JP2009533348A - Tlr7およびtlr8に対する安定化免疫調節rna(simra)化合物 - Google Patents
Tlr7およびtlr8に対する安定化免疫調節rna(simra)化合物 Download PDFInfo
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- JP2009533348A JP2009533348A JP2009504348A JP2009504348A JP2009533348A JP 2009533348 A JP2009533348 A JP 2009533348A JP 2009504348 A JP2009504348 A JP 2009504348A JP 2009504348 A JP2009504348 A JP 2009504348A JP 2009533348 A JP2009533348 A JP 2009533348A
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Abstract
Description
発明の分野
本発明は、一般に、オリゴリボヌクレオチドを免疫調節剤として用いる免疫学および免疫治療の適用の分野に関する。とくに本発明は、安定化免疫調節RNA(SIMRA)組成物およびその使用方法に関する。かかる組成物および方法は、Toll様レセプター8(TLR8)、TLR7およびTLR8、並びにTLR7(TLR7)を介した免疫反応を調節するのに効果的である。
免疫応答には、該応答に係わる細胞のサブセットに基づく生得的応答および順応的応答の両方が含まれる。例えば、遅延型過敏性および細胞傷害性Tリンパ球(CTL)の活性化などの古典的な細胞媒介機能に係わるTヘルパー(Th)細胞はTh1細胞であり、一方、B細胞の活性化に対してヘルパー細胞として係わる細胞はTh2細胞である。免疫応答のタイプは、抗原への暴露に対する応答において産生されるサイトカインおよびケモカインによって影響を受ける。サイトカインは、生じる免疫応答のタイプに直接的に影響するTヘルパー1(Th1)細胞とTヘルパー2(Th2)細胞とのバランスに影響することによって、免疫応答を制御する手段を提供する。バランスがTh1の数がより高い方へ向くと、細胞傷害性T細胞(CTL)の活性化を含む細胞媒介免疫応答が生じる。バランスがTh2の数がより高い方へ向くと、体液性または抗体免疫反応が生じる。これらの免疫応答のそれぞれは、Th1細胞およびTh2細胞から分泌されるサイトカインの異なる組み合わせをもたらす。Th1細胞およびTh2細胞によって分泌されるサイトカインの差異は、これら2つのサブセットの異なる生体機能の結果であるかもしれない。
第一の面において、本発明は、
新規なクラスの安定化免疫調節RNA(SIMRA)化合物、さらに以下に定義するもの、およびそれらの免疫応答の誘導および/または増強への使用を提供することにより、前記の要求を満たす。本発明による新規な化学物質は、免疫応答を誘導することに実質的により効果的であり、分解に対して実質的により感受性が低い免疫反応誘導および/または増強化合物を提供する。本発明による方法は、免疫治療の適用に対し、SIMRAによって産生するサイトカインプロフィールを改変することができる。
本発明は、免疫治療の適用のための免疫調節剤としてのオリゴヌクレオチドの治療的使用に関する。とくに、本発明は、TLR7のみ、TLR7およびTLR8、またはTLR8のみを介した免疫応答を調節する改善されたインビボでの安定性を有するRNAをベースとしたオリゴヌクレオチド(SIMRA化合物)を提供する。例えば、TLR7および/またはTLR8の安定したアゴニスト、またはSIMRA化合物による樹状細胞および他の抗原提示細胞の活性化を介し、様々な先天性および獲得免疫応答メカニズムを始めることによって、もたらされるサイトカインプロフィールは、病原体、感染細胞または腫瘍細胞の破壊、および抗原特異的抗体およびCTL応答の発生を導き得る。各々が参照として組み込まれるべく詳細かつ個別に示されているように、ここに言及する発行された特許、特許出願および文献は、同じ範囲で参照によってここに組み込まれる。ここに言及された任意の参照の任意の教示および本明細書との間に矛盾がある場合、後者が本発明の目的のために優先する。
