JP2023036657A - 修飾されたt細胞及びその使用方法 - Google Patents
修飾されたt細胞及びその使用方法 Download PDFInfo
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Abstract
Description
便宜上、明細書、実施例、及び添付の請求の範囲において使用されるいくつかの用語並びに語句の意味が、以下で提供される。別段示されないか、又は文脈から暗に示されていない限り、次の用語及び語句は、以下で提供される意味を含む。定義は、特定の実施態様を記載するのに役立つよう提供され、テクノロジーの範囲は、請求項によってのみ制限されるので、請求されたテクノロジーを制限することは意図されない。別段定義されない限り、本明細書において使用される全ての技術用語及び科学用語は、本テクノロジーが属する当該技術分野における当業者により一般に理解されるのと同じ意味を有する。当該技術分野における用語の使用と本明細書におけるその定義の間に明らかな食い違いが存在するなら、明細書内で提供される定義が優先する。
本発明において使用され得るT細胞(例えば、ヒトT細胞)は、エクスビボでの修飾及び拡大後、後に投与されるべきである対象から得られた自家細胞を含む。例えば、T細胞は、がん、感染性疾患、自己免疫疾患、若しくは形質細胞障害を有するか、又は有すると診断された個体から得ることができる。T細胞は、細胞の意図されるレシピエントと同じ種の遺伝子的に同一でない個体である、同種ドナーから得ることもできる。T細胞は、典型的には、例えば、静脈穿刺又は移植されたポート若しくはカテーテルを通じた回収により、対象から収集される末梢血から得られる。任意選択的に、血液は、白血球が、対象の血液から得られ、一方、他の血液成分が、対象に戻される、白血球除去を含むプロセスにより得ることができる。血液又は白血球除去産物(新鮮若しくは凍結保存)を処理して、当該技術分野において公知の方法を使用して、T細胞について濃縮する。したがって、例えば、密度勾配遠心分離(例えば、フィコールを使用して)及び/又はカウンターフロー遠心水簸を行い、単核細胞(T細胞を含む)について濃縮することができる。例えば、磁気ビーズ上にコーティングされたCD3/CD28抗体又は例えば、細胞表面に結合した抗CD3及び抗CD28抗体フラグメントを発現する人工抗原提示細胞(aAPC)(以下を参照)を利用するT細胞刺激工程は、T細胞を刺激し、他の細胞、例えば、B細胞を枯渇させるためにさらに行われ得る。次に、濃縮されたT細胞調製物のT細胞は、遺伝子修飾の対象にされ得る。末梢血の代替として、骨髄、リンパ節、脾臓、及び腫瘍を含む組織は、T細胞についての供給源として使用することができる。T細胞は、ヒト、霊長類、ハムスター、ウサギ、げっ歯類、ウシ、ブタ、ヒツジ、ウマ、ヤギ、イヌ又はネコ起源のものであり得るが、任意の他の哺乳類細胞が使用されてもよい。任意の態様のある特定の実施態様において、T細胞は、ヒトである。
T細胞を、本発明により、いくつかの方法で修飾して、治療方法(例えば、養子T細胞療法)においてそれらの使用を増強することができる。これらの修飾は、(i)例えば、CD3ζ、TRAC、及び/若しくはTRBC配列の欠損/変異(例えば、フレームシフト変異)による低減したCD3ζ、TRAC、並びに/又はTRBC発現、(ii)免疫監視回避を促進する一又は複数のタンパク質(例えば、TAP阻害剤若しくはHLA相同体)の発現(若しくはHLAクラスIの欠損及びHLA-Gの発現)、(iii)マーカー及び/又は自殺遺伝子の発現、並びに/或いは(iv)キメラ抗原受容体(CAR)又は異種性T細胞受容体のような、治療タンパク質の発現を含む。これらの種類の修飾のそれぞれの例が、以下で提供される。
T細胞受容体複合体は、可変のT細胞受容体α及びβ鎖、並びに3種のダイマーシグナル伝達分子:CD3δ/ε、CD3γ/ε、及びCD3ζ/ζを含む。本発明により、CD3ζ(本明細書において「CD3z」若しくは「CD3ゼータ」としても言及される)、TRAC、及び/又はTRBC遺伝子の発現は、低減されるか、又は除去される。これは、当該技術分野において公知の多数の方法の何れかを使用して達成され得る。1つの例において、CD3ζ配列(例えば、コード若しくは制御配列;例えば、2018年1月10日の、ENSEMBL ID ENSG00000198821を参照)、TRAC配列(例えば、コード若しくは制御配列)、及び/又はTRBC(例えば、コード若しくは制御配列)は、例えば、遺伝子編集方法を使用して、T細胞のゲノムから変異されるか、又は欠損される。したがって、例えば、RNA/DNAガイドエンドヌクレアーゼ(例えば、クラスター化して規則的な配置の短い回文配列リピート(CRISPR)/Cas9、Cpf1、及びアルゴノート)、転写活性化因子様エフェクター(TALE)ヌクレアーゼ、ジンクフィンガーヌクレアーゼ(ZFN)、又はメガヌクレアーゼを利用するアプローチは、本発明での使用に適合され得る。さらに、所望の配列特異性を達成するために、本発明において使用され得る、ヌクレアーゼの操作方法は、例えば、Kim(2014年);Kim(2012年);Belhaj等(2013年);Urnov等(2010年);Bogdanove等(2011年);Jinek等(2012年)、Silva等(2011年);Ran等(2013年);Carlson等(2012年);Guerts等(2009年);Taksu等(2010年);及びWatanabe等(2012年)において記載され、それらのそれぞれを、その全体が、出典明示により援用される。
機能的TCRの低減した又は除去された発現(例えば、CD3ζ、TRAC、及び/若しくはTRBC遺伝子欠損、例えば、フレームシフト変異に起因する)により特徴付けられる修飾されたT細胞は、本明細書に記載されるもののような、養子T細胞療法の状況において有利に使用され得る。以下でさらに記載される通り、これらの修飾されたT細胞をさらに修飾して、修飾されたT細胞を標的細胞(例えば、腫瘍細胞)に指向化させるために、キメラ抗原受容体(CAR)を発現させることができる。しかしながら、修飾されたT細胞の機能は、特に、同種遺伝子導入方法の状況において、一又は複数の追加の遺伝子修飾により、さらに改善され得る。より詳細には、内在性T細胞受容体の発現を欠く(例えば、本明細書に記載されるCD3ζ、TRAC、及び/若しくはTRBC遺伝子欠損又は変異に起因する)遺伝子修飾されたT細胞は、それらが投与される対象の免疫系(T細胞及びNK介在性拒絶)による攻撃を受けやすい。この攻撃の回避は、修飾されたT細胞におけるある特定の異種性タンパク質の発現により達成され得る。したがって、これらのタンパク質の発現を使用して、投与される、修飾されたT細胞の持続性を増加させることができる。この状況において使用され得る異種性タンパク質は、例えば、免疫回避を促進するウイルスタンパク質を含む。これらのタンパク質の例は、次に記載され、例えば、抗原プロセシングと関連する輸送体(TAP)阻害剤及びHLA相同体を含む。これらのタンパク質の発現はまた、発現した導入遺伝子に対する低減した免疫応答が望ましいことがある、自家設定において適用可能であり得る。
本発明の修飾されたT細胞になされ得る追加の修飾は、例えば、一又は複数のレポーター遺伝子の発現を含む。例えば、細胞内シグナル伝達ドメインを欠く、切断型上皮増殖因子受容体(EGFR)は、抗EGFRモノクローナル抗体を使用して、例えば、毒性の場合にはインビボでの枯渇のため使用され得る。
上で修飾されたCD3ζ、TRAC、及び/又はTRBC遺伝子、並びに上で記載された追加の任意選択的な修飾に加えて、本発明のT細胞をさらに任意選択的に修飾して、キメラ抗原受容体(CAR)のような、治療タンパク質を発現することができる。本明細書において使用される用語「キメラ抗原受容体」又は「CAR」又は「CAR(複数形)」は、T細胞(例えば、ナイーブT細胞、セントラルメモリーT細胞、エフェクターメモリーT細胞、若しくはその組合せ)にリガンド又は抗原特異性を移植する、操作されたT細胞受容体を指す。CARは、人工T細胞受容体、キメラT細胞受容体、又はキメラ免疫受容体としても知られている。
様々な実施態様において、本明細書に記載されるCARは、抗体試薬又は細胞外標的結合ドメインとしてのその抗原結合ドメインを含む。
