JPWO2019070021A1 - iPS細胞由来の遺伝的多様性を有するT細胞集団の製造方法 - Google Patents
iPS細胞由来の遺伝的多様性を有するT細胞集団の製造方法 Download PDFInfo
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Abstract
Description
〔1〕(1)採取した遺伝的多様性を有するT細胞集団から、目的の組織又は抗原に対して指向性を有するT細胞集団を濃縮する工程、(2)前記濃縮したT細胞集団をiPS細胞へと初期化し、遺伝的多様性を維持したままで、iPS細胞を培養する工程、及び(3)前記培養したiPS細胞から遺伝的多様性を有する再生T細胞集団を製造する工程を含む、iPS細胞を介して遺伝的多様性を有する再生T細胞集団を製造する方法、
〔2〕工程(1)の採取したT細胞集団が、治療対象の哺乳動物由来である、〔1〕に記載の方法、
〔3〕工程(1)の採取したT細胞集団が、腫瘍浸潤T細胞である、〔1〕又は〔2〕に記載の方法、
〔4〕工程(1)の採取したT細胞集団が、血液、リンパ節又は腔水由来である、〔1〕又は〔2〕に記載の方法、
〔5〕工程(1)が、抗原タンパク質又はペプチドでの刺激により活性化し、増殖したT細胞を分離するステップを含む、〔1〕〜〔4〕いずれか1項に記載の方法、
〔6〕工程(2)が、iPS細胞をクローン化せずに回収し、継代するステップを含む、〔1〕〜〔5〕いずれか1項に記載の方法、
〔7〕工程(3)で得られたT細胞集団が、αβT細胞集団、γδT細胞集団、ヘルパーT細胞集団、レギュラトリーT細胞集団、細胞傷害性T細胞集団、NKT細胞集団、又は腫瘍浸潤T細胞集団である、〔1〕〜〔6〕いずれか1項に記載の方法、
〔8〕工程(3)で得られたT細胞集団が、T細胞補充療法に使用するものである、〔1〕〜〔7〕いずれか1項に記載の方法、
〔9〕〔1〕〜〔8〕いずれか記載の方法により得られる再生T細胞集団、〔10〕生体内に存在するT細胞集団の遺伝的多様性を維持している、iPS細胞を介して得られる再生T細胞集団、
〔11〕〔9〕または〔10〕に記載の再生T細胞集団を含有する医薬組成物、
〔12〕自家的または同種的な移植によりがん治療対象を処置するための〔11〕に記載の医薬組成物、
〔13〕〔11〕または〔12〕に記載の医薬組成物を用いる、がん治療方法に関する。
本発明の工程(1)は、採取した遺伝的多様性を有するT細胞集団から、目的の組織又は抗原に対して指向性を有するT細胞集団を濃縮する工程である。
本発明の一態様において、「遺伝的多様性を有するT細胞集団」とは、生体内に存在するCD3及びCD45が陽性であるリンパ球であり、抗原を認識するT細胞受容体(TCR)の遺伝子配列が集団として多様な細胞集団である。生体内に存在するT細胞は、T前駆細胞が胸腺内で発生分化する際に、TCR遺伝子のランダムな組み換えが起こることで、個々のT細胞が異なるTCR遺伝子配列を有し、あらゆる抗原に対して免疫反応を引き起こすことが可能となっている。個々のT細胞が有するTCRはそれぞれ特異的に認識する抗原又はペプチド配列が決定しているものの、T細胞を集団として捉えることにより、そのT細胞集団が、多様な抗原を免疫対象としていることが理解できる。従って、生体から採取されたT細胞集団は、この意味で、遺伝的多様性を有するT細胞集団である。
生体内には、あらゆる抗原に対して反応できるように、非常に多様なT細胞が存在しているが、大半がT細胞補充療法で目的とする抗原とは無関係なT細胞である。そのため、iPS細胞への初期化を介して製造するT細胞の原料として、T細胞補充療法の対象となる癌、腫瘍又はウイルスに反応性のあるT細胞集団を、あらかじめ濃縮しておくことで、治療効果が飛躍的に高まると同時に、想定外の抗原に対する免疫反応を抑制し安全性を高めることが可能となる。
本発明の工程(2)は、前記濃縮したT細胞集団をiPS細胞へと初期化し、遺伝的多様性を維持したまま培養する工程である。
