JP7477112B2 - 操作された細胞およびその使用 - Google Patents
操作された細胞およびその使用 Download PDFInfo
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- JP7477112B2 JP7477112B2 JP2020564853A JP2020564853A JP7477112B2 JP 7477112 B2 JP7477112 B2 JP 7477112B2 JP 2020564853 A JP2020564853 A JP 2020564853A JP 2020564853 A JP2020564853 A JP 2020564853A JP 7477112 B2 JP7477112 B2 JP 7477112B2
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Description
本出願は、2018年6月19日に出願された特許協力条約出願番号PCT/CN2018/091789の優先権を主張し、上記出願は、あらゆる目的のために、その全体が参照により本明細書に引用される。
エフェクタ細胞活性においては、細胞外抗原結合ドメインおよび細胞内シグナル伝達ドメインを含む膜結合型受容体に結合するリガンドが関与し得る。抗原結合ドメインとそれに対応する標的との複合体の形成により、受容体そのものへのコンフォメーション的かつ/または化学的な改変がもたらされ得、これにより次には、細胞内に伝達される一連のシグナルが発生され得る。この相互作用を免疫細胞療法の開発のために利用する試みによって、期待できる有効性が示されてきたが、サイトカイン放出症候群などの望ましくない副作用を治療対象にもたらすオフターゲット毒性も示されてきた。これと他の副作用により、炎症性応答、臓器不全、および極端な例では、死亡にさらに至るおそれがある。
表1 抗原結合分子のAの配列
表8:細胞内共刺激シグナル伝達ドメイン
ビギノンB1;ルボキシル;サフィンゴール;サイントピン;SarCNU;サルコフィトールA;サルグラモスチム;Sdi1ミメティック;セムスチン;老化由来阻害剤1;センスオリゴヌクレオチド;シグナル伝達阻害剤;シグナル伝達モジュレータ;一本鎖抗原結合タンパク質;シゾフィラン;ソブゾキサン;ボロカプタートナトリウム;フェニル酢酸ナトリウム;ソルベロール;ソマトメジン結合タンパク質;ソネルミン;スパルホシン酸;スピカマイシンD;スピロムスチン;スプレノペンチン;スポンジスタチン1;スクアラミン;幹細胞阻害剤;幹細胞分裂阻害剤;スティピアミド;ストロメライシン阻害剤;スルフィノシン;超活性血管作用性小腸ペプチド拮抗薬;スラジスタ;スラミン;スワインソニン;合成グリコサミノグリカン;タリムスチン;タモキシフェンメチオジド;タウロムスチン;タザロテン;テコガランナトリウム;テガフール;テルラピリリウム;テロメラーゼ阻害剤;テモポルフィン;テモゾロミド;テニポシド;テトラクロロデカオキシド;テトラゾミン;タリブラスチン;チオコラリン;トロンボポイエチン;トロンボポイエチンミメティック;チマルファシン;チモポイエチン受容体作用剤;チモトリナン;甲状腺刺激ホルモン;エチルエチオプルプリンスズ;チラパザミン;二塩化チタノセン;トプセンチン;トレミフェン;全能性幹細胞因子;翻訳阻害剤;トレチノイン;トリアセチルウリジン;トリシリビン;トリメトレキサート;トリプトレリン;トロピセトロン;ツロステリド;チロシンキナーゼ阻害剤;チルホスチン類;UBC阻害剤;ウベニメクス;泌尿生殖洞由来成長阻害因子;ウロキナーゼ受容体拮抗薬;バプレオチド;バリオリンB;ベクタ系、赤血球遺伝子治療;ベラレソール;ベラミン;ベルジン(verdin);ベルテポルフィン;ビノレルビン;ビンキサルチン;ビタキシン;ボロゾール;ザノテロン;ゼニプラチン;ジラスコルブ;およびジノスタチンスチマラメルを含むが、これらに限定されない。
実施例1:抗BCMA sdAbの生成
免疫化
ライブラリ構築
バインダ単離および高スループットスクリーニング
表9 SPR親和性ランキングによる抗BCMA sdAbの推定結合親和性
実施例3:免疫細胞の調製
実施例4:T細胞トランスフェクション
実施例5:受容体発現の定量化
実施例6:細胞傷害性アッセイ
イプシロンTCRプラットフォームのBCMA抗体スクリーニング
複数成分系
実施例7:細胞の細胞傷害性アッセイ(ルシフェラーゼアッセイ)
%標的細胞溶解=(1-(RLUE:T-RLU最大放出)/(RLUT-RLU最大放出))×100
実施例8:サイトカイン放出の検出(IFNγおよびTNFα)
実施例9:インビボでの有効性
多発性骨髄腫の腫瘍異種移植によるBCMA CAR-TCR-Tのインビボでの有効性
NSGマウスにおけるOVCAR-8異種移植モデルによるMSLN FSHR CAR-TCR-Tのインビボでの有効性
実施例10:急速拡大プロトコル
表10 例示的配列
[項目1]
免疫細胞および/または標的細胞の活性を誘導するための系であって、
(a)第1のエピトープへの特異的な結合を示す第1の抗原結合ドメイン、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むキメラ抗原受容体(CAR)と、
第2のエピトープへの特異的な結合を示す第2の抗原結合ドメインを含む改変T細胞受容体(改変TCR)複合体とを備え、第2の抗原結合ドメインは、
(i)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、
(ii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/もしくはガンマ鎖、または
(iii)CD3ゼータ鎖
に連結される、
系。
[項目2]
第1のエピトープへの第1の抗原結合ドメインの結合、および/または第2のエピトープへの第2の抗原結合ドメインの結合は、系を発現する免疫細胞の免疫細胞活性を活性化する、項目1に記載の系。
[項目3]
2つ以上の抗原結合ドメインは、任意選択でタンデムに、(i)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、(ii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/またはガンマ鎖、(iii)CD3ゼータ鎖に連結され、2つ以上の抗原結合ドメインの、それぞれのエピトープへの結合は、系を発現する免疫細胞の免疫細胞活性を活性化する、項目1に記載の系。
