JP2023002709A - RNA送達に有利なpKa値を有する脂質を含むリポソーム - Google Patents
RNA送達に有利なpKa値を有する脂質を含むリポソーム Download PDFInfo
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Abstract
Description
本発明は、免疫のためのRNAの非ウイルス性送達の分野にある。
動物を免疫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、免疫原をコードするRNAは、免疫の目的で、リポソーム中で送達される。上記リポソームは、5.0~7.6の範囲のpKaを有する脂質を含む。理想的には、この範囲のpKaを有する脂質は、三級アミンを有する;このような脂質は、四級アミン基を有する脂質(例えば、DOTAPもしくはDC-Chol)とは異なって挙動する。生理学的pHにおいて、5.0~7.6の範囲のpKaを有するアミンは、中性のもしくは低下した表面電荷を有するのに対して、DOTAPのような脂質は、強力にカチオン性である。本発明者らは、四級アミン脂質(例えば、DOTAP)から形成されるリポソームが、三級アミン脂質(例えば、DLinDMA)から形成されるリポソームより、免疫原をコードするRNAの送達には適切性において劣ることを見いだした。
本発明は、免疫原をコードするRNAが封入されているリポソームを利用する。従って、上記RNAは、(天然ウイルスにおけるように)上記リポソームの脂質二重層によって任意の外部媒体(external medium)から分離されており、そしてこの方法での封入は、RNase消化からRNAを保護することが見いだされた。上記リポソームは、いくらかの外部RNA(例えば、それらの表面に)を含み得るが、上記RNAのうちの少なくとも半分(および理想的には、そのすべて)は、上記リポソームのコアに封入される。リポソーム内の封入は、例えば、参考文献1で開示される脂質/RNA複合体とは異なる。
上記のように、本発明は、RNA含有リポソームを調製するためのプロセスであって、(a)RNAと、脂質とを、上記脂質のpKa未満であるが、4.5を上回るpHにおいて混合する工程;次いで、(b)上記pHを、上記脂質のpKaを上回るように上昇させる工程を包含するプロセスを提供する。
本発明は、免疫原をコードするRNAのインビボ送達に有用である。上記RNAは、その送達部位において非免疫細胞によって翻訳され、上記免疫原の発現をもたらし、そしてまた、それは、免疫細胞に、I型インターフェロンおよび/もしくは炎症促進性サイトカイン(これらは、局所的なアジュバント効果を提供する)を分泌させる。上記非免疫細胞はまた、上記RNAに応答してI型インターフェロンおよび/もしくは炎症促進性サイトカインを分泌し得る。
本発明で使用されるRNA分子は、ポリペプチド免疫原をコードする。上記リポソームの投与後に、上記RNAは、インビボで翻訳され、そして免疫原は、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15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17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31および32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。
本発明のリポソームは、種々の疾患に対して被験体を免疫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、上記リポソームに加えて、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33において入手可能である。
参考文献14で開示される粒子とは対照的に、本発明のリポソーム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34~40などを参照のこと。
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尾部を有する。
RNAを、参考文献11および42の方法によって作製したリポソーム中に封入した。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[44]。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19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、そしてリポソーム封入レプリコンが、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。
脂質のpKaを、標準の温度および圧力の水において、以下の技術を使用して測定する:
