JP2007528368A - シクロフィリンa結合部位に基づく免疫原性組成物およびワクチンの開発方法 - Google Patents
シクロフィリンa結合部位に基づく免疫原性組成物およびワクチンの開発方法 Download PDFInfo
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Abstract
Description
ヒト免疫不全ウイルス(HIV)は、スローウイルスまたはレンチウイルス群のレトロウイルスであり、後天性免疫不全症候群(エイズ)の原因である。多くのエンベロープを有するウイルスのように、HIVはウイルスおよび細胞の膜を融合して、感染およびウイルス複製を導く。一旦それが宿主細胞に融合すると、HIVはそのゲノムをウイルスおよび細胞の膜を通過させて宿主細胞に移す。
1.ウイルス結合CypAと宿主/細胞ヘパリンとの相互作用。
2.CypA/ヘパリン相互作用による標的細胞へのウイルスの付着。
3.標的細胞のCD4分子へのgp120結合。この過程は、ケモカイン受容体(T細胞のためのCCR5およびマクロファージのためのCXCR4)としても知られる補助受容体タンパク質を必要とする。ウイルスは次に細胞と融合し始め、構造または配座の変化をもたらして他の受容体を露出させる。
4.gp41の融合ドメインまたはFタンパク質を露出させているgp120分子の配座の三次元変化および/または三次構造変化。
5.高次構造変化およびgp120の脱落の結果としてのgp41分子からのgp120の解離;
6.標的細胞の原形質膜を貫通する前のそれ自体へのgp41のフォールディング。
7.Fタンパク質のアンフォールディング。
8.ウイルス粒子および宿主細胞の膜の融合。
融合ペプチドの挿入は、対象の宿主細胞膜内の脂質の完全性を崩壊させる。Fタンパク質はウイルスおよび細胞の膜を結合するので、融合タンパク質がアンフォールドすると同時に、標的細胞の原形質膜およびウイルスの膜は互いにスプライシングされる。
したがって、HIVの一次作用はCD4 T細胞を減少させることであり、それは全体的な免疫活性を低下させる。上記のように、HIV感染はCD4 T細胞を中心に起こるが、B細胞、血小板、内皮細胞、上皮細胞、マクロファージ、その他にも感染する。CD4 T細胞が減少するに従って、B細胞反応は調節されなくなる。無効な抗体によるグロブリン過剰血症が、HIV進行の特徴である。さらに、細胞傷害性CD8 T細胞は無効にされ、ウイルス感染を認識して攻撃することができなくなる。これは、感染したCD4細胞で製造されたtatタンパク質による非感染CD8細胞のトランスフェクションが、原因の一部である。
HIVは、経時的に維持されずに最終的には感染の制御に失敗する、当初は強い細胞免疫反応を作動させるようである。(McMichael、2001)
免疫系の液性部門は、刺激により抗体を産生する形質細胞に分化するB細胞からなる。最初に出現する抗体はIgMであり、次に血中のIgGまたは分泌組織中のIgAである。これらの抗体の主要機能は、感染症およびそれらの毒素から保護することである。抗体はウイルスおよび毒素を中和するだけでなく、微生物をオプソニン化する。オプソニン作用は、抗体が、ウイルスまたは細菌が食細胞によってより簡単に摂取され、破壊されるようにする過程である。食細胞としては、多形核好中球(PMN)および組織マクロファージがある。PMNは、非感染性患者の血液で白血球の約60%を構成する。PMNおよび組織マクロファージの数は、ある種の感染障害により増減する可能性がある。例えば、腸チフスは白血球数の減少を特徴とする(すなわち白血球減少症)。PMNおよびマクロファージの両方とも、細菌およびウイルスを貪食により消費する。PMNはヘルパーT細胞に抗原を提示しないが、マクロファージおよび樹状細胞はする。
O2+e-→O2-
2O2-+2H+→H2O2(過酸化水素)+O2
Cl-+H2O2→ClO+H2O
1.他の補体成分と逐次的に結合してMAC(C5b,6,7,8,9)の生産をもたらす酵素C5コンバターゼを生成する
2.微生物のオプソニン化。貪食細胞はその細胞表面にC3bの受容体を有する。