[項目4]
免疫細胞活性は、免疫細胞のクローン増殖;免疫細胞によるサイトカイン放出;免疫細胞の細胞傷害性;免疫細胞の増殖;免疫細胞の分化、脱分化、または分化転換;免疫細胞の移動および/または輸送;免疫細胞の疲弊および/または再活性化;ならびに免疫細胞による、他の細胞間分子、代謝物、化学物質、またはそれらの組み合わせの放出からなる群より選択される、項目2または3に記載の系。
[項目5]
第1のエピトープへの第1の抗原結合ドメインの結合、および第2のエピトープへの第2の抗原結合ドメインの結合は、系を発現する免疫細胞の細胞傷害性を活性化し、細胞傷害性は、第1のエピトープへの第1の抗原結合ドメインの結合のみ、または第2のエピトープへの第2の抗原結合ドメインの結合のみと比較して増強される、項目1に記載の系。
[項目6]
第1のエピトープへの第1の抗原結合ドメインの結合、および第2のエピトープへの第2の抗原結合ドメインの結合は、系を発現する免疫細胞の細胞傷害性を活性化し、第1のエピトープへの第1の抗原結合ドメインの結合のみ、または第2のエピトープへの第2の抗原結合ドメインの結合のみと比較して、細胞傷害性の持続性を増大する、項目1に記載の系。
[項目7]
2つ以上の抗原結合ドメインのそれぞれのエピトープへの結合は、系が被験体の免疫細胞において発現されるとき、系を発現する免疫細胞の細胞傷害性を活性化し、第1のエピトープへの第1の抗原結合ドメインの結合のみと比較して、細胞傷害性の持続性を増大する、項目3に記載の系。
[項目8]
改変TCRは、
(i)第2の抗原結合ドメイン、
(ii)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、
(iii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/もしくはガンマ鎖、または、
(iv)CD3ゼータ鎖
に連結される第3の抗原結合ドメインを含む、項目1に記載の系。
[項目9]
CARは、1または複数の追加の抗原結合ドメインを含む、項目1に記載の系。
[項目10]
1または複数の追加の抗原結合ドメインは、1または複数の追加のエピトープへの特異的な結合を示す、項目9に記載の系。
[項目11]
1または複数の追加のエピトープは、第1のエピトープまたは第2のエピトープと同じである、項目10に記載の系。
[項目12]
1または複数の追加のエピトープは、第1のエピトープおよび第2のエピトープと異なる、項目10に記載の系。
[項目13]
1または複数の追加の抗原結合ドメインおよび第1の抗原結合ドメインは、タンデムに連結される、項目9に記載の系。
[項目14]
CARの細胞内シグナル伝達ドメインは、免疫受容体活性化チロシンモチーフ(ITAM)を含む、項目1に記載の系。
[項目15]
CARの細胞内シグナル伝達ドメインは、免疫受容体抑制チロシンモチーフ(ITIM)を含む、項目1に記載の系。
[項目16]
CARの細胞内シグナル伝達ドメインは、Fcγ受容体(FcγR)、Fcε受容体(FcεR)、Fcα受容体(FcαR)、新生児Fc受容体(FcRn)、CD3、CD3ζ、CD3γ、CD3δ、CD3ε、CD4、CD5、CD8、CD21、CD22、CD28、CD32、CD40L(CD154)、CD45、CD66d、CD79a、CD79b、CD80、CD86、CD278(ICOSとしても公知である)、CD247ζ、CD247η、DAP10、DAP12、FYN、LAT、Lck、MAPK、MHC複合体、NFAT、NF-κB、PLC-γ、iC3b、C3dg、C3d、およびZap70のシグナル伝達ドメインを含む、項目1に記載の系。
[項目17]
細胞内シグナル伝達ドメインは、CD3ζのシグナル伝達ドメインを含む、項目16に記載の系。
[項目18]
CARは、共刺激ドメインをさらに含む、項目1に記載の系。
[項目19]
共刺激ドメインは、MHCクラスI分子、TNF受容体タンパク質、免疫グロブリン様タンパク質、サイトカイン受容体、インテグリン、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、活性化NK細胞受容体、またはTollリガンド受容体のシグナル伝達ドメインを含む、項目18に記載の系。
[項目20]
共刺激ドメインは、2B4/CD244/SLAMF4、4-1BB/TNFSF9/CD137、B7-1/CD80、B7-2/CD86、B7-H1/PD-L1、B7-H2、B7-H3、B7-H4、B7-H6、B7-H7、BAFF-R/TNFRSF13C、BAFF/BlyS/TNFSF13B、BLAME/SLAMF8、BTLA/CD272、CD100(SEMA4D)、CD103、CD11a、CD11b、CD11c、CD11d、CD150、CD160(BY55)、CD18、CD19、CD2、CD200、CD229/SLAMF3、CD27リガンド/TNFSF7、CD27/TNFRSF7、CD28、CD29、CD2F-10/SLAMF9、CD30リガンド/TNFSF8、CD30/TNFRSF8、CD300a/LMIR1、CD4、CD40リガンド/TNFSF5、CD40/TNFRSF5、CD48/SLAMF2、CD49a、CD49D、CD49f、CD53、CD58/LFA-3、CD69、CD7、CD8α、CD8β、CD82/Kai-1、CD84/SLAMF5、CD90/Thy1、CD96、CDS、CEACAM1、CRACC/SLAMF7、CRTAM、CTLA-4、DAP12、デクチン-1/CLEC7A、DNAM1(CD226)、DPPIV/CD26、DR3/TNFRSF25、EphB6、GADS、Gi24/VISTA/B7-H5、GITRリガンド/TNFSF18、GITR/TNFRSF18、HLAクラスI、HLA-DR、HVEM/TNFRSF14、IA4、ICAM-1、ICOS/CD278、イカロス、IL2Rβ、IL2Rγ、IL7Rα、インテグリンα4/CD49d、インテグリンα4β1、インテグリンα4β7/LPAM-1、IPO-3、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、ITGAX、ITGB1、ITGB2、ITGB7、KIRDS2、LAG-3、LAT、LIGHT/TNFSF14、LTBR、Ly108、Ly9(CD229)、リンパ球機能関連抗原-1(LFA-1)、リンホトキシン-α/TNF-β、NKG2C、NKG2D、NKp30、NKp44、NKp46、NKp80(KLRF1)、NTB-A/SLAMF6、OX40リガンド/TNFSF4、OX40/TNFRSF4、PAG/Cbp、PD-1、PDCD6、PD-L2/B7-DC、PSGL1、RELT/TNFRSF19L、SELPLG(CD162)、SLAM(SLAMF1)、SLAM/CD150、SLAMF4(CD244)、SLAMF6(NTB-A)、SLAMF7、SLP-76、TACI/TNFRSF13B、TCL1A、TCL1B、TIM-1/KIM-1/HAVCR、TIM-4、TL1A/TNFSF15、TNF RII/TNFRSF1B、TNF-α、TRANCE/RANKL、TSLP、TSLP R、VLA1、およびVLA-6から選択される分子のシグナル伝達ドメインを含む、項目18に記載の系。
