JP2013533747A - 自己複製rna分子についてのビリオン様送達粒子 - Google Patents
自己複製rna分子についてのビリオン様送達粒子 Download PDFInfo
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Abstract
Description
本発明は、免疫化のための自己複製RNAの非ウイルス性送達の分野にある。
動物を免疫化するための核酸の送達は、数年間にわたり目標であった。種々のアプローチが、試験されてきており、それらとしては、DNAもしくはRNAの使用、ウイルスもしくは非ウイルス性送達ビヒクルの使用(またはさらには「裸の」ワクチンにおいて、送達ビヒクルなし)、複製もしくは非複製ベクターの使用、またはウイルスもしくは非ウイルス性ベクターの使用が挙げられる。
本発明によれば、核酸免疫化は、小粒子内に被包された、および/もしくは小粒子に吸着させられた自己複製RNAを送達することによって達成される。上記RNAは、目的の免疫原をコードし、上記粒子は、天然のウイルスの送達機能を摸倣することによって、このRNAを送達し得る。
本発明の粒子は、非ビリオン粒子である(すなわち、それらは、ビリオンではない)。従って、上記粒子は、タンパク質キャプシドを含まない。キャプシド粒子を作る必要性を回避することによって、本発明は、パッケージング細胞株を必要としないので、商業的生産のための容易なスケールアップおよび危険な感染性ウイルスが偶然に生成されてしまうリスクを最小にすることを可能にする。
種々の両親媒性脂質は、リポソームとして、RNA含有水性コアを被包するように、水性環境中で二重層を形成し得る。これら脂質は、アニオン性、カチオン性もしくは両性イオン性の親水性頭部(head group)を有し得る。アニオン性リン脂質からのリポソームの形成は、1960年代にさかのぼり、カチオン性リポソーム形成脂質は、1990年代以来研究されてきた。いくつかのリン脂質はアニオン性であるのに対して、他のものは、両性イオン性であり、他のものはカチオン性である。リン脂質の適切なクラスとしては、ホスファチジルエタノールアミン、ホスファチジルコリン、ホスファチジルセリン、およびホスファチジル−グリセロールが挙げられるが、これらに限定されず、いくつかの有用なリン脂質は、表1に列挙される。有用なカチオン性脂質としては、以下が挙げられるが、これらに限定されない:ジオレオイルトリメチルアンモニウムプロパン(DOTAP)、1,2−ジステアリルオキシ−N,N−ジメチル−3−アミノプロパン(DSDMA)、1,2−ジオレイルオキシ−N,Nジメチル−3−アミノプロパン(DODMA)、1,2−ジリノレイルオキシ−N,N−ジメチル−3−アミノプロパン(DLinDMA)、1,2−ジリノレニルオキシ−N,N−ジメチル−3−アミノプロパン(DLenDMA)。両性イオン性脂質としては、アシル両性イオン性脂質およびエーテル両性イオン性脂質が挙げられるが、これらに限定されない。有用な両性イオン性脂質の例は、DPPC、DOPCおよびドデシルホスホコリンである。上記脂質は、飽和もしくは不飽和であり得る。リポソームを調製するための少なくとも1つの不飽和脂質の使用は、好ましい。不飽和脂質が2つのテールを有する場合、両方のテールが、不飽和であり得、または上記不飽和脂質は、1つの飽和テールおよび1つの不飽和テールを有し得る。
種々のポリマーは、本発明に従って、RNAを被包もしくは吸着するように微粒子を形成し得る。実質的に非毒性のポリマーの使用は、レシピエントが上記粒子を安全に受容し得ることを意味し、生分解性ポリマーの使用は、上記粒子が、長期的な残存を回避するように送達後に代謝され得ることを意味する。有用なポリマーはまた、薬学的グレードの処方物の調製を補助するために、滅菌可能である。
第3の興味深い送達物質は、ポリマー、架橋剤、免疫原をコードする自己複製RNA、および荷電したモノマーの粒状反応生成物である。これら4種の成分は、液体として混合され得、型の中に配置され(例えば、ペルフルオロポリエーテルを含む)、次いで、硬化されて、上記型の形状および寸法に従って上記粒子が形成される。適切な製造法の詳細は、参考文献12に開示される。これら方法は、生分解性の架橋されたオリゴマーのポリマーナノ粒子(oligomeric polymer nanoparticle)を提供する。
