JP7082574B2 - 免疫療法用改変細胞 - Google Patents
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Description
i)抗原レセプター、および
ii)PD-L1に結合し、遮断する抗体
を発現する改変細胞を与える。
(a)免疫細胞を与えるステップと、
(b)前記抗原レセプターをコードする1つ以上の核酸および前記抗体をコードする1つ以上の核酸を前記細胞に導入するステップと、
(c)前記細胞により前記核酸を発現させるステップと、
を含む前記方法も与えられる。
ii)薬剤的に許容できる賦形剤。
を含む医薬組成物もさらに与えられる。
(a)本明細書に記載の組み換え免疫細胞を与えること、
(b)前記対象に前記免疫細胞を投与すること
を含む前記方法がさらに与えられる。
別段の定義がない限り、説明、図、および特許請求の範囲で使用される全ての他の科学用語および技術用語は、当業者によって一般的に理解されるような通常の意味を有する。本明細書で開示される改変細胞、抗体、抗原レセプター、核酸、ベクター、組成物、方法、および用途の実施または試験において、本明細書に記載された方法および材料と類似または均等の方法および材料を使用することができるが、好適な方法および材料を以下に記載する。本明細書で言及される全ての刊行物、特許出願、特許、および他の参考文献は、その全体で参照により援用される。矛盾する場合、定義を含む本明細書が優先する。材料、方法、および実施例は、例示的なものに過ぎず、限定するものではない。
i)抗原レセプター、および
ii)PD-L1を遮断する抗体
を発現する改変免疫細胞を与える。
i)それぞれ配列番号6、7、および8に示される可変重鎖(VH)CDR配列CDR-H1、CDR-H2、もしくはCDR-H3、またはそれらの変異体のうちの1つ以上、
ii)それぞれ配列番号3、4、および5に示される可変軽鎖(VL)CDR配列CDR-L1、CDR-L2、もしくはCDR-L3、またはそれらの変異体のうちの1つ以上、
を含む。
i)配列番号2の1つ以上のVH配列、および/もしくは
ii)配列番号1の1つ以上のVL配列
またはそれぞれの変異体
を含む。
1.非極性側鎖(例えば、グリシン、アラニン、バリン、ロイシン、イソロイシン、メチオニン)
2.非荷電極性側鎖(例えば、アスパラギン、グルタミン、セリン、スレオニン、チロシン、プロリン、システイン、トリプトファン)
3.塩基性側鎖(例えば、リシン、アルギニン、ヒスチジン、プロリン)
4.酸性側鎖(例えば、アスパラギン酸、グルタミン酸)
5.ベータ-分枝側鎖(例えば、スレオニン、バリン、イソロイシン)、および
6.芳香族側鎖(例えば、チロシン、フェニルアラニン、トリプトファン、ヒスチジン)
1.アラニン(A)をバリン(V)により置換すること
2.アルギニン(R)をリシン(K)により置換すること
3.アスパラギン(N)をグルタミン(Q)により置換すること
4.アスパラギン酸(D)をグルタミン酸(E)により置換すること
5.システイン(C)をセリン(S)により置換すること
6.グルタミン酸(E)をアスパラギン酸(D)により置換すること
7.グリシン(G)をアラニン(A)により置換すること
8.ヒスチジン(H)をアルギニン(R)またはリシン(K)により置換すること
9.イソロイシン(I)をロイシン(L)により置換すること
10.メチオニン(M)をロイシン(L)により置換すること
11.フェニルアラニン(F)をチロシン(Y)により置換すること
12.セリン(S)をスレオニン(T)により置換すること
13.トリプトファン(W)をチロシン(Y)により置換すること
14.フェニルアラニン(F)をトリプトファン(W)により置換すること
および/または
15.バリン(V)をロイシン(L)により置換すること
ならびにそれらの逆。プロリン(P)をアラニン(A)により置換するなどの他の置換も許容され、経験的に、または他の公知の保存的置換もしくは非保存的置換を踏まえて決定することができる。保存的置換はまた、非天然アミノ酸の使用を伴い得る。
(i)PD-L1、特にhPD-L1に対する特異的結合を保持し、好ましくはPD-L1とPD-1との間の相互作用を遮断し;かつ/または