・エタノール中の脂質の2mM溶液を、上記脂質を秤量し、エタノール中に溶解することによって調製する。エタノール:メタノール 9:1中の蛍光プローブトルエンニトロスルホン酸(TNS)の0.3mM溶液を、最初にメタノール中のTNSの3mM溶液を作製し、次いで、エタノールで0.3mMに希釈することによって調製する。
・それぞれ、濃度20mM、25mM、20mMおよび150mMのリン酸ナトリウム、クエン酸ナトリウム、酢酸ナトリウム、および塩化ナトリウムを含む水性緩衝液を、調製する。上記緩衝液を、8つの部分に分け、そのpHを、12N HClもしくは6N NaOHのいずれかで、4.44~4.52、5.27、6.15~6.21、6.57、7.10~7.20、7.72~7.80、8.27~8.33および10.47~11.12へと調整する。400μLの2mM脂質溶液および800μLの0.3mM TNS溶液を混合する。
・7.5μLのプローブ/脂質混合物を、1mL 96ウェルプレートの中の242.5μLの緩衝液に添加する。これを、8つすべての緩衝液で行う。混合した後、100μLの各プローブ/脂質/緩衝液混合物を、クリアボトム(clear bottom)250μL黒色96ウェルプレート(例えば、モデルCOSTAR 3904, Corning)に移す。この混合を行う便利な方法は、Tecan Genesis RSP150ハイスループット液体ハンドラーおよびGemini Softwareを使用することである。
・各プローブ/脂質/緩衝液混合物の蛍光を、322nm励起、431nm発光(オートカットオフ420nm)で測定する(例えば、SpectraMax M5分光光度計およびSoftMax pro 5.2ソフトウェアで)。
・測定後、上記96ウェルプレートにおける空のウェルのバックグラウンド蛍光値を、各プローブ/脂質/緩衝液混合物から差し引く。次いで、その蛍光強度値を、最低pHにおける値に対して正規化する。次いで、正規化した蛍光強度を、pHに対してプロットし、最適の線を、提供する。
・上記正規化した蛍光強度が0.5に等しい最適の線上の点を、見いだす。0.5に等しい正規化した蛍光強度に対応するpHを見いだし、上記脂質のpKaとみなす。
DlinDMAを使用する代わりとして、参考文献5のカチオン性脂質を使用する。これら脂質を、参考文献5に開示されるように合成しうる。
(RSV免疫原性)
さらなる研究は、RSV Fタンパク質をコードする自己複製レプリコン(vA317)で行った。BALB/cマウス(1群あたり4匹もしくは8匹の動物)に、0日目および21日目に、上記レプリコン(1μg)単独を、あるいは上記RV01脂質もしくはRV05脂質(上記を参照のこと;pKa 5.8もしくは5.85)で、またはRV13でリポソームとして処方されたレプリコンを、両側の筋肉内にワクチン接種(50μL/脚)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を有したが、RNAの量は異なった。上記RV05(01)リポソームは、40% カチオン性脂質、48% コレステロール、10% DSPC、および2% PEG-DMGを有した;上記RV05(02)リポソームは、60% カチオン性脂質、38% コレステロール、および2% PEG-DMGを有した。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するか、またはRV01(10)リポソーム(0.1μg DNA)によるか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。
RV01リポソームにおけるカチオン性脂質(DLinDMA)は、RV16、RV17、RV18もしくはRV19で置き換えられた。総IgG力価を、図17に示す。最低の結果は、RV19(すなわち、DOTMA四級アミン)で認められる。
異なる脂質を有するリポソームを、BHK細胞とともに一晩インキュベートし、タンパク質発現効力について評価した。RV05脂質発現でのベースラインから、10% 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(DPyPE)を上記リポソームに添加することによって18×、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×、および代わりにRV01を使用することによって900×増大し得た。
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。
本発明は以下の態様にも関する。
[1]水性コアを封入する脂質二重層を有するリポソームであって、ここで:(i)該脂質二重層は、5.0~7.6の範囲のpKaを有する脂質を含み;そして(ii)該水性コアは、免疫原をコードするRNAを含む、リポソーム。
[2]5.0~7.6の範囲のpKaを有する前記脂質は、三級アミンを有する、上記[1]に記載のリポソーム。
[3]5.0~7.6の範囲のpKaは、5.7~5.9の間である、上記[1]~[2]のいずれかに記載のリポソーム。
[4]5.0~7.6の範囲のpKaを有する前記脂質は、RV01、RV02、RV03、RV04、RV05、RV06、RV07、RV08、RV09、RV11、RV12、RV16もしくはRV17について本明細書で示される式を有する、上記[1]に記載のリポソーム。
