JP2021536240A - 改良された治療用t細胞 - Google Patents
改良された治療用t細胞 Download PDFInfo
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Abstract
Description
実施例における統計学的分析は、GraphPadソフトウェア(GraphPad Prism v5.0;GraphPad Software,San Diego,CA,USA)を使用して行う。対応のあるt検定を行った後、Newman−Keuls検定を行ってデータを解析する。結果を平均値±SEMとして示す。p値<0.05が有意であると考えられる。
CAR形質導入用レンチウイルスベクターは、所望のCARトランスジェニックを含み、細胞内で発現できるものでなければならない。それぞれ旧ベクターpPVLV1(図1A)と新ベクターpPVLV2(図1B)である、CARを発現するための第三世代レンチウイルスベクターを2種類設計した。pPVLV1は531bpの長いヒト伸長因子1α(EF1α)プロモーターを含み、pPVLV1は212bpの短いヒトEF1αプロモーターを含む。2種類のベクターに含まれる各エレメント及びその説明は、次の表1に記載される。
異なるプロモーターの影響をさらに証明するために、図3の2種のCAR−ルシフェラーゼレポーターベクターはpPVLV2に基づいて構築され、それらの違いはトランスジェニック発現を駆動するプロモーターのみであり、ここで、CAR−19はP2A−Fluc(ホタルルシフェラーゼ)カセットの上流にクローニングされ、ジシストロンを形成している(図3AとB)。
TGF−βは重要なT細胞抑制因子であり、標的細胞に対する治療用T細胞の殺傷作用を弱めたり消失させたりする可能性がある。臨床上、TGF−βは多くの腫瘍組織に広く発現し、腫瘍細胞に対する腫瘍特異的T細胞の殺傷活性を著しく抑制し、免疫治療が失敗する重要な原因である。一方、優性ネガティブTGF−βII型受容体(dominant negative TGF−βreceptor type II、DNRII)はTGF−βのネガティブ調節受容体であり、T細胞に対するTGF−βの抑制作用を抑制する。以下の実施例は、T細胞におけるCARとDNRIIの共発現の効果を検討する。DNRIIのアミノ酸配列はSEQ ID NO:17で示され、そのヌクレオチド配列はSEQ ID NO:18で示される。
T細胞に対するTFG−βの抑制作用は、TFG−βがその受容体に結合した後、SMAD2分子のリン酸化を行うことにより達成される。
IFN−γとTNF−αはT細胞が標的細胞を殺傷するマーカーサイトカインである。この2種のサイトカインの発現レベルが高いことは、標的細胞に対するT細胞の殺傷能力が高いことを示し、逆の場合は、殺傷能力が低いことを示している。
12日間形質導入したCAR−T−19細胞とCAR−T−19−DNRII細胞を用いて標的細胞殺傷実験を行った。
Claims (32)
- 外因性癌関連抗原特異的受容体タンパク質と優性ネガティブTGF−βII型受容体とをT細胞に共発現させることを含む、癌関連抗原を特異的に標的化する治療用T細胞の製造方法。
- 前記優性ネガティブTGF−βII型受容体は、TGF−βII型受容体の細胞内シグナル伝達ドメインを欠失しており、たとえば、前記優性ネガティブTGF−βII型受容体は、SEQ ID NO:18で示されるアミノ酸配列を含む、請求項1に記載の方法。
- 前記外因性癌関連抗原特異的受容体タンパク質は、T細胞受容体(TCR)及びキメラ型抗原受容体(CAR)から選択される、請求項1又は2に記載の方法。
- 前記TCRは癌関連抗原に特異的に結合し、前記CARは癌関連抗原に対する細胞外抗原結合ドメインを含む、請求項3に記載の方法。
- 前記CARは、scFvなどの癌関連抗原に特異的に結合する細胞外抗原結合ドメイン、CD8ヒンジ及び膜貫通ドメイン、CD3ζシグナル伝達ドメイン、及び4−1BB共刺激ドメインを含む、請求項4に記載の方法。
