JP5543050B2 - 抗原にリンクされた免疫刺激配列を含有する免疫調節組成物および該組成物を使用する方法 - Google Patents
抗原にリンクされた免疫刺激配列を含有する免疫調節組成物および該組成物を使用する方法 Download PDFInfo
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Description
本出願は、1999年11月15日出願の米国仮出願60/165,467号の優先権を主張し、上記出願明細書の全体を参考のため本明細書中に引用する。
本発明は免疫学、より具体的には、免疫応答を調節するために抗原に付着された免疫刺激(賦活)ポリヌクレオチド配列の使用に関する。
種々異なる病状、例えばウィルス感染、癌およびアレルギー反応に見られる病状を解消するための免疫応答は、宿主の健康全体にとって重要である。感染症、癌またはアレルギー反応の解消成功は、免疫応答の型および大きさに依存する。さらに免疫応答を導き出すのに抗原を使用する免疫化は、感染症、癌および/またはアレルギー反応を効果的に解消する助けとなり得る。免疫応答を導き出すのに用いられる抗原の型が、疾患によって異なるうえは、免疫系が上述の感染症および疾患全てに対処するのを可能にする免疫化法を有することが望ましい。より具体的には、免疫応答の示差調節を可能にする免疫化法を有することが望ましい。一般的に免疫化は体液(抗体)反応を引き起こす傾向を有しているものの、体液反応(例えばアナフィラキシー・ショック)から生じるおそれのある合併症を回避するために、別の型の免疫応答、つまり細胞免疫応答を引き起こすことが好ましい場合がある。
本発明は、相異なる区別可能な生物学的特性を有するISS抗原複合体クラス(すなわち集団)の組成物を提供する。変化する構造的かつ機能的な特徴について本明細書中に記載し、この特徴は全体的に見て、複合の変化する範囲、(特にTh1応答の観点における)免疫応答の平均調節機能のような変化する機能、抗原に結合するために抗原特異的抗体と競合する平均能力、および(抗原がアレルゲンである場合)ヒスタミン放出を抑制する能力を包含する。種々の実施態様を本明細書中に記載する。ISSは本明細書中に記載したようなあらゆる免疫刺激配列であってよい。抗原はあらゆる抗原であってよく、その一例として、病原菌、例えばB型肝炎ウィルス、HIV、乳頭腫ウィルス、(インフルエンザ・ウィルスのような)呼吸器ウィルス、マイコバクテリア、百日咳およびサルモネラ属と関連するアレルゲンおよび抗原が挙げられる。抗原はまた、癌、例えば腫瘍抗原と関連するあらゆる抗原であってもよい。
われわれは、ポリヌクレオチド免疫刺激配列(ISS)と抗原との複合の程度が免疫応答を示差調節することを発見した。例えば具体的に述べるならば、われゎれは、より大きい程度の複合が、抗原特異的抗体の産出全体を抑制することになる一方、Th1シフトを保つ(すなわちTh1関連のサイトカインが放出される)ことを発見した。さらにわれわれは、より大きな程度の複合が、アレルギー抗原使用時に、ヒスタミン放出抑制において著しく効果的であることを発見した。
本発明の実施においては、特記しない限り分子生物学(組み換え技術を含む)、微生物学、細胞生物学、生化学および免疫学のコンベンショナルな技術を採用することになる。このような技術は当業者の技能の範囲内にある。このような技術は「分子クローニング:実験室マニュアル(Molecular Cloning: A Laboratory Manual)」第2版(Sambrook他,1989);「オリゴヌクレオチド合成(Oligonucleotide Synthesis)」(M. J. Gait他, 1984);「動物細胞培養(Animal Cell Culture)」(R. I. Freshney編, 1987);「実験免疫学ハンドブック(Handbook of Experimental Immunology)」(D. M. WeirおよびC. C. Blackwell編);「哺乳類細胞のための遺伝子導入ベクター(Gene Transfer Vectors for Mammalian Cells)」(J. M. MillerおよびM. P. Calos編, 1987);「分子生物学の現行プロトコル(Current Protocols in Molecular Biology)」(F. M. Ausubel他編, 1987);「PCR:ポリメラーゼ鎖反応(The Polymerase Chain Reaction)」(Mullis他編, 