JP2020114865A - 免疫療法のためのrna製剤 - Google Patents
免疫療法のためのrna製剤 Download PDFInfo
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- JP2020114865A JP2020114865A JP2020068394A JP2020068394A JP2020114865A JP 2020114865 A JP2020114865 A JP 2020114865A JP 2020068394 A JP2020068394 A JP 2020068394A JP 2020068394 A JP2020068394 A JP 2020068394A JP 2020114865 A JP2020114865 A JP 2020114865A
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Abstract
Description
(i)ナノ粒子における正電荷数がナノ粒子における負電荷数を超えず、及び/又は
(ii)ナノ粒子が中性電荷又は正味の負電荷を有し、及び/又は
(iii)ナノ粒子における正電荷と負電荷との電荷比が1.4:1以下であり、及び/又は
(iv)ナノ粒子のゼータ電位が0以下である、
医薬組成物に関する。
以下に本発明を詳述するが、本発明は、本明細書に記載される特定の方法論、プロトコール及び試薬は様々でありうるため、これらに限定されないと理解すべきである。本明細書において使用する術語が、特定の実施形態を説明する目的のためのみの術語であり、付属の請求項によってのみ限定される本発明の範囲を限定しようとするものではないことも理解すべきである。他で規定されない限り、本明細書において使用する全ての技術用語及び科学用語は、当業者に通常理解されている意味と同じ意味を有する。
予見されるRNAリポプレックスを提供する限り、RNA及びリポソームからのRNAリポプレックスの形成についてリポソームを形成する任意の適切な方法を使用できる。リポソームは、逆相蒸散法(REV)、エタノール注射法、脱水-再水和法(DRV)、超音波処理又は他の適切な方法などの標準的な方法を使って形成しうる。
化学療法は、複合的なタイプのがんをケアする標準的なものである。最も一般的な化学療法剤は、急速に分裂する(がん細胞の主な特性の1つ)細胞を死滅させることにより作用する。したがって、従来の化学療法薬、例えばアルキル化剤、代謝拮抗物質、アントラサイクリン、植物アルカロイド、トポイソメラーゼインヒビター、及び細胞分裂又はDNA合成のいずれかに影響する他の抗腫瘍剤との組合せは、サプレッサ細胞を取り除くこと(免疫系の再起動)により、腫瘍細胞を免疫媒介性の殺傷により感受性にすることにより、又は免疫系の細胞の付加的な活性化により、本発明の治療効果を有意に改善する。化学療法及びワクチン接種ベースの免疫療法薬の相乗的な抗がん作用は、複数の研究において実証されている(例えば、Quoixら 2011: Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 12(12):1125〜33頁を参照されたい;Lisethら 2010: Combination of intensive chemotherapy and anticancer vaccines in the treatment of human malignancies: the hematological experience. J Biomed Biotechnol. 2010:6920979も参照されたい;Hirookaら 2009: A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Pancreas 38(3):e69〜74頁も参照されたい)。基本的に併用療法に適切である、利用可能な何百もの化学療法薬が存在する。本発明と組み合わせることができる化学療法薬のいくつかの(非限定の)例は、カルボプラチン(Paraplatin)、シスプラチン(Platinol、Platinol-AQ)、シクロホスファミド(Cytoxan、Neosar)、ドセタキセル(Taxotere)、ドキソルビシン(Adriamycin)、エルロチニブ(Tarceva)、エトポシド(VePesid)、フルオロウラシル(5-FU)、ゲムシタビン(Gemzar)、メシル酸イマチニブ(Gleevec)、イリノテカン(Camptosar)、メトトレキセート(Folex、Mexate、Amethopterin)、パクリタキセル(Taxol、Abraxane)、ソラフィニブ(Nexavar)、スニチニブ(Sutent)、トポテカン(Hycamtin)、ビンクリスチン(Oncovin、Vincasar PFS)、及びビンブラスチン(Velban)である。
がん手術(腫瘍を除去するためのオペレーション)は、依然として、がん治療の基礎である。手術は、任意の残存している腫瘍細胞を除去するために、他のがん治療と組み合わせることができる。外科的な方法を引き続く免疫療法処置と組み合わせることは、何度となく実証されてきた有望なアプローチである。
放射線療法は依然としてがん治療の重要な要素であり、全てのがん患者のおよそ50%が疾病の経過中に放射線療法を受けている。放射線療法の主なゴールは、がん細胞から彼等の倍加(細胞分裂)能を奪うことである。がんを治療するため使用される放射線のタイプは、光子放射線(X線及びガンマ線)及び粒子放射線(電子、プロトン及び中性子ビーム)である。放射線をがんの位置に送達するため2つの方式が存在する。外部のビーム照射は、高エネルギー線(光子、光子放射線又は粒子放射線)を腫瘍の位置に狙いを定めることにより、身体の外側から送達される。内部照射又は近接照射療法は、カテーテル又はシードに密封した放射性線源により、身体の内側から腫瘍部位に直接送達される。本発明と組み合わせて適用可能な放射線療法技術は、例えば、分割法(例えば、数週にわたり与えられる1.5〜3Gyの一日分割量で送達される分割レジメンにおける放射線療法)、3次元原体照射法(3DCRT;肉眼的腫瘍体積への放射線の送達)、強度変調放射線治療(IMRT;複数の放射線ビームのコンピュータ制御による強度の変調)、画像誘導放射線治療(IGRT;修正を見込んだプレ放射線治療イメージングを含む技術)、及び定位放射線治療(SRBT、僅か少数の治療の小部位に対する非常に高い個別の用量の放射線が送達される)である。放射線療法に関しては、総説(Baskarら 2012: Cancer and radiation therapy: current advances and future directions. Int. J Med Sci. 9(3):193〜199頁)を参照されたい。