[項目21]
第1の抗原結合ドメインおよび/または第2の抗原結合ドメインは、Fab、Fab'、F(ab') 2 、Fv、単鎖Fv(scFv)、ミニボディ、ダイアボディ、単一ドメイン抗体、軽鎖可変ドメイン(VL)、またはラクダ科動物抗体の可変ドメイン(V H H)を含む、項目1に記載の系。
[項目22]
第1の抗原結合ドメインおよび第2の抗原結合ドメインのうちの少なくとも1つは、受容体を含む、項目1に記載の系。
[項目23]
第1の抗原結合ドメインおよび第2の抗原結合ドメインのうちの少なくとも1つは、受容体のためのリガンドを含む、項目1に記載の系。
[項目24]
第1のエピトープおよび第2のエピトープは、異なる抗原上に存在する、項目1に記載の系。
[項目25]
第1のエピトープおよび第2のエピトープは、共通の抗原上に存在する、項目1に記載の系。
[項目26]
少なくとも1つのエピトープは、1または複数の細胞表面抗原上に存在する、項目1または10に記載の系。
[項目27]
1または複数の細胞表面抗原は、腫瘍関連抗原、チロシンキナーゼ受容体、セリンキナーゼ受容体、およびGタンパク質共役受容体である、項目26に記載の系。
[項目28]
第1のエピトープおよび/または第2のエピトープは、普遍的抗原上に存在する、項目1に記載の系。
[項目29]
第1のエピトープおよび/または第2のエピトープは、ネオ抗原上に存在する、項目1に記載の系。
[項目30]
第1のエピトープおよび/または第2のエピトープは、ネオエピトープである、項目1に記載の系。
[項目31]
第1のエピトープおよび/または第2のエピトープは、腫瘍関連抗原上に存在する、項目1に記載の系。
[項目32]
腫瘍関連抗原は、707-AP、ビオチン化分子、a-アクチニン-4、abl-bcr alb-b3(b2a2)、abl-bcr alb-b4(b3a2)、アディポフィリン、AFP、AIM-2、アネキシンII、ART-4、BAGE、BCMA、b-カテニン、bcr-abl、bcr-abl p190(e1a2)、bcr-abl p210(b2a2)、bcr-abl p210(b3a2)、BING-4、CA-125、CAG-3、CAIX、CAMEL、カスパーゼ-8、CD171、CD19、CD20、CD22、CD4、CD23、CD24、CD30、CD33、CD38、CD44v7/8、CD70、CD123、CD133、CDC27、CDK-4、CEA、CLCA2、CLL-1、CTAG1B、Cyp-B、DAM-10、DAM-6、DEK-CAN、DLL3、EGFR、EGFRvIII、EGP-2、EGP-40、ELF2、Ep-CAM、EphA2、EphA3、erb-B2、erb-B3、erb-B4、ES-ESO-1a、ETV6/AML、FAP、FBP、胎児アセチルコリン受容体、FGF-5、FN、FR-α、G250、GAGE-1、GAGE-2、GAGE-3、GAGE-4、GAGE-5、GAGE-6、GAGE-7B、GAGE-8、GD2、GD3、GnT-V、Gp100、gp75、GPC3、GPC-2、Her-2、HLA-A*0201-R170I、HMW-MAA、HSP70-2M、HST-2(FGF6)、HST-2/neu、hTERT、iCE、IL-11Rα、IL-13Rα2、KDR、KIAA0205、K-RAS、L1-細胞接着分子、LAGE-1、LDLR/FUT、ルイスY、L1-CAM、MAGE-1、MAGE-10、MAGE-12、MAGE-2、MAGE-3、MAGE-4、MAGE-6、MAGE-A1、MAGE-A2、MAGE-A3、MAGE-A6、MAGE-B1、MAGE-B2、リンゴ酸酵素、マンマグロビン-A、MART-1/メラン-A、MART-2、MC1R、M-CSF、メソテリン、MUC1、MUC16、MUC2、MUM-1、MUM-2、MUM-3、ミオシン、NA88-A、ネオ-PAP、NKG2D、NPM/ALK、N-RAS、NY-ESO-1、OA1、OGT、腫瘍胎児抗原(h5T4)、OS-9、Pポリペプチド、P15、P53、PRAME、PSA、PSCA、PSMA、PTPRK、RAGE、ROR1、RU1、RU2、SART-1、SART-2、SART-3、SOX10、SSX-2、サバイビン、サバイビン-2B、SYT/SSX、TAG-72、TEL/AML1、TGFαRII、TGFβRII、TP1、TRAG-3、TRG、TRP-1、TRP-2、TRP-2/INT2、TRP-2-6b、チロシナーゼ、VEGF-R2、WT1、α-葉酸受容体、およびκ-軽鎖からなる群より選択される、項目31に記載の系。
[項目33]
少なくとも1つのエピトープは、免疫チェックポイント受容体または免疫チェックポイント受容体リガンド上に存在する、項目1または10に記載の系。
[項目34]
免疫チェックポイント受容体または免疫チェックポイント受容体リガンドは、PD-1、PD-L1、PD-L2、CTLA-4、TIM-3、LAG3、TIGIT、BLTA、CD47、またはCD40である、項目33に記載の系。
[項目35]
少なくとも1つのエピトープは、サイトカインまたはサイトカイン受容体上に存在する、項目1または10に記載の系。
[項目36]
サイトカインまたはサイトカイン受容体は、CCR2b、CXCR2(CXCL1受容体)、CCR4(CCL17受容体)、Gro-a、IL-2、IL-7、IL-15、IL-21、IL-12、ヘパラナーゼ、CD137L、LEM、Bcl-2、CCL17、CCL19、またはCCL2である、項目35に記載の系。
[項目37]
少なくとも1つのエピトープは、主要組織適合性複合体(MHC)によって提示される抗原上に存在する、項目1または10に記載の系。
