JP7386535B2 - 単純ヘルペスウイルス糖タンパク質をコードする修飾mRNAワクチン及びその使用 - Google Patents
単純ヘルペスウイルス糖タンパク質をコードする修飾mRNAワクチン及びその使用 Download PDFInfo
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Description
さらに、RNAワクチンは、アジュバント活性及び抗原発現をエレガントに組み込み、それによってウイルス感染の関連性のある様相を模倣する。このことが、アジュバントの使用を必要とする不活性化ワクチンと比較してRNAワクチンの効能を増大させ、取り扱いと産生とが簡単化する。RNAは、Toll様受容体3、7、及び8、RIG-I、MDA5、PKR、並びに相乗的に作用し抗原特異性の適応B細胞応答及びT細胞応答の誘発を高める働きをし得る他の受容体を含む、ある範囲の特化された免疫性パターン認識受容体に対処可能である。重要なことには、トランスフェクト宿主細胞における抗原合成によって、mRNAワクチンが細胞抗原のプロセシング及び提示経路に抗原を直接導入し、MHC分子への接近を確立して、宿主MHCハプロタイプに関係なくT細胞応答を誘発する。これにより、B細胞を含めて、他の免疫応答と共に相乗的に作用し得るポリクローナルT細胞応答の誘発が可能になる。また、内因性の抗原産生が、免疫原性に積極的に影響し得る、忠実な翻訳後修飾(例えば、タンパク質プロセシング、グリコシレーション等)を確実にする。
一実施形態においては、本発明は、1又は複数の修飾mRNAを含む組成物であって、当該修飾mRNAのそれぞれが、単純ヘルペスウイルス(HSV)糖タンパク質又はその免疫原性断片をコードするものである、組成物を提供する。
糖タンパク質D
糖タンパク質C
糖タンパク質E
修飾mRNA
ヌクレオシド間結合における修飾
修飾した糖、核酸塩基、及びヌクレオシド間結合の組合せ
本発明はまた、本発明の組成物を投与する工程を含む、HSVに対して対象をワクチン接種し、HSV感染またはその症状もしくは徴候を治療する、妨害する、阻害する、その発生低減する、または抑制する方法を提供する。
本発明の組成物は、別の実施形態において、非経口、癌細胞近く(paracancerally)、経粘膜、経皮、筋肉内、静脈内、皮内、皮下、腹膜内、心室内、頭蓋内、膣内、鼻腔内、腫瘍内、または局所のような、当業者に公知の任意の方法により対象に投与され得る。
1つの実施形態において、本発明の方法は、接触工程に先立ち、改変されたmRNAをトランスフェクション試薬と混合する工程をさらに含む。別の実施形態において、本発明の方法は、トランスフェクション試薬と一緒に改変されたmRNAを投与する工程をさらに含む。別の実施形態において、トランスフェクション試薬は、陽イオン性脂質試薬である。
1つの実施形態において、本発明の組成物および方法において使用されるナノ粒子は、Cullis, P.、およびHope, M、(日付なし)、Lipid Nanoparticle Systems for Enabling Gene Therapies. Molecular therapy.、25(7)において記載される脂質ナノ粒子を含み、その全体が、本明細書において参照により取り込まれる。
HSV-2糖タンパク質C、DおよびE(gC2/gD2/gE2)外部ドメインを発現する改変したmRNA。改変したmRNA(gC2(配列番号10)をコードする、gD2(配列番号4)をコードする、およびgE2(配列番号16)をコードする)を、HSV-2 333株由来のHSV-2糖タンパク質C(gC2)アミノ酸27~426(配列番号11)、HSV-2 333株由来の糖タンパク質D(gD2)アミノ酸26~331(配列番号5)、およびHSV-2株2.12由来の糖タンパク質E(gE2)アミノ酸24~405(配列番号17)をコードするDNAコード配列に基づき調製した。
a)対照(多価C群):4つのアリコートに分け、4ヶ所の別々の部位にて投与した多価CmRNA/LNP。
b)gD2単独(gD2群):4つのアリコートに分け、4ヶ所の別々の部位にて投与したgD2mRNA/LNP10μg。
c)個々の三価(三価-I群):それぞれ2つのアリコートに分け、それぞれ2ヶ所の部位にて投与したgC2mRNA/LNP10μg、gD2mRNA/LNP10μg、gE2mRNA/LNP10μg。