抗体(好ましくは、モノクローナル抗体)は、様々な機構を通じてがん細胞に対する治療効果を達成する。それらは、アポトーシス又はプログラム細胞死を生じさせることに直接的な効果を有しうる。それらは、成長因子レセプターなどのシグナル伝達経路の成分をブロックし、腫瘍細胞の増殖を有効に停止させることができる。モノクローナル抗体を発現する細胞において、それらは抗イディオタイプ抗体形成を起こすことができる。間接的な効果には、単球及びマクロファージなどの細胞傷害性を有する細胞をリクルートすることが含まれる。このタイプの抗体媒介性の細胞殺傷は、抗体依存性細胞媒介性細胞傷害(ADCC)と呼ばれる。抗体はまた、補体に結合し、補体依存性細胞傷害(CDC)として知られる直接的な細胞傷害性が導かれる。外科的な方法を免疫療法的な薬物又は方法と組み合わせるアプローチは、例えば、Gadriら 2009: Synergistic effect of dendritic cell vaccination and anti-CD20 antibody treatment in the therapy of murine lymphoma. J Immunother. 32(4):333〜40頁において実証されているとおり、成功している。次のリストは、本発明と組み合わせて使用することができる抗がん抗体及び潜在的な抗体ターゲット(括弧内)のいくつかの非限定的な例を提供する:Abagovomab(CA-125)、Abciximab(CD41)、Adecatumumab(EpCAM)、Afutuzumab(CD20)、Alacizumab pegol(VEGFR2)、Altumomab pentetate(CEA)、Amatuximab(MORAb-009)、Anatumomab mafenatox(TAG-72)、Apolizumab(HLA-DR)、Arcitumomab(CEA)、Bavituximab(ホスファチジルセリン)、Bectumomab(CD22)、Belimumab(BAFF)、Bevacizumab(VEGF-A)、Bivatuzumab mertansine(CD44 v6)、Blinatumomab(CD19)、Brentuximab vedotin(CD30 TNFRSF8)、Cantuzumab mertansin(ムチン CanAg)、Cantuzumab ravtansine(MUC1)、Capromab pendetide(前立腺がん腫細胞)、Carlumab(CNTO888)、Catumaxomab(EpCAM、CD3)、Cetuximab(EGFR)、Citatuzumab bogatox(EpCAM)、Cixutumumab(IGF-1 レセプター)、Claudiximab(クローディン)、Clivatuzumab tetraxetan(MUC1)、Conatumumab(TRAIL-R2)、Dacetuzumab(CD40)、Dalotuzumab(インスリン様成長因子Iレセプター)、Denosumab(RANKL)、Detumomab(Bリンパ腫細胞)、Drozitumab(DR5)、Ecromeximab(GD3ガングリオシド)、Edrecolomab(EpCAM)、Elotuzumab(SLAMF7)、Enavatuzumab(PDL192)、Ensituximab(NPC-1C)、Epratuzumab(CD22)、Ertumaxomab(HER2/neu、CD3)、Etaracizumab(インテグリン αvβ3)、Farletuzumab(葉酸レセプター1)、FBTA05(CD20)、Ficlatuzumab(SCH 900105)、Figitumumab(IGF-1レセプター)、Flanvotumab(糖タンパク質75)、Fresolimumab(TGF-β)、Galiximab(CD80)、Ganitumab(IGF-I)、Gemtuzumab ozogamicin(CD33)、Gevokizumab(IL-1β)、Girentuximab(カルボニックアンヒドラーゼ9(CA-IX))、Glembatumumab vedotin(GPNMB)、Ibritumomab tiuxetan(CD20)、Icrucumab(VEGFR-1)、Igovoma(CA-125)、Indatuximab ravtansine(SDC1)、Intetumumab(CD51)、Inotuzumab ozogamicin(CD22)、Ipilimumab(CD152)、Iratumumab(CD30)、Labetuzumab(CEA)、Lexatumumab(TRAIL-R2)、Libivirumab(B型肝炎表面抗原)、Lintuzumab(CD33)、Lorvotuzumab mertansine(CD56)、Lucatumumab(CD40)、Lumiliximab(CD23)、Mapatumumab(TRAIL-R1)、Matuzumab(EGFR)、Mepolizumab(IL-5)、Milatuzumab(CD74)、Mitumomab(GD3ガングリオシド)、Mogamulizumab(CCR4)、Moxetumomab pasudotox(CD22)、Nacolomab tafenatox(C242抗原)、Naptumomab estafenatox(5T4)、Narnatumab(RON)、Necitumumab(EGFR)、Nimotuzumab(EGFR)、Nivolumab(IgG4)、Ofatumumab(CD20)、Olaratumab(PDGF-Rα)、Onartuzumab(ヒト細胞分散因子レセプターキナーゼ)、Oportuzumab monatox(EpCAM)、Oregovomab(CA-125)、Oxelumab(OX-40)、Panitumumab(EGFR)、Patritumab(HER3)、Pemtumoma(MUC1)、Pertuzuma(HER2/neu)、Pintumomab(腺癌抗原)、Pritumumab(ビメンチン)、Racotumomab(N-グリコリルノイラミン酸)、Radretumab(フィブロネクチンエキストラドメイン-B)、Rafivirumab(狂犬病ウイルス糖タンパク質)、Ramucirumab(VEGFR2)、Rilotumumab(HGF)、Rituximab(CD20)、Robatumumab(IGF-1レセプター)、Samalizumab(CD200)、Sibrotuzumab(FAP)、Siltuximab(IL-6)、Tabalumab(BAFF)、Tacatuzumab tetraxetan(アルファフェトプロテイン)、Taplitumomab paptox(CD19)、Tenatumomab(テネイシンC)、Teprotumumab(CD221)、Ticilimumab(CTLA-4)、Tigatuzumab(TRAIL-R2)、TNX-650(IL-13)、Tositumomab(CD20)、Trastuzumab(HER2/neu)、TRBS07(GD2)、Tremelimumab(CTLA-4)、Tucotuzumab celmoleukin(EpCAM)、Ublituximab(MS4A1)、Urelumab(4-1BB)、Volociximab(インテグリン α5β1)、Votumumab(腫瘍抗原 CTAA16.88)、Zalutumumab(EGFR)、Zanolimumab(CD4)。
