JP6986449B2 - ガンマデルタt細胞受容体(tcr)とキメラ抗原受容体(car)とを発現するt細胞 - Google Patents
ガンマデルタt細胞受容体(tcr)とキメラ抗原受容体(car)とを発現するt細胞 Download PDFInfo
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Description
(i)抗原結合ドメイン;
(ii)膜貫通ドメイン;および
(iii)共刺激細胞内シグナル伝達ドメイン
を含み;ここで細胞内シグナル伝達ドメインは、抗原の抗原結合ドメインへの結合に続いて共刺激シグナルをT細胞に与える、T細胞を提供する。
[配列番号1](aCD33−Fc−DAP10 CAR)
MAVPTQVLGLLLLWLTDARCDIQMTQSPSSLSASVGDRVTITCRASEDIYFNLVWYQQKPGKAPKLLIYDTNRLADGVPSRFSGSGSGTQYTLTISSLQPEDFATYYCQHYKNYPLTFGQGTKLEIKRSGGGGSGGGGSGGGGSGGGGSRSEVQLVESGGGLVQPGGSLRLSCAASGFTLSNYGMHWIRQAPGKGLEWVSSISLNGGSTYYRDSVKGRFTISRDNAKSTLYLQMNSLRAEDTAVYYCAAQDAYTGGYFDYWGQGTLVTVSSMDPAEPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVCARPRRSPAQEDGKVYINMPGRG
[配列番号2](aGD2−Fc−DAP10 CAR)
METDTLLLWVLLLWVPGSTGQVQLQESGPGLVKPSQTLSITCTVSGFSLASYNIHWVRQPPGKGLEWLGVIWAGGSTNYNSALMSRLTISKDNSKNQVFLKMSSLTAADTAVYYCAKRSDDYSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSENQMTQSPSSLSASVGDRVTMTCRASSSVSSSYLHWYQQKSGKAPKVWIYSTSNLASGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSGYPITFGQGTKVEIKRSDPAEPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIFWVCARPRRSPAQEDGKVYINMPGRG
(i)被験体からの細胞含有試料の単離;
(ii)本発明の第3の態様に記載の核酸試料または本発明の第4の態様に記載のベクターでの、細胞の形質導入またはトランスフェクション;および
(iii)(ii)からの細胞を被験体に投与すること
を含み得る。
T細胞は、それらのT細胞受容体(TCR)構成成分に基づいて2つのグループに分けられる。TCRヘテロ二量体は、95%のT細胞ではα鎖およびβ鎖からなる。これらは、抗原提示細胞上のMHC分子によって提示されるペプチドを介して外来抗原を認識し、適応免疫に必須のものである。
本発明のT細胞は、キメラ抗原受容体(CAR)を発現する。
MGTSLLCWMALCLLGADHADG
MSLPVTALLLPLALLLHAARP
MAVPTQVLGLLLLWLTDARC
細胞内ドメイン/内部ドメインは、典型的なCARのシグナル伝達部位である。
CARPRRSPAQEDGKVYINMPGRG
KRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAY
QRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKPEPACSP
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI
HRRACRKRIRQKLHLCYPVQTSQPKLELVDSRPRRSSTQLRSGASVTEPVAEERGLMSQPLMETCHSVGAAYLESLPLQDASPAGGPSSPRDLPEPRVSTEHTNNKIEKIYIMKADTVIVGTVKAELPEGRGLAGPAEPELEEELEADHTPHYPEQETEPPLGSCSDVMLSVEEEGKEDPLPTAASGK
TWQRRQRKSRRTI
KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ
SLKTHPLWRLWKKIWAVPSPERFFMPLYKGCSGDFKKWVGAPFTGSSLELGPWSPEVPSTLEVYSCHPPRSPAKRLQLTELQEPAELVESDGVPKPSFWPTAQNSGGSAYSEERDRPYGLVSIDTVTVLDAEGPCTWPCSCEDDGYPALDLDAGLEPSPGLEDPLLDAGTTVLSCGCVSAGSPGLGGPLGSLLDRLKPPLADGEDWAGGLPWGGRSPGGVSESEAGSPLAGLDMDTFDSGFVGSDCSSPVECDFTSPGDEGPPRSYLRQWVVIPPPLSSPGPQAS
