JP6932709B2 - Her2を標的とするキメラ抗原受容体 - Google Patents
Her2を標的とするキメラ抗原受容体 Download PDFInfo
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Description
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGSTSGGGSGGGSGGGGSSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS;配列番号1)又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体;CD4膜貫通ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体、CD8膜貫通ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体、CD28膜貫通ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体及びCD3ξ膜貫通ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体から選択される膜貫通ドメイン;共刺激ドメイン(例えば、CD28共刺激ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体;又は、4−1BB共刺激ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体;又は、CD28共刺激ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体及び4−1BB共刺激ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾(例えば置換)を有するその変異体の両方);並びに、CD3ξシグナル伝達ドメイン又は1〜5(例えば1又は2)のアミノ酸修飾を有するその変異体;を含む。
本明細書において記載されるHER2 scFvを含む1つのCARは、Her2scFv−IgG4(L235E、N297Q)−CD28tm−CD28gg−Zeta−T2A−CD19tと呼ばれる。このCARは:HER2を標的とするscFv;Fe受容体(FcRs)による結合を減らす様式でCH2領域内の2つの部位(L235E;N297Q)にて突然変異されたIgG4 Fe領域;CD28膜貫通ドメイン、CD28共刺激ドメイン及びCD3ξ活性化ドメインを含む様々な重要な特徴を含む。図1は、このCARのアミノ酸配列を示しており、CAR発現をモニターするために使用されるトランケート型CDI9配列の配列、及び、トランケート型CDI9配列の融合なしでCARが作製されるのを可能にするT2Aリボソームスキップ配列を含む。図2において示されているように、未成熟CARは:GMCSFRシグナルペプチド、HER2 scFv、スペーサーとして作用するIgG4、CD8膜貫通ドメイン、LLからGGへの配列変化を含む4−IBB共刺激ドメイン、Gly3つの配列、CD3ゼータ刺激ドメインを含む。転写物も、CARタンパク質配列の一部ではないT2Aリボソーム配列及びトランケート型CDI9配列をコードする。成熟CARは、未成熟CARと同一であるが、GMCSFシグナルペプチドを欠いている。
epHIV7ベクターは、HER2特異的CARの発現に使用することができるベクターであり、pHIV7ベクターから作製した。重要なことに、このベクターは、ヒトEFIプロモーターを使用してCARの発現を駆動する。ベクターの5´配列も3´配列も、HXBc2プロウイルスから以前に得たpv653RSNから得た。ポリプリン区域DNAフラップ配列(cPPT)を、NIH AIDS Reagent Repository由来のHIV−I株pNL4−3から得た。ウッドチャック転写後制御要素(WPRE)配列は以前に記載されている。
患者T細胞の形質導入のためのベクターは、以下のように調製することができる。CAR、及び、任意選択でトランケート型CD19;2)pCgp;3)pCMV−G;及び4)pCMV−Rev2等のマーカーを発現する各プラスミドに対して、種子バンクが生成され、種子バンクは、発酵槽を播種して十分な量のプラスミドDNAを生じるために使用される。プラスミドDNAは、レンチウイルスベクターの作製におけるその使用に先立ち、同一性、無菌性及びエンドトキシンについて試験される。