(ii)KinExA(登録商標)により測定して500pM未満、好ましくは250pM未満、100pM未満、75pM未満、50pM未満、40pM未満、30pM未満、20pM未満、より好ましくは10pM未満のヒトPD-L1に対するKDを有し;かつ/または
(iv)PD-L1への結合に関して本明細書に開示される抗体と競合し;かつ/または
(v)本明細書に開示される配列と少なくとも80%、好ましくは少なくとも85%、90%、95%、もしくは97%の配列同一性を有する。
(a)免疫細胞を与えるステップと、
(b)前記抗原レセプターをコードする1つ以上の核酸および前記抗体をコードする1つ以上の核酸を前記細胞に導入するステップと、
(c)前記細胞により前記核酸を発現させるステップと、
を含む前記方法も与える。
(i)ステップ(b)に記載の抗原レセプターとは異なる抗原特異性を有する1つ以上の他の抗原レセプターを前記細胞に導入し;かつ/またはステップ(b)に記載の抗体とは異なる抗原特異性を有する1つ以上の他の抗体を前記細胞に導入する追加のステップ、
を含み得る。
i)有効量の本明細書に記載の改変免疫細胞、または本明細書に記載の発現ベクター、および
ii)薬剤的に許容できる賦形剤
を含む医薬組成物にも関する。
(a)本明細書に記載の改変免疫細胞を与えること、および
(b)前記対象に前記免疫細胞を投与すること
を含む前記方法も与えられる。
本明細書で開示される配列は以下である。
配列番号1-scFVのVL
EIVMTQSPSTLSASVGDRVIITCQASEDIYSLLAWYQQKPGKAPKLLIYDASDLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQGNYGSSSSSSYGAVFGQGTKLTVLG
配列番号2-scFVのVH
EVQLVESGGGLVQPGGSLRLSCTVSGIDLSSYTMGWVRQAPGKGLEWVGIISSGGRTYYASWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARGRYTGYPYYFALWGQGTLVTVSS
配列番号3-scFVのCDR-L1
QASEDIYSLLA
配列番号4-scFVのCDR-L2
DASDLAS
配列番号5-scFVのCDR-L3
QGNYGSSSSSSYGAV
配列番号6-scFVのCDR-H1
IDLSSYTMG
配列番号7-scFVのCDR-H2
IISSGGRTYYASWAKG
配列番号8-scFVのCDR-H3
GRYTGYPYYFAL
配列番号9-scFV
EIVMTQSPSTLSASVGDRVIITCQASEDIYSLLAWYQQKPGKAPKLLIYDASDLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQGNYGSSSSSSYGAVFGQGTKLTVLGGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTVSGIDLSSYTMGWVRQAPGKGLEWVGIISSGGRTYYASWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARGRYTGYPYYFALWGQGTLVTVSS
配列番号10-リンカー
GGGGSGGGGSGGGGSGGGGS
配列番号11-フォーワードプライマー
TAACCATGGAGTTTGGGCTGAG
配列番号12-リバースプライマー
GACGCATGCTCAGCTCGACACGGTGACC
配列番号13-14g2a scFvのVL配列
配列番号14-14g2a scFvのVH配列
配列番号15-hIgG1シグナルペプチド
MEFGLSWLFLVAILKGVQ
配列番号16-抗GD2-CARのCDR-L1
RSSQSLVHRNGNTYLH
配列番号17-抗GD2-CARのCDR-L2
KVSNRFS
配列番号18-抗GD2-CARのCDR-L3
SQSTHVPPLT
配列番号19-抗GD2-CARのCDR-H1
SSFTGYNMN
配列番号20-抗GD2-CARのCDR-H2
AIDPYYGGTSYNQKFKG
配列番号21-抗GD2-CARのCDR-H3
GMEY
配列番号22-抗CSPG4 CARのCDR-L1
RASQTIYKNLH
配列番号23-抗CSPG4 CARのCDR-L2
YGSDSIS
