JP2022512958A - トランス共刺激分子と組み合わされた抗gpc3キメラ抗原受容体(car)及びその治療的用途 - Google Patents
トランス共刺激分子と組み合わされた抗gpc3キメラ抗原受容体(car)及びその治療的用途 Download PDFInfo
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Abstract
Description
本出願は、2018年11月7日に出願された米国仮出願第62/756,683号の出願日の利益を主張するものである。参照により、先の出願の内容全体を本明細書に援用する。
本明細書中で使用する場合、共刺激ポリペプチドは、共刺激経路を調節(例えば刺激)する能力を有するポリペプチドを指す。そのようなポリペプチドは、共刺激経路を任意の機序によって調節(例えば増進)し得る。いくつかの例では、共刺激ポリペプチドは、共刺激受容体またはその共刺激シグナル伝達ドメインを含み得る。他の例では、共刺激ポリペプチドは、妥当な場合には共刺激受容体またはそのシグナル伝達ドメインのリガンドを含み得る。そのようなリガンドは、同属の共刺激受容体に結合すると共刺激シグナル伝達経路を誘発し得る。あるいは、共刺激ポリペプチドは、本明細書に開示される共刺激受容体のいずれかに対する天然に存在するリガンドの活性を模倣した天然に存在しないポリペプチドであり得る。そのような天然に存在しないポリペプチドは、共刺激受容体に対して特異的な一本鎖作動性抗体、例えば、4-1BBに対して特異的であり4-1BBLの活性を模倣したscFvであり得る。
CD28(配列番号12)
MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
CD80(配列番号13)
MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLSCGHNVSVEELAQTRIYWQKEKKMVLTMMSGDMNIWPEYKNRTIFDITNNLSIVILALRPSDEGTYECVVLKYEKDAFKREHLAEVTLSVKADFPTPSISDFEIPTSNIRRIICSTSGGFPEPHLSWLENGEELNAINTTVSQDPETELYAVSSKLDFNMTTNHSFMCLIKYGHLRVNQTFNWNTTKQEHFPDNLLPSWAITLISVNGIFVICCLTYCFAPRCRERRRNERLRRESVRPV
CD86(配列番号14)
MDPQCTMGLSNILFVMAFLLSGAAPLKIQAYFNETADLPCQFANSQNQSLSELVVFWQDQENLVLNEVYLGKEKFDSVHSKYMGRTSFDSDSWTLRLHNLQIKDKGLYQCIIHHKKPTGMIRIHQMNSELSVLANFSQPEIVPISNITENVYINLTCSSIHGYPEPKKMSVLLRTKNSTIEYDGVMQKSQDNVTELYDVSISLSVSFPDVTSNMTIFCILETDKTRLLSSPFSIELEDPQPPPDHIPWITAVLPTVIICVMVFCLILWKWKKKKRPRNSYKCGTNTMEREESEQTKKREKIHIPERSDEAQRVFKSSKTSSCDKSDTCF
ICOS(配列番号15)
MKSGLWYFFLFCLRIKVLTGEINGSANYEMFIFHNGGVQILCKYPDIVQQFKMQLLKGGQILCDLTKTKGSGNTVSIKSLKFCHSQLSNNSVSFFLYNLDHSHANYYFCNLSIFDPPPFKVTLTGGYLHIYESQLCCQLKFWLPIGCAAFVVVCILGCILICWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL
ICOSL(配列番号16)
MRLGSPGLLFLLFSSLRADTQEKEVRAMVGSDVELSCACPEGSRFDLNDVYVYWQTSESKTVVTYHIPQNSSLENVDSRYRNRALMSPAGMLRGDFSLRLFNVTPQDEQKFHCLVLSQSLGFQEVLSVEVTLHVAANFSVPVVSAPHSPSQDELTFTCTSINGYPRPNVYWINKTDNSLLDQALQNDTVFLNMRGLYDVVSVLRIARTPSVNIGCCIENVLLQQNLTVGSQTGNDIGERDKITENPVSTGEKNAATWSILAVLCLLVVVAVAIGWVCRDRCLQHSYAGAWAVSPETELTGHV
B7-H3(配列番号17)
MLRRRGSPGMGVHVGAALGALWFCLTGALEVQVPEDPVVALVGTDATLCCSFSPEPGFSLAQLNLIWQLTDTKQLVHSFAEGQDQGSAYANRTALFPDLLAQGNASLRLQRVRVADEGSFTCFVSIRDFGSAAVSLQVAAPYSKPSMTLEPNKDLRPGDTVTITCSSYQGYPEAEVFWQDGQGVPLTGNVTTSQMANEQGLFDVHSILRVVLGANGTYSCLVRNPVLQQDAHSSVTITPQRSPTGAVEVQVPEDPVVALVGTDATLRCSFSPEPGFSLAQLNLIWQLTDTKQLVHSFTEGRDQGSAYANRTALFPDLLAQGNASLRLQRVRVADEGSFTCFVSIRDFGSAAVSLQVAAPYSKPSMTLEPNKDLRPGDTVTITCSSYRGYPEAEVFWQDGQGVPLTGNVTTSQMANEQGLFDVHSVLRVVLGANGTYSCLVRNPVLQQDAHGSVTITGQPMTFPPEALWVTVGLSVCLIALLVALAFVCWRKIKQSCEEENAGAEDQDGEGEGSKTALQPLKHSDSKEDDGQEIA
VISTA(配列番号18)
MGVPTALEAGSWRWGSLLFALFLAASLGPVAAFKVATPYSLYVCPEGQNVTLTCRLLGPVDKGHDVTFYKTWYRSSRGEVQTCSERRPIRNLTFQDLHLHHGGHQAANTSHDLAQRHGLESASDHHGNFSITMRNLTLLDSGLYCCLVVEIRHHHSEHRVHGAMELQVQTGKDAPSNCVVYPSSSQDSENITAAALATGACIVGILCLPLILLLVYKQRQAASNRRAQELVRMDSNIQGIENPGFEASPPAQGIPEAKVRHPLSYVAQRQPSESGRHLLSEPSTPLSPPGPGDVFFPSLDPVPDSPNFEVI
TMIGD2(配列番号19)
MGSPGMVLGLLVQIWALQEASSLSVQQGPNLLQVRQGSQATLVCQVDQATAWERLRVKWTKDGAILCQPYITNGSLSLGVCGPQGRLSWQAPSHLTLQLDPVSLNHSGAYVCWAAVEIPELEEAEGNITRLFVDPDDPTQNRNRIASFPGFLFVLLGVGSMGVAAIVWGAWFWGRRSCQQRDSGNSPGNAFYSNVLYRPRGAPKKSEDCSGEGKDQRGQSIYSTSFPQPAPRQPHLASRPCPSPRPCPSPRPGHPVSMVRVSPRPSPTQQPRPKGFPKVGEE
B7-H6(配列番号20)
MTWRAAASTCAALLILLWALTTEGDLKVEMMAGGTQITPLNDNVTIFCNIFYSQPLNITSMGITWFWKSLTFDKEVKVFEFFGDHQEAFRPGAIVSPWRLKSGDASLRLPGIQLEEAGEYRCEVVVTPLKAQGTVQLEVVASPASRLLLDQVGMKENEDKYMCESSGFYPEAINITWEKQTQKFPHPIEISEDVITGPTIKNMDGTFNVTSCLKLNSSQEDPGTVYQCVVRHASLHTPLRSNFTLTAARHSLSETEKTDNFSIHWWPISFIGVGLVLLIVLIPWKKICNKSSSAYTPLKCILKHWNSFDTQTLKKEHLIFFCTRAWPSYQLQDGEAWPPEGSVNINTIQQLDVFCRQEGKWSEVPYVQAFFALRDNPDLCQCCRIDPALLTVTSGKSIDDNSTKSEKQTPREHSDAVPDAPILPVSPIWEPPPATTSTTPVLSSQPPTLLLPLQ
B7-H7(配列番号21)
MKAQTALSFFLILITSLSGSQGIFPLAFFIYVPMNEQIVIGRLDEDIILPSSFERGSEVVIHWKYQDSYKVHSYYKGSDHLESQDPRYANRTSLFYNEIQNGNASLFFRRVSLLDEGIYTCYVGTAIQVITNKVVLKVGVFLTPVMKYEKRNTNSFLICSVLSVYPRPIITWKMDNTPISENNMEETGSLDSFSINSPLNITGSNSSYECTIENSLLKQTWTGRWTMKDGLHKMQSEHVSLSCQPVNDYFSPNQDFKVTWSRMKSGTFSVLAYYLSSSQNTIINESRFSWNKELINQSDFSMNLMDLNLSDSGEYLCNISSDEYTLLTIHTVHVEPSQETASHNKGLWILVPSAILAAFLLIWSVKCCRAQLEARRSRHPADGAQQERCCVPPGERCPSAPDNGEENVPLSGKV
4-1BB(配列番号22)
MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
4-1BBL(配列番号23)
MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE
4-1BBL-CD(細胞質側ドメインが欠損したもの、配列番号24)
MRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE
4-1BBL Q89A(配列番号25)
MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRAGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE
4-1BBL Q89A/CD(細胞質側ドメインが欠損したもの)(配列番号26)
MRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRAGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE
4-1BBL L115A(配列番号27)
MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGAAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE
4-1BBL L115A/CD(配列番号28)
MRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGAAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE
4-1BBL K127A(配列番号29)
MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYAEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE
4-1BBL Q227A(配列番号30)
MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWALTQGATVLGLFRVTPEIPAGLPSPRSE
BAFF(配列番号31)
MDDSTEREQSRLTSCLKKREEMKLKECVSILPRKESPSVRSSKDGKLLAATLLLALLSCCLTVVSFYQVAALQGDLASLRAELQGHHAEKLPAGAGAPKAGLEEAPAVTAGLKIFEPPAPGEGNSSQNSRNKRAVQGPEETVTQDCLQLIADSETPTIQKGSYTFVPWLLSFKRGSALEEKENKILVKETGYFFIYGQVLYTDKTYAMGHLIQRKKVHVFGDELSLVTLFRCIQNMPETLPNNSCYSAGIAKLEEGDELQLAIPRENAQISLDGDVTFFGALKLL
BAFFR(配列番号32)
MRRGPRSLRGRDAPAPTPCVPAECFDLLVRHCVACGLLRTPRPKPAGASSPAPRTALQPQESVGAGAGEAALPLPGLLFGAPALLGLALVLALVLVGLVSWRRRQRRLRGASSAEAPDGDKDAPEPLDKVIILSPGISDATAPAWPPPGEDPGTTPPGHSVPVPATELGSTELVTTKTAGPEQQ
CD27(配列番号33)
MARPHPWWLCVLGTLVGLSATPAPKSCPERHYWAQGKLCCQMCEPGTFLVKDCDQHRKAAQCDPCIPGVSFSPDHHTRPHCESCRHCNSGLLVRNCTITANAECACRNGWQCRDKECTECDPLPNPSLTARSSQALSPHPQPTHLPYVSEMLEARTAGHMQTLADFRQLPARTLSTHWPPQRSLCSSDFIRILVIFSGMFLVFTLAGALFLHQRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKPEPACSP
CD70(配列番号34)
MPEEGSGCSVRRRPYGCVLRAALVPLVAGLVICLVVCIQRFAQAQQQLPLESLGWDVAELQLNHTGPQQDPRLYWQGGPALGRSFLHGPELDKGQLRIHRDGIYMVHIQVTLAICSSTTASRHHPTTLAVGICSPASRSISLLRLSFHQGCTIVSQRLTPLARGDTLCTNLTGTLLPSRNTDETFFGVQWVRP
CD30(配列番号35)
MRVLLAALGLLFLGALRAFPQDRPFEDTCHGNPSHYYDKAVRRCCYRCPMGLFPTQQCPQRPTDCRKQCEPDYYLDEADRCTACVTCSRDDLVEKTPCAWNSSRVCECRPGMFCSTSAVNSCARCFFHSVCPAGMIVKFPGTAQKNTVCEPASPGVSPACASPENCKEPSSGTIPQAKPTPVSPATSSASTMPVRGGTRLAQEAASKLTRAPDSPSSVGRPSSDPGLSPTQPCPEGSGDCRKQCEPDYYLDEAGRCTACVSCSRDDLVEKTPCAWNSSRTCECRPGMICATSATNSCARCVPYPICAAETVTKPQDMAEKDTTFEAPPLGTQPDCNPTPENGEAPASTSPTQSLLVDSQASKTLPIPTSAPVALSSTGKPVLDAGPVLFWVILVLVVVVGSSAFLLCHRRACRKRIRQKLHLCYPVQTSQPKLELVDSRPRRSSTQLRSGASVTEPVAEERGLMSQPLMETCHSVGAAYLESLPLQDASPAGGPSSPRDLPEPRVSTEHTNNKIEKIYIMKADTVIVGTVKAELPEGRGLAGPAEPELEEELEADHTPHYPEQETEPPLGSCSDVMLSVEEEGKEDPLPTAASGK
CD30L(配列番号36)
MDPGLQQALNGMAPPGDTAMHVPAGSVASHLGTTSRSYFYLTTATLALCLVFTVATIMVLVVQRTDSIPNSPDNVPLKGGNCSEDLLCILKRAPFKKSWAYLQVAKHLNKTKLSWNKDGILHGVRYQDGNLVIQFPGLYFIICQLQFLVQCPNNSVDLKLELLINKHIKKQALVTVCESGMQTKHVYQNLSQFLLDYLQVNTTISVNVDTFQYIDTSTFPLENVLSIFLYSNSD
CD40(配列番号37)
MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
CD40L(配列番号38)
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
DR3(配列番号39)
MEQRPRGCAAVAAALLLVLLGARAQGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENHHNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQMFWVQVLLAGLVVPLLLGATLTYTYRHCWPHKPLVTADEAGMEALTPPPATHLSPLDSAHTLLAPPDSSEKICTVQLVGNSWTPGYPETQEALCPQVTWSWDQLPSRALGPAAAPTLSPESPAGSPAMMLQPGPQLYDVMDAVPARRWKEFVRTLGLREAEIEAVEVEIGRFRDQQYEMLKRWRQQQPAGLGAVYAALERMGLDGCVEDLRSRLQRGP
GITR(配列番号40)
MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEPLGWLTVVLLAVAACVLLLTSAQLGLHIWQLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGERSAEEKGRLGDLW
GITRL(配列番号41)
MTLHPSPITCEFLFSTALISPKMCLSHLENMPLSHSRTQGAQRSSWKLWLFCSIVMLLFLCSFSWLIFIFLQLETAKEPCMAKFGPLPSKWQMASSEPPCVNKVSDWKLEILQNGLYLIYGQVAPNANYNDVAPFEVRLYKNKDMIQTLTNKSKIQNVGGTYELHVGDTIDLIFNSEHQVLKNNTYWGIILLANPQFIS
HVEM(配列番号42)
MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGCSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFSPNGTLEECQHQTKCSWLVTKAGAGTSSSHWVWWFLSGSLVIVIVCSTVGLIICVKRRKPRGDVVKVIVSVQRKRQEAEGEATVIEALQAPPDVTTVAVEETIPSFTGRSPNH
LIGHT(配列番号43)