本発明の粒子は、(siRNAとは異なり)免疫原をコードする自己複製RNA分子を含む。上記粒子のインビボ投与の後、RNAは、上記粒子から放出され、細胞内で翻訳されて、上記免疫原をインサイチュで提供する。
本発明で使用される自己複製RNA分子は、ポリペプチド免疫原をコードする。上記粒子の投与後に、上記免疫原は、インビボで翻訳され、レシピエントにおける免疫応答を誘発し得る。上記免疫原は、細菌、ウイルス、真菌もしくは寄生生物に対して(あるいは、いくつかの実施形態において、アレルゲンに対して;および他の実施形態において、腫瘍抗原に対して)免疫応答を誘発し得る。上記免疫応答は、抗体応答(通常は、IgGを含む)および/もしくは細胞媒介性免疫応答を含み得る。上記ポリペプチド免疫原は、代表的には、対応する細菌、ウイルス、真菌もしくは寄生生物(またはアレルゲンもしくは腫瘍)ポリペプチドを認識する免疫応答を誘発するが、いくつかの実施形態において、上記ポリペプチドは、細菌、ウイルス、真菌もしくは寄生生物のサッカリドを認識する免疫応答を誘発するように、ミモトープとして作用し得る。上記免疫原は、代表的には、表面ポリペプチド(例えば、アドヘシン、ヘマグルチニン、エンベロープ糖タンパク質、スパイク糖タンパク質など)である。
Neisseria meningitidis:有用な免疫原としては、膜タンパク質、例えば、アドヘシン、オートトランスポーター、毒素、鉄獲得タンパク質、およびH因子結合タンパク質が挙げられるが、これらに限定されない。3種の有用なポリペプチドの組み合わせが、参考文献17に開示される。
Bordetella pertussis:有用な百日咳免疫原としては、百日咳毒素もしくはトキソイド(PT)、線維状ヘマグルチニン(FHA)、ペルタクチン、ならびに凝集原2および3が挙げられるが、これらに限定されない。
Streptococcus agalactiae:有用な免疫原としては、参考文献19に開示されるポリペプチドが挙げられるが、これらに限定されない。
Yersinia pestis:有用な免疫原としては、参考文献33および34に開示されるものが挙げられるが、これらに限定されない。
オルソミクソウイルス:有用な免疫原は、インフルエンザA、BもしくはCウイルスに由来し得る(例えば、ヘマグルチニン、ノイラミニダーゼもしくはマトリクスM2タンパク質)。上記免疫原がインフルエンザAウイルスヘマグルチニンである場合、それは、任意のサブタイプ(例えば、H1、H2、H3、H4、H5、H6、H7、H8、H9、H10、H11、H12、H13、H14、H15もしくはH16)に由来し得る。
本発明の粒子は、種々の疾患に対して被験体を免疫化するための薬学的組成物中の成分として有用である。これらの組成物は、代表的には、上記粒子に加えて、薬学的に受容可能なキャリアを含む。薬学的に受容可能なキャリアの詳細な考察は、参考文献35において入手可能である。
参考文献16で開示される粒子とは対照的に、本発明の粒子および薬学的組成物は、目的の免疫原に対する免疫応答を誘発するためのインビボでの使用のためのものである。
本発明のいくつかの実施形態において、上記RNAは、改変なしのヌクレオチドを含む(上記を参照のこと)。他の実施形態において、上記RNAは、必要に応じて、少なくとも1つの改変ヌクレオチドを含み得るが、以下の特徴のうちの1つ以上(既に上記で開示されている)もまた、必要とされる:
A. 上記RNAがリポソームとともに送達される場合、上記リポソームは、DSDMA、DODMA、DLinDMAおよび/もしくはDLenDMAを含む。
B. 上記RNAがリポソームに被包される場合、上記リポソーム中の脂質の親水性部分は、PEG化される。
C. 上記RNAがリポソームに被包される場合、上記リポソームの数で少なくとも80%が、20〜220nmの範囲の直径を有する。
