JP2017525361A - Ssea4抗原に特異的なキメラ抗原受容体 - Google Patents
Ssea4抗原に特異的なキメラ抗原受容体 Download PDFInfo
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Abstract
Description
本発明はまた、SSEA4に特異的なCARのアミノ酸配列をコードする配列を含む核酸(DNAまたはRNA)構築物を包含する。
a)細胞サンプルを準備するステップ、
b)遠心分離により細胞サンプルを調製するステップ、
c)細胞、優先的にはT細胞、T細胞サブセットまたはT細胞前駆体を磁性分離するステップ、
d)調節剤を使用する濃縮された細胞、優先的にはT細胞、T細胞サブセットまたはT細胞前駆体を活性化するステップ、
e)SSEA4−CARを発現するための細胞、優先的にはT細胞、T細胞サブセットまたはT細胞前駆体を遺伝子改変するステップ
f)培養チャンバー中での遺伝子改変されたT細胞、T細胞サブセットまたはT細胞前駆体を増殖させるステップ、
g)培養された細胞、優先的にはT細胞、T細胞サブセットまたはT細胞前駆体を洗浄するステップ。すべてのこれらのステップは、閉鎖された滅菌系において実施され得る。
別に定義されない限り、本明細書において使用される技術用語および科学用語は、本発明が属する技術分野の当業者によって一般に理解されるものと同一の意味を有する。
SSEA4と特異的に結合する、使用される抗体の免疫グロブリン重鎖および軽鎖の可変部分のアミノ酸配列は、それぞれ、配列番号1および配列番号2に示されるとおりであった。
使用されるリンカーは、図1に示されるようなCARの検出を可能にするエピトープ/タグを含み得る。エピトープ/タグの例として、YOL、cMYCまたはHISがある。抗SSEA4特異的結合断片は、SSEA4に特異的な抗体に由来する。ヒンジ領域は、例えば、IgGドメイン、CD8αまたはCD28に由来し得、CARの検出を可能にするエピトープ/タグを含み得る。膜貫通ドメインは、例えば、CD8αまたはCD28に由来し得、1〜3のシグナル伝達ドメインが続く。これらのドメインは、例えば、CD28、4−1BB、OX40またはCD3ζに由来し得る。
SSEA4−CARを、第3世代SIN−レンチウイルスベクター構築物中、ヒトPGKプロモーターの制御下にクローニングした。HEK 293T細胞の、この発現プラスミド、ならびに構造タンパク質gag−pol、revおよびVSV−Gエンベロープタンパク質をコードするさらなるプラスミドを用いる一時的トランスフェクションは、上清へのウイルスベクター粒子の放出をもたらした。ウイルスベクター粒子をその後、低速遠心分離によって濃縮し、−70℃で保存した。
MicroBeadsおよびMACS technology(登録商標)(Miltenyi Biotec GmbH、Germany)を使用してドナーアフェレーシスまたはバフィーコートサンプルから一次T細胞を単離し、90%を超える純度(CD3+細胞)に達した。磁性濃縮した細胞を洗浄し、200IU/mLヒト組換えIL−2(Miltenyi Biotec GmbH、Germany)を補充したTexMACS培地に再懸濁した。次いで、GMP TransAct CD3/CD28試薬(Miltenyi Biotec GmbH、Germany)の添加によってT細胞を刺激した。
SSEA4発現標的細胞またはSSEA4を発現しない細胞を、多様なエフェクター対標的細胞比で、増殖したSSEA4−CARを発現するT細胞とともに、対照として、形質導入されていないT細胞とともに5時間インキュベートした。特異的標的細胞死滅を、フローサイトメトリーによって分析した。
配列番号1
SSEA4 VH
QVQLKESGPG LVAPSQSLSI TCTVSGFSLS SQGVYWVRQP PGKGLEWLGA
IWAGGSTNYN SALMSRLSIS KDNSKSQVFL KMNSLQTDDT AMYYCARVDG
YRGYNMDYWG QGTSVTVSS
配列番号2
SSEA4 VL
ENVLTQSPAI MSASPGEKVT MTCSASSSVS YMHWYQQKSS TSPKLWIYDT
SKLASGVPGR FSGSGSGNSY SLTISSMEAE DVATYYCFQG SGYPLTFGAG TKLELK