d)組み合わせた三価(三価-C群):LNPに組み合わせ、4つのアリコートに分け、4ヶ所の別々の部位にて投与したgC2mRNA10μgおよびgD2mRNA10μgおよびgE2mRNA10μg。
哺乳類細胞に遺伝子導入したとき、予想分子量のタンパク質を発現する改変したmRNAの能力を検証した。gC2、gD2、またはgE2改変したmRNA0.1μgを、遺伝子導入のためのTransIT-mRNA(Mirus Bio LLC)を使用して、293T細胞に遺伝子導入した。18時間後、細胞を回収し、ウエスタンブロットのため抽出物を調製した。gC2、gD2およびgE2の外部ドメイン(標識mRNA-ecto)を発現するよう、mRNAを設計した。予想分子量についての対照として、mRNAコンストラクト(標識Bac-ecto)と同じアミノ酸を発現する精製バキュロウイルスタンパク質gC2、gD2、およびgE2を使用した(図1A~C)。
ELISAエンドポイントタイターを、1回目および2回目の免疫の28日後に採取した血清において評価した。免疫群は、次の通りであった: 多価C(4つのアリコートに分け、4ヶ所の別々の部位にて投与した多価CmRNA/LNP10μg)(対照);gD2(4つのアリコートに分け、4ヶ所の別々の部位にて投与したgD2mRNA/LNP10μg);三価-I(それぞれ2つのアリコートに分け、それぞれ2ヶ所の部位にて投与したgC2mRNA/LNP10μg、gD2mRNA/LNP10μg、gE2mRNA/LNP10μg);および三価-C(LNPに組み合わせ、4つのアリコートに分け、4ヶ所の別々の部位にて投与したgC2bmRNA10μgおよびgD2mRNA10μgおよびgE2mRNA10μg)。
TH1またはTH2免疫応答を主に刺激するmRNA免疫の能力を、IgG1(TH2)またはIgG2a(TH1)抗体を産生するかどうかを決定することにより試験した。全3種の抗原gC2、gD2およびgE2を用いてコーティングしたプレートにおいて、ELISAを行った。1回目または2回目の免疫後に得た血清を、抗原でコーティングしたプレートに加え、IgG1またはIgG2aを、HRP抗マウスIgG1またはIgG2aを使用して検出した。IgG1(図3A)およびIgG2a(図3B)タイターは、gD2および三価改変したmRNAワクチン接種を用いた免疫後に、有意に上昇した。さらに、IgG1(図3A)またはIgG2a(図3B)タイターは、1回目と比較して、2回目の改変したmRNA免疫後に有意に高かった、p<0.05(t検定)。
2回目の免疫の28日後に、血清を得て、1:25希釈から開始する、連続2倍希釈の血清、および補体の供給源としての10%ヒト血清を使用して、中和抗体タイターを決定した。HSV-1およびHSV-2についての個々の血清陰性から、ヒト血清を得た。改変したmRNA群は、それぞれ、多価C対照と有意に異なった(p<0.001;図4)。mRNA群のそれぞれは、互いに有意に異ならない一方、組み合わせた免疫原として投与した三価ワクチン接種(三価-C)を、3種のmRNA群のベストとして行った(図4)。
別々の部位にてそれぞれの糖タンパク質mRNAを用いて免疫した三価改変したmRNA群(三価-I群)の5匹の動物を、2回目の免疫の14日後に安楽死させた。T細胞アッセイのため、脾細胞を調製した。脾細胞を、バキュロウイルスにおいて調製した糖タンパク質サブユニット抗原または11個の重複するアミノ酸を含有する15種のアミノ酸ペプチドを用いて刺激した。CD4+およびCD8+T細胞応答を、それぞれ、図5および6において示す。
2回目の免疫の33日後、動物に、5×103PFUのHSV-2株MS(約400LD50)を膣内接種した。生存、後肢脆弱または麻痺および猫背の歩調からなる神経学的徴候、ならびに体重減少または増加について、動物を毎日観察した。多価C対照群における全ての動物は死亡し、一方、gD2単独、個別に投与した三価(標識三価-I)または組み合わせて投与した三価(標識三価-C)における全ての動物は生存した(図7A;多価C対照を用いた3つのmRNA/LNP群と比較するLog-rank(Mantel-Cox)によりp=0.002)。図7Bは、28日の間隔で2回の改変したmRNAワクチンの投与およびHSV-2の膣内負荷は、神経学的徴候または体重減少をもたらさないことを示す。ワクチンを投与し、HSV-2を膣内負荷した対照対象は、体重減少および神経学的徴候を示した。
