JP2020014474A - 呼吸器合胞体ウイルス(rsv)ワクチン - Google Patents
呼吸器合胞体ウイルス(rsv)ワクチン Download PDFInfo
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- 108010062760 transportan Proteins 0.000 description 1
- VXYADVIJALMOEQ-UHFFFAOYSA-K tris(lactato)aluminium Chemical compound CC(O)C(=O)O[Al](OC(=O)C(C)O)OC(=O)C(C)O VXYADVIJALMOEQ-UHFFFAOYSA-K 0.000 description 1
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Images
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/155—Paramyxoviridae, e.g. parainfluenza virus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/04—Immunostimulants
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1027—Paramyxoviridae, e.g. respiratory syncytial virus
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- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
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- A—HUMAN NECESSITIES
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- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
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- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18511—Pneumovirus, e.g. human respiratory syncytial virus
- C12N2760/18534—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
Description
配列番号1にしたがうアミノ酸配列:
MELPILKANA ITTILAAVTF CFASSQNITE EFYQSTCSAV SKGYLSALRT GWYTSVITIE LSNIKENKCN GTDAKVKLIN QELDKYKNAV TELQLLMQST TAANNRARRE LPRFMNYTLN NTKKTNVTLS KKRKRRFLGF LLGVGSAIAS GIAVSKVLHL EGEVNKIKSA LLSTNKAVVS LSNGVSVLTS KVLDLKNYID KQLLPIVNKQ SCRISNIETV IEFQQKNNRL LEITREFSVN AGVTTPVSTY MLTNSELLSL INDMPITNDQ KKLMSNNVQI VRQQSYSIMS IIKEEVLAYV VQLPLYGVID TPCWKLHTSP LCTTNTKEGS NICLTRTDRG WYCDNAGSVS FFPQAETCKV QSNRVFCDTM NSLTLPSEVN LCNVDIFNPK YDCKIMTSKT DVSSSVITSL GAIVSCYGKT KCTASNKNRG IIKTFSNGCD YVSNKGVDTV SVGNTLYYVN KQEGKSLYVK GEPIINFYDP LVFPSDEFDA SISQVNEKIN QSLAFIRKSDELLHHVNAGK STTNIMITTI IIVIIVILLS LIAVGLLLYC KARSTPVTLS KDQLSGINNI AFSN。
配列番号2にしたがうアミノ酸配列:
MSKNKDQRTA KTLEKTWDTL NHLLFISSGL YKLNLKSIAQ ITLSILAMII STSLIITAII FIASANHKVT LTTAIIQDAT SQIKNTTPTY LTQDPQLGIS FSNLSEITSQ TTTILASTTP GVKSNLQPTT VKTKNTTTTQ TQPSKPTTKQ RQNKPPNKPN NDFHFEVFNF VPCSICSNNP TCWAICKRIP NKKPGKKTTT KPTKKPTFKT TKKDLKPQTT KPKEVPTTKP TEEPTINTTK TNITTTLLTN NTTGNPKLTS QMETFHSTSS EGNLSPSQVS TTSEHPSQPS SPPNTTRQ。
配列番号3にしたがうアミノ酸配列:
MENTSITIEF SSKFWPYFTL IHMITTIISL LIIISIMTAI LNKLCEYNVF HNKTFELPRA RVNT。
配列番号4にしたがうアミノ酸配列:
METYVNKLHE GSTYTAAVQY NVLEKDDDPA SLTIWVPMFQ SSMPADLLIK ELANVNILVK QISTPKGPSL RVMINSRSAL LAQMPSKFTI CANVSLDERS KLAYDVTTPC EIKACSLTCL KSKNMLTTVK DLTMKTLNPT HDIIALCEFE NIVTSKKVII PTYLRSISVR NKDLNTLENI TTTEFKNAIT NAKIIPYSGL LLVITVTDNK GAFKYIKPQS QFIVDLGAYL EKESIYYVTT NWKHTATRFA IKPMED。
配列番号5にしたがうアミノ酸配列:
MALSKVKLND TLNKDQLLSS SKYTIQRSTG DSIDTPNYDV QKHINKLCGM LLITEDANHK FTGLIGMLYA MSRLGREDTI KILRDAGYHV KANGVDVTTH RQDINGKEMK FEVLTLASLT TEIQINIEIE SRKSYKKMLK EMGEVAPEYR HDSPDCGMII LCIAALVITK LAAGDRSGLT AVIRRANNVL KNEMKRYKGL LPKDIANSFY EVFEKHPHFI DVFVHFGIAQ SSTRGGSRVE GIFAGLFMNA YGAGQVMLRW GVLAKSVKNI MLGHASVQAE MEQVVEVYEY AQKLGGEAGF YHILNNPKAS LLSLTQFPHF SSVVLGNAAG LGIMGEYRGT PRNQDLYDAA KAYAEQLKEN
GVINYSVLDL TAEELEAIKH QLNPKDNDVE L。
配列番号6にしたがうアミノ酸配列:
MDPIINGNSA NVYLTDSYLK GVISFSECNA LGSYIFNGPY LKNDYTNLIS RQNPLIEHMN LKKLNITQSL ISKYHKGEIK LEEPTYFQSL LMTYKSMTSL EQIATTNLLK KIIRRAIEIS DVKVYAILNK LGLKEKDKIK SNNGQDEDNS VITTIIKDDI LSAVKDNQSH LKADKNHSTK QKDTIKTTLL KKLMCSMQHP PSWLIHWFNL YTKLNNILTQ YRSNEVKNHG FILIDNQTLS GFQFILNQYG CIVYHKELKR ITVTTYNQFL TWKDISLSRL NVCLITWISN CLNTLNKSLG LRCGFNNVIL TQLFLYGDCI LKLFHNEGFY IIKEVEGFIM SLILNITEED QFRKRFYNSM LNNITDAANK AQKNLLSRVC HTLLDKTVSD NIINGRWIIL LSKFLKLIKL AGDNNLNNLS ELYFLFRIFG HPMVDERQAM DAVKVNCNET KFYLLSSLSM LRGAFIYRII KGFVNNYNRW PTLRNAIVLP LRWLTYYKLN TYPSLLELTERDLIVLSGLR FYREFRLPKK VDLEMIINDK AISPPKNLIW TSFPRNYMPS HIQNYIEHEK LKFSESDKSR RVLEYYLRDN KFNECDLYNC VVNQSYLNNP NHVVSLTGKE RELSVGRMFA MQPGMFRQVQ ILAEKMIAEN ILQFFPESLT RYGDLELQKI LELKAGISNK SNRYNDNYNN YISKCSIITD LSKFNQAFRY ETSCICSDVL DELHGVQSLF SWLHLTIPHV TIICTYRHAP PYIRDHIVDL NNVDEQSGLY RYHMGGIEGW CQKLWTIEAI SLLDLISLKG KFSITALING DNQSIDISKP VRLMEGQTHA QADYLLALNS LKLLYKEYAG IGHKLKGTET YISRDMQFMS KTIQHNGVYY PASIKKVLRV GPWINTILDD FKVSLESIGS LTQELEYRGE SLLCSLIFRN VWLYNQIALQ LKNHAL
CNNK LYLDILKVLK HLKTFFNLDN IDTALTLYMN LPMLFGGGDP NLLYRSFYRR TPDFLTEAIV HSVFILSYYT NHDLKDKLQD LSDDRLNKFL TCIITFDKNP NAEFVTLMRD PQALGSERQA KITSEINRLA VTEVLSTAPN KIFSKSAQHY TTTEIDLNDI MQNIEPTYPH GLRVVYESLP FYKAEKIVNL ISGTKSITNI LEKTSAIDLT DIDRATEMMR KNITLLIRIL PLDCNRDKRE ILSMENLSIT ELSKYVRERS WSLSNIVGVT SPSIMYTMDI KYTTSTIASG IIIEKYNVNS LTRGERGPTK PWVGSSTQEK KTMPVYNRQV LTKKQRDQID LLAKLDWVYA SIDNKDEFMEELSIGTLGLT YEKAKKLFPQ YLSVNYLHRL TVSSRPCEFP ASIPAYRTTN YHFDTSPINR ILTEKYGDED IDIVFQNCIS FGLSLMSVVE QFTNVCPNRI ILIPKLNEIH LMKPPIFTGD VDIHKLKQVI QKQHMFLPDK ISLTQYVELF LSNKTLKSGS HVNSNLILAH KISDYFHNTY ILSTNLAGHW ILIIQLMKDS KGIFEKDWGE GYITDHMFIN LKVFFNAYKT YLLCFHKGYG KAKLECDMNT SDLLCVLELI DSSYWKSMSK VFLEQKVIKY ILSQDASLHR VKGCHSFKLW FLKRLNVAEF TVCPWVVNID YHPTHMKAIL TYIDLVRMGL INIDRIHIKN KHKFNDEFYT SNLFYINYNF SDNTHLLTKH IRIANSELEN NYNKLYHPTP ETLENILANP IKSNDKKTLN DYCIGKNVDS IMLPLLSNKK LVKSSAMIRT NYSKQDLYNL FPTVVIDRII DHSGNTAKSN QLYTTTSHQI SLVHNSTSLY CMLPWHHINR FNFVFSSTGC KISIEYILKD LKIKDPNCIA FIGEGAGNLL LRTVVELHPD IRYIYRSLKD CNDHSLPIEF LRLYNGHINI DYGENLTIPA TDATNNIHWS YLHIKFAEPI SLFVCDAELP VTVNWSKIII EWSKHVRKCK YCSSVNKCTL IVKYHAQDDI DFKLDNITIL KTYVCLGSKL KGSEVYLVLT IGPANIFPVF NVVQNAKLIL SRTKNFIMPK KADKESIDAN IKSLIPFLCY PITKKGINTA LSKLKSVVSG DILSYSIAGR NEVFSNKLIN HKHMNILKWFNHVLNFRSTE LNYNHLYMVE STYPYLSELL NSLTTNELKK LIKITGSLLY NFHNE。
