JP6464140B2 - 腫瘍抗原を直接認識するために組換えt細胞レセプターを使用するための組成物及び方法 - Google Patents
腫瘍抗原を直接認識するために組換えt細胞レセプターを使用するための組成物及び方法 Download PDFInfo
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- JP6464140B2 JP6464140B2 JP2016501939A JP2016501939A JP6464140B2 JP 6464140 B2 JP6464140 B2 JP 6464140B2 JP 2016501939 A JP2016501939 A JP 2016501939A JP 2016501939 A JP2016501939 A JP 2016501939A JP 6464140 B2 JP6464140 B2 JP 6464140B2
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Description
1.HLA-DRB1*01-拘束NY-ESO-1:96-106-特異的TR-CD4
(本明細書では、クローン「SB95」と呼ばれる)
2.HLA-DPB1*04-拘束NY-ESO-1:157-170-特異的TR-CD4
(本明細書では、クローン「5B8」と呼ばれる)
3.HLA-DPB1*04-拘束NY-ESO-1:157-170-特異的TR-CD4
(本明細書では、クローン「JM」と呼ばれる)
「JM」 HLA-DPB1*0401/0402-拘束NY-ESO-1157-170-特異的腫瘍認識CD4+T細胞クローン
(a) TCRα及びβ鎖のcDNAヌクレオチド配列
(a)TCRα及びβ鎖のcDNAヌクレオチド配列
(a)TCRα及びβ鎖のcDNAヌクレオチド配列
ウイルス形質導入は、マウス幹細胞ウイルスベクターpMSCV-由来プラスミド(pMIG-IIやpMIG-w等)を使用して行われた(図6A)。TCR-発現コンストラクトは、pMIGプラスミドのマルチクローニングサイト(MCS)に挿入された。pMIGプラスミドは、形質導入の有効性が、GFP発現によってモニターできるように、マルチクローニングサイトの後にIRES-GFPを有する。
PBMC(全細胞)が、密度勾配分離法によって得られ、使用するまで、90%のウシ胎児血清(FBS)と10%のジメチルスルホキシド(DMSO)中で、液体窒素タンク中で保管された。PBMC(3-4×106細胞/ウェル;24-ウェル培養プレート)は、培地(10%FBS、L-グルタミン、ストレプトマイシン、ペニシリン及びヒト組換えIL-2を含むRPMI1640培地)中で2日間、10μg/mLのフォトヘマグルチニン(PHA)によって多クローン的に活性化された。100μL培地中の1×105のプレ活性化PBMCが、PBS中の20〜25μg/mLのレトロネクチンでプレコートされ、PBS中の2%のウシ血清アルブミン(BSA)でブロックされた96ウェル培養プレートのウェルに添加された。いくつかの実験では、5μg/mLの抗CD3モノクローナル抗体(クローン:OKT3)が、レトロネクチンとともにコートされた。100μLのレトロウイルスを含む上清が、PBMCに添加され24時間インキュベートされた。レトロウイルス感染は、24時間ごとに2〜3回実施された。感染後、細胞は10〜14日間増殖され、機能分析のために使用された。
(1)pMIG-II/JM-TCR(II)
(2)pMIG-II/SB95-TCR(II)
(3)pMIG-w/JM-TCR(I)
(4)pMIG-w/SB95-TCR(I)
(5)pMIG-w/JM-TCR(II)
(6)pMIG-w/SB95-TCR(II)
Claims (8)
- T細胞レセプタ−(TCR)をコードする組換えポリヌクレオチドを含む改変ヒトT細胞であって、
前記T細胞が、NY-ESO-1抗原を発現している癌細胞を直接認識する能力を有し、前記癌細胞の直接認識は、前記癌細胞によって発現されたNY-ESO-1抗原への、TCRのヒト白血球抗原(HLA)クラスII-拘束性結合を含むこと、及び
前記組換えポリヌクレオチドが、配列番号3の配列を有するTCRα鎖及び配列番号4の配列を有するTCRβ鎖をコードするか、または前記組換えポリヌクレオチドが、配列番号11の配列を有するTCRα鎖及び配列番号12の配列を有するTCRβ鎖をコードすること
を特徴とする、改変ヒトT細胞。 - 前記α鎖及び/又は前記β鎖をコードする配列がイントロンを含まない、請求項1に記載の改変ヒトT細胞。
- 癌が発症または再発していると診断された、その疑いがある、またはそのリスクがある個体を予防及び/又は治療するための組成物であって、前記癌は、NY-ESO-1抗原を発現する癌細胞を有し、当該組成物は、T細胞レセプタ−(TCR)をコードする組換えポリヌクレオチドを含む改変ヒトT細胞を含み、前記T細胞は、NY-ESO-1抗原を発現している癌細胞を直接認識する能力を有し、前記癌細胞の直接認識は、前記癌細胞によって発現されたNY-ESO-1抗原への、TCRのヒト白血球抗原(HLA)クラスII-拘束性結合を含み、前記組換えポリヌクレオチドは、配列番号3の配列を有するTCRα鎖及び配列番号4の配列を有するTCRβ鎖をコードしているか、または配列番号11の配列を有するTCRα鎖及び配列番号12の配列を有するTCRβ鎖をコードしている、組成物。
- 前記改変ヒトT細胞がCD4 + T細胞である、請求項3に記載の組成物。
- 前記癌細胞が、膀胱癌細胞、脳癌細胞、乳癌細胞、胃癌細胞、食道癌細胞、頭頸部癌細胞、肝胆道癌細胞、腎臓癌細胞、卵巣癌細胞、非小細胞肺癌細胞、骨髄腫 、前立腺癌細胞、肉腫細胞、精巣癌細胞、メラノーマ細胞、またはそれらの組み合わせから選択される、請求項3に記載の組成物。
- T細胞レセプター(TCR)をコードする発現ベクターであって、当該TCRが、配列番号3の配列を有するα鎖及び配列番号4の配列を有するβ鎖、または配列番号11の配列を有するα鎖及び配列番号12の配列を有するβ鎖を有する、発現ベクター。
- 組換えT細胞レセプター(TCR)をコードする発現ベクターを製造する方法であって、当該方法が、配列番号3の配列を有するTCRα鎖及び配列番号4の配列を有するTCRβ鎖、または配列番号11の配列を有するTCRα鎖及び配列番号12の配列を有するTCRβ鎖をコードするポリヌクレオチド配列を発現ベクターに導入することを含む、ベクターの製造方法。
- さらに、前記発現ベクターを、前記TCRが発現されるように細胞に導入することを含む、請求項7に記載の方法。
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