JP5667062B2 - 免疫原特異的アジュバントとしての組換えタンパク粒 - Google Patents
免疫原特異的アジュバントとしての組換えタンパク粒 Download PDFInfo
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Description
本発明は、ワクチンまたは接種物用の免疫原特異的アジュバントを提供する。より具体的には、本発明は、組換え融合タンパク質を含有する組換えタンパク粒様会合体(RPBLA)を含んでなるワクチンまたは接種物アジュバントを提供する。該組換え融合タンパク質は、ペプチド結合された2つの配列を含み、一方の配列はタンパク粒誘導配列(PBIS)であり、他方は、ワクチンまたは接種物に存在するかまたはワクチンまたは接種物によりコードされる病原性ポリペプチド配列の一部に相当するT細胞刺激性ポリペプチドである。
タンパク粒(PB)は、タンパク質の蓄積に特化した細胞下のオルガネラ(または大きな小胞、直径約1〜3ミクロンで膜に取り囲まれている)。それらは天然では、種子などのいくつかの特定の植物組織で形成され、発芽や実生成長のための主要なアミノ酸供給源として働く。
「抗原」とは、抗体または受容体が結合するものを表して、また、CD4+T細胞の生成など、抗体の生産または細胞応答を誘導するものを表して歴史的に用いられてきた。より最近の用法では抗原の意味を抗体または受容体が結合するものに限定し、「免疫原」という用語は、抗体生産または細胞応答を誘導するものとして用いられる。本明細書で述べられているものが免疫原性かつ抗原性の双方である場合には、それを免疫原というか抗原というかは、一般にその意図される用法に従ってなされる。
(i)組換え融合タンパク質(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)を含有する粒子状組換えタンパク粒様会合体(RPBLA)および
(ii)融合タンパク質をコードする核酸分子(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)
の群から選択されるワクチンの投与を含んでなる。
(i)HPV E7遺伝子によりコードされるポリペプチド、
(ii)HIV−1 gag遺伝子によりコードされるポリペプチド、および
(iii)HIV−1 pol遺伝子によりコードされるポリペプチド
の群から選択される、第二の部分を含んでなるRPBLAを用いて行われる。
(i)組換え融合タンパク質(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分がT細胞刺激免疫原性ポリペプチドである)を含有する粒子状組換えタンパク粒様会合体(RPBLA)、
(ii)免疫原性ポリペプチドをコードする核酸分子、および
(iii)融合タンパク質をコードする核酸分子(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)
の群から選択される。
(i)組換え融合タンパク質(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)を含有する粒子状組換えタンパク粒様会合体(RPBLA)および
(ii)融合タンパク質をコードする核酸分子(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)
の群から選択される。
タンパク粒(PB)は唯一種子で適宜そう呼ばれているので、他の植物器官および非高等植物で生産される類似の構造は一般に合成PBまたは「組換えタンパク粒様集合物」(RPBLA)と呼ばれる。このようなRPBLAは、細胞の小胞体(ER)と会合して見られる膜に封入された融合タンパク質である。
文献で、多数のT細胞刺激免疫原性ポリペプチド配列が同定されている。一部のリストを下表に、1文字コードを用いて示す。
クローニングされたSouth African HIV単離株Du422(GenBank受託番号AF544010)からの、HIV−1 p24、p41およびRTをコードするDNAを、PCRを用いてZera(登録商標)と融合し、その後、大腸菌で、A.ツメファシエンス(A.tumefaciens)バイナリー発現ベクターpTRAc(Meyers, BMC Biotechnology 2008 8:53)にクローニングし、組換えクローンpTRAcRX3p24、pTRAcRX3p41およびpTRAcRX3RTを得た。
