JP2012070757A - 免疫刺激配列オリゴヌクレオチド及びその使用方法 - Google Patents
免疫刺激配列オリゴヌクレオチド及びその使用方法 Download PDFInfo
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Abstract
【解決手段】免疫調節ポリヌクレオチドであって:a)0,1,2,3,4又は5塩基離れている少なくとも2つのCGジヌクレオチドを含んで成るパリンドローム配列であって、1/3超がA及びTという塩基組成を有しており、且つ少なくとも8塩基の長さであるパリンドローム配列;及びb)(TCG)y(ここで、yは1又は2であり、(TCG)yの5’Tは前記ポリヌクレオチドの5’末端から0,1,2又は3塩基の位置にある)であって、前記パリンドローム配列の5’末端から0,1,又は2塩基離れている(TCG)y、を含んで成る、10塩基超の免疫調節ポリヌクレオチド。
【選択図】図1
Description
従ってこれまで、この方法はごく限られた成功をもたらしてきた。
免疫調製ポリヌクレオチドの同定を継続する必要がある。
本発明の組成物は、本明細書に記載の免疫調節ポリヌクレオチドを含んで成る。本発明の免疫調節ポリヌクレオチドは、a)少なくとも1つのCGジヌクレオチドを含む少なくとも8塩基の長さのパリンドローム配列及びb)前記ポリヌクレオチドの5’末端又はその付近の少なくとも1つのTCGトリヌクレオチド、を含む。
本発明の実施は、特に言及しない限りは、当該技術分野の範囲内である、分子生物学(組換え技術を含む)、微生物学、細胞生物学、生化学及び免疫学の通常の技術を使用するであろう。このような技術は、文献において十分に説明されており、これは例として、Molecular Cloning: A Laboratory Manual、第2版(Sambrookら、1989);Oligonucleotide Synthesis(M.J. Gait編集、1984);Animal Cell Culture(R.I. Freshney編集、1987);Handbook of Experimental Immunology(D.M. Weir及びC.C. Blackwell編集);Gene Transfer Vectors for Mammalian Cells(J.M. Miller及びM.P. Calos編集、1987);Current Protocols in Molecular Biology(F.M. Ausubelら編集、1987);PCR: The Polymerase Chain Reaction、(Mullisら編集、1994);Current Protocols in Immunology(J.E. Coliganら編集、1991);The Immunoassay Handbook(D. Wild編集、Stockton Press NY、1994);Bioconjugate Techniques(Gr例えば T. Hermanson編集、Academic Press社、1996);及び、Methods of Immunological Analysis(R. Masseyeff、W.H. Albert、及びN.A. Staines編集、Weinheim:VCH Verlags gesellschaft社、1993)を含む。
本願明細書において使用される単数形「ひとつの(a、an)」、及び「当該(the)」は、特に記さない限りは、複数の意味も含む。例えば、「ひとつの(an)」IMPは、1又は複数のIMPを含む。
用語「抗原に対するアレルギー反応」、「アレルギー」、及び「アレルギー状態」は、本発明の方法の一部の適用に関し同等に適切であると理解されかつ意図される。更に、本発明の方法は、アレルギー反応の予防に加え、予め存在するアレルギー状態の治療に関し同等に適切であるものを含むと理解されかつ意図される。
例えば、ヒスタミン放出を抑制する免疫調節ポリヌクレオチド及び抗原を含有する組成物は、例えば、抗原単独により誘導されたヒスタミン放出と比べて、ヒスタミン放出を低下する。別の例として、抗体産生を抑制する免疫調節ポリヌクレオチド及び抗原を含有する組成物は、例えば抗原単独により産生された抗体の程度及び/又はレベルと比べ、抗体の程度及び/又はレベルを低下する。
