JP4188687B2 - 免疫変調ポリヌクレオチド及びその使用法 - Google Patents
免疫変調ポリヌクレオチド及びその使用法 Download PDFInfo
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- JP4188687B2 JP4188687B2 JP2002553483A JP2002553483A JP4188687B2 JP 4188687 B2 JP4188687 B2 JP 4188687B2 JP 2002553483 A JP2002553483 A JP 2002553483A JP 2002553483 A JP2002553483 A JP 2002553483A JP 4188687 B2 JP4188687 B2 JP 4188687B2
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- bromocytosine
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- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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Description
本出願は、その全体を本願明細書に援用する、2000年12月27日に出願された米国特許仮出願第60/258,675号の優先権の利益を請求する。
本発明は、免疫賦活オリゴヌクレオチド配列(ISS)を含む免疫変調ポリヌクレオチドに関する。これは更に、免疫応答を変調するポリヌクレオチドの投与にも関する。
感染症又は他の抗原チャレンジに対して起こる免疫応答の型は、一般にこの反応に関連したヘルパーT(Th)細胞のサブセットにより特徴付けることができる。Th1サブセットは、遅発型過敏症及び細胞傷害性Tリンパ球(CTL)の活性化のような古典的細胞媒介型機能に寄与しているのに対し、Th2サブセットは、B細胞活性化のヘルパーとしてより効果的に機能する。抗原に対する免疫応答の型は、一般に抗原に対して反応している細胞により産生されたサイトカインにより影響される。Th1及びTh2細胞により分泌されたサイトカインの差異は、これら2種のサブセットの異なる生物学的機能を反映していると考えられる。例えば、Romagnani、Ann. Allergy Asthma Immunol.、85:9-18 (2000)を参照のこと。
別の局面において、本願明細書に開示されたISSのいずれかに関して、本発明の免疫変調ポリヌクレオチドは更に、1個又は複数のTCGA及び/又はT、5-ブロモシトシン、G、A配列(複数)を含むことができる。
別の局面において、本発明は、マイクロキャリア、特にサイズが10μm未満のマイクロキャリアへ連結された本発明の免疫変調ポリヌクレオチドを含む免疫変調ポリヌクレオチド/マイクロキャリア複合体を提供する。
本発明者らは、免疫賦活配列(ISS)を含む免疫変調ポリヌクレオチド、及びこれらの免疫変調ポリヌクレオチドを用い、個体、特にヒトにおいて、免疫応答を変調する方法を発見した。本発明の組成物は、本願明細書に説明されたようなISSを含む免疫変調ポリヌクレオチドを含有する。本発明の一部の免疫変調ポリヌクレオチドは更に、少なくとも1個のTCG又はT、5-ブロモシトシン、G配列を含む。一部の免疫変調ポリヌクレオチドにおいて、追加のTCG及び/又はT、5-ブロモシトシン、G配列(複数)は、ISSの5'末端へのT又はTC又はT、5-ブロモシトシンの付加により作出される。本発明者らは、特異的ISSを含む免疫変調ポリヌクレオチドは、効率的にヒト細胞を含む免疫細胞を変調することを発見した。本発明者らの発見は、ヒト細胞は、通常使用される実験動物、例えばマウス由来の細胞よりも、免疫変調ポリヌクレオチドによる免疫変調に対してより抵抗性があるので、特に興味深い。本発明者らは、本発明の一部のポリヌクレオチドは、例えヒト細胞においてであっても、効率的にIFN-αを刺激することも認めた。
更に本発明のISS-含有ポリヌクレオチドを備えるキットが提供される。これらのキットは更に、対象において免疫変調するための本発明の免疫変調ポリヌクレオチドの投与及び免疫変調ポリヌクレオチドに関する取扱説明書を備える。
本発明の実践は、特に言及しない限りは、当該技術分野の範囲内である、分子生物学(組換え技術を含む)、微生物学、細胞生物学、生化学及び免疫学の通常の技術を使用するであろう。このような技術は、文献において完全に説明されており、これは例として、Molecular Cloning: A Laboratory Manual、第2版(Sambrookら、1989);Oligonucleotide Synthesis(M.J. Gait編集、1984);Animal Cell Culture(R.I. Freshney編集、1987);Handbook of Experimental Immunology(D.M. Weir及びC.C. Blackwell編集);Gene Transfer Vectors for Mammalian Cells(J.M. Miller及びM.P. Calos編集、1987);Current Protocols in Molecular