配列番号7にしたがうアミノ酸配列:
MSRRNPCKFE IRGHCLNGKR CHFSHNYFEW PPHALLVRQN FMLNRILKSM DKSIDTLSEI SGAAELDRTE EYALGVVGVL ESYIGSINNI TKQSACVAMS KLLTELNSDD IKKLRDNEEL NSPKIRVYNT VISYIESNRK NNKQTIHLLK RLPADVLKKT IKNTLDIHKS ITINNPKELT VSDTNDHAKN NDTT。
配列番号8にしたがうアミノ酸配列:
MTMPKIMILP DKYPCSITSI LITSRCRVTM YNRKNTLYFN QNNPNNHMYS PNQTFNEIHW TSQDLIDTIQ NFLQHLGVIE DIYTIYILVS。
配列番号9にしたがうアミノ酸配列:
MEKFAPEFHG EDANNRATKF LESIKGKFTS PKDPKKKDSI ISVNSIDIEV TKESPITSNS TIINPTNETD DNAGNKPNYQ RKPLVSFKED PIPSDNPFSK LYKETIETFD NNEEESSYSY EEINDQTNDN ITARLDRIDE KLSEILGMLH TLVVASAGPT SARDGIRDAM VGLREEMIEK IRTEALMTND RLEAMARLRN EESEKMAKDT SDEVSLNPTS EKLNNLLEGN DSDNDLSLED F。
配列番号10にしたがうアミノ酸配列:
MGSNSLSMIK VRLQNLFDND EVALLKITCY TDKLIHLTNA LAKAVIHTIK LNGIVFVHVI TSSDICPNNN IVVKSNFTTM PVLQNGGYIW EMMELTHCSQ PNGLIDDNCE IKFSKKLSDS TMTNYMNQLS ELLGFDLNP。
配列番号11にしたがうアミノ酸配列:
MDTTHNDTTP QRLMITDMRP LSLETTITSL TRDIITHRFI YLINHECIVR KLDERQATFT FLVNYEMKLL HKVGSTKYKK YTEYNTKYGT FPMPIFINHD GFLECIGIKP TKHTPIIYKY DLNP。
配列番12にしたがうmRNA配列:
auggaguugccaauccucaaagcaaaugcaauuaccacaauccucgcugcagucacauuuugcuuugcuucuagucaaaacaucacugaagaauuuuaucaaucaacaugcagugcaguuagcaaaggcuaucuuagugcucuaagaacugguugguauacuaguguuauaacuauagaauuaaguaauaucaaggaaaauaaguguaauggaacagaugcuaagguaaaauugauaaaccaagaauuagauaaauauaaaaaugcuguaacagaauugcaguugcucaugcaaagcacaacagcagcaaacaaucgagccagaagagaacuaccaagguuuaugaauuauacacucaacaauaccaaaaaaaccaauguaacauuaagcaagaaaaggaaaagaagauuucuugguuuuuuguuagguguuggaucugcaaucgccaguggcauugcuguaucuaagguccugcacuuagaaggagaagugaacaagaucaaaagugcucuacuauccacaaacaaggccguagucagcuuaucaaauggaguuagugucuuaaccagcaaaguguuagaccucaaaaacuauauagauaaacaauuguuaccuauugugaauaagcaaagcugcagaauaucaaauauagaaacugugauagaguuccaacaaaagaacaacagacuacuagagauuaccagggaauuuaguguuaaugcagguguaacuacaccuguaagcacuuacauguuaacuaauagugaauuauugucauuaaucaaugauaugccuauaacaaaugaucagaaaaaguuaauguccaacaauguucaaauaguuagacagcaaaguuacucuaucauguccauaauaaaagaggaagucuuagcauauguaguacaauuaccacuauauggugugauagauacaccuuguuggaaauuacacacauccccucuauguacaaccaacacaaaagaagggucaaacaucuguuuaacaagaacugacagaggaugguacugugacaaugcaggaucaguaucuuucuucccacaagcugaaacauguaaaguucaaucgaaucgaguauuuugugacacaaugaacaguuuaacauuaccaagugaaguaaaucucugcaauguugacauauucaaucccaaauaugauuguaaaauuaugacuucaaaaacagauguaagcagcuccguuaucacaucucuaggagccauugugucaugcuauggcaaaacuaaauguacagcauccaauaaaaaucguggaaucauaaagacauuuucuaacgggugugauuauguaucaaauaaagggguggacacugugucuguagguaacacauuauauuauguaaauaagcaagaaggcaaaagucucuauguaaaaggugaaccaauaauaaauuucuaugacccauuaguauuccccucugaugaauuugaugcaucaauaucucaagucaaugagaagauuaaccagaguuuagcauuuauucguaaauccgaugaauuauuacaucauguaaaugcugguaaaucaaccacaaauaucaugauaacuacuauaauuauagugauuauaguaauauuguuaucauuaauugcuguuggacugcuccuauacuguaaggccagaagcacaccagucacacuaagcaaggaucaacugagugguauaaauaauauugcauuuaguaacuga。
配列番号13にしたがうmRNA配列:
auguccaaaaacaaggaccaacgcaccgcuaagacacuagaaaagaccugggacacucucaaucauuuauuauucauaucaucgggcuuauauaaguuaaaucuuaaaucuauagcacaaaucacauuauccauucuggcaaugauaaucucaacuucacuuauaauuacagccaucauauucauagccucggcaaaccacaaagucacacuaacaacugcaaucauacaagaugcaacaagccagaucaagaacacaaccccaacauaccucacucaggauccucagcuuggaaucagcuucuccaaucugucugaaauuacaucacaaaccaccaccauacuagcuucaacaacaccaggagucaagucaaaccugcaacccacaacagucaagacuaaaaacacaacaacaacccaaacacaacccagcaagcccacuacaaaacaacgccaaaacaaaccaccaaacaaacccaauaaugauuuucacuucgaaguguuuaacuuuguacccugcagcauaugcagcaacaauccaaccugcugggcuaucugcaaaagaauaccaaacaaaaaaccaggaaagaaaaccaccaccaagccuacaaaaaaaccaaccuucaagacaaccaaaaaagaucucaaaccucaaaccacuaaaccaaaggaaguacccaccaccaagcccacagaagagccaaccaucaacaccaccaaaacaaacaucacaacuacacugcucaccaacaacaccacaggaaauccaaaacucacaagucaaauggaaaccuuccacucaaccuccuccgaaggcaaucuaagcccuucucaagucuccacaacauccgagcacccaucacaacccucaucuccacccaacacaacacgccaguag。
配列番号14にしたがうmRNA配列:
auggaaaauacauccauaacaauagaauucucaagcaaauucuggccuuacuuuacacuaauacacaugaucacaacaauaaucucuuugcuaaucauaaucuccaucaugacugcaauacuaaacaaacuuugugaauauaacguauuccauaacaaaaccuuugaguuaccaagagcucgagucaacacauag。
配列番号15にしたがうmRNA配列:
auggaaacauacgugaacaagcuucacgaaggcuccacauacacagcugcuguucaauacaauguccuagaaaaagacgaugacccugcaucacuuacaauaugggugcccauguuccaaucaucuaugccagcagauuuacuuauaaaagaacuagcuaaugucaacauacuagugaaacaaauauccacacccaagggaccuucacuaagagucaugauaaacucaagaagugcauugcuagcacaaaugcccagcaaauuuaccauaugugcuaauguguccuuggaugaaagaagcaaacuggcauaugauguaaccacacccugugaaaucaaggcauguagucuaacaugccuaaaaucaaaaaauauguuaacuacaguuaaagaucucacuaugaagacacucaaccccacacaugauauuauugcuuuaugugaauuugaaaacauaguaacaucaaaaaaagucauaauaccaacauaccuaagauccaucagugucagaaauaaagaucugaacacacuugaaaauauaacaaccacugaauucaaaaaugccaucacaaaugcaaaaaucaucccuuacucaggauuacuauuagucaucacagugacugacaacaaaggagcauucaaauacauaaagccgcaaagucaauucauaguagaucuuggagcuuaccuagaaaaagaaaguauauauuauguuaccacaaauuggaagcacacagcuacacgauuugcaaucaaacccauggaagauuaa。
配列番号16にしたがうmRNA配列:
auggcucuuagcaaagucaaguugaaugauacacucaacaaagaucaacuucugucaucuagcaaauacaccauccaacggagcacaggagauaguauugauacuccuaauuaugaugugcagaaacacaucaauaaguuauguggcauguuauuaaucacagaagaugcuaaucauaaauucacuggguuaauagguauguuauaugcuaugucuagguuaggaagagaagacaccauaaaaauacucagagaugcgggauaucauguaaaagcaaauggaguagauguaacaacacaucgucaagacaucaaugggaaagaaaugaaauuugaaguguuaacauuggcaagcuuaacaacugaaauucaaaucaacauugagauagaaucuagaaaauccuacaaaaaaaugcuaaaagaaaugggagagguagcuccagaauacaggcaugauucuccugauugugggaugauaauauuauguauagcagcauuaguaauaaccaaauuggcagcaggggauagaucuggucuuacagccgugauuaggagagcuaauaauguccuaaaaaaugaaaugaaacguuacaaaggcuuacuacccaaggauauagccaacagcuucuaugaaguguuugaaaaacauccccacuuuauagauguuuuuguucauuuugguauagcacaaucuuccaccagagguggcaguagaguugaagggauuuuugcaggauuguuuaugaaugccuauggugcagggcaaguaaugcuacgguggggagucuuagcaaaaucaguuaaaaauauuauguuaggacaugcuagugugcaagcagaaauggaacaaguuguugagguuuaugaauaugcccaaaaauuggguggagaagcaggauucuaccauauauugaacaacccaaaagcaucauuauuaucuuugacucaauuuccucacuuuuccaguguaguauuaggcaaugcugcuggccuaggcauaaugggagaguacagagguacaccgaggaaucaagaucuauaugaugcagcaaaggcauaugcugaacaacucaaagaaaauggugugauuaacuacaguguauuagacuugacagcagaagaacuagaggcuaucaaacaucagcuuaauccaaaagauaaugauguagagcuuuga。
配列番号17にしたがうmRNA配列:
auggaucccauuauuaauggaaauucugcuaauguuuaucuaaccgauaguuauuuaaaagguguuaucucuuucucagaguguaaugcuuuaggaaguuacauauucaaugguccuuaucucaaaaaugauuauaccaacuuaauuaguagacaaaauccauuaauagaacacaugaaucuaaagaaacuaaauauaacacaguccuuaauaucuaaguaucauaaaggugaaauaaaauuagaagagccuacuuauuuucagucauuacuuaugacauacaagaguaugaccucguuggaacagauugcuaccacuaauuuacuuaaaaagauaauaagaagagcuauagaaauaagugaugucaaagucuaugcuauauugaauaaacuagggcuuaaagaaaaggacaagauuaaauccaacaauggacaggaugaagacaacucaguuauuacgaccauaaucaaagaugauauacuuucagcuguuaaggauaaucaaucucaucuuaaagcagacaaaaaucacucuacaaaacaaaaagacacaaucaaaacaacacucuugaagaaauuaauguguucaaugcagcauccuccaucaugguuaauacauugguuuaauuuauacacaaaauuaaacaacauauuaacacaguaucgaucaaaugagguuaaaaaccauggguuuauauugauagauaaucaaacucuuaguggauuucaauuuauuuugaaucaauaugguuguauaguuuaucauaaggaacucaaaagaauuacugugacaaccuauaaucaauucuugacauggaaagauauuagccuuaguagauuaaauguuuguuuaauuacauggauuaguaacugcuugaacacauuaaauaaaagcuuaggcuuaagaugcggauucaauaauguuaucuugacacaacuauuccuuuauggugauuguauacuaaagcuauuucacaaugagggguucuacauaauaaaagagguagagggauuuauuaugucucuaauuuuaaauauaacagaagaagaucaauucagaaaacgauuuuauaauaguaugcucaacaacaucacagaugcugcuaauaaagcucagaaaaaucugcuaucaagaguaugucauacauuauuagauaagacaguauccgauaauauaauaaauggcagauggauaauucuauuaaguaaguuccuuaaauuaauuaagcuugcaggugacaauaaccuuaacaaucugagugaacuauauuuuuuguucagaauauuuggacacccaaugguagaugaaagacaagccauggaugcuguuaaaguuaauugcaaugagaccaaauuuuacuuguuaagcaguuugaguauguuaagaggugccuuuauauauagaauuauaaaaggguuuguaaauaauuacaacagauggccuacuuuaagaaaugcuauuguuuuacccuuaagaugguuaacuuacuauaaacuaaacacuuauccuucuuuguuggaacuuacagaaagagauuugauuguguuaucaggacuacguuucuaucgugaguuucgguugccuaaaaaaguggaucuugaaaugauuauaaaugauaaagcuauaucacccccuaaaaauuugauauggacuaguuucccuagaaauuauaugccgucacacauacaaaacuauauagaacaugaaaaauuaaaauuuuccgagagugauaaaucaagaagaguauuagaguauuauuuaagagauaacaaauucaaugaaugugauuuauacaacuguguaguuaaucaaaguuaucucaacaacccuaaucaugugguaucauugacaggcaaagaaagagaacucaguguagguagaauguuugcaaugcaaccgggaauguucagacagguucaaauauuggcagagaaaaugauagcugaaaacauuuuacaauucuuuccugaaagucuuacaagauauggugaucuagaacuacaaaaaauauuagaauugaaagcaggaauaaguaacaaaucaaaucgcuacaaugauaauuacaacaauuacauuaguaagugcucuaucaucacagaucucagcaaauucaaucaagcauuucgauaugaaacgucauguauuuguagugaugugcuggaugaacugcaugguguacaaucucuauuuuccugguuacauuuaacuauuccucaugucacaauaauaugcacauauaggcaugcaccccccuauauaagagaucauauuguagaucuuaacaauguagaugaacaaaguggauuauauagauaucacaugggugguauugaaggguggugucaaaaacuauggaccauagaagcuauaucacuauuggaucuaauaucucucaaagggaaauucucaauuacugcuuuaauuaauggugacaaucaaucaauagauauaagcaaaccagucagacucauggaaggucaaacucaugcucaagcagauuauuugcuagcauuaaauagccuuaaauuacuguauaaagaguaugcaggcauaggucacaaauuaaaaggaacugagacuuauauaucacgagauaugcaauuuaugaguaaaacaauucaacauaacgguguauauuacccugcuaguauaaagaaaguccuaagagugggaccguggauaaacacuauacuugaugauuucaaagugagucuagaaucuauagguaguuugacacaagaauuagaauauagaggugaaagucuauuaugcaguuuaauauuuagaaauguaugguuauauaaucaaauugcucuacaauuaaaaaaucaugcguuauguaacaauaaauuauauuuggacauauuaaagguucugaaacacuuaaaaaccuuuuuuaaucuugauaauauugauacagcauuaacauuguauaugaauuuacccauguuauuuggugguggugaucccaacuuguuauaucgaaguuucuauagaagaacuccugauuuccucacagaggcuauaguucacucuguguucauacuuaguuauuauacaaaccaugacuuaaaagauaaacuucaagauuugucagaugauagauugaauaaguucuuaacaugcauaaucacguuugacaaaaacccuaaugcugaauucguaacauugaugagagauccucaagcuuuagggucugagagacaagcuaaaauuacuagugaaaucaauagacuggcaguuacagagguuuugaguacagcuccaaacaaaauauucuccaaaagugcacaacauuauaccacuacagagauagaucuaaaugauauuaugcaaaauauagaaccuacauauccucacgggcuaagaguuguuuaugaaaguuuacccuuuuauaaagcagagaaaauaguaaaucuuauaucagguacaaaaucuauaacuaacauacuggaaaagacuucugccauagacuuaacagauauugauagagccacugagaugaugaggaaaaacauaacuuugcuuauaaggauacuuccauuggauuguaacagagauaaaagagaaauauugaguauggaaaaccuaaguauuacugaauuaagcaaauauguuagggaaagaucuuggucuuuauccaauauaguugguguuacaucacccaguaucauguauacaauggacaucaaauauacaacaagcacuauagcuaguggcauaauuauagagaaauauaauguuaacaguuuaacacguggugagagaggaccaacuaaaccauggguugguucaucuacacaagagaaaaaaacaaugccaguuuauaauagacaaguuuuaaccaaaaaacaaagagaucaaauagaucuauuagcaaaauuggauuggguguaugcaucuauagauaacaaggaugaauucauggaagaacucagcauaggaacccuuggguuaacauaugaaaaggccaaaaaauuauuuccacaauauuuaagugucaacuauuugcaucgccuuacagucaguaguagaccaugugaauucccugcaucaauaccagcuuauagaacaacaaauuaucacuuugacacuagcccuauuaaucgcauauuaacagaaaaguauggugaugaagauauugacauaguauuccaaaacuguauaagcuuuggccuuagcuuaaugucaguaguagaacaauuuacuaauguauguccuaacagaauuauucucauaccuaagcuuaaugagauacauuugaugaaaccucccauauucacaggugauguugauauucacaaguuaaaacaagugauacaaaaacagcauauguuuuuaccagacaaaauaaguuugacucaauauguggaauuauucuuaaguaacaaaacacucaaaucuggaucucauguuaauucuaauuuaauauuggcacauaaaauaucugacuauuuucauaauacuuacauuuuaaguacuaauuuagcuggacauuggauucuaauuauacaacuuaugaaagauucuaaagguauuuuugaaaaagauuggggagagggauauauaacugaucauauguuuauuaauuugaaaguuuucuucaaugcuuauaagaccuaucucuuguguuuucauaaagguuauggcaaagcaaaacuggagugugauaugaacacuucagaucuucuauguguauuggaauuaauagacaguaguuauuggaagucuaugucuaagguauuuuuagaacaaaaaguuaucaaauacauucuuagccaagaugcaaguuuacauagaguaaaaggaugucauagcuucaaauuaugguuucuuaaacgucuuaauguagcagaauuuacaguuugcccuuggguuguuaacauagauuaucauccaacacauaugaaagcaauauuaacuuauauagaucuuguuagaaugggauugauaaauauagauagaauacacauuaaaaauaaacacaaauucaaugaugaauuuuauacuucuaaucucuuuuacauuaauuauaacuucucagauaauacucaucuauuaacuaaacauauaaggauugcuaauucagaauuagaaaauaauuacaacaaauuauaucauccuacaccagaaacccuagagaauauacuagccaauccgauuaaaaguaaugacaaaaagacacugaacgacuauuguauagguaaaaauguugacucaauaauguuaccauuguuaucuaauaagaagcuuguuaaaucgucugcaaugauuagaaccaauuacagcaaacaagaccuguacaaucuauucccuacgguugugaucgauagaauuauagaucauucagguaauacagccaaauccaaccaacuuuacacuacuacuucccaucaaauaucuuuagugcacaauagcacaucacuuuauugcaugcuuccuuggcaucauauuaauagauucaauuuuguauuuaguucuacagguuguaaaauuaguauagaguauauuuuaaaagaccuuaaaauuaaagauccuaauuguauagcauucauaggugaaggagcagggaauuuauuauugcguacagugguggaacuucauccugacauaagauauauuuacagaagucugaaagauugcaaugaucauaguuuaccuauugaguuuuuaaggcuauacaauggacauaucaacauugauuauggugaaaauuugaccauuccugcuacagaugcaaccaacaacauucauuggucuuauuuacauauaaaguuugcugaaccuaucagucuuuuuguaugugaugccgaauugccuguaacagucaacuggaguaaaauuauaauagaauggagcaagcauguaagaaaaugcaaguacuguuccucaguuaauaaauguacguuaauaguaaaauaucaugcucaagaugauauugauuucaaauuagacaauauaacuauauuaaaaacuuauguaugcuuaggcaguaaguuaaagggaucggagguuuacuuaguccuuacaauagguccugcaaauauauuuccaguauuuaauguaguacaaaaugcuaaauugauacuaucaagaaccaaaaauuucaucaugccuaagaaagcugauaaagagucuauugaugcaaauauuaaaaguuugauacccuuucuuuguuacccuauaacaaaaaaaggaauuaauacugcauugucaaaacuaaagaguguuguuaguggagauauacuaucauauucuauagcuggacggaaugaaguuuucagcaauaaacuuauaaaucauaagcauaugaacaucuuaaagugguucaaucauguuuuaaauuucagaucaacagaacuaaacuauaaccauuuauauaugguagaaucuacauauccuuaccuaagugaauuguuaaacagcuugacaacuaaugaacuuaaaaaacugauuaaaaucacagguagucuguuauacaacuuucauaaugaauaa。
配列番号18にしたがうmRNA配列:
Augucacgaaggaauccuugcaaauuugaaauucgaggucauugcuugaaugguaagagaugucauuuuagucauaauuauuuugaauggccaccccaugcacugcucguaagacaaaacuuuauguuaaacagaauacuuaagucuauggauaaaaguauagauaccuuaucagaaauaaguggagcugcagaguuggacagaacagaagaguaugcucuugguguaguuggagugcuagagaguuauauaggaucaauaaauaauauaacuaaacaaucagcauguguugccaugagcaaacuccucacugaacucaauagugaugauaucaaaaaacugagagacaaugaagagcuaaauucacccaagauaagaguguacaauacugucauaucauauauugaaagcaacaggaaaaacaauaaacaaacuauccaucuguuaaaaagauugccagcagacguauugaagaaaaccaucaaaaacacauuggauauccacaagagcauaaccaucaacaacccaaaagaauuaacuguuagugauacaaaugaccaugccaaaaauaaugauacuaccuga。
配列番号19にしたがうmRNA配列:
augaccaugccaaaaauaaugauacuaccugacaaauauccuuguaguauaacuuccauacuaauaacaaguagauguagagucacuauguauaaucgaaagaacacacuauauuucaaucaaaacaacccaaauaaccauauguacucaccgaaucaaacauucaaugaaauccauuggaccucacaagacuugauugacacaauucaaaauuuucuacagcaucuagguguuauugaggauauauauacaauauauauauuagugucauaa。
配列番号20にしたがうmRNA配列:
auggaaaaguuugcuccugaauuccauggagaagaugcaaacaacagggcuacuaaauuccuagaaucaauaaagggcaaauucacaucaccuaaagaucccaagaaaaaagauaguaucauaucugucaacucaauagauauagaaguaaccaaagaaagcccuauaacaucaaauucaaccauuauuaacccaacaaaugagacagaugauaaugcagggaacaagcccaauuaucaaagaaaaccucuaguaaguuucaaagaagacccuauaccaagugauaaucccuuuucaaaacuauacaaagaaaccauagagacauuugauaacaaugaagaagaaucuagcuauucauaugaagaaauaaaugaucagacgaacgauaauauaacugcaagauuagauaggauugaugaaaaauuaagugaaauacuaggaaugcuucacacauuaguaguagcaagugcaggaccuacaucugcuagggaugguauaagagaugccaugguugguuuaagagaagaaaugauagaaaaaaucagaacugaagcauuaaugaccaaugacagauuagaagcuauggcaagacucaggaaugaggaaagugaaaagauggcaaaagacacaucagaugaagugucucucaauccaacaucagagaaauugaacaaccuguuggaagggaaugauagugacaaugaucuaucacuugaagauuucuga。
配列番号21にしたがうmRNA配列:
augggcagcaauucguugaguaugauaaaaguuagauuacaaaauuuguuugacaaugaugaaguagcauuguuaaaaauaacaugcuauacugacaaauuaauacauuuaacuaaugcuuuggcuaaggcagugauacauacaaucaaauugaauggcauuguguuugugcauguuauuacaaguagugauauuugcccuaauaauaauauuguaguaaaauccaauuucacaacaaugccagugcuacaaaauggagguuauauaugggaaaugauggaauuaacacauugcucucaaccuaauggucuaauagaugacaauugugaaauuaaauucuccaaaaaacuaagugauucaacaaugaccaauuauaugaaucaauuaucugaauuacuuggauuugaucuuaauccauaa。
配列番号22にしたがうmRNA配列:
auggacacaacccacaaugauaccacaccacaaagacugaugaucacagacaugagaccguugucacuugagacuacaauaacaucacuaaccagagacaucauaacacacagauuuauauacuuaauaaaucaugaaugcauagugagaaaacuugaugaaagacaggccacauuuacauuccuggucaacuaugaaaugaaacuauugcacaaaguaggaagcacuaaauauaaaaaauauacugaauacaacacaaaauauggcacuuucccuaugccgauauucaucaaucaugauggguucuuagaaugcauuggcauuaagccuacaaagcauacucccauaauauacaaguaugaucucaauccauag。
CATCACATTT AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA AAAATGGAAA GAATCT(特許出願WO2013/143700の配列番号1369に対応する)。
アルブミン7の3’UTR
CATCACATTTAAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCT(特許出願WO2013/143700の配列番号1376に対応する配列番号25)
にしたがうヒトのアルブミンの断片に由来する核酸配列を含んでいる。
ホモサピエンス ヘモグロビン,α1(HBA1)の3’UTR
GCTGGAGCCTCGGTGGCCATGCTTCTTGCCCCTTGGGCCTCCCCCCAGCCCCTCCTCCCCTTCCTGCACCCGTACCCCCGTGGTCTTTGAATAAAGTCTGAGTGGGCGGC(特許出願WO2013/143700の配列番号1370に対応する、配列番号26)
ホモサピエンス ヘモグロビン,α2(HBA2)の3’UTR
GCTGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCCCTCCTTGCACCGGCCCTTCCTGGTCTTTGAATAAAGTCTGAGTGGGCAG(特許出願WO2013/143700の配列番号1371に対応する、配列番号27)
ホモサピエンス ヘモグロビン,β(HHB)の3’UTR
GCTCGCTTTCTTGCTGTCCAATTTCTATTAAAGGTTCCTTTGTTCCCTAAGTCCAACTACTAAACTGGGGGATATTATGAAGGGCCTTGAGCATCTGGATTCTGCCTAATAAAAAACATTTATTTTCATTGC(特許出願WO2013/143700の配列番号1372に対応する、配列番号28)
にしたがうヒトのαもしくはβグロビンに由来する核酸配列を含んでいるか、または当該核酸配列からなる。