[項目38]
MHCはHLAクラス1である、項目37に記載の系。
[項目39]
MHCはHLAクラス2である、項目37に記載の系。
[項目40]
項目1~39のいずれか一項に記載の系を発現する単離された宿主細胞。
[項目41]
宿主細胞は、免疫細胞である、項目40に記載の宿主細胞。
[項目42]
免疫細胞は、リンパ球である、項目41に記載の宿主細胞。
[項目43]
リンパ球はT細胞である、項目42に記載の宿主細胞。
[項目44]
リンパ球はα/βT細胞、および/またはγ/δT細胞である、項目42に記載の宿主細胞。
[項目45]
T細胞はCD8+T細胞である、項目43に記載の宿主細胞。
[項目46]
T細胞はCD4+T細胞である、項目43に記載の宿主細胞。
[項目47]
リンパ球はナチュラルキラー(NK)細胞である、項目42に記載の宿主細胞。
[項目48]
宿主細胞は、標的細胞中に同時に存在する2つの抗原に対して特異的な結合を示す、項目40~47のいずれか一項に記載の宿主細胞。
[項目49]
少なくとも2つの外因的に導入される抗原結合ドメインを含む抗原特異的免疫細胞であって、抗原結合ドメインのうちの1つは、T細胞受容体複合体(TCR複合体)に連結され、もう1つはキメラ抗原受容体(CAR)に連結され、抗原特異的免疫細胞は、少なくとも2つの外因的に導入される抗原結合ドメインによって認識される1または複数の抗原を発現する標的細胞に特異的に結合する、抗原特異的免疫細胞。
[項目50]
CARに連結される抗原結合ドメインは主に、抗原特異的免疫細胞と標的細胞との間の相互作用を媒介し、TCR複合体に連結される抗原結合ドメインは主に、抗原特異的免疫細胞と標的細胞との間の相互作用が生じるとき、免疫細胞活性を媒介する、項目49に記載の抗原特異的免疫細胞。
[項目51]
免疫細胞活性は、抗原特異的免疫細胞のクローン増殖;抗原特異的免疫細胞によるサイトカイン放出;抗原特異的免疫細胞の細胞傷害性;抗原特異的免疫細胞の増殖;抗原特異的免疫細胞の分化、脱分化、または分化転換;抗原特異的免疫細胞の移動および/または輸送;抗原特異的免疫細胞の疲弊および/または再活性化;ならびに抗原特異的免疫細胞による、他の細胞間分子、代謝物、化学物質、またはそれらの組み合わせの放出からなる群より選択される、項目50に記載の抗原特異的免疫細胞。
[項目52]
抗原特異的免疫細胞は、リンパ球である、項目49~51のいずれか一項に記載の抗原特異的免疫細胞。
[項目53]
リンパ球はT細胞である、項目52に記載の抗原特異的免疫細胞。
[項目54]
リンパ球はα/βT細胞、および/またはγ/δT細胞である、項目52に記載の抗原特異的免疫細胞。
[項目55]
T細胞は、CD4+T細胞またはCD8+T細胞である、項目53に記載の抗原特異的免疫細胞。
[項目56]
2つ以上の抗原結合ドメインは、任意選択でタンデムに、(i)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、(ii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/またはガンマ鎖、(iii)CD3ゼータ鎖に連結される、項目49に記載の抗原特異的免疫細胞。
[項目57]
リンパ球はナチュラルキラー(NK)細胞である、項目52に記載の抗原特異的免疫細胞。
[項目58]
免疫細胞の集団であって、個々の免疫細胞は、項目1~39のいずれか一項に記載の系を発現し、免疫細胞の集団を被験体における標的細胞集団に暴露させると、免疫細胞の集団は、約2日以内に少なくとも5%の標的細胞を死滅に誘導する点において、特徴付けられる、免疫細胞の集団。
[項目59]
免疫細胞の集団は、最大で約10 11 個の細胞を含む、項目58に記載の免疫細胞の集団。
[項目60]
免疫細胞はリンパ球を含む、項目58に記載の免疫細胞の集団。
[項目61]
リンパ球はT細胞である、項目60に記載の免疫細胞の集団。
[項目62]
リンパ球はα/β T細胞および/またはγ/δT細胞である、項目60に記載の免疫細胞の集団。
[項目63]
T細胞はCD4+T細胞である、項目61に記載の免疫細胞の集団。
[項目64]
T細胞はCD8+T細胞である、項目61に記載の免疫細胞の集団。
[項目65]
リンパ球はナチュラルキラー(NK)細胞である、項目60に記載の免疫細胞の集団。
[項目66]
免疫細胞および/または標的細胞の活性を誘導する方法であって、
(a)免疫細胞中の系を発現する段階と、
(b)標的細胞を、免疫細胞および/または標的細胞の活性を誘導する条件下で、免疫細胞に接触させる段階と、を備え、
免疫細胞において発現される系は、
第1のエピトープへの結合特異性を有する第1の抗原結合ドメイン、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むキメラ抗原受容体(CAR)と、
(i)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、
(ii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/もしくはガンマ鎖、または
(iii)CD3ゼータ鎖に連結される、第2の抗原結合ドメインを含む改変T細胞受容体(改変TCR)複合体と、を有する、
方法。
[項目67]
第1のエピトープへの第1の抗原結合ドメインの結合、および/または第2のエピトープへの第2の抗原結合ドメインの結合は、免疫細胞の細胞傷害性を活性化する、項目66に記載の方法。
[項目68]
2つ以上の抗原結合ドメインは、任意選択でタンデムに、(i)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、(ii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/またはガンマ鎖、(iii)CD3ゼータ鎖に連結される、項目66に記載の方法。
[項目69]
第1のエピトープへの第1の抗原結合ドメインの結合、および第2のエピトープへの第2の抗原結合ドメインの結合は、免疫細胞の細胞傷害性を活性化し、細胞傷害性は、第1のエピトープへの第1の抗原結合ドメインの結合のみ、または第2のエピトープへの第2の抗原結合ドメインの結合のみと比較して増強される、項目66に記載の方法。
[項目70]