GSTVYYQGKCLTWKGPRRQLPAWPAPLPPPCGSSAHLLPPVPGG
WWGDIWWKTMMELRSLDTQKATCHLQQVTDLPWTSVSSPVEREILYHTVARTKISDDDDEHTL
NRRRRRERRDLFTESWDTQKAPNNYRSPISTSQPTNQSMDDTREDIYVNYPTFSRRPKTRV
配列番号3と少なくとも75、80、85、90、95または99%の配列同一性を共有するその変異体を含み得るが、但し、その配列が有効な共刺激シグナル伝達ドメインを提供することを条件とする。
RSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
抗原結合ドメインは、抗原を認識するCARの部位である。抗体、抗体模倣体、およびT細胞受容体の抗原結合部位に基づく抗原結合ドメインを含む多くの抗原結合ドメインが当該分野で知られている。例えば、抗原結合ドメインは、モノクローナル抗体由来一本鎖可変フラグメント(scFv);標的抗原の天然リガンド;標的に対して十分な親和性を有するペプチド;単一ドメイン抗体;Darpin(設計アンキリン反復タンパク質)などの人工単一結合剤;またはT細胞受容体由来一本鎖を含み得る。
抗原結合ドメインは、腫瘍関連抗原(TAA)に結合し得る。
METDTLLLWVLLLWVPGSTGQVQLQESGPGLVKPSQTLSITCTVSGFSLASYNIHWVRQPPGKGLEWLGVIWAGGSTNYNSALMSRLTISKDNSKNQVFLKMSSLTAADTAVYYCAKRSDDYSWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSENQMTQSPSSLSASVGDRVTMTCRASSSVSSSYLHWYQQKSGKAPKVWIYSTSNLASGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYSGYPITFGQGTKVEIKRS
MAVPTQVLGLLLLWLTDARCDIQMTQSPSSLSASVGDRVTITCRASEDIYFNLVWYQQKPGKAPKLLIYDTNRLADGVPSRFSGSGSGTQYTLTISSLQPEDFATYYCQHYKNYPLTFGQGTKLEIKRSGGGGSGGGGSGGGGSGGGGSRSEVQLVESGGGLVQPGGSLRLSCAASGFTLSNYGMHWIRQAPGKGLEWVSSISLNGGSTYYRDSVKGRFTISRDNAKSTLYLQMNSLRAEDTAVYYCAAQDAYTGGYFDYWGQGTLVTVSSM
CARは、抗原結合ドメインを膜貫通ドメインと連結させ、抗原結合ドメインを内部ドメインから空間的に分離するスペーサー配列を含み得る。柔軟なスペーサーは、抗原結合ドメインが異なる方向に配向することを可能にし、結合を容易にする。
AEPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKD
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI
AEPKSPDKTHTCPPCPKDPK
膜貫通ドメインは、膜にまたがるCARの配列である。
FWVLVVVGGVLACYSLLVTVAFIIFWV
本発明は、本明細書に記載のCARをコードする核酸配列をさらに提供する。
ATGGCCGTGCCCACTCAGGTCCTGGGGTTGTTGCTACTGTGGCTTACAGATGCCAGATGTGACATCCAGATGACACAGTCTCCATCTTCCCTGTCTGCATCTGTCGGAGATCGCGTCACCATCACCTGTCGAGCAAGTGAGGACATTTATTTTAATTTAGTGTGGTATCAGCAGAAACCAGGAAAGGCCCCTAAGCTCCTGATCTATGATACAAATCGCTTGGCAGATGGGGTCCCATCACGGTTCAGTGGCTCTGGATCTGGCACACAGTATACTCTAACCATAAGTAGCCTGCAACCCGAAGATTTCGCAACCTATTATTGTCAACACTATAAGAATTATCCGCTCACGTTCGGTCAGGGGACCAAGCTGGAAATCAAAAGATCTGGTGGCGGAGGGTCAGGAGGCGGAGGCAGCGGAGGCGGTGGCTCGGGAGGCGGAGGCTCGAGATCTGAGGTGCAGTTGGTGGAGTCTGGGGGCGGCTTGGTGCAGCCTGGAGGGTCCCTGAGGCTCTCCTGTGCAGCCTCAGGATTCACTCTCAGTAATTATGGCATGCACTGGATCAGGCAGGCTCCAGGGAAGGGTCTGGAGTGGGTCTCGTCTATTAGTCTTAATGGTGGTAGCACTTACTATCGAGACTCCGTGAAGGGCCGATTCACTATCTCCAGGGACAATGCAAAAAGCACCCTCTACCTTCAAATGAATAGTCTGAGGGCCGAGGACACGGCCGTCTATTACTGTGCAGCACAGGACGCTTATACGGGAGGTTACTTTGATTACTGGGGCCAAGGAACGCTGGTCACAGTCTCGTCTATGGATCCCGCCGAGCCCAAATCTCCTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTCCCGTGGCCGGCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCGCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAACCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCCCTGCACAATCACTATACCCAGAAATCTCTGAGTCTGAGCCCAGGCAAGAAGGACCCCAAGTTCTGGGTCCTGGTGGTGGTGGGAGGCGTGCTGGCCTGTTACTCTCTCCTGGTGACCGTGGCCTTCATCATCTTCTGGGTGTGCGCCAGACCACGGCGGAGCCCAGCCCAGGAGGACGGCAAGGTGTACATCAACATGCCCGGCCGCGGCTGA
ATGGAGACCGACACCCTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCAGGCAGCACCGGCCAGGTGCAGCTGCAGGAGTCTGGCCCAGGCCTGGTGAAGCCCAGCCAGACCCTGAGCATCACCTGCACCGTGAGCGGCTTCAGCCTGGCCAGCTACAACATCCACTGGGTGCGGCAGCCCCCAGGCAAGGGCCTGGAGTGGCTGGGCGTGATCTGGGCTGGCGGCAGCACCAACTACAACAGCGCCCTGATGAGCCGGCTGACCATCAGCAAGGACAACAGCAAGAACCAGGTGTTCCTGAAGATGAGCAGCCTGACAGCCGCCGACACCGCCGTGTACTACTGCGCCAAGCGGAGCGACGACTACAGCTGGTTCGCCTACTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCTGGCGGAGGCGGCTCTGGCGGAGGCGGCTCTGGCGGAGGCGGCAGCGAGAACCAGATGACCCAGAGCCCCAGCAGCTTGAGCGCCAGCGTGGGCGACCGGGTGACCATGACCTGCAGAGCCAGCAGCAGCGTGAGCAGCAGCTACCTGCACTGGTACCAGCAGAAGAGCGGCAAGGCCCCAAAGGTGTGGATCTACAGCACCAGCAACCTGGCCAGCGGCGTGCCCAGCCGGTTCAGCGGCAGCGGCAGCGGCACCGACTACACCCTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAGCGGCTACCCCATCACCTTCGGCCAGGGCACCAAGGTGGAGATCAAGCGGTCGGATCCCGCCGAGCCCAAATCTCCTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTCCCGTGGCCGGCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCGCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAACCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCCCTGCACAATCACTATACCCAGAAATCTCTGAGTCTGAGCCCAGGCAAGAAGGACCCCAAGTTCTGGGTCCTGGTGGTGGTGGGAGGCGTGCTGGCCTGTTACTCTCTCCTGGTGACCGTGGCCTTCATCATCTTCTGGGTGTGCGCCAGACCACGGCGGAGCCCAGCCCAGGAGGACGGCAAGGTGTACATCAACATGCCCGGCCGCGGCTGA
配列比較は、目測で、またはより一般には、容易に入手可能な配列比較プログラムを用いて実施することができる。これらの公的および商業的に入手可能なコンピュータプログラムは、2つ以上の配列間の配列同一性を計算することができる。
本発明は、本発明の核酸配列を含むベクターも提供する。そのようなベクターは、核酸配列を宿主細胞に導入し、それが本発明の第1の態様の分子を発現および産生するように使用され得る。
本発明は、本発明のベクターまたはCAR発現T細胞を、薬学的に許容される担体、希釈剤または賦形剤、および場合により1つ以上のさらなる薬学的に活性なポリペプチドおよび/または化合物と一緒に含有する医薬組成物にも関する。そのような製剤は、例えば、静脈内注入に適した形態であり得る。
本発明は、本発明の核酸配列またはベクターを細胞に導入する工程を含む、本発明の細胞の作製方法にも関する。
特定のγδTCR受容体を発現するγδT細胞を有し得る。
