JP2020533338A - ワクチン分子 - Google Patents
ワクチン分子 Download PDFInfo
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- JP2020533338A JP2020533338A JP2020514273A JP2020514273A JP2020533338A JP 2020533338 A JP2020533338 A JP 2020533338A JP 2020514273 A JP2020514273 A JP 2020514273A JP 2020514273 A JP2020514273 A JP 2020514273A JP 2020533338 A JP2020533338 A JP 2020533338A
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Abstract
Description
第1の核酸構築物および第2の核酸構築物を含むDNAワクチンであって、
上記第1の核酸構築物および上記第2の核酸構築物は、第1の融合タンパク質および第2の融合タンパク質をコードし、
上記第1の融合タンパク質および上記第2の融合タンパク質は、動作可能に繋がった、ターゲティングユニット、ヘテロ二量体化ユニットおよび抗原性ユニットを含み、
各上記第1の融合タンパク質および上記第2の融合タンパク質における上記抗原性ユニットは、変異型抗原標的タンパク質であり、
上記第1の核酸構築物および上記第2の核酸構築物が細胞へ導入される場合、上記第1の融合タンパク質および上記第2の融合タンパク質が発現され、上記ヘテロ二量体化ユニットの会合を介して、第1のヘテロ二量体タンパク質が形成される、DNAワクチンを提供する。
ヘテロ二量体タンパク質分子を含むワクチン組成物であって、
上記ヘテロ二量体タンパク質分子は、第1の融合タンパク質モノマーおよび第2の融合タンパク質モノマーを含み、
上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーは、動作可能に繋がった、ターゲティングユニット、ヘテロ二量体化ユニット、および抗原性ユニットを含み、
各上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーのにおける上記抗原性ユニットは、異なる変異型抗原標的タンパク質をコードすることによって異なり、
上記ヘテロ二量体タンパク質分子は、上記二量体化ドメインの会合によって連結された2つの上記モノマーを含む、ワクチン組成物を提供する。
本技術の理解を容易にするために、いくつかの用語および語句を以下に定義する。詳細な説明の全体にわたって、さらなる定義を記載する。
第1の核酸構築物および第2の核酸構築物を含むDNAワクチンであって、第1の核酸構築物および第2の核酸構築物は、第1の融合タンパク質および第2の融合タンパク質をコードし、第1の融合タンパク質および第2の融合タンパク質は、動作可能に繋がった、ターゲティングユニット、ヘテロ二量体化ユニットおよび抗原性ユニットを含む、DNAワクチンを提供する。いくつかの実施形態において、各上記第1の融合タンパク質および上記第2の融合タンパク質における上記抗原性ユニットは、変異型抗原標的タンパク質である。いくつかの実施形態において、上記第1の核酸構築物および上記第2の核酸構築物が細胞へ導入される場合、上記第1の融合タンパク質および上記第2の融合タンパク質が発現され、上記ヘテロ二量体化ユニットの会合を介して、第1のヘテロ二量体タンパク質が形成される。これは、例えば、図1および図8に概略的に示される。これらの図に見られるように、ワクチン核酸構築物の宿主細胞への導入は、ターゲティングユニット(抗MHCIIおよび抗NIPのようなscFvによって例示される)、ヘテロ二量体化ユニット(ACID/BASEドメインおよびバルスター/バルナーゼドメインによって例示される)、および異なる抗原性ユニット(Fv315ならびにPR8およびCal07由来のHAによって例示される)を含む単量体ユニットの産生をもたらす。発現に際して、ACIDドメインを有する単量体はBASEドメインを有する単量体と対合し、そして同様に、バルスタードメインを有する単量体はバルナーゼドメインを有する単量体と対合して、ヘテロ二量体タンパク質分子を形成する。本明細書中、本発明の融合タンパク質の例示的な配列が提供される。例えば、配列番号1および2は、ヒンジ領域とACID−ACID領域によって分離されるMIP1αターゲティングユニットおよびM315抗原性ユニットを有する融合タンパク質をコードする構築物の核酸配列を提供する。配列番号3は、融合タンパク質の対応するアミノ酸配列を提供する。配列番号4および5は、ヒンジ領域およびBASE−BASEドメインによって分離されるMIP1αターゲティングユニットおよびM315抗原性ユニットを有する融合タンパク質をコードする構築物の核酸配列を提供する。配列番号6は、融合タンパク質の対応するアミノ酸配列を提供する。例示された構築物および融合タンパク質はモジュラーであり、例えば、例示されたターゲティングユニットは、本明細書により詳細に記載されるように異なる標的化ユニットで置換されてもよく、例示された抗原性ユニットは、本明細書により詳細に記載されるように異なる抗原性ユニットで置換されてもよく、ヘテロ二量体化ドメインは、本明細書により詳細に記載されるように異なるヘテロ二量体化ドメインで置換されてもよいことが理解されるだろう。さらなる抗原性ユニットは、配列番号7〜13として提供されるものによって例示される。
本発明のワクチン分子は、好ましくは、標的抗原タンパク質(例えば、ウイルス、細菌、真菌または原生動物等の病原体由来の抗原タンパク質)または標的癌抗原の変異体である、異なる抗原性ユニットを含む。上述のように、変異体は、標的抗原タンパク質の変異体または標的抗原タンパク質の保存領域によって共有される配列の同一性の程度によって定義され得る。いくつかの実施形態において、変異体は、約30%、40%、50%、60%、70%、80%、90%、95%、96%、97%、98%または99%を超える配列同一性を有し得る。さらに他の実施形態において、長さが8、10、12、15、20、30、40、50または60個のアミノ酸を超え、長さが最大100〜200個のアミノ酸である変異型標的タンパク質内の保存領域は、約30%、40%、50%、60%、70%、80%、90%または95%を超える配列同一性を有し得る。本発明によれば、抗原性ユニットは、対象のような生物において1つ以上の抗体の産生を引き起こす物質である抗原を含む。それぞれの抗体は、特定の抗原に結合する。いくつかの文脈において、抗原性ユニットという用語は、主要組織適合性複合体(MHC)に結合し、T細胞受容体に提示され得る任意の分子または分子断片を指す。
