JP2011510640A - 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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- JP2011510640A JP2011510640A JP2010544630A JP2010544630A JP2011510640A JP 2011510640 A JP2011510640 A JP 2011510640A JP 2010544630 A JP2010544630 A JP 2010544630A JP 2010544630 A JP2010544630 A JP 2010544630A JP 2011510640 A JP2011510640 A JP 2011510640A
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- nucleic acid
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- acid molecule
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- uridine
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Abstract
【解決手段】式(I)(NuGlXmGnNv)aの核酸分子である。
【選択図】なし
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 (25)
- 式(I):
(NuGlXmGnNv)a
で表される核酸分子であって、
式中、
Gは、グアノシン、ウリジン、グアノシン類似体、及びウリジン類似体のいずれかであり、
Xは、グアノシン、ウリジン、アデノシン、チミジン、シチジン、及びこれらヌクレオチド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、ウリジン、アデノシン、チミジン、シチジン、及びこれらヌクレオチドの類似体から選択され、
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の少なくとも50%がグアノ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、ウリジン及びウリジン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の少なくとも50%がグアノシン及びその類似体のいずれかであり、
u、vは、独立して互いに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、
式(I)の核酸分子が、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ことを特徴とする核酸分子。 - 式(I)の核酸分子が、以下の配列番号1〜80で表される核酸配列のうち少なくとも1種の配列から選択されるコア構造GlXmGnを含む請求項1に記載の核酸分子:
−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)。 - 核酸分子が特定の式(II):
ポリ(X)s(NuGlXmGnNv)aポリ(X)t
で表される核酸分子であって、
式中、
G、X、N、a、l、m、n、u、及びvは、式(I)について上で定義した通りであり、
ポリ(X)は核酸のホモポリマー配列であって、Xは式(I)に係る核酸分子のXについて定義した任意の核酸であってもよく、
s、tは各々互いに独立して、約5〜100の整数、好ましくは約5〜70、より好ましくは約5〜50、更により好ましくは約5〜30、最も好ましくは約5〜20から選択される整数である、核酸分子を含み、
前記式(II)の核酸分子が少なくとも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請求項1及び2のいずれかに記載の核酸分子。 - 式(II)に係る核酸分子が、具体的には式(IIa):
ポリ(X)(NuGlXmGnNv)a
で表される核酸分子である請求項3に記載の核酸分子。 - 式(II)に係る核酸分子が、具体的には式(IIb):
ポリ(X)(NuGlXmGnNv)aポリ(X)
で表される核酸分子である請求項3に記載の核酸分子。 - ポリ(X)で表される核酸のホモポリマー配列が、単鎖RNA配列、部分的二本鎖RNA配列、及び二本鎖RNA配列のいずれかである請求項3から5のいずれかに記載の核酸分子。
- ポリ(X)で表される核酸分子のホモポリマー配列が、シチジンの単鎖配列(ポリ(C))、グアノシンの単鎖配列(ポリ(G))、アデノシンの単鎖配列(ポリ(A))、ウリジンの単鎖配列(ポリ(U))、イノシンの単鎖配列(ポリ(I))、イノシンとシチジン(cytoine)とのホモポリマー二本鎖配列(ポリ(I:C))、及びアデノシンとウリジンとのホモポリマー二本鎖配列(ポリ(A:U))から選択される請求項3から6のいずれかに記載の核酸分子。
- 核酸分子が特定の式(IIIa):
(Nu ステム1 GlXmGn ステム2 Nv)a
で表される核酸分子、及び式(IIIb):
(NuGlXmGnNv)a ステム1 Nw1 ステム2 Nw2
で表される核酸分子のいずれかであって、
式中、各々
G、X、N、a、l、m、n、u、及びvは、式(I)について上で定義した通りであり、
w1、w2は整数であって、互いに独立して式(I)の整数u、vについて上で定義した通りであり、
ステム1、ステム2は各々、パリンドローム配列であって、ステムループ構造を形成し、前記パリンドローム配列がアデノシン、グアノシン、シチジン、ウリジン、チミジン、及びこれらの類似体から選択される約5核酸〜50核酸、より好ましくは約5核酸〜40核酸、最も好ましくは約5核酸〜30核酸の長さを有する核酸配列により各々形成される核酸分子を含む請求項1及び2のいずれかに記載の核酸分子。 - 式(I)、(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が、以下の少なくともいずれかである請求項1から8のいずれかに記載の核酸分子、
RNA及びDNAのいずれかの形態である核酸分子、
単鎖、二本鎖、及び部分的二本鎖のいずれかである核酸分子、並びに
直鎖及び環状のいずれかである核酸分子。 - 式(I)、(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が単鎖RNA、二本鎖RNA、及び部分的二本鎖RNAのいずれかの形態であり、好ましくは部分的二本鎖RNAである請求項1から9のいずれかに記載の核酸分子。
- 式(I)、(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がRNAの形態で存在し、5’末端における「キャップ構造」、3’末端におけるポリ−Aテール、及び3’末端におけるポリ−Cテールの少なくともいずれかを更に有する請求項1から10のいずれかに記載の核酸分子。
- 核酸がインビトロ翻訳により調製される請求項1から11のいずれかに記載の核酸分子。
- 薬剤としての、特に免疫賦活剤としての請求項1から12のいずれかに記載の核酸分子。
- 請求項1から12のいずれかに記載の核酸分子と、薬学的に許容される担体と、任意的に更なる補助物質、添加剤、及びアジュバントの少なくともいずれかとを含有している医薬組成物。
- 少なくとも1種の薬学的活性成分を更に含む請求項14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、(治療活性)低分子量有機化合物(分子量5,000未満)、(治療活性)低分子量無機化合物(分子量5,000未満)、糖、抗原、抗体、病原体、弱毒化病原体、不活化病原体、(ヒト)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、これらは、例えば、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ていることが好ましい請求項15に記載の医薬組成物。
- 少なくとも1種の更なるアジュバントを含有している請求項14から16のいずれかに記載の医薬組成物であって、前記少なくとも1種の更なるアジュバントが、プロタミン、ヌクレオリン、スペルミン、及びスペルミジンのいずれかを含むポリペプチドを含むカチオン性ペプチド、キトサンを含むカチオン性多糖類、TDM、MDP、ムラミルジペプチド、プルロニクス、アルミニウム溶液(alum solution)、水酸化アルミニウム、ADJUMER(商標)(ポリホスファゼン);リン酸アルミニウムゲル;藻類由来のグルカン;アルガムリン;水酸化アルミニウムゲル(アルム);タンパク質高吸着性水酸化アルミニウムゲル;低粘度水酸化アルミニウムゲル;AF及びSPTのいずれか(スクアラン(5%)、Tween80(0.2%)、Pluronic L121(1.25%)、リン酸緩衝生理食塩水のエマルション、pH7.4);AVRIDINE(商標)(プロパンジアミン);BAY R1005(商標)((N−(2−デオキシ−2−L−ロイシルアミノ−b−D−グルコピラノシル)−N−オクタデシルドデカノイル−アミドヒドロアセテート);CALCITRIOL(商標)(1α,25−ジヒドロキシ−ビタミンD3);リン酸カルシウムゲル;CAPTM(リン酸カルシウムナノ粒子);コレラホロトキシン、コレラ毒素−A1−タンパク質−A−D−フラグメント融合タンパク質、前記コレラ毒素のサブユニットB;CRL 