本発明は、個体の免疫反応を調節するための免疫調節配列(IMP)を提供する。本発明の組成物は、免疫調節ポリヌクレオチド単独(あるいは、2又はそれ以上の免疫調節ポリヌクレオチドの組合せ)、あるいは別の免疫調節物質、例えばペプチド、抗原(後述する)及び/又は追加のアジュバントと複合して含んで成る。本発明の組成物は、免疫調節ポリヌクレオチド及び医薬として許容される賦形剤を含んで成ることができる。緩衝剤を含む医薬として許容される賦形剤は、当該技術分野において周知である。Remingtonの「The Science and Practice of Pharmacy」第20版、Mack Publishing社(2000)。
獣医学的用途及び動物における抗体産生のためには、フロイントのアジュバント(完全及び不完全の両方)のマイトジェン成分を使用することができる。
本発明の免疫調節ポリヌクレオチドは、少なくとも1つのCGジヌクレオチドを含む少なくとも8塩基の長さの少なくとも1つのパリンドローム配列(すなわちパリンドローム)を含む。IMPはまた、前記ポリヌクレオチドの5’末端又はその付近に少なくとも1つのTCGトリヌクレオチド配列も含む(すなわち、5’−TCG)。場合によっては、当該パリンドローム配列は5’−TCGの全部又は一部を含む。
態様によっては、(TCG(Nq))y配列はパリンドローム配列から0,1又は2塩基離れている。他の態様において、パリンドローム配列は(TCG(Nq))y配列の全部又は一部を含む。幾つかの態様において、p=1である場合、X1、X2、及びX3はそれぞれA又はTのいずれかである。幾つかの態様において、p=0である場合、X1、X2、及びX3のうちの少なくとも2つはA又はTのいずれかである。態様によっては、IMPは以下の配列(パリンドローム配列に下線を引いた):
5'-TCGTTCGAACGTTCGAACGA (配列番号88)、 全てのホスホジエステル結合;
5'-TsCsGsTTCGAACGTTCGsAsAsCsGsA (配列番号89)、ホスホロチオエート/ホスホジエステルキメラ;
5'-GsGsTCGAACGTTCGAGsGsGsGsGsG (配列番号26)、ホスホロチオエート/ホスホジエステルキメラ;
5'-TsCsGsTCGAACGTTCGAGsGsGsGsGsG (配列番号33)、ホスホロチオエート/ホスホジエステルキメラ;
5'-TsCsGsTGCATCGATGCAGGsGsGsGsG (配列番号34)、ホスホロチオエート/ホスホジエステルキメラ、
を含んで成る。
5'-uCGuCGAACGTTCGAGATG (配列番号21)、u=2’−O−メチル−ウリジン;
5'-TcGTCGAACGTTCGAGATG (配列番号22)、c=2’−O−メチル−シチジン;
5'-TCGTcGAACGTTCGAGATG (配列番号23)、c=2’−O−メチル−シチジン;
5'-TBGTBGAABGTTBGAGATGAT (配列番号28)、B=5−ブロモ−2’−デオキシシチジン、
を含んで成る。
糖修飾を行い、かつIMPの調製におけるリン酸修飾と組合せることもできる。
従って、IMPは2’−デオキシウリジン及び/又は2−アミノ−2’−デオキシアデノシンを含むことがある。
精製法は当該技術分野において公知である。他の調製法は、免疫調節ポリヌクレオチド及び抗原の組合せを含む。
抗原は、免疫調節ポリヌクレオチドと同時投与することができ、及び/又は免疫調節ポリヌクレオチド及び抗原を含んで成る組成物において(及びこれらの組成物の調製において)使用することができる。
原生動物の感染性物質は、マラリア原虫、リーシュマニア種、トリパノソーマ種及び住血吸虫種を含む。真菌は、カンジダ・アルビカンス(Candida albicans)を含む。
Vaccine、11:S46-51 (1993);Kodihalliら、J. Virol、71:3391-3396 (1997);Ahmeidaら、Vaccine、11:1302-1309 (1993);Chenら、Vaccine、17:653-659 (1999);Govorkova及びSmimov、Acta Virol.、41:251-257 (1997);Koideら、Vaccine、13:3-5 (1995);Mbawuikeら、Vaccine、12:1340-1348 (1994);Tamuraら、Vaccine、12:310-316 (1994);Tamuraら、Eur. J. Immunol.、22:477-481(1992);Hirabayashiら、Vaccine、8:595-599 (1990)である。他の抗原ポリペプチドの例は、類属-又は亜類属-特異的抗原であり、これは多くの感染性物質について公知であり、アデノウイルス、単純ヘルペスウイルス、パピローマウイルス、呼吸器合胞体ウイルス(RSV)及びポックスウイルスを含むが、これらに限定されるものではない。