RICK−B)、TNFRSF10C(TRAIL R3DcR1、LIT、TRID)、TNFRSF10D(TRAIL R4DcR2、TRUNDD)、TNFRSF11A(RANK ODF R、TRANCE R)、TNFRSF11B(OPG OCIF、TR1)、TNFRSF12(TWEAK R FN14)、TNFRSF13B(TACI)、TNFRSF13C(BAFF R)、TNFRSF14(HVEM ATAR、HveA、LIGHT R、TR2)、TNFRSF16(NGFR p75NTR)、TNFRSF17(BCMA)、TNFRSF18(GITR AITR)、TNFRSF19(TROY TAJ、TRADE)、TNFRSF19L(RELT)、TNFRSF1A(TNF R1CD120a、p55−60)、TNFRSF1B(TNF RII CD120b、p75−80)、TNFRSF26(TNFRH3)、TNFRSF3(LTbR TNF RIII、TNFC R)、TNFRSF4(OX40 ACT35、TXGP1 R)、TNFRSF5(CD40 p50)、TNFRSF6(Fas Apo−1、APT1、CD95)、TNFRSF6B(DcR3M68、TR6)、TNFRSF7(CD27)、TNFRSF8(CD30)、TNFRSF9(4−1 BB CD137、ILA)、TNFRSF21(DR6)、TNFRSF22(DcTRAIL R2TNFRH2)、TNFRST23(DcTRAIL R1 TNFRH1)、TNFRSF25(DR3Apo−3、LARD、TR−3、TRAMP、WSL−1)、TNFSF10(TRAIL Apo−2リガンド、TL2)、TNFSF11(TRANCE/RANKリガンドODF、OPGリガンド)、TNFSF12(TWEAK Apo−3リガンド、DR3リガンド)、TNFSF13(APRIL TALL2)、TNFSF13B(BAFF BLYS、TALL1、THANK、TNFSF20)、TNFSF14(LIGHT HVEMリガンド、LTg)、TNFSF15(TL1A/VEGI)、TNFSF18(GITRリガンドAITRリガンド、TL6)、TNFSF1A(TNF−aコネクチン、DIF、TNFSF2)、TNFSF1B(TNF−b LTa、TNFSF1))、TNFSF3(LTb TNFC、p33)、TNFSF4(OX40リガンドgp34、TXGP1)、TNFSF5(CD40リガンドCD154、gp39、HIGM1、IMD3、TRAP)、TNFSF6(FasリガンドApo−1リガンド、APT1リガンド)、TNFSF7(CD27リガンドCD70)、TNFSF8(CD30リガンドCD153)、TNFSF9 (4−1BBリガンドCD137リガンド)、TP−1、t−PA、Tpo、TRAIL、TRAIL R、TRAIL−R1、TRAIL−R2、TRANCE、トランスフェリン受容体、TRF、Trk、TROP−2、TSG、TSLP、腫瘍関連抗原CA 125、腫瘍関連抗原発現ルーイスY 関連炭水化物、TWEAK、TXB2、Ung、uPAR、uPAR−1、ウロキナーゼ、VCAM、VCAM−1、VECAD、VE−カドヘリン、VE−カドヘリン−2、VEFGR−1(fit−1)、VEGF、VEGFR、VEGFR−3(flt−4)、VEGI、VIM、ウイルス抗原、VLA、VLA−1、VLA−4、VNRインテグリン、フォンビルブラント因子、WIF−1、WNT1、WNT2、WNT2B/13、WNT3、WNT3A、WNT4、WNT5A、WNT5B、WNT6、WNT7A、WNT7B、WNT8A、WNT8B、WNT9A、WNT9A、WNT9B、WNT10A、WNT10B、WNT11、WNT16、XCL1、XCL2、XCR1、XCR1、XEDAR、XIAP、XPD、およびホルモンおよび成長因子の受容体。
タンパク質抗原の免疫原性を増大させるための一方法は、免疫系細胞、例えば抗原提示細胞(APC)を標的とする抗体または抗体断片に、抗原を組み込むことである。APCは、抗原のプロセシングを行い、それらを抗原に対する抗体を産生させるためにT細胞に提示する。このように、APCに抗原を送達することは、抗原に対する免疫反応を誘導する効率的な経路を提供する。
本技術の二量体ワクチン分子は、ヘテロ二量体化ドメインを含む。特に、二量体ワクチン分子の各ポリペプチドは、他のポリペプチド上のヘテロ二量体化ユニットと特異的に相互作用してヘテロ二量体化ドメインを形成するヘテロ二量体化ユニットを含む。従って、本明細書で使用される「ヘテロ二量体化ドメイン」という用語は、2つのヘテロ二量体化ユニット、例えば、以下により詳細に記載されるようなACIDおよびBASEヘテロ二量体化ユニット、またはバルスターおよびバルナーゼヘテロ二量体化ユニットの相互作用によって形成される二量体分子中のドメインを指す。ヘテロ二量体化ドメインの具体的な例示としては、ACID/BASEヘテロ二量体化ドメインおよびバルスター/バルナーゼヘテロ二量体化ドメインが挙げられるが、これらに限定されない。
本明細書中に提供される技術は、二量体ワクチン分子をコードする核酸を含むDNAワクチンを提供する。いくつかの実施形態において、単一の核酸は、二量体化して二量体を形成する2つのポリペプチドを含む。いくつかの実施形態において、2つの別個の核酸は、二量体化して二量体を形成する2つのポリペプチドを含む(例えば、一方の核酸は一方のポリペプチドをコードし、他方の核酸は、他方の核酸をコードする)。種々の実施形態において、核酸は、細胞中に導入することができ、in vivoにおいてポリぺプチドを発現することができる任意の核酸である。
本明細書中に提供される技術によって提供されるような二量体ワクチン分子には、ワクチン、ワクチン成分である組成物、および/または本技術に係る二量体ワクチン分子(例えば、二量体ポリペプチド分子)、DNA/RNA配列、または発現ベクターを含む医薬品における使用が見出される。適宜、この医薬品は、薬学的に適合可能な担体をさらに含む。このような医薬品における好適な担体および剤形は、当業者に公知である。好適な担体は、例えば、リン酸緩衝食塩水、水、エマルジョン(例えば、油/水エマルジョン)、湿潤剤、滅菌溶液等である。医薬品は、経口投与または非経口投与することができる。非経口投与の方法は、局所投与、動脈内投与、筋肉内投与、皮下投与、髄内投与、髄腔内投与、脳室内投与、静脈内投与、腹腔内投与、または鼻腔内投与を含む。好適な用量は、主治医によって決定され、異なる因子(例えば、患者の年齢、性別および体重、投与の種類等)に依存する。
