JP5721441B2 - 免疫賦活剤/アジュバントとしての式(I)(NuGlXmGnNv)aで表される核酸分子及びその誘導体 - Google Patents
免疫賦活剤/アジュバントとしての式(I)(NuGlXmGnNv)aで表される核酸分子及びその誘導体 Download PDFInfo
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Description
(NuGlXmGnNv)a
の核酸(分子)であって、
式中、
Gは、グアノシン(グアニン)、ウリジン(ウラシル)、グアノシン(グアニン)類似体及びウリジン(ウラシル)類似体のいずれか、好ましくはグアノシン(グアニン)及びその類似体のいずれかであり;
Xは、グアノシン(グアニン)、ウリジン(ウラシル)、アデノシン(アデニン)、チミジン(チミン)、シチジン(シトシン)、及びこれらヌクレオチド(ヌクレオシド)の類似体のいずれか、好ましくはウリジン(ウラシル)及びその類似体のいずれかであり;
Nは、約4核酸〜50核酸、好ましくは約4核酸〜40核酸、より好ましくは約4核酸〜30核酸、或いは4核酸〜20核酸の長さを有する核酸配列であって、各Nは独立して、グアノシン(グアニン)、ウリジン(ウラシル)、アデノシン(アデニン)、チミジン(チミン)、シチジン(シトシン)、及びこれらヌクレオチド(ヌクレオシド)の類似体のいずれかから選択され;
aは、1〜20の整数、好ましくは1〜15の整数、最も好ましくは1〜10の整数であり;
lは、1〜40の整数であって、
lが1である場合、Gはグアノシン(グアニン)及びその類似体のいずれかであり、
lが1超である場合、これらヌクレオチド(ヌクレオシド)の少なくとも50%が、グアノシン(グアニン)及びその類似体のいずれかであり;
mは、整数であり且つ少なくとも3であって、
mが3である場合、Xはウリジン(ウラシル)及びその類似体のいずれかであり、
mが3超である場合、ウリジン(ウラシル)及びウリジン(ウラシル)の類似体のいずれかが少なくとも3個連続して存在し;
nは、1〜40の整数であって、
nが1である場合、Gはグアノシン(グアニン)及びその類似体のいずれかであり、
nが1超である場合、これらヌクレオチド(ヌクレオシド)の少なくとも50%が、グアノシン(グアニン)及びその類似体のいずれかであり;
u、vは、互いに独立して0〜50の整数であってもよく、好ましくは
uが0である場合、vは1以上であるか、或いは
vが0である場合、uは1以上であり、
本発明に係る式(I)の核酸分子は、少なくとも50ヌクレオチド、好ましくは少なくとも100ヌクレオチド、より好ましくは少なくとも150ヌクレオチド、更により好ましくは少なくとも200ヌクレオチド、最も好ましくは少なくとも250ヌクレオチドの長さを有する核酸(分子)を提供する。
本発明に係る式(I)の核酸分子の免疫原性を増加させる類似体、及び
施されている更なる修飾に干渉しない類似体。
グアノシン(グアニン)、ウリジン(ウラシル)、及びこれらの類似体のいずれかのうち少なくとも1種がコア構造エレメントGl及びGnの少なくともいずれかに存在していてもよく、任意的にコア構造エレメントGl及びGnの少なくともいずれかのヌクレオチドの少なくとも10%、20%、30%、40%、50%、60%、70%、80%、90%、或いは更には100%が、天然に存在するグアノシン(グアニン)、天然に存在するウリジン(ウラシル)、及びこれらの類似体(或いは本明細書に定義されるこれらの類似体の性質を示すもの)である。コア構造エレメントGl及びGnの少なくともいずれかは、天然に存在するグアノシン(グアニン)及び天然に存在するウリジン(ウラシル)の少なくともいずれかの少なくとも1種の類似体を含むことが好ましい。これらコア構造エレメントGl及びGnの少なくともいずれかのヌクレオチド(ヌクレオシド)が全て類似体であることが最も好ましい(同じ種類のヌクレオチド(ヌクレオシド)に対して同一の類似体であることが最も好ましいが(例えば、全てのグアノシン(グアニン)ヌクレオチドが、1−メチル−グアノシン(グアニン)として提供される)、類似体の種類は異なっていてもよい(例えば、少なくとも2種の異なるグアノシン類似体が天然に存在するグアノシンヌクレオチドに置き換わる)。
本発明に係る式(I)で表される核酸分子の免疫原性を増加させる類似体、及び
施されている更なる修飾に干渉しない類似体。
−GGUUUUUUUUUUUUUUUGGG(配列番号1);
−GGGGGUUUUUUUUUUGGGGG(配列番号2);
−GGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGG(配列番号3);
−GUGUGUGUGUGUUUUUUUUUUUUUUUUGUGUGUGUGUGU(配列番号4);
−GGUUGGUUGGUUUUUUUUUUUUUUUUUGGUUGGUUGGUU(配列番号5);
−GGGGGGGGGUUUGGGGGGGG(配列番号6);
−GGGGGGGGUUUUGGGGGGGG(配列番号7);
−GGGGGGGUUUUUUGGGGGGG(配列番号8);
−GGGGGGGUUUUUUUGGGGGG(配列番号9);
−GGGGGGUUUUUUUUGGGGGG(配列番号10);
−GGGGGGUUUUUUUUUGGGGG(配列番号11);
−GGGGGGUUUUUUUUUUGGGG(配列番号12);
−GGGGGUUUUUUUUUUUGGGG(配列番号13);
−GGGGGUUUUUUUUUUUUGGG(配列番号14);
−GGGGUUUUUUUUUUUUUGGG(配列番号15);
−GGGGUUUUUUUUUUUUUUGG(配列番号16);
−GGUUUUUUUUUUUUUUUUGG(配列番号17);
−GUUUUUUUUUUUUUUUUUUG(配列番号18);
−GGGGGGGGGGUUUGGGGGGGGG(配列番号19);
−GGGGGGGGGUUUUGGGGGGGGG(配列番号20);
−GGGGGGGGUUUUUUGGGGGGGG(配列番号21);
