JP7189860B2 - ヒト化抗EGFRvIIIキメラ抗原受容体を用いたがんの処置 - Google Patents
ヒト化抗EGFRvIIIキメラ抗原受容体を用いたがんの処置 Download PDFInfo
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Description
本発明は、米国国立衛生研究所(NIH)の第2R01 NS055140号および第1P01 CA1322714号の助成により行われた。政府は本発明において特定の権利を有する。
本願は、電子データによりASCIIフォーマットで提出した配列表を含み、該配列表は、言及によりその全体が本明細書に包含される。該ASCIIコピー(2014年2月20日作成)は、N2067-7000WO_SL.txtという名称であり、サイズは228,605バイトである。
とくにことわらない限り、本明細書で用いる全ての技術的用語は、本発明が属する分野の当業者が通常理解するのと同じ意味を有する。
本発明は、CARをコードする配列を含む組換えDNAコンストラクトを含み、ここで、該CARは、EGFRvIIIに特異的に結合する抗体断片、例えばEGFRvIIIに特異的に結合するヒト抗体断片を含む。局面の一において、該EGFRvIIIはヒトEGFRvIIIであり、該抗体断片をコードする核酸配列は、細胞内シグナル伝達ドメインをコードする核酸配列と隣接しており、同一リーディングフレーム中に存在する。該細胞内シグナル伝達ドメインは、同時刺激シグナル伝達ドメインおよび/または一次シグナル伝達ドメイン、例えばζ鎖を含んでいてよい。同時刺激ドメインは、同時刺激分子の細胞内ドメインの少なくとも一部を含む、CARの一部を指す。
局面の一において、本発明のCARは、抗原結合ドメインとも称される、標的特異的結合エレメントを含む。部位の選択は、標的細胞の表面を決定するリガンドの種類および数に依存する。例えば、抗原結合ドメインは、特定の病態と関連する標的細胞の細胞表面マーカーとして作用するリガンドを認識するように選択してよい。本発明のCARの抗原結合ドメインのリガンドとして作用し得る細胞表面マーカーの例としては、ウイルス性、バクテリア性および寄生性の感染症、自己免疫疾患およびがん細胞に関連するものが挙げられる。
抗EGFRvIII結合ドメイン、例えばscFv分子(例えば可溶性scFv)の安定性は、慣用の対照scFV分子または全長の抗体の生物物理学的な性質(例えば熱安定性)との相対により評価し得る。態様の一において、ヒト化scFvは、本明細書に記載のアッセイにおいて、対照結合分子(例えば慣用のscFV分子)よりも、約0.1℃、約0.25℃、約0.5℃、約0.75℃、約1℃、約1.25℃、約1.5℃、約1.75℃、約2℃、約2.5℃、約3℃、約3.5℃、約4℃、約4.5℃、約5℃、約5.5℃、約6℃、約6.5℃、約7℃、約7.5℃、約8℃、約8.5℃、約9℃、約9.5、約10℃、約11℃、約12℃、約13℃、約14℃または約15℃高い熱安定性を示す。
抗原結合ドメインの安定性は、例えば、後述する方法を用いて評価し得る。該方法により、最も安定性の低いドメインが最初にアンフォールディングするかまたは協調してアンフォールディングするマルチドメインユニット(例えば単一のアンフォールディング転移を示すマルチドメインタンパク質)の安定性の閾値が全体的に限定される、複数の熱アンフォールディング転移を検出することが可能になる。最も安定性の低いドメインは、複数の付加的な方法により特定し得る。どのドメインが全体の安定性を限定しているかを探索するために、変異を導入してよい。さらに、マルチドメインタンパク質のプロテアーゼ耐性を、最も安定性の低いドメインが天然でアンフォールディングを起こすことがDSCまたは他の分光測定法により知られている条件下で調べてよい(Fontana, et al., (1997) Fold. Des., 2: R17-26; Dimasi et al. (2009) J. Mol. Biol. 393: 672-692)。最も安定性の低いドメインが特定されると、このドメイン(またはその一部)をコードする配列を当該方法の試験配列として使用し得る。
該組成物の熱安定性は、多数の非限定的な生物物理または生化学技術により解析し得る。特定の態様において、熱安定性は、解析分光測定により評価される。
組成物の安定性は、その凝集性を測定することによって決定し得る。凝集は、多数の非限定的な生化学または生物物理学的な技術により測定し得る。例えば、組成物の凝集は、クロマトグラフィー、例えばサイズ交換クロマトグラフィー(SEC)により評価し得る。SECは、サイズに基づいて分子を分離する。イオンおよび小さい分子は内側に入れるが、大きい分子は入ることのできないポリマーゲルの半固体ビーズでカラムを充填する。タンパク質組成物をカラムの一番上にアプライすると、コンパクトな折りたたまれたタンパク質(すなわち非凝集タンパク質)は、大きなタンパク質凝集体にとって利用可能なものよりも体積の大きい溶媒に分散する。結果的に、大きな凝集体の方がカラム内を速く移動し、この方法によって混合物を分離し、その成分に分画することができる。各画分は(例えば光散乱)によって、ゲルからの溶出時に別に定量化し得る。したがって、組成物の凝集%は、画分の濃度をゲルにアプライしたタンパク質の全体濃度と比較することによって決定し得る。安定な組成物は、本質的に単一画分としてカラムから溶出し、ならびに溶出プロファイルまたはクロマトグラムにおいて本質的に単一のピークを示す。
組成物の安定性は、その標的結合親和性を決定することにより評価し得る。結合親和性を決定する方法として、多種多様な方法が当該分野で知られている。結合親和性の決定方法の一例は、表面プラズモン共鳴法を使用する。表面プラズモン共鳴は、例えば、BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.)を用いることによって、バイオセンサーマトリクス中のタンパク質の濃度を検出することで、生体特異的な相互作用をリアルタイムで解析することを可能にする、光学的な現象である。さらなる記載については、Jonsson, U., et al. (1993) Ann. Biol. Clin. 51:19-26; Jonsson, U., i (1991) Biotechniques 11:620-627; Johnsson, B., et al. (1995) J. Mol. Recognit. 8:125-131;およびJohnnson, B., et al. (1991) Anal. Biochem. 198:268-277を参照のこと。
膜貫通ドメインに関して、種々の態様において、CARは、CARの細胞外ドメインに結合する膜貫通ドメインを含むように設計されていてよい。膜貫通ドメインは、該膜貫通ドメインに隣接する1個以上の付加的なアミノ酸、例えば該膜貫通領域が由来するタンパク質の細胞外領域に結合する1個以上のアミノ酸(例えば細胞外領域の1、2、3、4、5、6、7、8、9、10~15個のアミノ酸) および/または該膜貫通タンパク質が由来するタンパク質の細胞内領域に結合する1個以上の付加的なアミノ酸(例えば細胞内領域の1、2、3、4、5、6、7、8、9、10~15個のアミノ酸)を含んでいてよい。局面の一において、該膜貫通ドメインは、使用するCARの他のドメインの1つに結合するものである。いくつかの態様において、膜貫通ドメインは、該ドメインが、同じまたは異なる表面膜タンパク質の膜貫通ドメインに結合するのを避けるため、例えば受容体複合体の他のメンバーとの相互作用を最小化するために、選択またはアミノ酸置換による変更を受けていてよい。局面の一において、膜貫通ドメインは、CART細胞表面の他のCARとホモ二量体を形成することができる。他の局面において、膜貫通ドメインのアミノ酸配列は、同一CART中に存在する天然の結合パートナーの結合ドメインとの相互作用を最小化するために、変更または置換を受けていてよい。
ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM (配列番号104)。いくつかの態様において、該ヒンジまたはスペーサーは次のヌクレオチド配列にコードされるヒンジを含む:
GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG (配列番号105)。
AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATT (配列番号107)。
CARの細胞質ドメインまたは領域は、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一般的に、該CARが導入される免疫細胞の正常なエフェクター機能の少なくとも1つの活性化に重要である。「エフェクター機能」という語は、細胞の特有の機能を指す。T細胞のエフェクター機能は、例えば、細胞溶解活性またはヘルパー活性、例えばサイトカインの分泌であり得る。したがって、「細胞内シグナル伝達ドメイン」という語は、エフェクター機能シグナルを伝達し、該細胞に特有の機能を果たさせるタンパク質の一部を指す。細胞内シグナル伝達ドメインは通常は全体を使用し得るが、鎖の全体を用いる必要はない場合も多い。該細胞内シグナル伝達ドメインの切断部分が用いられる程度において、該切断型部分は、エフェクター機能シグナルを伝達できる限り、インタクトなドメインの代わりに使用してよい。したがって、細胞内シグナル伝達ドメインという語は、エフェクター機能シグナルを伝達するのに十分な該細胞内シグナル伝達ドメインの任意の切断部分を含むことを意図する。
試験管内で転写されるRNA CARの作製方法を本明細書に記載する。本発明はまた、細胞に直接導入できる、CARをコードするRNAコンストラクトを提供する。導入に用いるmRNAの作製方法は、特別に設計したプライマーを用いたテンプレートの試験管内転写(IVT) の後にポリA付加を行い、3’および5’非翻訳配列 (「UTR」)、5’キャップおよび/または配列内リボソーム進入部位 (IRES)、発現する核酸配列、およびポリAテールを含む、典型的に50-2000塩基の長さのコンストラクトを作製する(配列番号116)ことを含んでいてよい。このように作製したRNAは、種々の細胞に効率的に導入することができる。局面の一において、該テンプレートは、CARのための配列を含む。