MEESVVRPSVFVVDGQTDIPFTRLGRSHRRQSCSVARVGLGLLLLLMGAGLAVQGWFLLQLHWRLGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLTGSGGPLLWETQLGLAFLRGLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLASTITHGLYKRTPRYPEELELLVSQQSPCGRATSSSRVWWDSSFLGGVVHLEAGEEVVVRVLDERLVRLRDGTRSYFGAFMV
TNFアルファ(配列番号44)
MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQREEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
TNFベータ(配列番号45)
MTPPERLFLPRVCGTTLHLLLLGLLLVLLPGAQGLPGVGLTPSAAQTARQHPKMHLAHSTLKPAAHLIGDPSKQNSLLWRANTDRAFLQDGFSLSNNSLLVPTSGIYFVYSQVVFSGKAYSPKATSSPLYLAHEVQLFSSQYPFHVPLLSSQKMVYPGLQEPWLHSMYHGAAFQLTQGDQLSTHTDGIPHLVLSPSTVFFGAFAL
OX40(配列番号46)
MCVGARRLGRGPCAALLLLGLGLSTVTGLHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGTQPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRDPPATQPQETQGPPARPITVQPTEAWPRTSQGPSTRPVEVPGGRAVAAILGLGLVLGLLGPLAILLALYLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI
OX40L(配列番号47)
MERVQPLEENVGNAARPRFERNKLLLVASVIQGLGLLLCFTYICLHFSALQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL
RELT(配列番号48)
MKPSLLCRPLSCFLMLLPWPLATLTSTTLWQCPPGEEPDLDPGQGTLCRPCPPGTFSAAWGSSPCQPHARCSLWRRLEAQVGMATRDTLCGDCWPGWFGPWGVPRVPCQPCSWAPLGTHGCDEWGRRARRGVEVAAGASSGGETRQPGNGTRAGGPEETAAQYAVIAIVPVFCLMGLLGILVCNLLKRKGYHCTAHKEVGPGPGGGGSGINPAYRTEDANEDTIGVLVRLITEKKENAAALEELLKEYHSKQLVQTSHRPVSKLPPAPPNVPHICPHRHHLHTVQGLASLSGPCCSRCSQKKWPEVLLSPEAVAATTPVPSLLPNPTRVPKAGAKAGRQGEITILSVGRFRVARIPEQRTSSMVSEVKTITEAGPSWGDLPDSPQPGLPPEQQALLGSGGSRTKWLKPPAENKAEENRYVVRLSESNLVI
TACI(配列番号49)
MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRRQRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYSTLGLCLCAVLCCFLVAVACFLKKRGDPCSCQPRSRPRQSPAKSSQDHAMEAGSPVSTSPEPVETCSFCFPECRAPTQESAVTPGTPDPTCAGRWGCHTRTTVLQPCPHIPDSGLGIVCVPAQEGGPGA
TL1A(配列番号50)
MAEDLGLSFGETASVEMLPEHGSCRPKARSSSARWALTCCLVLLPFLAGLTTYLLVSQLRAQGEACVQFQALKGQEFAPSHQQVYAPLRADGDKPRAHLTVVRQTPTQHFKNQFPALHWEHELGLAFTKNRMNYTNKFLLIPESGDYFIYSQVTFRGMTSECSEIRQAGRPNKPDSITVVITKVTDSYPEPTQLLMGTKSVCEVGSNWFQPIYLGAMFSLQEGDKLMVNVSDISLVDYTKEDKTFFGAFLL
TNFRII(配列番号51)
MAPVAVWAALAVGLELWAAAHALPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDFALPVGLIVGVTALGLLIIGVVNCVIMTQVKKKPLCLQREAKVPHLPADKARGTQGPEQQHLLITAPSSSSSSLESSASALDRRAPTRNQPQAPGVEASGAGEARASTGSSDSSPGGHGTQVNVTCIVNVCSSSDHSSQCSSQASSTMGDTDSSPSESPKDEQVPFSKEECAFRSQLETPETLLGSTEEKPLPLGVPDAGMKPS
BCMA(配列番号52)
MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR
EDA2R(配列番号53)
MDCQENEYWDQWGRCVTCQRCGPGQELSKDCGYGEGGDAYCTACPPRRYKSSWGHHRCQSCITCAVINRVQKVNCTATSNAVCGDCLPRFYRKTRIGGLQDQECIPCTKQTPTSEVQCAFQLSLVEADTPTVPPQEATLVALVSSLLVVFTLAFLGLFFLYCKQFFNRHCQRGGLLQFEADKTAKEESLFPVPPSKETSAESQVSENIFQTQPLNPILEDDCSSTSGFPTQESFTMASCTSESHSHWVHSPIECTELDLQKFSSSASYTGAETLGGNTVESTGDRLELNVPFEVPSP
TROY(配列番号54)
MALKVLLEQEKTFFTLLVLLGYLSCKVTCESGDCRQQEFRDRSGNCVPCNQCGPGMELSKECGFGYGEDAQCVTCRLHRFKEDWGFQKCKPCLDCAVVNRFQKANCSATSDAICGDCLPGFYRKTKLVGFQDMECVPCGDPPPPYEPHCASKVNLVKIASTASSPRDTALAAVICSALATVLLALLILCVIYCKRQFMEKKPSWSLRSQDIQYNGSELSCFDRPQLHEYAHRACCQCRRDSVQTCGPVRLLPSMCCEEACSPNPATLGCGVHSAASLQARNAGPAGEMVPTFFGSLTQSICGEFSDAWPLMQNPMGGDNISFCDSYPELTGEDIHSLNPELESSTSLDSNSSQDLVGGAVPVQSHSENFTAATDLSRYNNTLVESASTQDALTMRSQLDQESGAVIHPATQTSLQVRQRLGSL
LTBR(配列番号55)
MLLPWATSAPGLAWGPLVLGLFGLLAASQPQAVPPYASENQTCRDQEKEYYEPQHRICCSRCPPGTYVSAKCSRIRDTVCATCAENSYNEHWNYLTICQLCRPCDPVMGLEEIAPCTSKRKTQCRCQPGMFCAAWALECTHCELLSDCPPGTEAELKDEVGKGNNHCVPCKAGHFQNTSSPSARCQPHTRCENQGLVEAAPGTAQSDTTCKNPLEPLPPEMSGTMLMLAVLLPLAFFLLLATVFSCIWKSHPSLCRKLGSLLKRRPQGEGPNPVAGSWEPPKAHPYFPDLVQPLLPISGDVSPVSTGLPAAPVLEAGVPQQQSPLDLTREPQLEPGEQSQVAHGTNGIHVTGGSMTITGNIYIYNGPVLGGPPGPGDLPATPEPPYPIPEEGDPGPPGLSTPHQEDGKAWHLAETEHCGATPSNRGPRNQFITHD
EDAR(配列番号56)
MAHVGDCTQTPWLPVLVVSLMCSARAEYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKDCEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKECVGATSGASANFPGTSGSSTLSPFQHAHKELSGQGHLATALIIAMSTIFIMAIAIVLIIMFYILKTKPSAPACCTSHPGKSVEAQVSKDEEKKEAPDNVVMFSEKDEFEKLTATPAKPTKSENDASSENEQLLSRSVDSDEEPAPDKQGSPELCLLSLVHLAREKSATSNKSAGIQSRRKKILDVYANVCGVVEGLSPTELPFDCLEKTSRMLSSTYNSEKAVVKTWRHLAESFGLKRDEIGGMTDGMQLFDRISTAGYSIPELLTKLVQIERLDAVESLCADILEWAGVVPPASQPHAAS
NGFR(配列番号57)