3.抗体産生を大きく強化する、活性化されたB細胞表面のその受容体への結合。(Parham,Peter、The Immune System、Ch.7(2nd ed.、2004))
体液性反応は、HIVによる搾取の格好の対象であるこの系のある種の調節因子、例えば補体因子Hを含む。補体カスケードの活性を制限する能力を有するいかなる微生物も、理論的には免疫系の液性部門から身を守ることができるであろう。(Stoiber,Herbert、「Role of Complement in the control of HIV dynamics and pathogenis」、Vaccine 21:S2/77-S2/82(2003))したがって、補体カスケードは液性部門のアキレス腱である。
レトロウイルスは、抗体が存在しない場合も、補体系を活性化することができる。(Haurum,J.、AIDS、7(10)、1307〜13(1993))HIVエンベロープ糖タンパク質による補体活性化は、ウイルス感染細胞内で生産された自然のエンベロープタンパク上、ならびにグリコシル化組換えエンベロープタンパク上の糖へのMBPの結合によって媒介されることがわかった。(Haurum,John、AIDS、第7巻(10)、1307〜13頁(1993))(Speth,C.、Immunology Reviews、157、49〜67(1997))レトロウイルスエンベロープによる古典的補体経路およびレクチン経路の活性化は、エンベロープ糖タンパク質の炭化水素側鎖へのMBPの結合によって開始される。HIV-1、gp41の膜貫通タンパク質は、gp120と非共有結合的に結合することが示された。補体成分C1qも、gp41と結合する。gp41の細胞外部(外部ドメイン)で、3つの部位(aa 526〜538;aa 601〜613およびaa 625〜655)はgp120およびC1qの両方を結合する。したがって、C1qおよびgp120は、共に構造的かつ機能的に相同である。gp41およびC1qの間の相互作用はカルシウム依存性であり、カルシウム非依存性であるgp41およびgp120の結合と異なる。
懸命な努力にもかかわらず、HIV用の治療ワクチンはない。HIVライフサイクルの様々な段階が、発明者によって対象とされてきた。現在まで、免疫抑制性レトロウイルスHIV-1に対して有効な免疫反応を促進する組成物は見つけられていない。ウイルスのエンベロープスパイクに対する中和抗体の生産を誘発しようとして、大部分のHIVワクチンはウイルスの表面糖タンパク質のエンベロープ(gp160、gp120およびgp41)の一部を使用する。(Johnstonら、2001)高力価の中和抗体の生成に成功した例もある。この方法の背後にある考えは、これらの糖タンパク質と結合する抗体はウイルスを中和して感染を予防するということである。機能している免疫系は次に補体系を作動させ、これは溶解をもたらしてウイルスを破壊する。しかし、上述の体液性反応の障害は、これらのワクチンの効果を制限する。いくつかの薬剤または組成物(AZT、ddl、ddC、d4Tおよび3TC)は、逆転写を妨げる。これらの2',3'-ジデオキシヌクレオシド類似体はある種の系統に対して有効であるが、HIVのゲノム易変性に対して弱い。(Deeks,Steven、The Medical Management of Aids、Ch.6(6th ed.、1999))これらの医薬品は、毒性、コスト、複雑な治療計画、薬剤間相互作用ならびに薬剤耐性の問題にも直面する。