αグロビン遺伝子の3’UTRの、中央のα複合体結合部分(本明細書において「muag」とも呼ばれる)
GCCCGATGGGCCTCCCAACGGGCCCTCCTCCCCTCCTTGCACCG(特許出願WO2103/143700の配列番号1393に対応する配列番号29)
にしたがう、αグロビン遺伝子(例えば、ヒトのαグロビン遺伝子)の、中央のα複合体結合部分を含んでいるか、または当該中央のα複合体結合部分からなる。
式(I)(ステム境界配列なしのステム−ループ配列):
ステム1またはステム2の境界エレメントN1−6は、1〜6、好ましくは2〜6、より好ましくは2〜5、より一層好ましくは3〜5、最も好ましくは4〜5、または5のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびC、またはそのヌクレオチド類似物から選択されるヌクレオチドから選択され;)
ステム1[N0−2GN3−5]は、ステム2のエレメントと逆相補的または部分的に逆相補的であり、かつ5〜7ヌクレオチドの間の連続する配列であり;
N0−2は、0〜2、好ましくは0〜1、より好ましくは1のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびC、またはそのヌクレオチド類似物から選択されるヌクレオチドから選択され;
N3−5は、3〜5、好ましくは4〜5、より好ましくは4のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびC、またはそのヌクレオチド類似物から選択されるヌクレオチドから選択され;
Gは、グアノシンまたはその類似物であり、ステム2におけるその相補的なシチジンヌクレオチドがグアノシンによって置き換えられている条件のもとに、任意にシチジンまたはその類似物に置き換えられ得;
ループ配列[N0−4(U/T)N0−4]は、ステム1およびステム2のエレメントの間に配置されており、3〜5ヌクレオチド、より好ましくは4ヌクレオチドの連続する配列であり;
N0−4のそれぞれは、他のNから独立して、0〜4、好ましくは1〜3、より好ましくは1〜2のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびC、またはそのヌクレオチド類似物から選択されるヌクレオチドから選択され、U/Tは、ウリジンまたは任意にチミジンを表しており;
ステム2[N3−5CN0−2]は、ステム1のエレメントと逆相補的または部分的に逆相補的であり、かつ5〜7ヌクレオチドの間の連続する配列であり;
N3−5は、3〜5、好ましくは4〜5、より好ましくは4のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびC、またはそのヌクレオチド類似物から選択されるヌクレオチドから選択され;
N0−2は、0〜2、好ましくは0〜1、より好ましくは1のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびC、またはそのヌクレオチド類似物から選択されるヌクレオチドから選択され;
Cは、シチジンまたはその類似物であり、ステム1におけるその相補的なグアノシンヌクレオチドがシチジンに置き換えられている条件のもとに、グアノシンまたはその類似物に任意に置き換えられ得;
ステム1およびステム2は、互いに塩基対形成可能であり、例えばヌクレオチドAとU/Tと、またはGとCとのワトソン−クリック塩基対形成または非ワトソン−クリック塩基対形成(例えば、ゆらぎ塩基対形成、逆ワトソン−クリック塩基対形成、フーグスティーン塩基対形成、逆フーグスティーン塩基対形成)によって、塩基対形成がステム1およびステム2の間に生じ得る逆相補性配列を形成しているか、またはステム1およびステム2は、互いに塩基対形成可能であり、不完全な塩基対形成がステム1およびステム2の間に、2つのステムにおける1つ以上の塩基が他方のステムの逆相補的な配列において相補的な塩基を有していないことに基づいて、生じ得る部分的な逆相補性配列を形成している。
式(Ia)(ステム境界エレメントなしのステム−ループ配列):
式(Ib)(ステム境界エレメントなしのステム−ループ配列):
a.)5’キャップ構造、好ましくはm7GpppN;
b.)呼吸器合胞体ウイルス(RSV)の、好ましくは呼吸器合胞体ウイルス(RSV)の融合タンパク質Fに由来する、少なくとも1つの抗原ペプチドもしくは抗原タンパク質をコードしているコード領域;
c.)64のアデノシンを好ましく含んでいる。ポリ(A)配列;および
d.)任意に、30のシトシンを好ましく含んでいる、ポリ(C)配列
を含み得る。
好ましくは5’から3’方向に、
a.)5’キャップ構造、好ましくはm7GpppN;
b.)狂犬病ウイルスの、好ましくは狂犬病ウイルスの糖タンパク質G(RAV−G)に由来する、少なくとも1つの抗原ペプチドもしくは抗原タンパク質をコードしているコード領域;
c.)好ましくは64のアデノシンを含んでいる、ポリ(A)配列;
d.)任意に、好ましくは30のシトシンを含んでいる、ポリ(C)配列;ならびに
e.)好ましくは配列番号30にしたがう核酸配列の対応するRNA配列を含んでいる、ヒストン ステム−ループ
を含んでいる。
好ましくは5’から3’方向に、
a.)5’キャップ構造、好ましくはm7GpppN;
b.)呼吸器合胞体ウイルス(RSV)の、好ましくは呼吸器合胞体ウイルス(RSV)の融合タンパク質に由来する、少なくとも1つの抗原ペプチドもしくは抗原タンパク質をコードしているコード領域;
c.)任意に、好ましくは配列番号29にしたがう核酸配列の対応するRNA配列を含んでいる、アルファグロビン遺伝子に由来する3’UTRエレメント、その相同物、断片もしくはバリアント;
d.)好ましくは64のアデノシンを含んでいる、ポリ(A)配列;
e.)任意に、好ましくは30のシトシンを含んでいる、ポリ(C)配列;および
f.)好ましくは配列番号30にしたがう核酸配列の対応するRNA配列を含んでいる、ヒストン ステム−ループ
を含んでいる。
好ましくは5’から3’方向に、
a.)5’キャップ構造、好ましくはm7GpppN;
b.)任意に、TOP遺伝子に由来する、好ましくは配列番号23にしたがう核酸配列の対応するRNA配列に由来する、5’UTRエレメント、またはその断片もしくはバリアント;
c.)呼吸器合胞体ウイルス(RSV)の、好ましくは呼吸器合胞体ウイルス(RSV)の融合タンパク質Fに由来する、少なくとも1つの抗原ペプチドもしくは抗原タンパク質をコードしているコード領域;
d.)任意に、安定なmRNAをもたらす、遺伝子またはその相同物、断片もしくはバリアントに由来する(配列番号25にしたがう核酸配列の対応するRNAに由来する)3’UTRエレメント;
e.)好ましくは64のアデノシンを含んでいる、ポリ(A)配列;
f.)任意に、好ましくは30のシトシンを含んでいる、ポリ(C)配列;ならびに
g.)好ましくは配列番号30にしたがう核酸配列の対応するRNA配列を含んでいる、ヒストン ステム−ループ
を含んでいる。
好ましくは5’から3’方向に、
a)本明細書に規定されているような5’キャップ構造、好ましくはm7GpppN;
b)呼吸器合胞体ウイルス(RSV)の融合タンパク質F、糖タンパク質G、短い疎水性タンパク質SH、マトリクスタンパク質M、核タンパク質N、ラージポリメラーゼL、M2−1タンパク質、M2−2タンパク質リン酸タンパク質P、非構造タンパク質NS1、または非構造タンパク質NS2に由来する少なくとも1つの抗原ペプチドもしくは抗原タンパク質、またはその断片、バリアントもしくは誘導体をコードしている、好ましくは野生型mRNAのコード領域のG/C含有量と比べて、向上しているか、または最大化されているG/C含有量を有している、コード領域;
c)好ましくは安定なmRNAをもたらす遺伝子、より好ましくは配列番号29にしたがう核酸配列の対応するRNA、またはその相同物、断片もしくはバリアントに由来する、本明細書に規定されているような3’UTRエレメント;
d)好ましくは64のアデノシンからなる、ポリ(A)配列;
e)任意に、好ましくは30のシトシンからなる、ポリ(C)配列;ならびに
f)好ましくは配列番号30にしたがう核酸配列の対応するRNA配列、少なくとも1つのヒストン ステム−ループ配列
を含んでいる。
好ましくは5’から3’方向に、
a)本明細書に規定されているような5’キャップ構造、好ましくはm7GpppN;
b)本明細書に規定されているような5’UTRエレメント、好ましくはTOP遺伝子の5’UTR(好ましくは配列番号23にしたがう、5’末端オリゴピリミジントラクトを欠いている人のリボソームタンパク質ラージ32の5’UTR)、またはその断片、相同物もしくはバリアントに由来する核酸配列を含んでいるか、または当該核酸配列からなる5’UTRエレメント;
c)呼吸器合胞体ウイルス(RSV)の融合タンパク質F、糖タンパク質G,短い疎水性タンパク質SH、マトリクスタンパク質M、核タンパク質N、ラージポリメラーゼL、M2−1タンパク質、M2−2タンパク質、非構造タンパク質NS1もしくは非構造タンパク質NS2、またはその断片、バリアントもしくは誘導体に由来する少なくとも1つの抗原ペプチドまたは抗原タンパク質をコードしている、好ましくは野生型mRNAのコード領域のG/C含有量と比べて、向上されているか、または最大化されているG/C含有量を有している、コード領域;
d)3’UTRエレメント、好ましくは配列番号24にしたがうヒトのアルブミンの3’UTRもしくは対応するRNA、またはその相同物、断片もしくはバリアント;
e)好ましくは64のアデノシンからなる、ポリ(A)配列;
f)任意に、好ましくは20のシトシンからなる、ポリ(C)配列。
g)少なくとも1つのヒストン ステム−ループ、好ましくは配列番号30にしたがう核酸配列の対応するRNA配列
を含んでいる。
(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x (式(III))
(ここで、l+m+n+o+x=8〜15、l、m、nまたはoのそれぞれは互いに独立して、Arg、Lys、HisおよびOrnの全体の含有量がオリゴペプチドの全アミノ酸の50%に相当する条件において、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14または15から選択される任意の数字であり;Xaaは、Arg、Lys、HisまたはOrn以外の天然の(天然に存在する)、または非天然のアミノ酸から選択される任意のアミノ酸であり得;xは、Xaaの全体の含有量がオリゴペプチドの全アミノ酸の50%を超えない条件において0、1、2、3または4から選択される任意の数字であり得る)から選択され得る。これに関連して、特に好ましいカチオン性のペプチドは、例えば、Arg7、Arg8、Arg9、H3R9、R9H3、H3R9H3、YSSR9SSY、(RKH)4、Y(RKH)2Rなどである。これに関連して、WO2009/030481の開示事項は、参照によって本明細書に組み込まれる。
L−P1−S−[S−P2−S]n−S−P3−L 式(IV)
にしたがう重合体担体分子から選択され、
P1およびP3は、互いに同じか、または異なり、直鎖状または分枝鎖状の疎水性重合体鎖を表しており、P1およびP3のそれぞれは、成分P2(または当該成分がP1およびP2またはP3およびP2の間におけるリンカーとして使用される場合に、代替的に(AA)、(AA)x、もしくは[(AA)x]zおよび/またはさらなる成分(例えば、(AA)、(AA)x、[(AA)x]z、またはL)との縮合によってジスルフィド結合を形成可能な、少なくとも1つの−SH部分を示しており、直鎖状または分枝鎖状の疎水性重合体鎖は互いに独立して、ポリエチレングリコール(PEG)、ポリ−N−(2−ヒドロキシプロピル)メタクリルアミド、ポリ−2−(メタクリロキシルオキシ)エチルホスホリルクロリン、ポリ(ヒドロキシアルキルL−アスパラギン)、ポリ(2−(メタクリロキシルオキシ)エチルホスホリルクロリン)、ヒドロキシエチルスターチまたはポリ(ヒドロキシアルキルL−グルタミン)から選択され、疎水性重合体鎖は、約1kDa〜約100kDa、好ましくは約2kDa〜約25kDa;より好ましくは約2kDa〜約10kDa(例えば、約5kDa〜約25kDaまたは5kDa〜約10kDa)の分子量を示し;