MGAGATGRAMDGPRLLLLLLLGVSLGGAKEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNLIPVYCSILAAVVVGLVAYIAFKRWNSCKQNKQGANSRPVNQTPPPEGEKLHSDSGISVDSQSLHDQQPHTQTASGQALKGDGGLYSSLPPAKREEVEKLLNGSAGDTWRHLAGELGYQPEHIDSFTHEACPVRALLASWATQDSATLDALLAALRRIQRADLVESLCSESTATSPV
OPG(配列番号58)
MNNLLCCALVFLDISIKWTTQETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTVCKRCPDGFFSNETSSKAPCRKHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTLCEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQNKDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKPSDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLYQKLFLEMIGNQVQSVKISCL
RANK(配列番号59)
MAPRARRRRPLFALLLLCALLARLQVALQIAPPCTSEKHYEHLGRCCNKCEPGKYMSSKCTTTSDSVCLPCGPDEYLDSWNEEDKCLLHKVCDTGKALVAVVAGNSTTPRRCACTAGYHWSQDCECCRRNTECAPGLGAQHPLQLNKDTVCKPCLAGYFSDAFSSTDKCRPWTNCTFLGKRVEHHGTEKSDAVCSSSLPARKPPNEPHVYLPGLIILLLFASVALVAAIIFGVCYRKKGKALTANLWHWINEACGRLSGDKESSGDSCVSTHTANFGQQGACEGVLLLTLEEKTFPEDMCYPDQGGVCQGTCVGGGPYAQGEDARMLSLVSKTEIEEDSFRQMPTEDEYMDRPSQPTDQLLFLTEPGSKSTPPFSEPLEVGENDSLSQCFTGTQSTVGSESCNCTEPLCRTDWTPMSSENYLQKEVDSGHCPHWAASPSPNWADVCTGCRNPPGEDCEPLVGSPKRGPLPQCAYGMGLPPEEEASRTEARDQPEDGADGRLPSSARAGAGSGSSPGGQSPASGNVTGNSNSTFISSGQVMNFKGDIIVVYVSQTSQEGAAAAAEPMGRPVQEETLARRDSFAGNGPRFPDPCGGPEGLREPEKASRPVQEQGGAKA
DCR3(配列番号60)
MRALEGPGLSLLCLVLALPALLPVPAVRGVAETPTYPWRDAETGERLVCAQCPPGTFVQRPCRRDSPTTCGPCPPRHYTQFWNYLERCRYCNVLCGEREEEARACHATHNRACRCRTGFFAHAGFCLEHASCPPGAGVIAPGTPSQNTQCQPCPPGTFSASSSSSEQCQPHRNCTALGLALNVPGSSSHDTLCTSCTGFPLSTRVPGAEECERAVIDFVAFQDISIKRLQRLLQALEAPEGWGPTPRAGRAALQLKLRRRLTELLGAQDGALLVRLLQALRVARMPGLERSVRERFLPVH
TNFR1(配列番号61)
MGLSTVPDLLLPLVLLELLVGIYPSGVIGLVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVIFFGLCLLSLLFIGLMYRYQRWKSKLYSIVCGKSTPEKEGELEGTTTKPLAPNPSFSPTPGFTPTLGFSPVPSSTFTSSSTYTPGDCPNFAAPRREVAPPYQGADPILATALASDPIPNPLQKWEDSAHKPQSLDTDDPATLYAVVENVPPLRWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTPRREATLELLGRVLRDMDLLGCLEDIEEALCGPAALPPAPSLLR
FN14(配列番号62)
MARGSLRRLLRLLVLGLWLALLRSVAGEQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWPILGGALSLTFVLGLLSGFLVWRRCRRREKFTTPIEETGGEGCPAVALIQ
APRIL(配列番号63)
MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL
EDA-A2(配列番号64)
MGYPEVERRELLPAAAPRERGSQGCGCGGAPARAGEGNSCLLFLGFFGLSLALHLLTLCCYLELRSELRRERGAESRLGGSGTPGTSGTLSSLGGLDPDSPITSHLGQPSPKQQPLEPGEAALHSDSQDGHQMALLNFFFPDEKPYSEEESRRVRRNKRSKSNEGADGPVKNKKKGKKAGPPGPNGPPGPPGPPGPQGPPGIPGIPGIPGTTVMGPPGPPGPPGPQGPPGLQGPSGAADKAGTRENQPAVVHLQGQGSAIQVKNDLSGGVLNDWSRITMNPKVFKLHPRSGELEVLVDGTYFIYSQVYYINFTDFASYEVVVDEKPFLQCTRSIETGKTNYNTCYTAGVCLLKARQKIAVKMVHADISINMSKHTTFFGAIRLGEAPAS
TWEAK(配列番号65)
MAARRSQRRRGRRGEPGTALLVPLALGLGLALACLGLLLAVVSLGSRASLSAQEPAQEELVAEEDQDPSELNPQTEESQDPAPFLNRLVRPRRSAPKGRKTRARRAIAAHYEVHPRPGQDGAQAGVDGTVSGWEEARINSSSPLRYNRQIGEFIVTRAGLYYLYCQVHFDEGKAVYLKLDLLVDGVLALRCLEEFSATAASSLGPQLRLCQVSGLLALRPGSSLRIRTLPWAHLKAAPFLTYFGLFQVH
LTB(配列番号66)
MGALGLEGRGGRLQGRGSLLLAVAGATSLVTLLLAVPITVLAVLALVPQDQGGLVTETADPGAQAQQGLGFQKLPEEEPETDLSPGLPAAHLIGAPLKGQGLGWETTKEQAFLTSGTQFSDAEGLALPQDGLYYLYCLVGYRGRAPPGGGDPQGRSVTLRSSLYRAGGAYGPGTPELLLEGAETVTPVLDPARRQGYGPLWYTSVGFGGLVQLRRGERVYVNISHPDMVDFARGKTFFGAVMVG
NGF(配列番号67)
MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIAARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSKRSSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRDPNPVDSGCRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAVRRA
EDA-A1(配列番号68)
MGYPEVERRELLPAAAPRERGSQGCGCGGAPARAGEGNSCLLFLGFFGLSLALHLLTLCCYLELRSELRRERGAESRLGGSGTPGTSGTLSSLGGLDPDSPITSHLGQPSPKQQPLEPGEAALHSDSQDGHQMALLNFFFPDEKPYSEEESRRVRRNKRSKSNEGADGPVKNKKKGKKAGPPGPNGPPGPPGPPGPQGPPGIPGIPGIPGTTVMGPPGPPGPPGPQGPPGLQGPSGAADKAGTRENQPAVVHLQGQGSAIQVKNDLSGGVLNDWSRITMNPKVFKLHPRSGELEVLVDGTYFIYSQVEVYYINFTDFASYEVVVDEKPFLQCTRSIETGKTNYNTCYTAGVCLLKARQKIAVKMVHADISINMSKHTTFFGAIRLGEAPAS
APP(配列番号69)
MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMHMNVQNGKWDSDPSGTKTCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHPHFVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSEDKVVEVAEEEEVAEVEEEEADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAMSQSLLKTTQEPLARDPVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN
TRAIL(配列番号70)
