JP4989225B2 - 核酸親油性接合体 - Google Patents
核酸親油性接合体 Download PDFInfo
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- JP4989225B2 JP4989225B2 JP2006528305A JP2006528305A JP4989225B2 JP 4989225 B2 JP4989225 B2 JP 4989225B2 JP 2006528305 A JP2006528305 A JP 2006528305A JP 2006528305 A JP2006528305 A JP 2006528305A JP 4989225 B2 JP4989225 B2 JP 4989225B2
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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Description
本発明は概して、核酸親油性接合体、これらの組成物、およびその接合体を使用する方法に関連する。
細菌DNAは、B細胞およびナチュラルキラー細胞を活性化する免疫刺激効果を有するが、脊椎動物DNAはその効果を有さない(非特許文献1、非特許文献2および非特許文献3)。細菌DNAのこれらの免疫刺激効果は、特定の塩基内容(base context)(CpGモチーフ)における非メチル化CpGジヌクレオチドの存在の結果であり、その非メチル化CpGジヌクレオチドは、細菌DNAにおいて一般的であるが、脊椎動物DNAにおいてはメチル化されかつ十分に示されない(非特許文献4)。上記細菌DNAの免疫刺激効果は、これらのCpGモチーフを有する合成オリゴデオキシヌクレオチド(ODN)を用いて模倣され得る。このようなCpG ODNは、B細胞増殖、サイトカインの分泌および免疫グロブリンの分泌、ナチュラルキラー(NK)細胞の細胞溶解活性およびIFN−γ分泌、および樹状細胞(DC)の活性化、ならびに共起刺激分子を発現させ、そしてサイトカイン(特に、Th1様T細胞応答の発生の促進に重要なTh1様サイトカイン)の分泌を与える他の抗原提示細胞の活性化を含む、ヒトの白血球およびマウスの白血球に対する高い刺激効果を有する。ネイティブなホスホジエステル骨格のCpG ODNのこれらの免疫刺激効果は、そのCpGモチーフが、メチル化されるか、GpCに変換されるか、または別の方法で除去されるか、もしくは変化する場合、上記効果を劇的に減少させる点で、高度にCpG特異的である(非特許文献5)。
Tokunaga,T.ら、1988.Jpn.J.Cancer Res.79:682−686;Tokunaga,T.ら、1984,JNCI 72:955−962;Messina,J.P.ら、1991,J.Immunol.147:1759−1764 Applied oligonucleotide Technology,CA.SteinおよびA.M.Krieg,(編)中John Wiley and Sons,Inc.,New York,NY,431−448ページのKriegによる概説 Krieg.A.M.CpG motifs in bacterial DNA and their immune effects(2002)Annu.Rev.Immunol.20:709−760 Kriegら、1995 Nature 374:546−549;Krieg,1999 Biochim.Biophys.Acta 93321:1−10 Kriegら、1995 Nature 374:546−549;Hartmannら、1999 Proc.Natl.Acad.Sci USA 96:9305−10 Kriegら、1995 Nature 374:546‐549 Pisetsky,1996 J.Immunol.156:421−423 Hackerら、1998 EMBO J.17:6230−6240 Lipfordら、1998 Trends in Microbiol.6:496‐500 Yiら、1998 J.Immunol.160:5898−5906 Hartmannら、1999 Proc.Natl.Acad.Sci USA 96:9305−10 Liang,1996 J.Clin.Invest.98:1119−1129