任意の細胞表面部分は、CARにより標的にされ得る。最も頻繁には、標的は、人が、T細胞応答について標的化することを望む細胞上で異なって又は優先的に発現される細胞表面ポリペプチドである。これに関して、腫瘍抗原又は腫瘍関連抗原は、魅力的な標的をもたらし、これが、非腫瘍細胞若しくは組織への二次的な損傷を回避するか、又は少なくとも制限しながら、腫瘍細胞を標的にする手段をもたらす。腫瘍抗原又は腫瘍関連抗原の非限定的な例は、CD19、BCMA、CD37、CEA、未成熟ラミニン受容体、TAG-72、HPV E6及びE7、BING-4、カルシウムにより活性化されたクロライドチャネル2、サイクリンB1、9D7、Ep-CAM、EphA3、Her2/neu、テロメラーゼ、メソセリウン、SAP-1、サバイビン、BAGEファミリー、CAGEファミリー、GAGEファミリー、MAGEファミリー、SAGEファミリー、XAGEファミリー、NY-ESO-1/LAGE-1、PRAME、SSX-2、メランA/MART-1、Gp100/pmel17、チロシナーゼ、TRP-1/-2、MC1R、BRCA1/2、CDK4、MART-2、p53、Ras、MUC1、並びにTGF-βRIIを含む。
本明細書に記載されるそれぞれのCARは、必ず、細胞外標的結合ドメインを細胞内シグナル伝達ドメインに結び付ける膜貫通型ドメインを含む。
本明細書に記載されるそれぞれのCARは、共刺激分子の細胞内ドメイン、又は共刺激ドメインを含み得る。本明細書において使用される、用語「共刺激ドメイン」は、共刺激分子の細胞内シグナル伝達ドメインを指す。共刺激分子は、抗原への結合の際にTリンパ球の効率的な活性化及び機能に要求される第2のシグナルをもたらす抗原受容体又はFc受容体以外の細胞表面分子である。かかる共刺激分子の実例は、CARD11、CD2、CD7、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD223(LAG3)、CD270(HVEM)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、DAP10、LAT、NKD2C SLP76、TRIM、及びZAP70を含む。1つの実施態様において、細胞内ドメインは、4-1BBの細胞内ドメインである。
本明細書に記載されるCARは、細胞内シグナル伝達ドメインを含む。「細胞内シグナル伝達ドメイン」は、標的抗原への有効なCAR結合のメッセージを免疫エフェクター細胞の内部に移動して、エフェクター細胞機能、例えば、CARが結合した標的細胞への細胞傷害性因子の放出を含む、活性化、サイトカイン産生、増殖及び細胞傷害性活性、又は抗原の細胞外CARドメインへの結合後に誘発された他の細胞応答を誘発する際に関与するCARポリペプチドの一部を指す。
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号9)
RVKFSRSADAPAYQQGQNQLFNELNLGRREEFDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号10)
RVKFSRSADAPAYQQGQNQLFNELNLGRREEFDVLDKRRGRDPEMGGKPRRKNPQEGLFNELQKDKMAEAFSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号11)
RVKFSRSADAPAYQQGQNQLFNELNLGRREEFDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLFQGLSTATKDTFDALHMQALPPR(配列番号12)
本発明はまた、本明細書に記載される、修飾されたT細胞の生成において使用するためのコンストラクト及びベクターを提供する。様々な例において、本発明は、それぞれが、本発明の修飾されたT細胞において発現されるべき複数のタンパク質についての別々のコード配列を含む、コンストラクトを提供する。これらの別々のコード配列は、本明細書に記載される切断可能なリンカー配列により互いに分けられ得る。例えば、ウイルス2Aタンパク質(例えば、T2A、P2A、E2A、及びF2A)をコードする配列は、別々の遺伝子の間に置かれ、転写されたとき、生成されたポリタンパク質の切断を指示することができる。上で示された通り、本発明のコンストラクト及びベクターは、多数の異なる組合せの配列の何れかを含み得る。例えば、本発明のコンストラクト又はベクターは、任意選択的に、CARとの組合せで、UL40、US6、UL18、HLA-E、及びHLA-Gの一若しくは複数の全長又は部分配列(例えば、それぞれ)をコードする配列を含み得る。
本発明は、それを必要とする対象(例えば、疾患若しくは状態を有するか、又は有すると診断された対象)において、例えば、がん、感染性疾患、自己免疫疾患或いは障害、形質細胞疾患或いは障害、或いは移植に関連する状態を含む、疾患及び状態の処置並びに予防において使用するための方法並びに組成物を提供する。これらの方法は、本明細書に記載される方法でT細胞を修飾すること、次に、修飾されたT細胞を対象に投与することを含む。態様の何れかのいくつかの実施態様において、修飾されたT細胞(例えば、本明細書に記載される一又は複数の追加の修飾を含むCAR-T細胞)は、対象への投与に先立ち、刺激され、及び/又は活性化される。
本明細書において使用される用語としての「単位投薬形態」は、適当な1回の投与のための投薬量を指す。例示の目的で、単位投薬形態は、デリバリー装置、例えば、シリンジ又は静脈内ドリップバックに配置した治療剤の量であり得る。1つの実施態様において、単位投薬形態は、単一の投与において投与される。別の実施態様において、1回より多い単位投薬形態は、同時に投与することができる。
本明細書に記載される修飾されたT細胞(例えば、活性化されたCAR T細胞)は、他の公知の薬剤及び療法と組合されて使用され得る。本明細書において使用される「組み合わせて」投与されるは、2種(又はそれ以上の)異なる処置が、障害(例えば、疾患又は状態)に伴う対象の苦痛の経過中対象にデリバリーされること、例えば、2種以上の処置が、対象が、障害と診断された後、かつ障害が、治癒していないか、若しくは除去されていないか、又は処置が、他の理由のため中止される前に、デリバリーされることを意味する。いくつかの実施態様において、投与に関して重複が存在するように、1種の処置のデリバリーは、第2のデリバリーが始まるときに依然として生じている。これは、時に、本明細書において「同時」又は「並行デリバリー」として言及される。他の実施態様において、他方の処置のデリバリーが始まる前に、一方の処置のデリバリーが終わる。何れかの場合のいくつかの実施態様において、処置は、併用された投与のため、より有効である。例えば、第2の処置は、第1の処置の非存在下で投与されたなら観察されるものより、より有効である、例えば、同等の効果が、第2の処置を少なくして観察されるか、若しくは第2の処置は、第2の処置が、より高い程度に症状を低減するか、又は類似の状況が、第1の処置に関しても観察される。いくつかの実施態様において、デリバリーは、症状における低減、又は障害と関連する他のパラメーターが、他方の非存在下でデリバリーされた一方の処置で観察されるものより大きくなるようなデリバリーである。2種の処置の効果は、部分的に相加、全体的に相加、又は相加より大きくあり得る。デリバリーは、デリバリーされる第1の処置の効果が、第2がデリバリーされるとき、依然として検出可能であるようなデリバリーであり得る。本明細書に記載される修飾されたT細胞(例えば、活性化されたCAR T細胞)及び少なくとも1種の追加の治療剤は、同じ組成物において、又は別々の組成物において、同時に、又は連続して投与され得る。連続投与について、本明細書に記載される修飾されたT細胞(例えば、CARを発現する細胞)が、最初に投与され、追加の薬剤が、2番目に投与され得るか、又は投与の順が、逆であることもできる。CAR T療法及び/又は他の治療剤、手法若しくはモダリティは、活発な障害の期間中、又は寛解若しくはあまり活発でない疾患の期間中に、投与され得る。修飾されたT細胞療法は、別の処置前、処置と同時、処置後、又は障害の寛解中に、投与され得る。
,)-2-(2-モルホリノアセタミド)-4-フェニルブタンアミド)-ペンタンアミド);マリゾミブ(NPT0052);イキサゾミブクエン酸エステル(MLN-9708);デランゾミブ(CEP-18770);並びにO-メチル-N-[(2-メチル-5-チアゾリル)カルボニル]-L-セリル-O-メチル-N-[(llS’)-2-[(2R)-2-メチル-2-オキシラニル]-2-オキソ-l-(フェニルメチル)エチル]-L-セリンアミド(ONX-0912)を含む。