抗原を抗原提示細胞(APC)の標的とする融合タンパク質をコードするDNAワクチンは、免疫反応を誘導する高い能力を有する。この技術を、APC上のいくつかの異なる表面分子を同時に標的化して、いくつかの異なる抗原を送達することができるワクチン分子に拡張することは有用であろう。この実施例では、それぞれが4つの異なる融合部分を発現することができるヘテロ二量体ワクチン分子の産生について記載する。
[イントロンを有するMIP1α−2ACID−M315DNA配列(配列番号:1)]
ヌクレオチド由来のMIP1α:050〜256
ヒンジ:666〜716
リンカーを有するACID−ACID:717〜1022
リンカー:1023〜1037
M315抗原:1038〜1766
001 GGGTGACAAT GACATCCACT TTGCCTTTCT CTCCACAGGT GTGCATTCCG
051 CGCCATATGG AGCTGACACC CCGACTGCCT GCTGCTTCTC CTACAGCCGG
101 AAGATTCCAC GCCAATTCAT CGTTGACTAT TTTGAAACCA GCAGCCTTTG
151 CTCCCAGCCA GGTGTCATTT TCCTGACTAA GAGAAACCGG CAGATCTGCG
201 CTGACTCCAA AGAGACCTGG GTCCAAGAAT ACATCACTGA CCTGGAACTG
251 AACGCTGGTG AGTCGTACGC TAGCAAGCTT GGCCAGCGCA GGGAGGGAGG
301 GTGTCTGCTG GAAGCCAGGC TCAGCCCTCC TGCCTGGACG CATCCCGGCT
351 GTGCAGTCCC AGCCCAGGGC ACCAAGGCAG GCCCCGTCTG ACTCCTCACC
401 CGGAGGCCTC TGCCCGCCCC ACTCATGCTC AGGGAGAGGG TCTTCTGGCT
451 TTTTCCACCA GGCTCCGGGC AGGCACAGGC TGGATGCCCC TACCCCAGGC
501 CCTTCACACA CAGGGGCAGG TGCTGCGCTC AGAGCTGCCA AAAGCCATAT
551 CCAGGAGGAC CCTGCCCCTG ACCTAAGCCC ACCCCAAAGG CCAAACTCTC
601 TACTCACTCA GCTCAGACAC CTTCTCTCTT CCCAGATCTG AGTAACTCCC
651 AATCTTCTCT CTGCAGAGCT CAAAACCCCA CTTGGTGACA CAACTCACAC
701 ATGCCCACGG TGCCCAGGAG GTAGCAGCGG TGGAAAATTC GGCGGTTCCA
751 CTACAGCTCC ATCAGCTCAG CTCGAAAAAG AGCTCCAGGC CCTGGAGAAG
801 GAAAATGCAC AGCTGGAATG GGAGTTGCAA GCACTGGAAA AGGAACTGGC
851 TCAGGGAGGT GGTAGCGGAG GGTTAACCAA ATTCGGCGGT TCCACTACAG
901 CTCCATCAGC TCAGCTCGAA AAAGAGCTCC AGGCCCTGGA GAAGGAAAAT
951 GCACAGCTGG AATGGGAGTT GCAAGCACTG GAAAAGGAAC TGGCTCAGGG
1001 AGGTGGTAGC GGAGGGTTAA CCGGCCTCAG CGGCCTGGAT GTACAGCTTC
1051 AGGAGTCAGG ACCTGGCCTC GTGAAACCTT CTCAGTCTCT GTCTCTCACC
1101 TGCTCTGTCA CTGGCTACTC CATCACCAGT GGGTATTTCT GGAACTGGAT
1151 ACGGCAGTTT CCAGGAAACA AACTGGAATG GTTGGGCTTC ATAAAGTACG
1201 ACGGTAGCAA TGGCTACAAT CCATCTCTCA AAAATCGAGT TTCCATCACT
1251 CGTGACACAT CTGAGAACCA GTTTTTCCTG AAGTTGAATT CTGTGACTAC
1301 TGAGGACACA GCTACATATT ACTGTGCCGG AGATAATGAT CACCTCTACT
1351 ACTTTGACTA CTGGGGCCAA GGCACCACTC TCACAGTCTC CTCAGGTGGA
1401 GGCGGATCTG GCGGAGGTGG CTCTGGCGGT GGCGGATCGC AGGCTGTTGT
1451 GACTCAGGAA TCTGCACTCA CCACATCACC TGGTGGAACA GTCATACTCA
1501 CTTGTCGCTC AAGTACTGGG GCTGTTACAA CTAGTAACTA TGCCAACTGG
1551 ATACAAGAAA AACCAGATCA TTTATTCACT GGTCTAATCG GTGGTACCAG
1601 CAACCGAGCT CCAGGTGTTC CTGTCAGATT CTCAGGCTCC CTGATTGGAG
1651 ACAAGGCTGC CCTCACCATC ACAGGGGCAC AGACTGAGGA TGATGCAATG
1701 TATTTCTGTG CTCTATGGTT CAGAAACCAT TTTGTTTTCG GCGGTGGAAC
1751 CAAGGTCACT GTCCTATGAG GCCTGCAGGG CCGGTCCGTC GACTCTAGAG
[イントロンを有するMIP1α−2ACID−M315DNA配列(配列番号:2)]
CTCCACAGGTGTGCATTCCGCGCCATATGGAGCTGACACCCCGACTGCCTGCTGCTTCTCCTACAGCCGGAAGATTCCACGCCAATTCATCGTTGACTATTTTGAAACCAGCAGCCTTTGCTCCCAGCCAGGTGTCATTTTCCTGACTAAGAGAAACCGGCAGATCTGCGCTGACTCCAAAGAGACCTGGGTCCAAGAATACATCACTGACCTGGAACTGAACGCTGAGCTCAAAACCCCACTTGGTGACACAACTCACACATGCCCACGGTGCCCAGGAGGTAGCAGCGGTGGAAAATTCGGCGGTTCCACTACAGCTCCATCAGCTCAGCTCGAAAAAGAGCTCCAGGCCCTGGAGAAGGAAAATGCACAGCTGGAATGGGAGTTGCAAGCACTGGAAAAGGAACTGGCTCAGGGAGGTGGTAGCGGAGGGTTAACCAAATTCGGCGGTTCCACTACAGCTCCATCAGCTCAGCTCGAAAAAGAGCTCCAGGCCCTGGAGAAGGAAAATGCACAGCTGGAATGGGAGTTGCAAGCACTGGAAAAGGAACTGGCTCAGGGAGGTGGTAGCGGAGGGTTAACCGGCCTCAGCGGCCTGGATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTCAGTCTCTGTCTCTCACCTGCTCTGTCACTGGCTACTCCATCACCAGTGGGTATTTCTGGAACTGGATACGGCAGTTTCCAGGAAACAAACTGGAATGGTTGGGCTTCATAAAGTACGACGGTAGCAATGGCTACAATCCATCTCTCAAAAATCGAGTTTCCATCACTCGTGACACATCTGAGAACCAGTTTTTCCTGAAGTTGAATTCTGTGACTACTGAGGACACAGCTACATATTACTGTGCCGGAGATAATGATCACCTCTACTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTGGAGGCGGATCTGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGGCTGTTGTGACTCAGGAATCTGCACTCACCACATCACCTGGTGGAACAGTCATACTCACTTGTCGCTCAAGTACTGGGGCTGTTACAACTAGTAACTATGCCAACTGGATACAAGAAAAACCAGATCATTTATTCACTGGTCTAATCGGTGGTACCAGCAACCGAGCTCCAGGTGTTCCTGTCAGATTCTCAGGCTCCCTGATTGGAGACAAGGCTGCCCTCACCATCACAGGGGCACAGACTGAGGATGATGCAATGTATTTCTGTG CTCTATGGTTCAGAAACCATTTTGTTTTCGGCGGTGGAACCAAGGTCACTGTCCTATGAG
[MIP1α−2ACID−M315アミノ酸配列(配列番号:3)]
アミノ酸由来のMIP1α:7〜75
ヒンジ;76〜92
リンカーを有するACID−ACID:93〜194
リンカー:195〜199
M315抗原:200〜442
1 STGVHSAPYG ADTPTACCFS YSRKIPRQFI VDYFETSSLC SQPGVIFLTK RNRQICADSK
61 ETWVQEYITD LELNAELKTP LGDTTHTCPR CPGGSSGGKF GGSTTAPSAQ LEKELQALEK
121 ENAQLEWELQ ALEKELAQGG GSGGLTKFGG STTAPSAQLE KELQALEKEN AQLEWELQAL
181 EKELAQGGGS GGLTGLSGLD VQLQESGPGL VKPSQSLSLT CSVTGYSITS GYFWNWIRQF
241 PGNKLEWLGF IKYDGSNGYN PSLKNRVSIT RDTSENQFFL KLNSVTTEDT ATYYCAGDND
301 HLYYFDYWGQ GTTLTVSSGG GGSGGGGSGG GGSQAVVTQE SALTTSPGGT VILTCRSSTG
361 AVTTSNYANW IQEKPDHLFT GLIGGTSNRA PGVPVRFSGS LIGDKAALTI TGAQTEDDAM
421 YFCALWFRNH FVFGGGTKVT VL*
[イントロンを有するMIP1α−2BASE−M315DNA配列(配列番号:4)]
ヌクレオチド由来のMIP1α:050〜256
ヒンジ:666〜716
リンカーを有するBASE−BASE:717〜1022
リンカー:1023〜1037
M315抗原:1038〜1766
001 GGGTGACAAT GACATCCACT TTGCCTTTCT CTCCACAGGT GTGCATTCCG
051 CGCCATATGG AGCTGACACC CCGACTGCCT GCTGCTTCTC CTACAGCCGG
101 AAGATTCCAC GCCAATTCAT CGTTGACTAT TTTGAAACCA GCAGCCTTTG
151 CTCCCAGCCA GGTGTCATTT TCCTGACTAA GAGAAACCGG CAGATCTGCG
201 CTGACTCCAA AGAGACCTGG GTCCAAGAAT ACATCACTGA CCTGGAACTG
251 AACGCTGGTG AGTCGTACGC TAGCAAGCTT GGCCAGCGCA GGGAGGGAGG
301 GTGTCTGCTG GAAGCCAGGC TCAGCCCTCC TGCCTGGACG CATCCCGGCT
351 GTGCAGTCCC AGCCCAGGGC ACCAAGGCAG GCCCCGTCTG ACTCCTCACC
401 CGGAGGCCTC TGCCCGCCCC ACTCATGCTC AGGGAGAGGG TCTTCTGGCT
451 TTTTCCACCA GGCTCCGGGC AGGCACAGGC TGGATGCCCC TACCCCAGGC
501 CCTTCACACA CAGGGGCAGG TGCTGCGCTC AGAGCTGCCA AAAGCCATAT
551 CCAGGAGGAC CCTGCCCCTG ACCTAAGCCC ACCCCAAAGG CCAAACTCTC
601 TACTCACTCA GCTCAGACAC CTTCTCTCTT CCCAGATCTG AGTAACTCCC
651 AATCTTCTCT CTGCAGAGCT CAAAACCCCA CTTGGTGACA CAACTCACAC
701 ATGCCCACGG TGCCCAGGAG GTAGCAGCGG TGGAAAATTC GGCGGTTCCA
751 CTACAGCTCC ATCAGCTCAG TTGAAAAAGA AATTGCAAGC ACTGAAGAAA
801 AAGAACGCTC AGCTGAAGTG GAAACTTCAA GCCCTCAAGA AGAAACTCGC
851 CCAGGGAGGT GGTAGCGGAG GGTTAACCAA ATTCGGCGGT TCCACTACAG
901 CTCCATCAGC TCAGTTGAAA AAGAAATTGC AAGCACTGAA GAAAAAGAAC
951 GCTCAGCTGA AGTGGAAACT TCAAGCCCTC AAGAAGAAAC TCGCCCAGGG
1001 AGGTGGTAGC GGAGGGTTAA CCGGCCTCAG CGGCCTGGAT GTACAGCTTC