有益な免疫モジュレーション又は腫瘍阻害効果を誘起するための、本発明の抗原コード医薬組成物とサイトカイン、ケモカイン、共刺激分子及び/又はその融合タンパク質との併用用法は、本発明の別の実施形態である。免疫細胞の腫瘍への浸潤を増加させるために及び抗原提示細胞の腫瘍所属リンパ節(tumor-draining lymph node)への運動を容易にするために、C、CC、CXC及びCX3C構造を有する様々なケモカインが使用されうる。最も有望なケモカインのいくつかは、例えば、CCR7及びそのリガンドCCL19及びCCL21、さらにCCL2、CCL3、CCL5、及びCCL16である。他の例は、CXCR4、CXCR7及びCXCL12である。さらにまた、共刺激性又は調節性の分子、例えば、B7リガンド(B7.1及びB7.2)も有用である。他のサイトカイン、例えば、インターロイキン、特に(例えば、IL-1からIL17)、インターフェロン(例えば、IFNalpha1からIFNalpha8、IFNalpha10、IFNalpha13、lFNalpha14、IFNalpha16、IFNalpha17、IFNalpha21、IFNbeta1、IFNW、IFNE1及びIFNK)、造血性因子、TGF(例えば、TGF-α、TGF-β、及び他のメンバーのTGFファミリー)、最後に腫瘍壊死因子ファミリーのメンバーのレセプター及びそれらのリガンド、並びに他の刺激分子であって、41BB、41BB-L、CD137、CD137L、CTLA-4GITR、GITRL、Fas、Fas-L、TNFR1、TRAIL-R1、TRAIL-R2、p75NGF-R、DR6、LT.beta.R、RANK、EDAR1、XEDAR、Fn114、Troy/Trade、TAJ、TNFRII、HVEM、CD27、CD30、CD40、4-1BB、OX40、GITR、GITRL、TACI、BAFF-R、BCMA、RELT、及びCD95(Fas/APO-1)、糖質コルチコイド誘導性TNFR関連タンパク質、TNFレセプター関連アポトーシス媒介性タンパク質(TRAMP)及びデスレセプター6(DR6)を含むが、これらに限定されない分子も有用である。特に、CD40/CD40L及びOX40/OX40Lは、併用免疫療法のための重要な標的である、というのも、これらはT細胞の生存及び増殖に直接的な影響力があるからである。総説に関して、Lechnerら 2011: Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors. Immunotherapy 3 (11), 1317〜1340頁を参照されたい。
研究者は、クロストリジウム・ノビイ(Clostridium novyi)などの嫌気性菌を使って、低酸素腫瘍の内部を消費させた。その後、これらは腫瘍の酸素を含む側に接触した際に死滅するはずであり、それらが身体の残りの部分には無害であろうことを意味している。別の戦略は、非毒性のプロドラッグを毒性薬物に転換できる酵素で形質転換した嫌気性菌の使用である。腫瘍の壊死性及び低酸素性の領域においてその細菌が増殖することで、その酵素は唯一腫瘍において発現される。したがって、全身に適用されるプロドラッグは、腫瘍においてのみ毒性薬物に代謝される。このことは、非病原性の嫌気性菌であるクロストリジウム・スポロゲネス(Clostridium sporogenes)で有効であることが実証されている。
がん細胞の成長及び生存がキナーゼ活性の調節解除で厳密にインターロックされることから、補完的ながん治療のための潜在的な標的の別の大きなグループには、キナーゼインヒビターが含まれる。正常なキナーゼ活性を回復させて腫瘍成長を低減させるため、広範囲のインヒビターが使用されている。標的にされるキナーゼのグループには、レセプターチロシンキナーゼ、例えば、BCR-ABL、B-Raf、EGFR、HER-2/ErbB2、IGF-IR、PDGFR-α、PDGFR-β、c-Kit、Flt-4、Flt-3、FGFR1、FGFR3、FGFR4、CSF1R、c-Met、RON、c-Ret、ALK、細胞質のチロシンキナーゼ、例えば、c-SRC、c-YES、Abl、JAK-2、セリン/スレオニンキナーゼ、例えば、ATM、Aurora A&B、CDK、mTOR、PKCi、PLK、b-Raf、S6K、STK11/LKB1及び脂質キナーゼ、例えば、PI3K、SK1が含まれる。小分子キナーゼインヒビターは、例えば、PHA-739358、Nilotinib、Dasatinib、及びPD166326、NSC743411、Lapatinib(GW-572016)、Canertinib(CI-1033)、Semaxinib(SU5416)、Vatalanib(PTK787/ZK222584)、Sutent(SU11248)、Sorafenib(BAY 43-9006)及びLeflunomide(SU101)である。さらなる情報に関して、例えば、Zhangら 2009: Targeting cancer with small molecule kinase inhibitors. Nature Reviews Cancer 9, 28〜39頁を参照されたい。
Toll様レセプター(TLR)ファミリーのメンバーは、先天性免疫と適応性免疫の間の重要なリンクであり、多くのアジュバントの効果はTLRの活性化に依存する。がんに対して樹立された多数のワクチンは、ワクチン応答をブーストするためTLRに関するリガンドを取り込む。TLR2、TLR3、TLR4の他、特にTLR7及びTLR8は、受動免疫療法アプローチにおけるがん治療に関して調査された。密接に関連するTLR7及びTLR8は、免疫細胞、腫瘍細胞、及び腫瘍の微小環境に影響することにより抗腫瘍応答に寄与し、またヌクレオシドアナログ構造により活性化されうる。全てのTLRは、スタンドアローンの免疫療法又はがんワクチンアジュバントとして使用され、また本発明の製剤及び方法と相乗的に組み合わされうる。さらなる情報に関して、van Duinら 2005: Triggering TLR signaling in vaccination, Trends in Immunology, 27(1):49〜55頁を参照されたい。