1994);「免疫学の現行プロトコル(Current Protocols in Immunology)」(J. E. Coligan他編, 1991);「イムノアッセイ・ハンドブック(The Immunoassay Handbook)」(David Wild編, Stockton Press NY, 1994);および「免疫学的分析法(Methods of Immumological Analysis)」(R. Masseyeff, W. H. AlbertおよびN. A. Staines編, Weinheim: VCH Verlags gesellschaft mbH, 1993)のような文献に全体的に説明されている。
本明細書中に使用したように、単数形は、特記しない限り複数の意味を含む。例えばISSは1つまたは複数のISSを含む。
様々な構造特性かつ免疫調整特性を有する複合集団
概ね本発明および本明細書中に記載した複合分子のクラス、または集団は、以下のような多数の構造的および/または機能的特性のいずれかによって、区別および/または規定することができる:
(a) 抗原に付着またはリンクされたISS含有ポリヌクレオチドの平均数;
(b) 抗原に付着またはリンクされたISS含有ポリヌクレオチドの中位数
(c) 抗原の平均質量に対するISS含有ポリヌクレオチドの平均質量の比;
(d) 抗原の中位質量に対するISS含有ポリヌクレオチドの中位質量の比;
(e) (ii)抗原に対する抗原特異的抗体を阻害するのに必要な抗原濃度に対する、(i)抗原に対する抗原特異的抗体の結合を同一程度に阻害するのに必要なISS抗原複合体濃度の比(後述するように、これらの比は通常の場合、50%の阻害率で算出されるが、これに限定されるものではない);
(f) アレルゲンである抗原に関して、(ii)抗原感作された個体からの好塩基球からのヒスタミン放出に必要な抗原濃度に対する、(i)抗原感作された個体からの好塩基球からの同一程度のヒスタミン放出に必要なISS抗原複合体濃度の比(後述するように、これらの比は通常の場合、40%のヒスタミン放出率で算出されるが、これに限定されるものではない);
(g) (ii)抗原により引き出されたTh1関連抗体とTh2関連抗体との和に対する、(i)ISS抗原複合体により引き出されたTh1関連抗体とTh2関連抗体との和の比;
(h) (ii)ISS抗原複合体により引き出されたTh2関連抗体に対する、(i)ISS抗原複合体により引き出されたTh1関連抗体の比;
(i) 抗原単独の場合と比較して異なるサイトカイン産出プロフィル
(j) 「本発明の実施の形態」において上述したような、抗原特異的抗体産出を抑制する程度。
(a) 1抗原分子当たり、最小5.5個、より好ましくは6個の平均ISS含有ポリヌクレオチド;
(b) (i)ISS含有ポリヌクレオチドの平均質量と、(ii)抗原の平均質量との比が、(i)約35あるいは最小約35:(ii)約40、(i)約40あるいは最小約40:(ii)約40、または、(i)約45あるいは最小約45:(ii)約40である;
(c) (ii)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要な抗原濃度に対する、(i)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要なISS抗原複合体濃度の比が約3.5〜約6.0以上(例えば7.0,8.0,9.0,10,0,15,20,25,30,35,40,45,50またはこれ以上であるが、これらに限定されるものではない)であるか、あるいは、最小でほぼ以下の数値のいずれかである:3.5,4.0,4.5,5.0,5.5,6.0,6.5,7.0,8.0,9.0,10,15,20,25(範囲として表現するならば、上限は前記数値のいずれかであってよい);
(d) 抗原がアレルゲンである実施例に関して、(ii)抗原感作された個体からの好塩基球からの40%のヒスタミン放出に必要な抗原濃度に対する、(i)抗原感作された個体からの好塩基球からの40%のヒスタミン放出に必要なISS抗原複合体濃度の比が、約300を上回り、好ましくは約500を上回り、好ましくは約750を上回り、より好ましくは約1000を上回り、より好ましくは約1250を上回り、より好ましくは約1400を上回り、より好ましくは約1500を上回る(例えば750,1000,1250,1500,1750,2000,2250,2500,2750,3000,3500,4000,4500,5000,5500,6000を含むいずれかの数値が上限である);