例えば、本明細書に記載される状態の処置における、又は本明細書に記載される応答(例えば、がん細胞における低減)を誘導するための修飾されたT細胞(例えば、活性化されたCAR T細胞)の有効性は、熟練した臨床医により決定され得る。しかしながら、本明細書に記載される状態の徴候若しくは症状の一又は複数が、有益な様式で変更されるか、他の臨床上許容される症状が、改善されるか、若しくは向上されるか、又は所望の応答が、本明細書に記載される方法による処置後、例えば、少なくとも10%誘導されるなら、処置は、本明細書において使用される用語「有効な処置」であるとみなされる。有効性は、例えば、本明細書に記載される方法に従い処置される状態のマーカー、指標、症状、及び/若しくは発生率、又は任意の他の適当な測定可能なパラメーターを測定することにより、評価され得る。本明細書に記載される方法は、マーカーのレベル若しくは状態の症状を、例えば、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%又は少なくとも90%以上減少し得る。
CRISPRを使用して遺伝子ノックアウトを達成するために、発現の非存在下でフレームシフト変異を導く、標的ゲノム配列における挿入及び/又は欠損の生成によるCRISPR介在性遺伝子破壊を目的に、CD3ζの様々なコード配列を標的とするガイドを開発した。
T細胞の形質導入において使用するため、レンチウイルスベクターを構築した(図9)。ヌンチャク(pMGH81)は、3種の全長CMVタンパク質(UL40、US6、及びUL18)、コメツキムシ緑色ルシフェラーゼ(CBG;細胞殺傷アッセイ及びインビボ画像化において使用するため)、増強した緑色蛍光タンパク質(EGFP;下流の蛍光ソーティングのため)、並びにウイルス2Aタンパク質(T2a、P2A、E2A、及びF2A;コードされたポリタンパク質の切断を指示するため)を発現するコンストラクトである。CMVタンパク質は、上で説明した通り、T細胞を投与したレシピエントの免疫攻撃の回避を促進するよう機能する。
CD3ζと関連して上で記載したものと同様の方法を使用して、TRACを標的にした。TRACについて使用した特定のgRNAは、AGAGTCTCTCAGCTGGTACAであった。図14において示す通り、エレクトロポレーションの8日後/刺激の12日後の初代T細胞において、TRAC(AGAGTCTCTCAGCTGGTACA)又はCD3ζ(GTGGAAGGCGCTTTTCACCG)のノックアウトは、TCRの細胞表面発現のノックアウトを引き起こす。
1.CD3ζ、T細胞受容体アルファ鎖(TRAC)、及び/若しくはT細胞受容体ベータ鎖(TRBC)遺伝子の低減した又は除去された発現に起因して、T細胞受容体(TCR)の低減した又は除去された発現を有するよう修飾された、単離されたTリンパ球。
2.CD3ζ、TRAC及び/若しくはTRBC遺伝子、制御配列、コード配列、エクソン、又はその部分が変異し、低減した、ヌル、又は非機能的CD3ζ、CD3エータ、CD3シータ、TRAC及び/又はTRBC発現を生じるゲノムを含む、パラグラフ1の単離されたTリンパ球。
3.変異が欠損である、パラグラフ2の単離されたTリンパ球。変異は、任意選択的に、フレームシフト変異又は欠損であり得る。
4.変異が、T細胞受容体又はCD3ζシグナル伝達のアセンブリを破壊する、パラグラフ2又は3の単離されたTリンパ球。
5.CD3ζ、TRAC、及び/又はTRBC遺伝子が欠損しているゲノムを含む、パラグラフ1から4の何れか1つの単離されたTリンパ球。
6.CD3ζ、TRAC、及び/又はTRBC遺伝子のうちの2個の対立遺伝子が欠損しているゲノムを含む、パラグラフ5の単離されたTリンパ球。
7.CD3ζ、TRAC、及び/又はTRBC遺伝子の低減した発現が、ヌル発現である、パラグラフ1から6の何れか1つの単離されたTリンパ球。
8.CD3エータ又はCD3シータの低減した発現を有する、パラグラフ1から7の何れか1つの単離されたTリンパ球。
9.HLA遺伝子座、又はその部分が、欠損している、パラグラフ1から8の何れか1つの単離されたTリンパ球。
10.HLA遺伝子座が、染色体6上にある、パラグラフ9の単離されたTリンパ球。
11.減少したHLAクラスI発現をさらに有する、パラグラフ1から10の何れか1つの単離されたTリンパ球。
12.単離されたTリンパ球が、HLA-Gを発現するようさらに修飾された、パラグラフ1から11の何れか1つの単離されたTリンパ球。
13.Tリンパ球が投与される宿主からの免疫攻撃の回避においてTリンパ球を促進する異種性タンパク質をコードする遺伝子をさらに含む、パラグラフ1から12の何れか1つの単離されたTリンパ球。
14.異種性タンパク質が、T細胞又はNK介在性拒絶の回避を促進する、パラグラフ13の単離されたTリンパ球。
15.異種性タンパク質が、ウイルスタンパク質である、パラグラフ13又は14の単離されたTリンパ球。
16.ウイルスタンパク質が、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、単純ヘルペスウイルス(HSV)、及びウシヘルペスウイルス-1(BoHV-1)からなる群から選択されるウイルス由来である、パラグラフ15の単離されたTリンパ球。
17.ウイルスタンパク質が、CMV由来であり、US6、UL40、及びUL18からなる群から選択される、パラグラフ16の単離されたTリンパ球。
18.ウイルスタンパク質が、抗原プロセシングと関連する輸送体(TAP)を阻害する、パラグラフ16の単離されたTリンパ球。
19.ウイルスタンパク質が、CMV US6、HSV ICP47、BoHV-1 UL49.5、及びEBV BNLF2aからなる群から選択される、パラグラフ18の単離されたTリンパ球。
20.レポーター遺伝子をコードする遺伝子をさらに含む、パラグラフ1から19の何れか1つの単離されたTリンパ球。
21.レポーター遺伝子が、切断型上皮増殖因子受容体(EGFR)遺伝子、切断型前立腺特異的膜抗原(PSMA)、切断型低親和性神経成長因子受容体(LNGFR)、切断型CD19を含む、パラグラフ20の単離されたTリンパ球。
22.治療タンパク質をコードする遺伝子をさらに含む、パラグラフ1から21の何れか1つの単離されたTリンパ球。
23.治療タンパク質が、抗原受容体を含む、パラグラフ22の単離されたTリンパ球。
24.抗原受容体が、選択された標的抗原に対する特異性を付与する、パラグラフ23の単離されたTリンパ球。
25.抗原受容体が、選択されたリガンドに対する特異性を付与する、パラグラフ23の単離されたTリンパ球。
26.抗原受容体が、キメラ抗原受容体(CAR)である、パラグラフ23の単離されたTリンパ球。
27.CARが、細胞外ドメイン、膜貫通型領域ドメイン、及び細胞内領域ドメインを含む、パラグラフ26の単離されたTリンパ球。
28.細胞外ドメインが、1本鎖抗体を含み、細胞内ドメインが、T細胞活性化ドメインを含む、パラグラフ27の単離されたTリンパ球。
29.細胞死を誘導する遺伝子をさらに含む、パラグラフ1から28の何れか1つの単離されたTリンパ球。
30.遺伝子が、活性化可能な自殺遺伝子である、パラグラフ29の単離されたTリンパ球。
31.自殺遺伝子が、薬物により活性化される、パラグラフ30の単離されたTリンパ球。
32.自殺遺伝子が、カスパーゼ9アポトーシス促進分子に融合されたFK506結合ドメインを発現する、パラグラフ31の単離されたTリンパ球。
33.修飾されたTリンパ球を生成する方法であって、Tリンパ球においてCD3ζ、TRAC、及び/又はTRBC遺伝子を不活性化することを含む方法。
34.CD3ζ、TRAC、及び/又はTRBC遺伝子の不活性化が、ジンクフィンガーヌクレアーゼ(ZFN)、転写活性化因子様エフェクターヌクレアーゼ(TALEN)、及びクラスター化して規則的な配置の短い回文配列リピート(CRISPR/cas9系)の群から選択されるヌクレアーゼ又は系を使用して行われる、パラグラフ33の方法。
35.修飾されたTリンパ球が、パラグラフ1から32の何れか1つの修飾されたTリンパ球である、パラグラフ33又は34の方法。
36.疾患について対象を処置する方法であって、対象に、パラグラフ1から32の何れか1つの単離されたTリンパ球を投与することを含む方法。
37.疾患が、がん、感染性疾患、及び移植手法から生じる徴候からなる群から選択される、パラグラフ36の方法。
38.対象において免疫原性反応を低減する方法であって、対象に、パラグラフ1から32の何れか1つに記載のTリンパ球を投与することを含む方法。
39.Tリンパ球が、導入遺伝子を発現する、パラグラフ38の方法。