Biology(F.M. Ausubelら編集、1987);PCR: The Polymerase Chain Reaction、(Mullisら編集、1994);Current Protocols in Immunology(J.E. Coliganら編集、1991);The Immunoassay Handbook(D. Wild編集、Stockton Press NY、1994);Bioconjugate Techniques(Gr例えば T. Hermanson編集、Academic Press社、1996);及び、Methods of Immunological Analysis(R. Masseyeff、W.H. Albert、及びN.A. Staines編集、Weinheim:VCH Verlags gesellschaft社、1993)を含む。
本願明細書において使用される単数形「ひとつの(a、an)」、及び「この(the)」は、特に記さない限りは、複数の意味も含む。例えば、「ひとつの(an)」ISSは、1種又は複数のISSを含む。
本願明細書において互換的に使用される用語「ポリヌクレオチド」及び「オリゴヌクレオチド」は、1本鎖DNA(ssDNA)、2本鎖DNA(dsDNA)、1本鎖RNA(ssRNA)及び2本鎖RNA(dsRNA)、修飾されたオリゴヌクレオチド及びオリゴヌクレオチド又はそれらの組合せを含む。このオリゴヌクレオチドは、直鎖状又は環状の形状であることができ、もしくはこのオリゴヌクレオチドは、直鎖状又は環状の両セグメントを含むことができる。オリゴヌクレオチドは、一般にホスホジエステル連結を介して結合されたヌクレオシドのポリマーであるが、代わりの連結、例えばホスホロチオエートエステルも、オリゴヌクレオチドにおいて使用することができる。ヌクレオシドは、糖に結合した、プリン(アデニン(A)又はグアニン(G)もしくはそれらの誘導体)又はピリミジン(チミン(T)、シトシン(C)又はウラシル(U)、もしくはそれらの誘導体)塩基である。DNA中の4種のヌクレオシド単位(又は塩基)は、デオキシアデノシン、デオキシグアノシン、デオキシチミジン、及びデオキシシチジンと称されている。ヌクレオチドは、ヌクレオシドのリン酸エステルである。
用語「5’」は一般に、同じポリヌクレオチド又はオリゴヌクレオチドの別の領域又は位置から5'側(上流)のポリヌクレオチド又はオリゴヌクレオチドの領域又は位置を意味する。
「抗原-特異的免疫療法」は、抗原に関連し、かつ免疫応答の抗原-特異的変調を生じるような免疫療法を意味する。アレルギーの状況において、抗原-特異的免疫療法は脱感作療法を含むが、これらに限定されるものではない。
本願明細書において使用される用語「共投与」は、免疫応答を変調するために、十分に近い時間に、少なくとも2種の異なる物質を投与することを意味する。好ましくは、共投与は、少なくとも2種の異なる物質の同時投与を意味する。
「Th2-関連抗体」は、その産生及び/又は増加がTh2免疫応答に関連している抗体である。例えば、IgG1は、マウスのTh2-関連抗体である。本発明の目的に関して、Th2-関連抗体の測定値は、1種又は複数のこのような抗体の測定値であることができる。例えば、ヒトにおいて、Th2-関連抗体の測定値は、IgG2及び/又はIgG4の測定値を必然的に伴う。
本願明細書において使用される用語「含有する(comprising)」及びその同族語は、それらの包括的意味において使用され;すなわち用語「含む(including)」及びそれに相当する同族語と同等である。
本発明は、個体における免疫応答を変調するための免疫賦活配列(ISS)及び免疫変調ポリヌクレオチド(IMP)を提供する。各免疫変調ポリヌクレオチドは、少なくとも1個の免疫賦活配列(ISS)を含む。
本発明に従い、免疫変調ポリヌクレオチドは、少なくとも1個のISSを含み、かつ複数のISSを含むことができる。これらのISSは、このポリヌクレオチド内で隣接することができ、もしくはこのポリヌクレオチド内で追加のヌクレオチド塩基により隔てることができ、もしくはこのポリヌクレオチド内で重複することができる。ある態様において、免疫変調ポリヌクレオチドは、ISSからなる。
5'-X1 X2 A X3 C G X4 T C G-3' (配列番号:62)
(式中、X1は、T、G、C又はZであり(Z=5-ブロモシトシン);
X2は、T、G、A又はUであり;
X3は、T、A又はCであり;
X4は、T、G又はUである。);及び、
ISSは、5'-TGAACGTTCG-3' (配列番号:63)又は5'-GGAACGTTCG-3' (配列番号:64)ではない。
一部の態様において、免疫変調ポリヌクレオチドは、配列5'-TCGTCGAACGTTCGTTAACGTTCG-3' (配列番号:1)を含む。
5'-TGACTGTGAACGUTCGAGATGA-3' (配列番号:2);
5'-TCGTCGAUCGUTCGTTAACGUTCG-3' (配列番号:3);
5'-TCGTCGAUCGTTCGTUAACGUTCG-3' (配列番号:4);
5'-TCGTCGUACGUTCGTTAACGUTCG-3' (配列番号:5);
5'-TCGTCGAXCGUTCGTTAACGUTCG-3' (配列番号:6)、ここでX=2-アミノ-アデニン;
5'-TGATCGAACGTTCGTTAACGTTCG-3 (配列番号:7);
5'-TGACTGTGAACGUTCGGTATGA-3' (配列番号:8);
