JPWO2015108046A1 - 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 - Google Patents
抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 Download PDFInfo
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Abstract
Description
上記のオリゴヌクレオチドは,少なくとも2つのCpGモチーフの3’側にホスホロチオエート結合された核酸塩基が接続される。
そして,上記のオリゴヌクレオチドは,5’末端及び3’末端が,ホスホロチオエート結合されたS型の核酸塩基である。上記のオリゴヌクレオチドは,ホスホロチオエート修飾されていない塩基を少なくともひとつ以上含む。ホスホロチオエート修飾されていない塩基は,上記したCpGモチーフ以外の部分にも存在することが好ましい。
ヌクレオチドの合成方法は公知である。よって,本発明のヌクレオチドは公知の方法に従って製造できる。本発明のヌクレオチドは,例えば特許4580870号,又は国際公開2010/064146号パンフレットに開示された方法を採用できる。
I型アレルギーの例は,アレルギー性鼻炎、花粉症、気管支ぜん息、じんましん,アトピー性皮膚炎、アレルギー性結膜炎、食物アレルギー、及びアナフィラキシーである。
II型アレルギーの例は,自己免疫性溶血性貧血、血小板減少症、顆粒球減少症、新生児溶血性黄疸、悪性貧血、リウマチ熱、重症筋無力症、橋本病、及び円形脱毛症である。
III型アレルギーの例は,血清病、過敏性肺炎、ループス腎炎(慢性糸球体腎炎)、全身性エリテマトーデス、急性糸球体腎炎、関節リウマチ、リウマチ性肺炎、多発性動脈炎、アレルギー性血管炎、及びシェーグレン症候群である。
IV型アレルギーの例は,接触皮膚炎、橋本病、ベーチェット病、臓器移植後の拒絶反応、移植片対宿主病(GVHD)、及びギラン・バレー症候群である。
本発明の抗アレルギー作用の対象となるアレルギー疾患は,I型〜IV型の全てのアレルギーであるが,本発明は,特にI型アレルギーを抑えることができる。
CpGオリゴ核酸(mix体)
ホスホロアミダイト法を用いて合成し,HPLCにて精製したオリゴ核酸(Mix体)をジーンデザイン社から購入した。
核酸の鎖長延長を以下の(i)〜(iv)のステップを繰返すことにより行なった。
(i) 3% DCA(ジクロロ酢酸)/CH2Cl2(15秒),
(ii) 縮合(0.1M モノマーのMeCN溶液(下記参照)と1M PhIMT(1−フェニルイミダゾリウムトリフラート)のMeCN溶液の1:1混合溶液,5分)
(iii) キャップ化(0.5M CF3COImのTHF溶液と1M DMAN(1,8−ビスジメチルアミノナフタレン)のTHF溶液の1:1混合液,30秒),
(iv) 硫化(0.1M DDTTのMeCN用液,90秒)もしくは酸化(0.02M I2のH2O−ピリミジン(Pyridine)−THF溶液,15秒)。
チミジル酸H−ホスホネート(phosphonate)モノエステル(25マイクロmol)を脱水ピリジン,脱水トルエンで共沸乾燥後,MeCN−CMP(N−シアノメチルピロリジン)混合液(9:1,v/v;250μL)に溶かした。溶液にPh3PCl2(62.5マイクロmol)を加え10分間撹拌し,続いてAA−L(30マイクロmol;Sp体の場合はAA−D)を加えさらに10分間撹拌することで,モノマー溶液を調整した。
Bウイルス陰性カニクイザル血液(株式会社新日本科学から購入)をハンクス平衡塩(Hanks‘Balanced Salt Solution)で3倍希釈し,フィコール・パック・プラス(Ficoll−Paque PLUS)比重液に重層後,遠心分離(2,600 rpm,30 min)を行い,末梢血単核球(PBMC)画分を採取した。PBMCをRPMI培地(+1% ペニシリン・ストレプトマイシン)で洗浄した後,RPMI培地(+10%FBS,1% ペニシリンストレプトマイシン)に細胞濃度が3×106cells/mLとなるように調製した。その後,96ウェルU底プレートに播種し,種々のオリゴ核酸(オリゴDNA:DOTAP 1:3.2混合物)とともに5%CO2インキュベーターで17〜24時間培養した。培養終了後,遠心分離(500rpm,5min)により,培養上清を回収した。培養上清中のIFN−アルファの濃度をエライザキット(ELISA Kit)(PBL社)を用いて測定した。