TCMがCARを発現するために使用されることになる場合、適した患者細胞を以下のように調製することができる。第一に、Tリンパ球が、白血球フェレーシスによって患者から得られ、さらに、適切な同種又は自己T細胞のサブセット、例えばセントラルメモリーT細胞(TCM)が、CARを発現するように遺伝子改変され、次に、抗癌療法を達成するために、任意の臨床的に許容可能な手段によって患者に投与され戻される。
図3Aは、図1及び図2において描かれている2つのHER2特異的CAR構築物の概略図である。HER2(EQ)28ξにおいて、scFvは、CD28膜貫通ドメイン、細胞内CD28共刺激ドメイン及び細胞溶解性CD3ξドメインを含有する改変IgG4Fcリンカー(二重変異体、L235E;N297Q)によって膜に繋ぎ止められる。T2Aスキップ配列は、細胞トラッキングのために利用されるトランケート型CD19(CD19t)タンパク質からCARを分離する。HER2(EQ)BBξは、共刺激ドメインがCD28ではなく4−1BBであること、及び、膜貫通ドメインがCD28膜貫通ドメインではなくCD8膜貫通ドメインであることを除いて類似している。ヒトセントラルメモリー(TCM)細胞を、HER2(EQ)28ξ又はHER2(EQ)BBξのいずれかを発現するレンチウイルスベクターで遺伝子導入した。図3Bは、ヒトTCM表面表現型の代表的なFACSデータを描いている。図3Cは、HER2(EQ)28ξ又はHER2(EQ)BBξのいずれかを発現するレンチウイルスベクターで遺伝子導入されたTCMにおけるCD19及びタンパク質Lの発現に対するアッセイの結果を描いている。これらの結果からわかるように、CD19の発現によって評価された導入効率は、両方のCARに対して類似していた。しかし、タンパク質Lの発現は、HER2(EQ)28ξよりもHER2(EQ)BBξにおいて低く、HER2(EQ)BBξCARは、HER2(EQ)BBξよりも安定性が低いことを示唆している。細胞増殖の分析(図3D)が、いずれのCARもT細胞増殖に干渉しないことを示している。
HER2陰性細胞株(LCLリンパ腫、MDA−MB−468、U87グリオーマ)、低HER2発現細胞株(MDA−MB−361、231BR)及び高HER2発現細胞株(SKBR3、BT474、BBM1)を含む様々な乳癌細胞株を使用して、HER2(EQ)28及びHER2(EQ)BBξを特徴づけた。図4Aは、これらの細胞株のそれぞれのHER2発現レベルを描いている。フローサイトメトリー(CAR+T細胞にゲートのある)を使用して、MDA−MB−361腫瘍細胞との(低HER2発現)、又は、BBM1腫瘍細胞(高いHER2発現)との5時間の共培養に続くMock(形質導入されていない)、HER2(EQ)28ξ又はHER2(EQ)BBξ CAR T細胞におけるCD107a脱顆粒及びIFNyの産生を特徴づけた。この分析の結果が、図4Bにおいて示されている。類似の研究を、他の乳癌細胞株を用いて行い、その結果が図4Cにおいて要約されている。組換えHER2タンパク質又は腫瘍標的を用いた24時間の培養に続くHER2−CAR T細胞によるIFNγの生成を、ELISAによって測定し、この分析の結果が図4Dにおいて示されている。
フローサイトメトリーを使用して、Mock(形質導入されていない)、HER2(EQ)28ξ又はHER2(EQ)BBξ CAR T細胞の腫瘍標的との72時間の共培養に続く腫瘍細胞死滅を評価した。この分析の結果は、図5Aに示されている。HER2陰性MDA−MB−468又はHER2陽性BBM1細胞との72時間の共培養後の全CAR T細胞におけるPD−1及びLAG−3誘導を測定し、この分析の結果は、図5Bに示されている。HER2陰性(LCLリンパ腫、MDA−MB−468、U87グリオーマ)、低HER2発現(MDA−MB−361、231BR)又は高HER2発現(SKBR3、BT474、BBM1)である腫瘍標的との72時間の共培養に続くCD8+CAR T細胞におけるPD−1誘導を測定し、この分析の結果は、図5Cに示されている。これらの研究は、HER2(EQ)BBξが、HER2(EQ)28ξよりも低いPD−1誘導を引き起こすことを示唆している。0.25:1から2:1に及ぶエフェクター:腫瘍(E:T)比を有する腫瘍細胞死滅を、HER2(EQ)28ξCAR T細胞又はHER2(EQ)BBξCAR T細胞両方に対して測定した。この分析の結果は、図5Dに示されており、HER2(EQ)28ξもHER2(EQ)BBξも、in vitroで腫瘍細胞死滅において効果的であるということが示されている。MDA−MB−468又はBBMI細胞との72時間の共培養に続くHER2−CAR T細胞のCFSE増殖を、フローサイトメトリーによって測定した。この分析の結果は、図5Eに示されており、HER2(EQ)BBξCAR T細胞はHER2(EQ)28ξCAR T細胞よりも増殖するということが示されている。