負荷後2および4日目に、1群当たり10匹の動物から、膣スワブを得て、複製コンピテントHSV-2ウイルスについて培養した。図8に、結果を示す。多価C群における10匹中9匹の動物は、gD2群における10匹中3匹、および三価-Iまたは三価-C群における10匹中0匹と比較して、2日目(図8A)および4日目(図8B)にて陽性の培養物を有した(Fisher Exact試験によるP値は、三価群をgD2単独と比較して有意ではなかった;三価-Iまたは三価-Cを多価Cと比較して、p<0.001;gD2単独を多価Cと比較して、p=0.02)。
負荷後28日間、生殖器疾患について動物を毎日モニターした。スコア0を、疾患なしと指定し、1ポイントそれぞれを、肛門または生殖口周囲の毛の喪失、生殖紅斑、生殖器浸出液、および生殖組織の壊死と指定した(図9)。
4匹の動物を安楽死させた三価の組み合わせた群を除き、1群当たり5匹の動物を、負荷の4日後に安楽死させた。Us9遺伝子を検出するためのqPCRによるHSV-2DNA定量のため、後根神経節(DRG)を回収した。多価C群における全5匹の動物は、DRGにおいて検出したHSV-2DNAを有し、一方、gDmRNAにおける5匹中2匹の動物、個々の部位での三価mRNAにおける5匹中1匹の動物、および同じ部位にて投与した4匹中1匹の三価mRNAは、HSV-2DNAについて陽性であった(図10;マン・ホイットニー検定:多価Cと比較したgD2、p=0.03;多価Cと比較した、異なる部位での三価、p<0.01;多価Cと比較した、同じ部位での三価、p=0.14)。改変したmRNAで免疫した群の間の差は、有意でなかった。
gD2単独またはgC2、gD2およびgE2を発現する改変したmRNAワクチンは、HSV-2生殖器負荷に対する傑出した保護をもたらした。3種のタンパク質の発現は、負荷後2日目および4日目のタイターに基づき、gD2より有意に優れており、HSV-2DNAを用いた動物のより少ない数を、4日目のDRGにおいて検出した。
BALB/cメスマウスを、負の対照の動物として免疫しないままにするか、または28日間の間隔にて多価CmRNA-LNPまたは価改変したmRNA-LNPで皮内免疫した。多価CmRNA対照は、4つのアリコートに分け、4ヶ所の別々の部位にて投与した多価CmRNA-LNP10μgを受け取った。三価改変したmRNA群は、それぞれ、2つのアリコートに分け、それぞれ2ヶ所の部位にて投与したgC2mRNA-LNP10μg、gD2mRNA-LNP10μg、およびgE2mRNA-LNP10μgを受け取った。2回目の免疫の2週間後、1つの群当たり5匹の動物から、脾臓を回収し、フローサイトメトリーを行って、濾胞性ヘルパーT(Tfh)細胞(図11A;*p<0.05)および胚中心B細胞応答(図11B;*p<0.05)を検出した。
BALB/cマウスを、28日間の間隔にて、多価CmRNA-LNP10μg、gD2mRNA-LNP10μgまたはgC2、gD2、gE三価改変したmRNA-LNPそれぞれ10μgで2回皮内免疫した。三価mRNAを組み合わせ、LNPに組み合わせ、4つのアリコートに分け、4ヶ所の部位にて投与したgC2mRNA10μgおよびgD2mRNA10μgおよびgE2mRNA10μgを投与した。2回目の免疫の1ヶ月後、膣腔において、培地60μlを導入し、回復させた。gC2(図12A)、gD2(図12B)、およびgE2(図12C)に対するIgGタイターを、ELISAにより、1:50希釈の膣洗浄液にて決定した(図12A~C、多価C群においてn=10マウス、gD2mRNA群においてn=10および三価mRNA群においてn=25;***p<0.001;**p<0.01)。