本発明はHIVのキャプシドタンパク質上のサブユニットCypAエピトープまたは結合部位に基づく免疫原性組成物である。上記したように、この部位はキャプシド配列87 His-Ala-Gly-Pro-Ile-Ala 92にある。CypAは宿主誘導性であり突然変異誘発性ではないので、HIV上の対応する結合部位もいくぶん不変でなければならない。(Sherry,Barbaraら、Proc.Natl.Acad.Sci.、95、1758〜1763(1998))ala 88残基がより大きな残基のValまたはMetで置換されている、いくつかのHIV系統が単離された。宿主CypAと結合するこれら2つの突然変異の可能性の結晶構造は、最小限の三次元変化を示す。(Vajdon,Felix、「Crystal structure of cyclophilin A complexed with a binding site peptide from the HIV-1 capsid protein」、Protein Science 6(11)、2297〜2307(1997))有効な宿主免疫反応は、通常ウイルスのカプセルまたは封入構造の保存領域を対象とする。成熟および未熟な形のHAGPIAペプチド(またはHVGPIAまたはHMGPIAペプチド)を使用することができる。さらに、コードする遺伝子配列も、組換え型の細菌またはウイルスの実施形態を生産するために使用することができる。HIV-2およびSIVはCypAをパックしていないので、このような他のレンチウイルスは本発明で企図されていない。
1.免疫反応は、CypAタンパク質自体のいかなる成分でもなく、CypAのためのHIV-1ウイルス受容体に向けられる。
2.HIV-1 gagと同じCypA部位の受容体と結合する免疫抑制薬シクロスポリンは、自己免疫疾患をもたらさないことが示された。
3.CypAは、ヒトT細胞の生存または増殖のために必須でない。おそらく他のシクロフィリンファミリーメンバーまたはペプチジル-プロリルイソメラーゼ活性を示す他のタンパク質ファミリーによる機能的冗長性のために、CypAはタンパク質フォールディング細胞にとって一般的に重要ではないようである。
4.CypAは、約150のアミノ酸から構成されるタンパク質である。キャプシド配列(87 His-Ala-Gly-Pro-Ile-Al2 92)の6つのアミノ酸だけが、主なCypA結合部位を含む。HIV-1ビリオンのための結合部位が、タンパク質アンフォールディングにおいて宿主細胞によって用いられるのと同じ結合部位である可能性は低いようである。(Brighton、2001)
本サブユニットイムノゲンは、免疫反応および免疫記憶を引き起こすために、ペプチドまたはその部分、あるいはタンパク質またはタンパク質セグメントをコードする遺伝子配列を含む。本発明では、所望の免疫反応はHIVキャプシドタンパク質上のHAGPIAペプチド(またはHVGPIAまたはHMGPIAペプチド)、あるいはその部分、例えばコードする遺伝子に向けられる。重要なことは、組成物は正しく免疫系に提示されなければならない。核酸、ペプチドおよびタンパク質の単離および使用は、当業者には周知であり、また本明細書でも記載されている。
開発、調製および投与のための様々な方法が本発明によって企図される。そのような方法は、特定の系統への有効性および被験動物の反応に基づいて選択されることが予想される。図2で示すように、このサブユニット組成物は、調製目的についてタンパク質またはペプチドの単離、メッセンジャーRNAまたは核酸DNA/RNAの発現のように分類することができる。したがって、結合部位にはタンパク質またはそのタンパク質断片、およびその遺伝子発現または遺伝物質が含まれる。
1.HIVのキャプシドタンパク質上のCypA結合部位の精製および単離。
2.HIVのキャプシドタンパク質上のCypA結合部位を発現するメッセンジャーRNAのクローニング。
3.大腸菌などの適当な細菌、または酵母、またはウイルス、またはCypA結合部位の裸のDNA/RNA内へのキャプシドタンパク質のCypA結合エピトープの組換えDNA/RNAクローニングおよび発現。(Aroeti、1993)抗原提示細胞は食作用によって外来性タンパク質を取り込み、イムノゲンおよび免疫反応の提示を導く。上のリストに関して、実施形態1はタンパク質断片に依存するが、実施形態2〜3は核酸および組換技術に依存する。実施形態2〜3は、核酸の合成的in vitro製造を含むこともできる。(Aroeti、1993)