(e) (ii)(投与された抗原の単位質量で見た場合の)抗原によって引き出されたTh1およびTh2関連総抗体に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体によって引き出されたTh1およびTh2関連総抗体の力価比は、ほぼ以下のいずれかの数値であるか、あるいはほぼ以下のいずれかの数値未満である:10,7,5,4,3.5,3.0;2.5,2.0,1.5,1.0,0.75,0.5,0.4,0.3,0.2,0.1。
(g) (ii)(投与された複合体量と比較して、投与された抗原の単位質量で見た場合の)抗原によって引き出されたTh1関連抗体の力価に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体によって引き出されたTh1関連抗体の力価の比は、ほぼ以下のいずれかの数値であるか、あるいはほぼ以下のいずれかの数値未満である:60,55,50,45,40,35,30,25,20,15,10,5;
(h) (ii)ISS抗原複合体により引き出されたTh2関連抗体の力価に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体により引き出されたTh1関連抗体の力価の比は、ほぼ以下のいずれかの数値であるか、あるいはほぼ以下のいずれかの数値を上回る:4.0,4.5,5.0,5.5,6.0,6.5,7.0,7.5,8.0,8.5,9.0,9.5,10。範囲として表現するならば、上限は前記数値を含むあらゆる数値であってよく、15,20,25,30,40,50,60,75,80,90,100のような他の数値であってもよい。
(a) 1抗原分子当たり、約3個〜約5個の平均ISS含有ポリヌクレオチド;
(b) (i)ISS含有ポリヌクレオチドの平均質量と、(ii)抗原の平均質量との比が、(i)約20:(ii)約40、(i)約25:(ii)約40、または、(i)約30:(ii)約40である;
(c) (ii)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要な抗原濃度に対する、(i)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要なISS抗原複合体濃度の比が約2.5〜約3.0であるか、あるいは、約3.25である;
(d) 抗原がアレルゲンである実施例に関して、(ii)抗原感作された個体からの好塩基球からの40%のヒスタミン放出に必要な抗原濃度に対する、(i)抗原感作された個体からの好塩基球からの40%のヒスタミン放出に必要なISS抗原複合体濃度の比が、約100〜約200、あるいは約100、あるいは約75〜約250である;
(e) (ii)(投与された抗原の単位質量で見た場合の)抗原によって引き出されたTh1およびTh2関連総抗体に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体によって引き出されたTh1およびTh2関連総抗体の力価比は、約13、あるいは約10〜100または約12〜約100(または或る実施例では約12〜約50)である;
(f) (ii)(投与された複合体量と比較して10倍の、投与された抗原の単位質量で見た場合の)抗原によって引き出されたTh1およびTh2関連総抗体に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体によって引き出されたTh1およびTh2関連総抗体の力価比は、約1.3、あるいは約1.0〜約10または約1.20〜約10(または或る実施例では約1.2〜約5.0)である;
(g) (ii)(投与された複合体量と比較して、投与された抗原の単位質量で見た場合の)抗原によって引き出されたTh1関連抗体の力価に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体によって引き出されたTh1関連抗体の力価の比は、約70〜約500である;
(h) (ii)ISS抗原複合体により引き出されたTh2関連抗体の力価に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体により引き出されたTh1関連抗体の力価の比は、約2〜約4である。
(a) 1抗原分子当たり、約3個未満の平均ISS含有ポリヌクレオチド;
