JPWO2020017590A1 - AタイプCpGオリゴデオキシヌクレオチド含有脂質粒子 - Google Patents
AタイプCpGオリゴデオキシヌクレオチド含有脂質粒子 Download PDFInfo
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Abstract
Description
本発明は、その一態様において、AタイプCpGオリゴデオキシヌクレオチドを含有する、脂質粒子(本明細書において、「本発明の脂質粒子」と示すこともある。)に関する。以下にこれについて説明する。
本発明の脂質粒子は、AタイプCpGオリゴデオキシヌクレオチドの効果を安定に且つより強く発揮させることができる。このため、AタイプCpGオリゴデオキシヌクレオチドの効果(例えば、I型INF産生誘導作用、INF−α産生誘導作用等)を利用した種々の用途、例えば医薬、試薬等(本明細書において、「本発明の薬剤」と示すこともある。)の有効成分として、より具体的には、抗がん剤、免疫賦活剤等の有効成分としての利用が可能である。さらに具体的には、I型INF産生促進剤、INF−α産生促進剤、Th1 関連遺伝子発現促進剤等の有効成分としての利用が可能である。
カチオン脂質(#41: DOTAP、#45: DOTMA、又は#47: DODAP)を含むAタイプCpGオリゴデオキシヌクレオチド(D35:配列番号1:G_G_TGCATCGATGCAGGGG_G_G(「_(アンダーライン)」は、その両側のヌクレオシド同士がホスホロチオエート結合していることを示す。アンダーラインを挟まないヌクレオシド同士はホスホジエステル結合である。)) 含有脂質ナノ粒子のヒトPBMC(末梢血単核細胞)に対するIFN-α産生誘導を調べた。具体的には以下のようにして行った。
N/P比を変えたD35含有脂質ナノ粒子のヒトPBMC に対するIFN-α産生誘導を調べた。具体的には以下のようにして行った。
pH感受性脂質(DOPE)を添加して(又は添加せずに)透析溶液を変えて得られたD35含有脂質ナノ粒子のヒトPBMC に対するIFN-α産生誘導を調べた。具体的には以下のようにして行った。
DSPE-PEG-OMe(N-(Methylpolyoxyethylene oxycarbonyl)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine) の含有量及びそのPEG 鎖長を変えて得られたD35含有脂質ナノ粒子のヒトPBMC に対するIFN-α産生誘導を調べた。具体的には以下のようにして行った。
D35含有脂質ナノ粒子のTLR9依存性を調べた。具体的には以下のようにして行った。
MC38(1x106cells)を皮下移植後9、11、13、15、17 日目に薬剤(D35、又はD35含有脂質ナノ粒子(DSPE-PEG-OMe含有量0.5質量%))を計5 回腫瘍内投与し、腫瘍サイズを測定した。1回に投与するD35 核酸量はそれぞれ4.5ug/shot となるように調整した。
MC38(1x106cells)を皮下移植後9、11、13、15、17 日目にD35含有脂質ナノ粒子(DSPE-PEG-OMe含有量0.5質量%)を計5 回腫瘍内投与し、腫瘍サイズを測定した。またCD8T 細胞をdeplete するためにanti-CD8a 抗体(100ug/shot)又はコントロール抗体(100ug/shot)を皮下移植後6日目及び13日目に腹腔内投与した。1回に投与するD35 核酸量はそれぞれ4.5ug/shot となるように調整した。
試験例7の腫瘍(皮下移植後12日目)の凍結切片からmRNAを調製し、各種免疫関連遺伝子発現をqPCR法で測定した。その結果、D35含有脂質ナノ粒子の腫瘍内投与によって、多くの免疫関連遺伝子発現が上昇し、その上昇はCD8T 細胞をdeplete することで消失した。またTh1 関連遺伝子(STAT4, T-bet,IFNg)に顕著な遺伝子発現誘導を認めたことから、D35含有脂質ナノ粒子の腫瘍内投与は、腫瘍内免疫環境をTh1 型にシフトさせることで腫瘍退縮効果を発揮することが示唆された。
MC38(1x106cells)を皮下移植後9、11、13、15、17 日目に薬剤(D35、又はD35含有脂質ナノ粒子(DSPE-PEG-OMe含有量0.5質量%))を計5 回静脈内投与し、腫瘍サイズを測定した。1回に投与するD35 核酸量はそれぞれ25ug/shot となるように調整した。