タンパク質のエピトープは、1つのウイルス粒子またはウイルスの培養物から単離することができる。単一粒子の場合、酵素的(タンパク分解性)分解を使用することができる。例えば、成熟タンパク質は、成熟ウイルス粒子を個々のタンパク質成分に分解および酵素消化することによって、ウイルス粒子から単離することができる。「精製」は、治療的使用が可能になるように、単にタンパク質が十分他の細胞サブユニットまたは混在物を含まないことを意味する。組成物は、完全に純粋である必要はない。タンパク質部分をウイルスの培養物から単離することもできる。ウイルス構造の各タンパク質は、ウイルスの複製のために必要な量を超えて生産される。したがって、個々のウイルスタンパク質は、様々な培地におけるそのタンパク質の特有のサイズ、形、溶解特性、静電位、密度および/または浮力および沈降率に基づいてウイルス分離株から単離および分離することができる。したがって、この手法は、免疫反応を導き出すための特定のタンパク質断片またはペプチドの使用を含む。
一般に、核酸をベースにした組成物は、裸のDNA/RNA、組換えDNA/RNAまたはメッセンジャーRNAを含むことができる。裸のDNAに基づく組成物は、通常界面活性剤またはフェノールによる処理によってヒストン(小さなアンフォールドされた染色体タンパク質)またはタンパク質が取り除かれている結合部位をコードしているウイルス抗原のDNAを使用する。以下に詳細に議論されるように、組換えDNAは異なる生物からのDNA断片を再結合することによって作られる、遺伝子操作されたDNAである。両実施形態のDNA/RNAまたはmRNAは、当技術分野で公知の、本明細書で部分的に記載されている手法を使用して単離、精製および増幅することができる。
核酸の獲得は、3つの基本段階を必要とする。(1)プロセシングのために好まれる核酸を露出させるための細胞の溶解、(2)他の細胞成分からの核酸の分離、および(3)精製された形の核酸の回収。(Nichollss,Desmond、An Introduction to Genetic Engineering、Ch.3(2d ed.、2002))「精製」は、治療的使用が可能なように、単に核酸が十分他の細胞サブユニットまたは混在物を含まないことを意味する。
組換えDNAを生産する際に使用される方法は概念的に単純であり、当技術分野で公知である。HIVキャプシドタンパク質の遺伝子は、大腸菌などの担体のDNAに組み入れることができる。推奨する担体のリストを図3で示す。図4で示すように、細菌の担体は、プラスミド、染色体の組込みまたは組合せによってリボソームDNAを含むことができる。図5で示すように、ウイルスの担体は、核酸の染色体組込み、ウイルス外皮へのドナーDNAによってコードされるタンパク質の挿入、または両者の組合せによって組換技術を支えることができる。担体が複製するとき、イムノゲンは宿主染色体に挿入されるならば増殖する。プラスミドDNAは、非複製細胞中でも複製することができる。制限酵素による遺伝子の切断または単離は、本明細書で記載されている通りであり、また公知である。
電気泳動は、DNA断片の分離、同定、および精製を可能にする。マトリクスの多孔性は、得られる分離の程度を決定する。2つのゲル型、アガロースおよびポリアクリルアミドが当技術分野では一般的に使用されている。海藻から抽出されるアガロースは乾燥粉末として市販されており、これは適切な濃度でバッファー中に溶かされる。冷却によって、アガロースは硬化またはゲル化する。ポリアクリルアミドの孔の大きさはアガロースより小さいので、ポリアクリルアミドゲルを使用して小さな核酸分子を分離する。ポリアクリルアミドは、わずか1ヌクレオチド長さが異なるDNA分子を分離することができる。核酸サンプルをゲル中に置いてそれ全体に電位を印加することによって、電気泳動を行うことができる。DNAは負に帯電したリン酸基を含み、したがって正電極に移動する。マーカー色素、通常はブロモフェノールブルー(充填前にサンプルに加える)がゲルの端部に達するとき、電位を除去する。ゲル中の核酸は、挿入用色素臭化エチジウムで染色することによって目に見える状態にすることができ、UV光下で調べることができる(Nicholls、2002)。100,000もの多くの塩基対を含む大きなDNA断片は、パルスフィールドゲル電気泳動として知られる他の方法によって分離することができる。