[5]20~220nmの範囲の直径を有する、上記[1]~[4]のいずれかに記載のリポソーム。
[6]前記RNA分子は、(i)該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、上記[1]~[5]のいずれかに記載のリポソーム。
[7]前記RNA分子は、2個のオープンリーディングフレームを有し、そのうちの第1のものは、アルファウイルスレプリカーゼをコードし、そのうちの第2のものは、前記免疫原をコードする、上記[5]に記載のリポソーム。
[8]前記RNA分子は、9000~12000ヌクレオチド長である、上記[1]~[7]のいずれかに記載のリポソーム。
[9]前記免疫原は、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、上記[1]~[8]のいずれかに記載のリポソーム。
[10]前記免疫原は、呼吸器系合胞体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、上記[1]~[9]のいずれかに記載のリポソーム。
[11]上記[1]~[10]のいずれかに記載のリポソームを含む、薬学的組成物。
[12]脊椎動物において防御的免疫応答を惹起するための方法であって、該方法は、該脊椎動物に、有効量の、上記[1]~[10]に記載のリポソーム、または上記[11]に記載の薬学的組成物を投与する工程を包含する、方法。
[13]RNA含有リポソームを調製するためのプロセスであって、該プロセスは、リポソーム形成の際に、(a)RNAと、脂質とを、該脂質のpKa未満であるが4.5を上回るpHにおいて混合する工程;次いで、(b)該pHを、該脂質のpKaを上回るように上昇させる工程、を包含する、プロセス。
[14]上記[13]に記載のプロセスであって、ここで、工程(a)において使用されるRNAは、前記脂質の有機溶液と混合して、混合物を与えるために、水性溶液中に存在し、該混合物は、次いで、希釈されて、リポソームを形成し;そして前記pHは、リポソーム形成後に、工程(b)において上昇させられる、プロセス。
Claims (14)
- 水性コアを封入する脂質二重層を有するリポソームであって、ここで:(i)該脂質二重層は、5.0~7.6の範囲のpKaを有する脂質を含み;そして(ii)該水性コアは、免疫原をコードするRNAを含む、リポソーム。
- 5.0~7.6の範囲のpKaを有する前記脂質は、三級アミンを有する、請求項1に記載のリポソーム。
- 5.0~7.6の範囲のpKaは、5.7~5.9の間である、前記請求項のいずれかに記載のリポソーム。
- 5.0~7.6の範囲のpKaを有する前記脂質は、RV01、RV02、RV03、RV04、RV05、RV06、RV07、RV08、RV09、RV11、RV12、RV16もしくはRV17について本明細書で示される式を有する、請求項1に記載のリポソーム。
- 20~220nmの範囲の直径を有する、前記請求項のいずれかに記載のリポソーム。
- 前記RNA分子は、(i)該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、前記請求項のいずれかに記載のリポソーム。
- 前記RNA分子は、2個のオープンリーディングフレームを有し、そのうちの第1のものは、アルファウイルスレプリカーゼをコードし、そのうちの第2のものは、前記免疫原をコードする、請求項5に記載のリポソーム。
- 前記RNA分子は、9000~12000ヌクレオチド長である、前記請求項のいずれかに記載のリポソーム。
- 前記免疫原は、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、前記請求項のいずれかに記載のリポソーム。
- 前記免疫原は、呼吸器系合胞体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、前記請求項のいずれかに記載のリポソーム。
- 前記請求項のいずれかに記載のリポソームを含む、薬学的組成物。
- 脊椎動物において防御的免疫応答を惹起するための方法であって、該方法は、該脊椎動物に、有効量の、請求項1~10に記載のリポソーム、または請求項11に記載の薬学的組成物を投与する工程を包含する、方法。
- RNA含有リポソームを調製するためのプロセスであって、該プロセスは、リポソーム形成の際に、(a)RNAと、脂質とを、該脂質のpKa未満であるが4.5を上回るpHにおいて混合する工程;次いで、(b)該pHを、該脂質のpKaを上回るように上昇させる工程、を包含する、プロセス。
- 請求項13に記載のプロセスであって、ここで、工程(a)において使用されるRNAは、前記脂質の有機溶液と混合して、混合物を与えるために、水性溶液中に存在し、該混合物は、次いで、希釈されて、リポソームを形成し;そして前記pHは、リポソーム形成後に、工程(b)において上昇させられる、プロセス。
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