配列番号3
scFv VH−リンカー−VL
QVQLKESGPG LVAPSQSLSI TCTVSGFSLS SQGVYWVRQP PGKGLEWLGA
IWAGGSTNYN SALMSRLSIS KDNSKSQVFL KMNSLQTDDT AMYYCARVDG
YRGYNMDYWG QGTSVTVSSG GGGSGGGGSG GGGSENVLTQ SPAIMSASPG
EKVTMTCSAS SSVSYMHWYQ QKSSTSPKLW IYDTSKLASG VPGRFSGSGS
GNSYSLTISS MEAEDVATYY CFQGSGYPLT FGAGTKLELK
配列番号4
scFv VL−リンカー−VH
ENVLTQSPAI MSASPGEKVT MTCSASSSVS YMHWYQQKSS TSPKLWIYDT
SKLASGVPGR FSGSGSGNSY SLTISSMEAE DVATYYCFQG SGYPLTFGAG
TKLELKGGGG SGGGGSGGGG SQVQLKESGP GLVAPSQSLS ITCTVSGFSL
SSQGVYWVRQ PPGKGLEWLG AIWAGGSTNY NSALMSRLSI SKDNSKSQVF
LKMNSLQTDD TAMYYCARVD GYRGYNMDYW GQGTSVTVSS
配列番号5
全CAR配列:SSEA4−CAR VH−リンカー−VL
MDFQVQIFSF LLISASVIMS RQVQLKESGP GLVAPSQSLS ITCTVSGFSL
SSQGVYWVRQ PPGKGLEWLG AIWAGGSTNY NSALMSRLSI SKDNSKSQVF
LKMNSLQTDD TAMYYCARVD GYRGYNMDYW GQGTSVTVSS GGGGSGGGGS
GGGGSENVLT QSPAIMSASP GEKVTMTCSA SSSVSYMHWY QQKSSTSPKL
WIYDTSKLAS GVPGRFSGSG SGNSYSLTIS SMEAEDVATY YCFQGSGYPL
TFGAGTKLEL KAAALPAEPK SPDKTHTCPP CPAPPVAGPS VFLFPPKPKD
TLMIARTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSSLSPGKK
IYIWAPLAGT CGVLLLSLVI TLYCKRGRKK LLYIFKQPFM RPVQTTQEED
GCSCRFPEEE EGGCELLRVK FSRSADAPAY QQGQNQLYNE LNLGRREEYD
VLDKRRGRDP EMGGKPRRKN PQEGLYNELQ KDKMAEAYSE IGMKGERRRG
KGHDGLYQGL STATKDTYDA LHMQALPPR
配列番号6
全CAR配列:SSEA4−CAR VL−リンカー−VH
MDFQVQIFSF LLISASVIMS RENVLTQSPA IMSASPGEKV TMTCSASSSV
SYMHWYQQKS STSPKLWIYD TSKLASGVPG RFSGSGSGNS YSLTISSMEA
EDVATYYCFQ GSGYPLTFGA GTKLELKGGG GSGGGGSGGG GSQVQLKESG
PGLVAPSQSL SITCTVSGFS LSSQGVYWVR QPPGKGLEWL GAIWAGGSTN
YNSALMSRLS ISKDNSKSQV FLKMNSLQTD DTAMYYCARV DGYRGYNMDY
WGQGTSVTVS SAAALPAEPK SPDKTHTCPP CPAPPVAGPS VFLFPPKPKD
TLMIARTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSSLSPGKK
IYIWAPLAGT CGVLLLSLVI TLYCKRGRKK LLYIFKQPFM RPVQTTQEED
GCSCRFPEEE EGGCELLRVK FSRSADAPAY QQGQNQLYNE LNLGRREEYD
VLDKRRGRDP EMGGKPRRKN PQEGLYNELQ KDKMAEAYSE IGMKGERRRG
KGHDGLYQGL STATKDTYDA LHMQALPPR
Claims (14)