配列番号119で示される塩基配列を有するヌクレオチド(従来のヌクレオチド:化合物119)について実施例2と同様に実験を行い,IFN−アルファの濃度を測定した。その結果を表4に示す。
Bウイルス陰性カニクイザル血液(株式会社新日本科学から購入)をハンクス平衡塩(Hancks’ Balaced Salt Solution)で2倍希釈し,フィコール・パックプラス(Ficoll-Paque PLUS)比重液に重層後,遠心分離(2,600 rpm,30分)を行い,末梢血単核球(PBMC)画分を採取した。PBMCを洗浄用培地:RPMI+100 IU/mLペニシリン+100μg/mLストレプトマイシンで洗浄した後,アッセイ培地:RPMI+10%FBS+100IU/mLぺニシリン+100μg/mLストレプトマイシンに細胞濃度が3×106cells/mLとなるように調製した。その後,96ウェルU底プレートに播種し,種々の化合物(CpG ODN:DOTAP 1:3.2混合物)と共に5%CO2インキュベーターで16〜20時間培養した。培養終了後,遠心分離(500 rpm,5分)し培養上清を回収した。培養上清中のサイトカインプロファイルは,Milliplex MAP Kit Non−Human Primate Cytokine Magnetic Beads Panel(Merck)を用いてIFN−γ,IL−4,IL−6,IL−10,IL−12/23(p40),IL−8,TNF−αの7種のサイトカインを測定した。
サイトカインの結果は対照化合物(化合物119)の値を100%として表示した。いずれの化合物もサル末梢血単核球に対して,Th1サイトカインの産生誘導作用は強いが,Th2サイトカインに対してはほとんど影響を及ぼさず,Th1/Th2レシオは1以上を示した(表5)。
実験方法
モデルマウスの作製
7週齢のBALB/cAnNCrlCrljにOVAとALUMあるいは本化合物および百日咳毒素の混合液を腹腔内投与して初回感作とし,さらにこの5日後に追加感作としてOVA溶液を背部皮下投与することで,OVAによる全身感作を行った。その後,初回感作18日目以降から4日間,局所感作として1日1回OVA溶液を両側鼻腔にマイクロピペットで点鼻投与し,アレルギー症状を発症させた。
10μgの配列番号67で示される塩基配列を有するオリゴヌクレオチド(化合物67)をOVA初回感作時あるいは局所感作の1時間前に皮下投与し,アレルギー症状発症への影響を確認した。
OVA点鼻投与(局所感作)4日目の点鼻直後から1時間の鼻掻き回数を測定した。鼻掻き回数は,洗顔行動および前肢舐め行動等と区別し,マウスが前肢で鼻部を引っ掻いた行動のみを鼻掻き行動として測定した。その結果を表6及び図1に示す。
局所感作5日後に採取した血液を用いて,製造業者の指示書に従い,Mouse Serum Anti−OVA IgE Antibody Assay Kit(Chondrex,Inc.)を用いてOVA特異的IgEの測定を実施した。その結果を表7及び図2に示す。
アレルギー症状の指標である鼻掻き回数に対して,化合物67投与群は陽性対象であるクロルフェニラミンより弱いものの,OVA投与群と比較して鼻掻き回数の減少傾向を示した。さらに,化合物67のSp型立体異性体および立体混合体(mix)は,Sp立体制御体の方がmix体に比較して鼻掻き行動の改善傾向を示した。また、血中IgE量に対しては、化合物67投与群では顕著に低下していたが、陽性対象であるクロルフェニラミンにはそのような作用は認められなかった。
モデルマウスの作製(第3クール)
7週齢のBALB/cAnNCrlCrljにOVAのみ、あるいはALUMの混合液を腹腔内投与して初回感作とし、さらにこの5日後に追加感作としてOVA溶液あるいはOVA溶液と本化合物(配列番号67、Sp型立体異性体)の混合物を背部皮下投与することで、OVAによる全身感作を行った。その後、初回感作18日目以降から4日間、局所感作として1日1回OVA溶液を両側鼻腔にマイクロピペットで点鼻投与し、アレルギー症状を発症させた。
化合物67(10μg)をOVA追加感作時、初回感作後17日目あるいは局所感作1日目に皮下投与あるいは点鼻投与し、アレルギー症状発症への影響を確認した。
局所感作5日後に採取した血液を用いて、製造業者の指示書に従い、Mouse Serum Anti-OVA IgE Antibody Assay Kit(Chondrex,Inc.)を用いてOVA特異的IgEの測定を実施した。その結果を下記表及び図3に示す。