1051 AGGAGTCAGG ACCTGGCCTC GTGAAACCTT CTCAGTCTCT GTCTCTCACC
1101 TGCTCTGTCA CTGGCTACTC CATCACCAGT GGGTATTTCT GGAACTGGAT
1151 ACGGCAGTTT CCAGGAAACA AACTGGAATG GTTGGGCTTC ATAAAGTACG
1201 ACGGTAGCAA TGGCTACAAT CCATCTCTCA AAAATCGAGT TTCCATCACT
1251 CGTGACACAT CTGAGAACCA GTTTTTCCTG AAGTTGAATT CTGTGACTAC
1301 TGAGGACACA GCTACATATT ACTGTGCCGG AGATAATGAT CACCTCTACT
1351 ACTTTGACTA CTGGGGCCAA GGCACCACTC TCACAGTCTC CTCAGGTGGA
1401 GGCGGATCTG GCGGAGGTGG CTCTGGCGGT GGCGGATCGC AGGCTGTTGT
1451 GACTCAGGAA TCTGCACTCA CCACATCACC TGGTGGAACA GTCATACTCA
1501 CTTGTCGCTC AAGTACTGGG GCTGTTACAA CTAGTAACTA TGCCAACTGG
1551 ATACAAGAAA AACCAGATCA TTTATTCACT GGTCTAATCG GTGGTACCAG
1601 CAACCGAGCT CCAGGTGTTC CTGTCAGATT CTCAGGCTCC CTGATTGGAG
1651 ACAAGGCTGC CCTCACCATC ACAGGGGCAC AGACTGAGGA TGATGCAATG
1701 TATTTCTGTG CTCTATGGTT CAGAAACCAT TTTGTTTTCG GCGGTGGAAC
1751 CAAGGTCACT GTCCTATGAG GCCTGCAGGG CCGGTCCGTC GACTCTAGAG
[イントロンを有さないMIP1α−2BASE−M315DNA配列(配列番号:5)]
GTGCATTCCGCGCCATATGGAGCTGACACCCCGACTGCCTGCTGCTTCTCCTACAGCCGGAAGATTCCACGCCAATTCATCGTTGACTATTTTGAAACCAGCAGCCTTTGCTCCCAGCCAGGTGTCATTTTCCTGACTAAGAGAAACCGGCAGATCTGCGCTGACTCCAAAGAGACCTGGGTCCAAGAATACATCACTGACCTGGAACTGAACGCTGAGCTCAAAACCCCACTTGGTGACACAACTCACACATGCCCACGGTGCCCAGGAGGTAGCAGCGGTGGAAAATTCGGCGGTTCCACTACAGCTCCATCAGCTCAGTTGAAAAAGAAATTGCAAGCACTGAAGAAAAAGAACGCTCAGCTGAAGTGGAAACTTCAAGCCCTCAAGAAGAAACTCGCCCAGGGAGGTGGTAGCGGAGGGTTAACCAAATTCGGCGGTTCCACTACAGCTCCATCAGCTCAGTTGAAAAAGAAATTGCAAGCACTGAAGAAAAAGAACGCTCAGCTGAAGTGGAAACTTCAAGCCCTCAAGAAGAAACTCGCCCAGGGAGGTGGTAGCGGAGGGTTAACCGGCCTCAGCGGCCTGGATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTCAGTCTCTGTCTCTCACCTGCTCTGTCACTGGCTACTCCATCACCAGTGGGTATTTCTGGAACTGGATACGGCAGTTTCCAGGAAACAAACTGGAATGGTTGGGCTTCATAAAGTACGACGGTAGCAATGGCTACAATCCATCTCTCAAAAATCGAGTTTCCATCACTCGTGACACATCTGAGAACCAGTTTTTCCTGAAGTTGAATTCTGTGACTACTGAGGACACAGCTACATATTACTGTGCCGGAGATAATGATCACCTCTACTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTGGAGGCGGATCTGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGGCTGTTGTGACTCAGGAATCTGCACTCACCACATCACCTGGTGGAACAGTCATACTCACTTGTCGCTCAAGTACTGGGGCTGTTACAACTAGTAACTATGCCAACTGGATACAAGAAAAACCAGATCATTTATTCACTGGTCTAATCGGTGGTACCAGCAACCGAGCTCCAGGTGTTCCTGTCAGATTCTCAGGCTCCCTGATTGGAGACAAGGCTGCCCTCACCATCACAGGGGCACAGACTGAGGATGATGCAATGTATTTCTGTGCTCTATGGTTCAGAAACCATTTTGTTTTCGGCGGTGGAACCAAGGTCACTGTCCTATGAG
[MIP1α−2BASE−M315アミノ酸配列(配列番号:6)]
アミノ酸由来のMIP1α:4〜72
ヒンジ:73〜89
リンカーを有するACID−ACID:90〜191
リンカー:192〜196
M315抗原:197〜439
1 VHSAPYGADT PTACCFSYSR KIPRQFIVDY FETSSLCSQP GVIFLTKRNR
61 QICADSKETW
121 VQEYITDLEL NAELKTPLGD TTHTCPRCPG GSSGGKFGGS TTAPSAQLKK
181 KLQALKKKNA
241 QLKWKLQALK KKLAQGGGSG GLTKFGGSTT APSAQLKKKL QALKKKNAQL
301 KWKLQALKKK
361 LAQGGGSGGL TGLSGLDVQL QESGPGLVKP SQSLSLTCSV TGYSITSGYF
421 WNWIRQFPGN
KLEWLGFIKY DGSNGYNPSL KNRVSITRDT SENQFFLKLN SVTTEDTATY YCAGDNDHLY
YFDYWGQGTT LTVSSGGGGS GGGGSGGGGS QAVVTQESAL TTSPGGTVIL TCRSSTGAVT
TSNYANWIQE KPDHLFTGLI GGTSNRAPGV PVRFSGSLIG DKAALTITGA QTEDDAMYFC
ALWFRNHFVF GGGTKVTVL*