BALB/cマウスを、非免疫IgGの供給源として免疫しないままにするか、または多価CmRNA-LNPまたは三価mRNA-LNPを用いて皮内免疫した。多価CmRNA対照は、4つのアリコートに分け、4ヶ所の別々の部位にて投与した多価CmRNA-LNP10μgを受け取った。gD2mRNA群は、多価CmRNA-LNPについて記載した通り投与したgD2mRNA-LNP10μgを受け取った。三価改変したmRNA群は、1つのLNPに組み合わせ、4つのアリコートに分け、4ヶ所の部位にて投与したgC2mRNA-LNP10μg、gD2mRNA-LNP10μg、およびgE2mRNA-LNP10μgを受け取った。それぞれの群において10匹のマウスが存在した。10匹のマウス由来の血清をプールし、IgGを精製した。IgGを、12μg/200μlにて、gC2に結合している補体成分C3bをブロックするその能力について評価した。このブロッキングアッセイを使用して、免疫により産生された抗体が、gC2の免疫回避特性をブロックするかどうかを評価する。非免疫マウスIgG、多価CmRNA群由来のIgG、およびgD2mRNA群由来のIgGは、それぞれ、C3bに結合しているgC2をブロックしなかった。対照的に、三価mRNAで免疫したマウス由来のIgGは、gC2とC3bの間の相互作用を全体的にブロックした(図13、****p<0.0001)。
BALB/cマウス(n=5)を、それぞれ、2つのアリコートに分け、それぞれ2ヶ所の部位にて個々に投与したgC2mRNA-LNP10μg、gD2mRNA-LNP10μg、gE2mRNA-LNP10μgを使用して、三価改変したmRNAで免疫した。2回目の免疫の1ヶ月後、マウスを、メドロキシプロゲステロンを用いて処理し、5日後に、5×104PFU HSV-2株MS(2,000LD50)を膣内感染させた。動物を28日間続け、感染の2および4日後に、死亡、生殖器疾患、膣ウイルスタイターについて評価し、感染の28日後に、後根神経節(DRG)HSV-2DNAコピー数を評価した。三価mRNA-LNPワクチンを用いて免疫したマウスは、死亡せず、生殖器疾患を有さず、感染後2または4日目に検出したウイルスを有さないか、またはDRGにおいて検出したHSV-2DNAを有さなかった(表1)。
BALB/cマウスを、対照として多価CmRNA-LNPを用いて(15/群)またはgC2、gD2およびgE2mRNA-LNPのそれぞれ10μgを含有する三価mRNAを用いて(20/群)筋肉内免疫した。全多価C対照動物は、12日目までに死亡し、一方、三価mRNA群における全動物が生存した(図14A)。三価mRNA群において体重減少は生じず、一方、多価C対照動物は、体重の>15%を失った(図14B)。多価C群は、広大な生殖器疾患を発症し、一方、三価mRNAの動物は、生殖器疾患を有さなかった(図14C)。感染後7~12日目の安楽死の時に、9匹の多価C動物から、または三価mRNA群において28日目の実験の終わりに、DRGを回収した。多価C群における全動物は、DRGにおいて検出したHSV-2DNAを有し、一方、三価mRNA群においてHSV-2DNAについて陽性のものはいなかった(図14D)。2日目(図14E)および4日目(図14F)の膣ウイルス培養物は、多価C群において全15匹の動物において陽性であり、一方、培養物は、三価mRNA群における全20匹の動物において陰性であった。多価Cと三価群の間の差は、有意であり、それぞれの図についてp<0.001であった(図14A~14F)。
本明細書において以下の表2において提示する結果は、gC2、gD2およびgE2mRNA-LNPのそれぞれ10μgを含有する三価mRNAを用いて皮内または筋肉内のいずれかで免疫したBALB/cマウスにおける全ての結果の概要を表す(計64匹のマウスを研究した)。本発明者らは、HSV-2 333株由来のgC2アミノ酸27~426を含有するbac-gC2(27-426t)、HSV-1 333株由来のgD2アミノ酸26~331を含有するbac-gD2(306t)、およびHSV-2株2.12由来のgE2アミノ酸24~405を含有するbac-gE2(24-405t)のそれぞれ5μgをもちいて免疫したBALB/cマウスにおいて得た結果との比較を示す。gC2、gD2、gE2サブユニット抗原を、アジュバントとしてタンパク質1μg当たりCpG150μgおよびミョウバン25μgと混合し、筋肉内投与した。本発明者らが、先の実験で行った通り、マウスを、28日間の間隔で2回、三価mRNA-LNPを用いて免疫し、14日間の間隔で3回、サブユニット抗原を用いて免疫した。mRNAおよびサブユニット抗原実験を、同時に行った。表2において概説する結果は、多くの免疫応答パラメーターにおいて、および最も重要なことには、ワクチン有効性において三価サブユニット抗原ワクチンより三価mRNA-LNPワクチンの有意な優位性を示す。三価mRNA-LNPワクチンは、サブユニット抗原群における15/20(75%)と比較して、63/64(98%)匹のマウスにおいて安定化免疫を達成した。