腫瘍媒介性のエスケープ機構及び免疫抑制により影響される免疫モジュレートリーレセプターを標的にする治療に加えて、腫瘍環境を標的にする治療が存在する。血管形成インヒビターは、腫瘍が生存のため必要とする広範な血管の成長(血管形成)を予防する。腫瘍細胞により血管形成が促進されて、それらの栄養及び酸素需要の増加に対処することを、例えば、異なる分子をターゲティングすることによりブロックできる。本発明と組み合わされうる血管形成媒介性分子又は血管形成インヒビターの非限定的な例は、可溶性のVEGF(VEGFアイソフォーム VEGF121及びVEGF165、レセプターVEGFR1、VEGFR2及びコレセプター ニューロピリン-1及びニューロピリン-2)1及びNRP-1、アンギオポエチン2、TSP-1及びTSP-2、アンギオスタチン及び関連分子、エンドスタチン、バソスタチン、カルレティキュリン、血小板因子-4、TIMP及びCDAI、Meth-1及びMeth-2、IFN-α、IFN-β及びIFN-γ、CXCL10、IL-4、IL-12及びIL-18、プロトロンビン(クリングルドメイン-2)、抗トロンビンIIIフラグメント、プロラクチン、VEGI、SPARC、オステオポンチン、マスピン、カンスタチン、プロリフェリン関連タンパク質、レスチン及び薬物、例えば、ベバシズマブ、イトラコナゾール、カルボキシアミドトリアゾール、TNP-470、CM101、IFN-α、血小板因子-4、スラミン、SU5416、トロンボスポンジン、VEGFRアンタゴニスト、血管新生抑制性ステロイド+ヘパリン、軟骨由来の血管形成阻害因子、マトリックスメタロプロテイナーゼインヒビター、2-メトキシエストラジオール、テコガラン、テトラチオモリブデート、サリドマイド、トロンボスポンジン、プロラクチンα Vβ3インヒビター、リノマイド、タスキニモドである。総説に関して、Schoenfeld and Dranoff 2011: Anti-angiogenesis immunotherapy. Hum Vaccin. (9):976〜81頁を参照されたい。
小分子標的療法薬は、一般にがん細胞内の変異した、過剰発現した、又は他の点で決定的なタンパク質における酵素ドメインのインヒビターである。顕著な及び非限定的な例は、チロシンキナーゼインヒビターのイマチニブ(Gleevec/Glivec)及びゲフィチニブ(Iressa)である。がん治療のためのワクチンと組み合わせたいくつかのキナーゼをターゲティングするスニチニブリンゴ酸塩及び/又はソラフェニブトシル酸塩などの小分子の使用は、先の特許出願US2009004213にも記載されている。
本発明の製剤と一緒に併用療法アプローチに使用できる、利用可能な又は開発中のいくつかのウイルスベースのがんワクチンが存在する。このようなウイルスベクターの使用の1つの利点は、免疫活性化に必要な危険シグナルを作り出すウイルス感染の結果として起こる炎症反応で、免疫応答を開始する内因性の能力である。理想的なウイルスベクターは安全であるべきであり、また抗腫瘍性の特異的な応答をブーストすることを許容させる抗ベクター免疫応答を導入すべきではない。組換え型のウイルス、例えば、ワクシニアウイルス、単純ヘルペスウイルス、アデノウイルス、アデノ関連ウイルス、レトロウイルス及びアビポックスウイルスは動物の腫瘍モデルに使用されており、それらの有望な結果に基づいて、ヒト臨床試験が開始された。特に重要なウイルスベースのワクチンは、ウイルス様粒子(VLP)、ウイルスの外被膜からの特定のタンパク質を含有する小粒子である。ウイルス様粒子は、ウイルスからのいかなる遺伝物質も含有しなく、感染を引き起こすことはできないが、しかし、それらが構築されてそれらの被膜に腫瘍抗原を提示することができる。VLPは、様々なウイルス、例えば、B型肝炎ウイルス又はパルボウイルス科(例えば、アデノ関連ウイルス)、レトロウイルス科(例えば、HIV)、及びフラビウイルス科(例えば、C型肝炎ウイルス)を含む他のウイルスファミリーに由来しうる。一般的な総説に関して、Sorensen and Thompsen 2007: Virus-based immunotherapy of cancer: what do we know and where are we going? APMIS 115(11):1177〜93頁を参照されたい;がんに対するウイルス様粒子は、Buonaguroら 2011: Developments in virus-like particle-based vaccines for infectious diseases and cancer. Expert Rev Vaccines 10(11):1569〜83頁;及びGuillenら 2010: Virus-like particles as vaccine antigens and adjuvants: application to chronic disease, cancer immunotherapy and infectious disease preventive strategies. Procedia in Vaccinology 2 (2),128〜133頁において論評されている。
マルチエピトープの使用によって、ワクチン接種に関して有望な結果が示されている。高速シークエンシング技術とインテリジェントアルゴリズムシステムとの組合せによって、腫瘍のミュータノーム(mutanome)の探索が可能になり、本発明と組み合わせることができる個別化ワクチンに関するマルチエピトープが提供されうる。さらなる情報に関して、2007: Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides. J Immunother 30: 762〜772頁;さらにまた、Castleら 2012: Exploiting the mutanome for tumor vaccination. Cancer Res 72 (5):1081〜91頁を参照されたい。
例えば、腫瘍抗原ワクチン接種及びT細胞移入の組合せは、Rapoportら 2011: Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood 117(3):788〜97頁に記載されている。