本発明は部分的に、親油基に連結された免疫刺激性核酸に関連する。親油基に連結された特定の免疫刺激性核酸が、活性を上昇させたのに対して、他の免疫刺激性核酸への親油基の結合は、その分子の免疫刺激能力に対する効果が最小限であることが、見出されていた。
本発明のそれぞれの限界は、本発明の種々の実施形態を包含し得る。これにより、本発明のそれぞれの限界は、いずれか1つの要素、または要素の組み合わせを含み、その限界は、本発明のそれぞれの局面に含まれ得る。
1つの局面における本発明は、親油基に連結した免疫刺激性オリゴヌクレオチドの特定のサブクラスが、免疫刺激効果を媒介する工程において非常に効果的であるという発見を含む。これらの接合体は、癌、感染症、アレルギー、喘息および他の疾患を処置するために免疫系を刺激する工程に対して、治療的および予防的に有用である。
([N1PN2]n−X3)m)・(L)p
を有し得る。
C_G_A_C_G_T_C_G
C_G_T_C_G_A_C_G
T_C_G_A_C_G_T_C_G_A 配列番号112
C_G_A_C_G_T_C_G_A_C_G_T_C_G 配列番号113
C_G_G_C_G_G_C_C_G_C_C_G 配列番号114
G_A_C_G_A_T_C_G_T_C 配列番号115
が挙げられる。
a)ヌクレオシドの、3’末端および/または5’末端に位置するホスホジエステルヌクレオシド間架橋の、修飾されたヌクレオチド間架橋による置換;
b)ヌクレオシドの、3’末端および/または5’末端に位置するホスホジエステル架橋の、デホスホ(dephospho)架橋による置換;
c)糖リン酸骨格由来の糖リン酸ユニットの、別のユニットによる置換;
d)β−D−リボースユニットの、修飾された糖ユニットによる置換;ならびに
e)天然のヌクレオシド塩基の、修飾されたヌクレオシド塩基による置換より選択される。
配列番号108 5’−T_C_G_T_C_G_T_C_G_A_Chol
配列番号109 Chol−A_G_C_A_G_C_A_G_C_T−5’
本発明によって、上記1組の親油性接合体が、ヒト細胞に対して劇的な免疫刺激効果を有することが発見され、このことは、これらの接合体が、放射線または化学療法、および他の免疫調節適用に続く、ヒトのワクチン接種、癌の免疫療法、喘息の免疫療法、一般的な免疫機能の向上、造血回復の向上についての効果的な治療薬であることを示唆。
オリゴヌクレオチド。すべてのODNは、Coley Pharmaceutical Group(Langenfeld,Germany)から提供され、Limulusアッセイ(BioWhittaker,Verviers,Belgium)によって測定したエンドトキシンレベルは、検出不可能(<0.1EU/ml)であった。ODNを、エンドトキシンを含まない、滅菌したTris−EDTA(Sigma,Deisenhofen,Germany)に懸濁し、そして保存し、そして無菌条件下で操作して微生物汚染およびエンドトキシン汚染の両方を防いだ。すべての希釈を、発熱物質を含まないリン酸緩衝化生理食塩水(Life Technologies,Eggenstein,Germany)を使用して行った。
CpG ODN。使用したCpG ODNの配列はTCGTCGTTTTGTCGTTTTGTCGTT(配列番号116)およびT−C−G−A−C−G−T−C−G−A−コレステロール(配列番号13)であった。配列番号116のGpC類似物を、非CpGコントロールとして使用した。全てのODNは、Coley Pharmaceutical Group(Wellesley,MA)によって供給された。全てのODNを、エンドトキシンを含まない滅菌したTE(pH 8.0)(OmniPer(登録商標);EM Science,Gibbstown,NJ)中に再懸濁し、そして保存し、そして無菌条件下で操作して微生物汚染およびエンドトキシン汚染の両方を防いだ。アッセイのためのODNの希釈を、エンドトキシンを含まない滅菌したPBS(pH 7.2)(Sigma Chemical Company,St.Lois,MO)で行った。