5'-TGACTGTGACCGTTCGGTATGA-3' (配列番号:9);
5'-TGACTGTGATCGGTCGGTATGA-3' (配列番号:10);
5'-TCGTCGTGAACGTTCGAGATGA-3' (配列番号:12);
5'-TCGTCGGTATCGGTCGGTATGA-3' (配列番号:13);
5'-CTTCGAACGTTCGAGATG-3' (配列番号:14);
5'-CTGTGATCGTTCGAGATG-3' (配列番号:15);
5'-TGACTGTGAACGGTCGGTATGA-3' (配列番号:16);
5'-TCGTCGGTACCGTTCGGTATGA-3' (配列番号:17);
5'-TCGTCGGAACCGTTCGGAATGA-3' (配列番号:18);
5'-TCGTCGAACGTTCGAGATG-3' (配列番号:19);
5'-TCGTCGTAACGTTCGAGATG-3' (配列番号:20);
5'-TGACTGTGACCGTTCGGAATGA-3' (配列番号:21);
5'-TCGTCGAACGTTCGAACGTTCG-3' (配列番号:22);
5'-TCGTZGAACGTTCGAGATG-3' (配列番号:24)、ここでZ=5-ブロモシトシン;
5'-TCGTCGACCGTTCGGAATGA-3' (配列番号:25);
5'-TZGTZGACCGTTCGGAATGA-3' (配列番号:26)、ここでZ=5-ブロモシトシン;
5'-TCGTZGACCGTTCGGAATGA-3' (配列番号:27)、ここでZ=5-ブロモシトシン;
5'-TTCGAACGTTCGTTAACGTTCG-3' (配列番号:28);
5'-CTTZGAACGTTCGAGATG-3' (配列番号:29)、ここでZ=5-ブロモシトシン;
5'-TGATCGTCGAACGTTCGAGATG-3' (配列番号:30);
5'-TCGTCGAACGTTCGAGATGAT-3' (配列番号:132)。
5'-X1 X2 A X3 Z G X4 T C G-3' (配列番号:65)
(式中、Zは5-ブロモシトシンであり、X1は、T、G、C又はZ(Z=5-ブロモシトシン)、X2は、T、G、A又はUであり、X3は、T、A又はCであり、X4は、T、G又はUである。)、ここでISSは、5'-TGAAZGTTCG-3' (配列番号:66;Z=5-ブロモシトシン)ではない。
5'-TGACTGTGAAZGUTCGAGATGA-3' (配列番号:31);
5'-TCGTCGAAZGTTCGTTAAZGTTCG-3' (配列番号:32);
5'-TGACTGTGAAZGUTCGGTATGA-3' (配列番号:33);
5'-TGACTGTGAAZGUTCGGAATGA-3' (配列番号:34);
5'-TCGTCGGAAAZGUTCGGAATGA-3' (配列番号:35);
5'-TCGTZGAAZGUTCGGAATGA-3' (配列番号:36)。
5'-X1 X2 A X3 C G X4 T C G-3'(配列番号:133)
(式中X1はT、C又はZであり(Z=5-ブロモシトシン)、X2は、T、G、A又はUであり、X3は、T、A又はCであり、X4は、T、G又はUであり、ここで式は、5'-TGAACGTTCG-3'(配列番号:63)ではない。
5'-TGACTGTGAAZGTTCGAGATGA-3' (配列番号:37);
5'-TGACTGTGAAZGTTZGAGATGA-3' (配列番号:38);
5'-TGACTGTGAAZGTTCCAGATGA-3' (配列番号:39);
5'-TGACTGTGAACGTUCGAGATGA (配列番号:40);
5'-TGACTGTGAACGXTCGAGATGA-3' (配列番号:41)、ここでZ=5-ブロモシトシン;
5'-TGACTGTGAAZGTTCGTUATGA-3' (配列番号:42);
5'-TGACTGTGAAZGTTCGGTATGA-3' (配列番号:43);
5'-CTGTGAACGTTCGAGATG-3' (配列番号:44);
5'-TCGTZGTGAACGTTCGAGATGA-3' (配列番号:46);
5'-TGACTGTGAACGXTCGAGATGA-3' (配列番号:47)、ここでX=4-チオ-チミンであり;
5'-TGACTGTGAACXTTCXAGATGA-3' (配列番号:48)、ここでX=6-チオ-グアニンであり;
5'-TGACTGTGAACGTTCGTUATGA-3' (配列番号:49);
5'-TGACTGTGAACGTTCGTTATGA-3' (配列番号:50);
5'-TCGTTCAACGTTCGTTAACGTTCG-3' (配列番号:51);
5'-TGATTCAACGTTCGTTAACGTTCG-3' (配列番号:52);
5'-TCGTCGGAACGTTCGAGATG-3' (配列番号:55);
5'-TCGTCGGACGTTCGAGATG-3' (配列番号:56);
5'-TCGTCGTACGTTCGAGATG-3' (配列番号:57);
5'-TCGTCGTTCGTTCGAGATG-3' (配列番号:58)。
5'-(TCG)w Ny A X3 C G X4 T C G-3' (配列番号:126)