1005(ブロックコポリマーP1205);サイトカイン含有リポソーム;DDA(ジメチルジオクタデシルアンモニウムブロミド);DHEA(デヒドロエピアンドロステロン);DMPC(ジミリストイルホスファチジルコリン);DMPG(ジミリストイルホスファチジルグリセロール);DOC/アルム複合体(デオキシコール酸ナトリウム塩);フロイント完全アジュバント;フロイント不完全アジュバント;ガンマイヌリン;Gerbuアジュバント((i)N−アセチルグルコサミニル−(P1−4)−N−アセチルムラミル−L−アラニル−D−グルタミン(GMDP)と、(ii)ジメチルジオクタデシルアンモニウムクロリド(DDA)と、(iii)亜鉛−L―プロリン塩複合体(ZnPro−8)との混合物;GM−CSF);GMDP(N−アセチルグルコサミニル−(b1−4)−N−アセチルムラミル−L−アラニル−D−イソグルタミン);イミキモド(1−(2−メチプロピル)−1H−イミダゾ[4,5−c]キノリン−4−アミン);ImmTher(商標)(N−アセチルグルコサミニル−N−アセチルムラミル−L−Ala−D−イソGlu−L−Ala−グリセロールジパルミテート);DRV(脱水−再水和小胞から調製された免疫リポソーム);インターフェロン−γ;インターロイキン−1β;インターロイキン−2;インターロイキン−7;インターロイキン12;ISCOMS(商標)(「免疫賦活複合体」);ISCOPREP 7.0.3.(商標);リポソーム;LOXORIBINE(商標)(7−アリル−8−オキソグアノシン(グアニン));LT経口アジュバント(大腸菌に対して不安定なエンテロトキシン−プロトキシン);任意の組成のミクロスフィア及び微粒子;MF59(商標);(スクアレン−水エマルション);MONTANIDE ISA 51(商標)(精製不完全フロイントアジュバント);MONTANIDE ISA 720(商標)(代謝可能なオイルアジュバント);MPL(商標)(3−Q−デサシル−4’−モノホスホリルリピドA);MTP−PE及びMTP−PEリポソーム((N−アセチル−L−アラニル−D−イソグルタミニル−L―アラニン−2−(1,2−ジパルミトイル−sn−グリセロ−3−(ヒドロキシホスホリルオキシ))エチルアミド,一ナトリウム塩);MURAMETIDE(商標)(Nac−Mur−L−Ala−D−Gln−OCH3);MURAPALMITINE(商標)及びD−MURAPALMITINE(商標)(Nac−Mur−L−Thr−D−イソGln−sn−グリセロールジパルミトイル);NAGO(ノイラミニダーゼ−ガラクトースオキシダーゼ);任意の組成のナノスフェア及びナノ粒子のいずれか;NISV(非イオン界面活性剤小胞);PLEURAN(商標)(β−グルカン);PLGA、PGA、及びPLA(乳酸とグリコール酸とのコポリマー、乳酸ホモポリマー、及びグリコール酸ホモポリマー;ミクロスフィア及びナノスフェア);PLURONIC L121(商標);PMMA(ポリメチルメタクリレート);PODDS(商標)(プロテイノイドミクロスフィア);ポリエチレンカルバメート誘導体;ポリ−rA:ポリ−rU(ポリアデニル酸−ポリウリジル酸複合体);ポリソルベート80(Tween80);タンパク質コキレート(cochleate)(Avanti Polar Lipids,Inc.,Alabaster,AL);STIMULON(商標)(QS−21);Quil−A(Quil−Aサポニン);S−28463(4−アミノ−otec−ジメチル−2−エトキシメチル−1H−イミダゾ[4,5−c]キノリン−1−エタノール);SAF−1(商標)(「Syntex社のアジュバント製剤」);センダイプロテオリポソーム及びセンダイ含有脂質マトリックス;Span−85(ソルビタントリオレエート);Specol(Marcol52、Span−85、及びTween85のエマルション);スクアレン及びRobane(登録商標)(2,6,10,15,19,23−ヘキサメチルテトラコサン、及び2,6,10,15,19,23−ヘキサメチル−2,6,10,14,18,22−テトラコサヘキサン)のいずれか;ステアリルチロシン(オクタデシルチロシン塩酸塩);Theramid(登録商標)(N−アセチルグルコサミニル−N−アセチルムラミル−L−Ala−D−イソGlu−L−Ala−ジパルミトキシプロピルアミド);トレオニル−MDP(Termurtide(商標)或いは[thr 1]−MDP;N−アセチルムラミル−L−トレオニル−D−イソグルタミン);Ty粒子(Ty−VLP或いはウイルス様粒子);Walter−Reedリポソーム(水酸化アルミニウム上に吸着されているリピドAを含んでいるリポソーム)、Pam3Cysを含むリポペプチドからなる群から選択される免疫賦活剤、