ヒトPBMCを、配列番号36(CpG Bクラス)、配列番号39(CpG Cクラス)、非CpGコントロール、配列番号40(CpG Aクラス)、非CpGコントロールAクラス、または配列番号4(親油性接合体を有するCpG ODN)の濃度を増加して、48時間インキュベートした。上清を回収して、ELISAによってIFN−αを測定した。3つの血液供与体の平均±標準誤差を示す。結果を、図1に示す。親油性接合体を有するCpG ODN、CpG Cクラスオリゴヌクレオチド、およびCpG Aクラスオリゴヌクレオチドの全てが、IFN−α産生を誘導した。0.5μg/mlおよび2μg/mlの濃度の、親油性接合体を有するCpG ODNを測定し、約1000pg/mlおよび約3250pg/mlのIFN−α産生を、それぞれ誘導した。CpG Bクラスオリゴヌクレオチド、非CpGコントロールオリゴヌクレオチド、および非CpGコントロールAクラスオリゴヌクレオチドは、測定可能なIFN−α応答を全く誘導しなかった。
ヒトPBMCを、配列番号36(CpG Bクラス)、配列番号39(CpG Cクラス)、非CpGコントロール、配列番号40(CpG Aクラス)、非CpGコントロールAクラス、または配列番号4(親油性接合体を有するCpG ODN)の濃度を増加して、24時間インキュベートした。上清を回収して、ELISAによってIL−6を測定した。3つの血液供与体の平均±標準誤差を示す。結果を、図2に示す。このアッセイにおいて、2μg/mlの濃度の、親油性接合体を有するCpG ODNは、使用した他のODNと比較して、測定された最も高いIL−6の誘導(約750pg/ml)を示した。より低い濃度(0.031、0.125および0.5)において、親油性接合体を有するCpG ODNは、減少した有効性でIL−6を誘導した。CpG BクラスODN、CpG CクラスODN、および特定の伸長したCpG AクラスODNは全て、IL−6誘導における有効性を実証した。非CpGコントロールおよび非CpGコントロールAクラスオリゴヌクレオチドは、IL−6の誘導を示さないか、またはIL−6の誘導についての低い能力を示した。
ヒトPBMCを、配列番号36(CpG Bクラス)、配列番号39(CpG Cクラス)、非CpGコントロール、配列番号40(CpG Aクラス)、非CpGコントロールAクラス、または配列番号4(親油性接合体を有するCpG ODN)の濃度を増加して、24時間インキュベートした。上清を回収して、ELISAによってIL−6を測定した。3つの血液供与体の平均±標準誤差を示す。結果を、図3に示す。親油性接合体を有するCpG ODNは、IL−10産生に対する刺激において、顕著に減少した有効性を示した。使用した最も高い濃度である2μg/mlにおいてさえ、親油性接合体を有するCpG ODNは、IL−10刺激を顕著に誘導しなかった。同様の結果が、AクラスODNで得られたが、対照的に、BクラスODNおよびCクラスODNは、IL−10産生の誘導について、高い能力を示した。非CpGコントロールおよび非CpGコントロールAクラスオリゴヌクレオチドは、IL−10の誘導を示さないか、またはIL−10の誘導についての低い能力を示した。
ヒトTLR9を発現するHEK293細胞を、示されたODN濃度でインキュベートした。NFκB刺激を、ルシフェラーゼ活性を通じて測定した。刺激指数を、CpG ODNを添加しない培地のルシフェラーゼ活性を参照して計算した(ルシフェラーゼ活性の誘導倍数)。結果を、図4に示す。10μg/mlの使用した最も高い用量における、親油性接合体を有するCpG ODNは、約20の刺激指数を誘導した。相対的に、BクラスODNは、ずっと低い濃度である0.625μg/mlにおいて、20の刺激指数を誘導した。AクラスODNは、最も低いNFκB刺激を示し、そして測定された最も高い刺激指数は、10μg/mlのODN濃度に対して5であった。
3つの供与体のヒトPBMCを、示したODNと一緒に48時間インキュベートした。上清を回収して、ELISAによってIFN−αを測定した。それぞれのODNの活性化のレベルを、−:無し;+:低い;+/++:中間;+++/++++:強いによって示し、ならびにそれぞれのODNによって誘導された最大のIFN−αの量を示す。結果を、表2に示す。