ペプチドは、細胞表面レセプターに結合しうる又は腫瘍の周囲の細胞外基質に影響しうる。これらのペプチド(例えば、RGD)に付着させた放射性核種は、その核種が細胞の近傍において崩壊する場合に、結果としてがん細胞を死滅させる。特に、これらの結合モチーフのオリゴマー又はマルチマーは、これにより増強される腫瘍特異性及び結合活性を導くことができることから、多大なる関心が寄せられる。非限定的な例に関して、Yamada 2011: Peptide-based cancer vaccine therapy for prostate cancer, bladder cancer, and malignant glioma. Nihon Rinsho 69(9): 1657〜61頁を参照されたい。
相乗効果を生み出すため、本発明の製剤及び方法と組み合わせることができる多数の他のがん療法が存在する。非限定的な例は、アポトーシスをターゲットとする治療、温熱療法、ホルモン療法、テロメラーゼ療法、インスリン強化療法、遺伝子治療及び光線力学療法である。
本明細書において使用される技術及び方法は、本明細書に記載され、又はそれ自体既知の様式で、例えば、Sambrookら Molecular Cloning: A Laboratory Manual, 第2版 (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Yに記載のとおり実施される。キット及び試薬の使用を含む全ての方法は、具体的に指摘されない限り、製造者の情報にしたがって実施される。
材料及び方法
リポソーム調製
リポソームの製造を、異なるプロトコールにより行った。「フィルム法」又は「エタノール注射」を、リポソーム調製のため使用した。フィルム法について、脂質をクロロホルムに溶解し、適切な量を丸底フラスコに入れた。有機溶媒を回転式エバポレーター中で蒸発させ、フラスコを穏やかに振盪することにより乾いたフィルムを水又は緩衝剤/添加剤溶液で再構成した。典型的には、5mMの総脂質濃度を選択した。エタノール注射について、脂質を、適切なモル濃度比でエタノールに溶解して100〜400mMの範囲の総濃度とした。エタノール溶液を、撹拌下で水又は緩衝剤/添加剤の水溶液に注入した。リポソームのサイズを異なるポアサイズ(50〜400nm)のポリカーボネート膜をとおして押出しすることにより調整した、及び/又はリポソームを220〜450nmポアサイズの市販の無菌フィルターを通して濾過した、又は他のポアサイズ(1μm〜5μm)を有する臨床用途のフィルター(Sartorius、Gottingen、ドイツ、Millipore、Schwalbach、ドイツ)を使用した。
水相における最終的な脂質濃度は、5mMから25mMの間であった。脂質組成をHPLC分析で管理した。粒子サイズ及びゼータ電位を動的光散乱により決定した。
リポプレックス形成を異なるプロトコールにより行った。詳細な手順は、個々の実験で与えられる。いくつかの実験について、水中又は緩衝剤又は添加剤の存在下のリポソーム溶液でのRNA溶液の直接的なインキュベーションを行った。リポプレックスはまた、脂質のエタノール中溶液を水又は水性の緩衝剤/添加剤溶液中のRNA溶液と混合することにより形成することができた。選択される調製プロトコールは、所望の粒子特性及び生物学的な適用に依存し、それぞれの実験でさらに記載される。
粒子サイズ及びゼータ電位測定を、380 ZLSサブミクロン粒子/ゼータ電位分析計(PSS Nicomp、Santa Barbara、CA)において行った。サイズを、光子相関分光法(PCS)により、散乱角90°、平衡化時間2分間及び実行時間15分間で決定した。自己相関を、バルク集団の平均直径及び多分散指標(PI)についての情報を与える、強度-重みつきガウス分析を使って行った。
ゼータ電位を、水中で電界強度5V/cm及び電極間隔0.4cmを使って測定した。静電移動度を、Helmholtz-Smoluchowskiの式を使ってゼータ電位に変換した。全ての測定を23℃の温度で実施した。
非対称フローFFF(AF4)を、ロングチャンネル(275mm長)及びトリプル-アングルMALS光散乱検出器miniDAWN TREOS(Wyatt Technologie、Dernbach、ドイツ)を備えたEclipse 3+システムを使って、以下のハードウェア/パラメータを使って行った:
スペーサー:250μmスペーサー(幅21.5mm)
溶媒:10mM NaNO3
検出器フロー:1.0mL/min
フォーカスフロー:1.5mL/min
インジェクションフロー:0.2mL/min
クロスフローグラディエント:4mL/min(15分間固定、次に20分間で4mL/minから0.1mL/min)。
C57BL/6及びBALB/cマウスをJackson Laboratoriesから入手した。年齢(8〜10週齢)及び性別(雌性)が適合する動物を実験全体を通して使用した。
B16-OVAは、ニワトリ卵白アルブミン遺伝子(OVA)を発現しているB16-F10メラノーマ細胞株である。ヒト単球由来の未成熟DC(iDC)を、5日間、IL-4(1000U/ml)及びGM-CSF(1000U/ml)の存在下で精製CD14+単球から分化させた。
裸の抗原コードRNAのインビトロ転写のための全てのプラスミドは、3'のヒトβ-グロビンUTR(hBgUTR)及び120ヌクレオチドのポリ(A)テールにより特徴付けられ、また薬理学的に改善されたインビトロ転写RNAの生成を許容する、pST1-2hBgUTR-A120バックボーンに基づいた。SIINFEKL構築物は、ニワトリOVAのaa 257〜264を含有する。HA構築物は、主要な免疫優性MHCエピトープを組み合わせるために設計されたインフルエンザHAのコドン最適化部分配列(aa 60〜285をaa 517〜527に融合;インフルエンザ株A/PR/8/34)である。pSTI-ルシフェラーゼ-A120(Luc)は、ホタルルシフェラーゼ遺伝子(15)を含有する。RNAは、インビトロ転写により生成させた。RNAのCy5-UTPでの標識化(Cy5-RNA)は、HA構築物をテンプレートとして使って、製造者(Amersham Biosciences、Buckinghamshire、UK)の説明にしたがって行った。
他に記載がない限り、RNA及びリポソームは、標準プロトコールとして混合する前に1×RNaseフリーのリン酸緩衝生理食塩溶液(PBS)(Ambion)中で100μlの最終量に予備希釈した。希釈したRNA及びリポソームの混合の10分後に、200μlリポプレックス溶液をマウス静脈内に注射した。いくつかの実験に関して、PBSを154mMのRNeaseフリーのNaCl(Ambion)で置き換えた。
フローサイトメトリーに関するモノクローナル抗体は、BD Pharmingenから入手した。低張処理で溶血させた血液サンプルを、4℃で特異的なmABとインキュベートした。脾臓細胞をコラゲナーゼ(1mg/ml;Roche)で消化して得た。SIINFEKL特異的CD8+細胞のH-2Kb/SIINFEKLテトラマー(Beckman-Coulter)での定量は、以前に記載されている。フローサイトメトリーのデータを、FACS-Canto IIアナリティカルフローサイトメーターで取得し、FlowJo(Tree Star)ソフトウェアを使って分析した。