- SSEA4に特異的な抗原結合ドメインを含むキメラ抗原受容体(CAR)。
- 前記抗原結合ドメインが、配列番号1および配列番号2のアミノ酸配列を含む、請求項1に記載のCAR。
- 膜貫通ドメインおよび細胞内シグナル伝達ドメインを含み、膜貫通ドメインが、CD8および/またはCD28の膜貫通ドメインの配列を含み、細胞内シグナル伝達ドメインが、CD28、CD137およびCD3ζのうちの1種または複数の細胞内シグナル伝達ドメインの配列を含む、請求項1または2に記載のCAR。
- アミノ酸配列の配列番号5または配列番号6を含む、請求項1または2に記載のCAR。
- がんを患っている対象におけるがんの治療のための、請求項1から4のいずれか一項に記載のCARであって、前記がんのがん性細胞の少なくとも部分集団がSSEA4を発現するCAR。
- 前記がんが、ヒト乳がん、ヒト腎細胞癌(RCC)およびヒト卵巣がんからなる群から選択される、請求項5に記載のCAR。
- 請求項1から6のいずれか一項に記載のCARを発現する遺伝子操作された細胞の集団。
- T細胞またはNK細胞である、請求項7に記載の遺伝子操作された細胞の集団。
- 免疫療法において使用するための、請求項7または8に記載の遺伝子操作された細胞の単離された集団。
- 請求項1から6のいずれか一項に記載のCARを発現する遺伝子改変された細胞および薬学的に許容される担体を含む医薬組成物。
- がんを患っている対象におけるがんの治療の使用のための、請求項10に記載の医薬組成物であって、前記がんのがん性細胞の少なくとも部分集団がSSEA4を発現する医薬組成物。
- 前記がんの治療の併用使用のための、請求項11に記載の医薬組成物および化学療法薬。
- 前記がんが、ヒト乳がん、ヒト腎細胞癌(RCC)およびヒト卵巣がんからなる群から選択される、請求項11または12に記載の医薬組成物。
- 請求項1から6のいずれか一項に記載のCARをコードするヌクレオチド配列を含む核酸。
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JP2018509390A (ja) * | 2015-01-30 | 2018-04-05 | アカデミア シニカAcademia Sinica | 抗体の増強された有効性のための普遍的グリコフォームに関する組成物および方法 |
JP2021517450A (ja) * | 2018-03-20 | 2021-07-26 | チョウ ファーマ ユーエスエー インコーポレイテッド | Ssea4に結合するキメラ抗原受容体及びその使用 |
JP7378152B2 (ja) | 2018-03-20 | 2023-11-13 | チョウ ファーマ ユーエスエー インコーポレイテッド | Ssea4に結合するキメラ抗原受容体及びその使用 |
JP2022502453A (ja) * | 2018-10-02 | 2022-01-11 | オービーアイ ファーマ,インコーポレイテッド | 治療用腫瘍学薬剤との組み合わせにおける抗ssea−4抗体を用いた組み合わせ療法 |
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KR20170042774A (ko) | 2017-04-19 |
WO2016026742A1 (en) | 2016-02-25 |
CN106661129B (zh) | 2021-02-05 |
US20170283489A1 (en) | 2017-10-05 |
EP3182994A1 (en) | 2017-06-28 |
ES2767399T3 (es) | 2020-06-17 |
CN106661129A (zh) | 2017-05-10 |
US10273295B2 (en) | 2019-04-30 |
EP3182994B1 (en) | 2019-12-04 |
CA2958757C (en) | 2021-04-27 |
KR102387122B1 (ko) | 2022-04-14 |
JP6588084B2 (ja) | 2019-10-09 |
CA2958757A1 (en) | 2016-02-25 |
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