(b) (i)ISS含有ポリヌクレオチドの平均質量と、(ii)抗原の平均質量との比が、(i)約15:(ii)約40、あるいは(i)約15未満:(ii)約40(或る実施例では、(i)約10:(ii)約40あるいは(i)約10未満:(ii)約40である;
(c) (ii)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要な抗原濃度に対する、(i)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要なISS抗原複合体濃度の比が約2未満であるか、あるいは、約2.0である;
(d) 抗原がアレルゲンである実施例に関して、(ii)抗原感作された個体からの好塩基球からの40%のヒスタミン放出に必要な抗原濃度に対する、(i)抗原感作された個体からの好塩基球からの40%のヒスタミン放出に必要なISS抗原複合体濃度の比が、約75未満、あるいは約75(他の実施例では約60未満あるいは約60)〜約200、あるいは約75(他の実施例では約60未満あるいは約60)〜約100である;
(e) (ii)(投与された抗原の単位質量で見た場合の)抗原によって引き出されたTh1およびTh2関連総抗体に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体によって引き出されたTh1およびTh2関連総抗体の力価比は、約150、あるいはほぼ以下のいずれかの数値を上回る:100,150,200,250,300,350,400,450,500,550,660,650,700,750,800。範囲として表現するならば、上限は前記数値を含むあらゆる数値であってよい。
(g) (ii)抗原によって引き出されたTh1関連抗体の力価に対する、(i)(投与された複合体の1単位質量当たりで引き出された抗体で見た場合の)ISS抗原複合体によって引き出されたTh1関連抗体の力価の比は、約500以上、例えば約500以上、約600以上、約700以上、約800以上、約900以上、約1000以上である。範囲として表現するならば、上限は、例えば600,700,800,900,1000,1250,1500,1750,2000,2500,3000,3500,4000,4500,5000を含むあらゆる数であってよい。
(a) (ii)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要な抗原濃度に対する、(i)抗原に対する抗原特異的抗体の結合を50%阻害するのに必要なISS抗原複合体濃度の比が約1.5,2.0,2.25,3.0,3.25,3.5,3.75,4.0,4.25,4.50,4.75,5.0,5.25,5.5,5.75,6.0,6.5,7.0,7.5,8.0,8.5,9.0,9.5,10.0のいずれかを上回る。範囲として表現するならば、上限は前記数値を含むいずれの数値であってもよい(例えば複合体集団は、約2.0を上回ってよく、約2.0超〜約5.5未満であってよく、また、約2.0超〜20.0未満であってよい)。
本発明の複合集団は、上述のものを含む多数の方法のいずれかによって識別し、かつ/または特徴付けることができる。例えば構造の点から見ると、複合程度は以下のものによって説明することができる:抗原分子に対するISSの平均数、あるいは中位数;(b)抗原中の総リンケージ部位に対するISSの比;(c)抗原の(平均であれ中位であれ)質量に対する、ISSの(平均であれ中位であれ)質量の比;(d)抗原中のT細胞エピトープに対するISSの比;(e)抗原中のB細胞エピトープに対するISSの比。一例として免疫調節を含む機能の点から見ると、本発明の複合体集団は、(a)抗原特異的抗体応答度、例えばIgG応答度;(b)Th2関連抗体に対するTh1関連抗体の比;(c)ヒスタミン放出の抑制度;(d)抗原に結合するための抗原特異的抗体との競合度;(e)Th2関連免疫応答の抑制度;(f)インターフェロンのようなTh1関連サイトカインの分泌;(g)IL−4および/またはIL−5のようなTh2関連サイトカインの分泌。
ISS抗原複合の程度は、当業者に良く知られたあらゆる数のタンパク質・核酸測定法を使用して、突き止めることができる。例えば、複合の反応生成物を分析するのには、抗原および/またはタンパク質特異的検出法(例えば抗原特異的抗体および/またはクーマシー・ブルー染色)および核酸特異的検出法(例えば検出可能に標識付けされたDNAプローブとのハイブリッド形成)が用いられてよい。適切な定量基準を用いれば、抗体に対するポリヌクレオチド量が突き止められる。