(式中、wは1-2であり、yは0-2であり、Nはいずれかの塩基であり、X3は、T、A又はCであり、X4は、T、G又はUである。)。このようなISS配列を含む免疫変調ポリヌクレオチドは、配列番号:1、11、12、13、17、18、14、19、55、20、22、25、28及び30を含むが、これらに限定されるものではない。
TCGAACGTTCG (配列番号:102)、TCGTCGAACGTTCG (配列番号:98)、TCGTGAACGTTCG (配列番号:103)、TCGGTATCGGTCG (配列番号:104)、TCGGTACCGTTCG (配列番号:105)、TCGGAACCGTTCG (配列番号:106)、TCGGAACGTTCG (配列番号:107)、TCGTCGGAACGTTCG (配列番号:108)、TCGTAACGTTCG (配列番号:109)、TCGTCGGAACGTTCG (配列番号:108)、TCGACCGTTCG (配列番号:110)、TCGTCGACCGTTCG (配列番号:111)、TCGTTAACGTTCG (配列番号:101)。
5'-(TXG)z Ny A X3 C G X4 T C G-3' (配列番号:127)
(式中zは1-2であり、yは0-2であり、Xは5-ブロモシトシンであり、Nは塩基のいずれかであり、X3は、T、A又はCであり、X4は、T、G又はUである。)。このようなISS配列を含む免疫変調ポリヌクレオチドは、配列番号:45、23、26及び29を含むが、これらに限定されるものではない。
5'-T C G T X G Ny A X3 C G X4 T C G-3'(配列番号:128)
(式中、yは0-2であり、Xは5-ブロモシトシンであり、Nは塩基のいずれかであり、X3は、T、A又はCであり、X4は、T、G又はUである。)。このようなISS配列を含む免疫変調ポリヌクレオチドは、配列番号:46、24及び27を含むが、これらに限定されるものではない。
5'-(TCG)w Ny A X3 X G X4 T C G-3' (配列番号:129)
(式中、wは1-2であり、yは0-2であり、Nは塩基のいずれかであり、X3は、T、A、又はCであり、Xは5-ブロモシトシンであり、X4は、T、G又はUである。)。このようなISS配列を含む免疫変調ポリヌクレオチドは、配列番号:35を含むが、これらに限定されるものではない。一部の態様において、このISSは、配列TCGGAAAXGTTCG (配列番号:120)又はTCGAAXGTTCG (配列番号:121)を含み、ここでXは5-ブロモシトシンである。
5'-(TXG)z Ny A X3 X G X4 T C G-3' (配列番号:130)
(式中、zは1-2であり、yは0-2であり、Xは5-ブロモシトシンであり、Nは塩基のいずれかであり、X3はT、A又はCであり、X4はT、G又はUである。)。一部の態様において、このISSは、配列TXGAAXGUTCG (配列番号:122)又はTXGAAXGTTCG (配列番号:123)を含み、ここでXは5-ブロモシトシンである。
5'-T C G T X G Ny A X3 X G X4 T C G-3' (配列番号:131)
(式中、yは0-2であり、Xは5-ブロモシトシンであり、Nは塩基のいずれかであり、X3はT、A又はCであり、X4はT、G又はUである。)。このようなISS配列を含む免疫変調ポリヌクレオチドは、配列番号:36を含むが、これらに限定されるものではない。一部の態様において、このISSは、配列TCGTXGAAXGUTCG (配列番号:124)又はTCGTXGAAXGTTCG (配列番号:125)を含み、ここでXは5-ブロモシトシンである。
抗原は、免疫変調ポリヌクレオチドと共投与することができ、及び/又は免疫変調ポリヌクレオチド及び抗原を含有する組成物において(及びこれらの組成物の調製において)使用することができる。
抗原は、当該技術分野において公知の精製技術を用いて、それらの給源から単離することができ、より都合がよいことには、組換え法を用いて作出することができる。
抗原と共に使用する場合、ISSは、多くの方法で抗原と共に投与することができる。一部の態様において、ISS-含有ポリヌクレオチド及び抗原は、互いに空間的近傍で、又は混合して(すなわち、溶液中)投与することができる。以下に説明するように、空間的近傍は、多くの方法により達成することができ、これは複合(連結)、キャプシド封入、プラットフォームへの付着(affixation)又は表面への吸着による。一般に、及び最も好ましくは、ISS-含有ポリヌクレオチド及び抗原は、ISS及び抗原の混合物としての投与と比べ、生じた免疫応答が増強されるのに有効な距離で近傍に会合されている。
非-共有的に連結された複合体は、ビオチン-ストレプトアビジン複合体のような非-共有的相互作用を含むことができる。ビオチニル基は、例えば、ISSの修飾された塩基へ結合することができる。Rogetら、Nucleic Acids Res.、17:7643-7651 (1989)。ストレプトアビジン残基のペプチド部分への組込みは、ストレプトアビジンが複合したペプチド及びビオチニル化されたオリゴヌクレオチドの非-共有的に結合した複合体の形成を可能にする。
更に被包組成物は、多種多様な成分により構成される。これらは、ミョウバン、脂質、リン脂質、脂質膜構造(LMS)、ポリエチレングリコール(PEG)、及び他のポリマー、例えばポリペプチド、糖ペプチド、及び多糖などを含むが、これらに限定されるものではない。
