JP5271471B2 - 免疫促進性オリゴデオキシヌクレオチド - Google Patents
免疫促進性オリゴデオキシヌクレオチド Download PDFInfo
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- JP5271471B2 JP5271471B2 JP2002501476A JP2002501476A JP5271471B2 JP 5271471 B2 JP5271471 B2 JP 5271471B2 JP 2002501476 A JP2002501476 A JP 2002501476A JP 2002501476 A JP2002501476 A JP 2002501476A JP 5271471 B2 JP5271471 B2 JP 5271471B2
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Description
本発明は、免疫促進性のオリゴデオキシ核酸分子(ODN)およびそのようなODNを含有する医薬組成物に関する。
ワクチンは、他のいかなる医学的介入よりも多くの生命(および資源)を救うことができる(ノッサル(Nossal)、1998)。世界的なワクチン接種プログラムのおかげで多くの致死的疾患の発症率は急激に減少している。この見方は疾患の完成されたパネル(whole panel)、たとえば、結核、ジフテリア、百日咳、麻疹および破傷風にはあてはまるが、AIDSなどの大抵のウイルス感染症を含む多数の感染疾患に対する有効なワクチンは存在しない。また、感染性であるか非感染性であるかを問わず、マラリアおよび癌を含めて毎年何百万もの患者の何百万もの人命を奪う他の疾患に対するワクチンも存在しない。さらに、抗生物質に耐性の細菌および微生物の急激な出現は他の治療を要求しており、ワクチンは必然の選択となってきている。最後に、ワクチンに対する大いなる必要性はまた、心血管性疾患または癌または創傷よりもむしろ感染疾患が世界的に死亡および不具の最大の原因であるという事実によっても説明される(ブルーム(Bloom)およびウィダス(Widdus)、1998)。
最近の知見は、原生生物または下等真核生物のDNAを哺乳動物(および、おそらく全てではないが大抵の脊椎動物)の先天免疫系(しかしながら、おそらく獲得免疫系も)によって認識されるさらなるパターンとして記載している(クリーグ(Krieg)、1996;リップフォード(Lipford)ら、1998)。
しかしながら、この作用はイノシンおよびシトシン残基を含むリボ核酸に厳格に限られている(WO98/16247)。
(発明が解決しようとする技術的課題)
本発明の発明者らによる研究は、非メチル化CpGモチーフを含むODNは免疫系を刺激するうえで有効であるが、本質的な欠点、とりわけ特異性(高いバックグラウンド)および高い全身的なTNF−α産生などの副作用に関する欠点を有することを示している。高い全身的なTNF−α放出はトキシックショック症候群を引き起こすことが知られており、これは患者の死を引き起こしうるものである。
それゆえ、本発明の目的は、そのようなCpG配列に基づくODNのような激しい副作用を有することのない適当な新規なODNを提供することである。さらに、本発明の目的は、知られたODNを含有する医薬組成物の副作用を低減すること、および動物、とりわけヒトを含む哺乳動物のワクチン接種に適した有効な免疫促進特性を備えた、安全かつ有効な充分に許容できる(well-tolerable)医薬組成物を提供することである。
NMPはいずれも、デオキシアデノシン−、デオキシグアノシン−、デオキシイノシン−、デオキシシトシン−、デオキシウリジン−、デオキシチミジン−、2−メチル−デオキシイノシン−、5−メチル−デオキシシトシン−、デオキシプソイドウリジン−、デオキシリボースプリン−、2−アミノ−デオキシリボースプリン−、6−S−デオキシグアニン−、2−ジメチル−デオキシグアノシン−またはN−イソペンテニル−デオキシアデノシン−モノホスフェートまたは−モノチオホスフェートよりなる群から選ばれた2'デオキシヌクレオシドモノホスフェートまたはモノチオホスフェート、
NUCは、デオキシアデノシン−、デオキシグアノシン−、デオキシイノシン−、デオキシシトシン−、デオキシウリジン−、デオキシチミジン−、2−メチル−デオキシイノシン−、5−メチル−デオキシシトシン−、デオキシプソイドウリジン−、デオキシリボースプリン−、2−アミノ−デオキシリボースプリン−、6−S−デオキシグアニン−、2−ジメチル−デオキシグアノシン−またはN−イソペンテニル−デオキシアデノシンよりなる群から選ばれた2'デオキシヌクレオシド、
aおよびbは0〜100の整数であり、ただしa+bは4〜150である、
BおよびEは核酸分子の5'末端または3'末端の一般的な基)
