JP7206227B2 - 造血幹細胞の選択的除去と置換のための組成物と方法 - Google Patents
造血幹細胞の選択的除去と置換のための組成物と方法 Download PDFInfo
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Description
本出願は、2017年3月13日に提出された仮出願USSN62/470,814号、及び2017年12月7日に提出されたUSSN62/596,062号の利益を主張し、その内容全体をそれぞれ参照により本明細書に取り込む。
2018年3月2日に作成されたサイズが229KBの「POTH-026_001WO_SeqList.txt」という名前のテキストファイルの内容を、参照によりその全体を本明細書に取り込む。
本開示は、分子生物学、より具体的には、造血幹細胞(HSC)を選択的に標的とするキメラリガンド受容体を発現する細胞、及びその作製と使用方法に関する。
1 XDKKYSIGLA IGTNSVGWAV ITDEYKVPSK KFKVLGNTDR HSIKKNLIGA LLFDSGETAE
61 ATRLKRTARR RYTRRKNRIC YLQEIFSNEM AKVDDSFFHR LEESFLVEED KKHERHPIFG
121 NIVDEVAYHE KYPTIYHLRK KLVDSTDKAD LRLIYLALAH MIKFRGHFLI EGDLNPDNSD
181 VDKLFIQLVQ TYNQLFEENP INASGVDAKA ILSARLSKSR RLENLIAQLP GEKKNGLFGN
241 LIALSLGLTP NFKSNFDLAE DAKLQLSKDT YDDDLDNLLA QIGDQYADLF LAAKNLSDAI
301 LLSDILRVNT EITKAPLSAS MIKRYDEHHQ DLTLLKALVR QQLPEKYKEI FFDQSKNGYA
361 GYIDGGASQE EFYKFIKPIL EKMDGTEELL VKLNREDLLR KQRTFDNGSI PHQIHLGELH
421 AILRRQEDFY PFLKDNREKI EKILTFRIPY YVGPLARGNS RFAWMTRKSE ETITPWNFEE
481 VVDKGASAQS FIERMTNFDK NLPNEKVLPK HSLLYEYFTV YNELTKVKYV TEGMRKPAFL
541 SGEQKKAIVD LLFKTNRKVT VKQLKEDYFK KIECFDSVEI SGVEDRFNAS LGTYHDLLKI
601 IKDKDFLDNE ENEDILEDIV LTLTLFEDRE MIEERLKTYA HLFDDKVMKQ LKRRRYTGWG
661 RLSRKLINGI RDKQSGKTIL DFLKSDGFAN RNFMQLIHDD SLTFKEDIQK AQVSGQGDSL
721 HEHIANLAGS PAIKKGILQT VKVVDELVKV MGRHKPENIV IEMARENQTT QKGQKNSRER
781 MKRIEEGIKE LGSQILKEHP VENTQLQNEK LYLYYLQNGR DMYVDQELDI NRLSDYDVDA
841 IVPQSFLKDD SIDNKVLTRS DKNRGKSDNV PSEEVVKKMK NYWRQLLNAK LITQRKFDNL
901 TKAERGGLSE LDKAGFIKRQ LVETRQITKH VAQILDSRMN TKYDENDKLI REVKVITLKS
961 KLVSDFRKDF QFYKVREINN YHHAHDAYLN AVVGTALIKK YPKLESEFVY GDYKVYDVRK
1021 MIAKSEQEIG KATAKYFFYS NIMNFFKTEI TLANGEIRKR PLIETNGETG EIVWDKGRDF
1081 ATVRKVLSMP QVNIVKKTEV QTGGFSKESI LPKRNSDKLI ARKKDWDPKK YGGFDSPTVA
1141 YSVLVVAKVE KGKSKKLKSV KELLGITIME RSSFEKNPID FLEAKGYKEV KKDLIIKLPK
1201 YSLFELENGR KRMLASAGEL QKGNELALPS KYVNFLYLAS HYEKLKGSPE DNEQKQLFVE
1261 QHKHYLDEII EQISEFSKRV ILADANLDKV LSAYNKHRDK PIREQAENII HLFTLTNLGA
1321 PAAFKYFDTT IDRKRYTSTK EVLDATLIHQ SITGLYETRI DLSQLGGD (配列番号3)。
1 mkrnyilglA igitsvgygi idyetrdvid agvrlfkean vennegrrsk rgarrlkrrr
61 rhriqrvkkl lfdynlltdh selsginpye arvkglsqkl seeefsaall hlakrrgvhn
121 vneveedtgn elstkeqisr nskaleekyv aelqlerlkk dgevrgsinr fktsdyvkea
181 kqllkvqkay hqldqsfidt yidlletrrt yyegpgegsp fgwkdikewy emlmghctyf
241 peelrsvkya ynadlynaln dlnnlvitrd enekleyyek fqiienvfkq kkkptlkqia
301 keilvneedi kgyrvtstgk peftnlkvyh dikditarke iienaelldq iakiltiyqs
361 sediqeeltn lnseltqeei eqisnlkgyt gthnlslkai nlildelwht ndnqiaifnr
421 lklvpkkvdl sqqkeipttl vddfilspvv krsfiqsikv inaiikkygl pndiiielar
481 eknskdaqkm inemqkrnrq tnerieeiir ttgkenakyl iekiklhdmq egkclyslea
541 ipledllnnp fnyevdhiip rsvsfdnsfn nkvlvkqeeA skkgnrtpfq ylsssdskis
601 yetfkkhiln lakgkgrisk tkkeylleer dinrfsvqkd finrnlvdtr yatrglmnll
661 rsyfrvnnld vkvksinggf tsflrrkwkf kkernkgykh haedaliian adfifkewkk
721 ldkakkvmen qmfeekqaes mpeieteqey keifitphqi khikdfkdyk yshrvdkkpn
781 relindtlys trkddkgntl ivnnlnglyd kdndklkkli nkspekllmy hhdpqtyqkl
841 klimeqygde knplykyyee tgnyltkysk kdngpvikki kyygnklnah lditddypns
901 rnkvvklslk pyrfdvyldn gvykfvtvkn ldvikkenyy evnskcyeea kklkkisnqa
961 efiasfynnd likingelyr vigvnndlln rievnmidit yreylenmnd krppriikti
1021 asktqsikky stdilgnlye vkskkhpqii kkg (配列番号4)。