1.樹状細胞、マクロファージおよびランゲルハンス細胞を含めた抗原提示細胞によるDNAの取り込みおよび抗原の発現;
2.抗原提示細胞として働くかあるいはその役割が推定されているトランスフェクトした筋細胞による抗原提示;および
3.トランスフェクトした筋細胞から、適切なT細胞に対する抗原を次いで提示する抗原提示細胞への抗原の移動(Kiyono、1996)。
1.マウス中のB型肝炎表面抗原(Davisら、1993、1994)
2.マウス中の単純ヘルペスウイルス1糖タンパク質B(Manickanら、1995)
3.ウシ中のウシヘルペスウイルス1糖タンパク質IV(Coxら、1993)
4.マウス中の狂犬病ウイルス糖タンパク質(Xiangら、1994、1995)
5.マウス中のマラリアスポロゾイト周囲タンパク質(Sedegahら、1994;Hoffmanら、1994)
6.マウス中のリーシュマニアgp63(XuおよびLiew1995)
7.マウス中のリンパ球性脈絡髄膜炎ウイルス(LCMV)NP(Pedroz Martinsら、1995;Yokoyamaら、1995)
8.マウス中の癌胎児性抗原(Conryら、1994)
9.ラット中のMHCクラスI抗原(Geisslerら、1994)
10.ウサギ中のワタオウサギ乳頭腫ウイルス(CRPV)L1(Donnellyら、1996)
11.マウス中のM結核予防抗原85複合タンパク質(Huygenら、1996)(Kaufmann、1996)
1.狂犬病ウイルス糖タンパク質(Xiangら、1994)
2.マラリアスポロゾイト周囲タンパク質(Sedegahら、1994)
3.リンパ球性脈絡髄膜炎ウイルスNP(Pedroz Martinsら、1995;Yokoyamaら、1995;Zarozinskiら、1995)
4.HIVエンベロープタンパク質(Wangら、1994;Shiverら、1995)
5.ヒト第IX因子(Katsumiら、1994)
6.MHCクラス1(Geisslerら、1994;Plautzら、1994;Huiら、1994)
1.市販の供給源から適切なプラスミドベクターを選択するステップ、
2.被験体のHIVDNAを単離するステップ、
3.プラスミドDNAおよびHIVDNAの制限酵素による切断/修飾を実施するステップ、
4.HIV由来の特定の遺伝子を単離するステップ、
5.選択したHIVDNA遺伝子をPCR増幅するステップ、
6.プラスミドDNAから遊離リン酸(PO4)基を酵素により除去するステップ、
7.プラスミドDNAを大腸菌などの細菌細胞に形質転換するステップ、
8.リガーゼを投与してDNA鎖を1つにまとめるステップ
1.レシピエント細胞を塩化カルシウムの氷冷溶液中に浸すステップ(これによって、まだ完全には理解されていない方法でコンピテンシーを誘導する);
2.プラスミドDNAと細胞を混合させて、それらを氷上で20〜30分間インキュベートするステップ;
3.熱ショックを与えて(2分間、42℃)、DNAの細胞への進入を可能にするステップ;
4.形質転換細胞を栄養ブロス中で37℃において60〜90分間インキュベートするステップ。これによってプラスミドを確立することができ、最終的にはプラスミド核酸の表現型発現が可能になる;および
5.細胞およびプラスミドベクターを複製に適した選択培地上に置くステップ。
図3中に示すように、rDNA/RNAは細菌またはウイルス担体によって送達することができる。
C.2.3.1 細菌担体
生弱毒化細菌は、DNA/RNAの担体として働くことができる。細菌は、キャプシドタンパク質またはその一部分上にCypA結合部位をコードする、遺伝子を有し発現することができる。キャプシドタンパク質のDNA/RNAを増幅、精製および投与することができる環境を細菌は与える。細菌担体は当技術分野で一般的な細菌担体を含むことができ、例示的な型はサルモネラ、BCG、大腸菌、Strepococcus gordonii、Lactocci/Lactobacilli、ビブリオコレラ、Yersinia enterocholitica、フレクスナー赤痢菌、およびリステリアモノサイトゲネスである。サルモネラ、BCG、および大腸菌が好ましい。