iPS細胞の製造方法は当該分野で公知である。本発明の一態様において、iPS細胞は、好ましくは、工程(1)で濃縮したT細胞集団へ初期化因子を導入することによって製造される。ここで、初期化因子としては、例えば、Oct3/4、Sox2、Sox1、Sox3、Sox15、Sox17、Klf4、Klf2、c-Myc、N-Myc、L-Myc、Nanog、Lin28、Fbx15、ERas、ECAT15-2、Tcl1、beta-catenin、Lin28b、Sall1、Sall4、Esrrb、Nr5a2、Tbx3又はGlis1等の遺伝子又は遺伝子産物が挙げられ、これらの初期化因子は、単独で用いても良く、組み合わせて用いても良い。
iPS細胞を培養する場合、好ましくは、継代が行われる。しかし、一般的な継代方法では、継代に用いる細胞以外の細胞は破棄されてしまうので、遺伝的多様性を有するT細胞集団から樹立されたiPS細胞集団の多様性が次第に失われていってしまう。
本発明の工程(3)は、前記培養したiPS細胞から遺伝的多様性を有する再生T細胞集団を製造する工程である。
造血前駆細胞(Hematopoietic Progenitor Cells (HPC) )とは、リンパ球、好酸球、好中球、好塩基球、赤血球、又は巨核球等の血球系細胞に分化可能な細胞である。本発明の一態様において、造血前駆細胞と造血幹細胞は、区別されるものではなく、特に断りがなければ同一の細胞を示す。造血幹細胞/前駆細胞は、例えば、表面抗原であるCD34及び/又はCD43が陽性であることによって認識できる。
本発明において、「CD4CD8両陽性T細胞」とは、T細胞のうち、表面抗原のCD4及びCD8が共に陽性である細胞(CD8+CD4+)を意味し、T細胞は、表面抗原であるCD3及びCD45が陽性であることによって認識できることから、CD4CD8両陽性T細胞は、CD4、CD8、CD3及びCD45が陽性である細胞として同定することができる。CD4CD8両陽性T細胞は、誘導によってCD4陽性細胞又はCD8陽性細胞へと分化させることができる。
本発明において、「p38阻害剤」とは、p38タンパク質(p38MAPキナーゼ)の機能を阻害する物質として定義される。本発明の一態様において、例えば、p38の化学的阻害剤、p38のドミナントネガティブ変異体、又はそれをコードする核酸等が挙げられるが、これらに限定されない。
23、VX-702、並びにFR167653が挙げられるが、これらに限定されない。これらの化合物は市販されており、例えばSB203580、SB202190、SC239063、SB220025及びPD169316についてはCalbiochem社、SCl0-469及びSCIO-323についてはScios社等から入手可能である。
本発明の一態様において、SDF-1 (Stromal cell-derived factor 1)は、SDF-1α又はその成熟型だけでなく、SDF-1β、SDF-1γ、SDF-1δ、SDF-1ε若しくはSDF-1φ等のアイソフォーム、又はそれらの成熟型であってもよく、或いはこれらの任意の割合の混合物等であってもよい。好ましくは、SDF-1αが使用される。尚、SDF-1は、CXCL-12又はPBSFと称される場合もある。
「CD8陽性T細胞」とは、T細胞のうち、表面抗原のCD8が陽性である細胞(CD8+CD4-)を意味し、細胞傷害性T細胞とも呼ばれる。T細胞は、表面抗原であるCD3及びCD45が陽性であることによって認識できることから、CD8陽性T細胞は、CD8、CD3及びCD45が陽性であり、CD4が陰性である細胞として同定することができる。
採取したT細胞集団に対し、CD3及びCD28抗体で標識された磁気ビーズを用いて活性化刺激を与え、200U/ml IL-2、10ng/ml IL-7、10ng/ml IL-15を添加したRPMI-1640培地(10%ウシ胎児血清、1%Penicillin-Streptomycin-Glutamineを含む)中で2日間培養を行った。
続いて、T細胞を15mlチューブへ回収し、約250μlのRPMI-1640培地に浮遊させた後、CytoTune-iPS 2.0キット(株式会社IDファーマ社:#DV-0304)を用いて、MOI=5となる力価で初期化に必要な4因子(Oct3/4、Sox2、Klf4及びc-Myc)を含むセンダイウイルスを培地に添加し、37℃で2時間インキュベートを行った。インキュベート後には、RPMI-1640培地を用いてT細胞を洗浄し、培地中からウイルスを除去した。
iPS細胞のコロニーが肉眼で確認できるほど大きくなった段階で、iPS細胞を、新しくiMatrix-511をコーティングした6cmディッシュへと継代した。