配列番号24-抗CSPG4 CARのCDR-L3
LQGYSTPWT
配列番号25-抗CSPG4 CARのCDR-H1
YTFTDYSMH
配列番号26-抗CSPG4 CARのCDR-H2
WINTATGEPTYADDFKG
配列番号27-抗CSPG4 CARのCDR-H3
YYDY
配列番号28-抗CSPG4 CARのVL配列
LDIKLTQSPSILSVTPGETVSLSCRASQTIYKNLHWYQQKSHRSPRLLIKYGSDSISGIPSRFTGSGSGTDYTLNINSVKPEDEGIYYCLQGYSTPWTFGGGTKLEIKR
配列番号29-抗CSPG4 CARのVH配列
QVKLKESGPELKKPGETVKISCKASGYTFTDYSMHWVKKTPGKGLKWLGWINTATGEPTYADDFKGRFAISLETSARTVYLQINNLRNEDTATYFCFSYYDYWGQGTTVTVSS
配列番号30-抗GPC3 CARのCDR-L1
RSSQSLVHSNRNTYLH
配列番号31-抗GPC3 CARのCDR-L2
KVSNRFS
配列番号32-抗GPC3 CARのCDR-L3
SQNTHVPPT
配列番号33-抗GPC3 CARのCDR-H1
YTFTDYEMH
配列番号34-抗GPC3 CARのCDR-H2
ALDPKTGDTAYSQKFKG
配列番号35-抗GPC3 CARのCDR-H3
FYSYTY
配列番号36-抗GPC3 CARのVL
DVVMTQSPLSLPVTPGEPASISCRSSQSLVHSNRNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQNTHVPPTFGQGTKLEIKR
配列番号37-抗GPC3 CARのVH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGALDPKTGDTAYSQKFKGRVTLTADKSTSTAYMELSSLTSEDTAVYYCTRFYSYTYWGQGTLVTVSS
配列番号38-抗GPC3 CARのVH
QVQLQQSGAELVRPGASVKLSCKASGYTFTDYEMHWVKQTPVHGLKWIGALDPKTGDTAYSQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRFYSYTYWGQGTLVTVSA
配列番号39-抗5T4 CARのCDR-L1
YSFTGYYMH
配列番号40-抗5T4 CARのCDR-L2
RINPNNGVTLYNQKFKD
配列番号41-抗5T4 CARのCDR-L3
STMITNYVMDY
配列番号42-抗5T4 CARのCDR-H1
KASQSVSNDVA
配列番号43-抗5T4 CARのCDR-H2
YTSSRYA
配列番号44-抗5T4 CARのCDR-H3
QQDYNSPPT
配列番号45-抗5T4 CARのVL
SIVMTQTPTFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPTLLISYTSSRYAGVPDRFIGSGYGTDFTFTISTLQAEDLAVYFCQQDYNSPPTFGGGTKLEIKR
配列番号46-抗5T4 CARのVH
EVQLQQSGPDLVKPGASVKISCKASGYSFTGYYMHWVKQSHGKSLEWIGRINPNNGVTLYNQKFKDKAILTVDKSSTTAYMELRSLTSEDSAVYYCARSTMITNYVMDYWGQVTSVTVSS
配列番号47-41BB共刺激ドメイン
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
配列番号48-CD3ゼータ細胞内ドメイン
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号49-CD28共刺激ドメイン
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
配列番号50-サバイビン特異的TCR、ベータ鎖
DAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQAPKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDAAMYLCATSRGDSTAEPQHFGDGTRLSIL