の構造を有する免疫促進性のオリゴデオキシ核酸分子(ODN)によって解決される。
ポリ−ICすなわちWO98/16247において言及された分子などのようなイノシン含有RNA分子についてある種の免疫促進作用が記載されてはいるが、驚くべきことにデオキシイノシン残基を含むデオキシ核酸分子が良好な免疫促進性のODNであることがわかった。
本発明によるI−ODNは、組換え法により単離するかまたは化学的に合成することができる。後者の場合、本発明によるI−ODNはまた修飾したオリゴヌクレオチドを含んでいてよく、そのような修飾したオリゴヌクレオチドは、メチルホスホネートや他のリンベースの修飾オリゴヌクレオチド、たとえば、ホスホトリエステル、ホスホアミデートおよびホスホロジチオレートなどの標準的な化学変換を用いて合成することができる。しかしながら、他の非リンベースの修飾オリゴヌクレオチドを用いることができ(スターチャック(Stirchak)ら、3月17日(I989)、6129−6141)、モノホスフェートまたはモノチオホスフェートが本発明に使用するのに好ましい2'デオキシヌクレオシドモノホスフェートである。
これに対して、従来技術で免疫促進性であるとして記載されているイノシンおよびシチジン含有リボ核酸分子は、分子量が200,000を遥かに超える大きくて比較的定められていないポリ核酸であった(Sigma Chemicalsより市販されているポリイノシン−ポリシチジン酸の分子量は220,000〜460,000(少なくとも500〜1000のC+I残基)の範囲である)。本発明による分子は遥かに長さが短く、長さおよび組成がよく定められたDNA分子であり、製品における再現性の高いものである。
hhh wdi dhh h、
nhh hhh wdi nhh hhh hhh wn、
nhh wdi din hhh hdi ndi nh、
nhh hhh wdi dhh hhh hhh wnまたは
nhh wdi did hhh hdi ddi dh
(式中、nはいずれも、デオキシアデノシン−、デオキシグアノシン−、デオキシシトシン−またはデオキシチミジン−モノホスフェートまたは−モノチオホスフェートよりなる群から選ばれた2'−デオキシヌクレオシドモノホスフェートまたはモノチオホスフェート、
hはいずれも、デオキシアデノシン−、デオキシシトシン−またはデオキシチミジン−モノホスフェートまたは−モノチオホスフェートよりなる群から選ばれた2'−デオキシヌクレオシドモノホスフェートまたはモノチオホスフェート、
iは、デオキシイノシン−モノホスフェートまたは−モノチオホスフェート、
wはいずれも、デオキシアデノシン−またはデオキシチミジン−モノホスフェートまたは−モノチオホスフェートよりなる群から選ばれた2'−デオキシヌクレオシドモノホスフェートまたはモノチオホスフェート、
dはいずれも、デオキシアデノシン−、デオキシグアノシン−またはデオキシチミジン−モノホスフェートまたは−モノチオホスフェートよりなる群から選ばれた2'−デオキシヌクレオシドモノホスフェートまたはモノチオホスフェート)。
gacitt、
iacitt、
gaictt、
iaictt
(式中、aはデオキシアデノシン−モノホスフェートまたは−モノチオホスフェート、
gはデオキシグアノシン−モノホスフェートまたは−モノチオホスフェート、
iはデオキシイノシン−モノホスフェートまたは−モノチオホスフェート、
cはデオキシシトシン−モノホスフェートまたは−モノチオホスフェート、
tはデオキシチミジン−モノホスフェートまたは−モノチオホスフェート)。
それゆえ、本発明はまた本発明によるODNを含む医薬組成物にも関する。
本発明の組成物に使用する抗原は重要ではない。もちろん、異なる抗原の混合物を本発明に従って用いることも可能である。好ましくは、ウイルスまたは細菌病原体に由来する、または真菌または寄生虫に由来するタンパク質またはペプチドをそのような抗原(誘導体化した抗原またはグリコシル化したまたは脂質化した(lipidated)抗原または多糖または脂質を含む)として用いる。他の好ましい抗原の採取源は腫瘍抗原である。好ましい病原体は、ヒト免疫不全ウイルス(HIV)、A型およびB型肝炎ウイルス、C型肝炎ウイルス(HCV)、ラウス肉腫ウイルス(RSV)、エプスタインバーウイルス(EBV)、インフルエンザウイルス、ロタウイルス、スタフィロコッカス・アウレウス(Staphylococcus aureus)、クラミジア・ニューモニア(Chlamydia pneumonias)、クラミジア・トラコマチス(Chlamydia trachomatis)、ミコバクテリウム・チューバーキュローシス(Mycobacterium tuberculosis)、ストレプトコッカス・ニューモニア(Streptococcus pneumonias)、バシラス・アントラシス(Bacillus anthracis)、ビブリオ・コレラ(Vibrio cholerae)、プラスモジウム(Plasmodium)種(Pl. falciparum, Pl. vivaxなど)、アスペルギルス(Aspergillus)種またはカンジダ・アルビカンス(Candida albicans)から選択される。