特に、Adju−phos、Alhydrogel、Rehydragel等のアルミニウム塩類、CFA、SAF、IFA、MF59、Provax、TiterMax、Montanide、Vaxfectin等のエマルション、Optivax(CRL1005)、L121、Poloaxmer4010)等のコポリマー、Stealth等のリポソーム、BIORAL等のコキレート、QS21、Quil A、Iscomatrix、ISCOM等の植物由来のアジュバント、例えばTomatine、PLG、PMM、イヌリン等の生体高分子、Romurtide、DETOX、MPL、CWS、マンノース、CpG7909、ISS−1018、IC31、イミダゾキノリン、Ampligen、Ribi529、IMOxine、IRIV、VLP、コレラ毒素、熱不安定性毒素、Pam3Cys、フラゲリン、GPIアンカー、LNFPIII/Lewis X、抗微生物ペプチド、UC−1V150、RSV融合タンパク質、cdiGMP等の微生物由来のアジュバントを挙げることができる同時賦活に好適な好ましいアジュバント、例えばCGRP神経ペプチド等を挙げることができる拮抗剤として好適な好ましいアジュバント、
プロタミン、ヌクレオリン、スペルミン、スペルミジン、及び他のカチオン性ペプチド或いはカチオン性タンパク質のいずれかを含むデポー及び送達に好適なカチオン性化合物或いはポリカチオン性化合物、例えばポリ−L−リジン(PLL)、ポリアルギニン、塩基性ポリペプチド、HIV結合ペプチド、Tat、HIV−1 Tat(HIV)、Tat由来ペプチド、Penetratin、VP22由来ペプチド或いは類似ペプチドを含む細胞透過性ペプチド(CPP)、HSV VP22(単純ヘルペス)、MAP、KALA、或いはタンパク質伝達ドメイン(PTD、PpT620、プロリンリッチペプチド、アルギニンリッチペプチド、リジンリッチペプチド、MPG−ペプチド(1及び複数のいずれか)、Pep−1、L−オリゴマー、カルシトニンペプチド(1及び複数のいずれか)、アンテナペディア由来ペプチド(特にショウジョウバエのアンテナペディア由来)、pAntp、pIsl、FGF、ラクトフェリン、Transportan、Buforin−2、Bac715−24、SynB、SynB(1)、pVEC、hCT−由来ペプチド、SAP、プロタミン、スペルミン、スペルミジン、或いはヒストン;以下の全式を有する以下のタンパク質及びペプチドから選択することができる好ましいカチオン性タンパク質、ポリカチオン性タンパク質、カチオン性ペプチド、或いはポリカチオン性ペプチド:(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x(式中、l+m+n+o+xは8〜15であり、l、m、n、及びoは互いに独立して0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、或いは15から選択される任意の数であってもよいが、但しArg、Lys、His及びOrnの総含量は該オリゴペプチドの全アミノ酸の少なくとも50%であり、XaaはArg、Lys、His或いはOrnを除くネイティブ(天然に存在する)アミノ酸或いは非ネイティブアミノ酸から選択される任意のアミノ酸であってもよく、xは0、1、2、3、或いは4から選択される任意の数であってもよいが、但しXaaの総含量は該オリゴペプチドの全アミノ酸の50%を超えない)、カチオン性多糖類、例えばキトサン、ポリブレン、ポリエチレンイミン(PEI)を含むカチオン性ポリマー、DOTMA:[1−(2,3−シオレイルオキシ)プロピル)]−N,N,N−トリメチルアンモニウムクロリドを含むカチオン性脂質、DMRIE、ジ−C14−アミジン、DOTIM、SAINT、DC−Chol、BGTC、CTAP、DOPC、DODAP、DOPE:ジオレイルホスファチジルエタノールアミン、DOSPA、DODAB、DOIC、DMEPC、DOGS:ジオクタデシルアミドグリシルスペルミン、DIMRI:ジミリスト−オキシプロピルジメチルヒドロキシエチルアンモニウムブロミド、DOTAP:ジオレオイルオキシ−3−(トリメチルアンモニオ)プロパン、DC−6−14:O,O−ジテトラデカノイル−N−(α−トリメチルアンモニオアセチル)ジエタノールアミンクロリド、CLIP1:rac−[(2,3−ジオクタデシルオキシプロピル)(2−ヒドロキシエチル))−ジメチルアンモニウムクロリド、CLIP6:rac−[2(2,3−ジヘキサデシルオキシプロピル−オキシメチルオキシ)エチル]トリメチルアンモニウム、CLIP