配列番号51-サバイビン特異的TCR、アルファ鎖
GESVGLHLPTLSVQEGDNSIINCAYSNSASDYFIWYKQESGKGPQFIIDIRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGDSAVYFCAETVTDSWGKLQFGAGTQVVVTPD
配列番号52-WT-1特異的TCR、CDR1アルファ
SSYSPS
配列番号53-WT-1特異的TCR、CDR2アルファ
YTSAATL
配列番号54-WT-1特異的TCR、CDR3アルファ
WSPFSGGGADGLT
配列番号55-WT-1特異的TCR、CDR3アルファ
SPFSGGGADGLT
配列番号56-WT-1特異的TCR、CDR1ベータ
DFQATT
配列番号57-WT-1特異的TCR、CDR2ベータ
SNEGSKA
配列番号58-WT-1特異的TCR、CDR3ベータ
SARDGGEG
配列番号59-WT-1特異的TCR、CDR3ベータ
RDGGEGSETQY
配列番号60-WT-1特異的TCR、アルファ鎖
MLLLLVPVLEVIFTLGGTRAQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPSLFWYVQHPNKGLQLLLKYTSAATLVKGINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVVSPFSGGGADGLT
配列番号61-WT-1特異的TCR、ベータ鎖
MLLLLLLLGPGSGLGAVVSQHPSWVICKSGTXVKIECRSLDFQATTMFWYRQFPKQSLMLMATSNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYICSARDGGEG
配列番号62-WT-1特異的TCR、アルファ鎖
MLLLLVPVLEVIFTLGGTRAQSVTQLDSHVSVSEGTPVLLRCNYSSSYSPSLFWYVQHPNKGLQLLLKYTSAATLVKGINGFEAEFKKSETSFHLTKPSAHMSDAAEYFCVVSPFSGGGADGLT
配列番号63-WT-1特異的TCR、ベータ鎖
MLLLLLLLGPGSGLGAVVSQHPSWVICKSGTSVKIECRSLDFQATTMFWYRQFPKQSLMLMATSNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYICSARDGGEGSETQY
293T細胞はATCCから入手し、神経芽腫腫瘍細胞株CHLA-255はDr Leonid Metelitsa Baylor College of Medicine(テキサス州ヒューストン)から親切にも提供された。細胞を、10%FBS(Corning)、1%GlutaMAX、および1%ペニシリン/ストレプトアビジン(Gibco)を含有し、293TについてはIMDM(Gibco)を含み、CHLA-255についてはRPMI 1640(Gibco)を含む培地で、37℃で5%CO2を含む加湿雰囲気中で維持した。
ヒトPD-L1の中和
抗PD-L1 scFv(配列番号9参照)は、ウサギCDRを含むヒト化タンパク質である。PD-L1のPD-1への結合を阻害するその能力を競合ELISAによって試験した。簡潔に述べると、rhPD-L1 Fc融合体を96ウェルマイクロプレート上にコーティングした。ブロッキング後、scFvの段階希釈物をプレートに加え、室温で1時間インキュベートした。scFv希釈液の半分をビオチン化PD-1 Fc融合体で置き換え、結合したPD-1をストレプトアビジン-HRPで検出した。
scFvの安定性に影響し得る2つの異なるプロセスを観察することができる。第一に、scFvは二量体化されやすく、その後オリゴマー化され、さらに凝集および沈殿することもよくある。第二に、より小さいフラグメントをもたらすscFvの分解は、時間が経つにつれて起こり得る。