[ヘテロ二量体に使用される複数の骨髄腫抗原scFv315の配列]
配列番号:7。アミノ酸配列:VH−リンカー−VL
DVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYFWNWIRQFPGNKLEWLGFIKYDGSNGYNPSLKNRVSITRDTSENQFFLKLNVTTEDTATYYCAGDNDHLYYFDYWGQGTTLTVSSGGGGSGGGGSGGGGSQAVVTQESALTTSPGGTVILTCRSSTGAVTTSNYANWIQEKPDHLFTGLIGGTSNRAPGVPVRFSGSLIGDKAALTITGAQTEDDAMYFCALWFRNHFVFGGGTKVTVL
配列番号:8。DNA:VH−リンカー−VL
GATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTCAGTCTCTGTCTCTCACCTGCTCTGTCACTGGCTACTCCATCACCAGTGGGTATTTCTGGAACTGGATACGGCAGTTTCCAGGAAACAAACTGGAATGGTTGGGCTTCATAAAATACGACGGTAGCAATGGCTACAATCCATCTCTCAAAAATCGAGTTTCCATCACTCGTGACACATCTGAGAACCAGTTTTTCCTGAAGTTGAATTCTGTGACTACTGAGGACACAGCTACATATTACTGTGCCGGAGATAATGATCACCTCTACTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGTGGAGGCGGATCTGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGGCTGTTGTGACTCAGGAATCTGCACTCACCACATCACCTGGTGGAACAGTCATACTCACTTGTCGCTCAAGTACTGGGGCTGTTACAACTAGTAACTATGCCAACTGGATACAAGAAAAACCAGATCATTTATTCACTGGTCTAATCGGTGGTACCAGCAACCGAGCTCCAGGTGTTCCTGTCAGATTCTCAGGCTCCCTGATTGGAGACAAGGCTGCCCTCACCATCACAGGGGCACAGACTGAGGATGATGCAATGTATTTCTGTGCTCTATGGTTCAGAAACCATTTTGTTTTCGGCGGTGGAACCAAGGTCACTGTCCTATGAG
[ヘテロ二量体に使用されるリンパ腫抗原scFvA20の配列]
VH以前のリンカーに下線を付し、VHとVLとの間のリンカーを太字で表記する。
配列番号:11.VH−リンカー−VL
MVQLQQSGPDLVKPGMSVKLSCKTLGYNFSDKWIHWIKQKPGRGLEWVGRIDPSNGDTDYNADFKTPATLTVDRPSNTAYLELNNLTSGDSAVYYCSISGDYSACDYWGQGTELTVSSGGGGSGGGGSGGGGSDVVMTQTPLSLAVSLGDHVKMSCRCNQSLVNSHGDSFLHWFLQKPGQSPKLLIYKVSSRFFGVPERFSGSGSGTDFTLEISRVEAEDLGIYFCSQGAHVPWTFGGGTKLEVK
〔実施例2.標的DNAワクチンの二価性によるB細胞媒介性反応の増加〕
多価抗原は、B細胞膜上のBCR間の架橋を誘導することができ、これはB細胞活性化に必須であると考えられる。初期のB細胞活性化モデルは、これらの架橋がB細胞を活性化するために必要であることを示した(16、17)。効率的なB細胞活性化のための他のモデルは、最近示されており、それらの各々は、重要な因子として価数を組み込んでいる(17〜20)。in vitroおよびin vivoモデルの両方で、多価抗原は、より効力のあるB細胞シグナル伝達および抗体反応を誘導するが、単価抗原は、同様にB細胞反応を活性化することができることが示されている(21〜28)。
本実施例では、ACID/BASEヘテロ二量体ワクチンが、マウスにおける骨髄ホーミングMOPC.315腫瘍モデル(MOPC.315BM)からマウスを保護することを示す実験について記載する(Hofgaard, P. O., et al., 2012. PLoS One 7: e51892)。
本実施例では、18個の赤血球凝集素(HA)のサブタイプを含む混合ワクチンとして試験されたACID/BASEヘテロ二量体について記載した。
本明細書中に引用される以下の参考文献は、全ての目的のためにそれらの全体が参照として援用される。
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Claims (53)
- 第1の核酸構築物および第2の核酸構築物を含むDNAワクチンであって、
上記第1の核酸構築物および上記第2の核酸構築物は、第1の融合タンパク質および第2の融合タンパク質をコードし、
上記第1の融合タンパク質および上記第2の融合タンパク質は、動作可能に繋がった、ターゲティングユニット、ヘテロ二量体化ユニットおよび抗原性ユニットを含み、
各上記第1の融合タンパク質および上記第2の融合タンパク質における上記抗原性ユニットは、変異型抗原標的タンパク質であり、
上記第1の核酸構築物および上記第2の核酸構築物が細胞へ導入される場合、上記第1の融合タンパク質および上記第2の融合タンパク質が発現され、上記ヘテロ二量体化ユニットの会合を介して、第1のヘテロ二量体タンパク質が形成される、DNAワクチン。 - 上記第1の核酸構築物および上記第2の核酸構築物の一方における上記ヘテロ二量体化ユニットは、ACIDヘテロ二量体化ユニットであり、上記第1の核酸構築物および上記第2の核酸構築物の他方における上記ヘテロ二量体化ユニットは、相互作用して、上記第1のヘテロ二量体タンパク質であるACID/BASEヘテロ二量体化ドメインを形成するBASEヘテロ二量体化ユニットである、請求項1に記載のDNAワクチン。
- 上記第1の核酸構築物および上記第2の核酸構築物の一方における上記ヘテロ二量体化ユニットは、バルスターヘテロ二量体化ユニットであり、上記第1の核酸構築物および上記第2の核酸構築物の他方における上記ヘテロ二量体化ユニットは、相互作用して、上記第1のヘテロ二量体タンパク質であるバルスター/バルナーゼヘテロ二量体化ドメインを形成するバルナーゼヘテロ二量体化ユニットである、請求項1に記載のDNAワクチン。
- 上記第1の融合タンパク質および上記第2の融合タンパク質の上記ターゲティングユニットは同一である、請求項1に記載のDNAワクチン。
- 上記第1の融合タンパク質および上記第2の融合タンパク質の上記ターゲティングユニットは異なっている、請求項1に記載のDNAワクチン。