浸透させた葉の組織 およそ10gを液体窒素中で摩砕し、20mlのバッファーPBP3(100mM Tris pH8、50mM KCl、6mM MgCl2、10mM EDTAおよび0.4M NaCl)に再懸濁させた。この懸濁液を3分間ホモジナイズした後、ミラクロス(Calbiochem(登録商標), San Diego, CAから入手可能な孔径22〜25mmのレーヨンポリエステルとアクリル系結合剤からなる、ゼラチン状のホモジネートおよびプロトプラスト単離用の迅速濾材)で濾過した。濾液を密度ステップ勾配の上にのせた。この勾配はバッファーPBP3で作製した7ml容の15、25、35および45%濃度Optiprep(登録商標)密度勾配媒体からなった。この勾配をBeckman SW28ローターにて4℃、80000Xgで2分間遠心分離した。ペレットを500μlのバッファーPBP3に再懸濁させ、分析のためにアリコートを保存した。残りを−70℃で保存した。
HIV群試験
雌BALB/cマウス(8〜10週齢)を適当数の群に分けた(5匹/群)。
群1−vDNAプライム
群2−vDNAプライム+vDNAブースト
群3−vDNAプライム+RPBLAブースト
群4−RPBLAプライム
DNAワクチン接種
6〜8週齢の雌C57BL/6マウスの各前脛骨筋に、DNAを注射する5〜6日前に10μMのカルジオトキシン50μlを注射した。ワクチン接種では、50μlのプラスミドDNA(1μg/PBSμl)を各前処理筋肉に注射した。10日後にマウスを犠牲にし、脾臓から脾細胞を単離した。
腫瘍保護および退縮試験は本質的に(Ohlschlager et al., Vaccine 2006 24(2):2880-2893)に記載されているように行った。プロトコールの具体的な修正は対応する実施例に示されている。
HIV抗原
12日目または40日目に回収し、各群マウス5匹からプールした脾臓から脾細胞の単細胞懸濁液を調製した。IFN−γ ELISPOT応答を、マウスIL−2またはIFN−γ ELISPOTセット(BD Pharmingen)を用いて測定した。脾細胞を最終容量200μlのR10培養培地(10%熱不活性化FCS(Gibco)を加えた、15mM β−メルカプトエタノール、100Uペニシリン/mlおよび100?μgストレプトマイシンを含有するRPMI)中、5×105/ウェルで、3反復で播種した。
総ての試験で、ELISPOTは(Steinberg et al., 2005 Vaccine 23:1149?1157)に本質的に記載されているようにex vivoで行った。ネズミIFN−γElispotアッセイはex vivoで、また、最初に(Ohlschlager et al., 2006)に記載されているように各in vitro再負荷の5または6日後に行った。グランザイムB Elispotアッセイは、IFN−γElispotアッセイと同様に行った。このアッセイでは、抗マウスグランザイム捕捉抗体(100ng/ウェル、クローンR4−6A2;PharMingen, San Diego, USA)およびビオチン化抗マウスグランザイム検出抗体(50ng/ウェル、クローンXMG1.2;PharMingen, San Diego, USA)を用いた。
ウエスタンブロットはLAV Blot I市販キット(Biorad)を用いて行った。接種マウスからのマウス血清を用い、アルカリ性ホスファターゼコンジュゲートヤギ抗マウスIgGで抗体を検出した。
対応する構築物(pRX3−p24、pRX3−p41またはpRX3−RT)でアグロインフィルトレーションされた葉組織およそ10gを液体窒素中で摩砕し、20mlのバッファーPBP3(100mM Tris pH8、50mM KCl、6mM MgCl2、10mM EDTAおよび0.4M NaCl)に再懸濁させた。これを、ポリトロンホモジナイザーを用いて氷上で3分間ホモジナイズした後、ミラクロスで濾過した。対応する濾液を、バッファーPBP3で作製した7ml容の15、25、35および45%濃度Optiprep(登録商標)密度勾配媒体を含んでなる密度ステップ勾配の上にのせた。この勾配をBeckman SW28ローターにて4℃、80,000xgで2時間遠心分離した。ペレットを500μlのバッファーPBP3に再懸濁させ、光学顕微鏡でRPBLAの存在を確認し、分析のためにアリコートを保存した。残りを−70℃で保存した。
