JP2005237328A - インターフェロンアルファを誘導する免疫刺激オリゴヌクレオチド - Google Patents
インターフェロンアルファを誘導する免疫刺激オリゴヌクレオチド Download PDFInfo
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- JP2005237328A JP2005237328A JP2004053795A JP2004053795A JP2005237328A JP 2005237328 A JP2005237328 A JP 2005237328A JP 2004053795 A JP2004053795 A JP 2004053795A JP 2004053795 A JP2004053795 A JP 2004053795A JP 2005237328 A JP2005237328 A JP 2005237328A
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Abstract
【解決手段】特定の塩基配列を有する8種類の塩基配列を有するもののうち、何れかからなる免疫刺激オレゴヌクレオチドを有効成分として含む医薬品であって、生体に投与することによりTh1型免疫応答が誘導されるため、投腫瘍免疫賦活剤や感染症・癌ワクチンアジュバントおよび抗アレルギー剤として利用できる。
【選択図】なし
Description
GGACGATCGTCGGGGGGGGG(配列番号:1)
GGGACGATCGTCGGGGGGGG(配列番号:2)
GGGGACGATCGTCGGGGGGG(配列番号:3)
GGGGGGGACGATCGTCGGGG(配列番号:4)
GGGGGGGGACGATCGTCGGG(配列番号:5)
GGGGGGGGGACGATCGTCGG(配列番号:6)
GGGGGGGGGGACGATCGTCG(配列番号:7)
GGGGGGGGGCACGATCGTGG(配列番号:8)
の何れかから成る免疫刺激オリゴヌクレオチドを提供する。
GGGGGGGGGGACGATCGTCG(配列番号:7)から成るオリゴヌクレオチドが特に好ましい。
本発明はまた、配列番号1〜8の何れかの塩基から成る免疫刺激オリゴヌクレオチドを有効成分とし、さらに免疫調節因子を含んでなる医薬を提供する。本発明は特に、配列番号7の塩基配列から成る免疫刺激オリゴヌクレオチドを有効成分とし、さらに免疫調節因子を含む医薬を提供する。前記免疫調節因子は、例えば抗原又はアジュバントである。
CpG DNAが被験体に投与されると抗原非特異的な自然免疫が活性化される。その後、一定期間後に抗原を投与すると、抗原特異的Th1免疫が強く誘導される。これらの抗原は、当該分野の公知の物質、即ち、細胞、細胞抽出物、蛋白質、ペプチド、ポリサッカライド、ポリサッカライド結合体、脂質、糖脂質、炭水化物、デオキシリボ核酸、リボ核酸、ウイルス抽出物、ウイルス、細菌、真菌、寄生生物、およびアレルゲン、または抗原をコードする核酸であり、実施形態により任意に選択される。
別の方法として、CpG DNAは、抗原ならびに免疫調節因子(サイトカイン、ケモカインなどを含むがこれらに限定されない)あるいは他のアジュバントと組み合わせて投与され得る。
本発明の特有の配列を有するCpG DNAは、現在までに報告されている非修飾型CpG含有ヌクレオチドに比べて、IFN-αの産生を10倍以上強力に誘導することを発見した事に基づいている。このIFN-αの強力な誘導は、後に続く免疫サーキットの活性化をもたらし、結果としてTh1型免疫応答を誘導し活性化するという利点がある。
本明細書中で使用される「抗原」は、免疫応答を引き起こし得る分子である。抗原としては以下に挙げられるがそれらに限定されない:細胞、細胞抽出物、多糖、多糖結合体、脂質、糖脂質、炭水化物、ペプチド、蛋白質、ウイルス、及びウイルス抽出物。用語:抗原は、宿主免疫系により外来であるとして認識される任意の型の分子である。抗原としては、癌抗原、微生物抗原及びアレルゲンが挙げられるがこれらに限定されない。
治療に使用するためには、適切な有効量のCpG DNAを適切な剤形(CpG DNA単独または核酸複合体など)で標的細胞(例えばPDC)に取り込まれるように任意の様式により被験体に投与し得る。好ましい投与経路は、経口、経皮(皮下、皮内、静脈内、腹腔内、筋肉内など)、経鼻、気管内および粘膜が挙げられるが、これらに限定されない。
