JP2023027118A - ノロウイルスs粒子ベースのワクチンならびにその作製および使用方法 - Google Patents
ノロウイルスs粒子ベースのワクチンならびにその作製および使用方法 Download PDFInfo
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Abstract
Description
本出願は、2017年3月28日に出願された米国仮出願第62/477,481号の優先権および利益を主張するものであり、上記出願の内容は、その全体および全ての目的のために組み込まれる。
本発明は、国立衛生研究所によって授与されるXJへのR21 AI092434-01A1およびR56 AI114831-01A1の下で、政府の支援を受けてなされた。政府は本発明に一定の権利を有する。
特に明記しない限り、用語は、関連技術分野の当業者による従来の用法に従って理解されるべきである。矛盾する場合は、定義を含む本書が優先する。好ましい方法および材料を以下に記載するが、本明細書に記載のものと類似または同等の方法および材料を本発明の実施または試験に使用することができる。本明細書で言及される全ての刊行物、特許出願、特許および他の参考文献は、参照によりその全体が組み込まれる。本明細書で開示される材料、方法、および例は、例示に過ぎず、限定することを意図するものではない。
プラスミド構築物。1)グルタチオン-S-トランスフェラーゼ(GST)-タグ付きSドメインタンパク質の発現構築物。GII.4 NoV株VA387のヒンジコード配列を有するSドメイン(GenBank AC#:AY038600.3;残基1~221)を、pGEX-4T-1ベクター(GST Gene Fusion System、GE Healthcare Life Sciences)の複数のクローニング部位に、BamH1/Sal I部位を介して挿入した。得られたSドメインタンパク質は、間にトロンビン切断部位を有するN末端GSTを有していた。2)Hisx6融合SR69Aドメイン発現用のプラスミド構築物。R69A変異を有する同じNoV Sドメインヒンジコード配列を、pET-24bベクター(Novagen)の複数のクローニング部位に、BamH1/Not I部位を介して挿入した。得られたSドメインタンパク質は、C末端が融合したHisx6ペプチドを有していた。3)SR69A-VP8キメラタンパク質発現用のDNA構築物。WA株のVP8(GenBank AC#:VPXRWA)の64から231のアミノ酸配列に相当する、P[8]ヒトRV株BM14113のRV VP8コード配列を含むDNAフラグメントを、SR69Aドメインの末端-ヒンジにそれらの間にリンカー(4つのヒスチジン)を挟んだ状態で融合させた。RV株BM14113は、RV陽性の便試料から直接単離された[45]。Hisx6-ペプチドを精製目的でVP8抗原のC末端に付加した。4)SR69A/V57C/M140C-VP8、SR69A/V57C/Q58C/S136C-VP8、およびSR69A/V57C/Q58C/S136C/M140C-VP8キメラタンパク質の発現構築物。このDNA構築物は、SR69A-VP8キメラタンパク質の発現構築物に、他の2つ(V57C/M140C)、3つ(V57C/Q58C/S136C)、または4つ(V57C/Q58C/S136C/M140C)の変異を、部位特異的突然変異誘発によって導入することによって作製した。5)。SR69A/V57C/Q58C/S136C-mVP8キメラタンパク質発現用のプラスミド構築物。この構築物には、SR69A/V57C/Q58C/S136C-VP8構築物のようなDNA配列が含まれていたが、VP8コード配列が、ネズミRV EDIM(乳児マウスの流行性下痢)株のVP8をコードする配列に置き換えられた[50]。加えて、Plasmodium falciparum寄生体3D7株のスポロゾイト表面タンパク質(CSP)の表面TSR抗原(GenBank AC#:CAB38998、残基309~375)を含む、様々な病原体の抗原を提示する他のSR69AV57C/Q58C/S136Cベースのキメラ粒子用に構築されたDNA[51]、A型インフルエンザウイルスのM2eエピトープ[52、53]、およびE型肝炎ウイルスのPドメイン抗原[54~56] を、RV VP8コード配列が、対応する抗原をコードするものに置き換えられているSR69A V57C/Q58C/S136C-VP8キメラタンパク質を、出発構築物として用いて構築した。