本発明は、本発明に記載の、1つ以上のCARコンストラクトをコードする核酸分子を提供する。局面の一において、該核酸分子はメッセンジャーRNA転写物として提供される。局面の一において、該核酸分子はDNAコンストラクトとして提供される。
増殖および遺伝的修飾に先だって、T細胞源を対象より得る。「対象」という語は、免疫応答を誘発し得る生体(例えば哺乳類)を指すことを意図する。対象の例としては、ヒト、イヌ、ネコ、マウス、ラットおよびそれらのトランスジェニック種が挙げられる。T細胞は多数の供給源、例えば末梢血単核細胞、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位由来の組織、腹水、胸水貯留、、脾臓組織および腫瘍から得てよい。本発明の特定の局面において、当該分野で利用可能な任意のT細胞株を用いてよい。本発明の特定の局面において、T細胞は、当該分野で公知の任意の技術、例えばFicollTM分離を用いて、対象から回収した血液のユニットから得てよい。好ましい局面の一において、個人の循環血由来の細胞をアフェレーシスにより得る。該アフェレーシス産物は典型的に、リンパ球、例えばT細胞、単球、顆粒球、B細胞、他の有核白血球、赤血球および血小板を含む。局面の一において、アフェレーシスにより回収される細胞は、洗浄して血漿画分を除き、その後の処理工程のために細胞を適当なバッファーまたは媒体中に入れてよい。本発明の局面の一において、細胞をリン酸緩衝化生理食塩水 (PBS)で洗浄する。他の局面において、洗浄液は、カルシウムを含まず、また、マグネシウムを含まないか、または全てではなくても多くの二価性カチオンを含まなくてよい。カルシウム非存在下では、最初の活性化工程が、活性の増強を引き起こし得る。当業者には容易に理解し得ることであるが、洗浄工程は、当業者に公知の方法、例えば半自動化「フロースルー」遠心分離 (例えば、Cobe 2991 cell processor, the Baxter CytoMateまたはHaemonetics Cell Saver 5)を製造者の指示にしたがって用いることによって達成し得る。洗浄後、該細胞は、種々の生体適合性バッファー、例えばCa-不含有、Mg-不含有PBS、PlasmaLyte Aまたはバッファーを含むか、または含まない他の生理食塩水溶液に再懸濁してよい。あるいは、アフェレーシス試料の望ましくない成分を除いて、細胞を培養培地に直接再懸濁してもよい。
凍結工程およびそれに続く融解工程により、該細胞集団中の顆粒球およびある程度の単球が除去されることにより、より均一な産物が得られる。血漿および血小板を除去する洗浄工程の後、細胞を凍結溶液に懸濁してよい。当該分野では多くの凍結溶液およびパラメーターが公知であり、本発明で有用であるが、1つの方法として20% DMSOおよび8% ヒト血清アルブミンを含むPBS、または10% デキストラン40および5% デキストロース、20% ヒト血清アルブミンおよび7.5% DMSOを含むか、または31.25% Plasmalyte-A、31.25% デキストロース5%、0.45% NaCl、10% デキストラン40および5%デキストロース、20%ヒト血清アルブミンおよび7.5% DMSOを含む培養培地または、例えばHespanおよびPlasmaLyte Aを含む他の適当な細胞凍結培地の使用が挙げられ、次いで、細胞は-80℃に、1分あたり1℃の速度で凍結され、液体窒素タンク中の気相に保存される。制御凍結の他の方法ならびに、制御されない-20℃または液体窒素への急冷を用いてもよい。
T細胞は一般的に、例えば、米国特許第6,352,694号; 第6,534,055号; 第6,905,680号; 第6,692,964号; 第5,858,358号; 第6,887,466号; 第6,905,681号; 第7,144,575号; 第7,067,318号; 第7,172,869号; 第7,232,566号; 第7,175,843号; 第5,883,223号; 第6,905,874号; 第6,797,514号; 第6,867,041号; および米国特許出願公開第20060121005号に記載の方法を用いて活性化および増殖させ得る。
EGFRvIIIは内皮増殖因子受容体の腫瘍特異的、リガンド非依存性、構成的活性化バリアントである。本発明は、EGFRvIIIと関連する疾患および障害の処置用組成物および方法を提供する。EGFRvIIIと関連する疾患または障害の例は神経膠腫である。
i) 細胞の増殖、ii) CARをコードする核酸の細胞への導入またはiii) 該細胞の凍結保存。
本明細書に記載の、CAR発現細胞は、他の公知の薬剤および療法と組み合わせて用いてよい。本明細書において、「組み合わせて」投与するとは、2つの(またはそれより多くの) 異なる処置が、対象の障害に関する苦痛の経過において該対象に送達されること、例えば該2つ以上の処置が、対象が障害についての診断を受けた後であるが、該障害が治療されるかもしくは除去されるか、または処置が他の理由で終了するよりも前に該対象に送達されることを指す。いくつかの態様において、第2の処置の送達が開始したときに第1の処置の送達は未だ進行中であるため、投与期間に重なりが見られる。このことを、本明細書中において、「同時」または「同時的な送達」と称する場合もある。他の態様において、1つの処置の送達はもう1つの処置が開始する前に終了する。いずれの場合においても、いくつかの態様において、該処置は、組合せ投与であるためにより有効である。例えば、第2の処置は、第1の処置なしに投与する場合よりもより効果的である、例えば、第2の処置が少なくても同等の効果が見られるか、または第2の処置が症候をより大幅に減少させる。または、同等の状況が第1の処置についてみられる。いくつかの態様において、送達は、症候または該障害に関連する他のパラメーターの低下が、一方の処置がない場合のもう1方の処置について観察されるよりも大きくなるように行われる。かかる2つの処置の効果は部分的に相加的であっても、全体的に相加的であっても、または相加よりも優れたものであってもよい。該送達は、第2の処置が送達されるときに、第1の処置の効果が未だ検出できるように行ってもよい。
本発明の医薬組成物は、CAR発現細胞、例えば、本明細書に記載する、複数のCAR発現細胞を、1つ以上の薬学的または生理学的に許容される担体、希釈剤または賦形剤と組合せて、含んでいてよい。該組成物は、緩衝液、例えば中性の緩衝化食塩水およびリン酸緩衝化食塩水等;炭水化物、例えばグルコース、マンノース、スクロースまたはデキストラン、マンニトール;タンパク質;ポリペプチドまたはアミノ酸、例えばグリシン;抗酸化剤;キレート剤、例えばEDTAまたはグルタチオン;アジュバント(例えば水酸化アルミニウム);および保存料を含んでいてよい。本発明の組成物は、局面の一において、静脈内投与用に製剤される。
次の実験は、抗体ベースのキメラ抗原受容体(CAR)によって表面タンパク質EGFRvIIIに対するように改変されたヒトT細胞が、NSGマウスにおいてEGFRvIII+モデルの多形神経膠芽腫を除去するのに有効であるかどうかを確かめるために計画した。さらに、これらの細胞の生着性および持続性を評価するための実験を計画した。3つの異なる形態のCARを試験し、これらは、2つの異なる一本鎖可変断片 (EGFRvIII抗原に結合するCARの部位)および細胞内シグナル伝達ドメイン (4-1BBおよびCD3ζを含み、CD28を含むものと含まないものがある)を含む。
NSGマウスモデル
免疫欠損NOD/scid/γcヌル(NSG) マウスのコロニーが近年確立された。NSGマウスは、T細胞およびB細胞、ナチュラルキラー細胞を欠損し、樹状細胞の機能が損傷している。活性化T細胞の移植は、NSGマウスにおいて、従来のNOD/scid/β2Mヌル マウスモデルよりも優れた結果を示したことが確認されている。したがって、該NSGモデルをヒト異種間移植試験に用いた。
EGFRvIIIに対するモノクローナルおよびポリクローナルAbの多くは、野生型のEGFRまたは他の非特異的なタンパク質に対する交差反応性を示すが、モノクローナル抗体(mAb) 3C10は、本来EGFRvIII特異的な融合部を含む14アミノ酸によって免疫化されたマウスから開発されたものであり、EGFRvIIIを高い特異性で認識し、野生型のEGFRに対する結合が無視できる程度にしか検出されないことが示されている (Okamoto et al., 1996 Br J Cancer 73:1366-1372)。T細胞の導入には研究グレードのレンチウイルスベクターを用いた。
マウスに注入する細胞はヒトT細胞である。ヒト単核細胞濃縮アフェレーシス産物は、University of Pennsylvania Human Immunology Coreの健康なボランティアドナーの白血球除去により得られる。全ての検体は、University Institutional Review Boardの承認したプロトコルにしたがって回収し、各ドナーから同意書を得ている。T細胞をRosetteSep human T cell enrichment cocktail (Stemcell Technologies, Vancouver, Canada)を用いてネガティブ選択する。T細胞をTRP研究室に移し、ここで研究用グレードのCD3/28ビーズを用いて活性化し、グルタミン、10% FBS、20mM Hepes、100U/ml ペニシリンおよび100ug/ml ストレプトマイシンを含むRPMI中で増殖させる。パッケージレンチベクターを直接活性化培養物に添加してから24時間後にベクターの形質導入が起こる。細胞を5日目にビーズから離し、増殖をCoulter Multisizer 3(Beckman Coulter, Fullerton, CA)を用いて、サイズ (fl)変化および総細胞数の変化について、濃度を0.7E6~2E6個/mlに維持しながら経過観察を行う。CAR導入T細胞についての形質導入効率を、ヤギ抗マウス抗体 (GAM、3C10-ベースCARに対する) またはヤギ抗ヒト抗体 (GAH、139ベースCARに対する)のいずれかで染色することによりフローサイトメトリーにより試験する。マウス1個体あたり1x106個のCAR+ T細胞を、試験の0日目に尾静脈注射して注入する。