(HMFG)、ムチン(MUC1)、MAGE抗原、BAGE抗原、GAGE抗原、gp100、前立腺特異抗原(PSA)及びチロシナーゼを含む。免疫ベースの避妊剤は、IMPと共に投与された精子タンパク質を含んで成ることにより形成することができる。Leaら、Biochim. Biophys. Acta、1307:263 (1996)。
抗原と共に使用する場合、IMPは、多くの方法で抗原と共に投与することができる。
一部の態様において、IMP及び抗原は、互いに空間的近傍で、又は混合して(すなわち、溶液中)投与することができる。以下に説明するように、空間的近傍は、多くの方法により達成することができ、これは複合(連結)、キャプシド封入、プラットフォームへの付着(affixation)又は表面への吸着による。一般に、且つ最も好ましくは、IMP及び抗原は、IMP及び抗原の混合物としての投与と比べ、生じた免疫反応が増強されるのに有効な距離で近傍に会合されている。
細胞型に特異的な細胞表面マーカーに対し特異性を伴う抗体は、当該技術分野において公知であり、かつ当該技術分野において公知の方法により容易に調製される。
一般に、プラットフォームは、IMP及び抗原の適当な結合部位を含むか、又はこれを含むように誘導体化される。加えて、又は代わりに、IMP及び/又は抗原は、誘導体化され、適当な連結基を提供する。例えば、単純なプラットフォームは、ペプチドのような二官能性リンカー(すなわち、2個の結合部位を有する)である。更なる例を下文で論じる。
R1S(CH2CH2O)nCH2CH2O(CH2)MCO2R2(式中、n=0〜200、m=1又は2であり、R1=H又は保護基、例えばトリチルであり、R2=H又はアルキル又はアリールであり、例えば、4−ニトロフェニルエステルである)。これらのリンカーは、アミド結合を介したアミノ基を含む第二分子へのチオエーテルを介して、ハロアセチル、マレインアミドなどのようなチオール反応基を含む分子の結合において有用である。これらのリンカーは、結合の順番に関して柔軟であり、すなわちチオエーテルは最初又は最後に形成することができる。
IMPは、免疫調節ポリヌクレオチド/マイクロキャリア(IMP/MC)複合体の形で投与することができる。従って、本発明は、IMP/MC複合体を含んで成る組成物を提供する。
一般に、この技術において、生分解性ポリマー、例えばポリ無水物、ポリ(アルキル−α−シアノアクリレート)及びポリ(α−ヒドロキシエステル)、例えばポリ(乳酸)、ポリ(グリコール酸)、ポリ(D、L−乳酸−コ-グリコール酸)及びポリ(カプロラクトン)などが、塩化メチレンのような適当な有機溶媒に溶解され、エマルションの分散相(DP)を構成する。DPは、例えばポリビニルアルコール(PVA)又はポリビニルピロリドン(PVP)のような溶解した界面活性剤を含んで成る過剰容量の水性連続相(CP)への高速ホモジナイゼーションにより乳化される。CP中の界面活性剤は、孤立しかつ適当なサイズのエマルション液滴を形成することを確実にする。その後有機溶媒が、CPに抽出され、かつ引き続きこの系の温度を上昇することにより蒸発させる。その後固形マイクロ粒子は、遠心又は濾過により分離され、かつ例えば凍結乾燥又は真空の適用により乾燥され、その後4℃で貯蔵される。
この捕獲ヌクレオチドは、当該技術分野において公知のいずれかの方法により、MCへ結合することができ、かつ好ましくは5’又は3’末端においてIMPと共有結合される。
IMPは、レシピエントの免疫反応を調節するために、陽イオン性縮合剤、IMP、及び安定化剤を含んで成る組成物(すなわち、CIS組成物)として投与されうる。米国特許第60/402,968号を参照のこと。態様によっては、CIS組成物は抗原及び/又は脂肪酸も含んで成ることがある。