第1のエピトープへの第1の抗原結合ドメインの結合、および第2の抗原結合ドメインの結合は、免疫細胞の細胞傷害性を活性化し、第1のエピトープへの第1の抗原結合ドメインの結合のみ、または第2のエピトープへの第2の抗原結合ドメインの結合のみと比較して、細胞傷害性の持続性を増大する、項目66に記載の方法。
[項目71]
免疫細胞の細胞傷害性は、標的細胞の死滅を誘導する、項目67~70のいずれか一項に記載の方法。
[項目72]
標的細胞はがん細胞である、項目71に記載の方法。
[項目73]
標的細胞は造血細胞である、項目71に記載の方法。
[項目74]
標的細胞は固形腫瘍細胞である、項目71に記載の方法。
[項目75]
標的細胞は、心臓、血管、唾液腺、食道、胃、肝臓、胆嚢、膵臓、腸、結腸、直腸、肛門、内分泌腺、副腎、腎臓、尿管、膀胱、リンパ節、扁桃腺、咽頭扁桃腺、胸腺、脾臓、皮膚、筋肉、脳、脊髄、神経、卵巣、卵管、子宮、膣、乳腺、精巣、前立腺、陰茎、咽頭、喉頭、気管、気管支、肺、横隔膜、軟骨、靭帯、および腱のうちの1または複数において同定される細胞である、項目71に記載の方法。
[項目76]
免疫細胞はリンパ球である、項目66~75のいずれか一項に記載の方法。
[項目77]
リンパ球はT細胞である、項目76に記載の方法。
[項目78]
リンパ球はα/βT細胞、および/またはγ/δT細胞である、項目76に記載の方法。
[項目79]
T細胞は、CD4+T細胞またはCD8+T細胞である、項目77に記載の方法。
[項目80]
2つ以上の抗原結合ドメインの、それぞれのエピトープへの結合は、系が被験体の免疫細胞において発現されるとき、系を発現する免疫細胞の細胞傷害性を活性化し、第1のエピトープへの第1の抗原結合ドメインの結合のみと比較して、細胞傷害性の持続性を増大する、項目66に記載の方法。
[項目81]
リンパ球はナチュラルキラー(NK)細胞である、項目76に記載の方法。
[項目82]
1または複数のポリヌクレオチドを含む組成物であって、1または複数のポリヌクレオチドは、
(a)第1のエピトープへの結合特異性を有する第1の抗原結合ドメイン、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むキメラ抗原受容体(CAR)と、
(b)第2のエピトープへの特異的な結合を示す第2の抗原結合ドメインを含む改変T細胞受容体(改変TCR)複合体と、
をコードし、第2の抗原結合ドメインは、
(i)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、
(ii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/もしくはガンマ鎖、または
(iii)CD3ゼータ鎖
に連結される、
組成物。
[項目83]
1または複数のポリヌクレオチドは、それに動作可能に連結されるプロモータを含む、項目82に記載の組成物。
[項目84]
改変免疫細胞を作製する方法であって、
項目82または83に記載の組成物を免疫細胞において発現させることによって、免疫細胞を遺伝子改変し、それにより改変免疫細胞を作製する段階
を含む、方法。
[項目85]
(a)第1の抗原結合ドメインを含むキメラ抗原受容体(CAR)および第2の抗原結合ドメインを含む改変T細胞受容体(改変TCR)複合体を有する抗原特異的免疫細胞を、被験体に投与する段階であって、被験体のがんの標的細胞は、第1の抗原結合ドメインおよび/または第2の抗原結合ドメインによって認識される1または複数の抗原を発現し、抗原特異的免疫細胞は標的細胞に特異的に結合する、段階と、
(b)標的細胞に対する、抗原特異的免疫細胞の免疫細胞活性を誘導する条件下で、第1の抗原結合ドメインおよび/または第2の抗原結合ドメインを介して標的細胞を抗原特異的免疫細胞と接触させる段階であって、それによりがんの標的細胞の死滅を誘導する、段階と
を備える、被験体のがんを治療する方法。
[項目86]
(a)抗原特異的免疫細胞を、被験体に投与する段階であって、抗原特異的免疫細胞は、項目1~36のいずれか一項に記載の系を発現する遺伝子改変免疫細胞である段階と、
(b)被験体のがんの標的細胞に対する、抗原特異的免疫細胞の免疫細胞活性を誘導する条件下で、標的細胞を抗原特異的免疫細胞と接触させる段階であって、それによりがんの標的細胞の死滅を誘導する、段階と
を含む、被験体のがんを治療する方法。
[項目87]
免疫細胞を遺伝子改変して抗原特異的免疫細胞を得る段階をさらに含む、項目86に記載の方法。
[項目88]
免疫細胞活性は、抗原特異的免疫細胞のクローン増殖;抗原特異的免疫細胞によるサイトカイン放出;抗原特異的免疫細胞の細胞傷害性;抗原特異的免疫細胞の増殖;抗原特異的免疫細胞の分化、脱分化、または分化転換;抗原特異的免疫細胞の移動および/または輸送;抗原特異的免疫細胞の疲弊および/または再活性化;ならびに抗原特異的免疫細胞による、他の細胞間分子、代謝物、化学物質、またはそれらの組み合わせの放出からなる群より選択される、項目85または86に記載の方法。
[項目89]
免疫細胞活性は、抗原特異的免疫細胞の細胞傷害性である、項目88に記載の方法。
[項目90]
標的細胞に対する抗原特異的免疫細胞の細胞傷害性は、被験体のがんの、少なくとも10%の低減をもたらす、項目89に記載の方法。
[項目91]
免疫細胞活性は、抗原特異的免疫細胞によるサイトカイン放出である、項目88に記載の方法。
[項目92]
第1の抗原結合ドメインの結合のみ、または第2の抗原結合ドメインの結合のみと比較して、第1の抗原結合ドメインおよび第2の抗原結合ドメインの両方が、それぞれのエピトープに結合するとき、免疫細胞活性の持続性は増大する、項目85~91のいずれか一項に記載の方法。
[項目93]
がんは、膀胱癌、骨癌、脳癌、乳癌、子宮頸癌、大腸癌、食道癌、胃癌、神経膠腫、頭頚部癌、腎臓癌、白血病、急性骨髄性白血病(AML)、多発性骨髄腫、肝臓癌、肺癌、リンパ腫、黒色腫、中皮腫、髄芽腫、卵巣癌、膵臓癌、前立腺癌、直腸癌、皮膚癌、精巣癌、気管癌、および外陰部癌から選択される、項目85~92のいずれか一項に記載の方法。
[項目94]
抗原特異的免疫細胞はリンパ球である、項目85~93のいずれか一項に記載の方法。
[項目95]
リンパ球はT細胞である、項目94に記載の方法。
[項目96]
リンパ球はα/βT細胞、および/またはγ/δT細胞である、項目94に記載の方法。
[項目97]
T細胞はCD4+T細胞である、項目95に記載の方法。
[項目98]
T細胞はCD8+T細胞である、項目95に記載の方法。
[項目99]
リンパ球はナチュラルキラー(NK)細胞である、項目94に記載の方法。