40.Tリンパ球が、内在性T細胞受容体シグナル伝達分子との低減した競合を有する、パラグラフ38の方法。
41.Tリンパ球が、対象に関して自家である、パラグラフ36から40の何れか1つの方法。
42.Tリンパ球が、対象に関して異種である、パラグラフ36から40の何れか1つの方法。
43.修飾されたTリンパ球が、インビボで拡大される、パラグラフ36から42の何れか1つの方法。
44.修飾されたTリンパ球が、対象の血液において拡大される、パラグラフ36から43の何れか1つの方法。
45.修飾されたTリンパ球が、投与に先立ち、インビトロで拡大される、パラグラフ36から44の何れか1つの方法。
46.治療タンパク質及び免疫系回避を促進する異種性タンパク質をコードする遺伝子を含むベクター。
47.異種性タンパク質が、ウイルスタンパク質である、パラグラフ46のベクター。
48.ウイルスタンパク質が、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、単純ヘルペスウイルス(HSV)、及びウシヘルペスウイルス-1(BoHV-1)からなる群から選択されるウイルス由来である、パラグラフ47のベクター。
49.ウイルスタンパク質が、CMV由来であり、US6、UL40、及びUL18からなる群から選択される、パラグラフ48のベクター。
50.ウイルスタンパク質が、抗原プロセシングと関連する輸送体(TAP)を阻害する、パラグラフ48のベクター。
51.ウイルスタンパク質が、CMV US6、HSV ICP47、BoHV-1 UL49.5、及びEBV BNLF2aからなる群から選択される、パラグラフ50のベクター。
52.治療タンパク質がCARである、パラグラフパラグラフ46から51の何れか1つのベクター。
53.パラグラフ46から52のベクターの一又は複数をTリンパ球に形質導入する方法。
54.パラグラフ33から35又は53の何れか1つの方法により作製された修飾されたTリンパ球若しくは細胞株、又はその継代培養物。
55.パラグラフ1から32の何れか1つの少なくとも1個の修飾されたTリンパ球を含む薬学的組成物。
56.(a)パラグラフ33から35又は53の何れか1つの方法により修飾されたTリンパ球の集団を調製する工程、及び(b)修飾されたTリンパ球を対象に投与する工程を含む、対象を処置する方法。
57.Tリンパ球が、処置されるべき対象に由来する、パラグラフ56の方法。
58.Tリンパ球が、健常ドナーに由来する、パラグラフ56の方法。
1.CD3ζ、T細胞受容体アルファ鎖(TRAC)、及び/若しくはT細胞受容体ベータ鎖(TRBC)遺伝子の低減した又は除去された発現に起因して、T細胞受容体(TCR)の低減した又は除去された発現を有するよう修飾された、単離されたTリンパ球。
2.CD3ζ、TRAC及び/若しくはTRBC遺伝子、制御配列、コード配列、エクソン、又はその部分が変異し、低減した、ヌル、又は非機能的CD3ζ、CD3エータ、CD3シータ、TRAC及び/又はTRBC発現を生じるゲノムを含む、パラグラフ1の単離されたTリンパ球。
3.変異が欠損である、パラグラフ2の単離されたTリンパ球。変異は、任意選択的に、フレームシフト変異又は欠損であり得る。
4.変異が、T細胞受容体又はCD3ζシグナル伝達のアセンブリを破壊する、パラグラフ2又は3の単離されたTリンパ球。
5.CD3ζ、TRAC、及び/又はTRBC遺伝子が欠損しているゲノムを含む、パラグラフ1から4の何れか1つの単離されたTリンパ球。
6.CD3ζ、TRAC、及び/又はTRBC遺伝子のうちの2個の対立遺伝子が欠損しているゲノムを含む、パラグラフ5の単離されたTリンパ球。
7.CD3ζ、TRAC、及び/又はTRBC遺伝子の低減した発現が、ヌル発現である、パラグラフ1から6の何れか1つの単離されたTリンパ球。
8.CD3エータ又はCD3シータの低減した発現を有する、パラグラフ1から7の何れか1つの単離されたTリンパ球。
9.HLA遺伝子座、又はその部分が、欠損している、パラグラフ1から8の何れか1つの単離されたTリンパ球。
10.HLA遺伝子座が、染色体6上にある、パラグラフ9の単離されたTリンパ球。
11.減少したHLAクラスI発現をさらに有する、パラグラフ1から10の何れか1つの単離されたTリンパ球。
12.単離されたTリンパ球が、HLA-Gを発現するようさらに修飾された、パラグラフ1から11の何れか1つの単離されたTリンパ球。
13.Tリンパ球が投与される宿主からの免疫攻撃の回避においてTリンパ球を促進する異種性タンパク質をコードする遺伝子をさらに含む、パラグラフ1から12の何れか1つの単離されたTリンパ球。
14.異種性タンパク質が、T細胞又はNK介在性拒絶の回避を促進する、パラグラフ13の単離されたTリンパ球。
15.異種性タンパク質が、ウイルスタンパク質である、パラグラフ13又は14の単離されたTリンパ球。
16.ウイルスタンパク質が、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、単純ヘルペスウイルス(HSV)、及びウシヘルペスウイルス-1(BoHV-1)からなる群から選択されるウイルス由来である、パラグラフ15の単離されたTリンパ球。
17.ウイルスタンパク質が、CMV由来であり、US6、UL40、及びUL18からなる群から選択される、パラグラフ16の単離されたTリンパ球。
18.ウイルスタンパク質が、抗原プロセシングと関連する輸送体(TAP)を阻害する、パラグラフ16の単離されたTリンパ球。
19.ウイルスタンパク質が、CMV US6、HSV ICP47、BoHV-1 UL49.5、及びEBV BNLF2aからなる群から選択される、パラグラフ18の単離されたTリンパ球。
20.レポーター遺伝子をコードする遺伝子をさらに含む、パラグラフ1から19の何れか1つの単離されたTリンパ球。
21.レポーター遺伝子が、切断型上皮増殖因子受容体(EGFR)遺伝子、切断型前立腺特異的膜抗原(PSMA)、切断型低親和性神経成長因子受容体(LNGFR)、切断型CD19を含む、パラグラフ20の単離されたTリンパ球。
22.治療タンパク質をコードする遺伝子をさらに含む、パラグラフ1から21の何れか1つの単離されたTリンパ球。
23.治療タンパク質が、抗原受容体を含む、パラグラフ22の単離されたTリンパ球。
24.抗原受容体が、選択された標的抗原に対する特異性を付与する、パラグラフ23の単離されたTリンパ球。
25.抗原受容体が、選択されたリガンドに対する特異性を付与する、パラグラフ23の単離されたTリンパ球。
26.抗原受容体が、キメラ抗原受容体(CAR)である、パラグラフ23の単離されたTリンパ球。
27.CARが、細胞外ドメイン、膜貫通型領域ドメイン、及び細胞内領域ドメインを含む、パラグラフ26の単離されたTリンパ球。
28.細胞外ドメインが、1本鎖抗体を含み、細胞内ドメインが、T細胞活性化ドメインを含む、パラグラフ27の単離されたTリンパ球。
29.細胞死を誘導する遺伝子をさらに含む、パラグラフ1から28の何れか1つの単離されたTリンパ球。
30.遺伝子が、活性化可能な自殺遺伝子である、パラグラフ29の単離されたTリンパ球。
31.自殺遺伝子が、薬物により活性化される、パラグラフ30の単離されたTリンパ球。
32.自殺遺伝子が、カスパーゼ9アポトーシス促進分子に融合されたFK506結合ドメインを発現する、パラグラフ31の単離されたTリンパ球。
33.修飾されたTリンパ球を生成する方法であって、Tリンパ球においてCD3ζ、TRAC、及び/又はTRBC遺伝子を不活性化することを含む方法。
34.CD3ζ、TRAC、及び/又はTRBC遺伝子の不活性化が、ジンクフィンガーヌクレアーゼ(ZFN)、転写活性化因子様エフェクターヌクレアーゼ(TALEN)、及びクラスター化して規則的な配置の短い回文配列リピート(CRISPR/cas9系)の群から選択されるヌクレアーゼ又は系を使用して行われる、パラグラフ33の方法。
35.修飾されたTリンパ球が、パラグラフ1から32の何れか1つの修飾されたTリンパ球である、パラグラフ33又は34の方法。
36.疾患について対象を処置する方法であって、対象に、パラグラフ1から32の何れか1つの単離されたTリンパ球を投与することを含む方法。
37.疾患が、がん、感染性疾患、及び移植手法から生じる徴候からなる群から選択される、パラグラフ36の方法。
38.対象において免疫原性反応を低減する方法であって、対象に、パラグラフ1から32の何れか1つに記載のTリンパ球を投与することを含む方法。