BALB/cマウス脾細胞を、示された濃度の配列番号13またはコントロールの配列番号117と一緒に24時間(図5a〜b)、または6時間(図5c)インキュベートした。SNを回収し、そしてサイトカインをELISAによって測定した。図5aに示すように、親油性接合体を有するCpG ODNは、用量依存的様式で、IL−6産生を誘導した。試験した最も高いODN濃度(10μg/ml)において測定されたIL−6応答は、約900pg/mlであった。コントロールの非CpG ODNは、全くIL−6誘導を刺激しなかった。図5bは親油性接合体を有するCpG ODNによるIL−12の誘導を示す。その親油性接合体を有するCpG ODNは、用量依存的様式で、IL−12産生を誘導し、使用した最も高いODN濃度(10μg/ml)において測定されたIL−12応答は、約3750pg/mlであった。対照的に、コントロールの非CpG ODNは、任意のIL−12産生を刺激しなかった。図5cは、コントロールの非CpG ODNと比較して、親油性接合体を有するCpG ODNは、約140pg/mlのTNF−αを誘導したが、対照的に、コントロールの非CpG ODNは、任意のTNF−α産生をほとんど誘導しなかった。
TLR9+/+マウス由来のBalb/c脾細胞(図6a)またはTLR9−/−マウス由来のBalb/c脾細胞(図6b)を、示した濃度の配列番号13、またはコントロールの配列番号117と一緒に24時間インキュベートした。SNを回収し、そしてIL−12p40をELISAによって測定した。図6aは、親油性接合体を有するCpG ODNが、IL−12用量反応を誘導し、それは、TLR依存性であったことを示す。使用した。親油性接合体を有する最も高いCpG ODNの濃度(10μg/ml)は、1200pg/mlのIL−12濃度を誘導した。対照的に、コントロールの非CpG ODNは、使用したいずれの濃度においても、任意のIL−12産生をほとんど誘導しなかった。図6bは、親油性接合体を有するCpG ODNおよびコントロールの非CpG ODNの両方が、10μg/mlの濃度においてでさえ、TLR欠乏性細胞中で任意のIL−12産生をほとんど誘導しなかったことを示す。
Balb/cマウス(n=5)に、500μgの配列番号13を皮下注射し、そしてそのマウスをODN投与の、1時間後、2時間後、3時間後、6時間後、8時間後、12時間後、および24時間後に採血した。血漿を、ELISAによって、IP−10について試験した(図7)。図7に示すように、親油性接合体を有するCpG ODNは、時間依存的様式でIP−10の産生を刺激した。注射後の最初の3時間の間は、検出可能なIP−10誘導はなかった。注射後6時間において、IP−10濃度を、500pg/mlまで増加した。注射後8時間において、IP−10刺激は、約2000pg/mlで頂点に達した。注射後12時間において、IP−10濃度は、約500pg/mlまで減少し、注射後6時間において測定された刺激と等しくなった。注射後24時間において、検出可能なIP−10産生の刺激はなかった。コントロールのPBS処置は、試験したいずれの時点においてもIP−10産生の誘導を示さなかった。
Balb/cマウス(n=3)に、500μgの配列番号13、または500μlのPBS(ネガティブコントロール)を静脈内注射し、そしてODN投与の、3時間後および8時間後に採血した。血漿は、ELISAによって、サイトカインまたはケモカインについて試験した(図8)。塗りつぶした棒=3時間;斜線の棒=8時間である。図8aは、親油性接合体を有するCpG ODNが、IP−10の産生を時間依存的様式で刺激し、それぞれ、3時間および8時間において、約9000pg/mlおよび4000pg/mlの、IP−10が刺激されたことを示す。対照的に、コントロールの非CpG ODN(配列番号117)は、同じ時点において、任意のIP−10産生を刺激しなかった。図8bは、親油性接合体を有するCpG ODNによるIL−12産生の刺激が、3時間(約20,000pg/mlのIL−12を産生した)では、8時間(約25,000pg/mlのIL−12を産生した)より、より低かったことを示す。コントロールの非CpG ODNは、試験したいずれの時点においても、任意のIL−12産生を誘導しなかった。図8cは、親油性接合体を有するCpG ODNが、時間依存的様式でIL−6の産生を刺激したことを示す。注射後3時間において、IL−6産生は、250pg/ml〜500pg/mlの範囲であったが、注射後8時間においては、そのIL−6産生は、約400pg/mlであった。コントロールの非CpG ODNは、PBSコントロールと比較して、IL−6産生の有意な誘導を示さなかった。