−GGGGGGGGUUUUUUUGGGGGGG(配列番号22);
−GGGGGGGUUUUUUUUGGGGGGG(配列番号23);
−GGGGGGGUUUUUUUUUGGGGGG(配列番号24);
−GGGGGGGUUUUUUUUUUGGGGG(配列番号25);
−GGGGGGUUUUUUUUUUUGGGGG(配列番号26);
−GGGGGGUUUUUUUUUUUUGGGG(配列番号27);
−GGGGGUUUUUUUUUUUUUGGGG(配列番号28);
−GGGGGUUUUUUUUUUUUUUGGG(配列番号29);
−GGGUUUUUUUUUUUUUUUUGGG(配列番号30);
−GGUUUUUUUUUUUUUUUUUUGG(配列番号31);
−GGGGGGGGGGGUUUGGGGGGGGGG(配列番号32);
−GGGGGGGGGGUUUUGGGGGGGGGG(配列番号33);
−GGGGGGGGGUUUUUUGGGGGGGGG(配列番号34);
−GGGGGGGGGUUUUUUUGGGGGGGG(配列番号35);
−GGGGGGGGUUUUUUUUGGGGGGGG(配列番号36);
−GGGGGGGGUUUUUUUUUGGGGGGG(配列番号37);
−GGGGGGGGUUUUUUUUUUGGGGGG(配列番号38);
−GGGGGGGUUUUUUUUUUUGGGGGG(配列番号39);
−GGGGGGGUUUUUUUUUUUUGGGGG(配列番号40);
−GGGGGGUUUUUUUUUUUUUGGGGG(配列番号41);
−GGGGGGUUUUUUUUUUUUUUGGGG(配列番号42);
−GGGGUUUUUUUUUUUUUUUUGGGG(配列番号43);
−GGGUUUUUUUUUUUUUUUUUUGGG(配列番号44);
−GUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUG(配列番号45);
−GGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGG(配列番号46);
−GGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGG(配列番号47);
−GGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGG(配列番号48);
−GGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGG(配列番号49);
−GGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGG(配列番号50);
−GGGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGGG(配列番号51);
−GGGGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGGGG(配列番号52);
−GGGGGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGGGGG(配列番号53);
−GGUUUGG(配列番号54);
−GGUUUUGG(配列番号55);
−GGUUUUUGG(配列番号56);
−GGUUUUUUGG(配列番号57);
−GGUUUUUUUGG(配列番号58);
−GGUUUUUUUUGG(配列番号59);
−GGUUUUUUUUUGG(配列番号60);
−GGUUUUUUUUUUGG(配列番号61);
−GGUUUUUUUUUUUGG(配列番号62);
−GGUUUUUUUUUUUUGG(配列番号63);
−GGUUUUUUUUUUUUUGG(配列番号64);
−GGUUUUUUUUUUUUUUGG(配列番号65);
−GGUUUUUUUUUUUUUUUGG(配列番号66);
−GGGUUUGGG(配列番号67);
−GGGUUUUGGG(配列番号68);
−GGGUUUUUGGG(配列番号69);
−GGGUUUUUUGGG(配列番号70);
−GGGUUUUUUUGGG(配列番号71);
−GGGUUUUUUUUGGG(配列番号72);
−GGGUUUUUUUUUGGG(配列番号73);
−GGGUUUUUUUUUUGGG(配列番号74);
−GGGUUUUUUUUUUUGGG(配列番号75);
−GGGUUUUUUUUUUUUGGG(配列番号76);
−GGGUUUUUUUUUUUUUGGG(配列番号77);
−GGGUUUUUUUUUUUUUUUGGGUUUUUUUUUUUUUUUGGGUUUUUUUUUUUUUUUGGG(配列番号78);
−GGGUUUUUUUUUUUUUUUGGGGGGUUUUUUUUUUUUUUUGGG(配列番号79);
−GGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGG(配列番号80)。
(NuClXmCnNv)a
に係る代替核酸分子により解決することができる:
式中、
Cは、シチジン(シトシン)、ウリジン(ウラシル)、シチジン(シトシン)類似体、及びウリジン(ウラシル)類似体のいずれか、好ましくはシチジン(シトシン)及びその類似体のいずれかであり;
Xは、グアノシン(グアニン)、ウリジン(ウラシル)、アデノシン(アデニン)、チミジン(チミン)、シチジン(シトシン)、及び上記ヌクレオチド(ヌクレオシド)の類似体のいずれか、好ましくはウリジン(ウラシル)及びその類似体のいずれかであり、
Nは互いに独立して、約4核酸〜50核酸、好ましくは約4核酸〜40核酸、より好ましくは約4核酸〜30核酸、或いは4核酸〜20核酸の長さを有する核酸配列であって、各Nは独立して、グアノシン(グアニン)、ウリジン(ウラシル)、アデノシン(アデニン)、チミジン(チミン)、シチジン(シトシン)、及びこれらヌクレオチド(ヌクレオシド)の類似体のいずれかから選択され、
