JP6307190B2 - 阻害性オリゴヌクレオチド及びその使用 - Google Patents
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Description
TLR9の刺激によって誘導されるNF−κΒの活性化に対する阻害性ODNの影響
<実験方法>
CAL−1/NFκΒ−GFP細胞系を、細胞ベースのアッセイにおいてNF−κΒ転写因子の活性をモニタリングするために樹立した。NFκΒコンセンサス転写応答エレメントによって働くGFPレポーター遺伝子をコードするベクターを、エレクトロポレーションによって、ヒト形質細胞様DC細胞系CAL−1にトランスフェクトした。トランスフェクトされた細胞を、ゼオシンでさらに選択した。(A)TLR9アゴニストCpG2395によって誘導されたGFP発現を評価した。簡潔に述べると、CAL−1/NFκΒ−GFP細胞(1×105個/ウェル)を96ウェル平底プレート(Costar)に播種し、CpG2395(1μΜ)と共に又は無しで培養した。細胞を、37℃で、5%C02加湿インキュベーター内で、6時間インキュベートした。細胞におけるGFP発現レベルを、フローサイトメーター(FACS Calibur、BD Bioscience Co.Ltd)によって評価した。GFP陽性細胞のパーセンテージを、図に記載した。(B)CAL−1/NFκΒ−GFP細胞(1×105個/ウェル)を、(CCT)7、(CCT)8、及び(CCT)9(0.1μΜ、0.3μΜ、1.0μΜ)と共に2時間、プレインキュベートした。細胞を、CpG2395(1μΜ)で6時間刺激した。細胞におけるGFP発現レベルを、フローサイトメーター(FACS Calibur、BD Bioscience Co.Ltd)によって評価した。各条件におけるGFP陽性細胞のパーセンテージを、図に記載した。
図1に示されるように、GFPは、CpG2395の刺激によってCAL−1/NFκΒ−GFP細胞において誘導され、このことは、NF−κΒの活性化がTLR9の刺激によって誘導されたことを示している。さらに、このGFP発現は、阻害性ODNの付加によってブロックされた。阻害性ODNの濃度が高いほど、CAL−1/NFκΒ−GFP細胞におけるGFP発現の誘導の良好な阻害が示されたため、阻害活性の用量依存性が裏付けられた(最大阻害は、1.0μΜの各阻害性ODNで観察された)。(CCT)9は、(CCT)8又は(CCT)7よりも優れた有効性で、GFP発現をブロックした。これらのデータは、本発明者らが調べた阻害性ODNが、ヒト細胞系においてTLR9アゴニストによって誘導されるNF−κΒの活性化を抑制し得ることを示す。
TLR9の刺激によって誘導されるNF−κΒの活性化に対する阻害性ODNの抑制活性の比較
<実験方法>
CAL−1/NFκΒ−GFP細胞(1×105個/ウェル)を、上記の様々な阻害性ODNと共に、2時間プレインキュベートした。細胞を、CpG2395(1μΜ)で6時間刺激した。各条件における細胞のGFP発現レベルを、フローサイトメーター(FACS Calibur、BD Bioscience Co.Ltd)によって評価した。CpG2395単独でのGFP陽性細胞のパーセンテージを、グラフにおいて100%と規定した。各条件におけるGFP陽性のパーセンテージを、数値から計算した。
図2Aに示されるように、NF−κΒの活性化についての阻害活性の用量依存性が、各阻害性ODNにおいて裏付けられた。(CCT)8は、CpG2395によって誘導されるGFP発現を阻害し、ヒトpDC細胞系において(CCT)6及び(CCT)7よりも良好な活性を示した。(CCT)9は、(CCT)8よりも良好な有効性で、GFP発現を強力にブロックした。(CCT)10、(CCT)11、及び(CCT)12は、(CCT)9よりもはるかに良好な阻害活性を示した。これらの結果は、長いODNの方が短いODNよりも良好な活性を有することを示唆する。しかし、(CCT)14及び(CCT)16の阻害活性は、(CCT)12の活性と同一であり(図2B)、このことは、(CCT)12並びに(CCT)14及び(CCT)16が、TLR9の刺激によって誘導されるNF−κΒ活性の阻害について最大の有効性を有し得ることを示唆している。