天然NoV Sドメインの低粒子形成効率。出願人の研究は、発現ベクターpGEX-4T-1を使用したE.coli中でのGII.4 NoV(VA387)のヒンジを有する天然のSドメインの産生から開始し、約51kDaの分子量(MW)を有するGST-Sドメイン融合タンパク質をもたらした(図1、AおよびB)。GSTがセファロースビーズに結合したままである間、GSTを含まない約25kDaの遊離Sドメインタンパク質(図1C)を、トロンビン切断により得た。Sタンパク質のEM観察により、集合したS粒子と同等である可能性が最も高い、直径約20nmの薄い層のリング状構造がほとんどないことが明らかになった(図1D)。S粒子形成効率を決定するために、Sドメインタンパク質のゲル濾過クロマトグラフィーを実施し、2つの広いピークが明らかになった(図1E)。SDS PAGE(図1F)に続いてNoV VLP過免疫血清[15]を使用したウェスタン分析(データ図示せず)およびN末端配列決定(図2、以下を参照)により、両方のピークがSタンパク質であることを確認した。800kDaを超える高MWを有するピーク1は、自己集合化S粒子または複合体を表すはずであり、一方ピーク2は、Sドメインモノマー(約25kDa)および/またはダイマー(約50kDa)であるはずである。
この研究では、出願人は、単純な細菌発現系を介して高効率で統一された60価のNoV S60粒子を産生するための新しい技術を開発した。これは、NoVキャプシドの内部シェルを自然に構築するNoV VP1 Sドメインのホモタイプの相互作用、ならびにSドメインタンパク質を安定化させ、Sドメイン間相互作用を強化するためのいくつかの改変を活用することによって達成された。具体的には、出願人は、R69A変異を導入して、そうでなければ、Sタンパク質の容易な分解をもたらす、天然のシェル上の露出したプロテアーゼ切断部位を破壊した。加えて、出願人は、三重(V57C/Q58C/S136'C)または四重(V57C/Q58C/S136'C/M140'C)ステイン変異を、2つの隣接するSドメイン間の立体的に近い残基の2つの対(V57/M140'およびQ58/S136'、図6)に導入して、Sドメイン間ジスルフィド結合を確立して、天然のNoVシェルで示すものよりも強いSドメイン間相互作用を確立した。最終的に、生物工学によって作られたSドメインは、簡単なE.coli系によって高収率で容易に産生され、S60粒子の高効率での自己形成をもたらした。
[1]Tan M,Jiang X.Norovirus P particle:a subviral nanoparticle for vaccine development against norovirus,rotavirus and influenza virus。Nanomedicine(Lond)2012;7:889-97。
Claims (23)
- S粒子を含む抗原提示のための多価二十面体組成物であって、前記S粒子が、
a)ノロウイルス(NoV)Sドメインタンパク質と、
b)前記ノロウイルスSドメインタンパク質に作動可能に連結されたリンカータンパク質ドメインと、
c)前記リンカーに作動可能に連結された抗原タンパク質ドメインと、を含む組換え融合タンパク質を含む、多価二十面体組成物。 - 前記組成物が、二十面体対称構造を有する、請求項1に記載の多価二十面体組成物。
- 前記組成物が、抗原提示のための60個の部位を含む、請求項1または2に記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、前記NoV Sドメインタンパク質のプロテイナーゼ切断部位に変異を含み、前記変異が、前記部位をトリプシン切断に対して耐性を示す、請求項1~3のいずれかに記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、前記プロテイナーゼ切断部位に対する変異を含み、前記変異が、69位または70位にあり、前記変異が、前記部位をトリプシン切断に対して耐性を示す、請求項1~4のいずれかに記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、前記プロテイナーゼ切断部位に対する変異を含み、前記変異が、R69位で発生し、好ましくは前記変異が、前記プロテイナーゼ切断部位を破壊するのに十分なK以外の任意のアミノ酸であり、より好ましくは、前記変異が、R69Aである、請求項1~5のいずれかに記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、前記プロテイナーゼ切断部位に対する変異を含み、前記変異が、N70位で発生し、好ましくは前記変異が、前記プロテイナーゼ切断部位を破壊するのに十分なP以外の任意のアミノ酸である、請求項1~6のいずれかに記