腫瘍内に送達されたHER2 CAR T細胞の活性を、患者由来の乳房から脳への転移モデルにおいて評価した。図6A〜6Cは、腫瘍のH&E染色である。マウスを、Mock(形質導入されていない)又はHER2(EQ)BBξCAR T細胞で腫瘍内への直接の注入により処置した。図6D〜6Fは、腫瘍の光学イメージングの結果を描いており、図6G〜6Iは、腫瘍注入後3日、8日又は14日に局所的に処置したマウスに対するカプラン・マイヤー生存曲線である。これらの研究は、HER2(EQ)BBξCAR T細胞が、腫瘍に直接注入された場合に、in vivoで強力な抗腫瘍効力を有することを示している。
図9〜14は、異なるリンカーを有する種々のCARのアミノ酸配列を描いている。具体的には、CARは、HER2を標的とするscFvと膜貫通ドメインとの間の部分の配列及び長さが異なる。膜貫通ドメインは、CD8、CD28又はCD28ggである。共刺激ドメインは、4−1BB又はCD28である。全てがCD3ζ刺激ドメインを有する。いずれの場合にも、T2Aスキップ配列が、細胞トラッキングのために利用されるトランケート型CD19(CD19t)タンパク質からCARを分離する。
Claims (14)
- キメラ抗原受容体をコードする核酸分子であって、前記キメラ抗原受容体は、配列番号26及び27から選択されるアミノ酸配列又はその1〜5のアミノ酸修飾を有するその変異体を含む、核酸分子。
- 配列番号26及び27から選択されるアミノ酸配列又は1〜5のアミノ酸修飾を有するその変異体を含むポリペプチドを発現する、請求項1に記載の核酸分子。
- 前記キメラ抗原受容体は、配列番号26及び27から選択されるアミノ酸配列を含む、請求項1に記載の核酸分子。
- 前記1〜5のアミノ酸修飾は、1又は2のアミノ酸修飾である、請求項1に記載の核酸分子。
- 前記1〜5のアミノ酸修飾は、1〜5のアミノ酸置換である、請求項1に記載の核酸分子。
- キメラ抗原受容体をコードする発現カセットを含むベクターによって形質導入されたヒトT細胞の集団であって、前記キメラ抗原受容体は、配列番号26及び27から選択されるアミノ酸配列又は1〜5のアミノ酸修飾を有するその変異体を含む、ヒトT細胞の集団。
- 前記T細胞は、セントラルメモリーT細胞の集団で構成される、請求項6に記載のヒトT細胞の集団。
- 患者におけるHER2発現脳がんの治療方法で用いられる、キメラ抗原受容体をコードする発現カセットを含むベクターによって形質導入された自己ヒトT細胞又は同種ヒトT細胞の集団であって、前記自己ヒトT細胞又は同種ヒトT細胞の集団は、前記患者に投与され、かつ、前記キメラ抗原受容体は、配列番号26及び27から選択されるアミノ酸配列又は1〜5のアミノ酸修飾を有するその変異体を含む、自己ヒトT細胞又は同種ヒトT細胞の集団。
- 前記ヒトT細胞の集団は、CD62L+メモリーT細胞を含む、請求項8に記載の自己ヒトT細胞又は同種ヒトT細胞の集団。
- 前記がんは、乳房から脳への転移である、請求項8に記載の自己ヒトT細胞又は同種ヒトT細胞の集団。
- 前記形質導入されたヒトT細胞は、前記患者からT細胞を取得するステップ、セントラルメモリーT細胞を単離するために前記T細胞を処理するステップ、及び、キメラ抗原受容体をコードする発現カセットを含むウイルスベクターを用いて前記セントラルメモリー細胞の少なくとも一部に形質導入を行うステップを含む方法によって調製され、キメラ抗原受容体は、配列番号26及び27から選択されるアミノ酸配列又は1〜5のアミノ酸修飾を有するその変異体を含む、請求項8に記載の自己ヒトT細胞又は同種ヒトT細胞の集団。
- 前記T細胞は、腫瘍内又は脳室内に投与される、請求項8に記載の自己ヒトT細胞又は同種ヒトT細胞の集団。
- 配列番号26及び27から選択されるアミノ酸配列と少なくとも95%同一であるアミノ酸配列を含むポリペプチドをコードする核酸分子。
- 配列番号26及び27から選択されるアミノ酸配列又は1〜5のアミノ酸修飾を有するその変異体と同一であるアミノ酸配列を含むポリペプチドを発現するT細胞。
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CN108779174A (zh) | 2018-11-09 |
CN116063574A (zh) | 2023-05-05 |
CN108779174B (zh) | 2022-11-29 |
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