JP2016513960A - T細胞ターゲティングを調節することができるサイトメガロウイルスベクター - Google Patents
T細胞ターゲティングを調節することができるサイトメガロウイルスベクター Download PDFInfo
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Abstract
Description
本発明を、国立衛生研究所によって拠出された助成金番号PO1 AI094417の合衆国政府の支援を得て実施した。合衆国政府は本発明に一定の権利を有する。
生物に反復して感染させることができるヒトまたは動物のサイトメガロウイルス(CMV)ベクターを本明細書中に開示する。CMVベクターは、異種タンパク質抗原をコードする核酸配列および活性なUL131タンパク質をコードする核酸配列を含む。1つの例では、CMVベクターは、活性なUL128タンパク質を発現するが活性なUL130タンパク質を発現しない核酸配列を含む。別の例では、CMVベクターは、活性なUL130タンパク質をコードするが、活性なUL128タンパク質を発現しない。
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活性なUL128およびUL130を欠くが(ΔUL128−130)、活性なUL131を含むRhCMV68−1株(Hansen,SGら,J Virol 77,6620(2003);本明細書中で参考として援用される)由来のRhCMV/gagベクターによって誘発されたSIVgag特異的CD8+T細胞応答のエピトープターゲティングプロフィールを、より一般的なベクターおよびSIV自体によって誘発されるプロフィールと比較した。フローサイトメトリー細胞内サイトカイン染色を使用して、全SIVgagタンパク質を対象とする125の連続する15merペプチド(11アミノ酸の重複)の各々に対するCD8+T細胞応答を個別に定量した。全部で29頭のアカゲザル(RM)を使用した:14頭にΔUL128−130RhCMV/gagベクターでワクチン接種した。4頭にエレクトロポレーションを行ったDNA/gag+インターロイキン(IL)−12をワクチン接種した。3頭にアデノウイルス(Ad)5/gagをワクチン接種し、別の3頭にワクシニアウイルス(MVA)/gagをワクチン接種した。別の5頭に、自然発生的なウイルス制御を有するSIV(SIVmac239)を予め感染させた。
MHC−I拘束性エピトープは、典型的には8〜10アミノ酸長であり、上記のタイプ1短縮パターンと一致する「末端閉鎖」MHC−1結合溝(Rammensee HGら,Ann Rev Immunol 11,213(1993);本明細書中で参考として援用される)の特性に適合するように結合ポケット(アンカー残基)に会合する位置特異的アミノ酸を有する。対照的に、タイプ2短縮パターンは、MHCII拘束性エピトープにより典型的である(典型的にはより長く、通常12merコアを超え、特異的アンカー残基を欠き、長さの不均一性により耐性を示す(Southwood Sら,J Immunol 160,3363(1998)およびChelvanayagam G,Hum Immunol 58,61(1997);その両方が本明細書中で参考として援用される)。これは、RhCMV/gagベクターワクチン接種RMにおけるタイプ2 SIVgagエピトープを認識するCD8+T細胞がMHC−II拘束性であり得ることを示唆していた。これに関して、クラスII拘束性CD8+T細胞応答は明らかに普通ではないが、かかる応答は、マウス(Mizuochi Tら,J Exp Med 168,437(1988);Suzuki Hら,J Immunol 153,4496(1994);Matechak EOら,Immunity 4,337(1996);Shimizu T and Takeda S,Eur J Immunol 27,500(1997);Tyznik AJら,J Exp Med 199,559(2004);Pearce ELら,J Immunol 173,2494(2004);その全てが本明細書中で参考として援用される)およびヒト(Heemskerk MHら,Proc Natl Acad Sci USA 98,6806(2001);Rist Mら,Blood 114,2244(2009);Hirosawa Tら,Cancer Sci 102,1281(2011);その全てが本明細書中で参考として援用される)の両方で以前に報告されており、有意義なTCRシグナル伝達にはそれぞれのMHC−IIまたはMHC−Iとの特異的なCD4またはCD8共受容体会合が必要ないということが証明されている(Viola Aら,J Exp Med 186,1775(1997)およびLustgarten Jら,Eur J Immunol 21,2507(1991);その両方が本明細書中で参考として援用される)。