ハートレイ系メスモルモットを、免疫せず、感染させないままにし(負の群、n=10)、1ヶ月の間隔で3回、多価CmRNA-LNP20μg(n=10)またはgC2、gD2、gE改変したmRNA-LNPのそれぞれ20μg(n=10)を用いて皮内免疫した。最終免疫の1ヶ月後、多価Cおよび三価mRNA群における動物に、5×105PFUのHSV-2株MS(50LD50)を膣内感染させた。死亡、感染の急性期(1~14日目)中の生殖器病変、および感染の再発期(15~60日目)中の生殖器病変について、動物を観察した。多価C対照群において、10匹中7匹の動物が死亡ししたか、または感染の7~20日後に人間的に安楽死させ、一方、三価群における動物および未処理(感染させていない)の動物のいずれも死亡しなかった(図15A)。多価C群は、急性生殖器疾患を発症している10匹中9匹の動物を含む、感染の急性期中の中央値6.4日目に生殖器病変を有し、一方、三価群または未処理(感染させていない)群における動物はいずれも、急性生殖器疾患を発症しなかった(図15B)。多価C動物は、再発生殖器病変を発症している3匹中2匹の動物を含む、感染の再発期中の中央値3.7日目に生殖器病変を有していた(図15C)。対照的に、三価で免疫したモルモットおよび未処理(感染させていない)の動物は、再発生殖器病変を有さなかった(図15C)。
結論:三価改変したmRNA-LNPは、モルモットにおいて急性および再発生殖器病変に対する傑出した保護をもたらした。
本発明は、例えば、以下の項目を提供する。
(項目1)
1又は複数のヌクレオシド修飾mRNAを含む組成物であって、前記ヌクレオシド修飾mRNAのそれぞれが、単純ヘルペスウイルス(HSV)糖タンパク質又はその免疫原性断片をコードし、また前記ヌクレオシド修飾mRNAは、1又は複数のプソイドウリジン残基を含む、組成物。
(項目2)
前記1又は複数のプソイドウリジン残基は、m1Ψ(1-メチルプソイドウリジン)を含む、項目1記載の組成物。
(項目3)
前記1又は複数のプソイドウリジン残基は、m 1 acp 3 Ψ(1-メチル-3-(3-アミノ-5-カルボキシプロピル)プソイドウリジン、Ψm(2’-O-メチルプソイドウリジン、m 5 D(5-メチルジヒドロウリジン)、m 3 Ψ(3-メチルプソイドウリジン)、又はこれらの任意の組合せを含む、項目1記載の組成物。
(項目4)
1又は複数の前記ヌクレオシド修飾mRNAが、a)HSV糖タンパク質D(gD)若しくはその免疫原性断片、b)HSV糖タンパク質C(gC)若しくはその免疫原性断片、及びc)HSV糖タンパク質E(gE)若しくはその免疫原性断片、又はこれらの任意の組合せをコードする、項目1から3のいずれか一項に記載の組成物。
(項目5)
前記HSV糖タンパク質は、HSV-1糖タンパク質を含む、項目4記載の組成物。
(項目6)
前記HSV糖タンパク質は、HSV-2糖タンパク質を含む、項目4記載の組成物。
(項目7)
HSVのgD免疫原性断片の前記免疫原性断片をコードする前記ヌクレオシド修飾mRNAは、HSV-2 333株由来のアミノ酸26~331又は別のHSV株由来の相同配列を含む、項目6記載の組成物。
(項目8)
前記ヌクレオシド修飾mRNAの核酸配列は、配列番号4に明記するとおりである、項目7記載の組成物。
(項目9)
HSV gCの前記免疫原性断片は、そのC3b結合ドメイン、そのプロパージン干渉ドメイン、そのC5干渉ドメイン、又は前記C3b結合ドメイン、プロパージン干渉ドメイン、若しくはC5干渉ドメインの断片のいずれかを含む、項目4から8のいずれか一項に記載の組成物。
(項目10)
HSV gCの前記免疫原性断片をコードする前記ヌクレオシド修飾mRNAは、HSV-2 333株由来のアミノ酸27~426又は別のHSV株由来の相同配列を含む、項目6から9のいずれか一項に記載の組成物。
(項目11)
前記ヌクレオシド修飾mRNAの核酸配列は、配列番号10に明記するとおりである、項目10記載の組成物。
(項目12)
