JP2020513191A - 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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Abstract
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 (49)
- 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(配列番号配列番号1、配列番号配列番号2)、IRF8(配列番号配列番号5、配列番号配列番号6)、PU.1(配列番号配列番号7、配列番号配列番号8)、TCF4(配列番号配列番号13、配列番号配列番号14)、およびそれらの混合物からなるリストから選択される配列と少なくとも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。 - 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から選択される配列と少なくとも95%同一である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、先行請求項に記載の組成物。 - 前記単離された転写因子の組み合わせが、
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)
のコードされた組み合わせから選択される、先行請求項のいずれかに記載の組成物。 - 前記単離された転写因子の組み合わせが、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)のコードされた組み合わせである、先行請求項のいずれかに記載の組成物。
- 前記単離された転写因子のコードされた組み合わせが、BATF3(配列番号1、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)、およびTCF4(配列番号13、配列番号14)の組み合わせである、先行請求項のいずれかに記載の組成物。
- 前記細胞が、多能性幹細胞、複能性幹細胞、分化細胞、腫瘍細胞、癌細胞、およびそれらの混合物からなるリストから選択される、先行請求項のいずれかに記載の組成物。
- 樹状細胞への、多能性幹細胞、複能性幹細胞、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のリプログラミングまたは誘導因子としての、先行請求項のいずれかに記載の組成物。
- 抗原提示細胞への、腫瘍細胞、癌細胞、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のリプログラミングまたは誘導因子としての、先行請求項のいずれかに記載の組成物。
- 前記抗原が、癌抗原、自己抗原、アレルゲン、病原性および/または感染性生物体からの抗原である、抗原提示細胞のリプログラミングまたは誘導因子としての、先行請求項のいずれかに記載の組成物。
- 獣医学またはヒト医療、特に免疫療法、または神経変性疾患もしくは加齢疾患、または癌もしくは感染性疾患における使用、あるいは薬物スクリーニングとしての使用のための、先行請求項のいずれかに記載の組成物。
- 前記多能性幹細胞、複能性幹細胞または分化細胞が、ホ乳動物の多能性幹細胞、複能性幹細胞または分化細胞、特にマウスまたはヒト細胞である、先行請求項のいずれかに記載の組成物。
- 請求項1〜11のいずれか1項に記載の2種の単離された転写因子の少なくとも組み合わせ、好ましくは3種の転写因子のコードされた組み合わせ、より好ましくは4種の転写因子のコードされた組み合わせをコードした構築物またはベクター。
- 前記3種の単離された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(配列番号7、配列番号8)、IRF8(配列番号5、配列番号6)、BATF3(配列番号1、配列番号2);または
IRF8(配列番号5、配列番号6)、PU.1(配列番号7、配列番号8)、BATF3(配列番号1、配列番号2)
である、先行請求項に記載の構築物またはベクター。 - 前記ベクターが、ウイルスベクター、特にレトロウイルス、アデノウイルス、レンチウイルス、ヘルペスウイルス、ポックスウイルス、またはアデノ随伴ウイルスベクターである、請求項12〜13のいずれかに記載のベクター。
- 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であって、
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、配列番号1、配列番号2、配列番号5、配列番号6、配列番号7、配列番号8、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約95%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、
前記形質導入された細胞を、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、方法。 - 前記配列が、
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)
からなる群から選択される、先行請求項に記載の方法。 - 前記配列が、以下の組み合わせ:
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)
からなる群から選択される、先行請求項に記載の方法。 - 前記配列が、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)、好ましくは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)の組み合わせである群から選択される、先行請求項に記載の方法。