tatkdtydalhmqalppr(配列番号18)のアミノ酸配列を含み、この配列は、c-KITに特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpgpggrarhcslpvssnhvcisrgeghhilqcqlkcklyvlvpaepgsspkpwiyrtsnlasgvparfsgsgsgtsysltissmeaedaatyycqqyhsypptfgagtklelkssggggsggggggssrsslevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvssakttppsvtsgqagqhhhhhhgaypydvpdyastttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号19)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvssggggsggggsggggsdivlsqspaimsaspgekvtiscsasssvsymywyqqkpgsspkpwiyrtsnlasgvparfsgsgsgtsysltissmeaedaatyycqqyhsypptfgagtklelktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号20)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvssssggggsggggggssrssldivlsqspaimsaspgekvtiscsasssvsymywyqqkpgsspkpwiyrtsnlasgvparfsgsgsgtsysltissmeaedaatyycqqyhsypptfgagtklelktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号21)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpdivlsqspaimsaspgekvtiscsasssvsymywyqqkpgsspkpwiyrtsnlasgvparfsgsgsgtsysltissmeaedaatyycqqyhsypptfgagtklelkggggsggggsggggsevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号22)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpdivlsqspaimsaspgekvtiscsasssvsymywyqqkpgsspkpwiyrtsnlasgvparfsgsgsgtsysltissmeaedaatyycqqyhsypptfgagtklelkssggggsggggggssrsslevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号23)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvssggggsggggsggggsdivltqspaimsaspgekvtiscsasssvsymywyqqkpgqpprlliylvsnlesgvparfsgsgsgtdftlnihpveeedaatyycqqyhsypptfgagtkleiktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号24)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvssssggggsggggggssrssldivltqspaimsaspgekvtiscsasssvsymywyqqkpgqpprlliylvsnlesgvparfsgsgsgtdftlnihpveeedaatyycqqyhsypptfgagtkleiktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号25)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpdivltqspaimsaspgekvtiscsasssvsymywyqqkpgqpprlliylvsnlesgvparfsgsgsgtdftlnihpveeedaatyycqqyhsypptfgagtkleikggggsggggsggggsevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号26)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。特定の実施態様において、標的HSCを除去する複数の免疫細胞のうちの少なくとも1種は、CD133に特異的に結合するCARを含み、任意選択的にこのCARは、malpvtalllplalllhaarpdivltqspaimsaspgekvtiscsasssvsymywyqqkpgqpprlliylvsnlesgvparfsgsgsgtdftlnihpveeedaatyycqqyhsypptfgagtkleikssggggsggggggssrsslevklvesgpelkkpgetvkisckasgytftdysmhwvnqapgkglkwmgwintetgepsyaddfkgrfafsletsastaylqinnlknedtatyfcatdygdyfdywgqgttltvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(配列番号27)のアミノ酸配列を含み、この配列は、CD133に特異的に結合するscFvを含む。
複数の治療用HSCのうちの少なくとも1種のHSCが遺伝子改変含む方法を含む本開示の方法の特定の実施態様において、遺伝子改変は、DNA結合ドメインとエンドヌクレアーゼドメインとを含む組成物によって導入される。特定の実施態様において、DNA結合ドメインはガイドRNAを含む。特定の実施態様において、DNA結合ドメインは、Cas9、転写活性化因子様エフェクターヌクレアーゼ(TALEN)、セントロメア及びプロモーター因子1(Cpf1)、又は亜鉛フィンガーヌクレアーゼ(ZFN)から単離又は誘導された配列を含む。
1 XDKKYSIGLA IGTNSVGWAV ITDEYKVPSK KFKVLGNTDR HSIKKNLIGA LLFDSGETAE
61 ATRLKRTARR RYTRRKNRIC YLQEIFSNEM AKVDDSFFHR LEESFLVEED KKHERHPIFG
121 NIVDEVAYHE KYPTIYHLRK KLVDSTDKAD LRLIYLALAH MIKFRGHFLI EGDLNPDNSD
181 VDKLFIQLVQ TYNQLFEENP INASGVDAKA ILSARLSKSR RLENLIAQLP GEKKNGLFGN
241 LIALSLGLTP NFKSNFDLAE DAKLQLSKDT YDDDLDNLLA QIGDQYADLF LAAKNLSDAI
301 LLSDILRVNT EITKAPLSAS MIKRYDEHHQ DLTLLKALVR QQLPEKYKEI FFDQSKNGYA
361 GYIDGGASQE EFYKFIKPIL EKMDGTEELL VKLNREDLLR KQRTFDNGSI PHQIHLGELH
421 AILRRQEDFY PFLKDNREKI EKILTFRIPY YVGPLARGNS RFAWMTRKSE ETITPWNFEE
481 VVDKGASAQS FIERMTNFDK NLPNEKVLPK HSLLYEYFTV YNELTKVKYV TEGMRKPAFL
541 SGEQKKAIVD LLFKTNRKVT VKQLKEDYFK KIECFDSVEI SGVEDRFNAS LGTYHDLLKI
601 IKDKDFLDNE ENEDILEDIV LTLTLFEDRE MIEERLKTYA HLFDDKVMKQ LKRRRYTGWG
661 RLSRKLINGI RDKQSGKTIL DFLKSDGFAN RNFMQLIHDD SLTFKEDIQK AQVSGQGDSL
721 HEHIANLAGS PAIKKGILQT VKVVDELVKV MGRHKPENIV IEMARENQTT QKGQKNSRER
781 MKRIEEGIKE LGSQILKEHP VENTQLQNEK LYLYYLQNGR DMYVDQELDI NRLSDYDVDA
841 IVPQSFLKDD SIDNKVLTRS DKNRGKSDNV PSEEVVKKMK NYWRQLLNAK LITQRKFDNL
901 TKAERGGLSE LDKAGFIKRQ LVETRQITKH VAQILDSRMN TKYDENDKLI REVKVITLKS
961 KLVSDFRKDF QFYKVREINN YHHAHDAYLN AVVGTALIKK YPKLESEFVY GDYKVYDVRK
1021 MIAKSEQEIG KATAKYFFYS NIMNFFKTEI TLANGEIRKR PLIETNGETG EIVWDKGRDF
1081 ATVRKVLSMP QVNIVKKTEV QTGGFSKESI LPKRNSDKLI ARKKDWDPKK YGGFDSPTVA
1141 YSVLVVAKVE KGKSKKLKSV KELLGITIME RSSFEKNPID FLEAKGYKEV KKDLIIKLPK
1201 YSLFELENGR KRMLASAGEL QKGNELALPS KYVNFLYLAS HYEKLKGSPE DNEQKQLFVE
1261 QHKHYLDEII EQISEFSKRV ILADANLDKV LSAYNKHRDK PIREQAENII HLFTLTNLGA
1321 PAAFKYFDTT IDRKRYTSTK EVLDATLIHQ SITGLYETRI DLSQLGGD (配列番号28)。