ISS抗原複合体の投与に応答して発生した抗体の抗原特異性、抗体クラスおよび/またはサブクラスを突き止めるために、当業者に知られた種々の方法を用いることができる。例えば、種々のISS抗原複合体に応答して産出された抗体の量、特異性および/または型を検出して測定するのに、標準的なELISAフォーマット検定が用いられてよい。この検定では、例えば、抗原が基質に付着され、ISS抗原複合体から採取された血清とともに保温される。次いで、基質結合抗原に付着された抗原特異的抗体の量が、抗体特異的試薬、例えばIgGa1、IgGa2、IgGa3、IgGa4などに特異的な抗体を用いて突き止められる。抗原に対する抗原特異的抗体の結合を阻害するのに必要なISS抗原複合体の濃度を突き止めるのに、当業者によく知られた方法、例えば本明細書中に記載したような競合的ELISA検定が用いられてよい。
(i) (ii)抗原によって引き出されたTh1関連抗体およびT2関連抗体の和に対する、(i)ISS抗原複合体によって引き出されたTh1関連抗体およびT2関連抗体の和;
(ii) (ii)抗原によって引き出されたTh1関連抗体に対する、(i)ISS抗原複合体によって引き出された(1つまたは複数の)Th1関連抗体;
(iii) (ii)抗原によって引き出されたTh2関連抗体に対する、(i)ISS抗原複合体によって引き出された(1つまたは複数の)Th2関連抗体であってよい。
本発明によれば、免疫調節ポリヌクレオチドは少なくとも1つのISSを含有しており、複数のISSを含有することができる。これらのISSはポリヌクレオチド中で隣接することができ、または、ポリヌクレオチド中で付加的なヌクレオチド塩基によって隔離することもできる。
GACGCTCC;GACGTCCC;GACGTTCC;GACGCCCC;
AGCGTTCC;AGCGCTCC;AGCGTCCC;AGCGCCCC;
AACGTCCC;AACGCCCC;AACGTTCC;AACGCTCC;
GGCGTTCC;GGCGCTCC;GGCGTCCC;GGCGCCCC;
GACGCTCG;GACGTCCG;GACGCCCG;GACGTTCG;
AGCGCTCG;AGCGTTCG;AGCGTCCG;AGCGCCCG;
AACGTCCG;AACGCCCG;AACGTTCG;AACGCTCG;
GGCGTTCG;GGCGCTCG;GGCGTCCG;GGCGCCCG。
GACGCT;GACGTC;GACGTT;GACGCC;GACGCU;
GACGUC;GACGUU;GACGUT;GACGTU;AGCGTT;
AGCGCT;AGCGTC;AGCGCC;AGCGUU;AGCGCU;
AGCGUC;AGCGUT;AGCGTU;AACGTC;AACGCC;
AACGTT;AACGCT;AACGUC;AACGUU;AACGCU;
AACGUT;AACGTU;GGCGTT;GGCGCT;GGCGTC;
GGCGCC;GGCGUU;GGCGCU;GGCGUC;GGCGUT;
GGCGTU。
5’−TGACCGTGAACGTTCGAGATGA−3’(SEQ ID NO:2);
5’−TCATCTCGAACGTTCCACAGTCA−3’(SEQ ID NO:3);
5’−TGACTGTGAACGTTCCAGATGA−3’(SEQ ID NO:4);
5’−TCCATAACGTTCGCCTAACGTTCGTC−3’(SEQ ID NO:5);
5’−TGACTGTGAABGTTCCAGATGA−3’(SEQ ID NO:6)、Bは5−ブロモシトシン;
5’−TGACTGTGAABGTTCGAGATGA−3’(SEQ ID NO:7)、Bは5−ブロモシトシン;および
5’−TGACTGTGAABGTTBGAGATGA−3’(SEQ ID NO:8)、Bは5−ブロモシトシン。
本発明の複合集団においては、あらゆる抗原を使用することができる。
表1
組換えアレルゲン
本明細書中に記載した組成物において、ISS含有ポリヌクレオチドは抗原と複合されている。ISS部分は、共有相互作用および/または非共有相互作用を含む種々の方法で、複合体の抗原部分とカップリングすることができる。
本発明はまた、キットおよび組成物、例えば、本明細書に記載した複合集団のいずれかを含んで成る製剤を提供する。