剖検時(局所感作5日後)に採取したBALFを遠心分離(4℃、800×g、10分間)し、上清を除去後、沈査を500μLのPBSで再懸濁した。細胞数に合わせて希釈率を適宜変更し、チュルク液と混合してカウントを実施した。その結果を下記表及び図4に示す。
化合物67のSp型立体異性体を局所感作前日(初回感作17日目)に投与した群では、陽性対象であるクロルフェニラミン、あるいはOVA投与群と比較してアレルギー症状の指標である血中IgEの顕著な低下を示した。さらに、気管支肺胞洗浄液(BALF)中における白血球数は化合物67のSp型立体異性体投与群全てにおいて、好中球の減少傾向を示したが、しては、化合物67投与群では顕著に低下していたが、陽性対象であるクロルフェニラミンにはそのような作用は認められなかった。
Claims (9)
- 5’−X1CpGX2−3’からなる配列であるCpGモチーフを2〜4個含む14〜32ヌクレオチド長のオリゴヌクレオチドを含むアジュバンドであって,
前記CpGは,リン酸骨格修飾を有さない非メチル化CpGであり,
前記X1は,A又はTであり,
前記X2は,A又はTであり,
少なくとも2つのCpGモチーフの3’側にホスホロチオエート結合された核酸塩基が接続され,
5’末端及び3’末端は,ホスホロチオエート結合されたS型の核酸塩基であり,
前記オリゴヌクレオチドは,ホスホロチオエート修飾されていない塩基を少なくともひとつ以上含む,
アジュバンド。 - 請求項1に記載のアジュバンドであって,
前記X1は,Aであり,
前記X2は,Tであり,
前記ホスホロチオエート結合された核酸塩基は,ホスホロチオエート結合された第1のS化Tである,
アジュバンド。 - 請求項2に記載のアジュバンドであって,
前記第1のS化Tの3’側にホスホロチオエート結合された第2のS化Tを含み,
5‘末端に隣接する塩基は,ホスホロチオエート結合されたS型の核酸塩基であり,
3’末端に隣接する塩基は,ホスホロチオエート結合されたS型の核酸塩基である,
アジュバンド。 - 請求項1に記載のアジュバンドであって,
前記オリゴヌクレオチドは,配列番号4,5,9,10,20,22,23,29,30,31,39,53,54,55,59,64,65,66,67,68,69,70,71,74,75,76,77,78,81又は84で示される塩基配列を有するオリゴヌクレオチドである,
アジュバンド。 - 請求項1に記載のアジュバンドであって,
前記オリゴヌクレオチドは,
以下式Iで示されるオリゴヌクレオチド(配列番号67で示される塩基配列を有するオリゴヌクレオチド)であるか,
式Iで示されるオリゴヌクレオチドから1又は2個の塩基が欠失,置換,付加又は挿入された配列からなるオリゴヌクレオチドであって,抗アレルギー作用を有するオリゴヌクレオチドである,
アジュバンド。
TSPCSPGACGTTSPTSPTSPGACGTTSPTSPTSPGACGSPTSPT (式I) - 請求項1〜5のいずれかに記載のアジュバンドを含む,抗アレルギー剤。
- 請求項6に記載の抗アレルギー剤であって,アレルギー性鼻炎の治療剤である剤。
- 請求項1〜5のいずれかに記載のアジュバンドを含み,
前記オリゴヌクレオチドを有効成分として含む,抗アレルギー剤。 - 請求項8に記載の抗アレルギー剤であって,アレルギー性鼻炎の治療剤である剤。
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WO2011005761A1 (en) | 2009-07-06 | 2011-01-13 | Ontorii, Inc | Novel nucleic acid prodrugs and methods use thereof |
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SG11201500243WA (en) * | 2012-07-13 | 2015-04-29 | Shin Nippon Biomedical Lab Ltd | Chiral nucleic acid adjuvant |
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US10322173B2 (en) | 2019-06-18 |
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