RhCMV/SIVベクターワクチン接種によって生成および維持されたSIV特異的CD8+T細胞の通常でないエピトープ特異性は、これらの応答を支配する特に非従来型のMHC−II拘束性集団の機能的潜在性に関する問題を提起する。第1に、これに関して、最適なペプチド(タイプ1およびタイプ2の両方)に対する応答を100000倍超の希釈倍率のペプチド濃度で証明することができるので(図4A)、これらのスーパートープ特異的CD8+T細胞応答は、標準的なICSアッセイで使用した高ペプチド濃度の人為的結果ではない。第2に、タイプ1およびタイプ2スーパートープ特異的応答はワクチン接種直後に惹起され(図4B)、RhCMV/SIVベクターワクチン接種RMについて前に報告したパターンで(Hansen SGら,Nature 473,523(2011);本明細書中で参考として援用される)全身に協調的に分布している(図4Cおよび4D)。第3に、RhCMV特異的CD8+T細胞およびRhCMV/SIVベクター誘発SIV特異的T細胞について以前に報告されるように(Hansen SGら,Nat Med 15,293(2009);本明細書中で参考として援用される)、タイプ1およびタイプ2スーパートープ特異的T細胞の両方は、エフェクターメモリーT細胞分化を示す同一の表現型(CCR7−、CD28−)およびこのエフェクター−メモリー表現型と一致する同一の多機能プロフィール(高いTNF、IFN−γ、およびMIP−1αの産生、高CD107内在化(脱顆粒)、および低IL−2産生)を示す(図4Eおよび4F)。エフェクターメモリー分化がAg駆動であると考えられるので、これらのデータは、ワクチン接種したRMでは、これらのCD8+T細胞がタイプ1およびタイプ2のエピトープに等価にin vivo曝露されると示唆される。
この通常でないCD8+免疫応答に関連し、前記応答を潜在的に担う候補CMV遺伝子を同定するために、内因性CMV最初期(IE)タンパク質に対するCD8+T細胞応答も非従来型のエピトープ(特に、MHC−IIによって拘束されるスーパートープ)をターゲティングするかどうかを最初に問うた。これを、野生型RhCMV(コロニー流行株)で天然に感染させたRMおよび例示的なΔUL128−130欠損68.1株RhCMV/SIVベクターをワクチン接種したRMの評価によって決定した。驚くほどのことではないが、ΔUL128−130ベクターをワクチン接種したRMは、同一RMにおいてSIVgag特異的CD8+T細胞応答と同一のターゲティング特性を有するIE特異的CD8+T細胞応答が証明された:30超の異なるIEエピトープ/RM(抗MHC−IIで遮断されたエピトープ特異的応答の大部分および抗MHC−Iで遮断された少数の部分が含まれる)。
RhCMV68.1株を、RhCMV/SIVベクター構築におけるその使用前に線維芽細胞培養において複数回継代し、この株はUL130遺伝子の一部および全UL128遺伝子を欠失することが元の野生分離株と異なる(Gillら,Virology 447,208(2013);本明細書中で参考として援用される)。UL128およびUL130の遺伝子は、5’−UL131−UL130−UL128−3’の順序でUL131と共に単一のmRNA上にコードされる(Lilja AEら,2008 前出)。3つ全ての遺伝子がこの単一の「多シストロン性」mRNAによってコードされ、且つこのmRNAの全3’末端が68−1中で欠如しているので、以前にはHansen SGら,Science 340,1237874 doi,24 May 2013(本明細書中で参考として援用される)において、68.1の欠如によりHCMV UL128、130、および131遺伝子の3つ全ての活性RhCMVオルソログ(Rh157.6、157.4、および157.5)を発現できると考えられていた。MHC−II拘束性CD8+T細胞のプライミングの調整におけるUL128、UL130、およびUL131の個別の機能を決定するために、本発明者らは、これらの各遺伝子を個別に欠くRhCMV/SIVgagベクターを生成した。UL128−130「修復」RhCMV−68−1.2ウイルス(Liljaら 2008 前出)を本発明者らの出発点として使用して、本発明者らは、ΔUL128RhCMV/gag、ΔUL130/RhCMVgag、およびΔUL131/RhCMVgagを生成し、これらの各構築物を予めRhCMVを天然に感染させた2頭のRMに接種した。図6に示すように、UL128を欠くがUL130およびUL131を含むRhCMVは、両動物においてSIVgagに対するT細胞応答を誘導した。同様に、UL130を欠くがUL131およびUL128を含むRhCMVは、両動物においてSIVgagに対するT細胞応答を誘導した。対照的に、UL131を欠くがUL130およびUL128のインタクトな遺伝子を含むRhCMVは、CMV陽性動物において免疫応答を誘導することができなかった。これらのデータは、機能的UL131遺伝子にはCMV陽性動物の重複感染が必要であることを示唆している。