HSV gEの前記免疫原性断片は、HSV-2 2.12株由来のアミノ酸24~405又は別のHSV株由来の相同配列を含む、項目6から11のいずれか一項に記載の組成物。
(項目13)
前記ヌクレオシド修飾mRNAの核酸配列は、配列番号16に明記するとおりである、項目12記載の組成物。
(項目14)
1又は複数の前記ヌクレオシド修飾mRNAが、a)HSV糖タンパク質B(gB)若しくはその免疫原性断片、b)HSV糖タンパク質H(gH)若しくはその免疫原性断片、c)HSV糖タンパク質L(gL)若しくはその免疫原性断片、d)HSV糖タンパク質I(gI)若しくはその免疫原性断片、又はe)これらの任意の組合せをコードする、項目1から13のいずれか一項に記載の組成物。
(項目15)
前記ヌクレオシド修飾mRNAのうちの1又は複数は、ポリA尾部をさらに含む、項目1から14のいずれか一項に記載の組成物。
(項目16)
前記ヌクレオシド修飾mRNAのうちの1又は複数は、m7GpppGキャップ、3’-O-メチル-m7GpppGキャップ、又はアンチリバースキャップアナログをさらに含む、項目1から15のいずれか一項に記載の組成物。
(項目17)
前記ヌクレオシド修飾mRNAのうちの1又は複数は、キャップ非依存性翻訳エンハンサーをさらに含む、項目1から16のいずれか一項に記載の組成物。
(項目18)
前記ヌクレオシド修飾mRNAのうちの1又は複数は、翻訳を促進する5’及び3’の非翻訳領域をさらに含む、項目1から17のいずれか一項に記載の組成物。
(項目19)
前記ヌクレオシド修飾mRNAのうちの1又は複数は、ナノ粒子、脂質、ポリマー、コレステロール、又は細胞透過性ペプチドの中にカプセル化される、項目1から18のいずれか一項に記載の組成物。
(項目20)
前記ナノ粒子は、リポソームナノ粒子である、項目19記載の組成物。
(項目21)
対象における単純ヘルペスウイルス(HSV)感染を治療する方法であって、前記対象に、項目1から20のいずれか一項に記載のヌクレオシド修飾mRNAの組成物を投与する工程を含む、方法。
(項目22)
対象における単純ヘルペスウイルス(HSV)感染の発生を抑制、阻害、又は低減する方法であって、前記対象に、項目1から20のいずれか一項に記載のヌクレオシド修飾mRNAの組成物を投与する工程を含む、方法。
(項目23)
前記HSV感染は、HSV-1感染を含む、項目21から22のいずれか一項に記載の方法。
(項目24)
前記HSV感染は、HSV-2感染を含む、項目21から22のいずれか一項に記載の方法。
(項目25)
前記HSV感染は、一次HSV感染を含む、項目21から24のいずれか一項に記載の方法。
(項目26)
前記HSV感染は、一次HSV感染に続く、炎症、再発、又は口唇HSVを含む、項目21から24のいずれか一項に記載の方法。
(項目27)
前記HSV感染は、潜伏HSV感染の再活性化を含む、項目21から24のいずれか一項に記載の方法。
(項目28)
前記HSV感染は、HSV脳炎、HSV新生児感染、性器HSV感染、又は経口HSV感染を含む、項目21から27のいずれか一項に記載の方法。
(項目29)
対象における免疫応答を誘発する方法であって、前記対象に、項目1から20のいずれか一項に記載のヌクレオシド修飾mRNAの組成物を投与する工程を含む、方法。
(項目30)
投与工程は、筋肉内投与を含む、項目21から29のいずれか一項に記載の方法。
(項目31)
投与工程は、皮下投与を含む、項目21から29のいずれか一項に記載の方法。
(項目32)
投与工程は、皮内投与を含む、項目21から29のいずれか一項に記載の方法。
(項目33)
投与工程は、鼻腔内、膣内、又は直腸内の投与を含む、項目21から29のいずれか一項に記載の方法。
(項目34)
投与工程は、局所投与を含む、項目21から29のいずれか一項に記載の方法。
(項目35)
投与工程は、a)第一のHSV糖タンパク質をコードするヌクレオシド修飾mRNAを含む第一の組成物を投与すること、b)第二のHSV糖タンパク質をコードするヌクレオシド修飾mRNAを含む第二の組成物を投与すること、及びc)第三のHSV糖タンパク質をコードするヌクレオシド修飾mRNAを含む第三の組成物を投与することを含む、項目21から34のいずれか一項に記載の方法。
(項目36)