本発明の組成物を被包する際に使用するためのPEGは、化学物質供給業者から購入するか、もしくは当業者に公知の技術を使用し合成するかのいずれかである。
R1S(CH2CH2O)nCH2CH2O(CH2)mCO2R2(式中、n=0-200、m=1又は2であり、R1=H又は保護基、例えばトリチルであり、R2=H又はアルキル又はアリールであり、例えば、4-ニトロフェニルエステルである。)。これらのリンカーは、アミド結合を介したアミノ基を含む第二分子へのチオエーテルを介して、ハロアセチル、マレインアミドなどのようなチオール反応基を含む分子の結合において有用である。これらのリンカーは、結合の順番に関して柔軟であり、すなわちチオエーテルは最初又は最後に形成することができる。
ISS-含有ポリヌクレオチドは、免疫変調ポリヌクレオチド/マイクロキャリア(IMP/MC)複合体の形で投与することができる。従って、本発明は、IMP/MC複合体を含有する組成物を提供する。
本発明において有用なマイクロキャリアは、サイズが約150、120又は100μmであり、より一般的には約50〜60μm未満のサイズであり、好ましくは約10μm未満のサイズであり、かつ純水には不溶性である。本発明において使用されるマイクロキャリアは、好ましくは生分解性であるが、非生分解性マイクロキャリアも許容できる。マイクロキャリアは、通常「ビーズ」又は他の粒子のような固相であるが、生分解性ポリマー又は油分を含有する水中油乳剤のような液相のマイクロキャリアも企図されている。マイクロキャリアとしての使用が許容できる多種多様な生分解性及び非生分解性材料は、当該技術分野において公知である。
本発明は、本願明細書に説明したように、個体へISS-含有ポリヌクレオチドを投与することを含む、個体、好ましくは哺乳類、より好ましくはヒトにおいて、免疫応答を変調する方法を提供する。免疫変調は、Th1-型免疫応答の賦活及び/又はTh2-型免疫応答の阻害又は減弱を含むことができる。ISS-含有ポリヌクレオチドは、免疫応答を変調するのに十分な量で投与される。本願明細書に説明されたように、免疫応答の変調は、体液性及び/又は細胞性であることができ、かつ当該技術分野における標準の技術を用い及び本願明細書において説明されたように測定される。
本願明細書に説明されたように、ISS-含有ポリヌクレオチドは、その他の医薬物質及び/又は免疫原性物質及び/又は免疫賦活物質と一緒に投与することができ、かつそれらの生理的に許容できる担体と一緒にすることができる(従って本発明はこれらの組成物を含む)。ISS-含有ポリヌクレオチドは、本願明細書に説明されたもののいずれかであることができる。
従って、ISS-含有ポリヌクレオチドは、サイトカイン、アジュバント及び抗体を含むが、これらに限定されるものではない他の免疫療法剤と組合せて投与することができる。
本発明はキットを提供する。ある態様において、本発明のキットは、一般に本願明細書に説明されたような、ISS-含有ポリヌクレオチドを含む1個又は複数の容器を備える。これらのキットは更に、本願明細書に説明された方法(例えば、免疫変調、感染症の1種又は複数の症状の回復、IFN-γレベルの増加、IFN-αレベルの増加、又はIgE-関連障害の回復)のいずれかのための、ISS-含有ポリヌクレオチドの使用に関する取扱説明書の適当なセット、通常は書面による取扱説明書を備えることができる。
下記実施例は、本発明を例証するために提供されるが、限定するものではない。
実施例1:マウス細胞のISS-含有ポリヌクレオチドによる免疫変調
免疫変調ポリヌクレオチド(すなわち、ISSを含有する)又は対照ポリヌクレオチド(すなわち、ISSを伴わない)を、マウス脾細胞に対する免疫変調活性についてアッセイした。試験したポリヌクレオチドは、完全に修飾されたホスホロチオエートオリゴデオキシヌクレオチドであった。試験したポリヌクレオチドは、5'-TGACTGTGAACGTTCGAGATGA-3' (配列番号:59)(陽性対照)及び5'-TGACTGTGAACCTTAGAGATGA-3' (配列番号:60)(陰性対照)を使用した。
免疫変調ポリヌクレオチド(すなわち、ISSを含有する)、又はISSを伴わないポリヌクレオチド(5'-TGACTGTGAACCTTAGAGATGA-3 (配列番号:60)及び5'-TGACTGTGAAGGTTAGAGATGA-3' (配列番号:61))、SAC及び培地単独を含む対照試料を、ヒト末梢血単核細胞(PBMC)に対する免疫変調活性について試験した。試験したポリヌクレオチドは、完全に修飾されたホスホロチオエートオリゴデオキシヌクレオチドであった。
本発明のISS-含有ポリヌクレオチドの存在下におけるB型肝炎表面抗原(HBsAg)の投与に対する免疫応答を、ヒヒにおいて試験した。
HBsAgは、酵母において産生した組換えHBsAgであった。ヒヒ群(1群につき動物5匹)は、試験開始時に体重範囲が8〜31kg(群平均体重は13〜16kg)である雄及び雌のヒヒを含んだ。