RhCMV68−1が重複感染可能であるので、この結果はまた、多シストロン性mRNAの一部の欠失にもかかわらずRhCMV68−1が機能的UL131を含み、RhCMV68−1がΔUL128−130ベクターであることと一致していることを証明している。UL130またはUL128が単一欠失したベクターがMHC−II拘束性CD8+T細胞を誘発するかどうかをさらに決定するために、本発明者らは、MHC−IまたはMHC−II−遮断抗体の存在下でのSIVgagのアミノ末端部分に対応する25の重複15merペプチドに対するCD8+T細胞応答をモニタリングした。図7に示すように、個別のペプチドに対するMHC−IおよびMHC−II拘束性CD8+T細胞応答の両方が認められた。これらの結果は、UL128またはUL130のいずれかを欠くがUL131を含む単一欠失ベクターが非従来型のT細胞応答を誘導することができることを証明している。
上記実施例では、本発明者らは、UL128および/またはUL130を欠くベクターがCMV−IEタンパク質またはSIVgagタンパク質などのウイルス抗原に対してより一般的に認められるMHC−IよりもむしろMHC−IIに拘束される非従来型のCD8+T細胞を誘導することを証明した。ΔUL128−130ベクターが細菌抗原に対してMHC−II拘束性CD8+T細胞を誘導することもできるかどうかを決定するために、本発明者らは2つのMycobacterium tuberculosis抗原の融合タンパク質をΔUL128−130ベクターに挿入した。得られたベクターRhCMV/TBは、Mycobacterium tuberculosisの50kDa融合タンパク質ESAT6および抗原85Bをコードする(Derrick SCら、Vaccine 23、780−788(2004);本明細書中で参考として援用される)。ESAT6は初期分泌タンパク質であるのに対して、抗原85Bは結合し、Mycobacterium tuberculosisによって発現される最も豊富なタンパク質である(Brandt,J Immunol 157,3527(1996)本明細書中で参考として援用される)。3頭のRMにRhCMV68−1由来ベクターRhCMV/TBを接種し、個別のペプチドに対するCD8+T細胞応答を、MHC−IまたはMHC−IIを遮断する抗体の存在下でモニタリングした。図8に示すように、ワクチン接種した各動物は両方の抗原に対するCD8+T細胞応答を生じ、CD8+T細胞によってはMHC−Iによって拘束されたものもあれば、他のMHC−IIによって拘束されたものもあった。したがって、これらのデータは、UL128およびUL130を欠くCMVベクターによるMHC−II拘束性CD8+T細胞を誘導する能力がウイルス抗原に制限されず、他の異種抗原(細菌抗原が含まれる)に拡大することができることを証明している。
上記の実施例では、本発明者らは、UL128−130を欠くベクターがMHC−IおよびMHC−II拘束性のCD8+T細胞の両方を誘導するのに対して、UL128−130インタクトなベクターがMHC−I拘束性CD8+T細胞のみを誘導することを証明した。同一抗原を保有するがUL128およびUL130の存在に関して異なるベクターによる連続接種が異種抗原のエピトープ範囲を増大させるかどうかを決定するために、本発明者らは、ΔUL128−130(68−1)を予めワクチン接種した2頭のRMに別のラウンドのΔUL128−130(68−1)を接種後、UL128−130「修復」(68−1.2)RhCMVベクターを連続的に接種した。全ベクターがSIVgagを発現した。SIVgagに対する全CD8+T細胞応答を、ΔUL128−130(68−1由来)ベクターおよびUL128−130修復(68−1.2由来)ベクターの両方の再ワクチン接種によって追加免疫した一方で、68−1/SIVgagベクターでの以前のワクチン接種に起因する各動物中に存在する個別のペプチドに対する応答を、68−1/SIVgagベクターによって追加免疫したが、68−1.2/SIVgagベクターによって追加免疫しなかった(図9、上のパネル)。個別のペプチドがMHC−IおよびMHC−IIのいずれかによって拘束されたCD8+T細胞によって認識されたので、これらのデータは、UL128およびUL130を欠くベクターによって誘導されるエピトープ範囲がMHC−I拘束性T細胞についてさえインタクトなUL128およびUL130を含むベクターのエプトープ範囲と重複しないことを証明している。この結果は、同一抗原を保有するUL128/130欠失ベクターおよびUL128−130インタクトベクターでの同一個体の連続ワクチン接種が単一ベクターを用いた接種と比較して遥かに広い範囲のT細胞応答を誘導することをさらに示唆していた。この結論は、個別のSIVgagエピトープに対するCD8+T細胞応答が68−1/gagでの単一のワクチン接種、68−1/gagでの再ワクチン接種、および68−1.2/gagでのワクチン接種後に2頭のRMにおいてモニタリングされた場合に支持された。図9の下のパネルに示すように、同一タイプのベクターでの再ワクチン接種およびそのUL128−130組成が異なるベクターでのワクチン接種の両方により、以前のワクチン接種由来のT細胞応答を維持しながらさらなるSIVgagエピトープを認識する新規のT細胞が誘導された。各コアエピトープが9−12アミノ酸長であり、且つSIVgagが510のアミノ酸をコードすることを考慮して、これらの動物における連続ワクチン接種ストラテジーによって誘導された45−52エピトープは、全SIVgagポリペプチド配列の約90%を対象とする。本発明者らが知る限り、このエピトープ範囲レベルは任意の他のベクター系を使用して以前には認められなかった。