重要なことに、1.0μΜでの(CCT)8の阻害活性は、0.1μΜでの(CCT)11及び(CCT)12の阻害活性とほぼ同一であった。このデータは、(CCT)11及び(CCT)12が、ヒト細胞において、(CCT)8よりも、NF−κΒの活性化の阻害について10倍高い有効性を有することを示す。図2C及び2Dに示されるように、(CCT)8C及び(CCT)8CCは、(CCT)8よりも良好な阻害活性を示した。(CCT)10C及び(CCT)10CCが(CCT)10よりも良好な阻害活性を示すことも実証された。
ヒト細胞での、TLR9の刺激によって誘導される炎症性サイトカインの産生に対する阻害性ODNの抑制活性の比較
<実験方法>
ヒト形質細胞様DC細胞系CAL−1細胞を培養し(1×105個/ウェル)、96ウェル平底プレート(Costar)に播種し、阻害性ODNの存在下で、CpG2395(0.4μΜ)で、24時間刺激した(阻害性ODNの濃度は図に記載されている)。24時間の刺激の後、培養上清を回収し、炎症性サイトカインの産生を評価した。IL−6及びTNFαの産生のレベルを、製造者のプロトコルにおいて記載されているように、ELISAによって測定した(R&D systems Co.Ltd、Minneapolis、USA)。
図3に示されるように、CAL−1細胞において、CpG2395によって誘導されるIL−6及びTNFαの産生の両方は、阻害性ODNの付加によってブロックされた。IL−6及びTNFαの産生についての阻害活性の用量依存性が、各阻害性ODNにおいて裏付けられた。(CCT)9、(CCT)10、(CCT)11、及び(CCT)12は、CpG2395によって誘導されるIL−6及びTNFαの産生の両方を強力にブロックした。これらのODNの有効性は(CCT)8の有効性よりもはるかに良好であった。重要なことに、0.4μΜでの(CCT)8の阻害活性は、0.04μΜでの(CCT)11及び(CCT)12の阻害活性とほぼ同一であった。このデータは、(CCT)11及び(CCT)12が、ヒト細胞において、(CCT)8よりも10倍高い有効性を有することを示す。(CCT)11及び(CCT)12は、0.04uMでほぼ100%の阻害を示したため、本発明者らは、低濃度での阻害活性をさらに評価した(図4)。図に示されるように、(CCT)9及び(CCT)10は、(CCT)8よりもはるかに良好な有効性でTNFαの産生をブロックした。さらに、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16は、ヒト細胞において、非常に低い用量で、TNFαの産生の阻害についての強力な有効性を示した。これらの結果は、ODNを、自己免疫疾患、移植片拒絶、過敏症、自己抗原及び微生物による宿主免疫系の過剰刺激に関連する疾患などの、様々な免疫介在性の障害の治療のための治療薬として用いることができることを示唆する。IL−6及びTNFαは、関節リウマチ、胃炎、及び炎症性腸疾患などの疾患の発症について鍵となる役割を有することが報告されているため、本発明者らが調べたODNは、IL−6及びTNFαの阻害による疾患の治療のための治療薬として用いることができる。
マウス細胞での、TLR9の刺激によって誘導される炎症性サイトカインの産生に対する阻害性ODNの抑制活性の比較
<実験方法>
マウスDC細胞系D2SC/1細胞を培養し、D2SC/1(1×105個/ウェル)を96ウェル平底プレート(Costar)に播種し、阻害性ODNの存在下で、CpG1826(0.65μΜ)で、24時間刺激した(阻害性ODNの濃度は図に記載されている)。24時間の刺激の後、培養上清を回収し、炎症性サイトカインの産生を評価した。IL−6及びTNFαの産生のレベルを、製造者のプロトコルにおいて記載されているように、ELISAによって測定した(R&D systems Co.Ltd、Minneapolis、USA)。