本明細書に記載のとおり、本発明のIMPは、特に、IL−6、TNF−α、IFN−γ及びI型インターフェロン、例えばIFN−α及びIFN−ωの産生を刺激し、B細胞の増殖を刺激し、そして/あるいは形質細胞様樹状細胞を活性化して分化させることがある。本発明のIMPはまた、他のサイトカイン、ケモカイン及び活性化関連タンパク質、例えば、限定しないがIP−10(インターフェロン誘導タンパク質10kDa)、MCP−1(単球走化性タンパク質1)、MCP−2、MCP−3、MIG、MIP−3b、CD80、CD86、CD40、CD54及びMHCクラスIIの産生も刺激しうる。本発明のIMPはまた、IFN−α誘導遺伝子、限定しないが、2,5−オリゴアデニル酸合成酵素(2,5−OAS)、インターフェロン刺激遺伝子−54K(ISG−54K)及びグアニル酸結合タンパク質−1(GBP−1)の発現を刺激しうる。本発明の免疫調節ポリヌクレオチドはまた、形質細胞様樹状細胞のアポトーシスを遅らせるシグナルを提供しうる。本発明の免疫調節ポリヌクレオチドはまた、ナチュラルキラー(NK)細胞溶解活性も刺激しうる。従って、本発明のIMPは、個体の免疫反応を調節するのに特に有効である。
当業者には明らかであるように、正確な症状及びそれらの改善の方法は、治療されることが求められる障害に応じて決まるであろう。例えば、治療的ワクチンが結核に関するものである場合、ワクチンを伴うIMP治療は、咳、胸膜又は胸壁の疼痛、発熱及び/又は当該技術分野において公知の他の症状の軽減を生じる。ワクチンがアレルギー脱感作療法において使用されるアレルゲンである場合、この治療は、アレルギー症状の軽減(例えば、鼻炎、アレルギー性結膜炎、IgEの循環血中レベル、及び/又はヒスタミンの循環血中レベルの低下)を生じる。
瘍細胞に対するTh1-型反応の刺激は、免疫系による腫瘍細胞の直接及び/又はバイスタンダーの殺傷を生じ、これは癌細胞の減少及び/又は症状の軽減につながる。癌を有する個体へのIMPの投与は、腫瘍細胞に対するTh1−型免疫反応の刺激を生じる。このような免疫反応は、腫瘍細胞を、細胞性免疫系細胞(例えば、CTL)もしくは体液性免疫系の構成要素の直接作用によるか、又は免疫系により標的化された細胞に隣接する細胞に対するバイスタンダー作用のいずれかにより、殺傷される。例えば、Choら、Nat. Biotechnol.、18:509-514 (2000)参照。癌の状況において、IMPの投与は更に、1又は複数の例えば抗-腫瘍抗体のような追加の治療的物質の投与、化学療法様式及び/又は放射線療法を含み得る。抗-腫瘍抗体断片及び/又はそれらの誘導体、並びにモノクローナル抗-腫瘍抗体、それらの断片及び/又は誘導体を含むが、これらに限定されるものではない、抗-腫瘍抗体は、癌療法におけるこのような抗体試薬の投与のように、当該技術分野において公知である(例えば、RITUXAN(登録商標)(リツキシマブ);HERCEPTIN(登録商標)(トランスツヅマブ))。1又は複数の追加の治療的物質の投与は、IMPの投与の前、後及び/又は同時に行ってもよい。
幾つかの態様において、本発明は、個体、特にIFN−γレベルの増大を必要とする個体のIFN−γを増大又は刺激する方法であって、有効量のIMPを前記個体に投与することによりINF−γが増大する方法、を提供する。IFN−γの増大を必要とする個体は、IFN−γの投与に一般的に反応する障害を有する者である。そのような障害には、多くの炎症性疾患、例えば、限定しないが潰瘍性大腸炎を含む。その様な障害はまた、多くの繊維病、例えば、限定しないが特発性肺線維症(IPF)、強皮症、皮膚性放射線誘導型線維症、肝線維症、例えば住血吸虫症誘導型肝線維症、腎線維症並びにIFN−γの投与によって改善され得る他の症状を含む。本発明のIMP/MC複合体の投与は、IFN−γレベルの増大をもたらし、そして1又は複数の症候の回復、1又は複数の症候の安定化、あるいはIFN−γに応答する病気の進行の予防(例えば、追加の病変又は症候の軽減又は排除)をもたらす。
本明細書に記載のように、IMPは、その他の医薬物質及び/又は免疫原性物質及び/又は免疫刺激物質と一緒に投与することができ、かつそれらの生理的に許容できる担体と一緒にすることができる(従って本発明はこれらの組成物を含む)。IMPは、本明細書に記載されたもののいずれかであってもよい。
組成物中に等張剤、例えば、糖、マンニトール、ソルビトールなどのポリアルコール、塩化ナトリウムを含むことが好ましい。注射可能な組成物の延長された吸収は、組成物中に吸収を遅延する物質、例えばモノステアリン酸アルミニウム及びゼラチンを含んで成ることによりもたらされ得る。