全ての動物の血液を、免疫感作前、及び免疫感作後2週目に採取した。抗-HBsAg IgG力価は、下記のように測定した。ヒヒ血清試料は、AUSAB EIA市販キット(Abbott Labs社カタログ番号9006-24及び1459-05)により、ヒト血漿由来のHBsAgで被覆したビーズを用いて、分析した。試料は、0〜150mIU/mlの範囲の、ヒト血漿由来のHBsAg陽性及び陰性標準のパネルに沿って試験した。ビオチン複合したHBsAg及びウサギの抗-ビオチン-HRP複合した抗体は、検出に使用した二次抗体複合体として使用した。このアッセイは、オルト-フェニレンジアミン(OPD)で発色し、かつ吸光度を492nmで決定し600nmのバックグラウンドを減算した(Quantum II分光光度計、Abbott Labs社)。標本の吸光度値を用い、対応する濃度の抗-HBsAgを、1ml当たりのミリ国際単位/(mIU/ml)で、製造業者により確立されたパラメーターに従った検量線から決定した。希釈した標本について、定量は、0〜150mIU/mlの間の値を生じた標本吸光度を基に、希釈係数を掛け、最終濃度を得た。
第1群−20μg HBsAg;
第2群−20μg HBsAg + 1000μg 配列番号:59 (ISS);
第3群−20μg HBsAg + 1000μg 配列番号:60 (非-ISS);
第4群−20μg HBsAg + 1000μg 配列番号:38(ISS);
第5群−20μg HBsAg + 1000μg 配列番号:2 (ISS);
第6群−20μg HBsAg + 1000μg 配列番号:18 (ISS);
第7群−20μg HBsAg + 1000μg 配列番号:35 (ISS);
カチオン性ポリ(乳酸、グリコール酸)(PLGA)ミクロスフェアを、下記のように調製した。固有粘度0.41dl/g(0.1%クロロホルム、25℃)を持つポリ(D,L-ラクチド-コ-グリコリド)50:50ポリマー0.875gを、10%w/w濃度の塩化メチレン7.875gに、DOTAP 0.3gと共に溶解した。その後透明な有機相を、ポリビニルアルコール(PVA)水溶液(0.35%w/v)500mlに乳化し、実験用ミキサー(Silverson L4R、Silverson Instruments社)を用い、4000rpmで30分間室温でホモジネートした。その後システム温度を、温水を混合容器の外套を通して循環させることにより40℃に上昇した。同時に、攪拌速度を1500rpmに低下し、かつこれらの条件を2時間維持し抽出し、かつ塩化メチレンを蒸発させた。ミクロスフェア懸濁液を、冷水の循環を使って、室温に冷却した。
ポリヌクレオチドは、ヒトPBMCアッセイにおいて、免疫変調活性について、単独で及びカチオン性PLGAミクロスフェア(cPLGA)と複合して試験した。このヒトPBMCアッセイは、実施例2に説明したように行った。カチオン性PLGAミクロスフェアは、実施例4に説明したように調製した。ポリヌクレオチドは、単独物質として、又はcPLGAミクロスフェアとの組合せにおいて試験した。試験したポリヌクレオチドは、配列番号:59、60、1、及び132であった。全てのポリヌクレオチドは、100%のホスホロチオエート連結を含み、かつ20μg/mlの濃度で試験した。このcPLGAは、100μg/mlの濃度で添加した。ポリヌクレオチドをcPLGAで試験する際には、このポリヌクレオチド及びcPLGAは、室温で15分間予備混合し、その後この培養物に添加した。SAC(PANSORBIN(登録商標)CalBiochem、1/5000希釈)及びIMP(ISS-含有)、配列番号:59を、陽性対照として用い、かつ対照ポリヌクレオチドである配列番号:60及び細胞単独を、陰性対照として使用した。カチオン性PLGAも単独で試験した。SACは、Staph. Aureus (Cowan I)細胞物質を含んだ。試料は、1回のアッセイにつき4名の健常ドナーにおいてアッセイした。
Claims (42)
- 免疫賦活配列(ISS)を含む免疫変調ポリヌクレオチドであって、ここでISSは下記式:
5'-X1 X2 A X3 C G X4 T C G-3' (配列番号:62)
(式中、
X1は、T、G、C又はZであり、ここでZは5-ブロモシトシンであり;
X2は、T、G、A又はUであり;
X3は、T、A又はCであり;
X4は、T、G又はUであり;
但し、当該式は、5'-TGAACGTTCG-3' (配列番号:63)又は5'-GGAACGTTCG-3' (配列番号:64)ではない)
を含み、
上記免疫変調ポリヌクレオチドが、上記ISSの5’末端に直接又は間接的に隣接するTCG配列を含み、そしてさらに
当該免疫変調ポリヌクレオチドが、長さ25未満の塩基又は塩基対である、前記免疫変調ポリヌクレオチド。 - 免疫賦活配列(ISS)を含む免疫変調ポリヌクレオチドであって、ここでISSは下記式:
5'-X1 X2 A X3 C G X4 T C G-3' (配列番号:62)
(式中、
X1は、T、G、C又はZであり、ここでZは5-ブロモシトシンであり;
X2は、T、G、A又はUであり;
X3は、T、A又はCであり;
X4は、T、G又はUであり;
但し、当該式は、5'-TGAACGTTCG-3' (配列番号:63)又は5'-GGAACGTTCG-3' (配列番号:64)ではない)
を含み、
上記免疫変調ポリヌクレオチドが、上記ISSの5’末端に直接又は間接的に隣接するTZG配列(ここで、Zは5-ブロモシトシンである)を含み、