1 mkrnyilglA igitsvgygi idyetrdvid agvrlfkean vennegrrsk rgarrlkrrr
61 rhriqrvkkl lfdynlltdh selsginpye arvkglsqkl seeefsaall hlakrrgvhn
121 vneveedtgn elstkeqisr nskaleekyv aelqlerlkk dgevrgsinr fktsdyvkea
181 kqllkvqkay hqldqsfidt yidlletrrt yyegpgegsp fgwkdikewy emlmghctyf
241 peelrsvkya ynadlynaln dlnnlvitrd enekleyyek fqiienvfkq kkkptlkqia
301 keilvneedi kgyrvtstgk peftnlkvyh dikditarke iienaelldq iakiltiyqs
361 sediqeeltn lnseltqeei eqisnlkgyt gthnlslkai nlildelwht ndnqiaifnr
421 lklvpkkvdl sqqkeipttl vddfilspvv krsfiqsikv inaiikkygl pndiiielar
481 eknskdaqkm inemqkrnrq tnerieeiir ttgkenakyl iekiklhdmq egkclyslea
541 ipledllnnp fnyevdhiip rsvsfdnsfn nkvlvkqeeA skkgnrtpfq ylsssdskis
601 yetfkkhiln lakgkgrisk tkkeylleer dinrfsvqkd finrnlvdtr yatrglmnll
661 rsyfrvnnld vkvksinggf tsflrrkwkf kkernkgykh haedaliian adfifkewkk
721 ldkakkvmen qmfeekqaes mpeieteqey keifitphqi khikdfkdyk yshrvdkkpn
781 relindtlys trkddkgntl ivnnlnglyd kdndklkkli nkspekllmy hhdpqtyqkl
841 klimeqygde knplykyyee tgnyltkysk kdngpvikki kyygnklnah lditddypns
901 rnkvvklslk pyrfdvyldn gvykfvtvkn ldvikkenyy evnskcyeea kklkkisnqa
961 efiasfynnd likingelyr vigvnndlln rievnmidit yreylenmnd krppriikti
1021 asktqsikky stdilgnlye vkskkhpqii kkg (配列番号29)。
MAPKKKRKVEGIKSNISLLKDELRGQISHISHEYLSLIDLAFDSKQNRLFEMKVLELLVNEYGFKGRHLGGSRKPDGIVYSTTLEDNFGIIVDTKAYSEGYSLPISQADEMERYVRENSNRDEEVNPNKWWENFSEEVKKYYFVFISGSFKGKFEEQLRRLSMTTGVNGSAVNVVNLLLGAEKIRSGEMTIEELERAMFNNSEFILKYGGGGSDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDGSPKKKRKVSS(配列番号30)。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEI SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTGATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RMYIPNKPSK YGIKILMMCD
301 SGYKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPNEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF (配列番号1)と少なくとも75%、80%、85%、90%、95%、99%、又はその間の任意の割合で同一であるアミノ酸配列を含むか、又はそれからなる。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEI SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTGATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RMYIPNKPSK YGIKILMMCD
301 SGYKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPNEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF(配列番号1)の30位、165位、282位、又は538位の1つ以上にアミノ酸置換を有するアミノ酸配列を含む又はこれからなるpiggyBac(商標)(PB)トランスポサーゼ酵素である。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEV SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTSATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RVYIPNKPSK YGIKILMMCD
301 SGTKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPKEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF
(配列番号2)と、少なくとも75%、80%、85%、90%、95%、99%、又はその間の任意の割合で同一であるアミノ酸配列を含むか又はそれからなってもよい。
特定の実施態様において、配列番号1又は配列番号2の450位のアミノ酸置換は、アスパラギン酸(D)のアスパラギン(N)置換である。定の実施態様において、配列番号1又は配列番号2の509位のアミノ酸置換は、セリン(S)のグリシン(G)置換である。特定の実施態様において、配列番号1又は配列番号2の570位のアミノ酸置換は、アスパラギン(N)のセリン(S)置換である。特定の実施態様において、piggyBac(商標)トランスポサーゼ酵素は、配列番号1の194位にメチオニン(M)をバリン(V)置換を含み得る。piggyBac(商標)トランスポサーゼ酵素が、配列番号1の194位にメチオニン(M)のバリン(V)置換を有する特定の実施態様において、piggyBac(商標)トランスポサーゼ酵素は、配列番号1又は配列番号2の配列の372位、375位、及び450位にアミノ酸置換をさらに含み得る。特定の実施態様において、piggyBac(商標)トランスポサーゼ酵素は、配列番号1の194位にメチオニン(M)のバリン(V)置換を、配列番号1の372位にアルギニン(R)のアラニン(A)置換を、配列番号1の375位にリジン(R)のアラニン(A)置換を含み得る、特定の実施態様において、piggyBac(商標)トランスポサーゼ酵素は、配列番号1の194位のメチオニン(M)のバリン(V)置換を、配列番号1の372位にアルギニン(R)のアラニン(A)置換を、配列番号1の375位にリジン(K)のアラニン(A)置換を、及び配列番号1の450位にアスパラギン酸(D)のアスパラギン(N)置換を含み得る。
本開示の組成物及び方法は、キメラリガンド受容体/キメラ抗原受容体(CLR/CAR)を発現する遺伝子改変された免疫細胞を利用して、被験体中の標的細胞を選択的に除去する。さらに、本開示の組成物及び方法は、これらがいったん標的細胞を選択的に除去すると、これらのCLR/CAR発現免疫細胞の選択的除去を可能にする。特に興味深いのは、本開示の組成物及び方法が、選択的に破壊された被験体の本来の細胞に存在する遺伝的欠陥を修正するために、選択的に破壊された細胞集団を置き換えるために、又は被験体の本来の細胞集団を補足して、癌を含む遺伝、免疫、及び血液ベースの障害を治療するために、遺伝子改変された可能性のある治療細胞のその後の移植を可能にすることである。
幹細胞とその微小環境との相互作用は、維持、増殖、及び分化のための重要な手がかりを提供する。幹細胞が存在するこの物理的環境は、幹細胞微小環境又はニッチと呼ばれる場合がある。このニッチに関与する間質細胞及びその他の細胞は、可溶性因子及び結合因子を提供し、これらの因子はHSC制御に多くの効果をもたらす。