前記第一の組成物、前記第二の組成物、及び前記第三の組成物は、単一の投与部位において前記対象に投与される、項目35記載の方法。
(項目37)
前記第一の組成物、前記第二の組成物、及び前記第三の組成物は、異なる投与部位において前記対象に投与される、項目35記載の方法。
(項目38)
前記第一の組成物、前記第二の組成物、及び前記第三の組成物は、同時に投与される、項目35から37のいずれか一項に記載の方法。
(項目39)
前記第一の組成物、前記第二の組成物、及び前記第三の組成物は、連続して投与される、項目35から37のいずれか一項に記載の方法。
(項目40)
前記第一の組成物、前記第二の組成物、及び前記第三の組成物は、同一の投与経路で投与される、項目35から39のいずれか一項に記載の方法。
(項目41)
前記第一の組成物、前記第二の組成物、及び前記第三の組成物は、異なる投与経路で投与される、項目35から39のいずれか一項に記載の方法。
(項目42)
第一の投与の後で、前記ヌクレオシド修飾mRNAの組成物の1又は複数の追加投与を前記対象に対して投与する工程をさらに含む、項目21から41のいずれか一項に記載の方法。
(項目43)
前記HSV糖タンパク質又はその免疫原性断片を含む組成物を前記対象に対して投与する工程をさらに含む、項目21から41のいずれか一項に記載の方法。
(項目44)
前記HSV糖タンパク質を含む前記組成物は、前記ヌクレオシド修飾mRNAの組成物の投与の後で投与される、項目43記載の方法。
(項目45)
前記HSV糖タンパク質を含む前記組成物は、前記ヌクレオシド修飾mRNAの組成物の投与の前に投与される、項目43記載の方法。
(項目46)
前記HSV糖タンパク質は、gD、gC、gE又はこれらの組合せを含む、項目43から45のいずれか一項に記載の方法。
(項目47)
前記免疫応答は、CD4免疫応答を含む、項目29から46のいずれか一項に記載の方法。
(項目48)
前記免疫応答は、CD8免疫応答を含む、項目29から46のいずれか一項に記載の方法。
(項目49)
前記免疫応答は、濾胞性ヘルパーT細胞免疫応答を含む、項目29から46のいずれか一項に記載の方法。
(項目50)
前記免疫応答は、胚中心B細胞免疫応答を含む、項目29から46のいずれか一項に記載の方法。
(項目51)
前記免疫応答は、gC2、gD2、gE2又はこれらの組合せに対するIgG抗体応答を含む、項目29から46のいずれか一項に記載の方法。
Claims (22)
- (i)単純ヘルペスウイルス(HSV)感染を治療するための、または、HSV感染の発生を治療する、抑制する、阻害する、もしくは低減するための、あるいは、(ii)免疫応答を誘導するための組成物であって、
(a)配列番号5に対して少なくとも98%同一である配列を含む単純ヘルペスウイルス(HSV)糖タンパク質D(gD)のエクトドメインをコードするRNA;(b)配列番号11に対して少なくとも98%同一である配列を含むHSV糖タンパク質C(gC)のエクトドメインをコードするRNA;および(c)配列番号17に対して少なくとも98%同一である配列を含むHSV糖タンパク質E(gE)のエクトドメインをコードするRNAを含み、前記RNAのうちの1又は複数はヌクレオシド修飾RNAである、組成物。 - 前記ヌクレオシド修飾RNAが1又は複数のプソイドウリジン残基を含む、請求項1に記載の組成物。
- 前記1又は複数のプソイドウリジン残基は、m1Ψ(1-メチルプソイドウリジン)、m1acp3Ψ(1-メチル-3-(3-アミノ-5-カルボキシプロピル)プソイドウリジン、Ψm(2’-O-メチルプソイドウリジン、m5D(5-メチルジヒドロウリジン)、m3Ψ(3-メチルプソイドウリジン)、又はこれらの任意の組合せを含む、請求項2に記載の組成物。
- a)HSV糖タンパク質B(gB)若しくはその免疫原性断片、b)HSV糖タンパク質H(gH)若しくはその免疫原性断片、c)HSV糖タンパク質L(gL)若しくはその免疫原性断片、d)HSV糖タンパク質I(gI)若しくはその免疫原性断片、又はe)これらの任意の組合せをコードする1又は複数のRNAをさらに含む、請求項1に記載の組成物。
- 前記糖タンパク質のうちの1又は複数は、HSV-1由来である、請求項4に記載の組成物。
- 前記糖タンパク質のうちの1又は複数は、HSV-2由来である、請求項4に記載の組成物。