当該免疫変調ポリヌクレオチドが、長さ25未満の塩基又は塩基対である、前記免疫変調ポリヌクレオチド。 - 前記ISSが、TGAACGUTCG (配列番号:67)、TGACCGTTCG (配列番号:68)、TGATCGGTCG (配列番号:69)、TGATCGTTCG (配列番号:70)、TGAACGGTCG (配列番号:71)、GTAACGTTCG (配列番号:72)、GTATCGGTCG (配列番号:73)、GTACCGTTCG (配列番号:74)、GAACCGTTCG (配列番号:75)、ZGACCGTTCG (配列番号:76)(式中Zは5-ブロモシトシンである。)、CGAACGTTCG (配列番号:77)、CGACCGTTCG (配列番号:78)、ZGAACGTTCG (配列番号:79)(式中Zは5-ブロモシトシンである。)、TTAACGUTCG (配列番号:80)、TUAACGUTCG (配列番号:81)及びTTAACGTTCG (配列番号:82)からなる群より選択される、請求項1又は2記載の免疫変調ポリヌクレオチド。
- 前記ISSが、TGAACGUTCG (配列番号:67)、GAACCGTTCG (配列番号:75)、CGAACGTTCG (配列番号:77)、及びTTAACGTTCG (配列番号:82)からなる群から選択される、請求項3記載の免疫変調ポリヌクレオチド。
- 配列番号:1、3〜7、11〜14、17〜20、22、24、25、27、28、46、55及び132からなる群から選択される配列を含む、請求項1記載の免疫変調ポリヌクレオチド。
- 配列番号 : 23、24、26及び27からなる群から選択される配列を含む、請求項2記載の免疫変調ポリヌクレオチド。
- 免疫賦活配列(ISS)を含む、免疫変調ポリヌクレオチドであって、ここでISSは下記式:
5'-X1 X2 A X3 Z G X4 T C G-3' (配列番号:65)
(式中、
Zは5-ブロモシトシンであり;
X1は、T、G、C又はZであり、ここでZは5-ブロモシトシンであり;
X2は、T、G、A又はUであり;
X3は、T、A又はCであり;
X4は、T、G又はUであり、
但し、当該式は、5'-TGAAZGTTCG-3' (配列番号:66)ではなく、ここで、Zは5-ブロモシトシンである)を含み、そしてさらに
上記免疫変調ポリヌクレオチドが、上記ISSの5’末端に直接又は間接的に隣接するTCG配列を含み、
当該免疫変調ポリヌクレオチドが、長さ25未満の塩基又は塩基対である、前記免疫変調ポリヌクレオチド。 - 免疫賦活配列(ISS)を含む、免疫変調ポリヌクレオチドであって、ここでISSは下記式:
5'-X1 X2 A X3 Z G X4 T C G-3' (配列番号:65)
(式中、
Zは5-ブロモシトシンであり;
X1は、T、G、C又はZであり、ここでZは5-ブロモシトシンであり;
X2は、T、G、A又はUであり;
X3は、T、A又はCであり;
X4は、T、G又はUであり、
但し、当該式は、5'-TGAAZGTTCG-3' (配列番号:66)ではなく、ここで、Zは5-ブロモシトシンである)を含み、
上記免疫変調ポリヌクレオチドが、上記ISSの5’末端に直接又は間接的に隣接するTZG配列(ここで、Zは5-ブロモシトシンである)を含み、
当該免疫変調ポリヌクレオチドが、長さ25未満の塩基又は塩基対である、前記免疫変調ポリヌクレオチド。 - 前記ISSが、TGAAZGUTCG (配列番号:83)、TGACZGTTCG (配列番号:84)、TGATZGGTCG (配列番号:85)、GTATZGGTCG (配列番号:86)、GTACZGTTCG (配列番号:87)、GAACZGTTCG (配列番号:88)、GAAAZGUTCG (配列番号:89)、ZGACZGTTCG (配列番号:90)、CGAAZGTTCG (配列番号:91)、ZGAAZGTTCG (配列番号:92)、ZGAAZGUTCG (配列番号:93)、TTAAZGUTCG (配列番号:94)、TUAAZGUTCG (配列番号:95)及びTTAAZGTTCG (配列番号:96)からなる群から選択され、ここでZは5-ブロモシトシンである、請求項7又は8記載の免疫変調ポリヌクレオチド。
- 前記ISSが、ZGAAZGUTCG (配列番号:93)及びGAAAZGUTCG (配列番号:89)からなる群から選択され、ここでZは5-ブロモシトシンである、請求項9記載の免疫変調ポリヌクレオチド。
- 配列番号:35及び配列番号:36からなる群から選択される配列を含む、請求項7記載の免疫変調ポリヌクレオチド。
- 前記ISSの5’末端に間接的に隣接するTCG配列が、当該TCG配列の3'末端にAを含む、請求項1又は請求項7記載の免疫変調ポリヌクレオチド。
- 前記ISSの5’末端に間接的に隣接するTZG配列が、当該TZG配列の3'末端にAを含む、請求項2又は請求項8記載の免疫変調ポリヌクレオチド。
- 前記免疫変調ポリヌクレオチドが1本鎖である、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチド。
- 前記免疫変調ポリヌクレオチドが2本鎖である、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチド。
- 前記免疫変調ポリヌクレオチドが安定化されている、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチド。
- 前記ポリヌクレオチドがホスホロチオエート結合を含む、請求項16記載の免疫変調ポリヌクレオチド。
- 請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチドを含有する、免疫変調組成物。
- 医薬として許容できる賦形剤を更に含有する、請求項18記載の免疫変調組成物。