D. 上記RNAが微粒子とともに送達される場合、上記微粒子は、非毒性でかつ生分解性のポリマー微粒子である。
E. 上記RNAが微粒子とともに送達される場合、上記微粒子は、0.02μm〜8μmの範囲の直径を有する。
F. 上記RNAが微粒子とともに送達される場合、上記微粒子の数で少なくとも80%は、0.03〜7μmの範囲の直径を有する。
G. 上記RNAが微粒子とともに送達される場合、上記組成物は、凍結乾燥される。
H. 上記RNAは3’ポリAテールを有し、上記免疫原は、細菌、ウイルス、真菌もしくは寄生生物に対してインビボで免疫応答を誘発し得る。
I. 上記RNAは、(i)リポソーム、(ii)非毒性でかつ生分解性のポリマー微粒子から選択される送達系を用いて、金属イオンキレート化剤との組み合わせにおいて送達される。
本発明の粒子は、別段示されなければ、化学、生化学、分子生物学、免疫学および薬理学の、当該分野の技術内の従来の方法を使用する。このような技術は、文献中に十分に説明されている。例えば、参考文献36〜42などを参照のこと。
(RNAレプリコン)
種々のレプリコンは、以下で使用される。一般に、これらは、ベネズエラウマ脳炎ウイルス(VEEV)に由来する非構造タンパク質、シンドビス・ウイルス由来のパッケージングシグナル、およびシンドビス・ウイルスもしくはVEEV変異体に由来する3’UTRを有するハイブリッドアルファウイルスゲノムに基づく。上記レプリコンは、約10kb長であり、ポリAテールを有する。
微粒子を、500mgのPLG RG503(50:50 ラクチド/グリコリドモル比、MW約30kDa)および20mgのDOTAPを使用して、Omni Macro Homogenizerを使用して作製した。上記粒子懸濁物を、150rpmにおいて一晩振盪し、次いで、2〜8℃で貯蔵するために、40μm滅菌フィルタを通して濾過した。自己複製RNAを、上記粒子に吸着させた。1mLのPLG/RNA懸濁物を調製するために、PLG粒子懸濁物の必要容積をバイアルに添加し、ヌクレアーゼ非含有水を添加して、容積900μLにした。100μL RNA(10μg/mL)を、一定に振盪しながら上記PLG懸濁物に滴下した。PLG/RNAを、室温において30分間にわたってインキュベートした。再構成懸濁物1mLについて、45mg マンニトール、15mg スクロースおよび250〜500μgのPVAを添加した。上記バイアルを−80℃で凍結し、凍結乾燥した。
RNAを、参考文献7および44の方法によって作製したリポソーム中に被包した。上記リポソームを、10% DSPC(両性イオン性)、40% DlinDMA(カチオン性)、48% コレステロールおよび2% PEG結合体化DMG(2kDa PEG)から作製した。これら割合は、総リポソーム中の%モルに言及する。
骨髄由来樹状細胞(pDC)を、野生型マウスもしくは「Resq」(rsq1)変異系統から得た。上記変異系統は、そのTLR7レセプターのアミノ末端において点変異を有し、これは、リガンド結合に影響を及ぼさずにTLR7シグナル伝達を破壊する[46]。上記細胞を、DOTAP、リポフェクタミン2000で処方したレプリコンRNAもしくはリポソーム内のレプリコンRNAで刺激した。図17に示されるように、IL−6およびINFαは、WT細胞において誘導されたが、この応答は、変異マウスにおいてほぼ完全に排除された。これらの結果は、TLR7が、免疫細胞におけるRNA認識のために必要とされ、そしてリポソーム被包レプリコンが、免疫細胞に高レベルのインターフェロンおよび炎症促進性(pro−inflammatory)サイトカインの両方を分泌させ得ることを示す。
一般に、8つの異なる方法を、本発明に従うリポソームを調製するために使用した。これらは、方法(A)〜(H)として本文中で言及され、主に濾過およびTFF工程に関連して異なっている。詳細は、以下のとおりである。
様々な脂質でのリポソームを、BHK細胞とともに一晩インキュベートし、タンパク質発現能力について評価した。RV05脂質でのベースラインから、発現を、10% 1,2−ジフィタノイル(diphytanoyl)−sn−グリセロ−3−ホスホエタノールアミン(DPyPE)を上記リポソームに添加することによって18×に増大させることができ、10% 18:2(cis) ホスファチジルコリンを添加することによって10×に増大させることができ、そして代わりにRV01を使用することによって900×に増大させることができた。