組換えウイルスワクチンを工学処理して、それに対して宿主を保護しなければならない病原菌由来の遺伝子を発現させることができる。ベクターは媒体として働いて外来性遺伝子を宿主中に運び、核酸の転写および翻訳の後に、核酸によってコードされるタンパク質を宿主の免疫系に対して提示する。任意のワクチンと同様に、当然ながら、容認性に関する主な基準は安全性と有効性である。2つの観点から安全性に近づくことができる。免疫原の安全性は、事前の弱毒化または担体ウイルスに対する宿主の事前の予防接種によって良い安全記録を有する、ウイルスベクターを使用することによって確実にすることができる。第2に、合理的かつ信頼できる方法で、ウイルスを工学処理して安全性を改善することができる(Hughes、1998)。それに対して宿主が既に免疫処置されているウイルスベクターの使用は、記憶免疫応答によって免疫原がすぐに破壊され得る点で欠点を有する。それにもかかわらず、組換えDNAまたはRNAのいくつかの転写および翻訳が起こると思われる。好ましい方法は、組換えワクチン用の担体として、(担体ウイルスに対する事前の免疫処置無しで)弱毒化非毒性ウイルスを使用することであると思われる。
宿主細胞の活性化によって、メッセンジャーRNA(mRNA)へのウイルスDNAのHIV転写がもたらされる。HIVではウイルスRNAは、メッセンジャーおよびゲノムRNAとして働く。ウイルスDNAはmRNAに転写される。ウイルスmRNAは細胞質中に移動し、そこでウイルスmRNAは細胞内リボソームおよび細胞のトランスファーRNAと結合してウイルスタンパク質を生成する。メッセンジャーRNAは、ウイルスの遺伝情報を伝達する安定した鎖状の遺伝物質である。メッセンジャーRNAは、その安定性および有効性のため免疫原性組成物中に使用するのに魅力的である。メッセンジャーRNAは、タンパク質をコードする際にDNAより有効である。
DNAに基づく組成物は、従来のワクチンに優るいくつかの考えられる利点を与えることができる。1回の投与、長時間続く免疫、細胞仲介型免疫、および体液性応答を組換えDNA技術によって導入されるウイルス粒子の細胞内生成によって実現させることができる。対照的に、エンドサイトーシスによって内在化されるタンパク質に基づくサブユニットワクチンは一般に、細胞をCD8+T細胞認識に関して過敏にすることはない。
前に記したように、サブユニットタンパク質ワクチンは、細胞をCD8+T細胞認識に関して過敏にすることはできない。しかしながら、完全なタンパク質でCTL応答を初回抗原刺激することは、ISCOM(抗原をサイトゾルに送達するウイルスタンパク質を含み細胞傷害性T細胞の誘導を可能にする、脂質ミセルのマトリクス)またはリポソームなどの免疫刺激複合体中に抗原を取り込ませることによって行われてきている。さらに、動物中のクラスIMHC経路の抗原提示細胞を増大させるために、カチオン性脂質が使用されてきている。使用した1つのカチオン性脂質は、DOTAP(N-[1-(2,3-ジオレオイルオキシ)プロピル]-N,N,N-トリメチルアンモニウム硫酸メチル)であり、これはDNAトランスフェクション用に使用される市販のカチオン性脂質である。標的細胞を過敏にすることができる、他のカチオン性脂質が市販されている。これらの脂質は、1つまたは複数の正に帯電したアンモニウム基と結合した2つの長い疎水性アルキル鎖を有するDOTAPと構造が類似している。カチオン性脂質に関して示された作用機構は、全体的な正電荷を有するマクロ分子-脂質複合体と負に帯電した細胞表面の間の相互作用、次に細胞膜との融合を含む。対照的にpH感受性リポソームは、酸性環境のエンドソームと接触すると不安定になり、エンドソーム膜を破裂および/またはそれと融合してその中身を細胞質に放出すると考えられる。(Walker、1992)
