JP2013121962A - 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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- JP2013121962A JP2013121962A JP2013002571A JP2013002571A JP2013121962A JP 2013121962 A JP2013121962 A JP 2013121962A JP 2013002571 A JP2013002571 A JP 2013002571A JP 2013002571 A JP2013002571 A JP 2013002571A JP 2013121962 A JP2013121962 A JP 2013121962A
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Abstract
【解決手段】オリゴdIC26−mer、I−ODN1、I−ODN2、I−ODN3、I−ODN9およびI−ODN10などの特定の配列を有するものよりなる群から選ばれたオリゴデオキシ核酸分子を含む免疫促進用医薬組成物、更に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などのポリカチオン性ポリマーを含有する。
【選択図】なし
Description
(式中、XはいずれもOまたはS、
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。
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。
http://www.bbcm.univ.trieste. it/~tossi/pagl.html。
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、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:300mg/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:100mg/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/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 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。
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 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。
ODN17:
デオキシイノシンを含むチオホスフェート置換ODN:hhh wdi dhh h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 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。
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
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。
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)。
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。
Claims (6)
- オリゴdIC26−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)を含む免疫促進用医薬組成物。
- さらにポリカチオン性ポリマーを含む、請求項1に記載の免疫促進用医薬組成物。
- 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2に記載の免疫促進用医薬組成物。
- さらに活性成分を含む、請求項1ないし3のいずれかに記載の免疫促進用医薬組成物。
- さらに補助物質を含む、請求項1ないし4のいずれかに記載の免疫促進用医薬組成物。
- 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1ないし5のいずれかに記載の免疫促進用医薬組成物。
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