aは、1〜20の整数、好ましくは1〜15の整数、最も好ましくは1〜10の整数であり、
lは、1〜40の整数であって、
lが1である場合、Cはシチジン(シトシン)及びその類似体のいずれかであり、
lが1超である場合、これらヌクレオチド(ヌクレオシド)の少なくとも50%がシチジン(シトシン)及びその類似体のいずれかであり、
mは、整数であり且つ少なくとも3であって、
mが3である場合、Xはウリジン(ウラシル)及びその類似体のいずれかであり、
mが3超である場合、ウリジン(ウラシル)及びウリジン(ウラシル)の類似体のいずれかが少なくとも3個連続して存在し、
nは、1〜40の整数であって、
nが1である場合、Cはシチジン(シトシン)及びその類似体のいずれかであり、
nが1超である場合、これらヌクレオチド(ヌクレオシド)の少なくとも50%がシチジン(シトシン)及びその類似体のいずれかであり、
u、vは、互いに独立して0〜50の整数であってもよく、好ましくは
uが0である場合、vは1以上であるか、或いは
vが0である場合、uは1以上であり、
本発明に係る式(Ia)の核酸分子は、少なくとも50ヌクレオチド、好ましくは少なくとも100ヌクレオチド、より好ましくは少なくとも150ヌクレオチド、更により好ましくは少なくとも200ヌクレオチド、最も好ましくは少なくとも250ヌクレオチドの長さを有する。
本発明に係る式(Ia)で表される核酸分子の免疫原性を増加させる類似体、及び
施されている更なる修飾に干渉しない類似体。
シチジン(シトシン)、ウリジン(ウラシル)、及びこれらの類似体のいずれかのうち少なくとも1種がコア構造エレメントCl及びCnの少なくともいずれかに存在していてもよく、任意的にコア構造エレメントCl及びCnの少なくともいずれかのヌクレオチドの少なくとも10%、20%、30%、40%、50%、60%、70%、80%、90%、或いは更には100%が、天然に存在するシチジン(シトシン)、天然に存在するウリジン(ウラシル)、及びこれらの類似体(或いは本明細書に定義されるこれらの類似体の性質を示すもの)である。コア構造エレメントCl及びCnの少なくともいずれかが、天然に存在するシチジン(シトシン)及び天然に存在するウリジン(ウラシル)の少なくともいずれかの少なくとも1種の類似体を含むことが好ましい。これらのコア構造エレメントCl及びCnの少なくともいずれかのヌクレオチド(ヌクレオシド)が全て類似体であることが最も好ましい(同じ種類のヌクレオチド(ヌクレオシド)に対して同一の類似体であることが最も好ましいが(例えば、全てのシチジン(シトシン)ヌクレオチドが、2−チオ−シチジン(シトシン)として提供される)、類似体の種類は異なっていてもよい(例えば、少なくとも2種の異なるシチジン(シトシン)類似体が天然に存在するシチジン(シトシン)ヌクレオチドに置き換わる))。
−CCCUUUUUUUUUUUUUUUCCCUUUUUUUUUUUUUUUCCCUUUUUUUUUUUUUUUCCC(配列番号81)
−CCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCC(配列番号82)
−CCCUUUUUUUUUUUUUUUCCCCCCUUUUUUUUUUUUUUUCCC(配列番号83)。
配列番号84:
UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU GGG UGCGUUCCUA GAAGUACACG、
配列番号85:
UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU GGG UGCGUUCCUA GAAGUACACG、
AUCGCUUCGA GAACCUGGAU CC AAAAA AAAAA AAAAA CCC ACGCAAGGAU CUUCAUGUGC、
配列番号114(R820:(N100)2):
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAAACCGAGUUGCAUAUCUCAGAGUAUUGGCCCCCGUGUAGGUUAUUCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUCGCAUACUACGGUACUGGUGACAGACCUAGGUCGUCAGUUGACCAGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUUAGAUGUUACACUCUAUUAGAUC、
配列番号115(R719:(N100)5):
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAAACCGAGUUGCAUAUCUCAGAGUAUUGGCCCCCGUGUAGGUUAUUCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUCGCAUACUACGGUACUGGUGACAGACCUAGGUCGUCAGUUGACCAGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUUAGAUGUUACACUCUAUUAGAUCUCGGAUUACAGCUGGAAGGAGCAGGAGUAGUGUUCUUGCUCUAAGUACCGAGUGUGCCCAAUACCCGAUCAGCUUAUUAACGAACGGCUCCUCCUCUUAGACUGCAGCGUAAGUGCGGAAUCUGGGGAUCAAAUUACUGACUGCCUGGAUUACCCUCGGACAUAUAACCUUGUAGCACGCUGUUGCUGUAUAGGUGACCAACGCCCACUCGAGUAGACCAGCUCUCUUAGUCCGGACAAUGAUAGGAGGCGCGGUCAAUCUACUUCUGGCUAGUUAAGAAUAGGCUGCACCGACCUCUAUAAGUAGCGUGUCCUCUAG、
配列番号116(R720:(N100)10):