P2は、好ましくは約3〜約100のアミノ酸の長さ、より好ましくは約3〜約50のアミノ酸の長さ、より一層好ましくは約3〜25のアミノ酸(例えば、約3〜10、5〜15、10〜20または15〜25のアミノ酸)の長さ、より好ましくは約5〜20のアミノ酸の長さ、より一層好ましくは約10〜約20の長さを有している、ジスルフィド架橋された成分によって形成されている重合体担体のための、例えば本明細書に規定されているような、カチオン性またはポリカチオン性のペプチドまたはタンパク質であるか;または
約0.5kDa〜約30kDaの分子量(約1kDa〜約20kDa、より一層好ましくは約1.5kDa〜約10kDaの分子量)を典型的に有しているか、または約0.5kDa〜約100kDaの分子量(約10kDa〜約50kDa、より一層好ましくは約10kDa〜約30kDaの分子量が挙げられる)を有している、ジスルフィド架橋された成分によって形成されている重合体担体のための、例えば本明細書に規定されているような、カチオン性またはポリカチオン性のペプチドまたはタンパク質であり;
P2のそれぞれは、さらなる成分P2、または(複数の)成分P1および/またはP3、または代替的にさらなる成分(例えば(AA)、(AA)x、または[(AA)x]z)とジスルフィド結合を形成可能な、少なくとも2つの−SH部分を示し;
−S−S−(大括弧はより読みやすいように省略されている)は、(可逆的な)ジスルフィド結合であり、Sは、好ましくは、(可逆的な)ジスルフィド結合を有している硫黄または−SHを担持する部分を表す。(可逆的な)ジスルフィド結合は、いずれかの成分P1およびP2、P2およびP2、またはP2およびP3、または任意に、本明細書に規定されているようなさらなる成分(例えば、(AA)、(AA)x、または[(AA)x]zなど)の−SH部分の縮合によって好ましく形成され;−SH部分は、これらの成分の構造の一部であり得るか、もしくは以下に規定されているような修飾によって加えられ得;
Lは、互いに独立して、RGD、トランスフェリン、フォレート、シグナルペプチドもしくはシグナル配列、局在化シグナルもしくは局在化配列、核局在化シグナルもしくは核局在化配列(NLS)、抗体、細胞透過性ペプチド(例えば、TATまたはKALA)、リガンドもしくは受容体(例えば、サイトカイン、ホルモン、成長因子など)、小分子(例えば、マンノースもしくはガラクトースのような炭水化物、または合成リガンド)、小分子アゴニスト、受容体の阻害剤もしくはアンタゴニスト(例えば、RGDペプチド模倣類似物)、または本明細書に規定されているようなさらなるタンパク質などから選択され得る、存在し得るか、または存在し得ない選択性のリガンド(ligand)であり;
nは、典型的に約1〜50の範囲、好ましくは約1、2もしくは3〜30、より好ましくは約1、2、3、4もしくは5〜25の範囲、または好ましくは約1、2、3、4もしくは5〜20の範囲、または好ましくは約1、2、3、4もしくは5〜15の範囲、好ましくは約1、2、3、4もしくは5〜10の範囲(約4〜9、4〜10、3〜20、4〜20、5〜20もしくは10〜20の範囲、または約3〜15、4〜15、5〜15、10〜15の範囲、または約6〜11もしくは7〜10の範囲が挙げられる)から選択される整数である。最も好ましくは、nは、約1、2、3、4もしくは5〜10の範囲、より好ましくは1、2、3もしくは4〜9の範囲、1、2、3もしくは4〜8の範囲、または1、2もしくは3〜7の範囲にある。
・F+G(血清型A)+G(血清型B)
・F+G(血清型A)+G(血清型B)+M2−1
・F+G(血清型A)+G(血清型B)+N
・F+G(血清型A)+G(血清型B)+N+M2−1
・F+M2−1+N
・F+M2−1
・F+N
・F+G(血清型A)+G(血清型B)+N+M2−1+P+M−2+M+L
・F+G(血清型A)+G(血清型B)+N+M2−1+P+M2−2+M
・F+G(血清型A)+G(血清型B)+N+M−2+P+M2−2+L
・F+G(血清型A)+G(血清型B)+N+M−2+P+M+L
・F+G(血清型A)+G(血清型B)+N+M−2+M2−2+M+L
・F+G(血清型A)+G(血清型B)+N+P+M2−2+M+L
・F+G(血清型A)+G(血清型B)+M2−2+P+M2−2+L
である。
a)本発明のmRNA配列、複数の本発明のmRNA配列を含んでいる組成物、本発明の薬学的組成物、または本明細書に規定されているような本発明のmRNAを含んでいるキットもしくはキットの部分を準備すること;
b)mRNA配列番号、組成物、薬学的組成物またはキットもしくはキットの部分を、組織または生体に使用すること、または投与すること;
c)必要に応じてRNA免疫グロブリンを投与すること
を包含している。
以下に示されている図面は、単なる例証であり、さらなる一面において本発明を説明している。これらの図面は、それらに本発明を限定しているとは解釈されるべきではない。
メスのBALB/cマウスの内皮(i.d.)に、RSV−F long mRNAワクチン(160μgのR1691)またはバッファーコントロールとしての乳酸リンゲル液(RiLaバッファー)を注入した。1群の筋肉内(i.m.)に、10μgの不活性化RSV longワクチンを注入した。すべての動物は、21日および35日に追加注入を受け、血液サンプルを、実施例2に記載の通りに、プールされた抗体力価の決定のために49日に回収した。
明らかなように、RSV−F long mRNAワクチンは、サブクラスIgG1およびIgG2aの抗Fタンパク質抗体を誘導する。抗体力価はグラフに示されている(n=5 マウス/群)。
実験を実施例3に記載の通りに実施し、抗体の総IgG力価をELISAによって決定した。
明らかなように、抗体の力価は、最後の追加ワクチン接種後の少なくとも11か月にわたって安定である。
実験を実施例4に記載の通りに実施し、T細胞を、細胞内のサイトカイン染色によって、抗原特異的な、サイトカインの誘導について分析した。細胞を、RSV−Fペプチド(stim.F;KYKNAVTEL)またはコントロールのインフルエンザHAペプチド(stim.HA;IYSTVASSL)によって刺激した。グラフにおける線は中央値を表している(n=5 マウス/群)。
明らかなように、RSV Fusion(F)タンパク質特異的な多機能性CD8+T細胞を誘導し、対照的に、不活性化RSVに基づくワクチンは、Fタンパク質特異的なCD8+T細胞を誘導できない。
実験を実施例5に記載の通りに実施し、細胞を、ProMix RSV-M(15merペプチド)を用いた刺激後におけるサイトカインの抗原特異的な誘導について、細胞内サイトカイン染色によって分析した。グラフにおける線は、中央値を表している(n=5 マウス/群)。
明らかなように、RSV−N mRNAワクチンは、RSV核タンパク質(N)−特異的な多機能性CD8+T細胞をマウスにおいて誘導し、対照的に不活性化RSVに基づくワクチンは、Nタンパク質特異的なCD8+T細胞を誘導できない。
実験を実施例5に記載の通りに実施し、T細胞を、ProMix RSV-M(15merペプチド)を用いた刺激後におけるサイトカインの抗原特異的な誘導について、細胞内サイトカイン染色によって分析した。グラフにおける線は、中央値を表している(n=5 マウス/群)。
明らかなように、RSV−N mRNAワクチンは、RSV核タンパク質(N)特異的な多機能性CD4+T細胞を誘導し、対照的に、不活性化RSVに基づくワクチンは、Nタンパク質特異的なCD4+T細胞を誘導しない。
実験を実施例5に記載の通りに実施し、T細胞を、M2−1特異的な9merペプチドを用いた刺激後におけるサイトカインの抗原特異的な誘導について、細胞内サイトカイン染色によって分析した。グラフにおける線は、中央値を表している(n=5 マウス/群)。
明らかように、RSV−M2−1 mRNAワクチンは、RSV RSV−M2−1特異的な多機能性CD8+T細胞を誘導し、対照的に、不活性化RSVに基づくワクチンは、M2−1タンパク質特異的なCD8+T細胞をできない。
実験を実施例6に記載の通りに実施し、RSV−F特異的な総IgG力価を、49日にELISAによって決定した。血清を、後に示されている通り、異なる希釈率において分析した。
実験を実施例6に記載の通りに実施し、49日におけるウイルス中和力価を、プラーク形成アッセイによって決定した。
実験を実施例6に記載の通りに実施した。
(A)RSV抗原投与感染後の5日における肺の力価。mRNAワクチンを用いてワクチン接種されたすべての動物群は、実施されたウイルス力価測定の検出レベル以下のウイルス力価を示し、ウイルスの肺の力価についてワクチン接種されたコットンラットの防御を証明している。mRNAワクチンと比べて、ホルマリン不活性化RSVに基づくワクチンは、肺におけるウイルス力価を抑制できなかった。
(B)RSV抗原投与感染後の5日における鼻腔の力価。また、鼻腔組織におけるウイルス力価は、mRNAを用いてワクチン接種された群において大きく低下した。mRNAと比べて、ホルマリン不活性化ウイルスに基づくワクチンは、鼻腔のウイルス力価を低下させ得なかった。
実験を実施例7に記載の通りに実施した。
(A)RSV抗原投与感染後の5日における肺力価。mRNAを用いて皮内にワクチン接種されたすべての動物群は、バッファーコントロール群と比べて低下したウイルス力価を示し、ウイルスの肺の力価についてワクチン接種されたコットンラットの防御を証明している。RSV−F mRNA枠地温の前もっての単回用量は、肺におけるウイルス力価を効果的に低下させた。
(B)―RSV抗原投与感染後の5日における肺の力価。また、肺におけるウイルス力価は、mRNAを用いて筋肉内にワクチン接種された群において強く低下された。
以下に示されている実施例は、単に例示であり、さらなる様式において本発明を説明している。これらの実施例は、それらに本発明を限定することを意図されていない。
1.DNAコンストラクトおよびmRNAコンストラクトの調製
本実施例のために、RSV long株のRSV−Fタンパク質(R1691およびR2510)、RSV−F del554−574(R2821)変異タンパク質、RSV
N−タンパク質(R2831)およびRSV M2−1タンパク質(R2833)をコードしている複数のDNA配列を準備し、続くインビトロ転写反応に使用した。RSV−F del554−574変異タンパク質は、これまでに説明されている(Oomens et al. 2006. J. Virol. 80(21):10465-77)。
第1段落にしたがって調製したそれぞれのDNAプラスミドを、キャップ類似物(m7GpppG)の存在下において、T7ポリメラーゼを用いて、インビトロにおいて転写させた。続いて、mRNAを、PureMessenger(登録商標)(CureVac、Tubingen、Germany;国際公開第2008/07592号)を用いて精製した。
複合化試薬:プロタミン。
mRNAを、比率(1:2)(w/w)(免疫賦活成分)におけるプロタミンの、mRNAに対する添加によって、プロタミンと複合化させた。10分間のインキュベーション後に、抗原提示するmRNAとして使用された同量の遊離mRNAを加えた。
免疫化
BALB/cマウスに、RSV−f long mRNAワクチン(実施例1にしたがうR1691;25μg/マウス/ワクチン接種日)またはバッファーコントロールとしての乳酸リンゲル液)を皮下に(i.d.)、0日に、表2に示されている通りに注入した。コントロール群に、10μgの不活性化RSV longワクチンを筋肉内に(i.m.)、注入した。不活性化「呼吸器合胞体ウイルス抗原」(不活性化RSV long)を、INSTITUT VIRION/SERION GmbH-SERION IMMUNDIAGNOSTICA GmbHから購入した。不活性化ウイルスを、0.2μg/μLの最終濃度が達成されるように、滅菌PBSにおいて希釈した。すべての動物は、14日および28日に追加免疫を受けた。血液サンプルを、抗RSV F抗原の力価の決定のために42日に回収した。