したがって、本発明はタンパク質系組成物と核酸系組成物の両方を含み、これらを使用してキャプシドタンパク質上のCypA結合部位に対する免疫応答を誘導することができ、それに対する免疫記憶を生み出すことができると思われる。核酸系組成物はDNA、RNA、またはmRNAであってよい。組換え核酸担体は、細菌またはウイルスであってよい。組成物はCD8+T細胞応答を増大させるための、1つまたは複数の成分を含むことが好ましい。
本発明によって企図される免疫応答は、免疫応答を刺激する非特異的または特異的物質を使用することによって増大させることができる。本発明は、他の実施形態として以下に記載するものを含めた、適切な免疫刺激因子またはアジュバントと混合させることができる。このような組成物は、用途に応じて適切に使用することができる。当技術分野で知られている一般的な刺激因子またはアジュバントには、不完全フロイントアジュバント、リポソームなどがある。好ましい実施形態は、一般的なアジュバントおよび/または本明細書でさらに記載する組成物から採取された、1つまたは複数の刺激因子を含む。さらに、DNAは補体活性を増大させ、したがってDNAワクチンおよびアジュバントとして同時に使用することができる。(DPTワクチンは3つの別個のワクチン粒子から構成される。百日咳成分は他の2個のアジュバントとして働く。(Parham、:2004)。HIV疾患用の(好ましくはCypA結合部位の配列をコードする)DNAワクチンがCypAサブユニットワクチンのアジュバントとして働くと思われる、類似の状況がここで存在する。)
(1)硫酸化の量;15.6重量%まで硫酸化含量が高くなると、さらに高い補体活性化が生じた。2.43%未満の硫酸化含量に関しては、補体活性化は示されなかった;
(2)SSの濃度;高濃度は40〜50μg/mlの最大C3代謝回転で補体活性化をもたらす;および
(3)温度;4℃での全体の活性消失と共に、最大C3代謝回転が37℃において示された。
(Burger,R.ら、Immunology 33:827(1977))。可溶性と不溶性の両方の形のデキストラン(>5000分子量)が、補体活性化第2経路を活性化する。これはH因子の効果を阻害することによって行われる。(Burger,R.ら、European J.Immunology、pp.291〜295(1981))。低分子量硫酸デキストラン(<5000)はH因子の結合を増大させ、したがってそれは、補体活性化第2経路の活性を制限する。(Seppo Meriら、Proc.Natl.Acad.Sci、Vol87、pp3982〜3986(1990)。DNA様ヘパリンも、H因子の結合を増大させる。(Gardner,William D.、Biochemical and Biophysical Research Communications、Vol.94、pp61〜67(1980))
本発明のワクチン剤を構成する組成物を調製するために、精製、合成、または遺伝子工学の知られている方法を使用することができる。当業者はCypAのキャプシドタンパク質結合部位の断片を単離し精製することができ、あるいはそれををコードする配列を調製することができる。タンパク質断片、裸DNA/RNA、組換えDNA/RNA、またはメッセンジャーRNAを、担体または賦形剤などの、予想される投与法に適した医薬組成物中に取り込ませることができる。本発明に従った免疫応答が望ましい動物または被験体に、本発明の組成物を投与することができる;治療上有効な用量は、望ましい程度の特異的な免疫抑制を後進させるに必要な量であり、クロム放出アッセイ、細胞内サイトカインアッセイ、リンパ増殖アッセイ(LPA)、インターフェロンγ(IFN-γ)ELISpotアッセイ、およびMHCテトラマー結合アッセイなどの標準的手段を使用して決定されると思われる。MHCテトラマー結合アッセイが好ましい。これらと同じ実験用試験を施用して、非感染状態の被験体の免疫応答が測定されると思われる。
Claims (31)
- HIVに対する免疫反応を導き出す組成物であって、薬剤として許容される担体中にHIVキャプシドタンパク質上の少なくとも1つのCypA結合部位の有効量を含む組成物。
- 前記結合部位は組換え担体によって発現される、請求項1に記載の組成物。
- 前記組換え担体はウイルスである、請求項2に記載の組成物。