9:rac−[2(2,3−ジヘキサデシルオキシプロピル−オキシスクシニルオキシ)エチル]−トリメチルアンモニウム、オリゴフェクタミン、カチオン性ポリマー及びポリカチオン性ポリマーのいずれか、例えばβ−アミノ酸ポリマー或いは逆(reversed)ポリアミドを含む修飾ポリアミノ酸、PVP(ポリ(N−エチル−4−ビニルピリジニウムブロミド))を含む修飾ポリエチレン、pDMAEMA(ポリ(ジメチルアミノエチルメチルアクリレート))を含む修飾アクリレート、pAMAM(ポリ(アミドアミン))を含む修飾アミドアミン、ジアミン末端修飾1,4ブタンジオールジアクリレート−co−5−アミノ−1−ペンタノールポリマーを含む修飾ポリベータアミノエステル(PBAE)、ポリプロピルアミンデンドリマー或いはpAMAM系デンドリマーを含むデンドリマー、PEI:ポリ(エチレンイミン)、ポリ(プロピレンイミン)含むポリイミン(1及び複数のいずれか)、ポリアリルアミン、シクロデキストリン系ポリマー、デキストラン系ポリマー、キトサンを含む糖骨格系ポリマー、PMOXA−PDMSコポリマー等を含むシラン骨格系ポリマー、1以上のカチオン性ブロック(上記カチオン性ポリマーから(og)選択される)と、1以上の親水性ブロック或いは疎水性ブロック(例えばポリエチレングリコール)との組み合わせからなるブロックポリマー、
式(IV):GlXmGn(式中、Gはグアノシン、ウリジン、グアノシン類似体、及びウリジン類似体のいずれかであり;Xは、グアノシン、ウリジン、アデノシン、チミジン、シチジン、及びこれらヌクレオチ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Gはグアノ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Gで表されるヌクレオチドの少なくとも50%がグアノ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はウリジン及びその類似体のいずれかであり、mが3超である場合少なくとも3個の連続するウリジン及びウリジンの類似体のいずれかが存在し;nは、1〜40の整数であって、nが1である場合、Gはグアノシン及びその類似体のいずれかであり、nが1超である場合、Gで表されるヌクレオチドの少なくとも50%が、グアノシン及びその類似体のいずれかである)の核酸分子、
式(V):ClXmCn(式中、Cは、シチジン、ウリジン、シチジン類似体、及びウリジン類似体のいずれかであり;Xは、グアノシン、ウリジン、アデノシン、チミジン、シチジン、及びこれらヌクレオチ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はシチジン及びその類似体のいずれかであり、lが1超である場合Cで表されるヌクレオチドの少なくとも50%がシチジ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はウリジン及びその類似体のいずれかであり、mが3超である場合少なくとも3個の連続するウリジン及びウリジンの類似体のいずれかが存在し;nは、1〜40の整数であって、nが1である場合Cはシチジン及びその類似体のいずれかであり、nが1超である場合Cで表されるヌクレオチドの少なくとも50%が、シチジン及びその類似体のいずれかである)の核酸分子からなる群から選択される請求項14から16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14から17のいずれかに記載の医薬組成物。
- 癌疾患、自己免疫疾患、アレルギー、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から12のいずれかに記載の核酸分子の使用。
- 癌疾患が、結腸癌腫、黒色腫、腎癌腫、リンパ腫、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)、慢性リンパ性白血病(CLL)、胃腸腫瘍、肺癌腫、神経膠腫、甲状腺腫瘍、乳癌腫、前立腺腫瘍、ヘパトーム、各種ウイルス誘導性腫瘍(例えば、乳頭腫ウイルス誘導性癌腫(例えば子宮頚癌腫)、腺癌腫、ヘルペスウイルス誘導性腫瘍(例えばバーキットリンパ腫、EBV誘導性B細胞リンパ腫)、B型肝炎誘導性腫瘍(肝細胞癌腫)、HTLV−1誘導性リンパ腫、HTLV−2誘導性リンパ腫、聴神経腫/聴神経鞘腫、子宮頚癌、肺癌、咽頭癌、肛門癌腫、グリア芽腫、リンパ腫、直腸癌、星状細胞腫、脳腫瘍、胃癌、網膜芽腫、基底細胞腫、脳転移、髄芽腫、膣癌、膵臓癌、精巣癌、メラノーマ、甲状腺癌腫、膀胱癌、ホジキン症候群、髄膜腫、Schneeberger病、気管支癌腫、下垂体腫瘍、菌状息肉腫、食道癌、乳癌、類癌腫、神経鞘腫、棘細胞腫、バーキットリンパ腫、喉頭癌、腎癌、胸腺腫、体癌腫(corpus carcinoma)、骨癌、非ホジキンリンパ腫、尿道癌、CUP症候群、頭/頸部腫瘍、乏突起膠腫、外陰癌、腸癌、結腸癌、食道癌腫瘍、いぼ合併症、小腸腫瘍、頭蓋咽頭腫、卵巣癌、軟組織腫瘍/肉腫、卵巣癌、肝臓癌、膵臓癌腫、子宮頸癌腫、子宮内膜癌腫、肝転移、陰茎癌、舌癌、胆嚢癌、白血病、形質細胞腫、子宮癌、まぶた腫瘍、及び前立腺癌から選択される請求項19に記載の使用。