PD-L1に対する一価抗体および二価抗体の親和性を、KinExA 3200(Sapidyne Instruments、米国、カタログ番号5001)を用いた結合平衡除外法(Kinetic Exclusion Assay)(KinExA(登録商標))によって測定した。KinExA(登録商標)は、溶液中の未改変分子間の平衡結合親和性および動態を測定する。測定は、溶液中の対応する結合パートナーの濃度を測定するためのプローブとしてのみ作用するように、固相上に1つの相互作用パートナーを固定化することを必要とする。
PD-L1-Fc融合体に対するscFvの親和性を、0.02%アジ化ナトリウムを含むpH7.4のPBS中で、室温で測定した。2つの曲線を測定したが、一方は20pM scFv1を5時間のインキュベーション時間で使用し、もう一方は10pM scFv1で9時間のインキュベーション時間で行った。scFvのKD値は8.8pMであり、KinExA(登録商標)Proソフトウェアバージョン4.1.9または4.2.10.の「n曲線解析」を用いて計算した。
scFvをIgGフォーマットに再フォーマットし、最初ATCCから得、懸濁培養で無血清増殖に適合させた懸濁液適合CHO K1細胞で発現させた。IgG抗体をプロテインAクロマトグラフィー、続いてサイズ排除クロマトグラフィーにより精製した。PD-L1-Hisへの結合についてのKDを、0.02%アジ化ナトリウムを含むpH7.4のPBS中で、室温で2つの曲線を用いて計算した。一方の曲線は100pMのIgGを5時間のインキュベーション時間で使用し、もう一方は10pMのIgGを10時間のインキュベーション時間で使用した。ヒトPD-L1へのIgGの結合について計算されたKD値は2.77pMであった。結果は、IgGが、PD-L1に対するscFvの親和性よりも約3倍強い親和性でPD-L1に結合することを実証する。
他の種からのPD-L1に対するscFvの交差反応性を、ヒト(RnD Systems、米国、カタログ番号156-B7)、ラット(Sino Biological、中国、カタログ番号80450-R02H)、またはサル(Sino Biological、中国、カタログ番号90251-C02H)由来のPD-L1 Fc融合体を用いてELISAにより測定した。結果は、scFvがヒトおよびサルPD-L1に特異的に結合するが、ラットPD-L1には特異的に結合しないことを示した。サルPD-L1に対する抗PD-L1 scFvの交差反応性を、KinExA(登録商標)を用いてさらに調べた。KD値を、0.02%アジ化ナトリウムを含むpH7.4のPBS中で、室温で2つの曲線を用いて計算した。一方の曲線は50pMのscFvを6時間のインキュベーション時間で使用し、もう一方は10pMのscFvを16時間のインキュベーション時間で使用した。scFvについて計算されたKD値は3.3pMであった。結果は、scFvが、ヒトPD-L1に対する結合よりも約2.7倍強い親和性でサルPD-L1に結合することを実証する。
細胞表面上のPD-L1に結合するscFvの能力を、ES-2細胞(ATCC、米国、カタログ番号CRL-1978)の細胞外FACS染色によって測定した。結果は、scFvが、細胞の表面上に発現された天然型のPD-L1を特異的に認識することができることを実証する。
抗PD-L1 scFvをコードするDNAを、5’末端にNcoI制限部位を(フォーワードプライマー)、3’末端に終止コドンTGAおよび制限部位SphIを(リバースプライマー)付加するために、以下のプライマー:フォーワード:5'-TAACCATGG AGTTTGGGCTGAG-3'(配列番号11)およびリバース:5'-GACGCATGCTCAGCTCGACACGGTGACC-3’(配列番号号12)を用いて、PCRによって増幅した。PCR産物およびレトロウイルス骨格SFG(I)eGFPをNcoIおよびSphIで消化し、連結した。挿入物を配列決定して、クローニング中に変異が生じなかったことを確認した。最終ベクターをSFG.scFv.抗PD-L1(I)eGFPと命名した(図1参照)。IRESで発現されるレポーター遺伝子GFPを用いて、導入効率を評価する。293T細胞にレトロウイルスベクターおよびgag-polとRDFエンベロープをそれぞれコードする2つのプラスミドを移入することによって、一過性レトロウイルス上清を調製した。48時間で収集した上清を使用して、健康なドナーから単離された活性化T細胞に導入した。CD28(CAR.CD28もしくはCAR.28)または4-1BB(CAR.41BBもしくはCAR.BB)エンドドメインのいずれかを含むGD2抗原を標的とするCAR(GD2.CAR)をコードするレトロウイルスベクターは、以前に記載されている(Heczey A. et al, Blood.2014 Oct 30; 124(18):2824-33)。前記CARは、配列番号16~21のCDR配列を含む。