50μlのRNA溶液を、BioRadエレクトロポレーターを使って270V及び150μFのエレクトロポレーションパラメータでiDCへとエレクトロポレーションを行った。
Luc-RNAの取り込み及び翻訳をIVIS Luminaイメージングシステム(Caliper Life Sciences)を使ったインビボでのバイオルミネセンスイメージングにより評価した。簡単に述べると、D-ルシフェリン(150mg/kg体重)(BD Biosciences)の水溶液をRNAリポプレックスの投与の6時間後にi.p.注射した。その5分後、放射された光子を定量した(1分間の積算時間)。関心領域(ROI)におけるインビボのバイオルミネセンスをIVIS Livingイメージ4.0ソフトウェアを使って平均ラジアンス(光子/sec/cm2/sr)として定量した。動物内のルシフェラーゼ発現細胞から生じる透過光の強度を、黒色が最低強度及び白色が最高強度のバイオルミネセンスシグナルであるグレースケールイメージとして示す。マウスのグレースケールの参照イメージをLED低輝度照明下で得た。イメージをLiving Image4.0ソフトウェアを使ってスーパーインポーズした。
マウスのIFN-a(PBL)及びTNFa(eBioscience)を、製造者の説明にしたがった標準ELISAアッセイを使ってマウス血清において検出した。
防御的な免疫を決定するため、マウスは3回の免疫を受けた。その後、2×105 B16-OVA腫瘍細胞をC57BL/6マウスの側腹部にs.c.で接種した。治療的な免疫を評価のために、最初と同数の腫瘍細胞を接種した。次に、腫瘍が2mmから3mmの直径に達した後に、免疫を開始した。腫瘍サイズを3日毎に測定した。腫瘍の直径が15mmを超えたときに、動物を屠殺した。
RNAリポプレックスの粒子サイズ及びPIにおける緩衝剤/イオンの効果
カチオン性(正に荷電した)脂質DOTMA及び負に荷電したRNAの間の異なる電荷比+/-でのリポソーム及びRNAのリポプレックスを調製した。リポソームの物理化学的特性を動的光散乱(PCS)及びゼータ電位測定により調査した。
RNAリポプレックスの安定性における正電荷の効果
リポプレックスの安定性における正電荷の潜在的に有益な/有害な効果の付加的な評価に関して(例えば、図1b及び図cを参照されたい)、DOTMA/RNA電荷比1/1及び2/1でのDOTMA/Cholリポソーム(F5)[DOTMA/Chol(1:1 mol:mol)]及びRNAのリポプレックスの粒子サイズが、異なる緩衝液中で測定された(図2を参照されたい)。比較のため、純粋なリポソームのサイズも測定した。
RNAリポプレックスの粒子サイズにおける2価のカチオンにより媒介されるRNAの予備コンパクションの影響
複合体形成前に2価のカチオンを使ってRNAの予備コンパクションの影響を検査するために、電荷比(1/1)及び(1/2)でのF5/RNAリポプレックスの粒子サイズを、異なる量のCaCl2でのRNAのコンパクション後に決定した。ここでイオンは、実施例2及び実施例3に反して、リポプレックス形成前にRNAに添加された。最終的なリポソーム濃度は、全ケースで100μMであり、それに応じてRNA濃度が調整された。F5/RNA1/2についてRNA濃度は2倍にされたので、ここでのCaCl2濃度も2倍にされた。
RNAリポプレックスの物理化学的な特徴
DOTMAとRNAの間の異なる電荷比+/-でF4(DOTMA/DOPE)を有するRNAリポプレックスの物理化学的な特徴付けの結果を図4に示す。負に荷電したリポプレックスについて認められるとおり、1/1以上の+/-比では粒子サイズはコンスタントに約200nmである。ゼータ電位は、+/- 2/1から1/1まで単調に減少し、より高い過剰負電荷ではコンスタントのままである。これらの結果は、重要な粒子特性、すなわち粒子サイズ及びゼータ電位が、1/1比から始まる過剰RNAで不変であることを示唆する。この範囲において、明確に規定されたサイズのコロイドで安定な粒子が製造されうる。類似する結果をイオン及び緩衝液(PBS)の存在下でも得ることができる。
負に荷電したRNAリポプレックスの安定性/粒子サイズにおける緩衝液組成の効果
異なる緩衝液中のリポプレックスの安定性がさらに詳細に調査された。負電荷の過剰によって、潜在的に関連性のある緩衝系においてコロイドで安定なリポプレックスが導びかれるかどうかを検査するために、水中の及びPBS(1×)、塩化ナトリウム(150mM)、グルコース(5%)又はリン酸緩衝グルコースに対する濃縮緩衝液の添加後の、電荷比(1/2)でのF4/Luc-RNAリポプレックスの粒子サイズが決定された(図5を参照されたい)。
負電荷比と粒子サイズ/安定性の相関性
(1/1)と(1/2)の間の比でのリポプレックスのコロイド安定性がさらに調査された。1:1.8と1:1.2の間の電荷比を有するF4/RNAリポプレックスの粒子サイズが水中で測定された;図6を参照されたい。
RNAリポプレックスの平均粒子サイズ及びPI値における押出しの効果
本実験において、異なるサイズのリポプレックスが生産できることが示される。リポソーム又はRNAリポプレックスの平均粒子サイズ及びPI値における付加的な押出し工程の効果を決定するために、(異なるポア直径を有するポリカーボネート膜を使った)押出し実験を行った。水又はPBS中での未押出しF4(DOTMA/DOPE)及び押出しF4でのRNAリポプレックスの粒子のサイジングの結果は図7に示される。
粒子特性における凍結乾燥の効果
リポプレックスは、長期の貯蔵及び凝集について液体懸濁液中で安定ではない。この課題に取り組むための1つの技術は凍結乾燥である。粒子特性における凍結乾燥の効果が調査された。DOTMA/DOPEリポソーム(F4)の粒子サイズを凍結乾燥前並びに凍結乾燥及び水での再構成後に決定した(図8を参照されたい)。
粒子特性におけるDOTMA/DOPE比の効果
異なるDOTMA/DOPE比を有するリポソーム及びリポプレックスが製造された。非常に高いDOPE分率(90mol%)を有するリポソームはPBS中で不安定であった(図9)。リポプレックスに関して、粒子サイズは70mol%のDOPE分率で既に有意に増加した(図10)。他の全ての組成物は安定であった。
RNAリポプレックスのインビボ投与
BALB/cマウス(n=3)は、ルシフェラーゼ-RNA(20μg)と異なる量のF4リポソームを複合体化してF4:RNA比4.8:1、2.4:1、1.2:1、1.2:2、1.2:4を生じたものを静脈内に注射された。インビボ及びエクスビボでのルシフェラーゼ活性をリポプレックス注射の6時間後にインビボイメージングで評価した(代表的なマウス及び器官のセットを図11に示す)。図12は、図11に示される実験に由来する器官における総ルシフェラーゼシグナルの分布を示す。
