JP2006513273A - ウイルス感染を防止または処置するための組成物および方法 - Google Patents
ウイルス感染を防止または処置するための組成物および方法 Download PDFInfo
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Abstract
Description
本発明は、アレルギーおよび感染性疾患の国立機関(NIAID許諾番号AI−46457およびAI−13989)により出資された研究の経過においてなされた。米国政府は、本発明において一定の権利を有し得る。
3種のタイプの膜貫通タンパク質が、インフルエンザA型ビリオンおよびウイルスに感染した細胞の膜において発現される。赤血球凝集素およびノイラミニダーゼは、それぞれ〜510および〜420個のアミノ酸の大きい外部ドメインを有する糖タンパク質である。赤血球凝集素は、ホモ三量体として組み立てられ、ノイラミニダーゼは、ホモ四量体として組み立てられ、ウイルス膜上で、およびウイルス成熟の細胞部位において、長さが13〜14nmのロッド型の表面突起の密な層を形成する。現在のインフルエンザウイルスワクチンは、これらの糖タンパク質、特に赤血球凝集素に対する強力な抗体応答を誘発することを目的とし、このようなものとして抗体は、感染に対して高度に保護的であるとよく知られている。問題は、インフルエンザA型ウイルスが、これらの保護的な抗体により認識された決定因子を変化させる高度な性向を有し、これにより、これらの抗原的な変化を反映する更新されたワクチン株での反復されたワクチン接種が必要であることである。
本発明の1つの観点は、構造:
ここで、複合B細胞決定因子およびTヘルパー細胞(Th)決定因子を含む複合抗原剤(MAA)を接種した動物は、感染性ウイルスでのその後の攻撃に対して、顕著な耐性を示すことが見出された。本明細書中に定義したように、複合抗原剤は、動物において特異的な免疫応答を誘発することができる、1種より多いペプチドまたは核酸部分を含む剤である。B細胞決定因子は、抗体応答を誘発し、またT細胞応答を誘発することができる。ここで提供されるMAAの利点は、多数の抗原側鎖を、Lys−Gly繰り返しを含む核ペプチドに付着させ、これにより数種の構造的に結合した決定因子の提示を可能にすることができることである。さらに、Cys残基が、核ペプチドのN末端に結合する際には、2種の核ペプチドを、ジスルフィド結合を介して共有結合させて、抗原側鎖の数を有効に二倍化し、従って動物における免疫応答を改善することができる。さらに、ここで提供するMAAを、容易に化学的に合成することができるため、MAAの製造は、高度に制御され、汚染物は最小化される。
核酸配列が式I中に導入される場合には、前述の核酸配列を、スペーサーまたはリンカー分子、例えばヒドロキシ−カルボン酸を介して付着させることができる。
本明細書中に提供する例は、マウスにおける免疫応答を誘発するための式Iで表されるMAAの種々の誘導体を開示し、例示するものであり、本発明の範囲を限定しないことを意図する。本発明の範囲内の他の観点、利点および修正は、本発明が関連する当業者に明らかである。
3種の準直角に(quasi-orthogonally)除去可能なアミノ保護基の組み合わせを用いた、以下のもの:
Cys−Gly−Lys−Gly−Lys−Gly−Lys−β−Ala
(配列番号:6)からなるペプチド構成物Cys−主鎖および以下のもの:
ISC−CMは、2−メルカプトエタノールを0.05mMで、トランスフェリン(Sigma, St. Louis, MO)を0.005mg/mlで、グルタミン(JRH Biosciences, Lenexa, KS)を2mMで、およびゲンタマイシン(Mediatech, Herndon, VA)を0.05mg/mlで加えた、イスコーブダルベッコ(Iscove's Dulbecco's)培地(Life Technologies, Gaithersburg, MD)からなっていた。ISC−CMに、さらに、示したように、胎児ウシ血清(FCS)(HyClone Laboratories, Logan, UT)またはウシ血清アルブミン(BSA)(Sigma, St. Louis, MO)を加えた。リン酸緩衝生理食塩水、pH7.2に、3mMのNaN3を加えた(PBSN)。
PR8 (A/PR/8/34(H1N1))は、マウスに適合した株であった。PR8−SEQ14は、14個の異なるPR8(HA)特異性モノクローナル抗体の連続的な存在下でPR8から選択された逸脱突然変異体であった。X31は、H3およびN2をコードするものを除いて、すべてのPR8由来遺伝子を含む再構築ウイルスであり、これは、(A/Aichi/68(H3N2))からであった(Kilbourne (1969) Bull. WHO 41:643-5)。JAPは、(A/Japan/305/57(H2N2))であり、B/LEEは、B型インフルエンザウイルス株B/Lee/40であった。