「キメラリガンド受容体(CLR)」及び「キメラ抗原受容体(CAR)」という用語は、本開示を通して同義で使用される。本開示のキメラ受容体は、本開示の標的抗原及び/又は標的リガンドに特異的に結合し得る。
本開示のタンパク質足場は、フィブロネクチンIII型(FN3)リピートタンパク質、コード化又は相補的核酸、ベクター、宿主細胞、組成物、組み合わせ、配合物、デバイス、及びこれらを作製及び使用する方法に由来し得る。好適な実施態様において、タンパク質足場は、ヒトのテナシン-C(以下「テナシン」)由来の複数のFN3ドメインのコンセンサス配列から構成される。さらに好適な実施態様において、本発明のタンパク質足場は、15個のFN3ドメインのコンセンサス配列である。本開示のタンパク質足場は、例えば細胞標的タンパク質などの様々な分子に結合するように設計することができる。好適な実施態様において、本開示のタンパク質足場は、リガンドの野生型及び/又は変異型のエピトープに結合するように設計することができる。
本開示の少なくとも1つの足場タンパク質は、当該分野で公知のように、細胞株、混合細胞株、不死化細胞、又は不死化細胞のクローン集団によって任意選択的に産生することができる。例えば、Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, N.Y. (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, N.Y. (1989); Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, N.Y., (1997-2001) を参照されたい。
類似したタンパク質又は断片への特異的結合のためのタンパク質足場のスクリーニングは、ヌクレオチド(DNA又はRNA表示)又はペプチド表示ライブラリー、例えばインビトロ表示を使用して便利に達成することができる。この方法では、目的の機能又は構造を持つ個々のメンバーについて、ペプチドの大規模なコレクションをスクリーニングする。表示されるヌクレオチド又はペプチド配列は、長さが3~5000以上のヌクレオチド又はアミノ酸、しばしば5~100アミノ酸長で、しばしば約8~25アミノ酸長であり得る。ペプチドライブラリーを生成するための直接的な化学合成法に加えて、いくつかの組換えDNA法が記載されている。1つのタイプは、バクテリオファージ又は細胞の表面にペプチド配列を表示することである。各バクテリオファージ又は細胞には、特定の表示されたペプチド配列をコードするヌクレオチド配列が含まれている。そのような方法は、PCT特許公開第91/17271号、第91/18980号、第91/19818号、及び第93/08278号に記載されている。
本開示は、以下を含むキメラリガンド受容体/キメラ抗原受容体(CLR/CAR)を提供する:(a)リガンド認識領域を含む外部ドメイン、ここで、リガンド認識領域は少なくとも1つのセンチリンを含む;(b)膜貫通ドメイン、及び(c)少なくとも1つの同時刺激ドメインを含む内部ドメイン。本開示を通して使用されるように、センチリンを含むCLR/CARはカルチリンと呼ばれる。特定の実施態様において、リガンド認識領域は、2重特異性又はタンデムCLR/CARを生成するために2つのセンチリンを含んでもよい。特定の実施態様において、リガンド認識領域は、3重特異性CLR/CARを生成するために3つのセンチリンを含んでもよい。特定の実施態様において、外部ドメインはシグナルペプチドをさらに含んでもよい。あるいは又はさらに、特定の実施態様において、外部ドメインは、リガンド認識領域と膜貫通ドメインとの間にヒンジをさらに含んでもよい。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEI SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTGATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RMYIPNKPSK YGIKILMMCD
301 SGYKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPNEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF (配列番号1)と少なくとも75%、80%、85%、90%、95%、99%、又はその間の割合で同一であるアミノ酸配列を含むか又はそれからなる。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEI SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTGATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RMYIPNKPSK YGIKILMMCD
301 SGYKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPNEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF (配列番号1)の30位、165位、282位、又は538位の1つ以上にアミノ酸置換を有するアミノ酸配列を含むか又はそれからなるpiggyBac(商標)(PB)トランスポサーゼ酵素である。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEV SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTSATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RVYIPNKPSK YGIKILMMCD
301 SGTKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPKEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF (配列番号2)と、少なくとも75%、80%、85%、90%、95%、99%、又はその間の任意の割合で同一であるアミノ酸配列を含むか又はそれからなり得る。
本開示の誘導性アポトーシス促進性ポリペプチドは、既存の誘導性ポリペプチドよりも免疫原性がはるかに低いため優れている。本開示の誘導性アポトーシス促進性ポリペプチドは組換えポリペプチドであり、従って天然に存在しないが、本開示の誘導性アポトーシス促進性ポリペプチドを産生するように組換えられる配列は、宿主ヒト免疫系が「非自己」として認識できる非ヒト配列を含まず、従って本開示の誘導性アポトーシス促進性ポリペプチド、誘導性アポトーシス促進性ポリペプチドを含む細胞、又は誘導性アポトーシス促進性ポリペプチドを含む組成物、又は誘導性アポトーシス促進性ポリペプチドを含む細胞を受け取る被験体において、免疫応答を誘導する。
本開示のトランスポゾンは、例えば本開示のタンパク質足場、センチリン、又はカルチリンの1つ以上と本開示の選択遺伝子との間に位置する少なくとも1つの自己切断ペプチドを含み得る。本開示のトランスポゾンは、例えば、本開示のタンパク質足場、センチリン、又はカルチリンの1つ以上と本開示の誘導性アポトーシス促進性ポリペプチドとの間に位置する少なくとも1つの自己切断ペプチドを含み得る。本開示のトランスポゾンは、少なくとも2つの自己切断ペプチドを含むことができ、第1の自己切断ペプチドは、例えば本開示の誘導性アポトーシス促進性ポリペプチドの上流又はすぐ上流に位置し、及び第2の自己切断ペプチドは、例えば本開示の誘導性アポトーシス促進性ポリペプチドの下流又はすぐ上流に位置する。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEI SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTGATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RMYIPNKPSK YGIKILMMCD
301 SGYKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPNEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF (配列番号1)と少なくとも75%、80%、85%、90%、95%、99%、又はこれらの間の任意の割合の同一性を有するアミノ酸配列を含むか又はそれからなってよい。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEI SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTGATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RMYIPNKPSK YGIKILMMCD