RSV Fタンパク質をコードするvA317自己複製レプリコンを、0日目および21日目に、上記レプリコン(1μg)単独で、またはDlinDMA(「RV01」)もしくはDOTAP(「RV13」)とのリポソームとして処方して、両側の筋肉内ワクチン接種(50μL/脚)によって、BALB/cマウス(1群あたり4匹もしくは8匹の動物)に投与した。上記RV01リポソームは、40% DlinDMA、10% DSPC、48% コレステロールおよび2% PEG−DMGを有し、異なる量のRNAを伴った。上記RV13リポソームは、40% DOTAP、10% DPE、48% コレステロールおよび2% PEG−DMGを有した。比較のために、同じRSV−F抗原を発現する裸のプラスミドDNA(20μg)を、エレクトロポレーションを使用して、もしくはRV01(10)リポソーム(0.1μg DNA)とともに、のいずれかで送達した。4匹のマウスを、ナイーブコントロール群として使用した。
上記リポソーム群において認められる効果が、上記リポソーム成分にのみ起因していたのか、または上記被包に関連していたのかを評価するために、上記レプリコンを、被包形態(2つの異なる精製プロトコルとともに, 0.1μg RNA)において、またはリポソーム形成後に上記リポソームと混合して(非被包「リポプレックス」,0.1μg RNA)、または裸のRNA(1μg)として投与した。図10は、上記リポプレックスが、最低レベルの発現を与えたことを示す。このことは、被包がタンパク質発現に必須であることを示す。
群1 裸の自己複製性RSV−F RNA(vA317,0.1μg)
群2 リポソーム中に被包された自己複製性RSV−F RNA(vA317,0.1μg)
群3 空のリポソームに添加された自己複製性RSV−F RNA(vA317,0.1μg)
群4 Fサブユニットタンパク質(5μg)。
レプリコン「vA142」は、RSVの全長野生型表面融合(F)糖タンパク質をコードするが、その融合ペプチドは欠失しており、その3’末端は、リボザイム媒介性切断によって形成される。これを、3種の異なるマウス系統において試験した。
群1には、裸のレプリコン(1μg)を与えた。
群2には、40% DlinDMA、10% DSPC、48% Chol、2% PEG結合体化DMGを有するリポソーム「RV01(37)」中で送達した1μg レプリコンを与えた。
群3には、群2と同じものを与えたが、0.1μg RNAであった。
群4には、「RV17(10)」リポソーム(40% RV17(上記を参照のこと)、10% DSPC、49.5% コレステロール、0.5% PEG−DMG)中において1μg レプリコンを与えた。
群5には、「RV05(11)」リポソーム(40% RV07脂質、30% 18:2 PE(DLoPE)、28% コレステロール、2% PEG−DMG)中において1μg レプリコンを与えた。
群6には、「RV17(10)」リポソーム中において0.1μg レプリコンを与えた。
群7には、水酸化アルミニウムをアジュバント添加した5μg RSV−Fサブユニットタンパク質を与えた。
群8は、ナイーブコントロール(2匹の動物)であった。
DLinDMAをカチオン性脂質として有するRV01リポソームを使用して、サイトメガロウイルス(CMV)糖タンパク質をコードするRNAレプリコンを送達した。「vA160」レプリコンは、全長糖タンパク質HおよびL(gH/gL)をコードするのに対して、「vA322」レプリコンは、可溶性形態(gHsol/gL)をコードする。上記2種のタンパク質は、単一のレプリコン中の別個のサブゲノムプロモーターの制御下にある;2種の別個のベクター(1つは、gHをコードし、1つは、gLをコードする)の共投与は、良好な結果を与えなかった。
群1 gH FL/gLを発現するVRP(1×106 IU)
群2 ペンタマー、2A VRP(1×105 IU)