3種のM2e特異性ハイブリドーマ(M2−56、M2−80、M2−86)は、2種の連続的な感染で、第1にPR8で、および第2にX31で攻撃したBALB/cマウスから由来していた。融合の3日前に、マウスに、静脈内に(i.v.)、PBS中の5μgの(4)M2e−MAAを注射し、脾臓細胞をSp2/O骨髄腫細胞と融合させた。2種のハイブリドーマ(M2−1、M2−15)は、3種の連続的なヘテロサブタイプ的感染(第1にPR8で、第2にX31で、第3にJAPで)から回復したマウスから由来しており、鼻腔内で(i.n.)、5μgの(4)M2e−MAA並びに3μgのホスホロチオエート化オリゴデオキシヌクレオチド(ODN)c1826および0.5μgのコレラ毒素(CT)で追加免疫した。排出するリンパ節(表層、頸部および縦隔)からの細胞を、3日後に融合させた。ハイブリッド培養物を、ELISAにおいて(1)M2e−MAAおよび/またはJAPで感染したMadin Darbyイヌ腎臓(MDCK)細胞と反応する抗体の分泌について、スクリーニングした。これらのプロトコルにより発生したすべてのM2e特異性ハイブリドーマは、M2e−MAAおよびJAPで感染したMDCK細胞と交差反応した。ハイブリドーマ14C2は、業界において十分知られている(Zebedee and Lamb (1988) 上記)。
コスター(Costar)血清クラスター(serocluster)の、丸底のポリビニルプレートのウェルを、(1)M2e−MAAで、0.5μg/mlでPBSN中で25μlの(1)M2e−MAAと共に室温で一晩インキュベートする(蒸発を防止するために覆った)ことにより、被覆した。プレートを、アッセイの前に、1%BSAを含むPBSNで1〜2時間遮断した。JAP−MDCK ELISAプレートを、以下のようにして作成した:MDCK細胞を、ファルコン(Falcon)、マイクロテスト(microtest)、平坦底、96ウェル、ポリスチレン、tcプレートにおいて、典型的には、ウェルに、5%FCSを含むISC−CM100μl中で、4×104個のMDCK細胞を播種することにより、密集度において成長させた。1日のインキュベーション(37℃、6%CO2)の後に、単層を、PBSで洗浄して、血清成分を除去し、インキュベーション(37℃)により、JAPウイルスの〜106のTCID50を含む50μlのISC−CMで感染させた。1時間後、5%FCSを含む100μlのISC−CMを、各々のウェルに加え、インキュベーションを、前述のように、6〜7時間継続した。
抗原提示細胞(APC)を、実験未使用のBALB/cマウスの脾臓から調製した。パーコール(PERCOLL)(登録商標)(PHARMACIA(登録商標)、Uppsala, Sweden)を、細胞懸濁液に加えて、33%の最終濃度を得た。懸濁液を、小さい容積の70%パーコール(登録商標)と共に下に配置し、遠心分離(10分、600g、室温)して、細胞残骸および赤血球を除去した。33%/70%界面における細胞を収穫し、洗浄し、照射し(2200rad)、ISC−CM中に5×106個の細胞/mlにおいて懸濁させた。100μlを、平坦底組織培養プレートのウェルあたり分配した。ISC−CM中の抗原を、ウェルあたり50μlの容積で加えた。50μlの応答細胞懸濁液、典型的には107/mlにおけるMedLN細胞またはISC−CM中で4×105/mlにおけるThクローンを、ウェルあたり加えた。1μCiのH3−チミジンを、インキュベーションの3日目(Thクローン)または4日目(LN応答細胞)の間に加えた。次に、プレートを凍結させ、1回融解させ、細胞を、スカトロン(Skatron)細胞収穫装置(Skatron Instruments Inc., Sterling, VA)で、フィルターマット(Skatron Instruments Inc., Sterling, VA)上に収穫した。フィルターマットの打ち抜いた片を、シンチレーション流動体中に移送し、放射活性について計数した。
ワクチン接種したマウスからの脾臓細胞を、33%/70%パーコール(登録商標)勾配において提供したように精製し、応答細胞として用いた。A20細胞(H2d、MHC II群について陽性)を、PR8(106TCID50/106A20、37℃で1時間)で感染させ、4400radで照射し、洗浄し、刺激剤として用いた。培養液(6ml)を、T25ファルコン(Falcon)フラスコ中に配置し、25×106個の応答細胞および106個の刺激細胞を、5%FCSを含むISC−CM中に含んでいた。インキュベーション(静止、直立)の5日後に、生存細胞を、33%/70%パーコール(登録商標)勾配において精製し、計数し、標準的な方法(Mozdzanowska, et al. (1997) Virology 239:217-25)を用いて、4時間のインキュベーション期間の間の、PR8およびB/LEEで感染したP1.HTR標的細胞からの51Crの放出を誘発する能力について試験した。
50μlの合計容積での、M2e−MAAおよび補助剤を、麻酔したマウスの鼻腔上に配置し(ケタミンおよびキシラジンを腹腔内に、それぞれ70mg/体重1kgおよび7mg/体重1kgで注射した)、この結果、気道中へのこの吸引がもたらされた。50μlの1回の用量は、3μgのM2e−MAA、3μgのODN1826(Krieg, et al. (1995) Nature 374:546-9; Yi, et al. (1998) J. Immunol. 160:4755-61)および0.5μgのCT(Sigma, St. Louis, MO)を含んでいた。補助剤の組み合わせおよび投与は、標準的な方法(Mozdzanowska, et al. (1999) 上記)に基づいていた。追加免疫接種を、4〜5週間隔で投与した。M2e−MAAを有しない補助剤溶液を施与されたマウスを、負の対照として用い、第1にPR8で、第2にPR8−SEQ14での、2種の連続的な気道感染を施されたマウスを、正の対照として用いた。