MAMMEVQGGPSLGQTCVLIVIFTVLLQSLCVAVTYVYFTNELKQMQDKYSKSGIACFLKEDDSYWDPNDEESMNSPCWQVKWQLRQLVRKMILRTSEETISTVQEKQQNISPLVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKINSWESSRSGHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKNDKQMVQYIYKYTSYPDPILLMKSARNSCWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDHEASFFGAFLVG
B7-H4(配列番号71)
MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKASLCVSSFFAISWALLPLSPYLMLK
本明細書中で使用する場合、CARポリペプチド(CAR構築物としても知られる)は、宿主細胞の表面に発現し得る、細胞外抗原結合ドメイン、膜貫通ドメイン及び細胞質側シグナル伝達ドメインを含む天然に存在しない分子を指す。細胞外抗原結合ドメインは、医学的状態(例えば疾患)に関連する天然に存在する抗原を含めた標的抗原との、または疾患関連抗原を標的とした治療剤に複合している抗原部分との特異的な結合をする(つまりそれに対して特異的である)任意のペプチドまたはポリペプチドであり得る。
本明細書に記載のCARポリペプチドは細胞外抗原結合ドメインを含むが、このドメインは、CARポリペプチドが発現している免疫細胞の特異性を向け変えるものである。本明細書中で使用する場合、「細胞外抗原結合ドメイン」は、関心対象の標的抗原(例えばGPC3)に対する結合特異性を有するペプチドまたはポリペプチドを指す。本明細書に記載の細胞外抗原結合ドメインは、Fc受容体の細胞外ドメインを含まないものであり、また、免疫グロブリンのFc部分に結合しないものであり得る。Fc断片に結合しない細胞外ドメインは、2つのもの同士の結合活性が、従来のアッセイを用いて検出できないか、または従来のアッセイを用いてバックグラインドのもしくは生物学的に重要でない結合活性しか検出されないことを意味する。
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGALDPKTGDTAYSQKFKGRVTLTADKSTSTAYMELSSLTSEDTAVYYCTRFYSYTYWGQGTLV(配列番号74)
のアミノ酸配列を含んだ重鎖可変領域を含む。
DVVMTQSPLSLPVTPGEPASISCRSSQSLVHSNRNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQNTHVPPTFGQGTKLEI (配列番号75)
のアミノ酸配列を含んだ軽鎖可変領域を含む。
[結合]=[遊離]/(Kd+[遊離])
本明細書に記載のCARポリペプチドの膜貫通ドメインは、当技術分野で知られている任意の形態であり得る。本明細書中で使用する場合、「膜貫通ドメイン」は、細胞膜中、好ましくは真核生物細胞膜中で熱力学的に安定な任意のタンパク質構造を指す。本明細書において使用されるCARポリペプチドにおける使用に適合する膜貫通ドメインは、天然に存在するタンパク質から得られ得る。あるいはそれは、合成の天然に存在しないタンパク質セグメント、例えば、細胞膜中で熱力学的に安定な疎水性タンパク質セグメントであってもよい。
多くの免疫細胞は、細胞の増殖、分化及び生存を促進するためならびに細胞のエフェクター機能を活性化させるために抗原特異的シグナルの刺激に加えて共刺激を必要とする。いくつかの実施形態では、本明細書に記載のCARポリペプチドは少なくとも1つの共刺激シグナル伝達ドメインを含む。特定の実施形態では、CARポリペプチドは、CD28共刺激シグナル伝達ドメイン、または4-1BB(CD137)共刺激シグナル伝達ドメインを含有し得る。本明細書中で使用される「共刺激シグナル伝達ドメイン」という用語は、エフェクター機能などの免疫応答を誘導する細胞内でのシグナル伝達(副シグナル)を媒介する共刺激シグナル伝達タンパク質の少なくとも断片を指す。当技術分野で知られているように、T細胞などの免疫細胞の活性化には2つのシグナルが必要となることが多い:(1)T細胞受容体(TCR)と抗原提示細胞によって提示される抗原ペプチド/MHC複合体との係合が典型的にはTCR複合体の構成要素としてのCD3ζに促されて起こることによって誘発される、抗原特異的なシグナル(主シグナル)、及び(ii)共刺激受容体とそのリガンドとの相互作用によって誘発される共刺激シグナル(副シグナル)。共刺激受容体は、TCRによって誘発されるシグナル伝達に対する付加として共刺激シグナル(副シグナル)を伝達し、T細胞、NK細胞、マクロファージ、好中球または好酸球などの免疫細胞によって媒介される応答を調節する。
任意の細胞質側シグナル伝達ドメインを使用して本明細書に記載のCARポリペプチドを作り出すことができる。そのような細胞質側ドメインは、免疫細胞の増殖及び/または活性化につながる細胞シグナル伝達(主シグナル伝達)の誘発に関与する任意のシグナル伝達ドメインであり得る。本明細書に記載の細胞質側シグナル伝達ドメインは、当技術分野で知られているように免疫細胞を完全に活性化させるために共刺激または副シグナルを伝え送るものである共刺激シグナル伝達ドメインではない。
いくつかの実施形態では、本明細書に記載のCARポリペプチドは、細胞外抗原結合ドメインと膜貫通ドメインとの間に位置するヒンジドメインをさらに含む。ヒンジドメインは、タンパク質の2つのドメインの間に通常みられるアミノ酸セグメントであり、タンパク質の柔軟性及び互いに対する片方または両方のドメインの運動を可能にし得る。CARポリペプチドの膜貫通ドメインに対する細胞外抗原結合ドメインのそのような柔軟性及び運動を提供する任意のアミノ酸配列を使用することができる。
いくつかの実施形態では、CARポリペプチドは、ポリペプチドのN末端にシグナルペプチド(シグナル配列としても知られる)も含む。一般に、シグナル配列は、ポリペプチドを細胞内の所望の部位に指向するペプチド配列である。いくつかの実施形態では、シグナル配列はCARポリペプチドを細胞の分泌経路に指向し、脂質二重層内へのCARポリペプチドの組込み及び係留を可能にすることになる。本明細書に記載のCARポリペプチドにおける使用に適合した、天然に存在するタンパク質のシグナル配列または合成の天然に存在しないシグナル配列を含むシグナル配列は、当業者にとって明白であろう。いくつかの実施形態では、CD8αからのシグナル配列である。いくつかの実施形態では、シグナル配列はCD28からのものである。いくつかの実施形態では、シグナル配列は、ネズミカッパ鎖からのものである。さらに他の実施形態では、シグナル配列はCD16からのものである。
表1は、本明細書に記載のCARポリペプチドの例を示す。これらの例示的な構築物は、N末端からC末端に向かって順に、シグナル配列、抗原結合ドメイン(例えば、GPC3に対して特異的であるscFv断片)、ヒンジドメイン及び膜貫通部分を有する一方で、任意選択の共刺激ドメイン及び細胞質側シグナル伝達ドメインの位置については入れ替えができる。
本明細書に記載の共刺激ポリペプチド及び同じく本明細書に記載される抗GPC3 CARポリペプチド(CAR発現細胞、例えばCAR T細胞)の1つ以上が発現している遺伝子操作型宿主細胞(造血細胞、例えば、造血幹細胞及び免疫細胞、例えばT細胞またはNK細胞)を、本明細書に提供する。いくつかの実施形態では、宿主細胞は造血細胞またはその子孫である。いくつかの実施形態では、造血細胞は造血幹細胞であり得る。他の実施形態では、宿主細胞は免疫細胞、例えばT細胞またはNK細胞である。いくつかの実施形態では、免疫細胞はT細胞である。いくつかの実施形態では、免疫細胞はNK細胞である。他の実施形態では、免疫細胞は、樹立された細胞株、例えばNK-92細胞であり得る。
ATNFSLLKQAGDVEENPGP 配列番号72
のアミノ酸配列を有し得る。
共刺激ポリペプチド及び抗GPC3 CARポリペプチドが共発現している遺伝子操作型宿主細胞、例えば造血細胞、例えば本明細書に記載の免疫細胞を、CARポリペプチドの標的となる抗原が発現している疾患細胞を直接的または間接的に(例えば、CARポリペプチドが結合するタグに複合した治療剤によって)阻害するための免疫療法、例えばT細胞療法またはNK細胞療法に使用することができる。免疫細胞にCARポリペプチドと共に共発現した共刺激ポリペプチドは、腫瘍微小環境において低グルコース、低アミノ酸、低pH及び/または低酸素環境下で細胞が効果的に成長及び/または機能するのを可能にすることによって細胞免疫療法を容易にするであろう。非腫瘍特異的な反応の可能性を制限するためにmRNA電気穿孔を用いて共刺激ポリペプチド及び/またはCARポリペプチドを一過的に発現させることによって、臨床上の安全性がさらに強化され得る。
本明細書に記載の共刺激ポリペプチド及び抗GPC3 CARポリペプチドが発現している宿主細胞(例えば免疫細胞、例えばT細胞及びNK細胞)は、標的抗原が発現している細胞を阻害する及び/または例えば腫瘍微小環境において低グルコース環境、低アミノ酸環境、低pH環境及び/または低酸素環境の下で免疫細胞の成長及び/または増殖を増強するのに有用である。いくつかの実施形態では、対象は哺乳動物、例えば、ヒト、サル、マウス、ウサギまたは飼育哺乳動物である。いくつかの実施形態では、対象はヒトである。いくつかの実施形態では、対象はヒトがん患者である。いくつかの実施形態では、対象は、本明細書に記載の治療抗体のいずれかで付加的に治療されたことがある、またはそれで治療されている。