健康なヒトドナー由来の末梢血単核細胞(PBMC)を、Lymphoprep(Fresenius)密度勾配遠心分離によって単離した。一次T細胞を、44%Click's培地(Irvine Scientific)、44%RPMI 1640(Hyclone)、10%FBS(Hyclone)、1%Glutamax、および1%ペニシリン/ストレプトアビジンを含有する完全T細胞培地中でIL-7(10ng/mL)およびIL-15(5ng/mL)(PeproTech製)の存在下で培養した。T細胞を、24ウェルプレートで固定化抗CD3(1mcg/mL)(Miltenyi、カタログ番号:130-093-387)および抗CD28(1mcg/mL)(BD Biociences、カタログ番号:555725)を用い、サイトカインを含まないT細胞培地中0.5×106細胞/mLの濃度で活性化した。刺激の24時間後に、IL-7およびIL-15を培地に添加した。2日目までに、T細胞に、レトロウイルス上清SFG.scFv.抗PD-L1(I)eGFPおよび/またはGD2.CAR(レトロネクチンでコーティングした24ウェルプレート中1mL/ウェルのレトロウイルス上清)を導入した。GD2.CARを発現し、抗PD-L1 scFvを放出するT細胞を作製するために、両方のレトロウイルスコンストラクトによる同時導入を行った(1mL/ウェルのGD2.CAR上清プラス1mL/ウェルの抗PD-1 scFv)。非導入(NT)T細胞を、レトロネクチンでコーティングした非組織培養プレートに同じ濃度(0.25×106細胞/mL)で播種した。導入の72時間後、T細胞を洗浄し、計数し、IL-7/IL-15を含む完全T細胞培地に1×106細胞/mLで懸濁した。T細胞をインビトロで5日間増殖させ、次いで導入効率およびT細胞組成を評価するためにフローサイトメトリーによって分析した。開始の11~12日後、T細胞を機能分析で試験した。
T細胞の表現型を、CD3、CD4、CD8、CD60L、CD45RA、CD95、CD27、CD2、PD-L1のmAb(BD BioscienceまたはBiolegend)を用いて評価した。GD2.CAR発現は、抗イディオタイプ1A7 mAbを用いて検出し、続いて二次ラット抗マウスIgG1-PE mAb(BD Bioscience)で染色した。SFG.scFv.抗PD-L1(I)eGFPベクターの導入効率を、GFP発現を測定することによって評価した。GD2.CAR相対蛍光強度(RFI)を、CAR T細胞の平均蛍光強度(MFI)を非導入T細胞のMFIで割って算出した。図2に示すように、CD4およびCD8T細胞に、CD4/CD8比の変化なしに実施例2の抗PD-L1 scFvレトロウイルスコンストラクトを成功裏に導入できた。二重レトロウイルス導入時に、T細胞は、GD2.CARおよびeGFP抗PD-L1を同時発現した(図3)。抗PD-L1 scFvの導入は、T細胞増殖に影響を与えなかった(図4)。さらに、抗PD-L1 scFvの発現は、T細胞サブセット組成に影響を与えなかった(図5)。本実施例は、抗GD2 CARおよび抗PD-L1 scFvを同時発現するCAR T細胞の生成を実証する。
T細胞が抗PD-L1 scFvsを分泌することができるかどうかを試験するために、内因性TCRにより細胞を刺激した。非導入T細胞または抗PD-L1 scFv導入T細胞を、固定化抗CD3(1μg/ml、Miltenyi)および抗CD28(1μg/ml、BD Bioscences)抗CD3/CD28抗CD3/CD28抗体でコーティングされていない、またはコーティングされている組織培養処理24ウェルプレートに、2mL/ウェルの10%FBSを含むT細胞培地で0.5×106細胞/mLの濃度で播種した。18時間後、特異的サンドイッチELISAアッセイを用いてT細胞によって放出された抗PD-L1 scFvを定量するために、1mLの上清を収集した。マウス由来の抗scFvモノクローナル抗体の対応対をこのサンドイッチELISAに使用した。