ISS含有ポリヌクレオチド抗原複合体は、他の薬剤および/または免疫原性物質および/または免疫刺激物質と組み合わせて投与することができ、これらの製薬上許容可能なキャリアと組み合わせることができる。ISS含有ポリヌクレオチドは、上述のポリヌクレオチドのいずれかであってよい。SEQ ID NO:1で示したように、好ましくは、投与されるISS含有ポリヌクレオチドは、配列5’−T,C,G−3’から成る。好ましくは、投与されるISS含有ポリヌクレオチドは、式5’プリン,プリン,C,G,ピリミジン,ピリミジン,C,G−3’から成り;より好ましくは、5’−A,A,C,G,T,T,C,G−3’から成る。別の好ましい実施例は、SEQ ID NO:1を用いる。
本発明はまた、免疫応答を調節する方法を含む。この方法は、免疫応答の所望の調節が達成されるように複合体の集団(典型的にはこの集団と、製薬上許容可能な賦形剤とを含んで成る組成物である)を投与することを含んで成る。複合体の投与および免疫応答の評価については上述の通りである。
例1 AIC−L、AIC−MまたはAIC−Hの調製
AIC−L、AIC−MおよびAIC−Hは、ブタクサ・アレルゲンAmb a 1とISS含有ポリヌクレオチドSEQ ID NO:1とから成る共有複合体である。複合体の3つのクラス全ては、同じISS含有ポリヌクレオチドから調製され、同じヘテロ二官能価リンカーを採用する。Amb a 1に複合されたオリゴヌクレオチドの数は、クラスによって異なる。Amb a 1に結合されたオリゴヌクレオチドの数は、複合体のサイズまたは分子量を測定することによって見極めることができる(図12および13参照)。AIC−Lは1Amb a 1分子当たり2〜3個のオリゴヌクレオチド平均数を含有し、AIC−Mは3.5〜4.5個の平均数を、AIC−Hは5.5個を上回る平均数を含有している。AICのこれら3つのクラスは、後述のような異なる生物学的特性を有している。
トリカルボキシエチルホスフィン(TCEP)を、周囲温度に到達させ、10mM NaPO4/141mM NaCl/pH7.2中に溶解させた。5’ジスルフィドISSオリゴヌクレオチドを周囲温度に到達させ、同じ緩衝液中に溶解し、40℃で2時間、TCEP溶液で処理した。この材料を直接、隔離ステップに移した。
N−エチル・マレイミド(NEM)を周囲温度に到達させ、ジメチル・スルホキシド(DMSO)中に攪拌しながら溶解した。Amb a 1を溶かし、20℃で2時間、NEM溶液で処理した。スルホスクシニミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(sSMCC)を周囲温度に到達させ、DMSO中に溶解した。NEMブロックAmb a 1を20℃で2.5時間、sSMCCで処理した。この材料を直接、隔離ステップに移した。予めパックされた2つの脱塩カラムを直列につなぎ、10mM NaPO4/141mM NaCl/pH7.2緩衝液と釣り合わせた。Amb a 1活性化混合物をカラムに装てんし、マレイミド活性化Amb a 1を無勾配溶離した。
4モル当量の5’チオISSオリゴヌクレオチドと、1モル当量のマレイミド活性化Amb a 1とから成る混合物を保温することにより、粗AIC−L複合体を調製した。同様にして、ただし、5’チオISSオリゴヌクレオチドをそれぞれ7モル当量および17モル当量添加することにより、粗AIC−Mおよび粗AIC−Hを調製した。予めパックされたゲルろ過カラムを、10mM NaPO4/141mM NaCl/pH7.2緩衝液と釣り合わせ、粗AIC−L、粗AIC−Mおよび粗AIC−Hをカラムに装てんした。AICを10mM NaPO4/141mM NaCl/pH7.2緩衝液で無勾配溶離した。
10匹のBALB/cマウスから成る群を、尾の皮内において、1μgのAIC(H,M,L)で免疫化した。対照マウスに10μgのAmb a 1の同一注射を施した。第1回および第2回免疫化2週間後にマウスから血液を採取し、血清を調製し、Amb a 1特異的IgG1およびIgG2aをELISAによって測定した。マウスの系の場合、IgG1応答は、Th2型免疫応答と関連するのに対し、IgG2a応答はTh1型応答と関連する。
AIC−L、AIC−MおよびAmb a 1の抗体応答を表2に示す(平均力価±標準偏差)。AIC−Mは第1回免疫化後、極めて低いIgG1応答と、比較的高いIgG2a応答を引き起こした。第2回免疫化後、IgG2a応答がIgG1応答よりもなおも約5倍高いのに伴って、IgG1応答およびIgG2a応答は双方とも増大した。AIC−Lは、第1回および第2回免疫化後のAIC−Mよりも高いIgG1応答およびIgG2a応答を引き起こした。AIC−Lによる抗体応答もまた、IgG1応答よりもIgG2a応答に向かってより重く重み付けされた。IgG2a>IgG1を示す、AIC−MおよびAIC−Lに対する抗体応答は、Th1型免疫応答を示唆している。対照的に、修飾されていないAmb a 1は、第1回および第2回免疫化後に高いIgG1応答と低いIgG2a応答とを引き起こした。このような型の抗体応答は、Th2型免疫応答を示唆している。従ってAmb a 1のAIC−L修飾形およびAIC−M修飾形は、Th2型抗原(Amb a 1)の免疫応答を、Th1プロフィルに向かってシフトする。AIC−Lは、AIC−Mよりも高い総抗体応答を発生させると考えられた。