- 前記3種の単離された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(配列番号7、配列番号8)、IRF8(配列番号5、配列番号6)、BATF3(配列番号1、配列番号2)、または
IRF8(配列番号5、配列番号6)、PU.1(配列番号7、配列番号8)、BATF3(配列番号1、配列番号2)
である、先行請求項に記載の方法。 - 複数の単離された転写因子を形質導入された前記細胞を、少なくとも2日間、好ましくは少なくとも5日間、より好ましくは少なくとも8日間、さらにより好ましくは9日間培養する、先行請求項15〜19に記載の方法。
- 形質導入ステップが、IL−12をコードする核酸配列をコードする核酸配列;GM−CSFをコードする核酸配列;IL−7をコードする核酸配列;IL−10RNAを標的とするsiRNAをコードする核酸配列、およびそれらの混合物からなるリストから選択される少なくとも1種のベクターをさらに含む、先行請求項15〜20に記載の方法。
- 形質導入ステップが、免疫刺激性サイトカインをコードする核酸を含む少なくとも1種のベクターをさらに含む、先行請求項15〜21に記載の方法。
- 前記細胞が、多能性幹細胞、または複能性幹細胞、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、先行請求項15〜22に記載の方法。
- 前記細胞が、ホ乳動物細胞である、先行請求項15〜23に記載の方法。
- 前記多能性幹細胞、複能性幹細胞、または分化細胞が、内胚葉由来細胞、中胚葉由来細胞、または外胚葉由来細胞、間葉系幹細胞、造血系幹細胞、腸幹細胞などの複能性幹細胞、多能性幹細胞および細胞株からなる群から選択される、先行請求項15〜24に記載の方法。
- 前記細胞が、非ヒト細胞である、先行請求項15〜25のいずれかに記載の方法。
- 前記細胞が、マウス細胞である、先行請求項15〜26のいずれかに記載の方法。
- 前記細胞が、ヒト細胞である、先行請求項15〜27のいずれかに記載の方法。
- 前記細胞が、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、先行請求項15〜28のいずれかに記載の方法。
- 請求項15〜29のいずれかに記載の方法により得られる誘導樹状細胞。
- 前記細胞が、脾臓DC(天然のDC)よりも生来成熟しており、および/または抗原提示のための外因性活性化刺激にあまり依存しない、先行請求項に記載の誘導樹状細胞。
- 請求項15〜29のいずれかに記載の方法により得られる誘導抗原提示細胞。
- 前記抗原が、癌抗原、自己抗原、アレルゲン、病原性および/または感染性生物体からの抗原である、先行請求項に記載の誘導抗原提示細胞。
- 治療有効量の、請求項30〜31に記載の誘導樹状細胞、または請求項32〜33に記載の誘導抗原提示細胞、またはそれらの混合物と、医薬的に許容できる賦形剤と、を含む組成物。
- 獣医学またはヒト医療における使用のための、先行請求項1〜11、34のいずれかに記載の組成物。
- 免疫療法、または神経変性疾患の処置もしくは治療、または癌の処置もしくは治療、または感染性疾患の処置もしくは治療における使用のための、請求項34〜35のいずれかに記載の組成物。
- 抗ウイルス薬、鎮痛薬、抗炎症薬、化学療法薬、放射線療法薬、抗生物質、利尿剤、またはそれらの混合物をさらに含む、請求項34〜36のいずれかに記載の組成物。
- 充填剤、結合剤、崩壊剤もしくは滑沢剤、またはそれらの混合物をさらに含む、先行請求項34〜37のいずれかに記載の組成物。
- 皮内および経皮治療における使用のための、先行請求項34〜38のいずれかに記載の組成物。
- 注射製剤、特にインサイチュでの注射である、先行請求項34〜39のいずれかに記載の組成物。
- 獣医学またはヒト医療、特に免疫療法、または神経変性もしくは加齢疾患、または癌もしくは感染性疾患における使用、薬物スクリーニングとしての使用のための、先行請求項34〜40のいずれかに記載の組成物。
- 中枢および末梢神経系障害の処置、治療または診断における使用のための、先行請求項34〜41のいずれかに記載の組成物。
- 新生物、特に癌、即ち固形または血液腫瘍の処置、治療または診断における使用のための、先行請求項34〜42のいずれかに記載の組成物。
- 良性腫瘍、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、加齢黄斑変性、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、中空臓器癌、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、または骨髄腫の処置、診断または治療における使用のための、先行請求項34〜43のいずれかに記載の組成物。
- 真菌、ウイルス、クラミジア、細菌、ナノバクテリア、または寄生虫感染性疾患の処置、治療または診断における使用のための、先行請求項34〜44のいずれかに記載の組成物。
- HIV、SARSコロナウイルス、アジア風邪ウイルス、単純ヘルペス、帯状疱疹、肝炎、またはウイルス性肝炎の感染の処置、治療または診断における使用のための、先行請求項34〜45のいずれかに記載の組成物。
- アミロイド疾患、特にアミロイドAアミロイドーシス、アルツハイマー病、軽鎖(AL)アミロイドーシス、2型糖尿病、甲状腺の髄質癌、パーキンソン病、多発ニューロパシー、または海綿状脳症(クロイツフェルト・ヤコブ病)の処置、治療または診断における使用のための、先行請求項34〜46のいずれかに記載の組成物。
- 請求項1〜11、34〜47のいずれか1項に記載の組成物、または請求項30〜31に記載の誘導樹状細胞、または請求項32〜33に記載の誘導抗原提示細胞、またはそれらの混合物を含む、癌のためのワクチン。
- 請求項30〜31に記載の誘導樹状細胞、
請求項32〜33に記載の誘導抗原提示細胞、
先行請求項1〜11、34〜47のいずれかに記載の組成物、
請求項12〜14に記載のベクターもしくは構築物、またはそれらの混合物
の構成要素のうちの少なくとも1つを含むキット。
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