本開示に記載の組成物及び方法は、がんのための他の種類の療法、例えば、化学療法、外科手術、放射線、遺伝子療法など、または抗感染症療法と併せて利用され得る。そのような療法は、本開示に係る免疫療法と同時に、または逐次的に(任意の順序で)施され得る。付加的治療剤と共投与する場合、各薬剤の好適な治療的有効投薬量は相加作用または相乗作用ゆえに低くなり得る。
本開示は、本明細書に記載の組成物を使用するためのキットも提供する。例えば、本開示は、疾患細胞、例えば腫瘍細胞の成長を阻害する及び/または低グルコース環境、低アミノ酸環境、低pH環境及び/または低酸素環境で例えば腫瘍環境中で免疫細胞の成長及び/または増殖を増強するのに使用するための、共刺激ポリペプチドと抗GPC3 CARポリペプチドとが発現する共発現する免疫細胞(例えばTリンパ球またはNK細胞)の集団を含むキットも提供する。キットは、免疫細胞上に発現したCARポリペプチドに結合するものであるタグに複合した治療剤(例えば本明細書に記載のもの)をさらに含み得る。そのようなキットは、本明細書に記載されているような共刺激ポリペプチドとCARポリペプチドとが共発現するものである本明細書に記載の遺伝子操作型免疫細胞(例えばTリンパ球及び/またはNK細胞)の集団、及び任意選択のタグに複合した治療剤を含んだ、1つ以上の容器を含み得る。
本開示の実施は、特に指定されない限り、分子生物学(組換え技術を含む)、微生物学、細胞生物学、生化学及び免疫学の従来の技術を採用することになるが、これらは当業者の技量の範囲内である。そのような技術は、文献、例えば、Molecular Cloning:A Laboratory Manual,second edition(Sambrook,et al.,1989)Cold Spring Harbor Press、Oligonucleotide Synthesis(M.J.Gait,ed.1984)、Methods in Molecular Biology,Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis,ed.,1989)Academic Press、Animal Cell Culture(R.I.Freshney,ed.1987)、Introduction to Cell and Tissue Culture(J.P.Mather and P.E.Roberts,1998)Plenum Press、Cell and Tissue Culture:Laboratory Procedures(A.Doyle,J.B.Griffiths,and D.G.Newell,eds.1993-8)J.Wiley and Sons、Methods in Enzymology(Academic Press,Inc.)、Handbook of Experimental Immunology(D.M.Weir and C.C.Blackwell,eds.):Gene Transfer Vectors for Mammalian Cells(J.M.Miller and M.P.Calos,eds.,1987)、Current Protocols in Molecular Biology(F.M.Ausubel,et al.eds.1987)、PCR:The Polymerase Chain Reaction,(Mullis,et al.,eds.1994)、Current Protocols in Immunology(J.E.Coligan et al.,eds.,1991)、Short Protocols in Molecular Biology(Wiley and Sons,1999)、Immunobiology(C.A.Janeway and P.Travers,1997)、Antibodies(P.Finch,1997)、Antibodies:a practice approach(D.Catty.,ed.,IRL Press,1988-1989)、Monoclonal antibodies:a practical approach(P.Shepherd and C.Dean,eds.,Oxford University Press,2000)、Using antibodies:a laboratory manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999)、The Antibodies(M.Zanetti and J.D.Capra,eds.Harwood Academic Publishers,1995)、DNA Cloning:A practical Approach,Volumes I and II(D.N.Glover ed.1985)、Nucleic Acid Hybridization(B.D.Hames & S.J.Higgins eds.(1985>>;Transcription and Translation(B.D.Hames & S.J.Higgins,eds.(1984>>;Animal Cell Culture(R.I.Freshney,ed.(1986>>;Immobilized Cells and Enzymes(lRL Press,(1986>>;and B.Perbal,A practical Guide To Molecular Cloning(1984);F.M.Ausubel et al.(eds.)の中で十分に説明されている。
この実施例は、抗GPC3 CARと組み合わせて腫瘍壊死因子(TNF)スーパーファミリー共刺激ポリペプチドまたはB7/CD28スーパーファミリーの共刺激ペプチドをT細胞に発現させることでT細胞の活性を抗GPC3 CAR単独に比べて増強できることを実証する。
この実施例は、抗GPC3 CARと組み合わせて腫瘍壊死因子(TNF)スーパーファミリー共刺激ポリペプチドCD70、LIGHT及びOX40LをT細胞に発現させることで、複数回の再刺激の条件下で標的細胞の存在下においてT細胞の活性が抗GPC3 CAR単独に比べて増強されること、ならびにCAR中の共刺激ドメインが何であるかによって増強のレベルが決まることを実証する。これらの実験では、4-1BB共刺激ドメインを有する抗GPC3 CARポリペプチド(GPC3-CAR-4-1BB、配列番号1)のみ、CD28共刺激ドメインを有する抗GPC3 CARポリペプチド(GPC3-CAR-CD28、配列番号2)のみ、またはこれらのCAR変異体の各々とCD70(配列番号34)、LIGHT(配列番号43)もしくはOX40L(配列番号47)とがP2Aリボソームスキッピング配列によって隔てられたものをコードするウイルスを、T細胞に形質導入した。GPC3-CAR-4-1BBが発現しているT細胞、及びGPC3-CAR-4-1BBとCD70とが共発現している細胞を、抗CD70抗体で染色することによってフローサイトメトリーでCD70の発現について評価した。GPC3-CAR-4-1BBが単独で発現しているT細胞と比較して、GPC3-CAR-4-1BBとCD70とが共発現しているT細胞は、より高い蛍光強度によって証明される、より多くのCD70発現を示した(図10、パネルA及びB)。
この例は、4-1BB共刺激ドメインを有する抗GPC3 CARと組み合わせて腫瘍壊死因子(TNF)スーパーファミリー共刺激ポリペプチドCD70、LIGHT及びOX40LをT細胞に発現させることでT細胞の活性が抗GPC3 CAR単独に比べて増強されることを実証する。これらの実験では、4-1BB共刺激ドメインを有する抗GPC3 CARポリペプチド(GPC3-CAR-4-1BB、配列番号1)をコードするウイルス、またはP2Aリボソームスキッピング配列によって隔てられたGPC3-CAR-4-1BBとCD70(配列番号34)、LIGHT(配列番号43)もしくはOX40L(配列番号47)とをコードするウイルスを、T細胞に形質導入した。
この実施例は、4-1BB主要共刺激ドメインを含有する抗GPC3 CAR(GPC3-CAR-4-1BB、配列番号1)と組み合わせた場合に共刺激ポリペプチドCD70(配列番号34)が他の腫瘍壊死因子(TNF)スーパーファミリーメンバーと比較して実質的な機能的利点をもたらすことを実証する。これらの実験では、CARポリペプチド(配列番号1)のみ、またはP2Aリボソームスキッピング配列によって隔てられたCARポリペプチドとCD70(配列番号34)、LIGHT(配列番号43)もしくはOX40L(配列番号47)とをコードするウイルスをT細胞に形質導入した。
この実施例は、CD28主要共刺激ドメインを含有する抗GPC3 CAR(GPC3-CAR-CD28、配列番号2)と組み合わせた場合に共刺激ポリペプチドCD27(配列番号33)が、抑制性骨髄由来抑制細胞(MDSC)または制御性T細胞(Treg)を含有するアッセイにおいて実質的な機能的利点をT細胞にもたらすことを実証する。これらの実験では、GPC3-CAR-CD28(配列番号2)のみ、またはP2Aリボソームスキッピング配列によって隔てられGPC3-CAR-CD28とCD27(配列番号33)とをコードするウイルスをT細胞に形質導入した。