301 SGYKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPNEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF (配列番号1)の30位、165位、282位、又は538位の1つ以上にアミノ酸置換を有するアミノ酸配列を含むか又はそれからなるpiggyBac(商標)(PB)トランスポサーゼ酵素である。
1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEV SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG
61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG
121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTSATFRD TNEDEIYAFF
181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV
241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RVYIPNKPSK YGIKILMMCD
301 SGTKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ
361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC
421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN
481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPKEV
541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF (配列番号2)と少なくとも75%、80%、85%、90%、95%、99%、又はこれらの間の任意の割合の同一性を有するアミノ酸配列を含むか又はそれからなってもよい。
本開示は、本開示のCARを含むベクターを提供する。特定の実施態様において、ベクターはウイルスベクターである。ベクターは組換えベクターであってもよい。
本開示は、本開示のCARを含む細胞を提供する。本開示は、本開示のトランスポゾンを含む細胞を提供する。特定の実施態様において、本開示のCAR、トランスポゾン、又はベクターを含む細胞は、細胞表面でCARを発現し得る。細胞は、任意のタイプの細胞であり得る。
本開示は、細胞の表面上にキメラリガンド受容体/キメラ抗原受容体(CLR/CAR)を発現させる方法を提供し、この方法は、(a)細胞集団を得ること;(b)細胞集団中の少なくとも1つの細胞の細胞膜を横切ってCARを移動させるのに十分な条件下で、細胞集団に本開示のCAR又はCARをコードする配列を含む組成物を接触させ、それにより改変細胞集団を生成すること;(c)改変細胞集団をトランスポゾンの組み込みに適した条件下で培養すること;(d)細胞表面でCARを発現する改変細胞集団から少なくとも1つの細胞を拡張及び/又は選択することを含む。
本開示の組成物は、被験体からの天然HSCの選択的除去後の移植のための複数の造血幹細胞(HSC)を含み得る。
タンパク質足場をコードする本開示の核酸分子は、例えばmRNA、hnRNA、tRNA、又は任意の他の形態のRNAの形態、又は特に限定されるものではないが、クローニングによって得られるか合成的に生成されるcDNA及びゲノムDNAを含むDNAの形態、又はこれらの任意の組み合わせであり得る。DNAは、3本鎖、2本鎖、若しくは1本鎖、又はこれらの任意の組み合わせであり得る。DNA又はRNAの少なくとも1つの鎖の任意の部分は、センス鎖としても知られるコード鎖であり得るか、又はアンチセンス鎖とも呼ばれる非コード鎖であり得る。
本開示は、選択的ハイブリダイゼーション条件下で、本明細書に開示されるポリヌクレオチドにハイブリダイズする単離された核酸を提供する。すなわちこのポリヌクレオチド実施態様は、そのようなポリヌクレオチドを含む核酸を単離、検出、及び/又は定量化するために使用することができる。例えば、本発明のポリヌクレオチドを使用して、寄託されたライブラリー内の部分的又は完全長クローンを同定、単離、又は増幅することができる。いくつかの実施態様においてポリヌクレオチドは、ヒト又は哺乳動物の核酸ライブラリーからから単離されたゲノム若しくはcDNA配列、又はcDNAに相補的な配列である。
本開示の単離された核酸は、当該分野で公知のように、(a)組換え法、(b)合成技術、(c)精製技術、及び/又は(d)これらの組み合わせを使用して作製され得る。
本開示の単離された核酸組成物、例えばRNA、cDNA、ゲノムDNA、又はこれらの任意の組み合わせは、当業者に公知の任意の数のクローニング方法を使用して生物源から得ることができる。いくつかの実施態様において、ストリンジェントな条件下で本発明のポリヌクレオチドに選択的にハイブリダイズするオリゴヌクレオチドプローブを使用して、cDNA又はゲノムDNAライブラリー内の所望の配列が同定される。RNAの単離、及びcDNA、及びゲノムライブラリーの構築は、当業者に公知である。(例えば、前述のAusubel;又は前述のSambrookを参照)。
本開示のポリヌクレオチドの配列に基づくプローブを使用して、cDNA又はゲノムライブラリーをスクリーニングすることができる。同じ又は異なる生物中の相同遺伝子を分離するために、ゲノムDNA又はcDNA配列とハイブリダイズするプローブを使用することができる。当業者はアッセイにおいて、様々な程度のストリンジェンシーのハイブリダイゼーションを使用でき、ハイブリダイゼーション又は洗浄培地のいずれかが厳密であり得ることを理解するであろう。ハイブリダイゼーション条件がより厳しくなるにつれて、2本鎖形成が起きるためには、プローブと標的との間にはより高度の相補性がなければならない。ストリンジェンシーの程度は、温度、イオン強度、pH、及びホルムアミドなどの部分変性溶媒の存在の1つ以上によって制御できる。例えば、例えば0%から50%の範囲内でホルムアミドの濃度を操作することにより、反応物溶液の極性を変えることにより、ハイブリダイゼーションのストリンジェンシーは便利に変化する。検出可能な結合に必要な相補性(配列同一性)の程度は、ハイブリダイゼーション培地及び/又は洗浄培地のストリンジェンシーに応じて異なる。相補性の程度は、最適には100%、70~100%、又はその中の任意の範囲又は値である。しかし、ハイブリダイゼーション及び/又は洗浄媒体のストリンジェンシーを低下させることにより、プローブ及びプライマーのわずかな配列変化を補償できることを理解されたい。
本開示の単離された核酸は、既知の方法による直接的な化学合成によっても調製され得る(例えば、前述の Ausubel, et al.を参照)。化学合成は一般に1本鎖オリゴヌクレオチドを生成し、これは相補配列とのハイブリダイゼーションによって、又は1本鎖を鋳型として使用するDNAポリメラーゼによる重合を用いて、2本鎖DNAに変換することができる。当業者は、DNAの化学合成は約100以上の塩基の配列に制限され得るが、短い配列の連結によって、より長い配列が得られ得ることを認識するであろう。
本開示はさらに、本開示の核酸を含む組換え発現カセットを提供する。本開示の核酸配列、例えば本開示のタンパク質足場をコードするcDNA又はゲノム配列は、少なくとも1つの所望の宿主細胞に導入できる組換え発現カセットを構築するために使用できる。組換え発現カセットは、典型的には目的の宿主細胞におけるポリヌクレオチドの転写を指示する転写開始調節配列に作動可能に連結された本開示のポリヌクレオチドを含む。異種及び非異種(すなわち内因性)プロモーターの両方を使用して、本開示の核酸の直接の発現を指示することができる。
本開示はまた、当該技術分野で公知のように、本開示の単離された核酸分子を含むベクター、組換えベクターで遺伝子操作された宿主細胞、及び組換え技術による少なくとも1つのタンパク質足場の産生に関する。例えば、前述のSambrook、et al.、前述のAusubel, et al.(それぞれ参照により本明細書に完全に組み込まれる)を参照されたい。