AIC−L、AIC−MおよびAmb a 1に対する抗体応答を明示する第2の実験を表3に示す(平均力価±標準偏差)。この実験の結果は上述の実験と類似しているが、同一ではない。IgG1応答は全体的にこの実験において、上述の実験よりも高かった。その他の点では結論は同じである。Amb a 1のAIC−LおよびAIC−M双方の修飾形は、Th2型抗原(Amb a 1)の免疫応答を、Th1プロフィルに向かってシフトする。AIC−Lは、AIC−Mよりも高い総抗体応答を発生させると考えられる。
AIC−M、AIC−HおよびAmb a 1に対する抗体応答を表4に示す(平均力価±標準偏差)。AIC−Mは前の実験と類似の抗体応答を発生させ、IgG2a力価はIgG1力価よりも大きい。AIC−Hは、第1回および第2回双方の免疫化後、AIC−Mよりも低いIgG1およびIgG2aを引き起こす。AIC−Hによる抗体応答もまた、IgG1応答よりもIgG2a応答に向かってより重く重み付けされる。修飾されていないAmb a 1はやはり、第1回および第2回免疫化後に高いIgG1応答と低いIgG2a応答とを引き起こした。従って、Amb a 1のAIC−H修飾形およびAIC−M修飾形は、Th2型抗原(Amb a 1)の免疫応答を、Th1プロフィルに向かってシフトする。AIC−Hは、AIC−Mよりも高い総抗体応答を発生させると考えられる。
(表5に要約;平均力価±標準偏差)この実験は、表4に要約した結果を再現し、1つの付加的なAIC−Hロットを含む。この実験はAIC−MおよびAIC−Hが同様のTh1応答を発生させ、AIC−HがAIC−Mよりも低い抗体応答を発生させることを確証する。
マウスに第0週に、Th2応答を発生させるミョウバン中のAmb a 1を初回投与した。第15週に、これらのマウスにAmb a 1またはAIC−H(ロットBK 5)をそれぞれ10μgずつ、2週間の間隔を置いて三回注射して治療した(図1〜3参照、注射を矢印で示す)。Amb a 1に対して特異的なIgG1、IgEおよびIgG2aをELISAによって測定し、結果を図1〜3にそれぞれ示す。
この検定では、ブタクサアレルギーのヒト被験者の血液から、末梢血単核細胞(PBMCs)を調製した。これらの細胞を5μg/mlのAmb a 1、AIC−MまたはAIC−Hと共に2 x 106/mlで6日間培養した。上澄みを収穫し、上澄みのIFN−γ含量をELISAによって測定した。いくつかの細胞を第6日に、2.5μg/mlのフィトヘムアグルチニン(PHA)および10ng/mlのホルボール・12−ミリステート・13−アセテート(PMA)で24時間、再刺激した。その後、上澄み液を収穫して、上澄みのIL−4およびIL−5含量をELISAによって測定した。ブタクサアレルギーを有する被験者からのPBMCのサイトカイン応答を表8に示す(平均力価±標準偏差)。AIC−HおよびAIC−Mの双方は、ブタクサに対してアレルギー性を有する個体からの細胞中のTh1型サイトカイン応答を刺激することができる。対照的に、Amb a 1は、これらの細胞からTh2型サイトカイン応答、すなわち僅かなIFN−γおよび高レベルのIL−4およびIL−5を発生させた。これらのデータは、AIC−MおよびAIC−Hが、アレルギー性の個体からのPBMCs中のサイトカイン・プロフィルをシフトする上で、Th1型応答付勢を反映するのに効果的であることを示す。
種々異なるクラスの抗原ISS複合体を、マウスの細胞障害性Tリンパ球(CTL)活性を引き起こす能力に関してテストした。
Claims (17)
- 複合分子集団であって、該複合分子が、抗原と、免疫刺激配列(ISS)を含んで成るポリヌクレオチドとを含んで成り、当該集団中の複合程度が、1抗原分子あたり平均で少なくとも5.5のISS含有ポリヌクレオチドが存在するものである、複合分子集団。
- 1抗原分子あたり少なくとも6ISS含有分子が存在する、請求項1に記載の複合分子集団。
- 前記抗原がアレルゲンである、請求項1又は2に記載の集団。