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAAACCGAGUUGCAUAUCUCAGAGUAUUGGCCCCCGUGUAGGUUAUUCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUCGCAUACUACGGUACUGGUGACAGACCUAGGUCGUCAGUUGACCAGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUUAGAUGUUACACUCUAUUAGAUCUCGGAUUACAGCUGGAAGGAGCAGGAGUAGUGUUCUUGCUCUAAGUACCGAGUGUGCCCAAUACCCGAUCAGCUUAUUAACGAACGGCUCCUCCUCUUAGACUGCAGCGUAAGUGCGGAAUCUGGGGAUCAAAUUACUGACUGCCUGGAUUACCCUCGGACAUAUAACCUUGUAGCACGCUGUUGCUGUAUAGGUGACCAACGCCCACUCGAGUAGACCAGCUCUCUUAGUCCGGACAAUGAUAGGAGGCGCGGUCAAUCUACUUCUGGCUAGUUAAGAAUAGGCUGCACCGACCUCUAUAAGUAGCGUGUCCUCUAGAGCUACGCAGGUUCGCAAUAAAAGCGUUGAUUAGUGUGCAUAGAACAGACCUCUUAUUCGGUGAAACGCCAGAAUGCUAAAUUCCAAUAACUCUUCCCAAAACGCGUACGGCCGAAGACGCGCGCUUAUCUUGUGUACGUUCUCGCACAUGGAAGAAUCAGCGGGCAUGGUGGUAGGGCAAUAGGGGAGCUGGGUAGCAGCGAAAAAGGGCCCCUGCGCACGUAGCUUCGCUGUUCGUCUGAAACAACCCGGCAUCCGUUGUAGCGAUCCCGUUAUCAGUGUUAUUCUUGUGCGCACUAAGAUUCAUGGUGUAGUCGACAAUAACAGCGUCUUGGCAGAUUCUGGUCACGUGCCCUAUGCCCGGGCUUGUGCCUCUCAGGUGCACAGCGAUACUUAAAGCCUUCAAGGUACUCGACGUGGGUACCGAUUCGUGACACUUCCUAAGAUUAUUCCACUGUGUUAGCCCCGCACCGCCGACCUAAACUGGUCCAAUGUAUACGCAUUCGCUGAGCGGAUCGAUAAUAAAAGCUUGAAUU、
配列番号117(R821:(N40U20N40)2):
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUACAACGUAGCCGGUAUUUUUUUUUUUUUUUUUUUUUUGACCGUCUCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAGCUGAUGAAAGACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUUUUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCCAGCGAUGAUGCUGGCCCAGAUC、
配列番号118(Seq.R722:(N40U20N40)5):
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUACAACGUAGCCGGUAUUUUUUUUUUUUUUUUUUUUUUGACCGUCUCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAGCUGAUGAAAGACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUUUUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCCAGCGAUGAUGCUGGCCCAGAUCUUCGACCACAAGUGCAUAUAGUAGUCAUCGAGGGUCGCCUUUUUUUUUUUUUUUUUUUUUUUGGCCCAGUUCUGAGACUUCGCUAGAGACUACAGUUACAGCUGCAGUAGUAACCACUGCGGCUAUUGCAGGAAAUCCCGUUCAGGUUUUUUUUUUUUUUUUUUUUUCCGCUCACUAUGAUUAAGAACCAGGUGGAGUGUCACUGCUCUCGAGGUCUCACGAGAGCGCUCGAUACAGUCCUUGGAAGAAUCUUUUUUUUUUUUUUUUUUUUUUGUGCGACGAUCACAGAGAACUUCUAUUCAUGCAGGUCUGCUCUA、或いは
配列番号119(R723:(N40U20N40)10):
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUACAACGUAGCCGGUAUUUUUUUUUUUUUUUUUUUUUUGACCGUCUCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAGCUGAUGAAAGACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUUUUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCCAGCGAUGAUGCUGGCCCAGAUCUUCGACCACAAGUGCAUAUAGUAGUCAUCGAGGGUCGCCUUUUUUUUUUUUUUUUUUUUUUUGGCCCAGUUCUGAGACUUCGCUAGAGACUACAGUUACAGCUGCAGUAGUAACCACUGCGGCUAUUGCAGGAAAUCCCGUUCAGGUUUUUUUUUUUUUUUUUUUUUCCGCUCACUAUGAUUAAGAACCAGGUGGAGUGUCACUGCUCUCGAGGUCUCACGAGAGCGCUCGAUACAGUCCUUGGAAGAAUCUUUUUUUUUUUUUUUUUUUUUUGUGCGACGAUCACAGAGAACUUCUAUUCAUGCAGGUCUGCUCUAGAACGAACUGACCUGACGCCUGAACUUAUGAGCGUGCGUAUUUUUUUUUUUUUUUUUUUUUUUCCUCCCAACAAAUGUCGAUCAAUAGCUGGGCUGUUGGAGACGCGUCAGCAAAUGCCGUGGCUCCAUAGGACGUGUAGACUUCUAUUUUUUUUUUUUUUUUUUUUUCCCGGGACCACAAAUAAUAUUCUUGCUUGGUUGGGCGCAAGGGCCCCGUAUCAGGUCAUAAACGGGUACAUGUUGCACAGGCUCCUUUUUUUUUUUUUUUUUUUUUUUCGCUGAGUUAUUCCGGUCUCAAAAGACGGCAGACGUCAGUCGACAACACGGUCUAAAGCAGUGCUACAAUCUGCCGUGUUCGUGUUUUUUUUUUUUUUUUUUUUGUGAACCUACACGGCGUGCACUGUAGUUCGCAAUUCAUAGGGUACCGGCUCAGAGUUAUGCCUUGGUUGAAAACUGCCCAGCAUACUUUUUUUUUUUUUUUUUUUUCAUAUUCCCAUGCUAAGCAAGGGAUGCCGCGAGUCAUGUUAAGCUUGAAUU。
UAGCGAAGCU CUUGGACCUA CC UUUUU UUUUU UUUUU CCC UGCGUUCCUA GAAGUACACG(配列番号86)、
或いは
UAGCGAAGCU CUUGGACCUA CC UUUUU UUUUU
AUCGCUUCGA GAACCUGGAU GG AAAAA AAAAA
UUUUU CCC UGCGUUCCUA GAAGUACACG
AAAAA GGG ACGCAAGGAU CUUCAUGUGC
(配列番号87)。
ポリ(X)s(NuGlXmGnNv)aポリ(X)t
に係る核酸分子を含んでいてもよく、
前記本発明に係る式(II)の核酸分子は、同様に少なくとも50ヌクレオチド、好ましくは少なくとも100ヌクレオチド、より好ましくは少なくとも150ヌクレオチド、更により好ましくは少なくとも200ヌクレオチド、最も好ましくは少なくとも250ヌクレオチドの長さを有する。
ポリ(X)(NuGlXmGnNv)a
に係る核酸分子、及び式(IIb):
ポリ(X)(NuGlXmGnNv)aポリ(X)
に係る核酸分子を含んでいてもよく、
本発明に係る式(IIa)及び式(IIb)のいずれかで表される核酸分子は同様に、少なくとも50ヌクレオチド、好ましくは少なくとも100ヌクレオチド、より好ましくは少なくとも150ヌクレオチド、更により好ましくは少なくとも200ヌクレオチド、最も好ましくは少なくとも250ヌクレオチドの長さを有する。同様に他の定義も全て上記式(II)及び式(I)のいずれかについて記載したものを適用する。同様に前記式(II)、(IIa)、及び(IIb)は、式(Ib)に係る式に基づいて、即ちコア構造ClXmCnの導入に基づいて定義してもよい。
−CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUUU UUUUU GGG(配列番号88)
−CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUU
IIIIIIIIII IIIIIIIIII
U UUUUU GGG(配列番号89)
−CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUU
AAAAA AAAA
U UUUUU GGG(配列番号90)
A AAAAA
−CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUU
GGGGGGGGGG GGGGGGGGGG CC AAAAA AAAA
U UUUUU GGG(配列番号91)
A AAAAA CCC
−CCCCCCCCCC CCCCCCCCCC UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU GGG UGCGUUCCUA GAAGUACACG(配列番号92)
−CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUU
GGGGGGGGGG GGGGGGGGGG CC AAAAA AAAA
U UUUUU GGG UGCGUUCCUA GAAGUACACGUAG
A AAAAA CCC ACGCAAGGAU CUUCAUGUGCAUC
CGAAGCU CUUGGACCUA(配列番号93)
GCUUCGA GAACCUGGAU
−CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUU
CC AAAAA AAAA
U UUUUU GGG UGCGUUCCUA GAAGUACACGUAG
A AAAAA CCC ACGCAAGGAU CUUCAUGUGCAUC
CGAAGCU CUUGGACCUA(配列番号94)
GCUUCGA GAACCUGGAU。
(Nu ステム1 GlXmGn ステム2 Nv)a
に係る核酸分子、及び式(IIIb):
(Nu GlXmGn Nv)a ステム1 Nw1 ステム2 Nw2
に係る核酸分子のいずれかが得られ、ここで本発明に係る式(IIIa)及び式(IIIb)の少なくともいずれかで表される核酸分子は、少なくとも100ヌクレオチド、より好ましくは少なくとも150ヌクレオチド、更により好ましくは少なくとも200ヌクレオチド、最も好ましくは少なくとも250ヌクレオチドの長さを有する。同様に前記式(IIIa)及び式(IIIb)は、式(Ib)に係る式、即ちコア構造ClXmCnの導入に基づいて定義してもよい。
a)ステム1
UAGCGAAGCUCUUGGACCUA(配列番号95)
ステム2
UAGGUCCAAGAGCUUCGCUA(配列番号96)