ELISAプレートを、組換えヒトRSV融合糖タンパク質(rec.hu F-protein;最終濃度:5μg/mL)(Sino Biological Inc.)を用いて被覆した。被覆されたプレートを、所定の血清希釈物を用いてインキュベートし、Fタンパク質に対して特異的に結合することを、ビオチン化アイソトープに特異的な抗マウス抗体を、ABTS基質をともなったストレプトアビジン−HRP(ホースラディッシュペルオキシダーゼ)との組合せにおいて用いて、検出する。
図6から明らかなように、RSV−F long mRNAワクチンは、不活性化RSVに対する抗体力価に匹敵する、RSV Fタンパク質に対する抗体力価(総IgG、IgG1およびIgG2a)を含んでいる。
免疫化
BALB/cマウスの皮内(i.d.)に、20μgのRSV−F long mRNAワクチン(R1691)または乳酸リンゲル液(LiLa)バッファーを、表3に示されているワクチン接種予定にしたがって注入した。
図7から明らかなように、RSV−F long mRNAワクチンは、最後の追加免疫から11か月にわたる安定な抗体力価によって証明される通り、長期にわたる免疫応答を誘導した。
表4に示されているように、BALB/cマウスの皮内(i.d.)に、RSV−F long mRNAワクチン R1691、またはバッファーコントロールとしての乳酸リンゲル液(RiLa)を、0日に注入した。コントロール群の筋肉内(i.m.)に、10μgの不活性化RSV longワクチンを注入した。不活性化「呼吸器合胞体ウイルス抗原」(不活性化RSV)を、INSTITUT VIRION/SERION GmbH-SERION IMMUNDIAGNOSTICA GmbHから購入した。不活性化ウイルスを、0.2μg/μLの最終濃度が達成されるように滅菌PBSに希釈した。
ワクチン接種されたマウスおよびコントロールのマウスからの脾臓細胞を、標準的なプロトコルにしたがって分離した。簡単に説明すると、分離した脾臓細胞を細胞ろ過器に通してすりつぶし、PBS/1%FBSにおいて洗浄し、赤血球を溶解させた。PBS/1%FBSを用いた十分な洗浄段階の後に、脾臓細胞を、96ウェルプレート(2×106細胞/ウェル)に播いた。翌日に、細胞を、RSV−Fペプチド(KYKNAVTEL;5Mg/ml;H−2kdの再構築されたT細胞エピトープ)または無関係なインフルエンザHAタンパク質由来のコントロールペプチド(IYSTVASSL;5μg/ml;EMC Microcollectionsから購入した)、ならびに抗CD28抗体(BD Biosciences)を用いて、GolgiPlug(商標)/GolgiStop(商標)(ブレフェルディンAおよびモネンシンを含んでいるタンパク質輸送阻害剤;それぞれBD Biosciences)の混合物の存在下において、37℃において6時間にわたって刺激した。刺激の後に、細胞を洗浄し、Cytofix/Cytoperm試薬(BD Biosciences)を用いて、製造者のマニュアルにしたがって細胞内サイトカインのために染色した。以下の抗体:CD8−PECy7(1:200)、CD3−FITC(1:200)、IL2−PerCP−Cy5.5(1:100)、TNFα−PE(1:100)、IFNγ−APC(1:100)(eBioscience)、CD4−BD Horizon V450(1:200)(BD Biosciences)を染色のために使用し、1:100希釈されたFcγ−ブロックとともにインキュベートされた。生細胞/死細胞を区別するために、Aqua Dye(Invitrogen)を使用した。細胞を、Canto IIフローサイトメーター(Beckton Dickinson)を用いて回収した。フローサイトメトリーのデータを、FlowJoソフトウェア(Tree Star, Inc.)を用いて解析した。統計解析を、GraphPad Prismソフトウェア、Version 5.01を用いて実施した。群の間における統計的な差を、マンホイットニー検定によって評価した。
図8から明らかなように、RSV−Flong mRNAワクチン(R1691)は、RSV Fタンパク質を対象にしている、IFNγ陽性、TNFα陽性およびIFNγ/TNFα二重陽性の多機能性CD8+T細胞を誘導した。意外にも、不活性化RSVウイルスに基づくワクチンは、抗原特異的なCD8+T細胞を誘導し得なかった。
免疫化
表5に示されているように、BALB/cマウスの皮内(i.d.)に、異なる投与量のRSV−N mRNAワクチン R2381、RSV−M2−1 mRNAワクチン R2833、またはバッファーコントロールとしての乳酸リンゲル液(RiLa)を、0日に注入した。コントロール群の筋肉内(i.m.)に、10μgの不活性化RSV longワクチンを注入した。不活性化「呼吸器合胞体ウイルス抗原」(不活性化RSV long)を、INSTITUT VIRION/SERION GmbH-SERION IMMUNDIAGNOSTICA GmbHから購入した。不活性化ウイルスを、0.2μl/μLの最終濃度が達成されるように、滅菌PBSにおいて希釈した。すべての動物は、7日および21日に追加免疫を受けた。脾臓を、抗原特異的なT細胞の分析のために27日に回収した。
上述の通り、群4〜8 M2−1ペプチド(5μg/ml);(Proimmuneから提供されているSYIGSINNI);1〜3、群7および8 ProMix N(1μg/ml);コントロール:培地+DMSO+抗CD28、群1〜8。
図9から明らかな通り、RSV−N mRNAワクチン(R2831)は、RSV Nタンパク質を対象にしている、IFNγ陽性、TNFα陽性、およびIFNγ/IFNα二重陽性の多機能性CD8+T細胞をマウスにおいて誘導した。
Nタンパク質を対象にしている、IFNγ陽性、TNFα陽性およびIFNγ/TNFα二重陽性の多機能性CD4+T細胞をマウスにおいて誘導した。
RSVワクチン開発にとって、コットンラットは、特に抗原投与感染のために、一般に認められている動物モデルである。コットンラットは、強い肺病理をともなってホルマリン不活性化RSVウイルスワクチンに応答する。これは、強い疾患現象の観点からワクチン接種の安全の評価を可能にする。
抗RSV Fタンパク質抗体の誘導を、実施例2にしたがってELISAによって決定した。
血清を、ウイルス中和試験(VNT)によって分析した。簡単に説明すると、血清サンプルを、EMEMを用いて1:10に希釈し、熱不活性化し、1:4にさらに段階希釈した。希釈された血清サンプルを、室温において1時間にわたってRSV(25〜50PFU)とともにインキュベートし、24ウェルプレートにおけるHEp−2のコンフルエントな単層に2組にして播いた。5% CO2インキュベータにおける37℃の1時間にわたるインキュベーション後に、ウェルを、0.75%のメチルセルロース培地によって覆った。インキュベーションの4日後に、覆いを取り除き、細胞を、0.1%のクリスタルバイオレット染色によって固定し、それからすすぎ洗いし、風乾させた。対応する相互作用性の中和抗体の力価を、ウイルスコントロールの60%低下の終点において、決定した。
54日に、鼻腔組織を、回収し、ウイルスの力価測定のためにホモジナイズした。肺を、ひとまとまりにして回収し、ウイルスの力価測定(左の切片)、組織病理(右の切片)およびPCR分析(舌葉(lingular lobe))のために3つに切片化した。さらに、RSVウイルスゲノムのコピー数(RSV NS−1遺伝子のコピー数を測定することによって)およびサイトカインのmRNAレベルを、定量的逆転写ポリメラーゼ連鎖反応(pRT−PCR)によって決定した。
図12から明らかなように、単独(RSV−F=R2510;RSV−Fdel554−574)、または他のRSVタンパク質(RSV−N=R2831;RSV−M2−1=R2833)をコードしているmRNAとの組合せのいずれかにおけるRSV−F mRNAワクチンは、49日の総合IgG抗体によって示されている通り、コットンラットにおいてRSV Fに特異的な液性免疫応答を誘導する。
RSV Fタンパク質(F)または変異体RSV−Fタンパク質(F*)(RSV F
del554−574)をコードしているmRNAワクチンを、実施例1にしたがって調製した。単回ワクチン接種または数回ワクチン接種(初回および追加のワクチン接種)の作用を評価するために、これらのワクチンを、1回、2回または3回(表6に示す通り)にわたって投与した。2×50μlのワクチン体積を、コットンラットの背中の皮内(i.d.)に注入した。追加の群の、右後ろ脚の筋肉内(i.m.)に、1×100μlのワクチン体積によって免疫化した。コントロールとして、1群の筋肉内に、乳酸リンゲルバッファー(バッファー)を注入した。免疫化後に、コットンラットを、RSV/A2ウイルス(100μlにおける105PFU;Sigmovir)を用いた鼻腔内(i.n.)注入によって抗原投与した。コントロールとして、1群を、処理せず、ウイルスを用いて抗原投与しなかった(未処理)。
RSVウイルス力価の決定を、実施例6に記載の通りに実施した。
図17Aに示されているように、RSV Fタンパク質(F)または変異体RSV−Fタンパク質(F*)(RSV F del554−574)をコードしているmRNAワクチンを用いた、前もっての単回の皮内ワクチン接種は、バッファーコントロール群と比べて、肺におけるウイルス力価の低下に非常に有効であった。2回目および3回目のワクチン接種(「追加のワクチン接種」)は、検出レベルを下回って、ウイルス力価を低下させた。
Claims (32)
- 呼吸器合胞体ウイルス(RSV)の融合タンパク質F、糖タンパク質G、短い疎水性タンパク質SH、マトリクスタンパク質M、核タンパク質N、ラージポリメラーゼL、M2−1タンパク質、M2−2タンパク質、リンタンパク質P、非構造タンパク質NS1、または非構造タンパク質NS2に由来する少なくとも1つの抗原ペプチドもしくは抗原タンパク質、またはその断片、バリアントもしくは誘導体をコードしているコード領域を含んでおり、
上記コード領域のG/C含有量は、野生型mRNAのコード領域のGC含有量と比べて向上されており、好ましくは、上記GC富化されたmRNAの、コードされているアミノ酸配列は、野生型mRNAの、コードされているアミノ酸配列と比べて、変更されていない、mRNA配列。 - 上記コード領域は、呼吸器合胞体ウイルス(RSV)の融合タンパク質F、核タンパク質Nまたは糖タンパク質Gの全長タンパク質をコードしている、請求項1に記載のmRNA配列。
- 上記抗原ペプチドまたは抗原タンパク質は、RSV株ATCC VR−26 long由来である、請求項1または2に記載のmRNA配列。
- a)5’キャップ構造
b)ポリ(A)配列、
c)および任意に、ポリ(C)配列
をさらに含んでいる、請求項1〜3のいずれかに記載のmRNA配列。 - 上記ポリ(A)配列は、約25〜約400のアデノシンヌクレオチドの配列、好ましくは、約50〜約400のアデノシンヌクレオチドの配列、より好ましくは約50〜300のアデノシンヌクレオチドの配列、より一層好ましくは約50〜約250のアデノシンヌクレオチドの配列、最も好ましくは約60〜約250のアデノシンヌクレオチドの配列を含んでいる、請求項4に記載のmRNA配列。
- 少なくとも1つのヒストン ステム−ループをさらに含んでいる、請求項1〜5のいずれかに記載のmRNA配列。
- 上記少なくとも1つのヒストン ステム−ループは、以下の式(I)または(II):式(I)(ステム境界エレメントなしのステム−ループ配列):
式(II)(ステム境界エレメントありのステム−ループ配列):
から選択され、