用語「2’−置換リボヌクレオシド」または「2’−置換アラビノシド」は、一般に、ペントース部位の2’位の水酸基が置換して2’−置換または2’−O−置換リボヌクレオシドであるリボヌクレオシドまたはアラビノヌクレオシドを含む。ある態様において、かかる置換は、1〜6個の飽和または不飽和の炭素原子を含む低級ヒドロカルビル基、ハロゲン原子、または、6〜10個の炭素原子を有するアリール基によるものであり、ここでかかるヒドロカルビル基またはアリール基は、置換していなくても、あるいは、例えば、ハロゲン、ヒドロキシ、トリフルオロメチル、シアノ、ニトロ、アシル、アシルオキシ、アルコキシ、カルボキシル、カルボアルコキシまたはアミノ基で置換していてもよい。2’−O−置換リボヌクレオシドまたは2’−O−置換アラビノシドの例には、限定されないが、2’−アミノ、2’−フルオロ、2’−アリル、2’−O−アルキルおよび2’−プロパルギルリボヌクレオシドまたはアラビノシド、2’−O−メチルリボヌクレオシドまたは2’−O−メチルアラビノシドおよび2’−O−メトキシエトキシリボヌクレオシドまたは2’−O−メトキシエトキシアラビノシドがある。
免疫調節オリゴリボヌクレオチド合成
免疫調節オリゴリボヌクレオチドは、自動DNA/RNA合成でホスホルアミダイト化学を用いて化学的に合成される。TAC保護された(U以外の)2’−O−TBDMS RNAモノマー、A、G、CおよびUは、Sigma-Aldrichから購入した。7−デアザ−G、イノシンおよびロキソリビンモノマーは、ChemGenes Corporationから購入した。0.25Mの5−エチルチオ−1H−テトラゾール、PAC−無水物Cap AおよびCap Bは、Glen Researchから購入した。ジクロロメタン(DCM)中3%のトリクロロ酢酸(TCA)および5%の3H−1,2−ベンゾジチオール−3−オン−1,1−ジオキシド(Beaucage試薬)は自社製であった。
免疫調節オリゴリボヌクレオチドを固体支持体から開裂し、溶液をさらに65℃に加熱し、エキソ環状アミンの保護基を除去した。得られた溶液をSpeedVacで完全に乾燥した。
免疫調節オリゴリボヌクレオチドは、イオン交換HPLCで精製した。
カラム:Dionex DNAPac 100 カラム(22X250)
カラムヒーター:ChromTech TL-105 HPLC カラムヒーター、温度は80℃に設定した。
バッファーA:20mM Tris−HCl、pH7.0、20%アセトニトリル
バッファーB:3.0M NaCl、20mM Tris−HCl、pH7.0、20%アセトニトリル
流速:10ml/min
勾配:
0−2min:0%B
2−11min:0%Bから35%B
11−41min:35%Bから90%B
41−45min:100%B
Watersから購入したCC-18 Sep-Pakカートリッジを最初に10mlのアセトニトリル、続いて10mlの0.5M酢酸ナトリウムで調整した。10mlの免疫調節オリゴリボヌクレオチド溶液を装填した。次いで、15mlの水を塩の洗浄に用いた。免疫調節オリゴリボヌクレオチドは、最終的に、1mlの水中50%アセトニトリルによって溶出した。
最終溶液を0℃以下で貯蔵した。
装置:Beckman 5010
キャピラリー:62cm ssDNAキャピラリー
サンプル調製:0.2ODのSIMRA化合物を200μlのRNaseフリーの水に溶解した。
注入:5KVで5秒間の動電注入
実行条件:30℃、14KVで50分間
イオン交換HPLC分析
カラム:Dionex DNAPacガードカラム(22X250)
カラムヒーター:ChromTech TL-105 HPLCカラムヒーター、温度は80℃に設定した。
バッファーA:100mM Tris−HCl、pH8.0、20%アセトニトリル
バッファーB:2.0M LiCl、100mM Tris−HCl、pH8.0、20%アセトニトリル
流速:2ml/min 勾配:
0−2min:0%B
2−10min:0%Bから100%B
10−15min:100%B