本発明はキットを提供する。ある態様において、本発明のキットは、一般に本明細書に記載のような、IMPを含んで成る1又は複数の容器を含んで成る。当該キットは更に、本明細書に記載の方法(例えば、免疫調節、感染症の1又は複数の症候の回復、IFN-γレベルの増加、IFN-αレベルの増加、又はIgE-関連障害の回復)のいずれかのための、IMPの使用に関する適当な一連の取扱説明書であって、通常は書面による取扱説明書を含んで成ることがある。
この構成は、IMP/MC複合体が非共有結合により連結された場合に、好ましい。この形態は更に、IMP及びMCがヘテロ二官能性クロスリンカーにより架橋される場合にも好ましく;IMP又はMCのいずれかが、「活性化された」形で供給される(例えば、ヘテロ二官能性クロスリンカーに連結され、その結果IMPと反応性の部分が利用可能である)。
免疫調節ポリヌクレオチド(IMP)又は、免疫調節配列を含まないポリヌクレオチド(5'-TGACTGTGAACCTTAGAGATGA-3'(配列番号2))を含むコントロール試料、SAC及び培地単独がヒト末梢血単核細胞(PBMC)に対する免疫調節活性について試験された。
スタンダードの免疫調節ポリヌクレオチドである5'-TGACTGTGAACGTTCGAGATGA(配列番号1)も試験された。特に断らない限り、試験したポリヌクレオチドは十分に修飾されたホスホロチオエートオリゴデオキシヌクレオチドである。
4人のドナー由来のPBMCは、0.8、4.0又は20μg/mlのIMP又はコントロールで刺激した。IFN−α産生の刺激は上述のとおり評価し、そして4人のドナー由来の平均した結果を表4にて報告する。
配列番号34(キメラホスホロチオエート/ホスホロジエステル結合を含むもの)及び93(全ホスホロチオエート結合)は共に、ヒトPBMCからIFN−αを誘導した。
5'-TCGTCGA*A*CGT*T*CGAGATGAT (A* = 2−アミノ−dA;T*=2−チオ−dT)(配列番号190);
5'-TCG*TCG*AACG*TTCG*AG*ATG*AT (G* = 7−デアザ−8−アザ−dG)(配列番号187);
5'-TCG*AACG*TTCG*AACG*TTCG*AACG*TT (G* =7−デアザ−8−アザ−dG)(配列番号194);
5'-TCGTCGA*A*CGTTCGA*GA*TGA*T (A* =2−アミノ−dA)(配列番号188);
5'-TCGA*A*CGTTCGA*A*CGTTCGA*A*CGTT (A* =2−アミノ−dA)(配列番号197)。
ヒトB細胞を活性化させるIMPの能力は、IMPとのインキュベーションに応じてのB細胞の増殖及びIL−6産生を測定することにより決定した。ヒトPBMCは、CD19MACSビーズ(Miltenyi Biotec)とインキュベートし、そしてマグネットを通過させ、ポジティブ選択を通じてCD19+B細胞を分離した(FACSで決定した場合98%超のCD19+)。増殖アッセイのために、B細胞を96ウェルの丸底プレート内で1x105/ウェル(5x105/ml)に培養した。細胞を3つ一組で、2μg/mlIMP又はコントロールと一緒に72時間インキュベートした。培養期間の終了時、プレートを3H−チミジン(1μCi/ウェル、Amersham)でパルスラベルし、そして更に8時間インキュベートした。プレートを続いて回収し、そして標準的な液体シンチレーション技術を用いて放射能の取り込みを決定し、そしてデータを秒当たりカウント(cpm)で回収した。IL−6分泌については、B細胞を48ウェルプレート中5μg/mlIMP又はコントロールを含む0.5〜1x106/ウェルで培養し、そしてCytoSet抗体対とともにELISAを用いて、取扱説明書(BioSource)に従いIL−6についてアッセイした。最大/最小検出限界は4000/2pg/mlであった。
免疫調節ポリヌクレオチド又はコントロールポリヌクレオチドは、マウス脾細胞に対する免疫調節活性についてアッセイされた。試験したポリヌクレオチドは、十分に修飾されたホスホロチオエートオリゴデオキシヌクレオチドであった。ポリヌクレオチドの中でも、配列番号1(ポジティブコントロール)及び配列番号2(ネガティブコントロール)を試験した。