脳室内にU87-EGFRvIII腫瘍を有し、0日目にCAR+ T細胞の投与を受けたマウスに、続けてTMZを0~4日目に腹腔内注射(i.p.)する (1日1回、5日間): TMZは、DMEMに6.67mg/mlで溶解させる。各マウスは、腹腔内注射により50μLのTMZ溶液(333μg/投与; 約17 mg/kg/投与)の投与を受ける。
CART-EGFRvIII T細胞をCVPF(clinical cell and vaccine production facility)で調製し、該細胞産物は自家Tリンパ球である。CD3+ T細胞は、白血球除去産物から、向流遠心分離により単球を枯渇させることにより濃縮させる。0日目に、抗CD3/CD28 mAbコーティングした磁気ビーズを用いて、該濃縮T細胞を活性化させることにより、製造プロセスを開始する。T細胞培養物はEGFRvIII CARレンチウイルスベクターに暴露し、増殖させる。該T細胞調製工程は、静的な組織培養で開始し(0日目~5日目)、その後、必要であれば、灌流条件下でさらに増殖させるために、Waveバイオリアクターに移される。培養の終了時に、細胞から磁気ビーズを除き、洗浄して濃縮し、凍結保存する。修飾T細胞産物は、細胞数に合わせた体積で、凍結用の袋に入れ、冷凍速度制限冷凍庫を用いて凍結保存する (最終濃度は最大で108/ml)。凍結保存したEGFRvIII CAR T細胞産物を、≦-130℃で、監視されたフリーザー中で保存する。該試験の結果は次に記載する。
神経膠芽腫 (GBM)は最も一般的で最も悪性度の高い原発性の脳腫瘍であり、毎年米国で約12,000人のがん関連の死亡の原因となっている。GBMの患者は、化学療法 (テモゾロミド) と放射線(RT)両方の組合せ処置の後において、生存期間の中央値が15ヶ月より短い。自家T細胞、特にキメラ抗原受容体(CAR)を導入したT細胞を用いた養子細胞移入(ACT)療法は、近年の血液がんの試験において見込みがあることが示された。CART細胞を用いたACTは、GBMの患者に特に適当であり得る。これは、生体内の免疫化により誘導されるナイーブT細胞よりも生体外で調製される細胞の特異性、数および機能性の表現型ははるかに操作および制御がしやすいためである。
新しくGBMと診断されたEGFRvIII+を有する患者における、CART-EGFRvIII T細胞の安全性、耐用性および生着能を決定するために、単一群 (single-arm)非盲検予備試験を行った。全体的に、全ての対象に自家CART-EGFRvIII T細胞を投与する。好適な対象は白血球除去を行い、CART-EGFRvIII作製用に多数の末梢血単核球(PBMC)を得る。T細胞をPBMCより精製し、ヒト化3C10-CARレンチウイルスベクターを用いて形質導入し、試験管内で増殖させ、適当なアリコートで凍結保存する。注入する細胞は、0日目の注入の直前に、ベッドサイドで融解する。
miR-17-92発現は、1型の表現型およびT細胞の生存亢進をもたらす。神経膠芽腫(GBM) 患者由来のT細胞では、miR-17-92が発現低下していることが報告されている。キメラ抗原受容体を形質導入したT細胞(CAR-T細胞)を用いた養子移入療法の有効性を改善するために、miR-17-92および、タンデムのT細胞受容体CD3ζ鎖シグナル伝達モジュールおよびCD137 (4-1BB)およびCD28の同時刺激モチーフに結合した上皮増殖因子受容体バリアントIII (EGFRvIII)-特異的一本鎖可変断片 (scFv)からなるCARのための新規レンチウイルスベクター(pELNS-3C10-CAR)を構築した。EGFRvIIIを安定して発現するU87 GBM細胞 (U87-EGFRvIII)に対する抗原特異的な強い細胞障害性活性に加え、miR-17-92を共形質導入したCAR-T細胞は、miR-17-92の共形質導入を伴わないCAR-T細胞と比較して、トランスフォーミング増殖因子 (TGF)-βおよびテモゾロミドのT細胞抑制効果に対する耐性が改善された。脳室内にU87-EGFRvIII異種移植片を有するマウスでは、導入遺伝子由来のmiR-17-92発現がある場合でもない場合でも、CAR-T細胞は、同レベルの強い治療効果を示し、CAR-T細胞の制御できない増殖は見られなかった。しかしながら、これらのマウスの脳内に、U87-EGFRvIII細胞を再負荷したときは、共形質導入したCAR-T細胞の投与を受けたマウスでは、miR-17-92の共形質導入のないCAR-T細胞の処置を受けたマウスと比較して、保護が改善することが示された。これらのデータは、GBMの患者における有効性を高めるために、miR-17-92をCARに組み込み得ることを支持するものである。
ヒトEGFRvIII特異的なモノクローナル抗体(mAb) 3C10由来の一本鎖可変断片(scFv)を介してEGFRvIIIを認識するレンチウイルスベクター (pELNS-3C10-CAR) を作製した(図1A参照)。このコンストラクトでは、EF-1αプロモーターにより、3C10-由来scFv、CD28膜貫通ドメイン(TM)ならびに4-1BBおよび細胞内ドメイン (ICD)およびCD3ζドメインを組み込んだCAR融合タンパク質の発現を制御する。FG12-ベースの SIN(self-inactivating) ベクターを用いたレンチウイルスmiR-17-92コンストラクト (FG12-EF1a-miR-17/92 も作製した(図1B)。このベクターでは、EF-1αプロモーターがmiR-17-92を制御し、ヒトUbiCプロモーターが、形質導入細胞の追跡用の高感度緑色蛍光タンパク質(EGFP)マーカー遺伝子を制御する。このスキームで用いる用語は: RSV/HIV-1 5’LTR; ハイブリッドRSVプロモーター-R/U5末端反復配列、EF-1α; ヒト伸張因子1α-サブユニットプロモーター、VH; 3C10免疫グロブリンの重鎖の可変領域、VL; 3C10免疫グロブリンの軽鎖の可変領域、HIV-1 Δ-3’LTR; U3領域に欠損を有するSIN型3’末端反復配列、CMV/HIV-1 5’LTR; ハイブリッドCMVプロモーター-R/U5末端反復配列、UbiC; ユビキチンCプロモーター、である。
健康なドナー由来のCD3+ T細胞を、pELNS-3C10- CARを用いて形質導入し、それぞれ抗マウス(Fab’)2抗体およびEGFPを用いた3C10-CARおよびmiR-17-92の発現についてのフローサイトメトリーにより、該細胞の導入遺伝子の発現レベルを評価した(図2A、左)。ヒトT細胞上の3C10由来のscFvに特異的な抗マウスF(ab’)2 Abを用いることで、約半分 (48.9%)のT細胞がその表面に3C10-由来のscFvを発現していることが検出された。
過去の試験 (Sasaki et al., 2010, J. Transl Med 8:17)において、miR-17-92遺伝子導入マウス由来のCD4+ T細胞は、野生型マウス由来の対応物と比較すると、IFN-γ産生の増加を示し;ヒトJurkat T細胞のmiR-17-92による遺伝子導入は、活性化誘導細胞死 (AICD)を引き起こした。
脳室内に確立された(7日目) U87-EGFRvIII腫瘍を有する免疫不全NOD/scid/γc(-/-) (NSG) マウスにおけるCAR-T細胞の有効性を評価するための試験を行った。マウスは、miR-17-92共形質導入CAR-T細胞、miR-17-92の共形質導入のないCAR-T細胞またはモック形質導入T細胞の、尾静脈を介した単回静脈内(i.v.)注入を受けた(2 x 106個/マウス)。新しくGBMと診断された患者が日常的にTMZ療法を受けるのと同様に、TMZを、T細胞注入の日から開始して5日間毎日腹腔内(i.p.) 投与することを計画した (図4A)。図4Bは、カプラン・マイヤー解析を示す。CAR-T細胞で処理したマウス(miR-17-92の共形質導入を伴うかまたは伴わない)の生存中間値は、モック形質導入T細胞と比較して有意に上昇していた (p<0.05)。TMZおよびモック形質導入T細胞の投与を受けた対照マウスが全てT細胞注入の3週間 (21日)以内に死亡したように、TMZ処置そのものは、効果がなかった (図4B)。CAR-T細胞を注入した5匹のマウスのうちの1匹および、miR-17-92共形質導入CAR-T細胞を注入した5匹のマウスのうちの2匹が腫瘍の進行により22日までに死亡したが、これらの群の他のマウスは全て、40日よりも長く生存した。類似の結果を示す2回の独立した実験のうちの1回の結果を示す。miR-17-92-共形質導入CAR-T細胞とmiR-17-92を共形質導入していないCAR-T細胞を投与したマウス間では、生存に統計学的に有意な差は見られなかった(ログランク検定: p=0.5485)。
図4に示す試験において、マウスに注入したCAR-T細胞がU87-EGFRvIII腫瘍に対するホストの長期間の保護を提供し得るかどうかを決定するために、49日目に脳の反対側の半球にU87-EGFRvIII細胞を接種することにより生き残り個体を再負荷した(図5)。CAR-T細胞で処置した3個体全てにおいて、再負荷した腫瘍細胞が増殖したのに対し、miR-17-92-共形質導入CAR-T細胞で処置したマウスでは、バックグラウンドレベルを超えるBLIシグナルを示す個体がなかった。これらの結果は、miR-17-92クラスターの共形質導入が、CAR-T細胞の長期間の持続性をもたらし、それにより、腫瘍成長に対するホストの保護を延長することを強く示唆している。腫瘍の長期的測定は、2群のマウスの光子束±SDを示す。バックグラウンドの発光レベル (最大10^3 p/s)は、処置群の腫瘍を有するマウスと平行して、腫瘍を持たないマウスで観察されたレベルに基づいて決定した。