- 上記ターゲティングユニットは、抗原結合タンパク質である、請求項1に記載のDNAワクチン。
- 上記抗原結合タンパク質は、scFvである、請求項4に記載のDNAワクチン。
- 上記ターゲティングユニットは、抗原提示細胞(APC)ターゲティングユニットである、請求項1に記載のDNAワクチン。
- 上記APCターゲティングユニットは、MHC−II分子、CD40、CD11c、CD14、HLA−DP、Toll様受容体およびケモカイン受容体からなる群より選択される標的に結合する、請求項8に記載のDNAワクチン。
- 上記変異型抗原標的タンパク質は、約30%、40%、50%、60%、70%、80%、90%または95%を超える配列同一性を有するか、または約30%、40%、50%、60%、70%、80%、90%または95%を超える配列同一性を有する上記変異型抗原標的タンパク質中、長さが8、10、12、15、20、30、40、50または60アミノ酸を超え、長さが最大100〜200アミノ酸である保存ドメインを有する、請求項1に記載のDNAワクチン。
- 異なる上記変異型抗原標的タンパク質は、生物の異なる菌株または血清型由来である、請求項1に記載のDNAワクチン。
- 上記生物は、病原性生物である、請求項11に記載のDNAワクチン。
- 上記生物は、ウイルス、細菌、真菌および原生動物からなる群より選択される、請求項11に記載のDNAワクチン。
- 異なる上記変異型抗原標的タンパク質は、赤血球凝集素(HA)の変異体である、請求項1に記載のDNAワクチン。
- 上記ワクチンは、インフルエンザウイルスの少なくとも3、4、5または6および最大12または18の菌株または血清型由来のHAの変異体を含む、請求項14に記載のDNAワクチン。
- 上記インフルエンザウイルスは、グループ1のインフルエンザウイルスおよびグループ2のインフルエンザウイルスからなる群より選択される、請求項15記載のDNAワクチン。
- 上記グループ1のインフルエンザウイルスは、H1、H2、H5、H6、H8、H9、H11、H12、H13、H16、H17およびH18からなる群より選択され、上記グループ2のインフルエンザウイルスは、H3、H4、H7、H10、H14およびH15からなる群より選択される、請求項16に記載のDNAワクチン。
- 異なる上記変異型抗原標的タンパク質は、ガン抗原またはネオエピトープの変異体である、請求項1に記載のDNAワクチン。
- 少なくとも第3の核酸構築物および第4の核酸構築物をさらに含むDNAワクチンであって、
上記第3の核酸構築物および上記第4の核酸構築物は、第3の融合タンパク質および第4の融合タンパク質をコードし、
上記第3の融合タンパク質および上記第4の融合タンパク質は、動作可能に繋がった、ターゲティングユニット、ヘテロ二量体化ユニットおよび抗原性ユニットを含み、
各上記第3の融合タンパク質および上記第4の融合タンパク質における上記抗原性ユニットは、変異型抗原標的タンパク質である、請求項1に記載のDNAワクチン。 - 上記第1の融合タンパク質および上記第2の融合タンパク質を用いた細胞内での上記第3の融合タンパク質および上記第4の融合タンパク質の発現によって、ヘテロ二量体タンパク質の混合物が産生される、請求項19に記載のDNAワクチン。
- 上記第1の核酸構築物および上記第2の核酸構築物が細胞内で発現される場合、上記ヘテロ二量体タンパク質の産生は、同じ抗原標的タンパク質を含むホモ二量体タンパク質の産生が実質的に存在しないことを特徴とする、請求項1に記載のDNAワクチン。
- 上記第1の核酸構築物および上記第2の核酸構築物ならびに上記少なくとも第3の核酸構築物および第4の核酸構築物が細胞内で発現される場合、上記ヘテロ二量体タンパク質の産生は、同じ抗原標的タンパク質を含むホモ二量体タンパク質の産生が実質的に存在しないことを特徴とする、請求項20に記載のDNAワクチン。
- 上記融合タンパク質をコードする配列は、プロモータに動作可能に連結されている、請求項1に記載のDNAワクチン。
- ヘテロ二量体タンパク質分子を含むワクチン組成物であって、
上記ヘテロ二量体タンパク質分子は、第1の融合タンパク質モノマーおよび第2の融合タンパク質モノマーを含み、
上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーは、動作可能に繋がった、ターゲティングユニット、ヘテロ二量体化ユニット、および抗原性ユニットを含み、
各上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーにおける上記抗原性ユニットは、異なる変異型抗原標的タンパク質をコードすることによって異なり、
上記ヘテロ二量体タンパク質分子は、上記二量体化ドメインの会合によって連結された2つの上記モノマーを含む、ワクチン組成物。 - 上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーの一方における上記ヘテロ二量体化ユニットが、ACIDヘテロ二量体化ユニットであり、上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーの他方における上記ヘテロ二量体化ユニットは、相互作用して、上記第1のヘテロ二量体タンパク質であるACID/BASEヘテロ二量体化領域を形成するBASEヘテロ二量体化ユニットである、請求項24に記載のワクチン組成物。
- 上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーの一方における上記ヘテロ二量体化ユニットは、バルスターヘテロ二量体化ユニットであり、上記第1の融合タンパク質モノマーおよび上記第2の融合タンパク質モノマーの他方における上記ヘテロ二量体化ユニットは、相互作用して、上記第1のヘテロ二量体タンパク質であるバルスター/バルナーゼヘテロ二量体化ドメインを形成するバルナーゼヘテロ二量体化ユニットである、請求項24に記載のワクチン組成物。
- 上記第1の融合タンパク質および上記第2の融合タンパク質の上記ターゲティングユニットは同一である、請求項24に記載のワクチン組成物。
- 上記第1の融合タンパク質および上記第2の融合タンパク質の上記ターゲティングユニットは異なっている、請求項24に記載のワクチン組成物。
- 上記ターゲティングユニットは、抗原結合タンパク質である、請求項24に記載のワクチン組成物。
- 上記抗原結合タンパク質は、scFvである、請求項29に記載のワクチン組成物。
- 上記ターゲティングユニットは、抗原提示細胞(APC)ターゲティングユニットである、請求項24に記載のワクチン組成物。