本明細書で証明するとおり、免疫調節ポリヌクレオチドはPBMCからIFN−γ及び/又はIFN−αの産生を誘導しうる。IMPは、追加のサイトカイン遺伝子、ケモカイン遺伝子及び他の遺伝子のmRNA発現を誘導するために、定量PCR技術、TaqMan技術を用いて、ヒトPBMC上での活性についてアッセイされた。試験したポリヌクレオチドは、十分に修飾されたホスホロチオエートオリゴデオキシヌクレオチドである。ポリヌクレオチドの中でも、配列番号(ポジティブコントロール)及び配列番号2(ネガティブコントロール)を試験した。
本発明のIMPは、IMPのスタンダードと比較して向上したナチュラルキラー(NK)細胞溶解活性を刺激する。NK細胞溶解活性は、K562標的細胞の溶解を介してアッセイした。要約すると、PBMCは、10mg/mlのIMP(予め求めた至適量)又はネガティブコントロールポリペプチドで48時間培養液中で刺激した。処理したPBMCは、続いて、一定の範囲のエフェクター:標的比で、51Crを添加したK562腫瘍標的細胞と4時間共培養した。細胞溶解時に放出された51Crは、TopCountNXTシンチレーションカウンター(Packard)で測定し、そして秒当たりカウント(cpm)で記録した。
Claims (35)
- 免疫調節ポリヌクレオチドであって:
a)0,1,2,3,4又は5塩基離れている少なくとも2つのCGジヌクレオチドを含んで成るパリンドローム配列であって、少なくとも8塩基の長さであるパリンドローム配列;及び
b)(TCG)y(ここで、yは1又は2であり、(TCG)yの5’Tは前記ポリヌクレオチドの5’末端から0,1,2又は3塩基の位置にある)であって、前記パリンドローム配列の5’末端から0,1,又は2塩基離れている(TCG)y、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項1に記載の免疫調節ポリヌクレオチド。
- 前記パリンドローム配列が前記(TCG)y配列の全部又は一部を含む、請求項1に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)0,1,2,3,4又は5塩基離れている少なくとも2つのCGジヌクレオチドを含んで成るパリンドローム配列であって、少なくとも8塩基の長さであるパリンドローム配列;及び
b)(TCG)y配列(ここで、yは1又は2であり、(TCG)y配列の5’Tは前記ポリヌクレオチドの5’末端から0,1,2又は3塩基の位置にある)、
を含んで成り;
(a)のパリンドローム配列が前記(TCG)y配列の全部又は一部を含み;且つ
前記(TCG)y配列のCGが(a)のパリンドローム配列のCGジヌクレオチドのうちの1つであってもよい、免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項4に記載の免疫調節ポリヌクレオチド。
- 前記パリンドローム配列が前記(TCG)y配列の全部又は一部を含む、請求項4に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(X1X2CGX2’X1’(CG)p)z(配列番号156)(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−2、−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、X2及びX2’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基である);及び
b)少なくとも8塩基の長さのパリンドローム配列であって、(X1X2CGX2’X1’(CG)p)z配列の最初の(X1X2CGX2’X1’)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項7に記載の免疫調節ポリヌクレオチド。
- 配列番号27、配列番号39、配列番号53、配列番号55、配列番号113、配列番号175、及び配列番号172から成る群から選択される配列を含んで成る、請求項7に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(X1X2CGX3X3’CGX2’X1’(CG)p)z(配列番号159)