疾患の治療方法は、本発明のベクターまたはT細胞の治療的使用に関する。この点において、ベクターまたはT細胞は、疾患に関連する少なくとも1つの症状を軽減させる、縮小させるもしくは改善するためにおよび/または疾患の進行を減速させる、縮小させるもしくは阻むために、既存の疾患または状態を有する被験体に投与され得る。
健常ドナーの血液から、Ficoll密度勾配分離を用いてPBMCを抽出した。それらを、10%FCS、1%ペニシリン/ストレプトマイシン、100u/mlヒトIL−2および5μMゾレドロン酸を補充したRPMI 1640培地で5日間培養した。
LAN1およびTC71細胞系は共にGD2を発現することが知られている。
形質導入の24日後に共培養を開始し、照射されたGD2+(LAN1)およびGD2−(SK−N−SH)神経芽腫細胞(図7A)の存在下で、CARおよびTCRVδ2の存在についての細胞の連続分析を行った。
CD33発現の等価レベルが、3つのAML細胞株および単球において実証された(図8)。
Claims (12)
- ガンマデルタT細胞受容体(TCR)とキメラ抗原受容体(CAR)とを発現するT細胞であって、前記ガンマデルタTCRはガンマデルタT細胞活性化のためのシグナル1を提供するために用いられ、前記CARは共刺激シグナル2を提供するために用いられ、前記CARが、
(i)抗原結合ドメイン;
(ii)膜貫通ドメイン;および
(iii)T細胞シグナル伝達共受容体由来の共刺激細胞内シグナル伝達ドメインであって、標的抗原が前記CARの前記抗原結合ドメインに結合した際に共刺激シグナル2を提供し、該共刺激シグナル2を前記ガンマデルタT細胞に伝達し、シグナル1を前記ガンマデルタT細胞に伝達しない、共刺激細胞内シグナル伝達ドメイン;
を含み、
前記ガンマデルタTCRとCARとは、それぞれ各抗原に結合した際に、前記ガンマデルタTCRがシグナル1を提供し、前記CARが共刺激シグナル2を提供し、この場合にようやく前記ガンマデルタT細胞が完全に活性化され、前記ガンマデルタTCRに結合することができる第1抗原と前記CARに結合することができる第2抗原とを発現する標的細胞を殺傷することができるように配置され、
前記細胞内シグナル伝達ドメインは、DAP10、IL2−R、IL7−R、IL21−R、NKp30、NKp44またはDNAM−1(CD226)シグナル伝達ドメインを含む、T細胞。 - 前記抗原結合ドメインが、腫瘍関連抗原(TAA)に結合することができ、前記抗原結合ドメインが、GD2、CD33、CD19またはEGFRに結合することができる、請求項1に記載の細胞。
- 前記膜貫通ドメインが、CD8ストークまたはCD28膜貫通ドメインを含む、請求項1または2に記載の細胞。
- 前記細胞内シグナル伝達ドメインが、DAP10シグナル伝達ドメインを含む、請求項1〜3のいずれか一項に記載の細胞。
- 前記CARが、前記抗原結合ドメインと前記膜貫通ドメインとの間にスペーサードメインをさらに含む、請求項1〜4のいずれか一項に記載の細胞。
- 前記ガンマデルタTCRが、リン酸化抗原;主要組織適合複合体クラスI鎖関連A(MICA);主要組織適合複合体クラスI鎖関連B(MICB);NKG2Dリガンド1−6(ULBP1−6);CD1c;CD1d;内皮タンパク質C受容体(EPCR);リポヘキサペプチド;フィコエリスリンまたはヒスチジルtRNA合成酵素に結合することができる、請求項1〜5のいずれか一項に記載の細胞。
- 請求項1〜6のいずれか一項に記載の細胞を含む医薬組成物。
- 医薬に用いるための請求項7に記載の医薬組成物。
- ガンマデルタT細胞刺激剤の前、同時、または後に組み合わせる、請求項7に記載の医薬組成物。
- 前記ガンマデルタT細胞刺激剤が、イソペンテニルピロリン酸(IPP);IPP類似体;およびファルネシルピロリン酸合成酵素(FPPS)阻害剤から選択される、請求項9に記載の医薬組成物。
- 疾患の治療および/または予防で用いるための医薬組成物であって、前記疾患が、がん、微生物感染またはウイルス感染である、請求項7に記載の医薬組成物。
- 疾患の治療および/または予防のための医薬の製造における、請求項1〜6のいずれか一項に記載の細胞の使用。
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CA2982532A1 (en) | 2016-11-03 |
KR20180020140A (ko) | 2018-02-27 |
WO2016174461A1 (en) | 2016-11-03 |
CA2982532C (en) | 2023-10-03 |
SG11201708402UA (en) | 2017-11-29 |
US20180125890A1 (en) | 2018-05-10 |
US20220211756A1 (en) | 2022-07-07 |
IL255186A0 (en) | 2017-12-31 |
AU2016255611A1 (en) | 2017-11-02 |
JP2018514204A (ja) | 2018-06-07 |
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