図5に示されるように、マウスDC細胞系D2SC/1細胞において、CpG1826によって誘導されるIL−6及びTNFαの産生の両方は、阻害性ODNの付加によってブロックされた。IL−6及びTNFαの産生についての阻害活性の用量依存性が、各阻害性ODNにおいて裏付けられた。(CCT)9、(CCT)10、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16は、CpG1826によって誘導されるIL−6及びTNFαの産生の両方を強力にブロックした。重要なことに、これらのODNの有効性は(CCT)8の有効性よりもはるかに良好であった。図5Bに示されるように、0.1μΜでの(CCT)8は、CpG1826によって誘導されるTNFαの産生をほとんど阻害しなかった。しかし、同一の濃度での(CCT)10、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16は、TNFαの産生を強力に阻害した。このデータは、(CCT)10、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16が、マウス細胞において、TLR9の刺激について(CCT)8よりもはるかに良好な阻害的影響を有することを示す。
TLR9アゴニストで刺激されたヒトPBMCからのIFNαの産生に対する阻害性ODNの抑制活性。
<実験方法>
以下の試料において用いるヒト末梢単核球(huPBMC)を、フィコールハイパック(Pharmacia)密度勾配遠心分離によって末梢血から単離した(P.M.Daftarian et al.,(1996):Journal of Immunology,157,12〜20)。細胞を、10%FCS(v/v)及び抗生物質(1ml当たり100IUのペニシリン及び1ml当たり100IUのストレプトマイシン)を補ったRPMIにおいて、37℃で、5%C02加湿インキュベーター内で培養した。TLR9の刺激によって誘導されるPBMCからのIFNαの産生を評価した。簡潔に述べると、huPBMC(5×106個/ml)を96ウェル平底プレートに播種し、阻害性ODN(0.1μΜ)(CCT)8、(CCT)9、(CCT)10、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16の存在下で、CpG2216(1μΜ)で刺激した。IFNαの産生のレベルを測定するために、培養上清を回収した。IFNαの産生のレベルを、製造者のプロトコルにおいて記載されているように、ELISAによって測定した(R&D systems Co.Ltd、Minneapolis、USA)。
図6に示されるように、ヒトPBMCは、TLR9アゴニストCpG2216に応答してIFNαを産生した。(CCT)8は、CpG2216によって誘導されるIFNαの産生をブロックした。しかし、(CCT)8の抑制の有効性はそれほど強力ではなかった。(CCT)9、(CCT)10、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16は、(CCT)8よりも、CpG2216によるIFNαの産生について良好な阻害活性を示した。特に、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16は、CpG2216によって誘導されるIFNαの産生を強力に阻害した。これらの結果は、本発明者らが評価した阻害性ODNが、ヒトPBMCにおいて、TLR9及びIFNαの産生の阻害剤であり得ることを示す。IFNの増大した産生がSLEの発症の一因となることが十分に確立されている(Barrat FJ,et al.J Exp Med 2005;202:1131〜9;Wellmann U,et al.Proc Natl Acad Sci USA 2005;102:9258〜63)。内因性IFN誘導因子がSLE患者の血清内に存在することが報告されていることが実証されており(Kwok SK,et al.Arthritis Res Ther.2008;10(2):R29)、SLE患者は、IFNの産生の循環誘導因子を有し、SLE患者の血清は、健康な血液ドナーのPBMCの培養物において、TLR9を介してIFNの産生を誘導することが多い。本発明者らが調べたODNはIFNαの産生を効率的にブロックし得たため、本発明者らが評価したODNは、IFNの産生を阻害することによる、SLE患者の治療のための治療薬として用いることができる。