本明細書に示す結果は、3C10 scFvをCD3ζ鎖、CD137 (4-1BB)およびCD28とともに組み込んだ新規抗EGFRvIII-CAR (3C10-CAR)を導入したT細胞中のmiR-17-92の共発現の効果を示す。この結果は、miR-17-92の共発現は、TGF-βおよびテモゾロミドのT細胞増殖抑制効果に対する耐性を改善させることを示す。生体内では、3C10-CARおよびmiR-17-92の両方を共導入したT細胞は、3C10-CAR単独を導入したT細胞と比較して、治療効果をよく持続させることが示された。
マウスモノクローナル抗体(mAb) 3C10は、本来EGFRvIII特異的な融合部を含む14アミノ酸ペプチド(PEP3)を用いたマウスの免疫化により開発され、EGFRvIIIは高い特異性で認識したが、野生型のEGFRに対しては検出できる結合が見られなかった (Okamoto et al, British J. Cancer 1996, 73:1366-1372)。次に、mAb 3C10の一本鎖可変断片 (scFv)が作製され、3C10 scFvのcDNAが得られた。本来のmAbの結合活性および/または抗原特異性が、scFv形態では失われていることがしばしばであったが、該3C10 scFvはそのEGFRvIII特異的エピトープに対する選択的反応性を維持していた(Nakayashiki et al., Jpn. J.Cancer Res. 2000, 91:1035-1043)。
3C10scFv-CD28BBzeta CAR (アミノ酸) (配列番号1)
MALPVTALLLPLALLLHAARPGSEIQLQQSGAELVKPGASVKLSCTGSGFNIEDY YIHWVKQRTEQGLEWIGRIDPENDETKYGPIFQGRATITADTSSNTVYLQLSSLTS EDTAVYYCAFRGGVYWGPGTTLTVSSGGGGSGGGGSGGGGSHMDVVMTQSPL TLSVAIGQSASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLISLVSKLDSGVPDRFTGSGSGTDFTLRISRVEAEDLGIYYCWQGTHFPGTFGGGTKLEIKASTTTPAPR PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSL LVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKR GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQ GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
MALPVTALLLPLALLLHAARPGSEIQLQQSGAELVKPGASVKLSCTGSGFNIE
DYYIHWVKQRTEQGLEWIGRIDPENDETKYGPIFQGRATITADTSSNTVYLQLSSLTSEDTAVYYCAFRGGVYWGPGTTLTVSSGGGGSGGGGSGGGGSHMDVVMTQSPL TLSVAIGQSASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLISLVSKLDSGVPD RFTGSGSGTDFTLRISRVEAEDLGIYYCWQGTHFPGTFGGGTKLEIKASTTTPAPR PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSL VITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgccaggccgggatccgagattcagctgcag caatctggggcagaacttgtgaagccaggggcctcagtcaagctgtcctgcacaggttctggcttcaacattgaagactactatat tcactgggtgaagcagaggactgaacagggcctggaatggattggaaggattgatcctgagaatgatgaaactaaatatggccc aatattccagggcagggccactataacagcagacacatcctccaacacagtctacctgcaactcagcagcctgacatctgagga cactgccgtctattactgtgcctttcgcggtggagtctactgggggccaggaaccactctcacagtctcctcaggaggtggtggttccggtggtggtggttccggaggtggtggttcacatatggatgttgtgatgacccagtctccactcactctatcggttgccattggac aatcagcctccatctcttgcaagtcaagtcagagcctcttagatagtgatggaaagacatatttgaattggttgttacagaggccaggccagtctccaaagcgcctaatctctctggtgtctaaactggactctggagtccctgacaggttcactggcagtggatcagggac agatttcacactgagaatcagcagagtggaggctgaggatttgggaatttattattgctggcaaggtacacattttcctgggacgtt cggtggagggaccaagctggagataaaagctagcaccacgacgccagcgccgcgaccaccaacaccggcgcccaccatcg cgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgcacacgagggggctggacttcgcctgtgatttttgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaacagtggcctttattattttctgggtg aggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattacc agccctatgccccaccacgcgacttcgcagcctatcgctccaaacggggcagaaagaaactcctgtatatattcaaacaaccatt tatgagaccagtacaaactactcaagaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaactga gagtgaagttcagcaggagcgcagacgcccccgcgtacaagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccct caggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccgg aggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccc tgccccctcgc
Atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgccaggccgggatccgagattcagctgca gcaatctggggcagaacttgtgaagccaggggcctcagtcaagctgtcctgcacaggttctggcttcaacattgaagactactat attcactgggtgaagcagaggactgaacagggcctggaatggattggaaggattgatcctgagaatgatgaaactaaatatggc ccaatattccagggcagggccactataacagcagacacatcctccaacacagtctacctgcaactcagcagcctgacatctgaggacactgccgtctattactgtgcctttcgcggtggagtctactgggggccaggaaccactctcacagtctcctcaggaggtggtg gttccggtggtggtggttccggaggtggtggttcacatatggatgttgtgatgacccagtctccactcactctatcggttgccattg gacaatcagcctccatctcttgcaagtcaagtcagagcctcttagatagtgatggaaagacatatttgaattggttgttacagaggc caggccagtctccaaagcgcctaatctctctggtgtctaaactggactctggagtccctgacaggttcactggcagtggatcagg gacagatttcacactgagaatcagcagagtggaggctgaggatttgggaatttattattgctggcaaggtacacattttcctgggacgttcggtggagggaccaagctggagataaaagctagcaccacgacgccagcgccgcgaccaccaacaccggcgcccacc atcgcgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgcacacgagggggctgg acttcgcctgtgatatctacatctgggcgcccttggccgggacttgtggggtccttctcctgtcactggttatcaccctttactgcaa acggggcagaaagaaactcctgtatatattcaaacaaccatttatgagaccagtacaaactactcaagaggaagatggctgtagc tgccgatttccagaagaagaagaaggaggatgtgaactgagagtgaagttcagcaggagcgcagacgcccccgcgtacaagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccggg accctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccctcgc
MALPVTALLLPLALLLHAARPGSDIQMTQSPSSLSASVGDRVTITCRASQGIRNNL AWYQQKPGKAPKRLIYAASNLQSGVPSRFTGSGSGTEFTLIVSSLQPEDFATYYC LQHHSYPLTSGGGTKVEIKRTGSTSGSGKPGSGEGSEVQVLESGGGLVQPGGSLR LSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTNYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCAGSSGWSEYWGQGTLVTVSSASTTTPAPRP PTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLV ITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
Atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgccaggccgggatccgacatccagatgacccagagccctagcagcctgagcgccagcgtgggcgacagagtgaccatcacctgtcgggccagccagggcatcagaaaca acctggcctggtatcagcagaagcccggcaaggcccccaagagactgatctacgctgccagcaatctgcagagcggcgtgcc cagcagattcaccggaagcggctccggcaccgagttcaccctgatcgtgtccagcctgcagcccgaggacttcgccacctact actgcctgcagcaccacagctaccctctgaccagcggcggaggcaccaaggtggagatcaagcggaccggcagcaccagc ggcagcggcaagcctggcagcggcgagggaagcgaggtccaggtgctggaatctggcggcggactggtgcagcctggcggcagcctgagactgagctgtgccgccagcggcttcaccttcagcagctacgccatgtcttgggtccggcaggctcctggaaag ggcctggaatgggtgtccgccatcagcggctctggcggctccaccaactacgccgacagcgtgaagggccggttcaccatcagccgggacaacagcaagaacaccctgtatctgcagatgaacagcctgagagccgaggacaccgccgtgtactactgtgccgg cagcagcgggtggagcgagtactggggccagggcacactggtcacagtgtctagcgctagcaccacgacgccagcgccgc gaccaccaacaccggcgcccaccatcgcgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcgggggg cgcagtgcacacgagggggctggacttcgcctgtgatatctacatctgggcgcccttggccgggacttgtggggtccttctcctgtcactggttatcaccctttactgcaaacggggcagaaagaaactcctgtatatattcaaacaaccatttatgagaccagtacaaactactcaagaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaactgagagtgaagttcagcaggagcgcagacgcccccgcgtacaagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccctcgct
核酸配列:
・ 3C10 scFvヌクレオチド配列(マウス); (配列番号4)
GAGATTCAGCTGCAGCAATCTGGGGCAGAACTTGTGAAGCCAGGGGCCTCAGTCAAGCTGTCCTGCACAGGTTCTGGCTTCAACATTGAAGACTACTATATTCACTGGGTGAAGCAGAGGACTGAACAGGGCCTGGAATGGATTGGAAGGATTGATCCTGAGAATGATGAAACTAAATATGGCCCAATATTCCAGGGCAGGGCCACTATAACAGCAGACACATCCTCCAACACAGTCTACCTGCAACTCAGCAGCCTGACATCTGAGGACACTGCCGTCTATTACTGTGCCTTTCGCGGTGGAGTCTACTGGGGGCCAGGAACCACTCTCACAGTCTCCTCAGGAGGTGGTGGTTCCGGTGGTGGTGGTTCCGGAGGTGGTGGTTCACATATGGATGTTGTGATGACCCAGTCTCCACTCACTCTATCGGTTGCCATTGGACAATCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTCTCTGGTGTCTAAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACAGATTTCACACTGAGAATCAGCAGAGTGGAGGCTGAGGATTTGGGAATTTATTATTGCTGGCAAGGTACACATTTTCCTGGGACGTTCGGTGGAGGGACCAAGCTGGAGATAAAA
GACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCAGCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCAGCCAGGGCATCAGAAACAACCTGGCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGAGACTGATCTACGCTGCCAGCAATCTGCAGAGCGGCGTGCCCAGCAGATTCACCGGAAGCGGCTCCGGCACCGAGTTCACCCTGATCGTGTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACCACAGCTACCCTCTGACCAGCGGCGGAGGCACCAAGGTGGAGATCAAGCGGACCGGCAGCACCAGCGGCAGCGGCAAGCCTGGCAGCGGCGAGGGAAGCGAGGTCCAGGTGCTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGCAGCCTGAGACTGAGCTGTGCCGCCAGCGGCTTCACCTTCAGCAGCTACGCCATGTCTTGGGTCCGGCAGGCTCCTGGAAAGGGCCTGGAATGGGTGTCCGCCATCAGCGGCTCTGGCGGCTCCACCAACTACGCCGACAGCGTGAAGGGCCGGTTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCGGCAGCAGCGGGTGGAGCGAGTACTGGGGCCAGGGCACACTGGTCACAGTGTCTAGC
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGC CGCCAGGCCG
ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGC
AGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGT GCACACGAGGGGGCTGGACTTCGCCTGTGAT
ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACT
GGTTATCACCCTTTACTGC
AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGAC CAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAG AACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTT
TGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGA AGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGG AGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGC
ACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGC
CCTTCACATGCAGGCCCTGCCCCCTCGC
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAG
AACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTT
TGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGA
AGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGG
AGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGC
ACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGC
CCTTCACATGCAGGCCCTGCCCCCTCGC
・ 3C10 scFvアミノ酸配列(マウス); (配列番号11)
EIQLQQSGAELVKPGASVKLSCTGSGFNIEDYYIHWVKQRTEQGLEWIGRIDPEN DETKYGPIFQGRATITADTSSNTVYLQLSSLTSEDTAVYYCAFRGGVYWGPGTTL TVSSGGGGSGGGGSGGGGSHMDVVMTQSPLTLSVAIGQSASISCKSSQSLLDSDG KTYLNWLLQRPGQSPKRLISLVSKLDSGVPDRFTGSGSGTDFTLRISRVEAEDLGI
YYCWQGTHFPGTFGGGTKLEIK
DIQMTQSPSSLSASVGDRVTITCRASQGIRNNLAWYQQKPGKAPKRLIYAASNLQ SGVPSRFTGSGSGTEFTLIVSSLQPEDFATYYCLQHHSYPLTSGGGTKVEIKRTGS
TSGSGKPGSGEGSEVQVLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAP GKGLEWVSAISGSGGSTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CAGSSGWSEYWGQGTLVTVSS
MALPVTALLLPLALLLHAARP
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD
IYIWAPLAGTCGVLLLSLVITLYC
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
Kabatによって指定されるEGFRvIIICARについての予測CDRは以下の通りである:
CDR3は
CDR3は
CDR3は
臨床の現場では、マウスEGFRvIII抗体のヒト化が望ましく、ここで、マウス特異的残基は、該マウスCARコンストラクトを導入したT細胞を用いた処置を受けた患者において、ヒト抗マウス抗原 (HAMA)応答を誘発し得る。ハイブリドーマ由来のマウスEGFRvIII抗体のVHおよびVL配列を文献から抽出した(Morgan et al. (2012) Human Gene Therapy, 23: 1043-1953、上記)。マウスEGFRvIII抗体由来のCDR領域をヒト生殖系列受容体フレームワークVH1_1-fまたはVH5_5aならびにVK2_A17またはVK4_B3 (vBASE database)に移植することにより、ヒト化を行った。CDR領域に加えて、CDR領域の構造的な統合性を支持すると考えられるいくつかのフレームワーク残基、すなわちVK2 #36、#49、VK4 #2、#36、#46、#49、VH1 #2、#24、#76、#94およびVH5 #2、#24、#73、#76、#94がマウス配列から維持されていた。さらに、図9に示すように、ヒトJエレメントJH6およびJK4を、長鎖および軽鎖にそれぞれ用いた。得られたヒト化抗体のアミノ酸配列を、軽鎖については、VK2_A17/Hz1およびVK4_B3/Hz1とし、重鎖についてはVH1_1-f/Hz1、VH5_5-a/Hz1とした。残基の番号付けは、Kabat (上記Kabat E.A. et al, 1991)にしたがう。CDRの定義については、上記KabatおよびChothia et al, 1987を用いた。マウスEGFRvIIIから維持されているフレームワーク残基は枠囲いの太字/イタリックで示し、CDR残基には下線を付している。
マウスおよびヒト化VLおよびVHドメインをコードするDNA配列を得、該コンストラクトのコドンをヒト(Homo sapiens)由来の細胞での発現用に最適化した。
可溶性scFv断片を上述の標準的な分生物学的技術を用いて作製した。これらの可溶性scFvを、その安定性、細胞表面発現および結合特性を検討するための特徴付け試験に用いた。
各scFvコンストラクトの遺伝子導入のために、約3e8個の293F細胞を、PEIを遺伝子導入用試薬として、3:1 (PEI:DNA)の比で用いて、プラスミド100μgで遺伝子導入した。該細胞をEXPi293 Expression media (Invitrogen) 100ml中で、シェーカーフラスコ内で、37℃、125 rpm、8% CO2で増殖させた。培養物を6日後に回収し、タンパク質精製に用いた。
次の試験を、全てのヒト化EGFRvIII scFvバリアントがEGFRvIIIに対して匹敵する結合を示すが、野生型のEGFRには結合しないことを示すために行った。
最終CARコンストラクトに用いるScFvは、実施例1に記載のヒト化フレームワーク配列より得た。VLおよびVHドメインの順番は変動した (すなわちVL-VHまたはVH-VL方向)。可変ドメインを連結して表1のscFvを作製するのに (G4S)4 (配列番号113)リンカーを用いた。
EF1αプロモーター
GTGAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGA (配列番号97)。
以下の実験は、Jurkat細胞と初代T細胞の両方において試験管内の結合についての試験に基づいて、EGFRvIIIに対する親和性に違いがあると考えられることを示したものである。
CAR技術によってEGFRvIIIを標的化することの可能性を評価するために、ヒト化EGFRvIII scFv断片を、2つの異なる立体配置でCD3ζ鎖および4-1BB同時刺激分子を有するレンチウイルスCAR発現ベクター中にクローニングした。最適なコンストラクトをEGFRvIII+および野生型EGFR標的に対するEGFRvIII CAR導入T細胞のエフェクターT細胞応答の量および質に基づいて選択する。エフェクターT細胞応答としては、細胞増殖、増殖、倍加、サイトカイン産生および標的細胞死滅および細胞溶解活性(脱顆粒)が挙げられるがこれらに限定されるものではない。
CAR機能の初期特性化用のJurkatレポーター細胞株の作製
初代T細胞形質導入および活性化の代替として、Jurkat-NFAT レポーター細胞株をCARコンストラクトの機能活性の評価に用いてよい。Jurkat細胞株 (E6-1)に、NFAT-ルシフェラーゼレポーターコンストラクトを用いて遺伝子導入し、安定クローン細胞株 (JNL) をPMAおよびイオノマイシン刺激後のNFATの強力な誘導に基づくさらなる特性化のために選択した。該JNL細胞に、レンチウイルスベクターをMOI 5:1で用いて形質導入し、5~7日間増殖させた。アッセイで用いる前に、形質導入細胞(EGFRvIII CARを細胞表面に発現する細胞)のパーセンテージおよび該発現の相対蛍光強度を、LSRIIを用いたフローサイトメトリー解析により決定する。ヒストグラムプロットから、CARの相対発現レベルを、その相対蛍光強度を用いて、形質導入されたパーセンテージを比較することにより検討し得る。
JNLレポーター細胞株においてT細胞活性化を評価するために、JNLまたはCAR形質導入JNL細胞を、底部が透明の96ウェル黒色プレートに、1ウェルあたり50,000個加えた。標的細胞(BHK親細胞またはEGFRvIIIIまたは野生型EGFRのいずれかを発現するように操作されたBHK細胞) を該ウェルに添加してエフェクター細胞:標的細胞(E:T) の比率を1:2、1:1、1:0.3、1:0.1、1:0.03、1:01および1:0.003とした。PMAおよびイオノマイシンを活性化の陽性対照として用いる。細胞を37℃で16~24時間インキュベーションする。インキュベーションの終了時に、等しい体積のBright-Glo Luciferase assay reagentを各ウェルに添加する。該プレートを室温で10分間インキュベーションした後、ルミノメーターを用いて測定する。
ヒト化EGFRvIII-特異的CARレンチウイルス導入ベクターは、VSVg偽型レンチウイルス粒子にパッケージされるゲノム物質の作製に用いられる。レンチウイルス導入ベクターDNAは、VSVg、gag/polおよびrevの3つのパッケージング成分と混合され、それらを293T細胞にともに遺伝子導入するためのリポフェクタミン試薬と組み合わされる。24時間および48時間後に、培地を回収し、濾過して超遠心分離またはクロマトグラフィーにより濃縮する。得られたウイルス調製液を-80℃で保存する。形質導入ユニット数を、SupT1細胞における滴定により決定する。
ヒト化EGFRvIII-特異的CAR T細胞の機能的な死滅能、増殖能およびサイトカイン分泌能を評価するために、細胞を融解して一晩回復させる。ヒト化コンストラクトに加えて、マウスCAR9を比較目的で用いた。一方で、SS1-BBzはバックグラウンドCAR/T細胞効果のための、非標的化発現CARとして用いた。このフローベースの細胞毒性アッセイのために、標的細胞をCSFEで染色し、その存在を定量した。また、標的抗原レベルが同程度であることを確かめるために、標的細胞をEGFRvIII発現について染色した。EGFRvIII CAR T細胞の細胞溶解活性を、エフェクター細胞:標的細胞の比率を10:1、3:1、1:1、0.3:1および0:1のタイトレーションで測定し、ここでエフェクター細胞は、抗EGFRvIII CARを発現しているT細胞とする。適当な数のT細胞を、一定数の標的細胞と混合することによりアッセイを開始した。4または16時間後に、各混合物の全体積をとり、各ウェルを洗浄した。T細胞をCD3について染色し、全ての細胞を生/死マーカーである7AADで染色した。最後の洗浄の後、沈殿している細胞を、予め決定した数のカウントビーズとともに、特定の体積で懸濁した。細胞染色データをLSRIIフローサイトメトリーにより得、ビーズを用いてFlowJo softwareを用いて解析し、結果を定量化した。
ヒト化CART-EGFRvIII細胞のEGFRvIII標的細胞に対する認識能を試験するためのJurkatレポーターアッセイ
CARTコンストラクトの、標的結合後の活性化誘発能を、JNLレポーター細胞株を用いて測定した。JNL細胞株は、CARへの標的結合後に誘導されるNFAT-ルシフェラーゼレポーターコンストラクトを導入されている。JNL細胞を種々のCAR-EGFRvIIIコンストラクト(CAR9、CAR3、CAR6、CAR8およびCAR10)を用いて形質導入した。形質導入効率は、フローサイトメトリーにより評価し、全てのコンストラクトについて、約45~52%であることが示された。その後、JNL-CAR-EGFRvIII細胞を7つの異なるE:T比率で、3つの異なる標的細胞(親BHK、BHK-EGFRvIIIまたはBHK-野生型EGFR)を用いて刺激した。JNL親細胞および対照CARを発現するJNL細胞を、さらなる対照として用いた。図14の結果は、試験した全てのコンストラクトについて、有意な標的化誘発性の活性化が1:0.01という低い比率で起こり得ること、ならびに、E:T比率が高い場合に、CAR6およびCAR10が最も強く活性化を誘発することを示すものである。野生型EGFR発現細胞または対照CAR発現JNL細胞では、有意な活性化は観察されなかった。これらのデータは、該CARコンストラクトが、EGFRvIII標的に対して特異性を示し、野生型EGFR標的に対する交差反応を示さないことを示すものである。