群3 ペンタマー、2A VRP(1×106 IU)
群4 ペンタマー、IRES VRP(1×105 IU)
群5 リポソーム中に処方された自己複製RNA vA160(1μg)
群6 リポソーム中に処方された自己複製RNA vA526(1μg)
群7 リポソーム中に処方された自己複製RNA vA527(1μg)
群8 カチオン性ナノエマルジョン中に処方された自己複製RNA vA160(1μg)
群9 カチオン性ナノエマルジョン中に処方された自己複製RNA vA526(1μg)
群10 カチオン性ナノエマルジョン中に処方された自己複製RNA vA527(1μg)。
流体力学的送達は、細胞膜の物理的障壁(大きい、膜不透過性の化合物が細胞に入らないようにする)を克服するための大きな容積の溶液の迅速な注射によって生じた力を使用する。この現象は、DNAワクチンの細胞内送達に有用であることが以前示された。
群1には、裸のレプリコンを50μL/脚において0.2μg与えた。
群2には、裸のレプリコンを5μL/脚において0.2μg与えた。
群3には、リポソーム処方レプリコン(0.2μg,50μL/脚)を与えた。
群4には、リポソーム処方レプリコン(0.2μg,5μL/脚)を与えた。
ルシフェラーゼレポーター遺伝子(luc)を発現する自己複製RNAレプリコン(「vA311」)を、注射後のタンパク質発現の動態を研究するために使用した。BALB/cマウス(1群あたり5匹の動物)に、0日目に、以下の両側の筋肉内ワクチン接種(50μL/脚)を与えた:
群1 エレクトロポレーションを使用して送達される、ルシフェラーゼを発現するDNA(10μg)
群2 リポソーム中に処方された自己複製RNA(1μg)
群3 カチオン性ナノエマルジョンとともに処方された自己複製RNA(1μg)
群4 カチオン性ナノエマルジョンとともに処方された自己複製RNA(1μg)
群5 ルシフェラーゼを発現するVRP(1×106 IU)。
HIV gp140をコードするリポソーム被包RNAを、マウスの筋肉内、皮内、もしくは皮下に送達した。3つの経路すべてが、HIV特異的抗体の高い血清IgGレベルをもたらした(図15)、このレベルは、エレクトロポレーションされた筋肉内DNAに応じて認められた力価を超えていた。
マウスの代わりに、コットンラット(Sigmodon hispidis)において研究を行った。1μg用量において、リポソーム被包は、裸のRNAと比較して、F特異的IgG力価を8.3倍に増大させ、PRNT力価を9.5倍に増大させた。上記抗体応答の程度は、5×106 IU VRPによって誘導されるものに等しかった。裸のRNAおよびリポソーム被包RNAはともに、RSVチャレンジ(1×105 プラーク形成単位)から上記コットンラットを防御することができ、肺のウイルス負荷を少なくとも3.5対数低下させた。被包は、低下を約2倍に増大させた。
大型動物研究を、ウシにおいて行った。仔ウシ(4〜6週齢、約60〜80kg、5頭/群)を、0日目、21日目、86日目および146日目に、66μgの、全長RSV Fタンパク質をコードするレプリコンvA317で免疫化した。上記レプリコンを、リポソームの中に処方した。PBS単独を、陰性コントロールとして使用し、認可されたワクチンを陽性コントロールとして使用した(Fort Dodgeの「Triangle 4」,死滅ウイルスを含む)。すべての仔ウシに、146日目に、MF59エマルジョンをアジュバント添加した15μg Fタンパク質を与えた。1頭のウシに、86日目に、Triangle 4の代わりに間違ったワクチンで誤ってワクチン接種してしまったので、そのデータは、100日目から排除した。
DDPC 1,2−ジデカノイル−sn−グリセロ−3−ホスファチジルコリン
DEPA 1,2−ジエルコイル−sn−グリセロ−3−ホスフェート
DEPC 1,2−エルコイル−sn−グリセロ−3−ホスファチジルコリン
DEPE 1,2−ジエルコイル−sn−グリセロ−3−ホスファチジルエタノールアミン
DEPG 1,2−ジエルコイル−sn−グリセロ−3[ホスファチジル−rac−(1−グリセロール...)