試験例9の腫瘍(皮下移植後12日目)の凍結切片からmRNAを調製し、各種免疫関連遺伝子発現をqPCR法で測定した。その結果、腫瘍内の免疫の活性化を示唆するIfng, CXCL9 の発現増強を認めた。このことは静脈内投与でも腫瘍内投与時と同様の免疫的変化が腫瘍内で生じていることを示唆している。
MC38(1x106cells)を皮下移植後9、11、13、15、17 日目にD35含有脂質ナノ粒子(DSPE-PEG-OMe含有量0.5質量%)を計5 回静脈内投与し、腫瘍サイズを測定した。またCD8T 細胞をdeplete するためにanti-CD8a 抗体(100ug/shot)又はコントロール抗体(100ug/shot)を皮下移植後6日目及び13日目に腹腔内投与した。1回に投与するD35 核酸量はそれぞれ25ug/shot となるように調整した。
MC38(1x106cells)を皮下移植後9、11、13、15、17 日目に薬剤(D35含有脂質ナノ粒子(DSPE-PEG-OMe含有量0.5質量%)、antiPD-1抗体、又はこれらの組合せ)を計5 回投与し、腫瘍サイズを測定した。D35含有脂質ナノ粒子は腫瘍内投与とし、antiPD-1抗体は腹腔内投与とした。1回に投与するD35 核酸量はそれぞれ4.5ug/shot となるように調整した。
MC38(1x106cells)を皮下移植後9、11、13、15、17 日目に薬剤(D35含有脂質ナノ粒子(DSPE-PEG-OMe含有量0.5質量%)、antiPD-1抗体、又はこれらの組合せ)を計5 回投与し、腫瘍サイズを測定した。D35含有脂質ナノ粒子は静脈内投与とし、antiPD-1抗体は腹腔内投与とした。1回に投与するD35 核酸量はそれぞれ25ug/shot となるように調整した。
マウス(C57BL/6J)にD35、又はD35含有脂質ナノ粒子(DSPE-PEG-OMe含有量0.5質量%又は3.0質量%))を静脈内投与した。投与から1日後、血液を採取し、肝臓のパラフィン切片を作製した。血液中のALT及びASTレベルを測定キット(Transaminase CII-test Wako、富士フィルム和光純薬工業社製)で測定した。また、パラフィン切片をHE染色し、赤血球溶血の有無を判定した。
Claims (14)
- AタイプCpGオリゴデオキシヌクレオチドを含有する、脂質粒子。
- 前記脂質粒子が、外層、及び前記外層内に配置されたイオンコンプレックスを含む脂質粒子である、請求項1に記載の脂質粒子。
- 前記イオンコンプレックスがAタイプCpGオリゴデオキシヌクレオチドを含有する、請求項2に記載の脂質粒子。
- 前記外層が、両親媒性脂質が親水性部分を外側に向けて並んでいる脂質1分子膜である、請求項2又は3に記載の脂質粒子。
- 水溶性高分子修飾脂質の含有量が、前記脂質粒子を構成する脂質100質量%に対して0〜10質量%である、請求項1〜4のいずれかに記載の脂質粒子。
- 前記脂質粒子を構成する脂質中の窒素原子の個数(N)の前記AタイプCpGオリゴデオキシヌクレオチドを含有する核酸中のリン原子の個数(P)に対する比(N/P)が2.5以上である、請求項1〜5のいずれかに記載の脂質粒子。
- カチオン性脂質を含有する、請求項1〜6のいずれかに記載の脂質粒子。
- 前記カチオン性脂質が、1,2−ジオレオイルオキシ−3−トリメチルアンモニウム−プロパン(DOTAP)及び1,2−ジオレイルオキシ−3−トリメチルアンモニウム−プロパン(DOTMA)からなる群より選択される少なくとも1種である、請求項7に記載の脂質粒子。
- 脂質を含有するアルコール溶液と、AタイプCpGオリゴデオキシヌクレオチドを含有する水溶液とを混合する工程を含む、脂質粒子の製造方法。
- 前記工程がマイクロ流路を用いた反応系で行われる、請求項9に記載の製造方法。
- 請求項1〜8のいずれかに記載の脂質粒子を含有する、医薬。
- 請求項1〜8のいずれかに記載の脂質粒子を含有する、試薬。
- 請求項1〜8のいずれかに記載の脂質粒子を含有する、免疫賦活剤。
- 請求項1〜8のいずれかに記載の脂質粒子を含有する、抗がん剤。
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