- 前記癌関連抗原は、CD16、CD64、CD78、CD96、CLL1、CD116、CD117、CD71、CD45、CD71、CD123、CD138、ErbB2(HER2/neu)、癌胎児抗原(CEA)、上皮細胞接着分子(EpCAM)、上皮成長因子受容体(EGFR)、EGFRバリアントIII(EGFRvIII)、CD19、CD20、CD30、CD40、ジシアロガングリオシドGD2、乳管上皮ムチン、gp36、TAG−72、スフィンゴ糖脂質、グリオーマ関連抗原、β−ヒト絨毛性ゴナドトロピン、α−胎児グロブリン(AFP)、外来レクチン反応性AFP、サイログロブリン、RAGE−1、MN−CA IX、ヒトテロメラーゼ逆転写酵素、RU1、RU2(AS)、腸カルボキシエステラーゼ、mut hsp70−2、M−CSF、プロスターゼ(prostase)、プロスターゼ特異的抗原(PSA)、PAP、NY−ESO−1、LAGA−1a、p53、Prostein、PSMA、生存及びテロメラーゼ、前立腺癌腫瘍抗原−1(PCTA−1)、MAGE、ELF2M、好中球エラスターゼ、エフリンB2、CD22、インスリン成長因子(IGF1)−I、IGF−II、IGFI受容体、メソテリン、腫瘍特異的ペプチドエピトープを提示する主要組織適合性複合体(MHC)分子、5T4、ROR1、Nkp30、NKG2D、腫瘍間質抗原、フィブロネクチンの追加ドメインA(EDA)及び追加ドメインB(EDB)、テネイシン−CのA1ドメイン(TnC A1)、線維芽細胞関連タンパク質(fap)、CD3、CD4、CD8、CD24、CD25、CD33、CD34、CD133、CD138、Foxp3、B7−1(CD80)、B7−2(CD86)、GM−CSF、サイトカイン受容体、内皮因子、BCMA(CD269、TNFRSF17)、TNFRSF17(UNIPROT Q02223)、SLAMF7(UNIPROT Q9NQ25)、GPRC5D(UNIPROT Q9NZD1)、FKBP11(UNIPROT Q9NYL4)、KAMP3、ITGA8(UNIPROT P53708)、及びFCRL5(UNIPROT Q68SN8)から選択される、請求項1〜5のいずれか1項に記載の方法。
- 前記CARは、CD19に対する細胞外抗原結合ドメインを含み、たとえば、前記CARはSEQ ID NO:16で示されるアミノ酸配列を含む、請求項6に記載の方法。
- レンチウイルスベクターを含むレンチウイルス粒子を前記T細胞に形質導入することを含み、
前記レンチウイルスベクターは、自己切断ペプチドを介して連結された前記外因性癌関連抗原特異的受容体タンパク質と前記優性ネガティブTGF−βII型受容体を含む融合ポリペプチドをコードするヌクレオチド配列を含み、それにより、前記外因性癌関連抗原特異的受容体タンパク質と前記優性ネガティブTGF−βII型受容体を前記T細胞に共発現させる、請求項1〜7のいずれか1項に記載の方法。 - 前記自己切断ペプチドは2Aポリペプチドであり、たとえば、P2A、F2A、E2A若しくはT2Aポリペプチド、又はその機能的バリアントから選択される、請求項8に記載の方法。
- 融合ポリペプチドをコードする前記ヌクレオチド配列は、たとえばSEQ ID NO:13で示されるヌクレオチド配列を含むトランケートEF1αプロモーターに作動可能に連結されている、請求項8又は9に記載の方法。
- 前記レンチウイルスベクターは、5’LTR、ψエレメント、RREエレメント、cPPT/CTSエレメント、WPREエレメント、及び3’LTRから選択される少なくとも1つのエレメントをさらに含む、請求項8〜10のいずれか1項に記載の方法。
- 前記レンチウイルスベクターは、作動可能に連結された5’LTR、ψエレメント、RREエレメント、cPPT/CTSエレメント、前記トランケートEF1αプロモーター、融合ポリペプチドをコードする前記ヌクレオチド配列、WPREエレメント、及び3’LTRを含む、請求項11に記載の方法。
- 前記5’LTRは、SEQ ID NO:3又は11で示されるヌクレオチド配列を含み、前記ψエレメントは、SEQ ID NO:4又は12で示されるヌクレオチド配列を含み、前記RREエレメントは、SEQ ID NO:5で示されるヌクレオチド配列を含み、前記cPPT/CTSエレメントは、SEQ ID NO:6で示されるヌクレオチド配列を含み、前記WPREエレメントは、SEQ ID NO:9又は14で示されるヌクレオチド配列を含み、前記3’LTRは、SEQ ID NO:10又は15で示されるヌクレオチド配列を含む、請求項11又は12に記載の方法。
- 前記レンチウイルスベクターは、作動可能に連結された、SEQ ID NO:11で示されるヌクレオチド配列を含む5’LTR、SEQ ID NO:12で示されるヌクレオチド配列を含むψエレメント、SEQ ID NO:5で示されるヌクレオチド配列を含むRREエレメント、SEQ ID NO:6で示されるヌクレオチド配列を含むcPPT/CTSエレメント、SEQ ID NO:13で示されるヌクレオチド配列を含むトランケートEF1αプロモーター、融合ポリペプチドをコードする前記ヌクレオチド配列、SEQ ID NO:14で示されるヌクレオチド配列を含むWPREエレメント、及びSEQ ID NO:15で示されるヌクレオチド配列を含む3’LTRを含む、請求項13に記載の方法。