- 感染性疾患が、インフルエンザ、マラリア、SARS、黄熱、エイズ、ライムボレリア症、リーシュマニア症、炭疽病、髄膜炎、ウイルス感染症(例えば、エイズ、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)、インフルエンザ、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、インフルエンザ、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(幼年期跛行(lameness))、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)、細菌感染症(例えば、流産(前立腺炎症)、炭疽病、虫垂炎、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(尿道の炎症、結膜炎)、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、髄膜炎、細菌性髄膜炎、炭疽病、中耳炎、マイコプラズマ・ホミニス、新生児敗血症(絨毛羊膜炎)、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、トリッパー、ツツガムシ病、結核、発疹チフス、膣炎、軟性下疳等)、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(例えば、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(眼オンコセルカ症))、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(眠り病)、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(シガテラ中毒)、カンジダ症、皮膚リーシュマニア症、ラムブル鞭毛虫症(ジアルジア鞭毛虫症)、眠り病、エキノコックス属によって発症する感染性疾患、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、及び微小条虫(miniature tapeworm)から選択される請求項19に記載の使用。
- 自己免疫疾患が、I型自己免疫疾患、II型自己免疫疾患、III型自己免疫疾患、及びIV型自己免疫疾患のいずれか、例えば多発性硬化症(MS)、関節リウマチ、糖尿病、I型糖尿病(真性糖尿病)、全身性エリテマトーデス症(SLE)、慢性多発性関節炎、バセドー氏病、自己免疫性慢性肝炎、潰瘍性大腸炎、I型アレルギー疾患、II型アレルギー疾患、III型アレルギー疾患、IV型アレルギー疾患、線維筋痛、脱毛症、ベヒテレフ病、クローン病、重症筋無力症、神経皮膚炎、リウマチ性多発筋痛症、進行性全身性硬化症(PSS)、乾癬、ライター症候群、リウマチ性関節炎、乾癬、脈管炎等、或いはII型糖尿病からなる群から選択される請求項19に記載の使用。
- アレルギーが、アレルギー性喘息(鼻粘膜の腫脹を引き起こす)、アレルギー性結膜炎(充血及び結膜の掻痒感を引き起こす)、アレルギー性鼻炎(「花粉症」)、アナフィラキシー、血管浮腫、アトピー性皮膚炎(湿疹)、蕁麻疹、好酸球増加症、呼吸器アレルギー、昆虫咬傷アレルギー、皮膚アレルギー(湿疹、蕁麻疹等の様々な発疹及び(接触性)皮膚炎等を引き起こし、それらを含む)、食物アレルギー、及び薬物アレルギーからなる群から選択される請求項19に記載の使用。
- 請求項1から12のいずれかに記載の核酸分子或いは請求項14から18のいずれかに記載の医薬組成物と、任意的に前記核酸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。
- 医薬として有効な量の請求項1から12のいずれかに記載の核酸分子或いは請求項14から18のいずれかに記載の医薬組成物を、それを必要としている患者に投与することによる、癌疾患、感染性疾患、自己免疫疾患、及びアレルギーからなる群から選択される疾病或いは疾患を治療する方法。
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