39.Tリンパ球が、導入遺伝子を発現する、パラグラフ38の方法。
40.Tリンパ球が、内在性T細胞受容体シグナル伝達分子との低減した競合を有する、パラグラフ38の方法。
41.Tリンパ球が、対象に関して自家である、パラグラフ36から40の何れか1つの方法。
42.Tリンパ球が、対象に関して異種である、パラグラフ36から40の何れか1つの方法。
43.修飾されたTリンパ球が、インビボで拡大される、パラグラフ36から42の何れか1つの方法。
44.修飾されたTリンパ球が、対象の血液において拡大される、パラグラフ36から43の何れか1つの方法。
45.修飾されたTリンパ球が、投与に先立ち、インビトロで拡大される、パラグラフ36から44の何れか1つの方法。
46.治療タンパク質及び免疫系回避を促進する異種性タンパク質をコードする遺伝子を含むベクター。
47.異種性タンパク質が、ウイルスタンパク質である、パラグラフ46のベクター。
48.ウイルスタンパク質が、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、単純ヘルペスウイルス(HSV)、及びウシヘルペスウイルス-1(BoHV-1)からなる群から選択されるウイルス由来である、パラグラフ47のベクター。
49.ウイルスタンパク質が、CMV由来であり、US6、UL40、及びUL18からなる群から選択される、パラグラフ48のベクター。
50.ウイルスタンパク質が、抗原プロセシングと関連する輸送体(TAP)を阻害する、パラグラフ48のベクター。
51.ウイルスタンパク質が、CMV US6、HSV ICP47、BoHV-1 UL49.5、及びEBV BNLF2aからなる群から選択される、パラグラフ50のベクター。
52.治療タンパク質がCARである、パラグラフパラグラフ46から51の何れか1つのベクター。
53.パラグラフ46から52のベクターの一又は複数をTリンパ球に形質導入する方法。
54.パラグラフ33から35又は53の何れか1つの方法により作製された修飾されたTリンパ球若しくは細胞株、又はその継代培養物。
55.パラグラフ1から32の何れか1つの少なくとも1個の修飾されたTリンパ球を含む薬学的組成物。
56.(a)パラグラフ33から35又は53の何れか1つの方法により修飾されたTリンパ球の集団を調製する工程、及び(b)修飾されたTリンパ球を対象に投与する工程を含む、対象を処置する方法。
57.Tリンパ球が、処置されるべき対象に由来する、パラグラフ56の方法。
58.Tリンパ球が、健常ドナーに由来する、パラグラフ56の方法。
<配列表>
SEQUENCE LISTING
<110> THE GENERAL HOSPITAL CORPORATION
<120> MODIFIED T CELLS AND METHODS OF THEIR USE
<130> 51295-005WO3
<150> US 62/529,130
<151> 2017-07-06
<150> US 62/519,960
<151> 2017-06-15
<150> US 62/444,616
<151> 2017-01-10
<150> US 62/444,590
<151> 2017-01-10
<160> 12
<170> PatentIn version 3.5
<210> 1
<211> 183
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 1
Met Asp Leu Leu Ile Arg Leu Gly Phe Leu Leu Met Cys Ala Leu Pro
1 5 10 15
Thr Pro Gly Glu Arg Ser Ser Arg Asp Pro Lys Thr Leu Leu Ser Leu
20 25 30
Ser Pro Arg Gln Gln Ala Cys Val Pro Arg Thr Lys Ser His Arg Pro
35 40 45
Val Cys Tyr Asn Asp Thr Gly Asp Cys Thr Asp Ala Asp Asp Ser Trp
50 55 60
Lys Gln Leu Gly Glu Asp Phe Ala His Gln Cys Leu Gln Ala Ala Lys
65 70 75 80
Lys Arg Pro Lys Thr His Lys Ser Arg Pro Asn Asp Arg Asn Leu Glu
85 90 95
Gly Arg Leu Thr Cys Gln Arg Val Arg Arg Leu Leu Pro Cys Asp Leu
100 105 110
Asp Ile His Pro Ser His Arg Leu Leu Thr Leu Met Asn Asn Cys Val
115 120 125
Cys Asp Gly Ala Val Trp Asn Ala Phe Arg Leu Ile Glu Arg His Gly
130 135 140
Phe Phe Ala Val Thr Leu Tyr Leu Cys Cys Gly Ile Thr Leu Leu Val
145 150 155 160
Val Ile Leu Ala Leu Leu Cys Ser Ile Thr Tyr Glu Ser Thr Gly Arg
165 170 175
Gly Ile Arg Arg Cys Gly Ser
180
<210> 2
<211> 88
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 2
Met Ser Trp Ala Leu Glu Met Ala Asp Thr Phe Leu Asp Thr Met Arg
1 5 10 15
Val Gly Pro Arg Thr Tyr Ala Asp Val Arg Asp Glu Ile Asn Lys Arg
20 25 30
Gly Arg Glu Asp Arg Glu Ala Ala Arg Thr Ala Val His Asp Pro Glu
35 40 45
Arg Pro Leu Leu Arg Ser Pro Gly Leu Leu Pro Glu Ile Ala Pro Asn
50 55 60
Ala Ser Leu Gly Val Ala His Arg Arg Thr Gly Gly Thr Val Thr Asp
65 70 75 80
Ser Pro Arg Asn Pro Val Thr Arg
85
<210> 3
<211> 96
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 3
Met Pro Arg Ser Pro Leu Ile Val Ala Val Val Ala Ala Ala Leu Phe
1 5 10 15
Ala Ile Val Arg Gly Arg Asp Pro Leu Leu Asp Ala Met Arg Arg Glu
20 25 30
Gly Ala Met Asp Phe Trp Ser Ala Gly Cys Tyr Ala Arg Gly Val Pro
35 40 45
Leu Ser Glu Pro Pro Gln Ala Leu Val Val Phe Tyr Val Ala Leu Thr
50 55 60
Ala Val Met Val Ala Val Ala Leu Tyr Ala Tyr Gly Leu Cys Phe Arg
65 70 75 80
Leu Met Gly Ala Ser Gly Pro Asn Lys Lys Glu Ser Arg Gly Arg Gly
85 90 95
<210> 4
<211> 60
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 4
Met Val His Val Leu Glu Arg Ala Leu Leu Glu Gln Gln Ser Ser Ala
1 5 10 15
Cys Gly Leu Pro Gly Ser Ser Thr Glu Thr Arg Pro Ser His Pro Cys
20 25 30
Pro Glu Asp Pro Asp Val Ser Arg Leu Arg Leu Leu Leu Val Val Leu
35 40 45
Cys Val Leu Phe Gly Leu Leu Cys Leu Leu Leu Ile
50 55 60
<210> 5
<211> 221
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 5