Claims (25)
- 免疫応答を調節するための組成物であって、以下:
(N1PN2)L
を含有し、N1およびN2は独立して、0〜100ヌクレオチド長の核酸であり、Pは、パリンドロームを含み、かつ少なくとも1つのYRジヌクレオチドを含む核酸であり、Yは、シトシンまたは修飾されたシトシンであり、そしてRは、グアニンまたは修飾されたグアニンであり、Lは、親油基であり、ここで、LはN1PN2の3’末端で該ヌクレオチドに連結されており、Lはコレステリル、修飾されたコレステリル、コレステロール誘導体、還元されたコレステロールおよび置換されたコレステロールからなる群より選択され、PはX1−Y−R−X2であり、X1およびX2は独立して、2、3または4ヌクレオチドである、組成物。 - N1PN2が、3〜14ヌクレオチド長である、請求項1に記載の組成物。
- Lが、リンカーによって、N1PN2中のヌクレオチドの2’位か、N1PN2中のヌクレオチドの複素環式塩基か、またはN1PN2中のホスホジエステル結合に連結される、請求項1に記載の組成物。
- 前記還元されたコレステロールが、コレスタンである、請求項1に記載の組成物。
- 前記式が、以下:
([N1PN2]n−X3)m)(L)p
を包含し、X3は、リンカーであり、mは、0〜20(好ましくは1〜10)の整数であり、nは、0〜20(好ましくは1〜10)の整数であり、pは、1〜10(好ましくは1)の整数であり、そして該オリゴヌクレオチドN1PN2は、4〜40ヌクレオチド長を有する、請求項1に記載の組成物。 - X3が、無塩基残基(dスペーサー)、トリエチレングリコール(スペーサー9)またはヘキサエチレングリコール(スペーサー18)のようなオリゴエチレングリコール、およびブタンジオールのようなアルカンジオールからなる群より選択される非ヌクレオチドリンカーである、請求項5に記載の組成物。
- 前記リンカーが、ホスホジエステル結合、ホスホロチオエート結合、メチルホスホネート結合、およびアミド結合からなる群より選択される結合を介して、前記オリゴヌクレオチドに結合される、請求項5に記載の組成物。
- X1が、チミジン、デオキシウリジン、および5−置換デオキシウリジンからなる群より選択されるピリミジンであり、そして/あるいはX 2 が、パリンドローム、または逆方向反復であり、該パリンドロームまたは該逆方向反復が、少なくとも1つの非メチル化CpGモチーフを含む、請求項1に記載の組成物。
- 前記オリゴヌクレオチドN1PN2が、4〜20ヌクレオチド長を有する、請求項1に記載の組成物。
- 前記オリゴヌクレオチドN1PN2が、6〜14ヌクレオチド長を有する、請求項1に記載の組成物。
- 前記オリゴヌクレオチドが、少なくとも1つの安定化したヌクレオチド間結合を含み、該安定化したヌクレオチド間結合が、YとRとの間の結合であり、そして該安定化したヌクレオチド間結合が、ホスホロチオエート結合である、請求項1に記載の組成物。
- 核酸をさらに含有する、請求項1に記載の組成物であって、
該核酸が、
(a)少なくとも1つのYRジヌクレオチド、
(b)少なくとも1つの1本鎖領域、および
(c)少なくとも1つの2本鎖領域
を含む核酸であり、該核酸は、少なくとも1つの親油基と連結されており、Yは、シトシンまたは修飾されたシトシンであり、そしてRは、グアニンまたは修飾されたグアニンであり、そして該核酸は、少なくとも1つの露出した5’末端を有する、組成物。 - 前記核酸が、少なくとも2つの親油基に連結される、請求項12に記載の組成物。
- 前記親油基が、前記核酸の3’末端でヌクレオチドに連結される、請求項12に記載の組成物。