この実施例は、マウスのGPC3発現異種移植モデルにおいてGPC3-CAR-4-1BBでの腫瘍壊死因子(TNF)スーパーファミリー共刺激ペプチドCD70、LIGHT及びOX40Lの発現が、GPC3-CAR-4-1BB単独と比較して抗腫瘍活性の上昇をもたらすことを実証する。皮下ヒト肝細胞癌(HCC)異種移植モデル(Hep G2、Hep 3b、及びJHH7)をNSG(商標)(NOD scidガンマ、NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ、005557系)マウスに樹立した。
この実施例は、GPC3-CAR-CD28が単独で発現しているT細胞と比較して、T細胞における腫瘍壊死因子(TNF)スーパーファミリー共刺激ペプチドCD27とGPC3-CAR-CD28との共発現が、マウスのGPC3発現異種移植モデルにおいて抗腫瘍活性の上昇をもたらすことを実証する。皮下ヒト肝細胞癌(HCC)異種移植モデル(JHH7)をNSG(商標)(NOD scidガンマ、NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ、005557系)マウスに樹立した。
上記実施例は、抗GPC3 CARと組み合わせて腫瘍壊死因子(TNF)スーパーファミリー共刺激ポリペプチドまたはB7/CD28スーパーファミリー共刺激ペプチドを発現させることで試験管内及びインビボでのT細胞の活性を抗GPC3 CAR単独に比べて増強できることを実証している。上記データは以下のようにまとめることができる:
●GPC3-4-1BB CAR+CD70、GPC3-4-1BB CAR+LIGHT、及びGPC3-4-1BB CAR+OX40L
○親CAR-4-1BBに比べて改善された、親CAR-4-1BBと比較する反復刺激アッセイにおける増殖
■CAR-4-1BB+LIGHTの組合せに特異的であり、CAR-CD28+LIGHTは、親CAR-CD28を上回る改善を示さない
○親CAR-4-1BBに比べて改善された、反復刺激後のIL-2、IFN-ガンマ及びIL-17A産生
○親CAR-4-1BBに比べて改善された、単回刺激増殖アッセイにおける増殖
○親CAR-4-1BBに比べて改善された、刺激後のIL-2産生
●GPC3-4-1BB CAR+CD70、GPC3-4-1BB CAR+LIGHT
○親CAR-4-1BBに比べて向上した、マウスの腫瘍モデルにおけるインビボでの有効性
●GPC3-4-1BB CAR+CD70
○親CAR-4-1BBに比べて向上した、マウスの腫瘍モデルにおけるインビボでのT細胞持続性
●GPC3-CD28 CAR+CD27
○親CAR-CD28に比べて改善された増殖
○親CAR-CD28に比べて改善されたIL-2産生
○親CAR-CD28に比べて向上した、MDSC抑制に対する耐性
○親CAR-CD28に比べて向上した、Treg抑制に対する耐性
○親CAR-CD28に比べて向上した、マウスの腫瘍モデルにおけるインビボでの有効性
この実施例は、抗GPC3 CARと組み合わせて腫瘍壊死因子(TNF)スーパーファミリー共刺激ポリペプチドまたはB7/CD28スーパーファミリー共刺激ペプチドをT細胞に発現させることでT細胞の活性を抗GPC3 CAR単独に比べて増強できることを実証する。
表2.親4-1BB含有または親CD28含有CAR変異体と比較したときの、抗GPC3 CARと共刺激ポリペプチドとが共発現している変異体の試験管内での増殖及びIL-2放出の採点。
本明細書中に開示される特徴は全て、任意の組合せで組み合わされ得る。本明細書中に開示される各特徴を、同じ、等価な、または類似する目的に役立つ代替特徴で置き換えてもよい。したがって、開示される各特徴は、特に明記しない限り全般的な一連の均等物または類似する特徴のほんの一例であるにすぎない。
いくつかの本発明の実施形態を本明細書中で説明及び例示してきたが、当業者であれば、機能を実施するための、及び/または結果及び/または本明細書に記載の利点の1つ以上を得るための他の様々な手段及び/または構造を容易に考え付くであろうし、そのような変形形態及び/または改変形態は本明細書に記載の本発明の実施形態の範囲に入るとみなされる。より広くは、当業者であれば、本明細書に記載の全てのパラメータ、寸法、材料及び配置が例示を意図したものであり、本発明の教示内容が用いられる具体的な用途または複数の用途によって実際のパラメータ、寸法、材料及び/または配置が決まるであろうことを、容易に理解するであろう。当業者であれば、慣習的な実験しか用いずに本明細書に記載の具体的な本発明の実施形態の多くの均等物を認識するかまたは見出せるであろう。したがって、上記実施形態が例としてのみ提示されていること、ならびに本発明の実施形態の具体的に記載され特許請求されている以外の実施が別記の特許請求の範囲及びその均等物の範囲の中でなされ得ることは理解されるべきである。本開示の本発明の実施形態は、本明細書に記載の各個の特徴、システム、物品、材料、キット及び/または方法に関するものである。加えて、2つ以上のそのような特徴、システム、物品、材料、キット及び/または方法の任意の組合せは、そのような特徴、システム、物品、材料、キット及び/または方法が相互に矛盾していない場合に本開示の本発明の範囲に含まれる。
Claims (55)
- 遺伝子操作型造血細胞であって、
(i)キメラ抗原受容体(CAR)ポリペプチドと、
(ii)共刺激ポリペプチドと
を共発現し、
前記CARポリペプチドが、
(a)細胞外抗原結合ドメインであってグリピカン-3(GPC3)に対して特異的である前記細胞外結合ドメイン、
(b)膜貫通ドメイン、及び
(c)細胞質側シグナル伝達ドメイン
を含むものであり、
前記共刺激ポリペプチドが、B7/CD28スーパーファミリーのメンバー、腫瘍壊死因子(TNF)スーパーファミリーのメンバー、またはそのリガンドであり、前記共刺激ポリペプチドが外来核酸にコードされている、前記造血細胞。 - 前記共刺激ポリペプチドが、
CD28、CD80、CD86、ICOS、ICOSL、B7-H3、B7-H4、VISTA、TMIGD2、B7-H6、及びB7-H7
からなる群から選択されるB7/CD28スーパーファミリーのメンバーまたはそのリガンドである、請求項1に記載の造血細胞。 - 前記共刺激ポリペプチドが、
4-1BB、4-1BBL、BAFF、BAFFR、CD27、CD70、CD30、CD30L、CD40、CD40L、DR3、GITR、GITRL、HVEM、LIGHT、TNFベータ、OX40、OX40L、RELT、TACI、TL1A、TNFアルファ、TNFRII、BCMA、EDAR2、TROY、LTBR、EDAR、NGFR、OPG、RANK、DCR3、TNFR1、FN14(TweakR)、APRIL、EDA-A2、TWEAK、LTb(TNF-C)、NGF、EDA-A1、APPアミロイド前駆体タンパク質(APP)、及びTRAIL
からなる群から選択されるTNFスーパーファミリーのメンバーまたはそのリガンドである、請求項1に記載の造血細胞。 - 前記CARポリペプチドが少なくとも1つの共刺激シグナル伝達ドメインをさらに含む、請求項1~3のいずれか1項に記載の造血細胞。
- 前記少なくとも1つの共刺激シグナル伝達ドメインが、
4-1BB、CD28、CD28LL→GG変異体、OX40、ICOS、CD27、GITR、ICOS、HVEM、TIM1、LFA1及びCD2
からなる群から選択される共刺激分子のものである、請求項4に記載の造血細胞。 - (i)前記CARポリペプチドがCD28共刺激分子の共刺激ドメインを含み、かつ
(ii)前記共刺激ポリペプチドがBAFFRまたはCD27である、
請求項4に記載の造血細胞。 - 前記CD28共刺激分子が配列番号12のアミノ酸配列を含む、請求項6に記載の造血細胞。
- (i)前記CARポリペプチドが4-1BB共刺激分子の共刺激ドメインを含み、かつ
(ii)前記共刺激ポリペプチドがCD70、LIGHTまたはOX40Lである、
請求項4に記載の造血細胞。 - 前記4-1BB共刺激分子が配列番号22のアミノ酸配列を含む、請求項8に記載の造血細胞。
- 前記CD70が配列番号34のアミノ酸配列を含み、前記LIGHTが配列番号43のアミノ酸配列を含み、前記OX40Lが配列番号47のアミノ酸配列を含む、請求項8または請求項9に記載の造血細胞。
- 前記(a)の細胞外抗原結合ドメインが、GPC3に対して特異的な一本鎖抗体断片(scFv)である、請求項1~10のいずれか1項に記載の造血細胞。
- 前記scFvが、配列番号74として示される重鎖可変領域、及び配列番号75として示される軽鎖可変領域を含む、請求項11に記載の造血細胞。
- 前記(b)の膜貫通ドメインが1回貫通型膜タンパク質のものである、請求項1~12のいずれか1項に記載の造血細胞。
- 前記膜貫通ドメインが、CD8α、CD8β、4-1BB、CD28、CD34、CD4、FcεRIγ、CD16A、OX40、CD3ζ、CD3ε、CD3γ、CD3δ、TCRα、CD32、CD64、VEGFR2、FAS及びFGFR2Bからなる群から選択される膜タンパク質である、請求項13に記載の造血細胞。