0.3ODの免疫調節オリゴリボヌクレオチドを20%ポリアクリルアミドゲルにロードし、4ワットの定電力でおよそ5時間で実行した。ゲルを短波長のUV光下で見た。
ヒトPBMCの単離
新鮮に取られた健康なボランティアの血液(CBR Laboratories, Boston, MA)由来の末梢血単核細胞(PBMC)をFicoll密度勾配遠心分離法(Histopaque-1077, Sigma)によって単離した。
新鮮に取られた健康なボランティアの血液(CBR Laboratories, Boston, MA)由来の末梢血単核細胞(PBMC)をFicoll密度勾配遠心分離法(Histopaque-1077, Sigma)によって単離した。pDCは、製造者の指示に従い、BDCA4細胞単離キット(Miltenyi Biotec)を用いてポジティブ選択によってPBMCから単離した。
ヒトPBMCを5x106細胞/mlを用いて48ウェルプレートに静置した。pDCを1X106細胞/mlを用いて96ウェルディッシュに静置した。DPBS(pH7.4;Mediatech)に溶解したSIMRAを細胞培養物に終濃度100.0μg/mlで添加した。次いで、細胞を37℃、24時間インキュベートし、懸濁液をluminex multiplexまたはELISAアッセイのために集めた。実験は三連のウェルで行った。IFN−α、IL−6またはTNF−αのレベルは、サンドウィッチELISAで測定した。サイトカイン抗体および標品を含む必要な試薬は、PharMingenから購入した。
HEK293/ヒトTLR7またはHEK293/ヒトTLR8細胞(Invivogen, San Diego, CA)を5%CO2インキュベーター中、250μl/ウェルの10%熱不活性化FBS添加DMEMで48ウェルプレートで培養した。
マウスTLR9またはヒトTLR3、7または8を安定的に発現するHEK293細胞(Invivogen, San Diego, CA)を5%CO2インキュベーター中、250μl/ウェルの10%熱不活性化FBS添加DMEMで48ウェルプレートで培養した。80%のコンフルエンスで、培養物は、培養培地中、4μl/mlのlipofectamine(Invitrogen, Carlsbad, CA)の存在下、400ng/mlのSEAP(ヒト胚性アルカリホスファターゼの分泌型)レポータープラスミド(pNifty2-Seap)(Invivogen)で一過性にトランスフェクトした。プラスミドDNAおよびlipofectamineを無血清培地で分けて希釈して、5分間室温でインキュベートした。インキュベーションの後、希釈したDNAおよびlipofectamineを混合し、混合物を20分間室温でインキュベートした。100ngのプラスミドDNAおよび1μlのlipofectamineを含むDNA/lipofectamine混合物の25μlのアリコートを細胞培養プレートの各ウェルに添加し、培養を4時間継続した。
トランスフェクションの後、培地をフレッシュな培養培地に置き換え、SIMRAを培養物に添加し、そして培養を18時間継続した。SIMRA処置の終わりに、30μlの培養上清を各処置から取り、製造者のプロトコール(Invivogen)に従ってSEAPアッセイに用いた。
簡単に、培養上清をp−ニトロフィニルホスフェート基材でインキュベートし、発生した黄色の色を405nmでプレートリーダーで測定した。データをPBS対照に対するNF−κB活性の倍数増加として示す。(Putta MR et al, Nucleic Acids Res., 2006, 34:3231-8)
BALB/cマウスを3つのマウスのグループに分けた。培養したCT26.CL25細胞を静注(i.v.)した(4x105細胞/マウス)。次いで、本発明によるRNAをベースとしたオリゴヌクレオチド(SIMRA化合物)または対照を50mg/kgの投与量でマウスに皮下投与(s.c.)した。最初の用量の投与から4時間後、血清はマウスから得られ、IL−12レベルをELISAで測定した。結果を図9に示す。マウスは、CT26.CL25細胞の静注後、24時間、72時間および144時間に皮下投与を受けた。14日目にマウスを屠し、肺を採取した。図10は、多数の腫瘍小塊が肺に見られた。