[項目100]
式:
A-X-B-Y-C-Z-D
(式中、
Aは、配列番号47~56からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含み、
Bは、配列番号57~66からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含み、
Cは、配列番号67~76からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含み、
Dは、配列番号77~86からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含み、
Xは、配列番号87~96からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含み、
Yは、配列番号97~106からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含み、かつ、
Zは、配列番号107~116からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含む。)
を有する抗原結合分子。
[項目101]
抗原結合分子は、37℃で表面プラズモン共鳴法によって測定されるとき、100nm、90nm、80nm、70nm、60nm、50nm、40nm、30nm、20nm、10nm、または1nm、またはそれより低い、ヒトBCMAに対する結合親和性(K D )を示す、項目100に記載の抗原結合分子。
[項目102]
抗原結合分子は、配列番号14~23からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含む、項目100に記載の抗原結合分子。
[項目103]
抗原結合分子は、配列番号14~23からなる群より選択される配列を含む、項目100に記載の抗原結合分子。
[項目104]
1または複数の抗原結合ドメインを含む改変T細胞受容体(改変TCR)複合体であって、1または複数の抗原結合ドメインは、
(iv)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、
(v)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/もしくはガンマ鎖、または
(vi)CD3ゼータ鎖、
に連結され、1または複数の抗原結合ドメインのうちの少なくとも1つまたは2つは、項目100~103のいずれか一項に記載の抗原結合分子を含む、改変TCR複合体。
[項目105]
1または複数の抗原結合ドメインのうちの少なくとも1つまたは2つは、配列番号3~23および38~46からなる群より選択される任意の1つに対して少なくとも80%または90%の同一性を有する配列を含む、項目104に記載の改変TCR複合体。
[項目106]
2つ以上の抗原結合ドメインを含む、項目104に記載の改変TCR複合体。
[項目107]
2つ以上の抗原結合ドメインは、改変TCR複合体の別々の鎖に連結される、項目104に記載の改変TCR複合体。
[項目108]
2つ以上の抗原結合ドメインは、改変TCR複合体の1本の鎖に連結される、項目104に記載の改変TCR複合体。
[項目109]
2つ以上の抗原結合ドメインは、改変TCR複合体の1本の鎖にタンデムに連結される、項目104に記載の改変TCR複合体。
[項目110]
改変TCR複合体の別の鎖に連結される1または複数の抗原結合ドメインをさらに含む、項目109に記載の改変TCR複合体。
[項目111]
2つ以上のエピトープへの特異的結合を示す2つ以上の抗原結合ドメインを含む、改変T細胞受容体(改変TCR)複合体であって、2つ以上の抗原結合ドメインは、
(i)T細胞受容体のアルファ鎖、ベータ鎖、ガンマ鎖、およびデルタ鎖から選択される少なくとも1つのTCR鎖、
(ii)表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/もしくはガンマ鎖、または
(iii)CD3ゼータ鎖
に連結される、改変TCR複合体。
[項目112]
2つ以上の抗原結合ドメインは、改変TCR複合体の別々の鎖に連結される、項目111に記載の改変TCR複合体。
[項目113]
2つ以上の抗原結合ドメインは、改変TCR複合体の1本の鎖に連結される、項目111に記載の改変TCR複合体。
[項目114]
2つ以上の抗原結合ドメインは、改変TCR複合体の1本の鎖にタンデムに連結される、項目113に記載の改変TCR複合体。
[項目115]
改変TCR複合体の別の鎖に連結される1または複数の抗原結合ドメインをさらに含む、項目114に記載の改変TCR複合体。
[項目116]
2つ以上の抗原結合ドメインは、BCMAに結合する、項目111に記載の改変TCR複合体。
[項目117]
2つ以上の抗原結合ドメインは、BCMAの同じエピトープに結合する、項目116に記載の改変TCR複合体。
[項目118]
2つ以上の抗原結合ドメインは、抗BCMA sdAbである、項目111に記載の改変TCR複合体。
[項目119]
2つ以上の抗原結合ドメインは、配列番号3~23のうちの任意の1つに対して少なくとも80%の配列同一性を有する配列から選択される、項目111に記載の改変TCR複合体。
[項目120]
2つ以上の抗原結合ドメインは、表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/またはガンマ鎖にタンデムに連結される、項目111に記載の改変TCR複合体。
[項目121]
項目104~120のいずれか一項に記載の改変TCR複合体を含む、抗原特異的免疫細胞。
[項目122]
それぞれのエピトープへの特異的な結合を示す1または複数の抗原結合ドメイン、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むキメラ抗原受容体(CAR)をさらに備える、項目121に記載の抗原特異的免疫細胞。
[項目123]
CARの1または複数の抗原結合ドメインは、タンデムに配置される、項目122に記載の抗原特異的免疫細胞。
[項目124]
それぞれのエピトープへの特異的な結合を示す1または複数の抗原結合ドメイン、膜貫通ドメイン、および細胞内シグナル伝達ドメインを、それぞれが含む2つ以上のキメラ抗原受容体(CAR)をさらに備える、項目121に記載の抗原特異的免疫細胞。