tgtacatagattaaccctagaaagataatcatattgtgacgtacgttaaagataatcatgcgtaaaattgacgcatgtgttttatcggtctgtatatcgaggtttatttattaatttgaatagatattaagttttattatatttacacttacatactaataataaattcaacaaacaatttatttatgtttatttatttattaaaaaaaaacaaaaactcaaaatttcttctataaagtaacaaaacttttatcgaatacctgcagcccgggggatgcagagggacagcccccccccaaagcccccagggatgtaattacgtccctcccccgctagggggcagcagcgagccgcccggggctccgctccggtccggcgctccccccgcatccccgagccggcagcgtgcggggacagcccgggcacggggaaggtggcacgggatcgctttcctctgaacgcttctcgctgctctttgagcctgcagacacctggggggatacggggaaaagttgactgtgcctttcgatcgaaccatggacagttagctttgcaaagatggataaagttttaaacagagaggaatctttgcagctaatggaccttctaggtcttgaaaggagtgggaattggctccggtgcccgtcagtgggcagagcgcacatcgcccacagtccccgagaagttggggggaggggtcggcaattgaaccggtgcctagagaaggtggcgcggggtaaactgggaaagtgatgtcgtgtactggctccgcctttttcccgagggtgggggagaaccgtatataagtgcagtagtcgccgtgaacgttctttttcgcaacgggtttgccgccagaacacaggtaagtgccgtgtgtggttcccgcgggcctggcctctttacgggttatggcccttgcgtgccttgaattacttccacctggctgcagtacgtgattcttgatcccgagcttcgggttggaagtgggtgggagagttcgaggccttgcgcttaaggagccccttcgcctcgtgcttgagttgaggcctggcctgggcgctggggccgccgcgtgcgaatctggtggcaccttcgcgcctgtctcgctgctttcgataagtctctagccatttaaaatttttgatgacctgctgcgacgctttttttctggcaagatagtcttgtaaatgcgggccaagatctgcacactggtatttcggtttttggggccgcgggcggcgacggggcccgtgcgtcccagcgcacatgttcggcgaggcggggcctgcgagcgcggccaccgagaatcggacgggggtagtctcaagctggccggcctgctctggtgcctggcctcgcgccgccgtgtatcgccccgccctgggcggcaaggctggcccggtcggcaccagttgcgtgagcggaaagatggccgcttcccggccctgctgcagggagctcaaaatggaggacgcggcgctcgggagagcgggcgggtgagtcacccacacaaaggaaaagggcctttccgtcctcagccgtcgcttcatgtgactccacggagtaccgggcgccgtccaggcacctcgattagttctcgagcttttggagtacgtcgtctttaggttggggggaggggttttatgcgatggagtttccccacactgagtgggtggagactgaagttaggccagcttggcacttgatgtaattctccttggaatttgccctttttgagtttggatcttggttcattctcaagcctcagacagtggttcaaagtttttttcttccatttcaggtgtcgtgagaattctaatacgactcactatagggtgtgctgtctcatcattttggcaaagattggccaccaagcttgtcctgcaggagggtcgacgcctctagacgggcggccgctccggatccacgggtaccgatcacatatgcctttaattaaacactagttctatagtgtcacctaaattccctttagtgagggttaatggccgtaggccgccagaattgggtccagacatgataagatacattgatgagtttggacaaaccacaactagaatgcagtgaaaaaaatgctttatttgtgaaatttgtgatgctattgctttatttgtaaccattataagctgcaataaacaagttaacaacaacaattgcattcattttatgtttcaggttcagggggaggtgtgggaggttttttcggactctaggacctgcgcatgcgcttggcgtaatcatggtcatagctgtttcctgttttccccgtatccccccaggtgtctgcaggctcaaagagcagcgagaagcgttcagaggaaagcgatcccgtgccaccttccccgtgcccgggctgtccccgcacgctgccggctcggggatgcggggggagcgccggaccggagcggagccccgggcggctcgctgctgccccctagcgggggagggacgtaattacatccctgggggctttgggggggggctgtccctctcaccgcggtggagctccagcttttgttcgaattggggccccccctcgagggtatcgatgatatctataacaagaaaatatatatataataagttatcacgtaagtagaacatgaaataacaatataattatcgtatgagttaaatcttaaaagtcacgtaaaagataatcatgcgtcattttgactcacgcggtcgttatagttcaaaatcagtgacacttaccgcattgacaagcacgcctcacgggagctccaagcggcgactgagatgtcctaaatgcacagcgacggattcgcgctatttagaaagagagagcaatatttcaagaatgcatgcgtcaattttacgcagactatctttctagggttaatctagctagccttaagggcgcctattgcgttgcgctcactgcccgctttccagtcgggaaacctgtcgtgccagctgcattaatgaatcggccaacgcgcggggagaggcggtttgcgtattgggcgctcttccgcttcctcgctcactgactcgctgcgctcggtcgttcggctgcggcgagcggtatcagctcactcaaaggcggtaatacggttatccacagaatcaggggataacgcaggaaagaacatgaccaaaatcccttaacgtgagttttcgttccactgagcgtcagaccccgtagaaaagatcaaaggatcttcttgagatcctttttttctgcgcgtaatctgctgcttgcaaacaaaaaaaccaccgctaccagcggtggtttgtttgccggatcaagagctaccaactctttttccgaaggtaactggcttcagcagagcgcagataccaaatactgttcttctagtgtagccgtagttaggccaccacttcaagaactctgtagcaccgcctacatacctcgctctgctaatcctgttaccagtggctgctgccagtggcgataagtcgtgtcttaccgggttggactcaagacgatagttaccggataaggcgcagcggtcgggctgaacggggggttcgtgcacacagcccagcttggagcgaacgacctacaccgaactgagatacctacagcgtgagctatgagaaagcgccacgcttcccgaagggagaaaggcggacaggtatccggtaagcggcagggtcggaacaggagagcgcacgagggagcttccagggggaaacgcctggtatctttatagtcctgtcgggtttcgccacctctgacttgagcgtcgatttttgtgatgctcgtcaggggggcggagcctatggaaaaacgccagcaacgcggcctttttacggttcctggccttttgctggccttttgctcacatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagtcagaagaactcgtcaagaaggcgatagaaggcgatgcgctgcgaatcgggagcggcgataccgtaaagcacgaggaagcggtcagcccattcgccgccaagctcttcagcaatatcacgggtagccaacgctatgtcctgatagcggtccgccacacccagccggccacagtcgatgaatccagaaaagcggccattttccaccatgatattcggcaagcaggcatcgccatgggtcacgacgagatcctcgccgtcgggcatgctcgccttgagcctggcgaacagttcggctggcgcgagcccctgatgctcttcgtccagatcatcctgatcgacaagaccggcttccatccgagtacgtgctcgctcgatgcgatgtttcgcttggtggtcgaatgggcaggtagccggatcaagcgtatgcagccgccgcattgcatcagccatgatggatactttctcggcaggagcaaggtgagatgacaggagatcctgccccggcacttcgcccaatagcagccagtcccttcccgcttcagtgacaacgtcgagcacagctgcgcaaggaacgcccgtcgtggccagccacgatagccgcgctgcctcgtcttgcagttcattcagggcaccggacaggtcggtcttgacaaaaagaaccgggcgcccctgcgctgacagccggaacacggcggcatcagagcagccgattgtctgttgtgcccagtcatagccgaatagcctctccacccaagcggccggagaacctgcgtgcaatccatcttgttcaatcataatattattgaagcatttatcagggttcgtctcgtcccggtctcctcccaatgcatgtcaatattggccattagccatattattcattggttatatagcataaatcaatattggctattggccattgcatacgttgtatctatatcataata (配列番号62)。
タンパク質足場は、特に限定されるものではないが、プロテインA精製、硫酸アンモニウム沈殿若しくはエタノール沈殿、酸抽出、陰イオン若しくは陽イオン交換クロマトグラフィー、ホスホセルロースクロマトグラフィー、疎水性相互作用クロマトグラフィー、親和性クロマトグラフィー、ヒドロキシルアパタイトクロマトグラフィー、レクチンクロマトグラフィーを含む公知の方法により、組換え細胞培養物から回収及び精製することができる。高速液体クロマトグラフィー(「HPLC」)もまた精製に使用することができる。例えば、Colligan, Current Protocols in Immunology、又は Current Protocols in Protein Science, John Wiley & Sons, NY, N.Y., (1997-2001)、例えば第1、4、6、8、9、10章を参照されたい(これらのそれぞれは参照によりその全体が本明細書に組み込まれる)。
本開示のタンパク質足場を構成するアミノ酸はしばしば略記される。アミノ酸の指定は、当該分野でよく理解されているように、1文字コード、3文字コード、名前、又は3つのヌクレオチドコドンでアミノ酸を指定することにより示すことができる(Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994)。本開示のタンパク質足場は、本明細書で特定されるように、自然突然変異又はヒトによる操作のいずれかからの1つ以上のアミノ酸置換、欠失、又は付加を含むことができる。機能に不可欠な本開示のタンパク質足場中のアミノ酸は、部位特異的突然変異誘発又はアラニン走査突然変異誘発などの当該分野で知られている方法によって特定することができる(例えば、前述のAusubel、第8章、15章;Cunningham and Wells, Science 244:1081-1085 (1989))。後者の操作では、分子内のすべての残基に単一のアラニン変異が導入される。次に、得られた変異体分子は、生物活性、例えば少なくとも1つの中和活性について試験される。タンパク質足場の結合に非常に重要な部位はまた、結晶化、核磁気共鳴、光親和性標識などの構造解析によっても同定することができる(Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992))。
白血球アフェレーシス産物又は血液は、閉鎖システム及び標準的な方法(例えば、COBE Spectra Apheresis System)を使用して、臨床現場の被験者から採取することができる。好ましくは産物は、標準の病院又は施設の白血球アフェレーシス手順に従って、標準の白血球アフェレーシス回収バッグに回収される。例えば、本開示の方法の好適な実施態様において、白血球アフェレーシスに通常使用されるものを超える追加の抗凝固剤又は血液添加物(ヘパリンなど)は含まれない。
T細胞組成物、T細胞産物組成物、非刺激T細胞組成物、休止T細胞組成物、又はこれらの任意の部分は、例えば電気穿孔法などのヌクレオフェクション方策を使用して遺伝子改変することができる。ヌクレオフェクションされる細胞の総数、ヌクレオフェクション反応の総容量、及び試料調製の正確なタイミングを最適化して、高い生存活性を有し、高効率でヌクレオフェクションされ、ヌクレオフェクション後の生存活性の向上を示し、より望ましい細胞表現型を示し、及び/又は拡張技術の追加によるより大きく/迅速な拡張を示す細胞を得ることができる。
本開示の遺伝子改変細胞(遺伝子改変T細胞を含む)は、エキスパンダー技術を使用して拡張させることができる。本開示のエキスパンダー技術は、市販のエキスパンダー技術を含んでもよい。本開示の例示的なエキスパンダー技術は、TCRを介した本開示の遺伝子改変T細胞の刺激を含む。本開示の遺伝子改変T細胞の刺激のためのすべての手段が企図されるが、TCRを介した本開示の遺伝子改変T細胞の刺激は好ましい方法であり、優れたレベルの殺傷能力を有する産物を生じる。
遺伝子改変細胞の割合は、本開示の拡張プロセス中又は後に評価され得る。本開示の遺伝子改変細胞によるトランスポゾンの細胞性発現は、蛍光活性化細胞ソーター解析(FACS)によって測定され得る。例えばFACSは、本開示のCARを発現する細胞又はT細胞の割合を決定するために使用され得る。あるいは又はさらに、遺伝子改変細胞又はT細胞の純度、本開示の遺伝子改変細胞又はT細胞によって発現されるCARの平均蛍光強度(MFI)、CARリガンドを発現する標的細胞の脱顆粒及び/又は殺傷を媒介するCARの能力、及び/又はCAR+T細胞の表現型を評価することができる。
本開示の医薬製剤は、注入、凍結保存、及び/又は保存のためにバッグに分配されてもよい。
本開示は、それを必要とする被験体への投与のための改変免疫細胞及びHSCを提供する。本開示の改変された細胞は、室温及び体温を含む任意の温度での保存のために配合することができる。本開示の改変細胞は、凍結保存及びその後の解凍のために配合することができる。本開示の改変細胞は、無菌包装から、被験体に直接投与するために医薬的に許容し得る担体に配合することができる。本開示の改変細胞は、最小レベルの細胞機能及びCAR/カルチリン発現を確保するために、細胞生存活性及び/又はCAR/カルチリン発現レベルの指標を用いて、医薬的に許容し得る担体に配合することができる。本開示の改変細胞は、さらなる拡張を阻害し、及び/又は細胞死を防ぐために、1つ以上の試薬を用いて、処方された密度で医薬的に許容し得る担体に配合することができる。
piggyBacの発現と機能はiC9安全スイッチを人間のpanT細胞に組み込んだ
ヒトpanT細胞は、4つのpiggyBacトランスポゾンのうちの1つと共にAmaxa 4Dヌクレオフェクターを使用してヌクレオフェクションされた。「モック」条件を受けた改変T細胞は、空のpiggyBacトランスポゾンでヌクレオフェクションされた。改変T細胞は、治療薬(カルチリンをコードする配列)のみを含むpiggyBacトランスポサーゼ、又は組み込みiC9配列と治療薬(カルチリンをコードする配列)とを含むpiggyBacトランスポサーゼのいずれかを受け取った。
c-kit(CD117)及びプロミニン-1(CD133)を標的とするCAR-T細胞による造血細胞の枯渇