カニクイザルを、1グループあたり4匹のサルで3グループに分けた(2つは生理食塩水のグループ)。次いで、本発明によるRNAをベースとしたオリゴヌクレオチド(SIMRA化合物)または対照を5mg/kgの投与量でサルに皮下投与(s.c.)した。他の用量(例えば、1mg/kg)もまた所望の効果を有し得る。投与の8、16および24時間後、サルから血清を採取し、免疫応答におけるサイトカインおよびケモカインのレベルおよび変化を測定した。結果を図12〜15に示す。
前述の発明が、明確化および理解を目的として詳細に記載されている一方、当然のことながら、当業者であれば、本発明の開示を読むことにより、形態および詳細のさまざまな変形を、本発明の真の範囲および特許請求の範囲から逸脱することなく想到することができる。
Claims (25)
- 安定化免疫調節RNA(SIMRA)化合物を含む、TLR8、TLR7およびTLR8、またはTLR7に対するアゴニスト。
- SIMRAが、3’または5’付着またはこれらの組み合わせを介して結合するRNAベースのオリゴヌクレオチドの少なくとも2つを含む、請求項1に記載のアゴニスト。
- RNAベースのオリゴヌクレオチドが、3’末端または5’末端で互いに直接結合する、請求項2に記載のアゴニスト。
- RNAベースのオリゴヌクレオチドの3’末端または5’末端が、非ヌクレオチドリンカーと結合する、請求項2に記載のアゴニスト。
- 非ヌクレオチドリンカーが、アルキルリンカーまたはアミノリンカーであり、ここでアルキルまたはアミノシンカーは、選択的に、分枝または非分枝、環状または非環状、置換または非置換、飽和または不飽和、キラル、アキラルまたはラセミ混合物であってもよい、請求項4に記載のアゴニスト。
- アルキルリンカーが、約2〜約18個の炭素原子を有し得る、請求項5に記載のアゴニスト。
- アルキルリンカーが、約3〜約9個の炭素原子を有し得る、請求項5に記載のアゴニスト。
- アルキルリンカーが、1,2,3−プロパントリオール、グリセロール、1,2,4−ブタントリオール、2−ヒドロキシメチル−1,3−プロパンジオール、1,1,1−トリス(ヒドロキシメチル)エタン、2−アミノ−2−(ヒドロキシメチル)1,3−プロパンジオール、トリス(ヒドロキシメチル)ニトロメタン、1,1,1−トリ(ヒドロキシメチル)プロパン、1,2,6−ヘキサントリオール、1,3,5−ヘキサントリオール、1,3,5−ペンタントリオール、3−メチル−1,3,5−ペンタントリオール、1,2,3−ヘプタントリオール、2−(ヒドロキシメチル)1,4−ブタンジオール、1,3−ジ(ヒドロキシメチル)フェノール、1,3,5−トリ(ヒドロキシメチル)ベンゼン、1,3−ジ(ヒドロキシエトキシ)−2−ヒドロキシ−プロパン、1,3−ジ(ヒドロキシプロポキシ)−2−ヒドロキシ−プロパン、D−ガラクタール、1,3,5−トリス(2−ヒドロキシエチル)シアヌル酸または1,3,5−トリス(4−ヒドロキシフェニル)ベンゼンから選択される、請求項5に記載のアゴニスト。
- RNAベースのオリゴヌクレオチドの少なくとも1つが、修飾オリゴリボヌクレオチドを含む、請求項1に記載のアゴニスト。
- 修飾オリゴリボヌクレオチドが、7−デアザ−G、アラ−G、6−チオ−G、イノシン、イソ−G、ロキソリビン、TOG(7−チオ−8−オキソ)−G、8−ブロモ−G、8−ヒドロキシ−G、5−アミノホルマイシンB、オキソホルマイシン、7−メチル−G、9−p−クロロフェニル−8−アザ−G、9−フェニル−G、9−ヘキシル−グアニン、7−デアザ−9−ベンジル−G、6−クロロ−7−デアザグアニン、6−メトキシ−7−デアザグアニン、8−アザ−7−デアザ−G(PPG)、2−(ジメチルアミノ)グアノシン、7−メチル−6−チオグアノシン、8−ベンジルオキシグアノシン、9−デアザグアノシン、9−ベンジル−8−ヒドロキシ−2−(2−メトキシエトキシ)アデニン、2−アミノ−N2−O−、メチルアデノシン、8−アザ−7−デアザ−A、7−デアザ−A、ビダラビン、2−アミノアデノシン、N1−メチルアデノシン、8−アザアデノシン、5−ヨードツベルサイジン、1−(B−D−リボフラノシル)−2−オキソ−7−デアザ−8−メチル−プリンおよび4−チオ−Uまたはこれらの組み合わせを含む、請求項9に記載のアゴニスト。