(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−2、−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、X2及びX2’は自己相補的ヌクレオシドであり、X3及びX3’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基である);及び
b)少なくとも10塩基の長さのパリンドローム配列であって、(X1X2CGX3X3’CGX2’X1’(CG)p)z配列の最初の(X1X2CGX3X3’CGX2’X1’)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項10に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(X1X2X3X4X5CGX5’X4’X3’X2’X1’(CG)p)z(配列番号160)
(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−3、−2、−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、X2及びX2’は自己相補的ヌクレオシドであり、X3及びX3’は自己相補的ヌクレオシドであり、X4及びX4’は自己相補的ヌクレオシドであり、X5及びX5’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基である);及び
b)少なくとも12塩基の長さのパリンドローム配列であって、(X1X2X3X4X5CGX5’X4’X3’X2’X1’(CG)p)z配列の最初の(X1X2X3X4X5CGX5’X4’X3’X2’X1’)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項12に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(CGX1X1’CG(CG)p)z(配列番号161)
(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−2、−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基にある);及び
b)少なくとも8塩基の長さのパリンドローム配列であって、CGX1X1’CG(CG)p)z配列の最初の(CGX1X1’CG)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項14に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(X1CGCGX1’(CG)p)z(配列番号162)
(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基にある);及び
b)少なくとも8塩基の長さのパリンドローム配列であって、(X1CGCGX1’(CG)p)z配列の最初の(X1CGCGX1’)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項16に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(X1X2CGCGX2’X1’(CG)p)z(配列番号163)
(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−2、−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、X2及びX2’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基にある);及び
b)少なくとも8塩基の長さのパリンドローム配列であって、(X1X2CGCGX2’X1’(CG)p)z配列の最初の(X1X2CGCGX2’X1’)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項18に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(X1X2X3CGCGX3’X2’X1’(CG)p)z(配列番号164)
(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−3、−2、−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、X2及びX2’は自己相補的ヌクレオシドであり、X3及びX3’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基にある);及び