ヒトCAR-T細胞が特異的に活性化され、HSCの表面に抗原的に発現されることが知られているマーカーであるヒトc-kit(CD117)又はプロミニン-1(CD133)を有する造血細胞を枯渇させる能力を証明する試験を行った。CAR構築物のパネルからリード候補を選択するために、ヒト末梢血から単離されたCD3/CD28刺激panT細胞を、c-kit又はCD133に対するCAR候補のそれぞれをコードするmRNAを用いてまず電気穿孔した(図5)。CAR表面発現のレベルは、フローサイトメトリーによりトランスフェクトされたT細胞で決定された(図6A)。次に、mRNAでトランスフェクトしたCAR-T細胞を、c-kit又はCD133のいずれかを発現するマウス又はヒト細胞株(EML-C1及びTF-1)、並びにヒト初代BM細胞と同時培養することにより、インビトロ機能アッセイを実施した。リード抗c-kit及び抗CD133 CAR候補は、表面での発現レベルと、CD107a発現による脱顆粒を介するCAR-T細胞の特異的活性化から同定された(図6B及びC)。さらに、CAR-T殺傷能力を評価するためにCAR-T細胞とヒト骨髄を2日間にわたって同時培養した後、CD34、CD117、及びCD133細胞表面抗原のフローサイトメトリー分析を行い、造血コロニー(CFU)の生成のために、ヒト増殖因子(MethoCult(商標)、H4434)を補足したメチルセルロース培養液に細胞を12日間にわたって播種した。6つの抗c-kit CAR-T細胞候補のうち3つを用いて培養後に、CD34+/CD117+細胞の比率の低下が見られたが、7つの抗CD133 CAR-T候補のうち3つについてCD34+/CD133+細胞の低下が観察された(図6D)。CFU機能アッセイは、8つの抗c-kit CAR-T細胞候補のうち7つによる骨髄中の造血前駆細胞の効果的な枯渇を示した(図6E)。従って、これらのデータは、BMにおける内因性HSCの枯渇のための最小毒性移植処方に対する我々の新しいアプローチを支持し、移植された同種異系又は遺伝子修正された幹細胞による置換を可能にする。
、インビトロ機能アッセイを実施した。CFU機能アッセイは、8つの抗c-kit CAR-T細胞候補のうち3つにより、骨髄中のヒト造血前駆細胞の効果的な枯渇を示すが(図9A)、8つの抗c-kit CAR-T細胞候補のうち4つについて、サル骨髄前駆細胞の枯渇が観察される(図9B)ことを示した。
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本開示の特定の実施態様を例示し説明してきたが、本開示の精神及び範囲から逸脱することなく、他のさまざまな変更及び修正を行うことは可能である。添付の特許請求の範囲には、本開示の範囲内にあるすべてのそのような変更及び修正が含まれる。
Claims (18)
- 被験体の少なくとも1種の標的造血幹細胞(HSC)を除去するための組成物であって、前記組成物は、少なくとも1種の標的HSC上のc-KITに特異的に結合する1つ以上のキメラリガンド受容体(CLR)を発現する複数のT細胞を含み、c-KITへの1つ以上のCLRの特異的結合はT細胞を活性化し、そして、活性化されたT細胞は標的HSCの死を誘発し、そして、
少なくとも1つのCLRは、
(a)外部ドメインであって、
i)ヒトCD8αシグナルペプチドを含むシグナルペプチド、
ii)配列番号73のアミノ酸配列を含むscFv、及び
iii)ヒトCD8αヒンジドメインを含むヒンジドメイン、
を含む外部ドメイン、
(b)ヒトCD8α膜貫通ドメインを含む膜貫通ドメイン、
(c)ヒト4-1BB同時刺激ドメインを含む同時刺激ドメイン、及び
(d)ヒトCD3ζ内部ドメインを含む内部ドメイン、
を含む、組成物。 - 前記複数のT細胞を除去する工程をさらに含む、請求項1に記載の使用のための組成物。
- 複数の治療用造血幹細胞(HSC)を含む組成物の有効量を被験体に投与することをさらに含む、請求項2に記載の使用のための組成物。
- 前記T細胞が、誘導性カスパーゼポリペプチド又は誘導性カスパーゼポリペプチドをコードする核酸配列を含む、請求項1~3のいずれか1項に記載の使用のための組成物。
- 前記誘導性カスパーゼポリペプチドが以下を含む、請求項4に記載の使用のための組成物:
(a)リガンド結合領域、
(b)リンカー、及び
(c)切断型カスパーゼ9ポリペプチド。 - 前記複数のT細胞を除去する工程が、誘導剤の有効量を被験体に投与してカスパーゼポリペプチドを誘導し、それによりT細胞の死を開始させることを含む、請求項4に記載の使用のための組成物。
- 前記被験体が、免疫系疾患又は障害、自己免疫疾患又は障害、癌、炎症性障害、貧血、凝固障害、出血状態、血球、血液中を循環する免疫細胞、骨髄細胞、又はその前駆細胞に現れる疾患又は障害の遺伝的又はエピジェネティックマーカーを有するか、又は発症するリスクがあるか、あるいは、前記被験体が、免疫無防備状態である、請求項1~3のいずれか1項に記載の使用のための組成物。
- 前記癌が、リンパ腫、白血病、骨髄腫、又は悪性免疫増殖性疾患である、請求項7に記載の使用のための組成物。
- 前記シグナルペプチドが、配列番号31のアミノ酸配列を含む、請求項1に記載の使用のための組成物。
- 前記ヒンジドメインが、配列番号40のアミノ酸配列を含む、請求項1に記載の使用のための組成物。
- 前記膜貫通ドメインが、配列番号33のアミノ酸配列を含む、請求項1に記載の使用のための組成物。
- 前記内部ドメインが、配列番号36のアミノ酸配列を含む、請求項1に記載の使用のための組成物。
- 前記同時刺激ドメインが、配列番号38のアミノ酸配列を含む、請求項1に記載の使用のための組成物。
- 前記1つ以上のCLRが、
(a)外部ドメインであって、
i)配列番号31のアミノ酸配列を含むシグナルペプチド、
ii)配列番号73のアミノ酸配列を含むscFv、
iii)配列番号40のアミノ酸配列を含むヒンジドメイン、
を含む外部ドメイン、
(b)配列番号33のアミノ酸配列を含む膜貫通ドメイン、
(c)配列番号38のアミノ酸配列を含む同時刺激ドメイン、
(d)配列番号36のアミノ酸配列を含む内部ドメイン、
を含む、請求項1~3のいずれか1項に記載の使用のための組成物。 - 前記1つ以上のCLRが、配列番号15のアミノ酸配列を含む、請求項14に記載の使用のための組成物。
- 前記T細胞が、前記CLRをコードする核酸配列を含むトランスポゾンを用いて前記1つ以上のCLRを発現するように遺伝的に改変されている、請求項1~3のいずれか1項に記載の使用のための組成物。
- 前記トランスポゾンが、前記1つ以上のCLRをコードする核酸配列、誘導性カスパーゼポリペプチドをコードする核酸配列、及び選択遺伝子を含むpiggyBac(登録商標)(PB)トランスポゾンである、請求項16に記載の使用のための組成物。
- 前記複数のT細胞の少なくとも5%、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも35%、少なくとも40%、少なくとも45%、少なくとも50%、少なくとも55%、少なくとも60%、少なくとも65%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%、又は100%が、前記1つ以上のCLRを発現する、請求項1~3のいずれか1項に記載の使用のための組成物。
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AU2018235756A1 (en) | 2019-10-10 |
US11744861B2 (en) | 2023-09-05 |
IL269203A (en) | 2019-11-28 |
WO2018169948A1 (en) | 2018-09-20 |
CN117959418A (zh) | 2024-05-03 |
US20240226153A9 (en) | 2024-07-11 |
IL269203B1 (en) | 2024-05-01 |
JP2020510101A (ja) | 2020-04-02 |
US20200078402A1 (en) | 2020-03-12 |
CN110650743B (zh) | 2023-12-29 |
EP3595682A1 (en) | 2020-01-22 |
AU2018235756B2 (en) | 2024-08-08 |
KR20190124304A (ko) | 2019-11-04 |
IL311608A (en) | 2024-05-01 |
SG10202109731YA (en) | 2021-10-28 |
US20240131067A1 (en) | 2024-04-25 |
CA3056227A1 (en) | 2018-09-20 |
SG11201908418RA (en) | 2019-10-30 |
JP2023026580A (ja) | 2023-02-24 |
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