- 前記ウイルスはヘルペスウイルスである、請求項3に記載の組成物。
- 前記ヘルペスウイルスはエプスタイン-バーウイルスである、請求項4に記載の組成物。
- 前記ウイルスはポリオウイルスである、請求項3に記載の組成物。
- ノイラミニダーゼ、トリプシンまたは他の適当なシアル酸を除去する酵素で処理されている、請求項3に記載の組成物。
- 前記組換え担体は細菌である、請求項2に記載の組成物。
- 前記細菌はBacillus Calmette Guerinである、請求項8に記載の組成物。
- 前記細菌はListeria monocytogenesである、請求項8に記載の組成物。
- ノイラミニダーゼ、トリプシンまたは他の適当なシアル酸を除去する酵素で処理されている、請求項8に記載の組成物。
- 前記組換え担体は酵母である、請求項2に記載の組成物。
- 前記酵母はSaccharomyces cerevisiaeである、請求項12に記載の組成物。
- 前記結合部位はメッセンジャーRNAによって発現される請求項1に記載の組成物。
- HIVに対する免疫反応を導き出す医薬品を調製するための請求項1に記載の組成物の使用。
- 動物において免疫反応を導き出す方法であって、薬剤として許容される担体中にHIVキャプシドタンパク質の少なくとも1つのCypA結合部位エピトープの有効量を含む組成物を投与することを含む方法。
- 前記組成物は経口、口腔内、経粘膜、舌下、経鼻、直腸内、経膣、眼内、筋肉内、リンパ内、静脈内、皮下、経皮、皮内、腫瘍内、局所、肺内、吸入、注射、または体内移植により投与される、請求項16に記載の方法。
- 前記組成物はカプセル、ゲルキャップ、錠剤、腸溶カプセル剤、カプセル化粒子、散剤、坐薬、注射、軟膏、クリーム、インプラント、パッチ、液剤、吸入薬またはスプレー剤によって投与される、請求項16に記載の方法。
- 免疫刺激剤と組み合わされている、請求項1に記載の組成物。
- 前記免疫刺激剤がアジュバントである、請求項19に記載の組成物。
- 前記免疫刺激剤が前記組成物に結合できる形の少なくとも1つのマンノースから構成される多糖類を含む、請求項19に記載の組成物。
- 前記免疫刺激剤は前記組成物に結合できる形のタイコ酸を含む、請求項19に記載の組成物。
- 前記免疫刺激剤は前記組成物に結合できる形のザイモサンを含む、請求項19に記載の組成物。
- 前記免疫刺激剤は前記組成物に結合できる多糖類カプセルを有するcryptococcus neoformans血清型Cを含む、請求項19に記載の組成物。
- 前記免疫刺激剤はヘパリンに結合できる形のプロタミンを含む、請求項19に記載の組成物。
- 前記免疫刺激剤はヘパリナーゼを含む、請求項19に記載の組成物。
- 前記免疫刺激剤はC3bの生成を強化するように適応された形のコブラ毒因子を含む請求項19に記載の組成物。
- 前記コブラ毒因子はdCVFである請求項27に記載の組成物。
- 前記免疫刺激剤はC3コンバターゼ活性を強化するように適応された形のニッケルを含む、請求項19に記載の組成物。
- 前記免疫刺激剤はH因子を吸収できる硫酸化ポリアニオンを含む、請求項19に記載の組成物。
- H因子を強化できる前記組成物中のポリアニオンは前記組成物から実質的に除去されている、請求項1に記載の組成物。
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Non-Patent Citations (1)
Title |
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JPN6010047992, Li,Q. et al, "Design of a Gag pentapeptide analogue that binds human cyclophilin A more efficiently than the entir", J Med Chem, 2000, 43(9), 1770−9 * |
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