動物:全部で165頭の目的に合うように交配された遺伝子背景がインドの雄または雌の若年アカゲザル(Macaca mulatta)を本研究で使用した(68−1株RhCMV/SIVベクター(野生型または遺伝子改変型、単独またはその後に従来のワクチンまたはウイルス抑制SIV感染で異種プライミングを行った)でワクチン接種した110頭のマカク、SIV感染のみの47頭のマカク(SIVmac239またはSIVmac251)、およびRhCMVのコロニー流行株で天然に感染した8頭の非ワクチン接種マカクが含まれる)。NIHの実験動物の管理と使用に関する指針の基準下で、Oregon National Primate Research Center Institutional Animal Care and Use Committeeに承認された全てのマカクを使用した。これらの実験で使用したマカクは、オナガザル(cercopithicine)ヘルペスウイルス1、D型サルレトロウイルス、およびサルTリンパ球向性ウイルスタイプ1を持たなかった。Mamu−A*01、Mamu−A*02、Mamu−B*08、およびMamu−B*17対立遺伝子のMHC−I遺伝子型同定を、Loffredo JTら、J Virol 81、8827(2007)(本明細書中で参考として援用される)に記載の配列特異的プライミングポリメラーゼ連鎖反応(PCR)によって行った。選択したマカクに対して大規模シーケンシングによってDRB−遺伝子型同定を行った。簡潔に述べれば、Mamu−DRB領域のアンプリコンを、高信頼性Phusion(登録商標)ポリメラーゼ(NEBiolabs)およびユニバーサルMHC−DRB特異的プライマーの対(5’−CGTATCGCCTCCCTCGCGCCATCAG−MID−CTGGTCCTGTCCTGTTCTCC−配列番号1;5’−CTATGCGCCTTGCCAGCCCGCTCAG−MID−TGGAAGGTCCAGTCTCCATT−配列番号2)を用い、以下の熱サイクル条件を使用したPCRによるcDNAの増幅によって作製した:98℃で3分間、(98℃で5秒間、60℃で10秒間、72℃で20秒間)を25サイクル、および72℃で5分間。一次cDNA−PCR産物を、AMpureXP磁性ビーズ(Beckman Coulter Genomics)を使用して精製した。Lib−Aキット(Roche/454 Life Sciences)を使用したエマルションPCR、ビーズ精製、およびRoche/454 GS Junior装置を使用したピロシーケンシング手順を、製造者の説明書通りに行った。配列アセンブリのためのGeneious−Pro(登録商標)バイオインフォマティクスソフトウェア(Biomatters Ltd.)と併せてLabkeyデータベースを使用してデータを分析した。免疫学的アッセイのための単核球調製物を、記載のように(Pitcher CJら,J Immunol 168,29(2002)およびVeazey RSら,Science 280,427(1998);その両方が本明細書中で参考として援用される)血液、骨髄、気管支肺胞洗浄液(BAL)、リンパ節、脾臓、肝臓、骨髄、および腸粘膜から得た。精製CD8+T細胞(純度90%超)を、CD8マイクロビーズおよびLSカラム(Miltenyi Biotec)を使用してPBMCから得た。SIV+マカクの血漿ウイルス量を、定量的リアルタイム逆転写PCR(RT−PCR)(60)によって決定した。SIV+マカクは、血漿ウイルス量が2.0×104コピー/ml未満である場合にSIVコントローラーと見し、血漿ウイルス量が3.0×103コピー/ml未満である場合にeliteコントローラーと見なした。
Claims (18)
- 異種タンパク質抗原をコードする第1の核酸配列;
UL128またはそのオルソログをコードする第2の核酸配列;および
UL131またはそのオルソログをコードする第3の核酸配列
を含む、ヒトまたは動物のサイトメガロウイルスベクターであって、
前記ベクターが活性なUL130タンパク質を発現しない、ベクター。 - 異種タンパク質抗原をコードする第1の核酸配列;
UL130またはそのオルソログをコードする第2の核酸配列;および
UL131またはそのオルソログをコードする第3の核酸配列
を含む、ヒトまたは動物のサイトメガロウイルスベクターであって、