b)少なくとも10塩基の長さのパリンドローム配列であって、(X1X2X3CGCGX3’X2’X1’(CG)p)z配列の最初の(X1X2X3CGCGX3’X2’X1’)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項20に記載の免疫調節ポリヌクレオチド。
- 免疫調節ポリヌクレオチドであって:
a)5’−Nx(TCG(Nq))yNw(CGX1X2X2’X1’CG(CG)p)z(配列番号165)
(ここで、Nはヌクレオシドであり、x=0〜3であり、y=1〜4であり、w=−2、−1、0、1又は2であり、p=0又は1であり、q=0、1又は2であり、且つz=1〜20であり、X1及びX1’は自己相補的ヌクレオシドであり、X2及びX2’は自己相補的ヌクレオシドであり、且つ、(TCG(Nq))y配列の5’Tは前記ポリヌクレオチドの5’末端から0〜3塩基にある);及び
b)少なくとも8塩基の長さのパリンドローム配列であって、(CGX1X2X2’X1’CG(CG)p)z配列の最初の(CGX1X2X2’X1’CG)を含んで成るパリンドローム配列、
を含んで成る免疫調節ポリヌクレオチド。 - 前記パリンドローム配列が、1/3超がA及びTという塩基組成を有する、請求項22に記載の免疫調節ポリヌクレオチド。
- 請求項1に記載の免疫調節ポリヌクレオチドを含んで成る免疫調節組成物。
- 個体の免疫反応を調節する方法であって、前記個体の免疫反応を調節するのに十分な量の請求項1に記載の免疫調節ポリヌクレオチドを個体に投与することを含んで成る方法。
- 個体の免疫反応を調節する方法であって、前記個体の免疫反応を調節するのに十分な量の請求項4に記載の免疫調節ポリヌクレオチドを個体に投与することを含んで成る方法。
- 個体のインターフェロン−ガンマ(IFN−γ)を増大させる方法であって:
請求項1に記載の免疫調節ポリヌクレオチドを、前記個体に対し、前記個体のIFN−γを増大させるのに十分な量投与することを含んで成る方法。 - 個体のインターフェロン−ガンマ(IFN−γ)を増大させる方法であって:
請求項4に記載の免疫調節ポリヌクレオチドを、前記個体に対し、前記個体のIFN−γを増大させるのに十分な量投与することを含んで成る方法。 - 個体のインターフェロン−アルファ(IFN−α)を増大させる方法であって:
請求項1に記載の免疫調節ポリヌクレオチドを、前記個体に対し、前記個体のIFN−αを増大させるのに十分な量投与することを含んで成る方法。 - 個体のインターフェロン−アルファ(IFN−α)を増大させる方法であって:
請求項4に記載の免疫調節ポリヌクレオチドを、前記個体に対し、前記個体のIFN−αを増大させるのに十分な量投与することを含んで成る方法。 - 個体のインターフェロン−アルファ(IFN−α)を増大させる方法であって:
請求項7に記載の免疫調節ポリヌクレオチドを、前記個体に対し、前記個体のIFN−αを増大させるのに十分な量投与することを含んで成る方法。 - 個体の感染症の症候を回復させる方法であって:
有効量の請求項1に記載の免疫調節ポリヌクレオチドを前記個体に投与することを含んで成り、ここで、有効量とは前記感染症の症候を回復させるのに十分な量である、方法。 - 個体の感染症の症候を回復させる方法であって:
有効量の請求項4に記載の免疫調節ポリヌクレオチドを前記個体に投与することを含んで成り、ここで、有効量とは前記感染症の症候を回復させるのに十分な量である、方法。 - 個体のIgE関連障害の症候を回復させる方法であって:
有効量の請求項1に記載の免疫調節ポリヌクレオチドを、IgE関連障害を有する個体に投与することを含んで成り、ここで、有効量とは前記IgE関連障害の症候を回復させるのに十分な量である、方法。 - 個体のIgE関連障害の症候を回復させる方法であって:
有効量の請求項4に記載の免疫調節ポリヌクレオチドを、IgE関連障害を有する個体に投与することを含んで成り、ここで、有効量とは前記IgE関連障害の症候を回復させるのに十分な量である、方法。
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