Met Asn Lys Phe Ser Asn Thr Arg Ile Gly Phe Thr Cys Ala Val Met
1 5 10 15
Ala Pro Arg Thr Leu Ile Leu Thr Val Gly Leu Leu Cys Met Arg Ile
20 25 30
Arg Ser Leu Leu Cys Ser Pro Ala Glu Thr Thr Val Thr Thr Ala Ala
35 40 45
Val Thr Ser Ala His Gly Pro Leu Cys Pro Leu Val Phe Gln Gly Trp
50 55 60
Ala Tyr Ala Val Tyr His Gln Gly Asp Met Ala Leu Met Thr Leu Asp
65 70 75 80
Val Tyr Cys Cys Arg Gln Thr Ser Asn Asn Thr Val Val Ala Phe Ser
85 90 95
His His Pro Ala Asp Asn Thr Leu Leu Ile Glu Val Gly Asn Asn Thr
100 105 110
Arg Arg His Val Asp Gly Ile Ser Cys Gln Asp His Phe Arg Ala Gln
115 120 125
His Gln Asp Cys Pro Ala Gln Thr Val His Val Arg Gly Val Asn Glu
130 135 140
Ser Ala Phe Gly Leu Thr His Leu Gln Ser Cys Cys Leu Asn Glu His
145 150 155 160
Ser Gln Leu Ser Glu Arg Val Ala Tyr His Leu Lys Leu Arg Pro Ala
165 170 175
Thr Phe Gly Leu Glu Thr Trp Ala Met Tyr Thr Val Gly Ile Leu Ala
180 185 190
Leu Gly Ser Phe Ser Ser Phe Tyr Ser Gln Ile Ala Arg Ser Leu Gly
195 200 205
Val Leu Pro Asn Asp His His Tyr Ala Leu Lys Lys Ala
210 215 220
<210> 6
<211> 368
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 6
Met Met Thr Met Trp Cys Leu Thr Leu Phe Val Leu Trp Met Leu Arg
1 5 10 15
Val Val Gly Met His Val Leu Arg Tyr Gly Tyr Thr Gly Ile Phe Asp
20 25 30
Asp Thr Ser His Met Thr Leu Thr Val Val Gly Ile Phe Asp Gly Gln
35 40 45
His Phe Phe Thr Tyr His Val Asn Ser Ser Asp Lys Ala Ser Ser Arg
50 55 60
Ala Asn Gly Thr Ile Ser Trp Met Ala Asn Val Ser Ala Ala Tyr Pro
65 70 75 80
Thr Tyr Leu Asp Gly Glu Arg Ala Lys Gly Asp Leu Ile Phe Asn Gln
85 90 95
Thr Glu Gln Asn Leu Leu Glu Leu Glu Ile Ala Leu Gly Tyr Arg Ser
100 105 110
Gln Ser Val Leu Thr Trp Thr His Glu Cys Asn Thr Thr Glu Asn Gly
115 120 125
Ser Phe Val Ala Gly Tyr Glu Gly Phe Gly Trp Asp Gly Glu Thr Leu
130 135 140
Met Glu Leu Lys Asp Asn Leu Thr Leu Trp Thr Gly Pro Asn Tyr Glu
145 150 155 160
Ile Ser Trp Leu Lys Gln Asn Lys Thr Tyr Ile Asp Gly Lys Ile Lys
165 170 175
Asn Ile Ser Glu Gly Asp Thr Thr Ile Gln Arg Asn Tyr Leu Lys Gly
180 185 190
Asn Cys Thr Gln Trp Ser Val Ile Tyr Ser Gly Phe Gln Thr Pro Val
195 200 205
Thr His Pro Val Val Lys Gly Gly Val Arg Asn Gln Asn Asp Asn Arg
210 215 220
Ala Glu Ala Phe Cys Thr Ser Tyr Gly Phe Phe Pro Gly Glu Ile Asn
225 230 235 240
Ile Thr Phe Ile His Tyr Gly Asn Lys Ala Pro Asp Asp Ser Glu Pro
245 250 255
Gln Cys Asn Pro Leu Leu Pro Thr Phe Asp Gly Thr Phe His Gln Gly
260 265 270
Cys Tyr Val Ala Ile Phe Cys Asn Gln Asn Tyr Thr Cys Arg Val Thr
275 280 285
His Gly Asn Trp Thr Val Glu Ile Pro Ile Ser Val Thr Ser Pro Asp
290 295 300
Asp Ser Ser Ser Gly Glu Val Pro Asp His Pro Thr Ala Asn Lys Arg
305 310 315 320
Tyr Asn Thr Met Thr Ile Ser Ser Val Leu Leu Ala Leu Leu Leu Cys
325 330 335
Ala Leu Leu Phe Ala Phe Leu His Tyr Phe Thr Thr Leu Lys Gln Tyr
340 345 350
Leu Arg Asn Leu Ala Phe Ala Trp Arg Tyr Arg Lys Val Arg Ser Ser
355 360 365
<210> 7
<211> 338
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 7
Met Val Val Met Ala Pro Arg Thr Leu Phe Leu Leu Leu Ser Gly Ala
1 5 10 15
Leu Thr Leu Thr Glu Thr Trp Ala Gly Ser His Ser Met Arg Tyr Phe
20 25 30
Ser Ala Ala Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala
35 40 45
Met Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ser
50 55 60
Ala Cys Pro Arg Met Glu Pro Arg Ala Pro Trp Val Glu Gln Glu Gly
65 70 75 80
Pro Glu Tyr Trp Glu Glu Glu Thr Arg Asn Thr Lys Ala His Ala Gln
85 90 95
Thr Asp Arg Met Asn Leu Gln Thr Leu Arg Gly Tyr Tyr Asn Gln Ser
100 105 110
Glu Ala Ser Ser His Thr Leu Gln Trp Met Ile Gly Cys Asp Leu Gly
115 120 125
Ser Asp Gly Arg Leu Leu Arg Gly Tyr Glu Gln Tyr Ala Tyr Asp Gly
130 135 140
Lys Asp Tyr Leu Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala
145 150 155 160
Asp Thr Ala Ala Gln Ile Ser Lys Arg Lys Cys Glu Ala Ala Asn Val