RX3−p24含有RPBLAの投与により誘発された細胞性免疫応答を測定するため、4群のマウスに次のように接種した:(i)DNAワクチンを接種したマウス(pTHGagx1)、(ii)DNAワクチンを接種し、別の用量の同じおよびDNAワクチンで追加免疫したマウス(pTHGagx2)、(iii)DNAワクチンを接種し、RX3−p24を含むが、さらなるDNAを含まないRPBLAで追加免疫したマウス(pTHGag+RX3−p24)、および(iv)RX3−p24単独を含むRPBLAを接種したマウス(RX3−p24)。
AIDSのリスクは、p24抗体の力価が低下した個体で著しく高まることが示されており、これは高い抗p24抗体力価が無病状態の維持に必要であり得ることを示唆している。
従前に示されているように、HIV Gagタンパク質のp17およびp24断片(p17/24)の融合から得られたp41は、HIV−1ゲノムにおいて最も高い密度のCTLエピトープを含む(Novitsky et al., J. Virol. 2002 76(20):10155-10168)。これに関して、RX3−p41融合タンパク質を含むRPBLAの、免疫系の細胞応答誘発効率を調べた。
HIVに対して有効な多価ワクチンは数種の抗原を含むことから、HIVウイルスタンパク質RTを用いて同様の研究を行った。
HIV抗原をコードするDNAワクチンは包括的に研究され、動物モデルならびにヒトにおいて体液性および細胞性双方の免疫応答を誘導することが示されている(Estcourt et al., Immunol. Rev. 2004 199:144-155)。しかしながら、DNAワクチンは安全であることが示されているが、免疫は低く、かつ、一時的レベルの免疫応答を生じるに過ぎなかった。
密度勾配によるRPBLAの単離はRPBLA高富化画分の回収を可能とするが、ある程度の夾雑物が一緒に精製される。夾雑物をできる限り除去するために、融合タンパク質(RX3−p24、RX3−p41、RX3−RTおよびRX3−E7SH)を対応するRPBLA画分から20mM Tris pH8、2%DOC、10mM DTTに可溶化し、軽く振盪させながら室温で1時間インキュベートし、RP−FPLCにて精製した。95%を超える純度で〆RX3融合タンパク質を含有する溶出画分をプールし、凍結乾燥させた。対応するペレットを蒸留水中、200mMのNaClおよび50mMのCaClの存在下で回収した。これらの条件で、RX3ペプチドを含む融合タンパク質は自発的に再組み立てられ、in vitroにおいて植物ERの外部でRPBLAを再形成する。
RX3と融合されたHPV−16抗原E7SH(pRX3−E7SH)でアグロインフィルトレーションされた葉組織およそ10gを液体窒素中で摩砕し、20mlのバッファーPBP3(100mM Tris pH8、50mM KCl、6mM MgCl2、10mM EDTAおよび0.4M NaCl)に再懸濁させた。これを、ポリトロンホモジナイザーを用いて氷上で3分間ホモジナイズした後、ミラクロスで濾過した。対応する濾液を、バッファーPBP3で作製した7ml容の15、25、35および45%濃度Optiprep(登録商標)密度勾配媒体を含んでなる密度ステップ勾配の上にのせた。この勾配をBeckman SW28ローターにて4℃、80,000xgで2時間遠心分離した。ペレットを500μlのバッファーPBP3に再懸濁させ、光学顕微鏡でRPBLAの存在を確認し、分析のためにアリコートを保存した。残りを−70℃で保存した。
RPBLAを含むRX3−E7SHの投与により誘導される細胞性免疫応答を測定するため、5つのマウス群に以下のように接種した:(i)E7SH抗原を含むDNAワクチンで背一種したマウス(pTHamp−E7SH)、(ii)配列:
特異的に活性化された脾細胞が細胞溶解活性を持っていたかどうかを調べるために、51Cr放出アッセイを行った。51Cr放出アッセイは、他所に記載されているように[Steinberg et al., (2005) Vaccine 23(9):1149?1157]、ネズミ脾臓細胞のin vitro再負荷から5〜6日後に行った。特定の標的(RX3−E7またはpTHamp−E7SH細胞)の特異的溶解が、タンパク質およびDNAに基づくワクチンの対照標的(RX3−GfpまたはpTHamp細胞)の溶解より少なくとも10%高かった場合の動物を陽性とスコアリングした。初回のin vitro再負荷後に、E7WT発現RMA−E7形質転換体に対する強い特異的細胞溶解活性が示された(下表参照)。
治療用腫瘍ワクチンの目的は定着腫瘍を根絶する有効な免疫応答を誘導することである。よって、in vivoにおいて定着したE7発現腫瘍細胞を管理することができた細胞性免疫応答を誘導できるかどうかを決定するためにE7SH遺伝子によるワクチン接種を検討した。4つの腫瘍退縮試験において、計80匹の動物に腫瘍形成用量の同系C3腫瘍細胞を移植した(0日目)。5〜18日目に腫瘍が平均サイズ4〜9mm2に達した際に、動物に(i)100μgのE7SHコードプラスミド(pTHamp−E7SH)、(ii)100μgのエンプティーpTHampベクター(pTHamp)、(iii)5μgのRX3−E7SHを含有するRPBLA(RX3−E7SH)、および(iv)IFA と同時投与される同量のRX3−E7SH RPBLA(RX3−E7SH/IFA)を接種した(0日目)。腫瘍サイズを、試験の終了時まで(14日目)、定規で計ることにより2日おきに測定した。
治療ワクチンに加え、RPBLAに基づく保護的(予防)ワクチンの適用という目的を考慮に入れ、RX3−E7SH含有RPBLAがE7発現同系腫瘍の増殖から動物を保護することができるかどうかを決定するために、再負荷試験を行った。
Claims (6)
- それを必要とする被験体において免疫原性ペプチドに対するT細胞性免疫応答を誘導するための医薬組成物であって、
融合タンパク質をコードする核酸(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)であるワクチンを含んでなり、
PBISが、γ−ゼイン、α−ゼイン、δ−ゼイン、β−ゼイン、イネプロラミンおよびγ−グリアジンからなる群から選択されるプロラミン中に存在するプロラミン配列を含むものである、医薬組成物。 - PBIS配列が、タンパク質をRPBLA発現細胞の小胞体(ER)に向けるシグナルペプチド配列をさらに含む、請求項1に記載の医薬組成物。
- 免疫原性ポリペプチド配列が、
(i)HPV E7遺伝子によりコードされるポリペプチド、
(ii)HIV−1 gag遺伝子によりコードされるポリペプチド、および
(iii)HIV−1 pol遺伝子によりコードされるポリペプチド
の群から選択される、請求項1または2に記載の医薬組成物。 - 核酸ワクチンを用いたワクチン接種に先行して、免疫原性ポリペプチドまたは免疫原性ポリペプチドをコードする核酸を含んでなる組成物を用いたプライミングワクチン接種または接種の工程が行われる、請求項1〜3のいずれか一項に記載の医薬組成物。
- プライミングワクチン接種または刺激工程に用いられる免疫原性ポリペプチドを含んでなる組成物が、
(i)組換え融合タンパク質(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)を含有する粒子状組換えタンパク粒様会合体(RPBLA)、
(ii)免疫原性ポリペプチドをコードする核酸分子、および
(iii)融合タンパク質をコードする核酸分子(該組換え融合タンパク質はペプチド結合された2つの部分を含み、第一の部分がタンパク粒誘導配列(PBIS)であり、第二の部分が免疫原性ポリペプチドである)
の群から選択され、
PBISが、γ−ゼイン、α−ゼイン、δ−ゼイン、β−ゼイン、イネプロラミンおよびγ−グリアジンからなる群から選択されるプロラミン中に存在するプロラミン配列を含むものである、請求項4に記載の医薬組成物。 - ワクチンが筋肉内に投与される、請求項1〜5のいずれか一項に記載の医薬組成物。
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