本発明の一つの態様において、本発明の医薬組成物は自己免疫疾患に関与するタンパク質またはタンパク質断片およびペプチドに対する耐性を付与するように働く。この態様に用いる抗原は、免疫系に対して寛容にするかまたは自己免疫プロセスに関与するエピトープに対する免疫応答をダウンレギュレーションするように働く。
好ましくは本発明による医薬組成物、とりわけワクチンの形態の医薬組成物は、ポリカチオン性ポリマー、好ましくはポリカチオン性ペプチド、とりわけポリアルギニン、ポリリシンまたは抗菌性ペプチドをさらに含む。
これらポリカチオン性化合物は化学的にまたは組換えにより製造してよく、あるいは天然の採取源に由来してもよい。
http://www.bbcm.univ.trieste. it/~tossi/pagl.html。
本発明においてポリカチオン性物質として使用するのに特に好ましいのは、カテリシジン(cathelicidin)由来の抗菌ペプチドまたはその誘導体(A1416/2000、参照のため本明細書中に引用する)、とりわけ哺乳動物、好ましくはヒト、ウシまたはマウスのカテリシジンに由来する抗菌ペプチド、または(ヒト)成長ホルモンなどの神経刺激性の化合物である。
本発明による医薬組成物の免疫促進作用が、各成分単独の作用の付加から予測されるものと比較して、あるいは抗原とともに用いたODNまたはポリカチオンの作用の付加から予測されるものと比較してさえも有意に高いことは非常に驚くべきことであった。
もちろん、式Iによる分子のイオン化した(塩)形態や互変異性の形態は式Iに包含される。
もちろん、本発明による医薬組成物は、補助物質、とりわけ薬理学的に許容しうる担体、緩衝液物質、安定化剤またはそれらの組み合わせをさらに含んでいてよい。
本発明の医薬組成物の投与経路は重要ではなく、たとえば、皮下、筋肉内、皮内または経皮注射が経口摂取とともに適している。
上記成分は同じ部位に同時に投与することもできるが、異なる部位に異なる時間で、または異なる期間で投与することも可能である。また、組成物または成分の全身性または局所性の投与をそれぞれ変えることも可能である。
実施例
すべての実験においてチオホスフェート置換ODN(ホスフェートをチオホスフェート残基で置換、以下、「チオホスフェート置換オリゴデオキシヌクレオチド」という)を用いたが(実施例6を除く)、これはそのようなODNがより高いヌクレアーゼ耐性を示すからである(バラス(Ballas)ら、1996;クリーグ(Krieg)ら、1995;パロンチ(Parronchi)ら、1999)。
マウス:
C57BI/6(Harlan/Olac)
ペプチド:
ニワトリ卵アルブミンのMHCクラスI(H−2Kb)拘束エピトープであるOVA257−264ペプチド(SIINFEKL)(ロッツシュク(Rotzschke)ら、1991)を標準固相F−moc化学合成法を用いて合成し、HPLC精製し、ついで純度をマススペクトロメトリーにより分析した。投与量:300μg/マウス。
平均重合度が60アルギニン残基のポリL−アルギニン;SIGMA chemicals。投与量:100μg/マウス。
CpG−ODN1668:
CpGモチーフを含むチオホスフェート置換ODN:tcc atg acg ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
デオキシイノシンを含有するチオホスフェート置換ODN:tcc ati aci ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
I−ODN2:
デオキシイノシンを含有するチオホスフェート置換ODN:tcc atg aci ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
I−ODN3:
デオキシイノシンを含有するチオホスフェート置換ODN:tcc ati aci ttc cti ati ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
1.OVA257-264
2.OVA257-264 + pR60
3.OVA257-264 + CpG1668
4.OVA257-264 + I−ODN1
5.OVA257-264 + I−ODN2
6.OVA257-264 + I−ODN3
7.OVA257-264 + CpG1668 + pR60
8.OVA257-264 + I−ODN1 + pR60
9.OVA257-264 + I−ODN2 + pR60