- 前記ヌクレオシド修飾RNAのうちの1又は複数は、
a)i)ポリA尾部;ii)m7GpppGキャップ、3’-O-メチル-m7GpppGキャップ、若しくはアンチリバースキャップアナログ;iii)キャップ非依存性翻訳エンハンサー;iv)翻訳を促進する5’及び3’の非翻訳領域;v)又はこれらの組合せをさらに含むか;
b)ナノ粒子、脂質、ポリマー、コレステロール、又は細胞透過性ペプチドの中にカプセル化されるか;
c)またはこれらの組合せである、請求項1に記載の組成物。 - 前記ナノ粒子は、リポソームナノ粒子である、請求項7に記載の組成物。
- 前記リポソームナノ粒子は、Acuitas Therapeuticsによる脂質ナノ粒子を含む、請求項8に記載の組成物。
- 前記ヌクレオシド修飾RNAのうちの1又は複数がさらにシグナル配列を含む、請求項1に記載の組成物。
- 前記シグナル配列が、
a. AUGACCCGCCUGACCGUGCUGGCCCUGCUGGCCGGCCUGCUGGCCUCCUCCCGCGCC(配列番号19)、
b. AUGCGCAUGCAGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCC(配列番号20)、または
c. AUGGCCAUCUCCGGCGUGCCCGUGCUGGGCUUCUUCAUCAUCGCCGUGCUGAUGUCCGCCCAGGAGUCCUGGGCC(配列番号21)
を含む、請求項10に記載の組成物。 - 前記HSV gDのエクトドメインをコードするRNAが、配列番号4のヌクレオチド200~1120に対して少なくとも75%の同一性を有するヌクレオチド配列からなり、前記HSV gCのエクトドメインをコードするRNAが、配列番号10のヌクレオチド200~1402に対して少なくとも75%の同一性を有するヌクレオチド配列からなり、前記HSV gEのエクトドメインをコードするRNAが、配列番号16のヌクレオチド200~1348に対して少なくとも75%の同一性を有するヌクレオチド配列からなり、
ここで、前記エクトドメインをコードしない前記RNAが、必要に応じて、シグナル配列;ポリ-A尾部;m7GpppGキャップ、3’-O-メチル-m7GpppGキャップ、または、アンチリバースキャップアナログ;キャップ非依存性翻訳エンハンサー;翻訳を促進する5’及び3’の非翻訳領域;または、これらの組み合わせを含む、請求項1に記載の組成物。 - 前記HSV gDのエクトドメインをコードするRNAが、配列番号4のヌクレオチド200~1120からなり、前記HSV gCのエクトドメインをコードするRNAが、配列番号10のヌクレオチド200~1402からなり、そして、前記HSV gEのエクトドメインをコードするRNAが、配列番号16のヌクレオチド200~1348からなる、請求項12に記載の組成物。
- 前記RNAの2つ以上が、ヌクレオシド修飾RNAである、請求項1に記載の組成物。
- 前記RNAの3つ全てが、ヌクレオシド修飾RNAである、請求項1に記載の組成物。
- 単純ヘルペスウイルス(HSV)感染を治療する又はHSV感染の発生を抑制、阻害若しくは低減するための、請求項1~15のいずれか一項に記載の組成物。
- 前記HSV感染は、HSV-1感染又はHSV-2感染を含む、請求項16に記載の組成物。
- 前記HSV感染は、一次HSV感染;一次HSV感染に続く、炎症、再発、又は口唇HSV;潜伏HSV感染の再活性化;あるいは、HSV脳炎、HSV新生児感染、性器HSV感染、又は経口HSV感染、又はこれらの組合せを含む、請求項16に記載の組成物。
- 前記組成物は、筋肉内、皮下、皮内、鼻腔内、膣内、直腸内、又は局所の投与用に製剤される、請求項16に記載の組成物。
- 免疫応答を誘発するための、請求項1~15のいずれか一項に記載の組成物。
- 前記免疫応答は、CD4免疫応答;CD8免疫応答;濾胞性ヘルパーT細胞免疫応答;胚中心B細胞免疫応答;gC2、gD2、gE2若しくはこれらの組合せに対するIgG抗体応答;又はこれらの組合せを含む、請求項20に記載の組成物。
- 前記組成物は、筋肉内、皮下、皮内、鼻腔内、膣内、直腸内、又は局所の投与用に製剤される、請求項20に記載の組成物。
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