b)ステム1
UAGGUCCAAGAGCUUCGCUA(配列番号96)
ステム2
UAGCGAAGCUCUUGGACCUA(配列番号95)
c)ステム1
GCCGCGGGCCG(配列番号97)
ステム2
CGGCCCGCGGC(配列番号98)
c)ステム1
CGGCCCGCGGC(配列番号98)
ステム2
GCCGCGGGCCG(配列番号97)
e)ステム1
GACACGGUGC(配列番号99)
ステム2
GCACCGUGCA(配列番号100)
f)ステム1
GCACCGUGCA(配列番号100)
ステム2
GACACGGUGC(配列番号99)
g)ステム1
ACCUAGGU(配列番号101)
ステム2
ACCUAGGU(配列番号101)
h)ステム1
UGGAUCCA(配列番号102)
ステム2
UGGAUCCA(配列番号102)
i)ステム1
CCUGC(配列番号103)
ステム2
GCAGG(配列番号104)
j)ステム1
GCAGG(配列番号105)
ステム2
CCUGC(配列番号106)
等が挙げられる。
−UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU GGG UAGGUCCAAG AGCUUCGCUA(配列番号107)
−UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU GGG UGCGUUCCUA GAAGUACACG GCCGCGGGCCG UGCGUUCCUA GAAGUACACG CGGCCCGCGGC UGCGUUCCUA GAAGUACACG(配列番号108)
(下線部はステム1及びステム2であり、GG UUUUU UUUUU UUUUU GGGはコア構造GlXmGnである)。
任意のヌクレオチド、
本発明の核酸分子の任意のヌクレオチドの塩基部分或いは糖部分、
3’末端及び5’末端の少なくともいずれか、並びに
上で定義した本発明に係る式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される核酸分子のリン酸骨格。
本発明によれば、本発明に係る核酸分子の3’末端及び5’末端の少なくともいずれかにおける末端脂質修飾が特に好ましい。末端修飾は配列内修飾に対して多数の利点を有する。一方配列内修飾はハイブリダイゼーション挙動に影響を与える場合があり、これは立体的に嵩高い(demanding)残基の場合には悪影響を有する恐れがある。他方末端のみ修飾されている本発明に係る脂質修飾核酸分子の合成調製の場合、上で定義した本発明に係る式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される核酸分子の合成は、大量に入手可能な市販モノマーを用いて実施することができ、先行技術で知られている合成プロトコルを用いることができる。
上で定義した本発明に係る式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される核酸分子の3’末端及び5’末端の少なくともいずれか、或いはリン酸骨格、並びに
上で定義した本発明に係る式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される核酸分子の任意のヌクレオチドの任意の塩基及び糖のいずれか。
本発明によれば、上で定義した本発明に係る式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される核酸分子の3’末端及び5’末端の少なくともいずれかにおける末端脂質修飾が特に好ましい。かかる末端化学修飾を用いて、本発明に従って多数の様々に誘導体化された核酸を得ることが可能である。上で定義した本発明に係る式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表されるかかる脂質修飾核酸分子を調製するプロセスは、脂質修飾の位置に応じて選択されること好ましい。
・カップリング工程、キャッピング工程、及び酸化工程における反応時間の延長、
・脱トリチル化工程数の増加、
・各工程後の洗浄工程の延長、
・通常アミダイトプロセス中に(亜リン酸トリエステルを酸化するために)必要な酸化工程後における、微量ヨウ素を除去するためのアスコルビン酸含有洗浄溶液(ジオキサン/水=9:1中0.1M)の使用、
が挙げられる。
或いは式(V):ClXmCn(式中、Cは、シチジン(シトシン)、ウリジン(ウラシル)、シチジン(シトシン)類似体、及びウリジン(ウラシル)類似体のいずれかであり;Xは、グアノシン(グアニン)、ウリジン(ウラシル)、アデノシン(アデニン)、チミジン(チミン)、シチジン(シトシン)、及び上記ヌクレオチド(ヌクレオシド)の類似体のいずれかであり;lは1〜40の整数であって、lが1である場合Cはシチジン(シトシン)及びその類似体のいずれかであり、lが1超である場合ヌクレオチド(ヌクレオシド)の少なくとも50%がシチジン(シトシン)及びその類似体のいずれかであり;mは整数であり且つ少なくとも3であって、mが3である場合Xはウリジン(ウラシル)及びその類似体のいずれかであり、mが3超である場合ウリジン(ウラシル)及びウリジン(ウラシル)の類似体のいずれかが少なくとも3個連続して存在し;nは1〜40の整数であって、nが1である場合、Cはシチジン(シトシン)及びその類似体のいずれかであり、nが1超である場合ヌクレオチド(ヌクレオシド)の少なくとも50%がシチジン(シトシン)及びその類似体のいずれかである)で表される核酸分子が挙げられる。
ホスホロアミダイト法(chemistry)を用いて自動固相合成により、本発明に係る一般式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される核酸分子の例として、RNAオリゴヌクレオチドを調製した(配列番号84〜85(式(I))、配列番号86〜87(式(Ia))、配列番号88〜94(式(II)、(IIa)、及び(IIb))、及び配列番号107〜108(式(IIIa)及び(IIIb))を含む)。いずれも場合もヌクレオチドのRNA特異的2’−ヒドロキシル基をTBDMS保護基で保護した。ホスホロチオエートの合成では、酸化にBeaucage試薬を用いた。メチルアミンを用いて担体物質の切断及び塩基不安定性保護基の切断を行い、トリエチルアミンヒドロフルオリドを作用させてTBDMS保護基を切断した。