10.OVA257-264 + I−ODN3 + pR60
注射1時間後に尾静脈より採血し、血清を調製して全身的なTNF−aの誘発をELISAを用いて決定した(図2)。
マウス:
C57B1/6(Harlan/0lac)
ペプチド:
ニワトリ卵アルブミンのMHCクラスI(H−2Kb)拘束エピトープであるOVA257-264ペプチド(SIINFEKL)(ロッツシュク(Rotzschke)ら、1991)を標準固相F−moc合成法を用いて合成し、HPLC精製し、ついで純度をマススペクトロメトリーにより分析した。投与量:300μg/マウス。
平均重合度が60アルギニン残基のポリL−アルギニン;SIGMA chemicals。投与量:100μg/マウス。
CpG−ODN1668:
CpGモチーフを含むチオホスフェート置換ODN:tcc atg acg ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
GpC−ODN:
非免疫原性のGpCモチーフを含むチオホスフェート置換ODN:tcc atg agc ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
デオキシイノシンを含有するチオホスフェート置換ODN:tcc atg aic ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
I−ODN10:
デオキシイノシンを含有するチオホスフェート置換ODN:tcc ati aic ttc cti ati ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
OVA257-264
OVA257-264 + pR60
OVA257-264 + CpG1668
OVA257-264 + GpC
OVA257-264 + I−ODN9
OVA257-264 + I−ODN10
OVA257-264 + CpG1668 + pR60
OVA257-264 + GpC + pR60
OVA257-264 + I−ODN9 + pR60
OVA257-264 + I−ODN10 + pR60
マウス:
C57B1/6(Harlan/Olac)
ペプチド:
マウスチロシナーゼ関連プロテイン2のMHCクラスI(H−2Kb)拘束エピトープであるTRP−2ペプチド(VYDFFVWL)(ブロム(Bllom)ら、1997)を標準固相F−moc合成法により合成し、HPLC精製し、ついで純度をマススペクトロメトリーにより分析した。投与量:300μg/マウス。
平均重合度が60アルギニン残基のポリL−アルギニン;SIGMA chemicals。投与量:100μg/マウス。
CpG−ODN1668:
CpGモチーフを含むチオホスフェート置換ODN:tcc atg acg ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
チオホスフェート置換ODN:nhh hhh wdi nhh hhh hhh wnをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
wdidin:
チオホスフェート置換ODN:nhh wdi din hhh hdi ndi nhをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
wdid:
チオホスフェート置換ODN:nhh hhh wdi dhh hhh hhh wnをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
wdidid:
チオホスフェート置換ODN:nhh wdi did hhh hdi ddi dhをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
1.TRP−2
2.TRP−2 + pR60
3.TRP−2 + CpG1668
4.TRP−2 + wdi
5.TRP−2 + wdidin
6.TRP−2 + wdid
7.TRP−2 + wdidid
8.TRP−2 + CpG1668 + pR60
9.TRP−2 + wdi + pR60
10.TRP−2 + wdidin + pR60
11.TRP−2 + wdid + pR60
12.TRP−2 + wdidid + pR60
実験群(1群5匹のマウス)
1.TRP−2181-188
2.TRP−2181-188 + pR60
3.TRP−2181-188 + CpG1668
4.TRP−2181-188 + I−ODN2
5.TRP−2181-188 + CpG1668 + pR60
6.TRP−2181-188 + I−ODN2 + pR60
注射1時間後に尾静脈より採血し、血清を調製して全身的なTNF−αおよびIL−6の誘発をサイトカイン特異的ELISAを用いて決定した(図7)。