- 請求項1〜14のいずれか1項に記載の方法により産生された、癌関連抗原を特異的に標的化する治療用T細胞。
- 癌関連抗原を特異的に標的化する治療用T細胞であって、
外因性癌関連抗原特異的受容体タンパク質と優性ネガティブTGF−βII型受容体とを共発現させ、
自己切断ペプチドを介して連結された前記外因性癌関連抗原特異的受容体タンパク質と前記優性ネガティブTGF−βII型受容体を含む融合ポリペプチドをコードするヌクレオチド配列を含むレンチウイルスベクターを含む治療用T細胞。 - 前記優性ネガティブTGF−βII型受容体はTGF−βII型受容体の細胞内シグナル伝達ドメインを欠失しており、たとえばSEQ ID NO:18で示されるアミノ酸配列を含む、請求項16に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記外因性癌関連抗原特異的受容体タンパク質は、T細胞受容体(TCR)及びキメラ型抗原受容体(CAR)から選択される、請求項16又は17に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記TCRは癌関連抗原に特異的に結合し、前記CARは癌関連抗原に対する細胞外抗原結合ドメインを含む、請求項18に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記CARは、scFvなどの癌関連抗原に特異的に結合する細胞外抗原結合ドメイン、CD8ヒンジ及び膜貫通ドメイン、CD3ζシグナル伝達ドメイン、及び4−1BB共刺激ドメインを含む、請求項19に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記癌関連抗原は、CD16、CD64、CD78、CD96、CLL1、CD116、CD117、CD71、CD45、CD71、CD123、CD138、ErbB2(HER2/neu)、癌胎児抗原(CEA)、上皮細胞接着分子(EpCAM)、上皮成長因子受容体(EGFR)、EGFRバリアントIII(EGFRvIII)、CD19、CD20、CD30、CD40、ジシアロガングリオシドGD2、乳管上皮ムチン、gp36、TAG−72、スフィンゴ糖脂質、グリオーマ関連抗原、β−ヒト絨毛性ゴナドトロピン、α−胎児グロブリン(AFP)、外来レクチン反応性AFP、サイログロブリン、RAGE−1、MN−CA IX、ヒトテロメラーゼ逆転写酵素、RU1、RU2(AS)、腸カルボキシエステラーゼ、mut hsp70−2、M−CSF、プロスターゼ(prostase)、プロスターゼ特異的抗原(PSA)、PAP、NY−ESO−1、LAGA−1a、p53、Prostein、PSMA、生存及びテロメラーゼ、前立腺癌腫瘍抗原−1(PCTA−1)、MAGE、ELF2M、好中球エラスターゼ、エフリンB2、CD22、インスリン成長因子(IGF1)−I、IGF−II、IGFI受容体、メソテリン、腫瘍特異的ペプチドエピトープを提示する主要組織適合性複合体(MHC)分子、5T4、ROR1、Nkp30、NKG2D、腫瘍間質抗原、フィブロネクチンの追加ドメインA(EDA)及び追加ドメインB(EDB)、テネイシン−CのA1ドメイン(TnC A1)、線維芽細胞関連タンパク質(fap)、CD3、CD4、CD8、CD24、CD25、CD33、CD34、CD133、CD138、Foxp3、B7−1(CD80)、B7−2(CD86)、GM−CSF、サイトカイン受容体、内皮因子、BCMA(CD269、TNFRSF17)、TNFRSF17(UNIPROT Q02223)、SLAMF7(UNIPROT Q9NQ25)、GPRC5D(UNIPROT Q9NZD1)、FKBP11(UNIPROT Q9NYL4)、KAMP3、ITGA8(UNIPROT P53708)、及びFCRL5(UNIPROT Q68SN8)から選択される、請求項16〜20のいずれか1項に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記CARはCD19に対する細胞外抗原結合ドメインを含み、たとえば、前記CARはSEQ ID NO:16で示されるアミノ酸配列を含む、請求項21に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記自己切断ペプチドは2Aポリペプチドであり、たとえばP2A、F2A、E2A若しくはT2Aポリペプチド、又はその機能的バリアントから選択される、請求項16〜22のいずれか1項に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 