165 170 175
Ala Glu Gln Arg Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu
180 185 190
His Arg Tyr Leu Glu Asn Gly Lys Glu Met Leu Gln Arg Ala Asp Pro
195 200 205
Pro Lys Thr His Val Thr His His Pro Val Phe Asp Tyr Glu Ala Thr
210 215 220
Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Ile Leu Thr
225 230 235 240
Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Val Glu Leu Val Glu
245 250 255
Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val
260 265 270
Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu
275 280 285
Gly Leu Pro Glu Pro Leu Met Leu Arg Trp Lys Gln Ser Ser Leu Pro
290 295 300
Thr Ile Pro Ile Met Gly Ile Val Ala Gly Leu Val Val Leu Ala Ala
305 310 315 320
Val Val Thr Gly Ala Ala Val Ala Ala Val Leu Trp Arg Lys Lys Ser
325 330 335
Ser Asp
<210> 8
<211> 358
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 8
Met Val Asp Gly Thr Leu Leu Leu Leu Leu Ser Glu Ala Leu Ala Leu
1 5 10 15
Thr Gln Thr Trp Ala Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser
20 25 30
Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr
35 40 45
Val Asp Asp Thr Gln Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro
50 55 60
Arg Met Val Pro Arg Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr
65 70 75 80
Trp Asp Arg Glu Thr Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg
85 90 95
Val Asn Leu Arg Thr Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly
100 105 110
Ser His Thr Leu Gln Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly
115 120 125
Arg Phe Leu Arg Gly Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr
130 135 140
Leu Thr Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala
145 150 155 160
Ala Gln Ile Ser Glu Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His
165 170 175
Gln Arg Ala Tyr Leu Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr
180 185 190
Leu Glu Lys Gly Lys Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr
195 200 205
His Val Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys
210 215 220
Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln
225 230 235 240
Asp Gly Glu Gly His Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro
245 250 255
Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser
260 265 270
Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro
275 280 285
Glu Pro Val Thr Leu Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro
290 295 300
Ile Val Gly Ile Ile Ala Gly Leu Val Leu Leu Gly Ser Val Val Ser
305 310 315 320
Gly Ala Val Val Ala Ala Val Ile Trp Arg Lys Lys Ser Ser Gly Gly
325 330 335
Lys Gly Gly Ser Tyr Ser Lys Ala Glu Trp Ser Asp Ser Ala Gln Gly
340 345 350
Ser Glu Ser His Ser Leu
355
<210> 9
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 9
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 10
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 10
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Phe
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 11
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 11
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Phe
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Phe Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Phe Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 12
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 12
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Phe
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
Claims (58)
- CD3ζ、T細胞受容体アルファ鎖(TRAC)、及び/若しくはT細胞受容体ベータ鎖(TRBC)遺伝子の低減した又は除去された発現に起因して、T細胞受容体(TCR)の低減した又は除去された発現を有するよう修飾された、単離されたTリンパ球。
- CD3ζ、TRAC及び/若しくはTRBC遺伝子、制御配列、コード配列、エクソン、又はその部分が変異し、低減した、ヌル、又は非機能的CD3ζ、CD3エータ、CD3シータ、TRAC及び/又はTRBC発現を生じるゲノムを含む、請求項1に記載の単離されたTリンパ球。
- 変異が、欠損及び/又はフレームシフト変異である、請求項2に記載の単離されたTリンパ球。
- 変異が、T細胞受容体又はCD3ζシグナル伝達のアセンブリを破壊する、請求項2に記載の単離されたTリンパ球。