図6Aに示すように、抗PD-L1 scFvは、固定化抗CD3/抗CD28抗体での刺激後に導入T細胞によって放出された。これらのT細胞は、それらの天然の内因性TCR/CD3複合体を発現する。この結果は、内因性TCR/CD3複合体を介した導入T細胞の活性化が、抗PD-L1 scFvの合成および細胞外分泌を誘発するのに十分であることを示唆している。定量的ELISAは、抗PD-L1 scFvが大量に分泌されたことを示した(図6A)。非導入細胞はscFvを分泌しなかった。抗PD-L1 scFvはレトロウイルスベクターの構成的に活性な5’LTRの制御下にあるので、コーティングされていないウェル上に播種した導入T細胞は、基礎レベルの抗PD-L1 scFvを放出したが、T細胞活性化時に有意に増加した。
導入および非導入T細胞(0.5×105細胞/ウェル)を、24ウェルプレートで、外因性サイトカインの非存在下で、1:5のエフェクター:標的(E:T)比で、腫瘍細胞株CHLA-255(2.5×105細胞/ウェル)と共培養した。共培養の7日後、T細胞を採取し、計数した。残留腫瘍細胞のパーセンテージが(フローサイトメトリーによって評価して)<5%であった場合、共培養の第2サイクルのために、同じ1:5のE:T比で新鮮な腫瘍細胞とT細胞を再播種した。さらに7~8日後、細胞を回収し、フローサイトメトリーで分析して、T細胞および残留腫瘍細胞を計数した。具体的には、CD3およびGD2抗体を用いて、T細胞および腫瘍細胞をそれぞれ染色した。フローサイトメトリーによる細胞計数には、CountBrightビーズ(Invitrogen)を使用した。培養の24時間後に上清も採取し、ELISA(R&D System)により製造業者の指示に従ってIFNガンマの放出を測定した。
Claims (9)
- i)抗原レセプター、及び
ii)PD-L1を結合する抗体
を発現する、ナチュラルキラーT(NKT)細胞である改変免疫細胞であって、
前記抗体が、
i)アミノ酸配列が配列番号6、7、及び8にそれぞれに示される可変重鎖(VH)CDR配列CDR-H1、CDR-H2、及びCDR-H3、
ii)アミノ酸配列が配列番号3、4、及び5にそれぞれ示される可変軽鎖(VL)CDR配列CDR-L1、CDR-L2、及びCDR-L3、
を含む、
前記改変免疫細胞。 - 前記抗体が、CD80及びPD-1の両方とのPD-L1相互作用を阻害する、請求項1に記載の改変免疫細胞。
- 前記抗原レセプターがキメラ抗原レセプター(CAR)であり、前記CARが、1つ以上の共刺激ドメインを含み、該共刺激ドメインがCD28,4-1BB(CD137)、ICOS、もしくはOX40(CD134)、又はそれらの機能的フラグメントである、請求項1又は2に記載の改変免疫細胞。
- 前記抗原レセプターがT細胞レセプター(TCR)であり、該TCRが内因性TCR又は改変TCRである、請求項1又は2に記載の改変免疫細胞。
- 前記抗体が、Fcドメインを含まない、Fab、Fab’、scFab、scFv、Fvフラグメント、ダイアボディ、単鎖ダイアボディ(scDb)、BiTE、及びDARTからなる群から選択される抗体フラグメントである、請求項1~4のいずれか1項に記載の改変免疫細胞。
- 前記抗体が、100pM未満のKDでヒトPD-L1に結合する、請求項1~5のいずれか一項に記載の改変免疫細胞。
- 前記抗体が、
i)配列番号2で表されるVH配列、及び
ii)配列番号1で表されるVL配列
を含む、請求項1~6のいずれか一項に記載の改変免疫細胞。 - 前記抗体が、配列番号9で表されるアミノ酸配列を含む、請求項1~7のいずれか一項に記載の改変免疫細胞。
- 前記細胞が、
i)1つ以上のサイトカインをさらに発現し、該サイトカインがIL-2、IL-4、IL-7、IL-12、IL-15、IL-21、若しくはMIP-1アルファであり、
ii)免疫抑制分子を標的とする1つ以上の抗体をさらに発現し、該免疫抑制分子がトランスフォーミング増殖因子-ベータ(TGF-β)、IL-10、Fas、CD47、CTLA-4、Tim-3、LAG-3、若しくはそれらのリガンドであり、又は
iii) 上記i)及びii)の両方である、請求項1~8のいずれか一項に記載の改変免疫細胞。
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