CD3+ T細胞は、健康なドナー由来のアフェレーシス産物または全血より得た。上述するように、T細胞をCD3xCD28ビーズで24時間刺激した後、濃縮レンチウイルス上清を用いて、MOI 3で形質導入を行った。細胞を培養により8~10日間増殖させた。
EGFRvIII特異的CAR T細胞の、標的結合への応答時の増殖能を増殖アッセイで評価した。分集団の細胞数をフローサイトメトリーにより計測した。ドナーT細胞を、ヒト化CAR、マウスCAR9またはSS1 (メソテリン標的化)のいずれかを用いて形質導入した。CARを標的細胞とともに、1:1または1:0で混合し、5日間共培養した。図15は、ND407 EGFRvIII CAR T細胞の抗原特異的な増殖能を示す。破線は播種したT細胞の数を示し、比較の結果、U87-EGFRvIIIとの結合は、増殖を誘発するが、これはEGFRvIII CAR T細胞集団に特異的であったのに対し、U87を標的とした場合、T細胞数の増殖は全く検出されなかった。ND407に対する相対的な応答は、CAR6およびCAR8が、CAR9またはCAR3よりも強いことを示す。CD3x28ビーズを用いた結果は、それらの刺激が2回目の活性化では増殖を誘導するのに十分ではなく、全く刺激を与えていない場合に近いことを示している。
EGFRvIII特異的CAR T細胞の標的死滅化能をクロム放出アッセイで試験した。ヒト神経膠芽腫細胞株U-87MGを、野生型EGFRまたはEGFRvIII変異体のいずれかを発現するように操作した。これらの操作細胞株を、死滅アッセイ(killing assay)の標的とした。次の3つのエフェクターCAR T細胞を用いて、標的細胞を死滅させる際の特異性を決定した; 1)マウス3C10 (CAR9)を発現するように形質導入したヒトT細胞、2)マウス3C10のヒト化バージョン (CAR6とも称される)を発現するように形質導入したヒトT細胞および、3) メソテリン、SS1に特異的なCARを形質導入したヒトT細胞。エフェクター細胞は全て、30%がCAR+導入形質を発現するように基準化した。標的細胞をクロム-51で標識し、共培養の直前に洗浄した。エフェクターおよび標的を指定の比率(E:T)で混合し、4時間インキュベーションした。
EGFRvIII特異的CAR T細胞の標的結合に応答したサイトカイン誘導能を、共培養アッセイで評価した。CAR T細胞を、標的結合細胞と、種々の標的:エフェクター比率 (0.3:1、1:1、3:1および10:1)で、18~24時間共培養した。標的細胞としては、野生型EGFR内在性タンパク質発現U87細胞(U87 wt)、EGFRvIII過剰発現U87細胞(U87-vIII)、BHK (ベビーハムスター腎臓細胞) 親細胞、ヒト野生型EGFRタンパク質過剰発現BHK細胞(BHK wt)またはヒトEGFRvIIIタンパク質過剰発現BHK細胞 (BHK-vIII)が挙げられる。18~24時間後、上清を培養から除き、Cytometric Bead Assay (CBA)を用いてサイトカインを解析した。結果は、 1) CAR6およびCAR9 T細胞がEGFRvIII-発現細胞に応答して同等のレベルのIFNγを誘発したことおよび、2)いずれのCAR T細胞集団も野生型EGFR発現細胞に対してIFNγの発現を誘発しなかったことを明らかに示すものである。重要なことに、これらのデータは、死滅アッセイ (killing assay)のデータおよび増殖データとともに、CAR6およびCAR9がEGFRvIIIに対して機能的な特異性を示し、抗腫瘍免疫応答促進能を有することを示すものである。
ヒト化抗EGFRvIII CAR T細胞は、マウス生体内で腫瘍量を低下させることが示された。例えば、#2173 (CAR6) ヒト化抗EGFRvIIIキメラ抗原受容体(CAR) レンチウイルス形質導入ヒトTリンパ球を確立U87vIII神経膠腫腫瘍で生体内処理した異種移植免疫不全NOD/SCID/cγ(-/-) マウスに静脈内送達した。5日目の確立したU87vIII皮下側腹部に腫瘍を有する対照マウスは、ドナーマッチさせた非CAR形質導入T細胞の投与を受け、該マウスの腫瘍は、キャリパーを用いた直接的な皮下腫瘍測定(長さの最大値x幅の最大値)および生体内イメージングシステム(IVIS)によって測定した光子放射の両方において急速に成長を示した。少ない数であっても(0.5-1x106)、CAR6形質導入細胞投与処置を受けたマウスでは、腫瘍成長は、用量依存的に低下した。
本明細書で引用するそれぞれ、および全ての特許明細書、特許出願および出版物は、参照によりその全体が本明細書に包含される。本発明は特定の局面について記載されているが、本発明の精神および範囲から離れなければ、他の局面およびバリエーションが当業者によって考慮され得るものであることは明らかである。末尾の特許請求の範囲は、かかる局面および相当するバリエーションを全て含むことを意図する。
Claims (33)
- キメラ抗原受容体(CAR)をコードする単離核酸分子であって、コードされたCARが、重鎖可変領域および軽鎖可変領域を含む抗EGFRvIII結合ドメイン、膜貫通ドメイン、および、一次シグナル伝達ドメイン、同時刺激ドメインまたは一次シグナル伝達ドメインおよび同時刺激ドメインの両方を含む細胞内シグナル伝達ドメインを含み:
(a)重鎖可変領域が:
(i)配列DYYIH(配列番号22)を含むCDR1;
(ii)配列RIDPENDETKYGPIFQG(配列番号23)を含むCDR2;および
(iii)配列RGGVY(配列番号24)を含むCDR3を含み;
(b)軽鎖可変領域が:
(i)配列KSSQSLLDSDGKTYLN(配列番号26)を含むCDR1;
(ii)配列LVSKLDS(配列番号27)を含むCDR2;および
(iii)配列WQGTHFPGT(配列番号28)を含むCDR3を含み;および
(c)抗EGFRvIII結合ドメインが:
(i)配列番号68の軽鎖可変領域および/または重鎖可変領域と少なくとも95%配列同一性を有する;または
(ii)配列番号68の軽鎖可変領域および/または重鎖可変領域の20個以下の変更を有する、
アミノ酸配列を含む、単離核酸分子。 - (a)抗EGFRvIII結合ドメインの軽鎖可変領域が、配列番号68の軽鎖可変領域のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含み、抗EGFRvIII結合ドメインの重鎖可変領域が、配列番号68の重鎖可変領域のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含む;または
(b)抗EGFRvIII結合ドメインの軽鎖可変領域が、配列番号68の軽鎖可変領域のアミノ酸配列を含み、抗EGFRvIII結合ドメインの重鎖可変領域が、配列番号68の重鎖可変領域のアミノ酸配列を含む、
請求項1に記載の単離核酸分子。 - 抗EGFRvIII結合ドメインが、配列番号68のアミノ酸配列を含む、請求項1または2に記載の単離核酸分子。
- (i)抗EGFRvIII結合ドメインをコードする核酸分子が、配列番号69のヌクレオチド配列と少なくとも95%配列同一性を有するヌクレオチド配列を含む;
(ii)抗EGFRvIII結合ドメインをコードする核酸分子が、配列番号69のヌクレオチド配列を含む;
(iii)コードされたCARが、配列番号73のアミノ酸配列、またはそれと少なくとも95%同一性を有するアミノ酸配列を含む;および/または
(iv)CARをコードする核酸分子が、配列番号72のヌクレオチド配列、またはそれと少なくとも95%同一性を有するヌクレオチド配列を含む、
請求項1~3のいずれか一項に記載の単離核酸分子。 - 抗EGFRvIII結合ドメインがヒトまたはヒト化抗体または抗体断片を含む、請求項1~4のいずれか一項に記載の単離核酸分子。
- 抗体断片がscFvである、請求項5に記載の単離核酸分子。
- (i)コードされたCARが、T細胞受容体のα鎖、β鎖またはζ鎖、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137およびCD154からなる群から選択されるタンパク質の膜貫通ドメインを含む膜貫通ドメインを含む;
(ii)膜貫通ドメインが、配列番号15のアミノ酸配列;配列番号15のアミノ酸配列に少なくとも1個の変更を有するが、20個以下の変更を有するアミノ酸配列;または配列番号15のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含む;および/または
(iii)膜貫通ドメインをコードする核酸分子が、配列番号8のヌクレオチド配列またはそれと少なくとも95%配列同一性を有するヌクレオチド配列を含む、
請求項1~6のいずれか一項に記載の単離核酸分子。 - 抗EGFRvIII結合ドメインが、ヒンジ領域によって膜貫通ドメインに結合している、請求項1~7のいずれか一項に記載の単離核酸分子。
- (i)ヒンジ領域が、配列番号14のアミノ酸配列またはそれと少なくとも95%配列同一性を有するアミノ酸配列を含む;または
(ii)ヒンジ領域をコードする核酸分子が、配列番号7のヌクレオチド配列またはそれと少なくとも95%配列同一性を有するヌクレオチド配列を含む、
請求項8に記載の単離核酸分子。 - 細胞内シグナル伝達ドメインが、一次シグナル伝達ドメインおよび同時刺激ドメイン、例えば、OX40、CD27、CD28、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)および4-1BB(CD137)からなる群から選択されるタンパク質の機能性シグナル伝達ドメインを含む、請求項1~9のいずれか一項に記載の単離核酸分子。
- (i)同時刺激ドメインが、配列番号16のアミノ酸配列;配列番号16のアミノ酸配列に少なくとも1個の変更を有するが、20個以下の変更を有するアミノ酸配列;または配列番号16のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含む;または
(ii)同時刺激ドメインをコードする核酸配列が、配列番号9のヌクレオチド配列またはそれと少なくとも95%配列同一性を有するヌクレオチド配列を含む、
請求項10に記載の単離核酸分子。 - (i)細胞内シグナル伝達ドメインが、一次シグナル伝達ドメインを含む;