Claims (19)
- 免疫細胞であって、
(a)第1のエピトープへの特異的な結合を示す第1の抗原結合ドメイン、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むキメラ抗原受容体(CAR)と、
(b)第2のエピトープへの特異的な結合を示す第2の抗原結合ドメインを含むT細胞受容体(TCR)複合体とを備え、前記第2の抗原結合ドメインは、
表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/もしくはガンマ鎖のN末端
に連結され、
前記第1のエピトープへの前記第1の抗原結合ドメインの結合、および/または前記第2のエピトープへの前記第2の抗原結合ドメインの結合は、免疫細胞活性を活性化する、免疫細胞。 - 前記TCRは、1つ以上の追加の抗原結合ドメインを含み、前記1つ以上の追加の抗原結合ドメインは、表面抗原分類3(CD3)のイプシロン鎖、デルタ鎖、および/またはガンマ鎖に連結され、前記1つ以上の追加の抗原結合ドメインの、それぞれのエピトープへの結合は、免疫細胞活性を活性化する、請求項1に記載の免疫細胞。
- 前記第2の抗原結合ドメインおよび前記1つ以上の追加の抗原結合ドメインが、タンデムに結合されている、請求項2に記載の免疫細胞。
- 前記1つ以上の追加の抗原結合ドメインが、前記第1のエピトープまたは前記第2のエピトープと同じである、1つ以上の追加のエピトープへの特異的な結合を示す、請求項2または3に記載の免疫細胞。
- 前記1つ以上の追加の抗原結合ドメインが、前記第1のエピトープまたは前記第2のエピトープと異なる、1つ以上の追加のエピトープへの特異的な結合を示す、請求項2または3に記載の免疫細胞。
- 前記CARは、1または複数の追加の抗原結合ドメインを含む、請求項1から5のいずれか一項に記載の免疫細胞。
- 前記CARの前記細胞内シグナル伝達ドメインは、免疫受容体活性化チロシンモチーフ(ITAM)、免疫受容体抑制チロシンモチーフ(ITIM)、または、Fcγ受容体(FcγR)、Fcε受容体(FcεR)、Fcα受容体(FcαR)、新生児Fc受容体(FcRn)、CD3、CD3ζ、CD3γ、CD3δ、CD3ε、CD4、CD5、CD8、CD21、CD22、CD28、CD32、CD40L(CD154)、CD45、CD66d、CD79a、CD79b、CD80、CD86、CD278(ICOSとしても公知である)、CD247ζ、CD247η、DAP10、DAP12、FYN、LAT、Lck、MAPK、MHC複合体、NFAT、NF-κB、PLC-γ、iC3b、C3dg、C3d、またはZap70のシグナル伝達ドメインを含む、請求項1から6のいずれか一項に記載の免疫細胞。
- 前記CARは、共刺激ドメインをさらに含み、前記共刺激ドメインは、MHCクラスI分子、TNF受容体タンパク質、免疫グロブリン様タンパク質、サイトカイン受容体、インテグリン、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、活性化NK細胞受容体、またはTollリガンド受容体のシグナル伝達ドメインを含むか、または、
2B4/CD244/SLAMF4、4-1BB/TNFSF9/CD137、B7-1/CD80、B7-2/CD86、B7-H1/PD-L1、B7-H2、B7-H3、B7-H4、B7-H6、B7-H7、BAFF-R/TNFRSF13C、BAFF/BlyS/TNFSF13B、BLAME/SLAMF8、BTLA/CD272、CD100(SEMA4D)、CD103、CD11a、CD11b、CD11c、CD11d、CD150、CD160(BY55)、CD18、CD19、CD2、CD200、CD229/SLAMF3、CD27リガンド/TNFSF7、CD27/TNFRSF7、CD28、CD29、CD2F-10/SLAMF9、CD30リガンド/TNFSF8、CD30/TNFRSF8、CD300a/LMIR1、CD4、CD40リガンド/TNFSF5、CD40/TNFRSF5、CD48/SLAMF2、CD49a、CD49D、CD49f、CD53、CD58/LFA-3、CD69、CD7、CD8α、CD8β、CD82/Kai-1、CD84/SLAMF5、CD90/Thy1、CD96、CDS、CEACAM1、CRACC/SLAMF7、CRTAM、CTLA-4、DAP12、デクチン-1/CLEC7A、DNAM1(CD226)、DPPIV/CD26、DR3/TNFRSF25、EphB6、GADS、Gi24/VISTA/B7-H5、GITRリガンド/TNFSF18、GITR/TNFRSF18、HLAクラスI、HLA-DR、HVEM/TNFRSF14、IA4、ICAM-1、ICOS/CD278、イカロス、IL2Rβ、IL2Rγ、IL7Rα、インテグリンα4/CD49d、インテグリンα4β1、インテグリンα4β7/LPAM-1、IPO-3、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、ITGAX、ITGB1、ITGB2、ITGB7、KIRDS2、LAG-3、LAT、LIGHT/TNFSF14、LTBR、Ly108、Ly9(CD229)、リンパ球機能関連抗原-1(LFA-1)、リンホトキシン-α/TNF-β、NKG2C、NKG2D、NKp30、NKp44、NKp46、NKp80(KLRF1)、NTB-A/SLAMF6、OX40リガンド/TNFSF4、OX40/TNFRSF4、PAG/Cbp、PD-1、PDCD6、PD-L2/B7-DC、PSGL1、RELT/TNFRSF19L、SELPLG(CD162)、SLAM(SLAMF1)、SLAMF6(NTB-A)、SLAMF7、SLP-76、TACI/TNFRSF13B、TCL1A、TCL1B、TIM-1/KIM-1/HAVCR、TIM-4、TL1A/TNFSF15、TNF RII/TNFRSF1B、TNF-α、TRANCE/RANKL、TSLP、TSLP R、VLA1、およびVLA-6からなる群より選択される分子のシグナル伝達ドメインを含む、請求項1から7のいずれか一項に記載の免疫細胞。 - 前記第1の抗原結合ドメイン、前記第2の抗原結合ドメイン、および前記追加の抗原結合ドメインのうちの少なくとも1つは、Fab、Fab'、F(ab')2、Fv、単鎖Fv(scFv)、ミニボディ、ダイアボディ、単一ドメイン抗体、軽鎖可変ドメイン(VL)、またはラクダ科動物抗体の可変ドメイン(VHH)を含む、請求項1から8のいずれか一項に記載の免疫細胞。