超低接着処理された6well plate(CORNING社: #3471)に、工程(2)で得られたiPS細胞を3x105〜6x105個/ウェルで播種し(DayO)、EB培地(StemPro34に10μg/mlヒトインスリン、5.5μg/ml ヒトトランスフェリン、5ng/ml 亜セレン酸ナトリウム、2mM L-グルタミン、45mM α-モノチオグリセロール、及び50μg/ml アスコルビン酸を添加)に10 ng/ml BMP4、5ng/ml bFGF、15ng/ml VEGF、2μM SB431542を加えて、低酸素条件下(5%O2)にて5日間培養を行った(Day5)。
前記の方法を用いて、肺癌患者の摘出腫瘍から分離された遺伝的多様性を有するT細胞集団からiPS細胞を樹立し、遺伝的多様性を有するT細胞へと再分化誘導を行った。
Claims (13)
- (1)採取した遺伝的多様性を有するT細胞集団から、目的の組織又は抗原に対して指向性を有するT細胞集団を濃縮する工程、
(2)前記濃縮したT細胞集団をiPS細胞へと初期化し、遺伝的多様性を維持したままで、iPS細胞を培養する工程、及び
(3)前記培養したiPS細胞から遺伝的多様性を有する再生T細胞集団を製造する工程を含む、iPS細胞を介して遺伝的多様性を有する再生T細胞集団を製造する方法。 - 工程(1)の採取したT細胞集団が、治療対象の哺乳動物由来である、請求項1に記載の方法。
- 工程(1)の採取したT細胞集団が、腫瘍浸潤T細胞である、請求項1又は2に記載の方法。
- 工程(1)の採取したT細胞集団が、血液、リンパ節又は腔水由来である、請求項1又は2に記載の方法。
- 工程(1)が、抗原タンパク質又はペプチドでの刺激により活性化し、増殖したT細胞を分離するステップを含む、請求項1〜4いずれか1項に記載の方法。
- 工程(2)が、iPS細胞をクローン化せずに回収し、継代するステップを含む、請求項1〜5いずれか1項に記載の方法。
- 工程(3)で得られたT細胞集団が、αβT細胞集団、γδT細胞集団、ヘルパーT細胞集団、レギュラトリーT細胞集団、細胞傷害性T細胞集団、NKT細胞集団、又は腫瘍浸潤T細胞集団である、請求項1〜6いずれか1項に記載の方法。
- 工程(3)で得られたT細胞集団が、T細胞補充療法に使用するものである、請求項1〜7いずれか1項に記載の方法。
- 請求項1〜8いずれか1項に記載の方法により得られる再生T細胞集団。
- 生体内に存在するT細胞集団の遺伝的多様性を維持している、iPS細胞を介して得られる再生T細胞集団。
- 請求項9または請求項10に記載の再生T細胞集団を含有する医薬組成物。
- 自家的または同種的な移植によりがん治療対象を処置するための請求項11に記載の医薬組成物。
- 請求項11または請求項12に記載の医薬組成物を用いる、がん治療方法。
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US20220233665A1 (en) * | 2019-06-14 | 2022-07-28 | Thyas Co. Ltd. | Medicinal composition |
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WO2016010155A1 (ja) * | 2014-07-18 | 2016-01-21 | 宏 河本 | 抗原特異的t細胞受容体遺伝子を有する多能性幹細胞の製造方法 |
WO2016076145A1 (ja) * | 2014-11-11 | 2016-05-19 | 新日鉄住金化学株式会社 | 非水電解液二次電池 |
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CN111164204A (zh) | 2020-05-15 |
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WO2019070021A1 (ja) | 2019-04-11 |
US20200345789A1 (en) | 2020-11-05 |
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