ステム1またはステム2の境界エレメントN1−6は、1〜6、好ましくは2〜6、より好ましくは2〜5、より一層好ましくは3〜5、最も好ましくは4〜5または5のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびCから選択されるヌクレオチド、またはそのヌクレオチド類似物から選択され;
ステム1[N0−2GN3−5]は、ステム2のエレメントと逆相補的または部分的に逆相補的であり、かつ5〜7のヌクレオチドの間の連続する配列であり;
N0−2は、0〜2、好ましくは0〜1、より好ましくは1のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびCから選択されるヌクレオチド、またはそのヌクレオチド類似物から選択され;
N3−5は、3〜5、好ましくは4〜5、より好ましくは4のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびCから選択されるヌクレオチド、またはそのヌクレオチド類似物から選択され、
Gは、グアノシンまたはその類似物であり、ステム2におけるその相補的なシチジンヌクレオチドがグアノシンによって置き換えられている条件のもとに、シチジンまたはその類似物に任意に置き換えられ得;
ループ配列[N0−4(U/T)N0−4)]は、ステム1およびステム2のエレメントの間に配置されており、3〜5のヌクレオチド、より好ましくは4のヌクレオチドの連続する配列であり;
N0−4のそれぞれは、他のNから独立して、0〜4、好ましくは1〜3、より好ましくは1〜2のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびCから選択されるヌクレオチド、またはそのヌクレオチド類似物から選択され;
U/Tは、ウリジン、または任意にチミジンを表しており;
ステム2[N3−5CN0−2]は、ステム1のエレメントと逆相補的または部分的に逆相補的であり、5〜7のヌクレオチドの間の連続する配列であり;
N3−5は、3〜5、好ましくは4〜5、より好ましくは4のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびCから選択されるヌクレオチド、またはそのヌクレオチド類似物から選択され;
N0−2は、0〜2、好ましくは0〜1、より好ましくは1のNの連続する配列であり、Nのそれぞれは、他のNから独立して、A、U、T、GおよびCから選択されるヌクレオチド、またはそのヌクレオチド類似物から選択され;
Cは、シチジンまたはその類似物であり、ステム1におけるその相補的なグアノシンヌクレオチドがシチジンに置き換えられている条件のもとに、グアノシンまたはその類似物に任意に置き換えられ得;
ステム1およびステム2は、互いに塩基対形成可能であり、塩基対形成がステム1およびステム2の間に生じ得る逆相補性配列を形成しているか、または不完全な塩基対形成がステム1およびステム2の間に生じ得る部分的な逆相補性配列を形成している、請求項6に記載のmRNA配列。 - 3’−UTRエレメントをさらに含んでいる、請求項1〜8のいずれかに記載のmRNA配列。
- 上記少なくとも1つの3’−UTRエレメントは、安定なmRNAをもたらす遺伝子の3’−UTR、またはその相同物、断片もしくはバリアントに由来する核酸配列を含んでいるか、または当該核酸配列からなる、請求項9に記載のmRNA配列。
- 上記3’−UTRエレメントは、アルブミン遺伝子、α−グロビン遺伝子、β−グロビン遺伝子、ヒストンヒドロキシラーゼ遺伝子、リポキシゲナーゼ遺伝子、およびコラーゲンアルファ遺伝子からなる群から選択される遺伝子の3’UTR、またはその相同物、断片もしくはバリアントに由来する核酸配列を含んでいる、化合物または当該核酸配列からなる、請求項10に記載のmRNA配列。
- 上記3’−UTRエレメントは、好ましくは配列番号29にしたがう核酸配列の対応するRNA配列を含んでいる、α−グロビン遺伝子の3’−UTR、またはその相同物、断片もしくはバリアントに由来する核酸配列を含んでいるか、または当該核酸配列からなる、請求項11に記載のmRNA配列。
- 好ましくは5’から3’方向に向かって、
a.)5’−キャップ構造、好ましくはm7GpppN;
b.)好ましくは呼吸器合胞体ウイルス(RSV)の融合タンパク質Fに由来する、呼吸器合胞体ウイルス(RSV)の少なくとも1つの抗原ペプチドまたは抗原タンパク質をコードしているコード領域
c.)好ましくは配列番号29にしたがう核酸配列に対応するRNA配列を含んでいる、アルファグロビン遺伝子に由来する核酸配列を含んでいるか、または当該核酸配列からなる3’−UTRエレメント、その相同物、断片またはバリアント
d.)好ましくは64のアデノシンを含んでいる、ポリ(A)配列;
e.)好ましくは30のシトシンを含んでいる、ポリ(C)配列;ならびに
f.)好ましくは配列番号30にしたがう核酸配列に対応する、mRNA配列を含んでいる、ヒストン−ステム−ループ
を含んでいる、請求項9〜12のいずれかに記載のmRNA配列。 - 上記mRNA配列は、配列番号31にしたがうRNA配列を含んでいる、請求項13に記載のmRNA配列。
- 上記少なくとも1つの3’−UTRエレメントは、脊椎動物のアルブミン遺伝子の3’−UTRもしくはそのバリアント、好ましくは哺乳類のアルブミン遺伝子の3’−UTRもしくはそのバリアント、より好ましくはヒトのアルブミン遺伝子の3’−UTRもしくはそのバリアント、より一層好ましくはGenBank Accession番号NM_000477.5にしたがうヒトのアルブミン遺伝子の3’−UTRもしくはそのバリアントに由来する核酸配列を含んでいるか、または当該核酸配列からなる、請求項9に記載のmRNA配列。
- 上記3’−UTRエレメントは、配列番号25にしたがう核酸配列、好ましくは対応するRNA配列、その相同物、断片またはバリアントに由来する、請求項15に記載のmRNA配列。
- TOP遺伝子の5’−UTR、好ましくは対応するRNA配列、またはその相同物、断片もしくはバリアント(好ましくは5’TOPモチーフを欠いている)に由来する核酸配列を含んでいるか、または当該核酸配列からなる5’−UTRエレメントを、さらに含んでいる、請求項1〜16のいずれかに記載のmRNA配列。
- 上記5’−UTRエレメントは、リボソームタンパク質をコードしているTOP遺伝子の5’−UTRに由来する核酸配列、好ましくは対応するRNA配列、またはそれらの相同物、断片もしくはバリアント(好ましくは5’TOPモチーフを欠いている)を含んでいるか、または当該核酸配列からなる、請求項17に記載のmRNA配列。
- 上記5’−UTRエレメントは、リボソーム巨大タンパク質(RPL)をコードしているTOP遺伝子の5’−UTR、またはそれらの相同物、断片もしくはバリアント(好ましくは5’TOPモチーフを欠いている)に由来する核酸配列を含んでいるか、または当該核酸配列からなる、より好ましくは配列番号23にしたがう核酸配列の対応するRNA配列を含んでいるか、または当該RNA配列からなる、請求項18に記載のmRNA配列。
- 好ましくは5’から3’方向に、
a.)5’−キャップ構造、好ましくはm7GpppN;
b.)TOP遺伝子の5’UTRに由来する核酸配列、その相同物、断片もしくはバリアントを含んでいるか、または当該核酸配列からなる、好ましくは配列番号23にしたがう核酸配列の対応するRNA配列を含んでいるか、または当該RNA配列からなる、5’−UTRエレメント;
c.)呼吸器合胞体ウイルス(RSV)の少なくとも1つの抗原ペプチドまたは抗原タンパク質(好ましくは呼吸器合胞体ウイルス(RSV)の融合タンパク質Fに由来する)をコードしているコード領域;
d.)安定なmRNAをもたらす遺伝子に由来する核酸配列、その相同物、断片もしくはバリアントを含んでいるか、または当該核酸配列からなる(好ましくは配列番号18にしたがう核酸配列の対応するRNA配列を含んでいるか、または当該RNA配列からなる)、3’UTRエレメント;
e.)好ましくは64のアデノシンを含んでいる、ポリ(A)配列;
f.)好ましくは30のシトシンを含んでいる、ポリ(C)配列;ならびに
g.)好ましくは配列番号30にしたがう核酸配列の対応するRNA配列を含んでいる、ヒストン−ステム−ループ
を含んでいる、請求項19に記載のmRNA配列。 - 配列番号32または33にしたがうRNA配列を含んでいる、請求項20に記載のmRNA配列。
- 任意に、mRNAの、カチオン性もしくはポリカチオン性の化合物、および/または重合体担体に対する約6:1(w/w)〜約0.25:1(w/w)、より好ましくは約5:1(w/w)〜約0.5:1(w/w)、最も好ましくは約3:1(w/w)〜約2:1(w/w)の範囲から選択される重量比において;または任意に、約0.1〜10の範囲、好ましくは約0.3〜4または0.3〜1の範囲、最も好ましくは約0.5〜1または0.7〜1の範囲、なかでも最も好ましくは約0.3〜0.9または0.5〜0.9の範囲における、mRNAの、カチオン性もしくはポリカチオン性の化合物および/または重合体担体の窒素/リン酸塩の比において、
カチオン性もしくはポリカチオン性の化合物、または重合体担体と会合しているか、または複合化されている、請求項1〜21に記載のmRNA配列。 - カチオン性のタンパク質またはペプチド、好ましくはプロタミンと会合しているか、または複合化されている、請求項22に記載のmRNA配列。
- 請求項1〜23のいずれかに記載のそれぞれのmRNA配列のうちの複数または2つ以上を含んでいる、組成物。
- 請求項1〜23のいずれかに規定されているmRNA配列または請求項24に規定されている組成物、ならびに任意に薬学的に許容可能な担体を含んでいる、薬学的組成物。
- 上記mRNAは、カチオン性もしくはポリカチオン性の化合物および/または重合体担体、好ましくは複数のカチオン性のタンパク質もしくはペプチド、最も好ましくはプロタミンと少なくとも部分的に複合化されている、請求項25に記載の薬学的組成物。
- 複合化されているmRNAの、遊離mRNAに対する比は、約5:1(w/w)〜約1:10(w/w)、より好ましくは約4:1(w/w)〜約1:8(w/w)、より一層好ましくは約3:1(w/w)〜約1:5(w/w)または1:3(w/w)の範囲から選択され、最も好ましくは、複合化されているmRNAの、遊離mRNAに対する比は、1:1(w/w)の比から選択される、請求項26に記載の薬学的組成物。
- 請求項1〜23のいずれかに規定されているmRNA配列、請求項24に規定されている組成物、請求項25〜27のいずれかに規定されている薬学的組成物の構成要素、ならびに任意に上記構成要素の投与および投与量に関する情報を有している技術的な指示書を含んでいる、キットまたはキットの部分。
- 医薬としての使用のための、請求項1〜23のいずれかに規定されているmRNA配列、請求項24に規定されている組成物、請求項25〜27のいずれかに規定されている薬学的組成物、ならびに請求項28に規定されているキットまたはキットの部分。
- RSV感染の処置または予防における使用のための、請求項1〜23のいずれかに規定されているmRNA配列、請求項24に規定されている組成物、請求項25〜27のいずれかに規定されている薬学的組成物、ならびに請求項28に規定されているキットまたはキットの部分。
- 上記処置は、RSVの免疫グロブリン、特にPalivizumabの投与と組み合わせられる、請求項30にしたがう使用のための、mRNA配列、組成物、薬学的組成物、ならびにキットまたはキットの部分。
- a)請求項1〜23のいずれかに規定されているmRNA配列、請求項24に規定されている組成物、請求項25〜27のいずれかに規定されている薬学的組成物、または請求項28に規定されているキットもしくはキットの部分を準備すること;
b)上記mRNA、組成物、薬学的組成物、またはキットもしくはキットの部分を、組織または生体に使用すること、または投与すること;
c)任意に、RSV免疫グロブリンを投与することを包含している、RSV感染の処置または予防の方法。
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