前記ベクターが活性なUL128タンパク質を発現しない、ベクター。 - 前記ベクターが、点変異、フレームシフト変異、またはUL128もしくはUL130の全てもしくは全て未満の欠失から選択される、UL128またはUL130における変異を含む、請求項1〜2に記載のベクター。
- 第4の核酸配列をさらに含み、前記第3の核酸配列がUL128またはUL130の発現を阻害するアンチセンス配列またはRNAi配列を含む、請求項1〜2のいずれかに記載のベクター。
- 前記異種抗原が病原体特異的抗原を含む、請求項1〜4に記載のベクター。
- 前記病原体特異的抗原が、ヒト免疫不全ウイルス、サル免疫不全ウイルス、またはMycobacterium tuberculosisに由来する、請求項5に記載のベクター。
- 被験体において異種抗原に対するCD8+T細胞応答を生成する方法であって、
有効量の第1のサイトメガロウイルス(CMV)ベクターを前記被験体に投与する工程であって、前記第1のCMVベクターが第1の異種抗原をコードする第1の核酸配列および活性なUL131タンパク質をコードする第2の核酸配列を含む、工程を含み、
ここで、前記第1のCMVベクターが活性なUL128タンパク質をコードしないか、活性なUL130タンパク質をコードせず、前記異種抗原に対する少なくとも10%の前記CD8+T細胞がMHCクラスIIによって提示されたエピトープに指向する、方法。 - 前記第1のCMVベクターが活性なUL128タンパク質をコードせず、且つ活性なUL130タンパク質をコードしない、請求項7に記載の方法。
- 前記応答が少なくとも50%のクラスII拘束性CD8+エピトープを含む、請求項7に記載の方法。
- 前記第1の異種抗原が病原体特異的抗原を含む、請求項7〜9のいずれかに記載の方法。
- 前記病原体特異的抗原が、ヒト免疫不全ウイルス、サル免疫不全ウイルス、またはMycobacterium tuberculosisに由来する、請求項10に記載の方法。
- 前記被験体が事前にCMVに暴露されている、請求項7〜11のいずれかに記載の方法。
- 前記被験体がヒトまたは非ヒト霊長類である、請求項7〜12のいずれかに記載の方法。
- 投与が前記CMVベクターの静脈内投与、筋肉内投与、腹腔内投与、または経口投与を含む、請求項7〜13のいずれかに記載の方法。
- 第2の異種抗原をコードする第3の核酸配列を含む第2のCMVベクターを前記被験体に投与する工程をさらに含む、請求項7に記載の方法。
- 前記第2のCMVベクターが、活性なUL128タンパク質および活性なUL130タンパク質をコードする、請求項15に記載の方法。
- 前記第1の異種抗原および前記第2の異種抗原が同一の抗原である、請求項15または16に記載の方法。
- 前記第2のCMVベクターを前記第1のCMVベクターの前、同時、または後に投与する、請求項15〜17に記載の方法。
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CA2904001A1 (en) | 2014-09-12 |
US20200140888A1 (en) | 2020-05-07 |
LT2964769T (lt) | 2018-12-10 |
JP6483033B2 (ja) | 2019-03-13 |
HRP20181930T1 (hr) | 2019-01-11 |
AU2014225886B2 (en) | 2020-04-16 |
AU2014225886A1 (en) | 2015-10-15 |
EP2964769A1 (en) | 2016-01-13 |
CA2904001C (en) | 2021-07-13 |
EP2964769B1 (en) | 2018-08-22 |
PL2964769T3 (pl) | 2019-03-29 |
SI2964769T1 (sl) | 2018-12-31 |
BR112015021945A2 (pt) | 2017-07-18 |
US9783823B2 (en) | 2017-10-10 |
BR112015021945A8 (pt) | 2019-12-03 |
EP3473723A1 (en) | 2019-04-24 |
US20180087069A1 (en) | 2018-03-29 |
EP2964769A4 (en) | 2016-08-31 |
DK2964769T3 (en) | 2018-12-10 |
ES2696703T3 (es) | 2019-01-17 |
US10316334B2 (en) | 2019-06-11 |
WO2014138209A1 (en) | 2014-09-12 |
US20160010112A1 (en) | 2016-01-14 |
AU2020204529A1 (en) | 2020-07-30 |
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