- CD3ζ、TRAC、及び/又はTRBC遺伝子が欠損しているゲノムを含む、請求項1に記載の単離されたTリンパ球。
- CD3ζ、TRAC、及び/又はTRBC遺伝子の2個の対立遺伝子が欠損しているゲノムを含む、請求項5に記載の単離されたTリンパ球。
- CD3ζ、TRAC、及び/又はTRBC遺伝子の低減した発現が、ヌル発現である、請求項1に記載の単離されたTリンパ球。
- CD3エータ又はCD3シータの低減した発現を有する、請求項1に記載の単離されたTリンパ球。
- HLA遺伝子座、又はその部分が、欠損している、請求項1に記載の単離されたTリンパ球。
- HLA遺伝子座が、染色体6上にある、請求項9に記載の単離されたTリンパ球。
- 減少したHLAクラスI発現をさらに有する、請求項1に記載の単離されたTリンパ球。
- 単離されたTリンパ球が、HLA-Gを発現するようさらに修飾された、請求項1に記載の単離されたTリンパ球。
- Tリンパ球が投与される宿主からの免疫攻撃の回避においてTリンパ球を促進する異種性タンパク質をコードする遺伝子をさらに含む、請求項1に記載の単離されたTリンパ球。
- 異種性タンパク質が、T細胞又はNK介在性拒絶の回避を促進する、請求項13に記載の単離されたTリンパ球。
- 異種性タンパク質が、ウイルスタンパク質である、請求項13に記載の単離されたTリンパ球。
- ウイルスタンパク質が、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、単純ヘルペスウイルス(HSV)、及びウシヘルペスウイルス-1(BoHV-1)からなる群から選択されるウイルス由来である、請求項15に記載の単離されたTリンパ球。
- ウイルスタンパク質が、CMV由来であり、US6、UL40、及びUL18からなる群から選択される、請求項16に記載の単離されたTリンパ球。
- ウイルスタンパク質が、抗原プロセシングと関連する輸送体(TAP)を阻害する、請求項16に記載の単離されたTリンパ球。
- ウイルスタンパク質が、CMV US6、HSV ICP47、BoHV-1 UL49.5、及びEBV BNLF2aからなる群から選択される、請求項18に記載の単離されたTリンパ球。
- レポーター遺伝子をコードする遺伝子をさらに含む、請求項1に記載の単離されたTリンパ球。
- レポーター遺伝子が、切断型上皮増殖因子受容体(EGFR)遺伝子、切断型前立腺特異的膜抗原(PSMA)、切断型低親和性神経成長因子受容体(LNGFR)、切断型CD19を含む、請求項20に記載の単離されたTリンパ球。
- 治療タンパク質をコードする遺伝子をさらに含む、請求項1に記載の単離されたTリンパ球。
- 治療タンパク質が、抗原受容体を含む、請求項22に記載の単離されたTリンパ球。
- 抗原受容体が、選択された標的抗原に対する特異性を付与する、請求項23に記載の単離されたTリンパ球。
- 抗原受容体が、選択されたリガンドに対する特異性を付与する、請求項23に記載の単離されたTリンパ球。
- 抗原受容体が、キメラ抗原受容体(CAR)である、請求項23に記載の単離されたTリンパ球。
- CARが、細胞外ドメイン、膜貫通型領域ドメイン、及び細胞内領域ドメインを含む、請求項26に記載の単離されたTリンパ球。
- 細胞外ドメインが、1本鎖抗体を含み、細胞内ドメインが、T細胞活性化ドメインを含む、請求項27に記載の単離されたTリンパ球。
- 細胞死を誘導する遺伝子をさらに含む、請求項1に記載の単離されたTリンパ球。
- 遺伝子が、活性化可能な自殺遺伝子である、請求項29に記載の単離されたTリンパ球。
- 自殺遺伝子が、薬物により活性化される、請求項30に記載の単離されたTリンパ球。
- 自殺遺伝子が、カスパーゼ9アポトーシス促進分子に融合されたFK506結合ドメインを発現する、請求項31に記載の単離されたTリンパ球。
- 修飾されたTリンパ球を生成する方法であって、Tリンパ球においてCD3ζ、TRAC、及び/又はTRBC遺伝子を不活性化することを含む方法。
- CD3ζ、TRAC、及び/又はTRBC遺伝子の不活性化が、ジンクフィンガーヌクレアーゼ(ZFN)、転写活性化因子様エフェクターヌクレアーゼ(TALEN)、及びクラスター化して規則的な配置の短い回文配列リピート(CRISPR/cas9系)の群から選択されるヌクレアーゼ又は系を使用して行われる、請求項33に記載の方法。
- 修飾されたTリンパ球が、請求項1に記載の修飾されたTリンパ球である、請求項33に記載の方法。
- 疾患について対象を処置する方法であって、対象に、請求項1に記載の単離されたTリンパ球を投与することを含む方法。
- 疾患が、がん、感染性疾患、及び移植手法から生じる徴候からなる群から選択される、請求項36に記載の方法。
- 対象において免疫原性反応を低減する方法であって、対象に、請求項1に記載のTリンパ球を投与することを含む方法。
- Tリンパ球が、導入遺伝子を発現する、請求項38に記載の方法。
- Tリンパ球が、内在性T細胞受容体シグナル伝達分子との低減した競合を有する、請求項38に記載の方法。
- Tリンパ球が、対象に関して自家である、請求項36に記載の方法。
- Tリンパ球が、対象に関して同種である、請求項36に記載の方法。
- 修飾されたTリンパ球が、インビボで拡大される、請求項36に記載の方法。
- 修飾されたTリンパ球が、対象の血液において拡大される、請求項36に記載の方法。
- 修飾されたTリンパ球が、投与に先立ち、インビトロで拡大される、請求項36に記載の方法。
- 治療タンパク質及び免疫系回避を促進する異種性タンパク質をコードする遺伝子を含むベクター。
- 異種性タンパク質が、ウイルスタンパク質である、請求項46に記載のベクター。
- ウイルスタンパク質が、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、単純ヘルペスウイルス(HSV)、及びウシヘルペスウイルス-1(BoHV-1)からなる群から選択されるウイルス由来である、請求項47に記載のベクター。
- ウイルスタンパク質が、CMV由来であり、US6、UL40、及びUL18からなる群から選択される、請求項48に記載のベクター。
- ウイルスタンパク質が、抗原プロセシングと関連する輸送体(TAP)を阻害する、請求項48に記載のベクター。
- ウイルスタンパク質が、CMV US6、HSV ICP47、BoHV-1 UL49.5、及びEBV BNLF2aからなる群から選択される、請求項50に記載のベクター。
- 治療タンパク質が、CARである、請求項46に記載のベクター。
- 請求項46に記載のベクターをTリンパ球に形質導入する方法。
- 請求項33に記載の方法により作製された修飾されたTリンパ球若しくは細胞株、又はその継代培養物。
- 請求項1に記載の少なくとも1個の修飾されたTリンパ球を含む薬学的組成物。
- (a)請求項33に記載の方法により修飾されたTリンパ球の集団を調製する工程、及び(b)修飾されたTリンパ球を対象に投与する工程を含む、対象を処置する方法。
- Tリンパ球が、処置されるべき対象に由来する、請求項56に記載の方法。
- Tリンパ球が、健常ドナーに由来する、請求項56に記載の方法。
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US11622977B2 (en) | 2017-05-12 | 2023-04-11 | Crispr Therapeutics Ag | Materials and methods for engineering cells and uses thereof in immuno-oncology |
US11166985B2 (en) | 2017-05-12 | 2021-11-09 | Crispr Therapeutics Ag | Materials and methods for engineering cells and uses thereof in immuno-oncology |
US20190038733A1 (en) | 2017-08-10 | 2019-02-07 | National University Of Singapore | T cell receptor-deficient chimeric antigen receptor t-cells and methods of use thereof |
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