TLR7/8の刺激によって誘導されるNF−κΒの活性化に対する阻害性ODNの抑制活性の比較
<実験方法>
CAL−1/NFκΒ−GFP細胞(1×105個/ウェル)を、先に記載した阻害性ODNと共に、2時間プレインキュベートした。細胞を、TLR7/8アゴニストガーディキモド又はCL264(Invivogen、USA)で、4時間刺激した。各条件におけるGFP発現レベルを、フローサイトメーター(FACS Calibur、BD Bioscience Co.Ltd)によって評価した。図7(A)CAL−1/NFκΒ−GFP細胞を、(CCT)6、(CCT)7、及び(CCT)8(0.1uM、0.3uM、及び1.0uM)の存在下で、TLR7/8アゴニストガーディキモド(2μg/ml)で、4時間刺激した。ガーディキモド単独でのGFP陽性細胞のパーセンテージを、グラフにおいて100%と規定した。各条件におけるGFP陽性のパーセンテージを、数値から計算した。図7(B)CAL−1/NFκΒ−GFP細胞を、(CCT)8、(CCT)9、(CCT)10、(CCT)11、(CCT)12、(CCT)14、及び(CCT)16(0.01uM、0.03uM、及び0.1uM)の存在下で、TLR7/8アゴニストCL264(1μg/ml)で、4時間刺激した。各条件におけるGFP陽性のパーセンテージを、先に記載したように計算した。
図7Aに示されるように、GFP発現は、ガーディキモドの刺激によってCAL−1/NFκΒ−GFP細胞において誘導され、このことは、NF−κΒの活性化がTLR7の刺激によって誘導されたことを示している。さらに、このGFP発現は、阻害性ODNの付加によってブロックされた。TLR7の刺激によるNF−κΒの活性化についての阻害活性の用量依存性が、各阻害性ODNにおいて裏付けられた。(CCT)6及び(CCT)7は、(CCT)8よりもガーディキモドの刺激について良好な活性を示し、一方、(CCT)8もまた、GFP発現をブロックした。重要なことに、1.0μΜでの(CCT)8の阻害活性もまた、0.1μΜでの(CCT)6及び(CCT)7の阻害活性と同一であった。このデータは、(CCT)6及び(CCT)7が、(CCT)8よりも、TLR7の刺激によって誘導されるNF−κΒの活性化の阻害について10倍高い有効性を有することを示す。図2に示されるように、(CCT)8は、(CCT)6及び(CCT)7よりも、TLR9の刺激について良好な阻害活性を示した。したがって、このことは、(CCT)6及び(CCT)7がTLR7の刺激について固有の阻害活性を有するが、TLR9の刺激については有さないことを示唆する。
Claims (21)
- 以下の一または複数の選択されるオリゴヌクレオチドを有効成分として含有することを特徴とする、対象における免疫介在性の障害を治療するための医薬組成物:
5’−cctcctcctcctcctcct−3’(配列番号15)、または
5’−cctcctcctcctcctcctcct−3’(配列番号16)
であって;
免疫介在性の障害が、自己免疫疾患、又は過敏症、又は移植片拒絶、又は微生物による宿主免疫系の過剰刺激に関連する疾患、又はNF−κBの活性化によって生じるNF−κΒ介在性の疾患、又はToll様受容体(TLR)の活性化によって生じるTLR介在性の疾患、或いはインターフェロンまたは炎症性サイトカインの過剰産生によって生じるサイトカイン介在性の疾患である、上記医薬組成物。 - 前記オリゴヌクレオチドのリン酸骨格が、部分的に若しくは完全にホスホロチオエート修飾されているか、又は非修飾である、請求項1に記載の医薬組成物。
- 前記オリゴヌクレオチドが、末端に1つのヌクレオチドを付加されており、かつTLR7/8の活性化を阻害する、請求項1又は2に記載の医薬組成物。
- 前記オリゴヌクレオチドが、末端の1つのヌクレオチドが削除されており、かつTLR7/8の活性化を阻害する、請求項1から3までのいずれか一項に記載の医薬組成物。
