが、5’から3’に向かって以下の順:
PU.1、IRF8、BATF3、または
IRF8、PU.1、BATF3
である、請求項11に記載の方法。 - 前記形質導入するステップが、免疫刺激性サイトカインをコードする核酸配列および/またはIL-10を標的とするsiRNAをコードする核酸配列を含む少なくとも1種のベクターをさらに含む、請求項11または12に記載の方法。
- 前記細胞が、分化細胞、内胚葉由来細胞、中胚葉由来細胞、外胚葉由来細胞、多能性幹細胞、間葉系幹細胞、造血系幹細胞、腸幹細胞を含む複能性幹細胞、線維芽細胞、臍帯血幹細胞、並びに癌細胞および細胞株からなる群から選択されるか、または前記細胞はヒトもしくはマウス線維芽細胞、またはホ乳動物臍帯血幹細胞である、請求項11~13のいずれか1項に記載の方法。
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CN114729320B (zh) * | 2019-11-25 | 2023-12-15 | 阿斯加德治疗有限公司 | 用于将细胞重新程序化为能够呈递抗原的树突细胞2型的组合物、方法及其用途 |
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US11345891B2 (en) | 2022-05-31 |
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