- 前記(b)の膜貫通ドメインが、天然に存在しない疎水性タンパク質セグメントである、請求項1~14のいずれか1項に記載の造血細胞。
- 前記(c)中の細胞質側シグナル伝達ドメインが免疫受容体チロシン依存性活性化モチーフ(ITAM)を含む、請求項1~15のいずれか1項に記載の造血細胞。
- 前記(c)の細胞質側シグナル伝達ドメインが、CD3ζまたはFcεR1γの細胞質側ドメインである、請求項16に記載の造血細胞。
- 前記CARポリペプチドが、前記(a)のC末端及び前記(b)のN末端に位置するヒンジドメインをさらに含む、請求項1~17のいずれか1項に記載の造血細胞。
- 前記ヒンジドメインが、CD28、CD16A、CD8αまたはIgGのものである、請求項18に記載の造血細胞。
- 前記ヒンジドメインが、天然に存在しないペプチドである、請求項18または請求項19に記載の造血細胞。
- 前記CARポリペプチドがそのN末端にシグナルペプチドをさらに含む、請求項1~20のいずれか1項に記載の造血細胞。
- 前記造血細胞が造血幹細胞または免疫細胞であり、任意選択的に前記免疫細胞が、ナチュラルキラー細胞、マクロファージ、好中球、好酸球またはT細胞である、請求項1~21のいずれか1項に記載の造血細胞。
- 前記免疫細胞が、
内在性T細胞受容体、内在性主要組織適合性複合体、内在性ベータ-2-ミクログロブリンまたはその組合せ
の発現が阻害または排除されたT細胞である、請求項22に記載の造血細胞。 - 前記造血細胞が、末梢血単核細胞(PBMC)、造血幹細胞(HSC)または人工多能性幹細胞(iPSC)に由来する、請求項1~23のいずれか1項に記載の造血細胞。
- 前記造血細胞が、
(A)前記共刺激ポリペプチドをコードする第1外来ヌクレオチド配列、及び
(B)前記CARポリペプチドをコードする第2外来ヌクレオチド配列
を全体として含んだ核酸または核酸セットを含む、請求項1~24のいずれか1項に記載の造血細胞。 - 前記核酸または前記核酸セットがRNA分子またはRNA分子のセットである、請求項25に記載の造血細胞。
- 前記造血細胞が、前記第1外来ヌクレオチド配列と前記第2外来ヌクレオチド配列とを両方含んだ前記核酸を含む、請求項25または請求項26に記載の造血細胞。
- 前記核酸が、前記第1外来ヌクレオチド配列と前記第2外来ヌクレオチド配列との間に位置する第3外来ヌクレオチド配列をさらに含み、前記第3外来ヌクレオチド配列が、リボソームスキッピング部位、配列内リボソーム進入部位(IRES)または第2プロモーターをコードする、請求項27に記載の造血細胞。
- 前記第3外来ヌクレオチド配列が、P2Aペプチドであるリボソームスキッピング部位をコードする、請求項30に記載の造血細胞。
- 前記核酸または前記核酸セットが、ベクターまたはベクターのセットの中に含まれている、請求項25~29のいずれか1項に記載の造血細胞。
- 前記ベクターまたはベクターのセットが、発現ベクターまたは発現ベクターのセットである、請求項30に記載の造血細胞。
- 前記ベクターまたはベクターのセットが、1つ以上のウイルスベクターを含む、請求項30または請求項31に記載の造血細胞。
- 前記1つ以上のウイルスベクターが、
レトロウイルスベクターであって、任意選択的にレンチウイルスベクターまたはガンマレトロウイルスベクターである、レトロウイルスベクター
である、請求項32に記載の造血細胞。 - (i)前記CARポリペプチド及び(ii)前記共刺激ポリペプチドをコードする前記核酸または前記核酸セットが、トランスポゾンまたは遺伝子編集によって前記造血細胞内に送達される、請求項25~29のいずれか1項に記載の造血細胞。
- 請求項1~34のいずれか1項に記載の造血細胞、及び薬学的に許容される担体を含む、医薬組成物。
- 対象においてGPC3が発現している細胞を阻害する方法であって、それを必要とする対象に、請求項1~34のいずれか1項に記載の造血細胞の集団または請求項35に記載の医薬組成物を投与することを含む、方法。
- 前記造血細胞が自家性である、請求項36に記載の方法。
- 前記造血細胞が同種異系である、請求項36に記載の方法。
- エクスビボで前記造血細胞を活性化させる、増殖させる、またはその両方を行う、請求項37または請求項38に記載の方法。
- 前記対象が、GPC3+がん細胞に関連するがんを患っているヒト患者である、請求項36~39のいずれか1項に記載の方法。
- 前記がんが、乳癌、胃癌、肺癌、皮膚癌、前立腺癌、大腸癌、腎細胞癌腫、卵巣癌、横紋筋肉腫、胚細胞癌、肝芽腫、中皮腫、膵臓癌、頭頸部癌、神経膠腫、神経膠芽腫、甲状腺癌、肝細胞癌、食道癌または子宮頸癌である、請求項40に記載の方法。
- 前記がんが、肝細胞癌腫、胃癌、乳癌または肺癌である、請求項40に記載の方法。
- 前記造血細胞が、
抗CD3抗体、抗CD28抗体、IL-2、フィトヘマグルチニン、及び操作型人工刺激細胞または粒子
のうちの1つ以上の存在下で活性化されたT細胞を含む免疫細胞である、請求項36~42のいずれか1項に記載の方法。 - 前記造血細胞が、
4-1BBリガンド、抗4-1BB抗体、IL-15、抗IL-15受容体抗体、IL-2、IL-12、IL-18、IL-21及びK562細胞
のうちの1つ以上の存在下で活性化されたナチュラルキラー細胞を含む免疫細胞である、請求項36~42のいずれか1項に記載の方法。 - 前記ヒト患者が、抗がん療法を受けている、または治療されたことがある、請求項40~44のいずれか1項に記載の方法。
- 前記対象に抗がん剤を投与することをさらに含む、請求項40~44のいずれか1項に記載の方法。
- (A)請求項1及び請求項4~22のいずれか1項に記載のCARポリペプチドをコードする第1ヌクレオチド配列、ならびに
(B)請求項1~3及び請求項6~11のいずれか1項に記載の共刺激ポリペプチドをコードする第2ヌクレオチド配列
を全体として含む、核酸または核酸セット。 - 前記核酸または前記核酸セットが、RNA分子またはRNA分子のセットである、請求項47に記載の核酸または核酸セット。
- 前記核酸が、前記第1ヌクレオチド配列と前記第2ヌクレオチド配列とを両方含み、ここで、前記核酸が、前記第1ヌクレオチド配列と前記第2ヌクレオチド配列との間に位置する第3ヌクレオチド配列をさらに含み、前記第3ヌクレオチド配列が、リボソームスキッピング部位、配列内リボソーム進入部位(IRES)または第2プロモーターをコードする、請求項47または請求項48に記載の核酸または核酸セット。
- 前記リボソームスキッピング部位がP2Aペプチドである、請求項49に記載の核酸または核酸セット。
- 前記核酸または前記核酸セットが、ベクターまたはベクターのセットの中に含まれている、請求項47~50のいずれか1項に記載の核酸または核酸セット。
- 前記ベクターまたはベクターのセットが、発現ベクターまたは発現ベクターのセットである、請求項51に記載の核酸または核酸セット。
- 前記ベクターまたはベクターのセットが、1つ以上のウイルスベクターを含む、請求項51または請求項52に記載の核酸または核酸セット。
- 前記1つ以上のウイルスベクターが、
レトロウイルスベクターであって、任意選択的にレンチウイルスベクターまたはガンマレトロウイルスベクターである、レトロウイルスベクター
である、請求項53に記載の核酸または核酸セット。 - インビボで改変型造血細胞を生み出す方法であって、それを必要とする対象に請求項47~54のいずれか1項に記載の核酸または核酸セットを投与することを含む、前記方法。
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- 2019-11-07 JP JP2021524959A patent/JP2022512958A/ja active Pending
- 2019-11-07 AU AU2019374828A patent/AU2019374828A1/en active Pending
- 2019-11-07 CN CN201980087101.8A patent/CN113260368B/zh active Active
- 2019-11-07 US US17/291,963 patent/US20220054545A1/en active Pending
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CN113260368A (zh) | 2021-08-13 |
CA3118889A1 (en) | 2020-05-14 |
WO2020097346A1 (en) | 2020-05-14 |
AU2019374828A1 (en) | 2021-05-27 |
EP3876950A1 (en) | 2021-09-15 |
US20220054545A1 (en) | 2022-02-24 |
CN113260368B (zh) | 2023-08-29 |
EP3876950A4 (en) | 2022-11-30 |
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