- 前記アレルゲンがAmb a 1である、請求項3に記載の集団。
- 製薬上許容可能な賦形剤に配合された請求項1〜4のいずれか1項に記載の集団を有することを特徴とする、組成物。
- 個体の免疫応答を調節するための医薬組成物であって、前記免疫応答を調節するのに充分な量の、請求項5に記載の組成物を含んで成る、前記医薬組成物。
- 前記調節が、Th1関連サイトカインの産出を刺激することを含んで成る、請求項6に記載の医薬組成物。
- 前記調節が、Th2関連サイトカインの産出を減少させることを含んで成る、請求項6に記載の医薬組成物。
- 前記調節が、抗原特異的抗体の産出を抑制することを含んで成る、請求項6に記載の医薬組成物。
- 個体のアレルギー状態を治療するための医薬組成物であって、前記アレルギー状態を軽減するのに充分な量の請求項3に記載の集団と製薬上許容可能な賦形剤とを含んで成る、前記医薬組成物。
- Th1関連サイトカインの産出を刺激する、請求項10に記載の医薬組成物。
- 個体内で抗原によって刺激されたIgEの産出を減少させるための医薬組成物であって、前記個体内で前記抗原によって刺激されたIgEを減少させるのに充分な量の請求項5に記載の組成物を含んで成る、前記医薬組成物。
- 個体のIgE関連障害を治療するための医薬組成物であって、前記個体のIgEの産出を減少させ前記障害を治療するのに充分な量の請求項5に記載の組成物を含んで成る、前記医薬組成物。
- 個体内のTh1リンパ球を刺激するための医薬組成物であって、前記個体内のTh1リンパ球を刺激するのに充分な量の請求項5に記載の組成物を含んで成る、前記医薬組成物。
- Th1関連サイトカインの産出を刺激する、請求項14に記載の医薬組成物。
- 個体内のTh2リンパ球を抑制するための医薬組成物であって、前記個体内のTh2リンパ球を抑制するのに充分な量の請求項5に記載の組成物を含んで成る、前記医薬組成物。
- Th2関連サイトカインの産出を抑制する、請求項16に記載の医薬組成物。
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US16546799P | 1999-11-15 | 1999-11-15 | |
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US09/713,136 US7223398B1 (en) | 1999-11-15 | 2000-11-14 | Immunomodulatory compositions containing an immunostimulatory sequence linked to antigen and methods of use thereof |
PCT/US2000/031385 WO2001035991A2 (en) | 1999-11-15 | 2000-11-15 | Immunomodulatory compositions containing an immunostimulatory sequence linked to antigen and methods of use thereof |
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JP (1) | JP5543050B2 (ja) |
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CA2391507C (en) | 2010-08-10 |
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JP2003513680A (ja) | 2003-04-15 |
CA2391507A1 (en) | 2001-05-25 |
EP1229933B1 (en) | 2007-03-28 |
WO2001035991A3 (en) | 2001-11-22 |
ATE357930T1 (de) | 2007-04-15 |
WO2001035991A2 (en) | 2001-05-25 |
DE60034140T3 (de) | 2015-09-03 |
AU1612101A (en) | 2001-05-30 |
EP1229933B2 (en) | 2015-06-17 |
US20070190073A1 (en) | 2007-08-16 |
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