CpG DNAの「有効量」とは、生物学的効果(IFN-αを主とするサイトカインの産生など)が認識されるのに必要かつ十分な量をいう。投与されるCpG DNAの有効量は、適用される疾患及びその状態、被験体の大きさなどに依存して変化し得る。
本発明はさらに、以下の実施例によって例示され、これらの実施例は、決して限定解釈されるべきではない。
G付加の場所と数の検討(G0-GACGA-Gn):GACGATCGTCをコアーシークエンスとして、3’ 末端のみにGを1〜10個 (n) 付加して下記(表1)の配列を合成し、これをPBMCに5μM加えて培養した。
G付加の場所と数の検討(Gm-GACGA-G0):5’末端のみにGを5〜10個(m)付加して下記(表2)の配列を合成し、PBMCに5μM添加し培養した。
G付加の場所と数の検討(Gm-GACGA-G10):実施例1と2を比較すると、5'末端側への付加に比べて3'末端側へのG付加は、少ない数のGで活性を誘導できるので、IFN-α誘導効率が高いと推定される。次に、3'末端のGの数を10に固定して5'末端側のG数mが0〜5および10の配列を合成し(表3)、PBMCに5μM加えて培養した。
IFN-αとIL-10産生の相関:実施例1〜3で検討した配列について、INF-αとIL-10の産生量を測定し、相関関係を調査した(図4〜6)。IL-10には免疫抑制作用があるので、その産生をできるだけ低く抑えた状態でIFN-αの産生を亢進する配列を見出す事を目的とした。3'末端側に10鎖のGを配置して5'末端にGを付加すると、IFN-α誘導活性の上昇に比例してIL-10誘導活性も上昇し、両者に相関性が認められる(図6)ため、目的の配列としてはあまり好ましくない。しかし、G0-GACGA-Gn型(図4)やGm-GACGA-G0型(図5)については明確な相関関係が得られず、特にGm-GACGA-G0型ではG付加によるIFN-α誘導活性の亢進が、IL-10の産生をbasal level近くに保ったままで認められたことから、この配列パターンを検討することによりIFN-αのみを誘導できるような好ましい配列の同定も可能であると考えた(図5)。
塩基数の決定:実施例1〜3の検討結果より、GACGATCGTCに高いIFN-α誘導活性をもたらすにはGを3'末端側または5'末端側に8〜10個置くほうがよいが、IL-10の産生を抑えるには5'末端側に偏在させるとよいと考えた。また、活性の誘導に必要なCpG DNAの総塩基数は約20個が至適であった(下記表4)。
Gm-GACGATCGTC-GnにおけるIFN-αの誘導:5'末端のGの数mと3'末端のGの数nの合計数を10に固定したGm-GACGATCGTC-Gn(m+n=10)のオリゴヌクレオチド11種類(下記表5)を合成し、PBMCに5μM加えて培養した。
Gm-GACGATCGTC-GnにおけるTNF-αの誘導:実施例6と同様な配列で示されるGm-GACGA-Gn(m+n=10)のオリゴヌクレオチド10種類(m=0〜9)について、PBMCに5μM加えて培養した上清中のTNF-α産生量を測定した(図8)。各配列におけるTNF-αの産生は、IFN-αの産生と同じパターンを示し、両者の活性には緩やかな相関性が認められた。
用量と活性の関係からみた活性強度の調査(1):Gm-GACGA-Gn(m+n=10)で示されるオリゴヌクレオチドの活性強度を調べるために、PBMCに添加する濃度を0.01〜5μMの5段階で比較した(図9)。その結果、m=7(n=3)及びm=1(n=9)の時に、非常に強いIFN-αの産生が認められた。それに対して、m=4(n=6)及びm=10,n=10の場合は活性が低かった。
用量と活性の関係からみた活性強度の調査(2):実施例8で調査したGm-GACGA-Gn(m+n=10)で示されるオリゴヌクレオチドの活性強度を詳細に調べるために、m=7,8,9(nはそれぞれ3,2,1)について調査した(図10)。その結果、m=9(n=1)のオリゴヌクレオチドに最大のIFN-α誘導活性が認められた。