- 少なくとも1つのエピトープは、腫瘍関連抗原、チロシンキナーゼ受容体、セリンキナーゼ受容体、Gタンパク質共役受容体、免疫チェックポイント受容体、免疫チェックポイント受容体リガンド、サイトカイン、サイトカイン受容体、および/または、主要組織適合性複合体(MHC)によって提示される抗原の上に存在する、請求項1から9のいずれか一項に記載の免疫細胞。
- 前記腫瘍関連抗原は、707-AP、ビオチン化分子、a-アクチニン-4、abl-bcr alb-b3(b2a2)、abl-bcr alb-b4(b3a2)、アディポフィリン、AFP、AIM-2、アネキシンII、ART-4、BAGE、BCMA、b-カテニン、bcr-abl、bcr-abl p190(e1a2)、bcr-abl p210(b2a2)、bcr-abl p210(b3a2)、BING-4、CA-125、CAG-3、CAIX、CAMEL、カスパーゼ-8、CD171、CD19、CD20、CD22、CD4、CD23、CD24、CD30、CD33、CD38、CD44v7/8、CD70、CD123、CD133、CDC27、CDK-4、CEA、CLCA2、CLL-1、CTAG1B、Cyp-B、DAM-10、DAM-6、DEK-CAN、DLL3、EGFR、EGFRvIII、EGP-2、EGP-40、ELF2、Ep-CAM、EphA2、EphA3、erb-B2、erb-B3、erb-B4、ES-ESO-1a、ETV6/AML、FAP、FBP、胎児アセチルコリン受容体、FGF-5、FN、FR-α、G250、GAGE-1、GAGE-2、GAGE-3、GAGE-4、GAGE-5、GAGE-6、GAGE-7B、GAGE-8、GD2、GD3、GnT-V、Gp100、gp75、GPC3、GPC-2、Her-2、HLA-A*0201-R170I、HMW-MAA、HSP70-2M、HST-2(FGF6)、HST-2/neu、hTERT、iCE、IL-11Rα、IL-13Rα2、KDR、KIAA0205、K-RAS、L1-細胞接着分子、LAGE-1、LDLR/FUT、ルイスY、L1-CAM、MAGE-1、MAGE-10、MAGE-12、MAGE-2、MAGE-3、MAGE-4、MAGE-6、MAGE-A1、MAGE-A2、MAGE-A3、MAGE-A6、MAGE-B1、MAGE-B2、リンゴ酸酵素、マンマグロビン-A、MART-1/メラン-A、MART-2、MC1R、M-CSF、メソテリン、MUC1、MUC16、MUC2、MUM-1、MUM-2、MUM-3、ミオシン、NA88-A、ネオ-PAP、NKG2D、NPM/ALK、N-RAS、NY-ESO-1、OA1、OGT、腫瘍胎児抗原(h5T4)、OS-9、Pポリペプチド、P15、P53、PRAME、PSA、PSCA、PSMA、PTPRK、RAGE、ROR1、RU1、RU2、SART-1、SART-2、SART-3、SOX10、SSX-2、サバイビン、サバイビン-2B、SYT/SSX、TAG-72、TEL/AML1、TGFαRII、TGFβRII、TP1、TRAG-3、TRG、TRP-1、TRP-2、TRP-2/INT2、TRP-2-6b、チロシナーゼ、VEGF-R2、WT1、α-葉酸受容体、およびκ-軽鎖からなる群より選択され、
前記免疫チェックポイント受容体または前記免疫チェックポイント受容体リガンドは、PD-1、PD-L1、PD-L2、CTLA-4、TIM-3、LAG3、TIGIT、BLTA、CD47またはCD40であり、
前記サイトカインまたは前記サイトカイン受容体は、CCR2b、CXCR2(CXCL1受容体)、CCR4(CCL17受容体)、Gro-a、IL-2、IL-7、IL-15、IL-21、IL-12、ヘパラナーゼ、CD137L、LEM、Bcl-2、CCL17、CCL19、またはCCL2であり、
前記MHCは、HLAクラス1またはHLAクラス2である、
請求項10に記載の免疫細胞。 - 前記第1の抗原結合ドメイン、前記第2の抗原結合ドメイン、前記TCRにおける前記1つ以上の追加の抗原結合ドメイン、および/または、前記CARにおける前記1つ以上の追加の抗原結合ドメインのそれぞれは、配列番号3~23、および38~46のいずれか1つのアミノ酸配列を含む、請求項1から11のいずれか一項に記載の免疫細胞。
- 前記第1のエピトープおよび前記第2のエピトープは共通の抗原上に存在する、請求項1から12のいずれか一項に記載の免疫細胞。
- 前記免疫細胞は、T細胞、ナチュラルキラー(NK)細胞、エフェクターT細胞、メモリT細胞、細胞障害性T細胞、NKT細胞、Tヘルパ細胞、KHYG細胞からなる群より選択される、請求項1から13のいずれか一項に記載の免疫細胞。
- 前記T細胞は、CD8+ T細胞、CD4+ T細胞、α/βT細胞、および/またはγ/δT細胞である、請求項14に記載の免疫細胞。
- 請求項1から15のいずれか一項に記載の免疫細胞を含む免疫細胞の集団であって、前記免疫細胞の集団は、前記免疫細胞の集団を被験体における標的細胞の集団に暴露させると、前記免疫細胞の集団は、約2日以内に少なくとも5%の前記標的細胞を死滅に誘導する点において、特徴付けられる、免疫細胞の集団。
- 請求項1から15のいずれか一項に記載の免疫細胞を含む、組成物。
- がんを有する被験体を治療するために用いられる組成物であって、治療有効量の、請求項1から15のいずれか一項に記載の免疫細胞を含む組成物。
- 前記がんは、膀胱癌、骨癌、脳癌、乳癌、子宮頸癌、大腸癌、食道癌、胃癌、神経膠腫、頭頚部癌、腎臓癌、白血病、急性骨髄性白血病(AML)、多発性骨髄腫、肝臓癌、肺癌、リンパ腫、黒色腫、中皮腫、髄芽腫、卵巣癌、膵臓癌、前立腺癌、直腸癌、皮膚癌、精巣癌、気管癌、および外陰部癌から選択される、請求項18に記載の組成物。
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CA3099075A1 (en) | 2019-12-26 |
AU2019291627A1 (en) | 2020-10-08 |
WO2019242632A1 (en) | 2019-12-26 |
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JP2021528049A (ja) | 2021-10-21 |
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