リポプレックスの臨床製剤
以前に確立されたプロトコールにしたがう製剤化は、2つの工程、すなわち、賦形剤として等張の塩化ナトリウム溶液を使うことによる所与のRNAの予備製剤化及び規定量のリポソームを添加することによるリポプレックス形成からなる。予備製剤化について、最初に4ml塩化ナトリウム(水中に、0.9% w/w)溶液が、シリンジによりNaClバイアルから取りだされ、RNAに添加される。次に、400μLのリポソーム(水中に、2.8mg/mL総脂質)が、リポソームバイアルから取りだされ、カニューレ(0.9mmの内径)を使ってRNA及び塩化ナトリウムの溶液に注入される。得られたRNAリポプレックス製剤(5.5ml)は、所望の用量の直接的な非経口注射により並びに点滴静注の調製後のいずれかで投与されうる。このために、RNAリポプレックス製剤から5.0mLが取りだされ、50mlの等張塩化ナトリウム溶液を含有している輸液バックに希釈される。このプロトコールにより、約300から500nmの粒子サイズを有するリポプレックス製剤は、ロバストで再現性のある様式で得られる;図28を参照されたい。
成分:
・RNA:10mM HEPES及び0.1mM EDTA中に0.5mg/ml
・賦形剤:0.9% NaCl
・リポソーム:2.68mM DOTMA、1.34mM DOPE、粒子サイズ(Zave)300〜500nm
・5mLシリンジ:(例えば、Omnifix、5mL、Luer Lock、B.Braun Melsungen AG(Melsungen、ドイツ)
・1mLシリンジ:Injekt-F Tuberculin、1mL、Luer Lock、B.Braun Melsungen AG(Melsungen、ドイツ)
・0.9×44mm、20G 1 1/2"、BD Microlance 3、Becton Dickinson S.A.(Fraga、スペイン)
粒子サイズの効果
リポプレックスの活性はサイズが増加するとともに増加することが実証される。リポプレックスの形成に使用されたリポソームのサイズはまた、リポプレックスのサイズに影響する。より大きなリポソームはまた、より大きなリポプレックスを導く。
塩化ナトリウム緩衝液
いくつかの実験は、リポソームの添加前に、PBS緩衝液をRNAに添加することにより、リポプレックスの活性の増加が導かれることを示した。ここでは、PBSの代わりに、通常の生理食塩溶液(0.9%、例えば、150mM NaCl)が、RNA凝縮に使用できることが実証される。このようなNaCl溶液は、承認された医療用医薬製品として利用可能であり、リポプレックス-IMPのロジスティック及び取扱いを容易にする。NaCl及びPBSの濃縮溶液もRNA濃縮のため使用することが可能であり、後に形成されるリポプレックスが同等の活性をもたらすことがさらに実証される。異なって濃縮されたNaCl溶液がリポプレックス形成前にRNAに添加される、さらに詳細なサイズ測定が示される。一般に、リポプレックスのサイズは、添加したNaCl溶液の濃度が減少するとともに増加する;図35を参照されたい。サイズの増加は活性の増加と相関するので(実施例13を参照されたい)、通常の生理食塩溶液の添加(濃縮生理食塩溶液ではなく)はより高い活性を生じると考えられる。
リポソーム/RNA電荷比
1.3から2の電荷比(カチオン性脂質とヌクレオチドの比)は、物理化学的特性及び生物活性に関して適切である。この比で、RNAのより高分率がリポプレックスに含まれると仮定される(比1:2について)。非押出しリポソームのリポプレックスのコロイド安定性、粒子特性及びルシフェラーゼ活性をさらに調査した。リポプレックスを等張の生理食塩溶液中でリポソーム/RNA電荷比1:2から1.9:2の間で会合させた、図36及び図37を参照されたい。リポプレックスについて、電荷比1.7:2で粒子サイズは長期にわたり有意に増加した。押出しリポソームのリポプレックスと一致して、1:2から1.6:2の間の電荷比を有するリポプレックスは、過剰RNAにおけるマイナーチェンジに対して不変であり、350nmから480nmの範囲の粒子サイズと共に0.3未満のPI値を示す。
Claims (46)
- 少なくとも1つの抗原をコードしているRNAを含むナノ粒子を含む医薬組成物であって、
(i)ナノ粒子における正電荷数がナノ粒子における負電荷数を超えず、及び/又は
(ii)ナノ粒子が中性電荷又は正味の負電荷を有し、及び/又は
(iii)ナノ粒子における正電荷と負電荷との電荷比が1.4:1以下であり、及び/又は
(iv)ナノ粒子のゼータ電位が0以下である、
医薬組成物。 - ナノ粒子における正電荷と負電荷との電荷比が1.4:1から1:8の間、好ましくは1.2:1から1:4の間である、請求項1に記載の医薬組成物。
- ナノ粒子が少なくとも1つの脂質を含む、請求項1又は2に記載の医薬組成物。
- ナノ粒子が少なくとも1つのカチオン性脂質を含む、請求項1から3のいずれか一項に記載の医薬組成物。
- 正電荷が少なくとも1つのカチオン性脂質により寄与され、負電荷がRNAにより寄与される、請求項4に記載の医薬組成物。
- ナノ粒子が少なくとも1つのヘルパー脂質を含む、請求項3から5のいずれか一項に記載の医薬組成物。
- ヘルパー脂質が中性脂質である、請求項6に記載の医薬組成物。
- 少なくとも1つのカチオン性脂質が、1,2-ジ-O-オクタデセニル-3-トリメチルアンモニウムプロパン(DOTMA)及び/又は1,2-ジオレオイル-3-トリメチルアンモニウム-プロパン(DOTAP)を含む、請求項4から7のいずれか一項に記載の医薬組成物。
- 少なくとも1つのヘルパー脂質が、1,2-ジ-(9Z-オクタデセノイル)-sn-グリセロ-3-ホスホエタノールアミン(DOPE)、コレステロール(Chol)及び/又は1,2-ジオレオイル-sn-グリセロ-3-ホスホコリン(DOPC)を含む、請求項6から8のいずれか一項に記載の医薬組成物。
- 少なくとも1つのカチオン性脂質と少なくとも1つのヘルパー脂質とのモル比が、10:0から3:7、好ましくは、9:1から3:7、4:1から1:2、4:1から2:3、7:3から1:1、又は2:1から1:1、好ましくは、約1:1である、請求項6から9のいずれか一項に記載の医薬組成物。
- 脂質が前記RNAとの複合体を形成し、及び/又は前記RNAをカプセル化する、請求項3から10のいずれか一項に記載の医薬組成物。
- 脂質が前記RNAをカプセル化しているベシクル中に含まれる、請求項3から11のいずれか一項に記載の医薬組成物。