a)マウスBDMC(骨髄由来樹状細胞)を刺激するために、オリゴフェクタミン3μLとFCS不含IMDM培地(BioWhittaker、カタログ番号BE12−722F)30μLとを混合し、室温で5分間インキュベートした。RNA形態である配列番号84〜94及び配列番号107〜108で表される核酸配列を有する核酸分子(1実験につきそれぞれの種類の核酸分子を用いた)6μgをFCS不含IMDM培地60μLと混合し、オリゴフェクタミン/IMDMと混合し、室温で20分間インキュベートした。次いでこの混合物(33μL)を、FCS不含IMDM培地200μL中に200,000個のマウスBDMCを含む96ウェルマイクロタイター培養プレートのウェル内で一晩培養した。4時間後20%FCS含有IMDM100μLを添加し、16時間共培養し、上清を除去し、サイトカインELISAによりインターロイキン−6(IL−6)及びインターロイキン−12(IL−12)について試験した。プロタミンと複合体化された免疫賦活作用を有するβ−ガラクトシダーゼ(lacZ)の非キャッピング野生型mRNAを用いて上記配列と同様にして比較試験を行った。
実験0日目及び10日目に、BALB/cマウス(1群当たり5匹)にβ−ガラクトシダーゼタンパク質及びアジュバント(本明細書で定義)を注入した。20日目にマウスを屠殺し、ELISAを用いたβ−ガラクトシダーゼタンパク質に対する抗体試験に血清を使用した。上記インビトロ培養と同様にしてIL−6、IL−12、及びTNFα値を測定した。
a)アジュバント形態の上で定義した本発明に係る一般式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される核酸分子、具体的には配列番号84〜94及び配列番号107〜108で表される核酸配列を有する核酸分子(1実験につきそれぞれの種類の核酸分子を用いた)の免疫原性を測定するために、ヒト細胞と共培養した。この目的のために、例えば2mMのL−グルタミン(BioWhittaker)、10U/mLのペニシリン(BioWhittaker)、及び10μg/mLのストレプトマイシンで富化したX−VIVO−15培地(BioWhittaker、カタログ番号BE04−418Q)中で、10μg/mLのRNA(β−ガラクトシダーゼをコードしているmRNA)及び任意的に10μg/mLのプロタミンとヒトPBMC細胞とを16時間共培養した。上清を除去し、IL−6及びTNFαの放出をELISAを用いて分析した。
この実験では、上で定義した式(I)に係る本発明の核酸分子のうち数種、即ち配列番号114〜119で表されるmRNA配列を有する核酸分子とDOTAP(Roche)とを配合した。
配列番号114(R820/(N100)2);
配列番号115(R719/(N100)5);
配列番号116(R720/(N100)10);
配列番号117(R821/(N40T20N40)2);
配列番号118(R722/(N40T20N40)5);及び
配列番号119(R723/(N40T20N40)10)
であった。
本発明に係る一般式(I)、(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれかで表される本発明の核酸分子は、治療される患者の固有免疫系を賦活するための免疫賦活剤として用いることができる。この免疫賦活特性は、例えば脂質修飾或いは追加的アジュバントの添加等、本発明の核酸分子に対する固有免疫反応を活発に賦活する化合物として当該技術分野において既知である他の化合物の添加により増強することができる。上で定義した本発明の核酸分子、具体的には構造(NuGlXmGnNv)aを有する式(I)に係る核酸分子及びその誘導体のいずれかは、例えば大腸菌等の細菌において著しく速やかに増幅される。式(I)の本発明の核酸分子(NvGlXmGnNu)a及びその誘導体のいずれかが部分的二本鎖核酸分子、及び単鎖核酸分子と二本鎖核酸分子との混合物のいずれかである場合更により有利である。その理由は、該式(I)(或いは式(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb)の少なくともいずれか)に係る本発明の(部分的二本鎖)核酸分子は、単鎖RNAに対するPAMP(病原体関連分子パターン)受容体(TLR−7及びTLR−8)、及び二本鎖RNAに対するPAMP受容体(TLR−3、RIG−I、及びMDA−5)に対応することにより、治療される患者の自然免疫反応を正に刺激することができるためである。受容体TLR−3、TLR−7、及びTLR−8はエンドソームに位置し、エンドソームに取り込まれたRNAにより活性化される。対照的にRIG−I及びMDA−5は細胞質性受容体であり、細胞質に直接取り込まれた、或いはエンドソームから放出された(エンドソーム放出或いはエンドソーム脱出)RNAにより活性化される。従って、式(I)の本発明の部分的二本鎖核酸分子(NuGlXmGnNv)a(或いは、その誘導体、例えば以下に定義する式(Ia)、(II)、(IIa)、(IIb)、(IIIa)及び(IIIb))に係る本発明の(部分的二本鎖)核酸分子)は、免疫賦活の様々なシグナル伝達カスケードを活性化することができ、それによって自然免疫反応を導くか、或いは自然免疫反応を著しく増強する。本発明の更なる利点は、固有免疫系を賦活するのに好ましい抗ウイルス性サイトカインIFNαを著しく誘導することである。それほど重要視されていないことが多いが、一般的に認められている免疫賦活核酸分子(例えばポリA:U及びポリI:C)は構造が不確定であり、そのために調節が限定される。
Claims (12)