DLOPC 1,2−リノレオイル−sn−グリセロ−3−ホスファチジルコリン
DLPA 1,2−ジラウロイル−sn−グリセロ−3−ホスフェート
DLPC 1,2−ジラウロイル−sn−グリセロ−3−ホスファチジルコリン
DLPE 1,2−ジラウロイル−sn−グリセロ−3−ホスファチジルエタノールアミン
DLPG 1,2−ジラウロイル−sn−グリセロ−3[ホスファチジル−rac−(1−グリセロール...)
DLPS 1,2−ジラウロイル−sn−グリセロ−3−ホスファチジルセリン
DMG 1,2−ジミリストイル−sn−グリセロ−3−ホスホエタノールアミン
DMPA 1,2−ジミリストイル−sn−グリセロ−3−ホスフェート
DMPC 1,2−ジミリストイル−sn−グリセロ−3−ホスファチジルコリン
DMPE 1,2−ジミリストイル−sn−グリセロ−3−ホスファチジルエタノールアミン
DMPG 1,2−ミリストイル−sn−グリセロ−3[ホスファチジル−rac−(1−グリセロール...)
DMPS 1,2−ジミリストイル−sn−グリセロ−3−ホスファチジルセリン
DOPA 1,2−ジオレオイル−sn−グリセロ−3−ホスフェート
DOPC 1,2−ジオレオイル−sn−グリセロ−3−ホスファチジルコリン
DOPE 1,2−ジオレオイル−sn−グリセロ−3−ホスファチジルエタノールアミン
DOPG 1,2−ジオレオイル−sn−グリセロ−3[ホスファチジル−rac−(1−グリセロール...)
DOPS 1,2−ジオレオイル−sn−グリセロ−3−ホスファチジルセリン
DPPA 1,2−ジパルミトイル−sn−グリセロ−3−ホスフェート
DPPC 1,2−ジパルミトイル−sn−グリセロ−3−ホスファチジルコリン
DPPE 1,2−ジパルミトイル−sn−グリセロ−3−ホスファチジルエタノールアミン
DPPG 1,2−ジパルミトイル−sn−グリセロ−3[ホスファチジル−rac−(1−グリセロール...)
DPPS 1,2−ジパルミトイル−sn−グリセロ−3−ホスファチジルセリン
DPyPE 1,2−ジフィタノイル−sn−グリセロ−3−ホスホエタノールアミン
DSPA 1,2−ジステアロイル−sn−グリセロ−3−ホスフェート
DSPC 1,2−ジステアロイル−sn−グリセロ−3−ホスファチジルコリン
DSPE 1,2−ジステアロイル(Diostearpyl)−sn−グリセロ−3−ホスファチジルエタノールアミン
DSPG 1,2−ジステアロイル−sn−グリセロ−3[ホスファチジル−rac−(1−グリセロール...)
DSPS 1,2−ジステアロイル−sn−グリセロ−3−ホスファチジルセリン
EPC 卵−PC
HEPC 水素化卵PC
HSPC 高純度水素化ダイズPC
HSPC 水素化ダイズPC
LYSOPC MYRISTIC 1−ミリストイル−sn−グリセロ−3−ホスファチジルコリン
LYSOPC PALMITIC 1−パルミトイル−sn−グリセロ−3−ホスファチジルコリン
LYSOPC STEARIC 1−ステアロイル−sn−グリセロ−3−ホスファチジルコリン
ミルクスフィンゴミエリンMPPC 1−ミリストイル,2−パルミトイル−sn−グリセロ 3−ホスファチジルコリン
MSPC 1−ミリストイル,2−ステアロイル−sn−グリセロ−3−ホスファチジルコリン
PMPC 1−パルミトイル,2−ミリストイル−sn−グリセロ−3−ホスファチジルコリン
POPC 1−パルミトイル,2−オレオイル−sn−グリセロ−3−ホスファチジルコリン
POPE 1−パルミトイル−2−オレオイル−sn−グリセロ−3−ホスファチジルエタノールアミン
POPG 1,2−ジオレオイル−sn−グリセロ−3[ホスファチジル−rac−(1−グリセロール)...]