- RNAベースの化合物が、さらに5’キャップを含む、請求項1〜10のいずれかに記載のアゴニスト。
- 5’キャップが、非ヌクレオチドリンカーである、請求項11に記載のアゴニスト。
- 請求項1〜10のいずれかに記載のアゴニストおよび薬学的に許容し得る担体を含む、医薬組成物。
- 脊椎動物において免疫応答を惹起する方法であって、該脊椎動物に薬学的に有効な量の請求項1〜10のいずれかに記載のSIMRA化合物を投与することを含む、前記方法。
- 癌、自己免疫疾患、気道炎症、炎症性障害、感染症、皮膚病、アレルギー、喘息または病原によって引き起こされた疾病を有する脊椎動物を治療的に処置する方法であって、かかる方法が、薬学的に有効な量の請求項1〜10のいずれかに記載のSIMRA化合物を患者に投与することを含む、前記方法。
- さらに、1または2以上の化学療法化合物を投与することを含む、請求項15に記載の方法。
- さらに、標的治療剤を投与することを含む、請求項15に記載の方法。
- さらに、抗体を投与することを含む、請求項15に記載の方法。
- さらに、DNAワクチンを投与することを含む、請求項15に記載の方法。
- さらに、ワクチンを投与することを含む、請求項15に記載の方法。
- さらに、抗原を投与することを含む、請求項15に記載の方法。
- 脊椎動物における癌、自己免疫疾患、気道炎症、炎症性障害、感染症、皮膚病、アレルギー、喘息または病原によって引き起こされた疾病を予防する方法であって、かかる方法が、薬学的に有効な量の請求項1〜10のいずれかに記載のSIMRA化合物を脊椎動物に投与することを含む、前記方法。
- さらに、1または2以上の化学療法化合物を投与することを含む、請求項22に記載の方法。
- さらに、標的治療剤を投与することを含む、請求項22に記載の方法。
- さらに、抗体を投与することを含む、請求項22に記載の方法。
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US8759310B2 (en) | 2014-06-24 |
KR20090029187A (ko) | 2009-03-20 |
US8106173B2 (en) | 2012-01-31 |
CA2648585C (en) | 2017-07-25 |
JP2014031373A (ja) | 2014-02-20 |
ES2564303T3 (es) | 2016-03-21 |
EP2021008A4 (en) | 2010-10-13 |
KR20120115412A (ko) | 2012-10-17 |
JP5761911B2 (ja) | 2015-08-12 |
KR101221589B1 (ko) | 2013-01-15 |
JP5669897B2 (ja) | 2015-02-18 |
AU2007235231A1 (en) | 2007-10-18 |
AU2007235231B2 (en) | 2012-04-12 |
CN101460178B (zh) | 2016-12-07 |
US20080171712A1 (en) | 2008-07-17 |
CN101460178A (zh) | 2009-06-17 |
CA2648585A1 (en) | 2007-10-18 |
US20140308300A1 (en) | 2014-10-16 |
WO2007117686A2 (en) | 2007-10-18 |
US20130202584A1 (en) | 2013-08-08 |
HK1127727A1 (zh) | 2009-10-02 |
EP2021008A2 (en) | 2009-02-11 |
US9243050B2 (en) | 2016-01-26 |
WO2007117686A3 (en) | 2008-06-26 |
EP2021008B1 (en) | 2015-12-02 |
MX2008012993A (es) | 2008-12-18 |
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