- 配列番号117、118又は119で表されるヌクレオチド配列からなること、又は配列番号117、118又は119で表されるヌクレオチド配列を含むことを特徴とするRNA分子。
- 薬剤として使用するための請求項1に記載のRNA分子。
- 請求項1に記載のRNA分子と、薬学的に許容される担体と、を含有する医薬組成物。
- 補助物質、添加剤、及びアジュバントの少なくともいずれかを更に含有する請求項3に記載の医薬組成物。
- 少なくとも1種の薬学的活性成分を更に含む請求項3から4のいずれかに記載の医薬組成物。
- 少なくとも1種の薬学的活性成分が、ペプチド、タンパク質、核酸、治療上有効な分子量5,000未満の低分子量有機化合物、治療上有効な分子量5,000未満の低分子量無機化合物、糖、抗原、抗体、病原体、弱毒化病原体、不活化病原体、細胞、細胞断片、細胞画分、及び他の治療剤からなる群から選択された請求項5に記載の医薬組成物。
- 少なくとも1種の薬学的活性成分が、脂質とポリカチオン性ペプチドを含むポリカチオン性化合物との少なくともいずれかと複合体化することによってトランスフェクション性が向上するようにされた請求項5から6のいずれかに記載の医薬組成物。
- 医薬組成物がワクチンである請求項3から7のいずれかに記載の医薬組成物。
- 癌疾患、及び感染性疾患のいずれかの治療用薬剤を調製するための請求項1に記載のRNA分子の使用。
- 前記癌疾患が、乳頭腫ウイルス誘導性癌腫、ヘルペスウイルス誘導性腫瘍、B型肝炎誘導性腫瘍、HTLV−1誘導性リンパ腫、及びHTLV−2誘導性リンパ腫を含むウイルス誘導性腫瘍;頭/頸部腫瘍;咽頭癌;喉頭癌;頭蓋咽頭腫;まぶた腫瘍;舌癌;神経膠腫;乏突起膠腫;神経鞘腫;網膜芽腫;髄膜腫;下垂体腫瘍;脳腫瘍;グリア芽腫;星状細胞腫;髄芽腫;脳転移;聴神経腫/聴神経鞘腫;甲状腺癌腫;甲状腺腫瘍;肺癌;肺癌腫;Schneeberger病;気管支癌腫;胃腸腫瘍;食道癌;食道癌腫瘍;胃癌;腸癌;小腸腫瘍;結腸癌腫;直腸癌腫;肝臓癌;ヘパトーム;肝転移;膵臓癌腫;膵臓癌;胆嚢癌;肛門癌腫;膀胱癌;尿道癌;腎癌腫;腎癌;精巣癌;陰茎癌;前立腺癌;前立腺腫瘍;外陰癌;膣癌;子宮癌;体癌腫(corpus carcinoma);子宮内膜癌腫;子宮頸癌腫;子宮頚癌;卵巣腫瘍;卵巣癌;乳癌腫;乳癌;黒色腫;基底細胞腫;棘細胞腫;いぼ合併症;骨癌;軟組織腫瘍/肉腫;形質細胞腫;急性骨髄性白血病(AML)、急性リンパ性白血病(ALL)、慢性骨髄性白血病(CML)、及び慢性リンパ性白血病(CLL)を含む白血病;ホジキン症候群、非ホジキンリンパ腫、バーキットリンパ腫、及び菌状息肉腫を含むリンパ腫;腺癌腫;胸腺腫;類癌腫;及びCUP症候群から選択される請求項9の使用。
- 前記感染性疾患が、インフルエンザ、マラリア、SARS、黄熱、エイズ、髄膜炎、尖圭コンジローマ、中空いぼ(hollow warts)、デング熱、三日熱、エボラウイルス、風邪、初夏髄膜脳炎(FSME)、流感、帯状疱疹、肝炎、単純ヘルぺスI型、単純ヘルぺスII型、眼部帯状疱疹、日本脳炎、ラッサ熱、マールブルグウイルス、麻疹、口蹄疫、単核症、耳下腺炎、ノーウォークウイルス感染、ファイファー腺熱、疱瘡、ポリオ、仮性クループ、第五病、狂犬病、いぼ、西ナイル熱、水痘、巨細胞ウイルス(CMV)等を含むウイルス感染症;
流産、炭疽病、虫垂炎、ライムボレリア症、ボツリヌス中毒、カンピロバクター、トラコーマクラミジア、コレラ、ジフテリア、鼠径肉芽腫、喉頭蓋炎、発疹チフス、ガス壊疽、淋病、野兎病、ヘリコバクターピロリ、百日咳、鼠径リンパ肉芽腫、骨髄炎、レジオネラ症、ハンセン病、リステリア症、肺炎、細菌性髄膜炎、中耳炎、マイコプラズマ・ホミニス、新生児敗血症、水癌、パラチフス、ペスト、ライター症候群、ロッキー山紅斑熱、サルモネラ菌パラチフス、サルモネラ菌発疹チフス、猩紅熱、梅毒、破傷風、ツツガムシ病、結核、発疹チフス、膣炎、軟性下疳等を含む細菌感染症;
アメーバ症、ビルハルツ住血吸虫症、シャーガス病、水虫、酵母菌斑(yeast fungus spots)、疥癬、マラリア、オンコセルカ症、真菌症、トキソプラスマ症、トリコモナス症、トリパノソーマ症、内臓リーシュマニア症、おしめ/おむつ皮膚炎、住血吸虫症、魚類中毒症、カンジダ症、皮膚リーシュマニア症、ランブル鞭毛虫症、眠り病を含む寄生虫、原生動物、及び真菌のいずれかによって発症する感染症;及び
魚類条虫(fish tapeworm)、キツネ条虫、イヌ条虫、シラミ、ウシ条虫、ブタ条虫、又は微小条虫(miniature tapeworm)を含むエキノコックス属によって発症する感染性疾患から選択される請求項9の使用。 - 請求項1に記載のRNA分子或いは請求項3から8のいずれかに記載の医薬組成物と、前記RNA分子或いは前記医薬組成物の投与及び用量に関する情報を記載した使用説明書とを備えるキット。
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EP (3) | EP2176408B9 (ja) |
JP (1) | JP5721441B2 (ja) |
KR (1) | KR101483715B1 (ja) |
CN (1) | CN101932707B (ja) |
AU (1) | AU2009210266B2 (ja) |
BR (1) | BRPI0907087B1 (ja) |
CA (1) | CA2710534C (ja) |
DK (1) | DK2176408T5 (ja) |
ES (1) | ES2537703T3 (ja) |
HR (1) | HRP20150528T2 (ja) |
HU (1) | HUE025027T2 (ja) |
MX (1) | MX2010008468A (ja) |
PL (1) | PL2176408T3 (ja) |
PT (1) | PT2176408E (ja) |
RU (1) | RU2545701C2 (ja) |
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