- 免疫応答を調節するための薬学的組成物であって、請求項1〜請求項14のいずれか1項に記載の組成物を、免疫応答を調節するのに有効な量で含有する、薬学的組成物。
- 前記組成物が、被験体の喘息を処置するための、該被験体への送達に適している、請求項15に記載の薬学的組成物。
- 前記組成物が、被験体のアレルギーを処置するための、該被験体への送達に適している、請求項15に記載の薬学的組成物。
- 前記組成物が、被験体の癌を処置するための、該被験体への送達に適している、請求項15に記載の薬学的組成物。
- 前記組成物が、被験体の感染症を処置するための、該被験体への送達に適している、請求項15に記載の薬学的組成物。
- 前記組成物が、被験体の自己免疫疾患を処置するための、該被験体への送達に適している、請求項15に記載の薬学的組成物。
- 前記組成物が、被験体の気道リモデリングを処置するための、該被験体への送達に適している、請求項15に記載の薬学的組成物。
- 請求項15に記載の薬学的組成物であって、該組成物がワクチンであり、そして抗原をさらに含有する、薬学的組成物。
- 前記オリゴヌクレオチドが、該オリゴヌクレオチドの、5’末端および3’末端における、少なくとも1つのホスホロチオエートヌクレオチド間結合を含む、請求項11に記載の組成物。
- (N1PN2)L
を含有する、免疫応答を調節するための組成物であって、N1およびN2は独立して、0〜100ヌクレオチド長の核酸であり、Pは、パリンドロームを含み、かつ少なくとも1つのYRジヌクレオチドを含む核酸であり、Yは、シトシンまたは修飾されたシトシンであり、そしてRは、グアニンまたは修飾されたグアニンであり、そしてLは、コレステロールであり、ここで、LはN1PN2の3’末端で該ヌクレオチドに連結されている、組成物。 - N1PN2が、5’TCGACGTCGT3’(配列番号111)、および5’TCGACGTCGA3’(配列番号112)からなる群より選択される、請求項24に記載の組成物。
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-
2004
- 2004-09-27 CA CA002536139A patent/CA2536139A1/en not_active Abandoned
- 2004-09-27 US US10/952,254 patent/US7615539B2/en not_active Expired - Fee Related
- 2004-09-27 EP EP04789138A patent/EP1663316A2/en not_active Withdrawn
- 2004-09-27 WO PCT/US2004/031748 patent/WO2005030259A2/en active Application Filing
- 2004-09-27 AU AU2004275876A patent/AU2004275876B2/en not_active Ceased
- 2004-09-27 JP JP2006528305A patent/JP4989225B2/ja not_active Expired - Fee Related
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AU2004275876B2 (en) | 2011-03-31 |
US7615539B2 (en) | 2009-11-10 |
WO2005030259A2 (en) | 2005-04-07 |
WO2005030259A3 (en) | 2005-11-10 |
EP1663316A2 (en) | 2006-06-07 |
JP2007506790A (ja) | 2007-03-22 |
US20050130911A1 (en) | 2005-06-16 |
AU2004275876A1 (en) | 2005-04-07 |
CA2536139A1 (en) | 2005-04-07 |
US20100183639A1 (en) | 2010-07-22 |
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