- 上記APCターゲティングユニットは、MHC−II分子、CD40、CD11c、CD14、HLA−DP、Toll様受容体、およびケモカイン受容体からなる群より選択される標的に結合する、請求項31に記載のワクチン組成物。
- 上記異なる変異型抗原標的タンパク質は、約30%、40%、50%、60%、70%、80%、90%または95%を超える配列同一性を有するか、または約30%、40%、50%、60%、70%、80%、90%または95%を超える配列同一性を有する上記変異型抗原標的タンパク質中、長さが8、10、12、15、20、30、40、50または60アミノ酸を超え、長さが最大100〜200アミノ酸である保存領域を有する、請求項24に記載のワクチン組成物。
- 上記異なる変異型抗原標的タンパク質は、生物の異なる菌株または血清型由来である、請求項24に記載のワクチン組成物。
- 上記生物は、病原性生物である、請求項34に記載のワクチン組成物。
- 上記生物は、ウイルス、細菌、真菌および原生動物からなる群より選択される、請求項34に記載のワクチン組成物。
- 上記異なる変異型抗原標的タンパク質は、赤血球凝集素(HA)の変異体である、請求項24に記載のワクチン組成物。
- 上記ワクチンは、インフルエンザウイルスの少なくとも3、4、5または6および最大12または18の菌株または血清型由来のHAの変異体を含む、請求項37に記載のワクチン組成物。
- 上記インフルエンザウイルスは、グループ1のインフルエンザウイルスおよびグループ2のインフルエンザウイルスからなる群より選択される、請求項38に記載のワクチン組成物。
- 上記グループ1のインフルエンザウイルスは、H1、H2、H5、H6、H8、H9、H11、H12、H13、H16、H17およびH18からなる群より選択され、上記グループ2のインフルエンザウイルスは、H3、H4、H7、H10、H14およびH15からなる群より選択される、請求項39に記載のワクチン構成。
- 上記異なる変異型抗原標的タンパク質は、ガン抗原またはネオエピトープの変異体である、請求項24に記載のワクチン組成物。
- 少なくとも第3の融合タンパク質モノマーおよび第4の融合タンパク質モノマーをさらに含むワクチン組成物であって、
上記第3の融合タンパク質モノマーおよび上記第4の融合タンパク質モノマーは、動作可能に繋がった、ターゲティングユニット、ヘテロ二量体化ユニットおよび抗原性ユニットを含み、
各上記第3の融合タンパク質モノマーおよび上記第4の融合タンパク質モノマーにおける上記抗原性ユニットは、上記変異型抗原標的タンパク質の異なる型をコードすることで異なる、請求項24に記載のワクチン組成物。 - 上記ワクチンは、上記第1のモノマーおよび上記第2のモノマーならびに少なくとも第3のモノマーおよび第4のモノマーの全ての考えられる組み合わせを有することを特徴とするヘテロ二量体タンパク質の混合物を含む、請求項42に記載のワクチン組成物。
- 同じ抗原標的タンパク質を含むホモ二量体タンパク質が実質的に存在しないことを特徴とする、請求項24に記載のワクチン組成物。
- 同じ抗原標的タンパク質を含むホモ二量体タンパク質が実質的に存在しないことを特徴とする、請求項42に記載のDNAワクチン。
- 請求項1〜45のいずれか1項に記載のDNAワクチンまたはワクチン組成物と、薬学的に許容可能な担体とを含む、医薬製剤。
- 請求項20〜45のいずれか1項に記載のワクチン組成物と、アジュバントとを含む、ワクチン製剤。
- 対象に、請求項1〜45のいずれか1項に記載のDNAワクチン,ワクチン組成物、医薬製剤またはワクチン製剤を投与することを含む、対象において変異型抗原標的タンパク質に対する免疫性を与える、または免疫反応を誘導する方法。
- 上記対象への、請求項1〜45のいずれか1項に記載のDNAワクチン,ワクチン組成物、医薬製剤またはワクチン製剤の第2の投与をさらに含む、請求項48に記載の方法。
- 上記対象に、1つ以上の標的でない変異型抗原標的タンパク質サブユニットを含む第2のDNAワクチン,ワクチン組成物、医薬製剤またはワクチン製剤を投与することをさらに含む、請求項48に記載の方法。
- 請求項1〜45のいずれか1項に記載のDNAワクチン,ワクチン組成物、医薬製剤またはワクチン製剤を必要とする対象において、免疫性を与えるまたは免疫反応を誘導するための、請求項1〜45のいずれか1項に記載のDNAワクチン,ワクチン組成物、医薬製剤またはワクチン製剤の使用。
- 病原体による感染を予防または治療するためのワクチンとしての、請求項1〜45のいずれか1項に記載のDNAワクチン,ワクチン組成物、医薬製剤またはワクチン製剤の使用。
- 癌を予防または治療するためのワクチンとしての、請求項1〜45のいずれか1項に記載のDNAワクチン,ワクチン組成物、医薬製剤またはワクチン製剤の使用。
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EP (1) | EP3678698A1 (ja) |
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US20230147574A1 (en) * | 2020-04-07 | 2023-05-11 | Evaxion Biotech A/S | Neoepitope immunotherapy with APC targeting unit |
EP4347623A1 (en) * | 2021-05-26 | 2024-04-10 | Evaxion Biotech A/S | Vaccination targeting intracellular pathogens |
WO2024100196A1 (en) | 2022-11-09 | 2024-05-16 | Nykode Therapeutics ASA | Co-expression of constructs and polypeptides |
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- 2018-09-07 US US16/645,140 patent/US20220118076A1/en active Pending
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US20220118076A1 (en) | 2022-04-21 |
JP2023156466A (ja) | 2023-10-24 |
WO2019048928A1 (en) | 2019-03-14 |
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