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、非天然ジスルフィド結合の結合部位を提供するのに十分な変異を含む、請求項1~7のいずれかに記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、前記多価二十面体S粒子の隣接するSドメインタンパク質間に、少なくとも1つの非天然ジスルフィド結合の結合部位、または少なくとも2つの非天然ジスルフィド結合の結合部位、または少なくとも3つの非天然ジスルフィド結合の結合部位を提供するのに十分なシステイン残基に立体的に互いに近い少なくとも2つのアミノ酸の変異を含む、請求項1~8のいずれかに記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、少なくとも1つの非天然ジスルフィド結合形成部位を提供するのに十分な変異を含み、前記変異が、V57C、Q58C、S136C、M140C、またはそれらの組み合わせから選択される、請求項1~9のいずれかに記載の多価二十面体組成物。
- 前記ノロウイルスSドメインタンパク質が、カリシウイルスのものであり、前記カリシウイルスが、単一カプシドタンパク質を180コピー有することを特徴とする、請求項1~10のいずれかに記載の多価二十面体組成物。
- 前記リンカーが、前記Sドメインタンパク質粒子と提示された抗原との間に空間および特定の柔軟性を提供するのに十分な長さのアミノ酸配列を含む、請求項1に記載の多価二十面体組成物。
- 前記リンカーが、3~6個のアミノ酸を含む、請求項1~12のいずれかに記載の多価二十面体組成物。
- 前記抗原タンパク質ドメインが、8個のアミノ酸から最大約300個のアミノ酸までのサイズ、または8個のアミノ酸から最大約400個のアミノ酸までのサイズ、または8個のアミノ酸から最大約500個のアミノ酸までのサイズを有する抗原を含む、請求項1~13のいずれかに記載の多価二十面体組成物。
- 前記抗原タンパク質ドメインが、ロタウイルス(RV)抗原を含む、請求項1~14のいずれかに記載の多価二十面体組成物。
- 前記抗原タンパク質ドメインが、RVスパイクタンパク質抗原(VP8抗原)を含む、請求項1~15のいずれかに記載の多価二十面体組成物。
- 前記抗原タンパク質ドメインが、マラリア原虫Plasmodium falciparumのスポロゾイト表面タンパク質(CSP)のTSR抗原、A型インフルエンザウイルスのHA1タンパク質およびM2eエピトープの受容体結合ドメイン、E型肝炎のPドメイン抗原、アストロウイルスの表面スパイクタンパク質、およびそれらの組み合わせから選択される抗原を含む、請求項1~16のいずれかに記載の多価二十面体組成物。
- 組換え融合タンパク質であって、
a)好ましくはプロテアーゼ部位を破壊するための1つ以上の変異、より好ましくはプロテアーゼ部位を破壊し、かつ1つまたは2つまたは3つのシステイン残基を導入するための1つ以上の変異を有する、ノロウイルス(NoV)Sドメインタンパク質と、
b)前記ノロウイルスSドメインタンパク質に作動可能に連結されたリンカータンパク質ドメインと、
c)前記リンカーに作動可能に連結された抗原タンパク質ドメインと、を含む、組換え融合タンパク質。 - 請求項1~17のいずれかに記載の多価二十面体構造を作製する方法であって、a)改変されたNoV Sドメインタンパク質を含む第1の領域を作製するステップであって、前記改変が、露出されたプロテアーゼ切断部位を破壊するのに十分な変異であって、前記変異がタンパク質分解を防止する変異、好ましくはR69A変異であり、Sドメイン間タンパク質ジスルフィド結合を形成するのに十分な前記ノロウイルス(NoV)Sドメインタンパク質中に1つ以上の変異を導入する変異、好ましくは、V57C、Q58C、S136CおよびM140C、ならびにそれらの組み合わせから選択される変異を含む、作製するステップと、b)リンカーおよび抗原を用いて、前記第1の領域を組換え発現するステップと、を含む、方法。
- 前記組成物が、E.coliで産生される、請求項19に記載の方法。
- 免疫応答の誘発を、それを必要としている個体において行う方法であって、請求項1~17のいずれか一項に記載の組成物を投与するステップ、好ましくは、前記組成物を、2回以上、または3回以上、または4回以上投与するステップを含む、方法。
- 請求項1~17のいずれかに記載の組成物の少なくとも1用量を含む容器。
- 請求項22に記載の1つ以上の容器、送達装置、および前記組成物の投与のための説明書を含むキット。
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