- 抗原を更に含む、請求項18記載の免疫変調組成物。
- 医薬として許容できる賦形剤を更に含有する、請求項20記載の免疫変調組成物。
- 生分解性マイクロキャリア(MC)に連結された請求項1又は 2に記載のポリヌクレオチドを含み、ここで該MCはサイズが10μm未満である、免疫変調ポリヌクレオチド/マイクロキャリア(IMP/MC)複合体。
- 生分解性マイクロキャリア(MC)に連結された請求項7 又は 8記載のポリヌクレオチドを含み、ここで該MCはサイズが10μm未満である、免疫変調ポリヌクレオチド/マイクロキャリア(IMP/MC)複合体。
- 個体における免疫応答を変調するための医薬組成物であって、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチドを、該個体の免疫応答を変調するのに十分量で含む、前記医薬組成物。
- 前記個体が、Th2-型免疫応答に関連した障害に罹患している、請求項24記載の医薬組成物。
- 前記Th2-型免疫応答に関連した障害が、アレルギー又は喘息である、請求項25記載の医薬組成物。
- 前記個体が感染症を有する、請求項24記載の医薬組成物。
- 個体におけるインターフェロン - γ (IFN- γ ) の増加するための医薬組成物であって、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチドを、個体においてIFN-γを増加するのに十分量で含む、前記医薬組成物。
- 前記個体が特発性肺線維症を有する、請求項28記載の医薬組成物。
- 個体においてインターフェロン - α (IFN- α ) を増加するための医薬組成物であって、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチドを、個体においてIFN-αを増大するのに十分量で含む、前記医薬組成物。
- 前記個体がウイルス感染症を有する、請求項30記載の医薬組成物。
- 個体においてインターフェロン - α (IFN- α ) を増加するための医薬組成物であって、請求項12記載の免疫変調ポリヌクレオチドを、個体においてIFN-αを増大するのに十分量で含む、前記医薬組成物。
- 前記個体がウイルス感染症を有する、請求項32記載の医薬組成物。
- 個体における感染症の症状を回復するための医薬組成物であって、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチドを有効量で含み、ここで有効量は該感染症の症状を回復するのに十分な量である、前記医薬組成物。
- 前記感染症が、細胞病原体により引き起された感染症である、請求項34記載の医薬組成物。
- 前記細胞病原体により引き起された感染症が、マイコバクテリア疾患、マラリア、リーシュマニア症、トキソプラズマ症、住血吸虫又は肝ジストマ症からなる群より選択される、請求項35記載の医薬組成物。
- 個体においてIgE-関連障害の症状を回復する医薬組成物であって、請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチドを有効量で含み、ここで該有効量がIgE-関連障害の症状を回復するのに十分な量である、前記医薬組成物。
- 前記IgE-関連障害がアレルギーである、請求項37記載の医薬組成物。
- 前記IgE-関連障害がアレルギー関連障害である、請求項37記載の医薬組成物。
- 前記IgE-関連障害が喘息である、請求項37記載の医薬組成物。
- 請求項 1 、 2 、 7 、又は 8 のいずれか一項に記載の免疫変調ポリヌクレオチドを備えるキット。
- 更に個体の免疫変調のための免疫変調ポリヌクレオチドの使用に関する取扱説明書を備える、請求項41記載のキット。
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CN1483079A (zh) | 2004-03-17 |
EP1364010B1 (en) | 2010-06-16 |
ES2347525T3 (es) | 2010-11-02 |
US20030049266A1 (en) | 2003-03-13 |
CA2430691A1 (en) | 2002-07-04 |
ATE471374T1 (de) | 2010-07-15 |
DE60142410D1 (de) | 2010-07-29 |
WO2002052002A2 (en) | 2002-07-04 |
NZ526322A (en) | 2005-06-24 |
AU2002231336B2 (en) | 2007-06-28 |
JP2004525616A (ja) | 2004-08-26 |
US8372413B2 (en) | 2013-02-12 |
WO2002052002A3 (en) | 2003-09-04 |
CN1293192C (zh) | 2007-01-03 |
KR20030064882A (ko) | 2003-08-02 |
EP1364010A2 (en) | 2003-11-26 |
KR100881923B1 (ko) | 2009-02-04 |
US20080207550A1 (en) | 2008-08-28 |
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