広範囲の用量における検討:次に、Gm-GACGA-Gn(m+n=10)で示されるオリゴヌクレオチドのIFN-α誘導活性が、CpG-DNAの低濃度領域及び高濃度領域においてどのように変化するのかを詳しく調査した。PBMCに添加する濃度0.05〜10μMの6段階について調査した(図11)。その結果、m=9(n=1)のCpG-DNAは、その他のオリゴヌクレオチドではほとんどIFN-α産生を誘導しない0.1μM濃度でも誘導活性を示した。1μM濃度で最大活性を示し、10μMまで活性を維持した。
パリンドローム中心塩基配列の重要性:以上に示したように、中心配列GACGATCGTCの両末端ポリGについて検討した結果、5’末端側に9鎖、3’末端側に1鎖のGを付加したG9-GACGA-G1に強いIFN-α誘導活性が得られたが、このようなGの配置が中心配列の異なるCpGパリンドロームにおいても同様に認められるか否かについて、下記(表6)に示すACAACGTTGTを対象に調査した(図12,13)。G付加はm=9(n=1),m=5(n=5),m=1(n=9),m=10(n=10)の4通り行った。
GACGATCGTCの変異型の検討:最後に、下記(表7)に示すようにG9-GACGA-G1のパリンドローム部分(GACGATCGTC)の塩基配列を一部分変化させることにより、IFN-α誘導活性がどのように変わるのかを検討した(図14)。パリンドローム構造を維持した状態で、CGをGCに置換(GAGCATGCTC)すると活性が消失した。また、ATをAAに置換(GACGAACGTC)またはATをTTに置換(GACGTTCGTC)して中央先端部分が非パリンドローム構造になると、IFN-α誘導活性が消失した。さらに、CpGパリンドローム構造は維持されるが中央先端塩基の順序がATからTAに変わる(GACGTACGTC)だけでも、免疫刺激活性がほとんど失われることが確認された。CpGパリンドロームの5'末端側のGをCに、3'末端側のCをGに置換した配列(CACGATCGTG)では、高濃度ではG9-GACGATCGTC-G1と同等の活性を有するが、0.1〜0.2μM濃度ではIFN-αの産生量は30〜40%に低下した。
G9-GACGA-G1のTh1型サイトカインとTh2型サイトカインの産生:G9-GACGA-G1の活性がTh1免疫の誘導に優位で働いているか否かを調査するため、IFN-α以外にTh1型免疫の指標となるIL-12とIFN-γ及びTh2型免疫の指標となるIL-4の産生を測定した。下記(表8)に示す各CpG DNAについて、PBMCに1μM添加した時に得られた培養上清中のサイトカイン産生量を調査した。
Claims (7)
- 一般式5'-Gm-GACGATCGTC-Gn-3'又は5'-Gm-CACGATCGTG-Gn-3'(式中、m及びnはそれぞれ独立に1〜9の整数であり、そしてm+n=10である)で示され、下記塩基配列:
GGACGATCGTCGGGGGGGGG(配列番号:1)
GGGACGATCGTCGGGGGGGG(配列番号:2)
GGGGACGATCGTCGGGGGGG(配列番号:3)
GGGGGGGACGATCGTCGGGG(配列番号:4)
GGGGGGGGACGATCGTCGGG(配列番号:5)
GGGGGGGGGACGATCGTCGG(配列番号:6)
GGGGGGGGGGACGATCGTCG(配列番号:7)
GGGGGGGGGCACGATCGTGG(配列番号:8)
の何れかから成る免疫刺激オリゴヌクレオチド。 - GGGGGGGGGGACGATCGTCG(配列番号:7)から成る、請求項1に記載した免疫刺激オリゴヌクレオチド。
- 請求項1又は2に記載の、配列番号1〜8の何れかの塩基配列から成る免疫刺激オリゴヌクレオチドを有効成分として含む医薬。
- 請求項1又は2に記載の、配列番号7の塩基配列から成る免疫刺激オリゴヌクレオチドを有効成分として含む医薬。
- 請求項1又は2に記載の、配列番号1〜8の何れかの塩基配列から成る免疫刺激オリゴヌクレオチドを有効成分とし、さらに免疫調節因子を含んでなる医薬。
- 請求項1又は2に記載の、配列番号7の塩基配列から成る免疫刺激オリゴヌクレオチドを有効成分とし、さらに免疫調節因子を含む医薬。
- 前記免疫調節因子が抗原又はアジュバントである、請求項5又は6に記載の医薬。
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