- 前記オリゴヌクレオチドが、1つの塩基が変更されており、かつTLR7/8の活性化を阻害する、請求項1から4までのいずれか一項に記載の医薬組成物。
- 前記オリゴヌクレオチドが他のDNA分子、プラスミド、又はウイルスベクターの一部を構成する、請求項1から5までのいずれか一項に記載の医薬組成物。
- 前記オリゴヌクレオチドがさらにリン酸骨格のホスホロチオエート化以外の化学修飾を受けている、請求項1から6までのいずれか一項に記載の医薬組成物。
- 前記オリゴヌクレオチドが、ペグ化を受けている、請求項1から7までのいずれか一項に記載の医薬組成物。
- 対象がヒト又は非ヒト脊椎動物である、請求項1から8までのいずれか一項に記載の医薬組成物。
- 薬学的に許容される担体をさらに含む、請求項1から9までのいずれか一項に記載の医薬組成物。
- 腸内投与、非経口投与、及び局所的投与、又は吸入を含む経路を介して対象に投与される、請求項1から10までのいずれか一項に記載の医薬組成物。
- 単独で又はさらなる活性成分と組み合わせて用いられる、請求項1から11までのいずれか一項に記載の医薬組成物。
- 免疫介在性の障害が、TLRの活性化によって生じるTLR介在性の疾患である、請求項1から12までのいずれか一項に記載の医薬組成物。
- 免疫介在性の障害が、NF−κBの活性化によって生じるNF−κΒ介在性の疾患である、請求項1から12までのいずれか一項に記載の医薬組成物。
- 免疫介在性の障害が、インターフェロンの過剰産生によって生じるサイトカイン介在性の疾患である、請求項1から12までのいずれか一項に記載の医薬組成物。
- 免疫介在性の障害が、炎症性サイトカインの過剰産生によって生じるサイトカイン介在性の疾患である、請求項1から12までのいずれか一項に記載の医薬組成物。
- Toll様受容体(TLR)介在性の疾患が、敗血症、拡張型心筋症、糖尿病、自己免疫性脳脊髄炎、全身性エリテマトーデス(SLE)、アテローム性動脈硬化症、喘息、慢性閉塞性肺疾患、EAE、又は臓器不全である、請求項1から12までのいずれか一項に記載の医薬組成物。
- NF−κΒ介在性の疾患が、関節リウマチ(RA)、胃炎、又は炎症性腸疾患である、請求項1から12までのいずれか一項に記載の医薬組成物。
- サイトカイン介在性の疾患が、敗血症又は多臓器不全症候群(MODS)である、請求項1から12までのいずれか一項に記載の医薬組成物。
- 自己免疫疾患が、全身性エリテマトーデス(SLE)、インスリン依存性(I型)糖尿病、炎症性関節炎、関節リウマチ、多発性硬化症、自己免疫性肝炎、慢性的侵攻性肝炎、自己免疫性溶血性貧血、自己免疫性血小板減少症、悪性貧血の自己免疫性萎縮性胃炎、自己免疫性脳脊髄炎、自己免疫性精巣炎、後天性血友 病、強直性脊椎炎、抗リン脂質症候群、ベーチェット症候群、心筋症、慢性的炎症性脱髄性多発性神経障害、瘢痕性類天疱瘡、寒冷凝集素症、多発性筋炎皮膚筋炎、円板状ループス、交感性眼炎、本態性混合型クリオグロブリン血症、線維筋痛、線維筋炎、ギランバレー症候群、特発性肺線維症、特発性血小板減少性紫斑病、IgA腎症、若年性関節炎、全身性硬化症、結節性多発動脈炎、多発性軟骨炎、皮膚筋炎、原発性無ガンマグロブリン血症、原発性胆汁性肝硬変、高免疫グロブリンE症候群、進行性全身性硬化症、乾癬、ライター症候群、サルコイドーシス、スティフマン症候群、ブドウ膜炎、血管炎、白斑、橋本甲状腺炎、グッドパスチャー疾患、悪性貧血、アジソン病、シェーグレン症候群、重症筋無力症、グレーブス病、アレルギー性脳脊髄炎、又は糸球体腎炎である、請求項1から12までのいずれか一項に記載の医薬組成物。
- 過敏症がアレルギー性外因性喘息、季節性アレルギー性鼻炎、全身性アナフィラキシー、自己免疫性溶血性貧血、胎児赤芽球症、グッドパスチャー疾患、アルサス反応、血清病、全身性エリテマトーデス、糸球体腎炎、接触皮膚炎及び同種移植片拒絶である、請求項1から12までのいずれか一項に記載の医薬組成物。
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