- ナノ粒子が10:0から1:9、好ましくは8:2から3:7、より好ましくは7:3から5:5のモル比でDOTMA及びDOPEを含むリポプレックスであり、DOTMAにおける正電荷とRNAにおける負電荷の電荷比が1.8:2から0.8:2、より好ましくは1.6:2から1:2、さらにより好ましくは1.4:2から1.1:2、さらにより好ましくは約1.2:2である、請求項1から12のいずれか一項に記載の医薬組成物。
- ナノ粒子が10:0から1:9、好ましくは8:2から3:7、より好ましくは7:3から5:5のモル比でDOTMA及びコレステロールを含むリポプレックスであり、DOTMAにおける正電荷とRNAにおける負電荷の電荷比が1.8:2から0.8:2、より好ましくは1.6:2から1:2、さらにより好ましくは1.4:2から1.1:2、さらにより好ましくは約1.2:2である、請求項1から12のいずれか一項に記載の医薬組成物。
- ナノ粒子が10:0から1:9、好ましくは8:2から3:7、より好ましくは7:3から5:5のモル比でDOTAP及びDOPEを含むリポプレックスであり、DOTMAにおける正電荷とRNAにおける負電荷の電荷比が1.8:2から0.8:2、より好ましくは1.6:2から1:2、さらにより好ましくは1.4:2から1.1:2、さらにより好ましくは約1.2:2である、請求項1から12のいずれか一項に記載の医薬組成物。
- ナノ粒子が、約50nmから約1000nm、好ましくは、約100nmから約800nm、好ましくは、約200nmから約600nm、例えば、約300nmから約500nmの範囲の平均直径を有する、請求項1から15のいずれか一項に記載の医薬組成物。
- ナノ粒子が、(i)水相におけるリポソームと水相におけるRNAとのインキュベーション、(ii)有機の水混和性溶媒、例えば、エタノールなどに溶解した脂質と水溶液中のRNAとのインキュベーション、(iii)逆相蒸発技術、(iv)生産物の凍結及び融解、(v)生産物の脱水及び再水和、(vi)生産物の凍結乾燥及び再水和、又は(vii)生産物の噴霧乾燥及び再水和のうちの1つ又は複数により入手可能である、請求項1から16のいずれか一項に記載の医薬組成物。
- ナノ粒子が、前記ナノ粒子への組込み前にRNAと二価のカチオンをインキュベートする工程を含む方法により及び/又は前記ナノ粒子への組込み前にRNAと一価のイオンをインキュベートする工程により及び/又は前記ナノ粒子への組込み前にRNAと緩衝液をインキュベートする工程により生産される、請求項1から17のいずれか一項に記載の医薬組成物。
- ナノ粒子が、ナノ粒子を押出しする工程及び/又は凍結乾燥する工程を含む方法により生産される、請求項1から18のいずれか一項に記載の医薬組成物。
- ナノ粒子の全身投与後に、脾臓におけるRNA発現が起こる、請求項1から19のいずれか一項に記載の医薬組成物。
- ナノ粒子の全身投与後に、肺及び/又は肝臓におけるRNA発現が起こらない又は本質的に起こらない、請求項1から20のいずれか一項に記載の医薬組成物。
- ナノ粒子の全身投与後に、脾臓におけるRNA発現が、肺におけるRNA発現の量の少なくとも5倍である、請求項1から21のいずれか一項に記載の医薬組成物。
- ナノ粒子の全身投与後に、脾臓における抗原提示細胞、好ましくはプロフェッショナル抗原提示細胞におけるRNA発現が起こる、請求項1から22のいずれか一項に記載の医薬組成物。
- 抗原提示細胞が樹状細胞及び/又はマクロファージである、請求項23に記載の医薬組成物。
- 全身投与が非経口投与による、好ましくは静脈内投与、皮下投与、皮内投与又は動脈内投与による、請求項20から24のいずれか一項に記載の医薬組成物。
- 抗原が、疾患関連抗原である、又は疾患関連抗原若しくは疾患関連抗原を発現している細胞に対する免疫応答を誘発する、請求項1から25のいずれか一項に記載の医薬組成物。
- 1つ又は複数の薬学的に許容される担体、賦形剤及び/又は添加剤をさらに含む、請求項1から26のいずれか一項に記載の医薬組成物。
- 少なくとも1つのアジュバントをさらに含む、請求項1から27のいずれか一項に記載の医薬組成物。
- 全身投与のために製剤化されている、請求項1から28のいずれか一項に記載の医薬組成物。
- 免疫応答、好ましくはがんに対する免疫応答を誘導するための、請求項1から29のいずれか一項に記載の医薬組成物。
- RNAが、シュードウリジン残基を含まない、好ましくは修飾ヌクレオシドを含まない、請求項1から30のいずれか一項に記載の医薬組成物。
- 抗原が関与する疾患、好ましくはがん疾患の予防的及び/又は治療的処置に使用するための、請求項1から31のいずれか一項に記載の医薬組成物。
- 請求項1から32のいずれか一項に記載の医薬組成物を対象に投与する工程を含む、脾臓における又は抗原提示細胞において抗原を発現している抗原提示細胞、好ましくはプロフェッショナル抗原提示細胞、好ましくは脾臓におけるプロフェッショナル抗原提示細胞に抗原を送達するための方法。
- 抗原提示細胞が樹状細胞及び/又はマクロファージである、請求項33に記載の方法。
- 請求項1から32のいずれか一項に記載の医薬組成物を対象に投与する工程を含む、対象において免疫応答、好ましくはがんに対する免疫応答を誘導するための方法。
- 請求項1から32のいずれか一項に記載の医薬組成物を対象に投与する工程を含む、対象においてT細胞を刺激する、プライミングする及び/又は拡大するための方法。
- 請求項1から32のいずれか一項に記載の医薬組成物を対象に投与する工程を含む、対象において抗原が関与する疾患、好ましくはがん疾患を治療する又は予防する方法。
- 請求項1から37のいずれか一項に規定される粒子。
- (a)塩化ナトリウム溶液中で製剤化されているRNAを用意する工程と、
(b)RNAにリポソームを添加する工程と
を含む、RNA含有ナノ粒子を生産するための方法。 - 塩化ナトリウム溶液が水溶液である、請求項39に記載の方法。
- 溶媒が水である、請求項39又は40に記載の方法。
- 塩化ナトリウム溶液が、約50から約300mM、好ましくは、約100から約200mM、好ましくは約150mMの塩化ナトリウムを含有する、請求項39から41のいずれか一項に記載の方法。
- 塩化ナトリウム溶液が等張塩化ナトリウム溶液である、請求項39から42のいずれか一項に記載の方法。
- リポソームが水中で製剤化されている、請求項39から43のいずれか一項に記載の方法。
- リポソームがリポソームをRNA製剤に注入することによりRNAに添加される、請求項39から44のいずれか一項に記載の方法。
- ナノ粒子が請求項1から45のいずれか一項に規定されるナノ粒子である、請求項39から45のいずれか一項に記載の方法。
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