融合ポリペプチドをコードする前記ヌクレオチド配列は、たとえばSEQ ID NO:13で示されるヌクレオチド配列を含むEF1αコアプロモーターであるトランケートEF1αプロモーターに作動可能に連結されている、請求項16〜23のいずれか1項に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記レンチウイルスベクターは、5’LTR、ψエレメント、RREエレメント、cPPT/CTS配列、WPREエレメント、及び3’LTRから選択される少なくとも1つのエレメントをさらに含む、請求項16〜24のいずれか1項に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記レンチウイルスベクターは、作動可能に連結された、5’LTR、ψエレメント、RREエレメント、cPPT/CTSエレメント、前記トランケートEF1αプロモーター、融合ポリペプチドをコードする前記ヌクレオチド配列、WPREエレメント、及び3’LTRを含む、請求項25に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記5’LTRはSEQ ID NO:3又は11で示されるヌクレオチド配列を含み、前記ψエレメントはSEQ ID NO:4又は12で示されるヌクレオチド配列を含み、前記RREエレメントはSEQ ID NO:5で示されるヌクレオチド配列を含み、前記cPPT/CTSエレメントはSEQ ID NO:6で示されるヌクレオチド配列を含み、前記WPREエレメントはSEQ ID NO:9又は14で示されるヌクレオチド配列を含み、前記3’LTRはSEQ ID NO:10又は15で示されるヌクレオチド配列を含む、請求項25又は26に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 前記レンチウイルスベクターは、作動可能に連結された、SEQ ID NO:11で示されるヌクレオチド配列を含む5’LTR、SEQ ID NO:12で示されるヌクレオチド配列を含むψエレメント、SEQ ID NO:5で示されるヌクレオチド配列を含むRREエレメント、SEQ ID NO:6で示されるヌクレオチド配列を含むcPPT/CTSエレメント、SEQ ID NO:13で示されるヌクレオチド配列を含むトランケートEF1αプロモーター、融合ポリペプチドをコードする前記ヌクレオチド配列、SEQ ID NO:14で示されるヌクレオチド配列を含むWPREエレメント、及びSEQ ID NO:15で示されるヌクレオチド配列を含む3’LTRを含む、請求項27に記載の癌関連抗原を特異的に標的化する治療用T細胞。
- 請求項15〜28のいずれか1項に記載の癌関連抗原を特異的に標的化する治療用T細胞と、医薬的に許容可能な担体と、を含む医薬組成物。
- 対象における癌を治療するための医薬品の製造における、請求項15〜28のいずれか1項に記載の癌関連抗原を特異的に標的化する治療用T細胞又は請求項29の医薬組成物の使用。
- 請求項15〜28のいずれか1項に記載の癌関連抗原を特異的に標的化する治療用T細胞又は請求項29に記載の医薬組成物の治療有効量を対象に投与することを含む、対象における癌を治療する方法。
- 前記癌は、肺癌、卵巣癌、結腸癌、直腸癌、メラノーマ、腎臓癌、膀胱癌、乳癌、肝臓癌、リンパ腫、悪性血液疾患、頭頸部癌、グリオーマ、胃癌、鼻咽頭癌、喉頭癌、子宮頸癌、子宮体腫、骨肉腫、骨癌、膵臓癌、皮膚癌、前立腺癌、子宮癌、肛門癌、精巣癌、卵管癌、子宮内膜癌、膣癌、陰部癌、ホジキン病、非ホジキンリンパ腫、食道癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、軟部肉腫、尿道癌、陰茎癌、慢性又は急性白血病(急性骨髄性白血病、慢性骨髄性白血病、急性リンパ球性白血病、慢性リンパ球性白血病を含む)、小児固形腫瘍、リンパ球性リンパ腫、膀胱癌、腎臓又は尿管癌、腎盂癌、中枢神経系(CNS)腫瘍、原発性CNSリンパ腫、腫瘍血管発生、脊柱腫瘍、脳幹神経グリオーマ、下垂体腺腫、カポジ肉腫、類表皮癌、扁平上皮癌、T細胞リンパ腫、環境誘発癌(アスベスト誘発癌を含む)、及び前記癌の組み合わせから選択され、たとえば、前記癌はB細胞急性リンパ球性白血病(B−ALL)である、前記請求項1〜31のいずれか1項に記載の方法、治療用T細胞、医薬組成物又は使用。
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