ワクチンにより誘発された保護の強度を、〜103MID50(50%マウス感染用量)のX31でのマウスのi.n.攻撃により試験した。3日後、マウスを麻酔し、心臓穿刺により放血させ、鼻、気管および肺組織を採集するために解剖した。感染性ウイルスの力価を、標準的な方法(McCluskie and Davis (2000) 上記)を用いた、MDCK細胞培養物または孵化鶏卵中の組織ホモジネートの滴定により、決定した。
野生型のウイルスM2eに対するTh依存性抗体応答を誘発するために、M2e−MAAは、B細胞エピトープを、野生型のウイルスにより誘発されたM2eと共有し、Th細胞に対して提示され得る決定因子を含んでいた。JAP−MDCK細胞およびM2e−MAAを、ELISAにおけるいくつかのM2e特異性モノクローナル抗体とのこれらの反応について比較した。14C2モノクローナル抗体は、精製されたウイルスM2(Zebedee and Lamb (1988) 上記)で免疫されたマウスから発生しており;すべての他の抗体は、連続的なインフルエンザA型ウイルス感染から回復し、融合の3日前に(4)M2e−MAAで追加免疫されたマウスから単離された。(4)M2e−MAAでの最終的な追加免疫を行って、M2e特異性ハイブリドーマの単離の頻度を増大させた。6種のM2e特異性モノクローナル抗体はすべて、M2e−MAAおよびJAP−MDCKの両方と良好に反応したが、4種は、JAP−MDCKに結合するにあたり、(1)M2e−MAAで1.5ng/ウェルで被覆されたウェルよりも、わずかに有効であり、2種は、わずかに有効ではなかった。データは、M2e−MAAが、野生型のウイルスにより誘発された四量体M2eのいくつかのB細胞決定因子を有効に模倣することを示した。
Claims (15)
- B細胞決定因子が、マトリックスタンパク質2またはこの相同体の外部ドメインを含む、請求項1に記載の複合抗原剤。
- 第1の、および第2の複合抗原剤のR1が、Cys−Glyであり、前記第1の、および第2の複合抗原剤の前記Cys残基が、共有結合して二量体を生成する、請求項1に記載の複合抗原剤。
- 請求項1に記載の複合抗原剤および薬学的に許容し得る担体を含む、組成物。
- 組成物がさらに補助剤を含む、請求項4に記載の組成物。
- 組成物がワクチンを含む、請求項4に記載の組成物。
- 組成物がワクチンを含む、請求項5に記載の組成物。
- ウイルス感染を防止または処置するための方法であって、被検者に、ウイルス感染の徴候または症候を防止または処置するのに有効な量の請求項4に記載の組成物を投与することを含む、前記方法。
- ウイルス感染を防止または処置するための方法であって、被検者に、ウイルス感染の徴候または症候を防止または処置するのに有効な量の請求項5に記載の組成物を投与することを含む、前記方法。
- ウイルス感染を防止または処置するための方法であって、被検者に、ウイルス感染の徴候または症候を防止または処置するのに有効な量の請求項6に記載の組成物を投与することを含む、前記方法。
- ウイルス感染を防止または処置するための方法であって、被検者に、ウイルス感染の徴候または症候を防止または処置するのに有効な量の請求項7に記載の組成物を投与することを含む、前記方法。
- ウイルス感染がインフルエンザA型ウイルスを含む、請求項8に記載の方法。
- ウイルス感染がインフルエンザA型ウイルスを含む、請求項9に記載の方法。
- ウイルス感染がインフルエンザA型ウイルスを含む、請求項10に記載の方法。
- ウイルス感染がインフルエンザA型ウイルスを含む、請求項11に記載の方法。
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JPN5005015232, KRAGOL. G. et al., ""Synthesis of a disulfide−linked octameric peptide construct carrying three different antigenic dete", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, Vol.11, P.1417−1420 * |
JPN5005015233, NIERYNCK, S. et al., ""A universal influenza A vaccine based on the extracellular domain of the M2 protein."", NATURE MEDICINE, 199910, Vol.5, No.10, P.1157−1163 * |
JPN5005015234, KRAGOL, G. et al., ""Orthogonal solid−phase synthesis of tetramannosylated peptide constructs carrying three independent", TETRAHEDRON, 2001, Vol.57, P.957−966 * |
JPN5005015235, MOZDZANOWSKA, K. et al., ""Induction of influenza type A virus−specific resistance by immunization of mice with a synthetic mu", VACCINE, 2003, Vol.21, P.2616−2626 * |
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