実験群(1群5匹のマウス)
1.TRP−2181-188
2.TRP−2181-188 + pR60
3.TRP−2181-188 + CpG1668
4.TRP−2181-188 + ODN17
5.TRP−2181-188 + CpG1668 + pR60
6.TRP−2181-188 + ODN17 + pR60
C57B1/6(Harlan/Olac)
ペプチド:
マウスチロシナーゼ関連プロテイン2のMHCクラスI(H−2Kb)拘束エピトープであるTRP−2ペプチド(VYDFFVWL)(ブロム(Bllom)ら、1997)を標準固相F−moc合成法により合成し、HPLC精製し、ついで純度をマススペクトロメトリーにより分析した。投与量:100μg/マウス。
平均重合度が60アルギニン残基のポリL−アルギニン;SIGMA chemicals。
投与量:100μg/マウス。
CpG−ODN1668:
CpGモチーフを含むチオホスフェート置換ODN:tcc atg acgttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
ODN17:
デオキシイノシンを含むチホスフェート置換ODN:hhh wdi dhhhをNAPS GmbH、ゲッチンゲンにより合成した(h=CAT、w=AT、d=GAT)。投与量:10ナノモル/マウス。
C57B1/6(Harlan/Olac)
ペプチド:
マウスチロシナーゼ関連プロテイン2のMHCクラスI(H−2Kb)拘束エピトープであるTRP−2ペプチド(VYDFFVWL)(ブロム(Bllom)ら、1997)を標準固相F−moc合成法により合成し、HPLC精製し、ついで純度をマススペクトロメトリーにより分析した。投与量:100μg/マウス。
平均重合度が60アルギニン残基のポリL−アルギニン;SIGMA chemicals。投与量:100μg/マウス。
CpG−ODN1668:
CpGモチーフを含むチオホスフェート置換ODN:tcc atg acgttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
I−ODN2:
デオキシイノシンを含むチオホスフェート置換ODN:tcc atg aci ttc ctg atg ctをNAPS GmbH、ゲッチンゲンにより合成した。投与量:5ナノモル/マウス。
マウス:
C57B1/6(Harlan/Olac)
卵アルブミン(OVA):
ニワトリ卵からの卵アルブミン、グレードV、SIGMA chemicals、A−5503、ロット54H7070:投与量:50μg/マウス。
平均重合度が60アルギニン残基のポリL−アルギニン;SIGMA chemicals、P−4663、ロット68H5903。投与量:100μg/マウス。
オリゴデオキシIC、26−mer(オリゴdIC 26-mer ):
オリゴdIC26-merを標準ホスホアミダイト化学により4μモルスケールで合成し、HPLC(NAPS GmbH、ゲッチンゲン、ドイツ)により精製した。投与量:5ナノモル/マウス。
1.OVA + オリゴdIC26-mer + pR
2.OVA + オリゴdIC26-mer
3.OVA + pR
4.OVA
これらデータは、オリゴdICおよびpRと組み合わせたOVAの注射がOVA特異的な体液性応答を促進することを示している。この応答は、初期の相ではTh1およびTh2の両者により誘発された抗体イソ型が産生されるが、その後、主としてTh1によって誘発された抗体が産生されるという特徴を有する。
Claims (8)
- 免疫促進用医薬組成物の製造のための、オリゴdIC 26−mer (配列番号1)、I−ODN1(配列番号2)、I−ODN2(配列番号3)、I−ODN3(配列番号4)、I−ODN9(配列番号5)およびI−ODN10(配列番号6)よりなる群から選ばれたオリゴデオキシ核酸分子(ODN)の使用。
- 該免疫促進用医薬組成物がワクチンである、請求項1に記載の使用。
- 請求項1に記載のODNおよび抗原を含む医薬組成物。
- さらにポリカチオン性ポリマーを含む、請求項3に記載の医薬組成物。
- 該ポリカチオン性ポリマーが、ポリカチオン性ペプチド、抗菌性ペプチド、3〜7の疎水性アミノ酸のリンカーによって隔てられた少なくとも2つのKLKモチーフを含む合成ペプチドまたは成長ホルモンである、請求項4に記載の医薬組成物。
- さらに活性成分を含む、請求項3ないし5のいずれかに記載の医薬組成物。
- さらに補助物質を含む、請求項3ないし6のいずれかに記載の医薬組成物。
- 請求項1に記載の1またはそれ以上のODNを1ng〜1g含む、請求項3ないし7のいずれかに記載の医薬組成物。
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