PSPC 1−パルミトイル,2−ステアロイル−sn−グリセロ−3−ホスファチジルコリン
SMPC 1−ステアロイル,2−ミリストイル−sn−グリセロ−3−ホスファチジルコリン
SOPC 1−ステアロイル,2−オレオイル−sn−グリセロ−3−ホスファチジルコリン
SPPC 1−ステアロイル,2−パルミトイル−sn−グリセロ−3−ホスファチジルコリン
Claims (16)
- 脊椎動物細胞へRNAをインビボで送達するための非ビリオン粒子であって、ここで、
(a)該粒子は、
(i)送達物質であって、免疫原をコードする自己複製RNA分子を被包している、送達物質、または
(ii)送達物質であって、免疫原をコードする自己複製RNA分子が、該送達物質に吸着させられている、送達物質
のいずれかを含み、
(b)該RNAは、改変されていないヌクレオチドを含む、
非ビリオン粒子。 - 前記粒子が、リポソームであり、前記RNAが、該リポソーム中に被包されている、請求項1に記載の粒子。
- 前記粒子が、非毒性かつ生分解性のポリマー微粒子であり、前記RNAが、該ポリマー微粒子に吸着させられている、請求項1に記載の粒子。
- 前記粒子が、ポリマー、架橋剤、荷電したモノマーおよび前記RNAを反応させることによって形成された、生分解性の架橋されたオリゴマーのポリマーナノ粒子である、請求項1に記載の粒子。
- 前記リポソームが、カチオン性頭部を有する脂質を含む、請求項2に記載の粒子。
- 前記リポソームが、両性イオン性頭部を有する脂質を含む、請求項2または請求項5に記載の粒子。
- 前記リポソームが、50nm〜220nmの範囲の直径を有する、請求項2、請求項5または請求項6に記載の粒子。
- 前記粒子が、ポリ(D,L−ラクチド−co−グリコリド)を含む、請求項3に記載の粒子。
- 前記粒子が、直径30nm〜7μmを有する、請求項3または請求項8に記載の粒子。
- 前記自己複製RNA分子が、
(i)該自己複製RNA分子からRNAを転写し得るRNA依存性RNAポリメラーゼ、および
(ii)免疫原
をコードする、前述の請求項のいずれかに記載の粒子。 - 前記RNA分子が、2個のオープンリーディングフレームを有し、該2個のオープンリーディングフレームの第1のものが、アルファウイルスレプリカーゼをコードし、該2個のオープンリーディングフレームの第2のものが、前記免疫原をコードする、請求項10に記載の粒子。
- 前記RNA分子が、9000〜12000ヌクレオチド長である、前述の請求項のいずれかに記載の粒子。
- 前記免疫原が、細菌、ウイルス、真菌もしくは寄生生物に対してインビボで免疫応答を誘発し得る、前述の請求項のいずれかに記載の粒子。
- 前記免疫原が、RSウイルス糖タンパク質Fに対してインビボで免疫応答を誘発し得る、請求項13に記載の粒子。
- 前述の請求項のいずれかに記載の粒子を含む、薬学的組成物。
- 脊椎動物において防御免疫応答を惹起するための方法であって、該方法は、請求項1〜14に記載の粒子、または請求項15に記載の薬学的組成物の有効量を、該脊椎動物に投与する工程を包含する、方法。
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JP2020528911A (ja) * | 2017-07-28 | 2020-10-01 | ヤンセン ファッシンズ アンド プリベンション ベーフェーJanssen Vaccines & Prevention B.V. | 異種repRNA免疫化のための方法および組成物 |
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