(ii)細胞内シグナル伝達ドメインが、同時刺激シグナル伝達ドメインを含む;
(iii)細胞内シグナル伝達ドメインが、4-1BBの機能性シグナル伝達ドメインおよびCD3ζの機能性シグナル伝達ドメインを含む;
(iv)同時刺激ドメインが、配列番号16のアミノ酸配列;配列番号16のアミノ酸配列に少なくとも1個の変更を有するが、20個以下の変更を有するアミノ酸配列;または配列番号16のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含み、一次シグナル伝達ドメインが、配列番号17または配列番号99のアミノ酸配列;配列番号17または配列番号99のアミノ酸配列に少なくとも1個の変更を有するが、20個以下の変更を有するアミノ酸配列、または配列番号17または配列番号99のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含む;
(v)細胞内シグナル伝達ドメインが、配列番号16のアミノ酸配列および配列番号17または配列番号99のアミノ酸配列を含み、細胞内シグナル伝達ドメインを含むアミノ酸配列が、同一フレーム内で、単一のポリペプチド鎖として発現する;および/または
(vi)細胞内シグナル伝達ドメインをコードする核酸分子が、配列番号9のヌクレオチド配列、またはそれと少なくとも95%配列同一性を有するヌクレオチド配列、および/または配列番号10または配列番号100のヌクレオチド配列、またはそれと少なくとも95%配列同一性を有するヌクレオチド配列を含む、
請求項1~11のいずれか一項に記載の単離核酸分子。 - CARが、リーダー配列を含む、請求項1~12のいずれか一項に記載の単離核酸分子。
- リーダー配列が、配列番号13のアミノ酸配列を含む、請求項13に記載の単離核酸分子。
- 請求項1~14のいずれか一項に記載の核酸分子によりコードされている単離CAR分子。
- 単離CAR分子が、配列番号73のアミノ酸配列またはそれと少なくとも95%配列同一性を有するアミノ酸配列を含む、請求項15に記載の単離CAR分子。
- 重鎖可変領域および軽鎖可変領域を含む抗EGFRvIII結合ドメイン、膜貫通ドメイン、および、一次シグナル伝達ドメイン、同時刺激ドメインまたは一次シグナル伝達ドメインおよび同時刺激ドメインの両方を含む細胞内シグナル伝達ドメインを含むキメラ抗原受容体(CAR)分子であって:
(a)重鎖可変領域が:
(i)配列DYYIH(配列番号22)を含むCDR1;
(ii)配列RIDPENDETKYGPIFQG(配列番号23)を含むCDR2;および
(iii)配列RGGVY(配列番号24)を含むCDR3を含み;
(b)軽鎖可変領域が:
(i)配列KSSQSLLDSDGKTYLN(配列番号26)を含むCDR1;
(ii)配列LVSKLDS(配列番号27)を含むCDR2;および
(iii)配列WQGTHFPGT(配列番号28)を含むCDR3を含み、および
(c)コードされた抗EGFRvIII結合ドメインが:
(i)配列番号68の軽鎖可変領域および/または重鎖可変領域と少なくとも95%配列同一性を有する;または
(ii)配列番号68の軽鎖可変領域および/または重鎖可変領域の20個以下の変更を有する、
アミノ酸配列を含む、キメラ抗原受容体(CAR)分子。 - CAR分子が請求項2~16のいずれか一項に記載のCARである、請求項17に記載の単離CAR分子。
- 重鎖可変領域および軽鎖可変領域を含む抗EGFRvIII結合ドメインであって:
(a)重鎖可変領域が:
(i)配列DYYIH(配列番号22)を含むCDR1;
(ii)配列RIDPENDETKYGPIFQG(配列番号23)を含むCDR2;および
(iii)配列RGGVY(配列番号24)を含むCDR3を含み;
(b)軽鎖可変領域が:
(i)配列KSSQSLLDSDGKTYLN(配列番号26)を含むCDR1;
(ii)配列LVSKLDS(配列番号27)を含むCDR2;および
(iii)配列WQGTHFPGT(配列番号28)を含むCDR3を含み、および
(c)抗EGFRvIII結合ドメインが:
(i)配列番号68の軽鎖可変領域および/または重鎖可変領域と少なくとも95%配列同一性を有する;または
(ii)配列番号68の軽鎖可変領域および/または重鎖可変領域の20個以下の変更を有する、
アミノ酸配列を含む、抗EGFRvIII結合ドメイン。 - 請求項1~14のいずれか一項に記載の核酸分子を含むベクター。
- (i)ベクターが、DNA、RNA、プラスミド、レンチウイルスベクター、アデノウイルスベクターおよびレトロウイルスベクターからなる群から選択される;
(ii)ベクターが、プロモーター、例えば、EF-1プロモーター、例えば、配列番号97のヌクレオチド配列を含むEF-1プロモーターをさらに含む;
(iii)ベクターが、試験管内で転写されたベクターである;
(iv)ベクターが、ポリ(A)テールを含むヌクレオチド配列をさらに含む;および/または
(v)ベクターが、3’UTRを含むヌクレオチド配列をさらに含む、
請求項20に記載のベクター。 - 請求項1~14のいずれか一項に記載の核酸分子、請求項15または16に記載の単離CAR分子、請求項17または18のいずれか一項に記載のCAR分子、または請求項20または21に記載のベクターを含む単離細胞。
- (i)細胞がT細胞、例えば、CD8+ T細胞である;および/または
(ii)細胞がヒト細胞である、
請求項22に記載の単離細胞、単離CAR分子、CAR分子、またはベクター。 - (i)請求項1~14のいずれか一項に記載の核酸分子または請求項20または21に記載のベクターでT細胞に形質導入することを含む、細胞を作製する;または
(ii)試験管内で転写されたRNAまたは合成RNAを細胞に導入することを含むRNA操作細胞集団を作製する、ここで、RNAが請求項1~14のいずれか一項に記載の核酸分子を含む、
試験管内または生体外での方法。 - 哺乳動物において抗腫瘍免疫を提供する方法において使用するための請求項22または23に記載の細胞であって、方法は有効量の細胞を哺乳動物に投与することを含む、細胞。
- EGFRvIIIの発現に関連する疾患に罹患している哺乳動物を処置する方法において使用するための請求項22または23に記載の細胞であって、方法は有効量の細胞を哺乳動物に投与することを含む、細胞。
- EGFRvIIIの発現に関連する疾患は、多形神経膠芽腫(GBM)、未分化星状細胞腫、巨細胞神経膠芽腫、膠肉腫、未分化乏突起神経膠腫、未分化上衣腫、脈絡叢がん、未分化神経節膠腫、松果体芽腫、髄上皮腫、上衣芽腫、髄芽腫、テント上原始神経外胚葉性腫瘍、AT/RT(非定型奇形腫様/ラブドイド腫瘍)、肺がん(例えば非小細胞肺がん)、乳がん、前立腺がん、卵巣がん、結腸直腸がんおよび膀胱がんからなる群から選択されるがんまたはその任意の組合せ、または任意のがんの転移である、請求項26に記載の細胞。
- 医薬として使用するための、請求項1~14のいずれか一項に記載の単離核酸分子、請求項15または16に記載の単離CAR分子、請求項17または18に記載のCAR分子、請求項20または21に記載のベクター、または請求項22または23に記載の細胞。
- 軽鎖可変領域および重鎖可変領域を含む、抗EGFRvIII結合ドメインまたは抗EGFRvIII結合ドメインを含むキメラ抗原受容体(CAR)、をコードする単離核酸分子であって、コードされた抗EGFRvIII結合ドメインが、配列番号68の軽鎖可変領域および/または重鎖可変領域を含み、そして
軽鎖可変領域が、配列番号26、27および28のアミノ酸配列をそれぞれ含む軽鎖(LC)CDR1、LC CDR2およびLC CDR3を含み;そして、重鎖可変領域が、配列番号22、23および24のアミノ酸配列をそれぞれ含む重鎖(HC)CDR1、HC CDR2およびHC CDR3を含み、そして
CARが、膜貫通ドメイン、および、一次シグナル伝達ドメイン、同時刺激ドメインまたは一次シグナル伝達ドメインおよび同時刺激ドメインの両方を含む細胞内シグナル伝達ドメインをさらに含む、
単離核酸分子。 - 軽鎖可変領域および重鎖可変領域を含む、単離抗EGFRvIII結合ドメインまたは抗EGFRvIII結合ドメインを含むキメラ抗原受容体(CAR)であって、抗EGFRvIII結合ドメインが、配列番号68の軽鎖可変領域および/または重鎖可変領域を含み、そして
軽鎖可変領域が、配列番号26、27および28のアミノ酸配列をそれぞれ含む軽鎖(LC)CDR1、LC CDR2およびLC CDR3を含み;そして、重鎖可変領域が、配列番号22、23および24のアミノ酸配列をそれぞれ含む重鎖(HC)CDR1、HC CDR2およびHC CDR3を含み、
CARが、膜貫通ドメイン、および、一次シグナル伝達ドメイン、同時刺激ドメインまたは一次シグナル伝達ドメインおよび同時刺激ドメインの両方を含む細胞内シグナル伝達ドメインをさらに含む、
単離抗EGFRvIII結合ドメインまたは抗EGFRvIII結合ドメインを含むキメラ抗原受容体(CAR)。 - 配列番号73のアミノ酸配列またはそれと少なくとも95%配列同一性を有する配列を含む、請求項30に記載の単離CAR分子。
- コードされたCARが、
(i)配列番号15のアミノ酸配列を含む膜貫通ドメイン;および
(ii)配列番号16のアミノ酸配列を有する4-1BBの機能性シグナル伝達ドメインおよび/または配列番号17または配列番号99のアミノ酸配列を有するCD3ζの機能性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
を含む、請求項29に記載の単離核酸分子。 - CARが、
(i)配列番号15のアミノ酸配列を含む膜貫通ドメイン;および
(ii)配列番号16のアミノ酸配列を有する4-1BBの機能性シグナル伝達ドメインおよび/または配列番号17または配列番号99のアミノ酸配列を有するCD3ζの機能性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
を含む、請求項30に記載の単離抗EGFRvIII結合ドメインまたはCAR。
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