JP2021505606A - I型インターフェロン遺伝子を刺激するための方法及びカチオン性脂質を含む組成物 - Google Patents
I型インターフェロン遺伝子を刺激するための方法及びカチオン性脂質を含む組成物 Download PDFInfo
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Abstract
Description
本出願は、2017年12月5日に出願された米国仮特許出願第62/594,815号の優先権及びすべての利益を主張し、これは、その全体が参照により本明細書に明示的に援用される。
本発明は、概して、カチオン性脂質の投与を含むI型IFNシグナル伝達経路を修飾するための方法及び組成物に関する。
過去10年間のI型インターフェロン(IFN−I)は、疾患に対する哺乳類の免疫応答において極めて重要であることが示されている。I型インターフェロンは、ウイルス感染によって直接誘導されるため、「ウイルス」インターフェロンと呼ばれている。対照的に、「免疫」IFN、すなわちIFN−γは、免疫応答の際にT細胞とナチュラルキラー(NK)細胞が受容体と結合した後に合成される。また、IFN−Iは、インターフェロンα受容体(IFNAR)を介したシグナル伝達を介した腫瘍細胞アポトーシス及び抗血管新生のインデューサーとしても十分に立証されている。治療的免疫応答におけるIFN−Iの重要な役割のため、現在、ワクチン、免疫療法及び他の免疫ベースの医薬の予防的及び治療的利益の両方を改善するために、IFN−Iを活性化する安全で有効な方法の同定に重点が置かれている。例えば、マウスを用いた前臨床研究では、IFN−Iは、抗原提示樹状細胞(DC)やCD4、CD8 T細胞など、免疫系の他の重要な細胞を直接活性化することが示されている。IFN−Iはまた、Tリンパ球によって認識される腫瘍細胞の抗原提示を増加させ、したがって、癌免疫療法において重要な潜在的役割を示す。
一実施形態では、本明細書に請求される新規な方法は、対象自身の腫瘍に由来する抗原などの1つ以上の自己抗原とカチオン性脂質の投与を含む。別の実施形態では、本方法は、合成ペプチド、組換えタンパク質、RNAもしくはDNA又はそれらの活性断片などの1つ以上の非自己抗原と組み合わせたカチオン性脂質を含む組成物の投与を含むが、これらに限定されない。それぞれの場合において、目的はI型インターフェロンを活性化して、強力な抗原特異的CD8+T細胞応答の誘導を促進することである。抗原は、当業者に公知の任意の疾患関連抗原であり得る。
B型肝炎ウイルス(肝細胞癌)、C型肝炎ウイルス(ヘプトーマ)、エプスタインバーウイルス(EBV)(バーキットリンパ腫、鼻咽頭癌、免疫抑制された個人におけるPTLD)、HTLVL(成人T細胞白血病)、発癌性ヒトパピローマウイルス16、18、33、45型(成人子宮頸癌)、及びヘリコバクターピロリ(B細胞胃リンパ腫)が含まれる。哺乳動物及びより詳細にはヒトにおける抗原として役立つ他の医学的に関連する微生物は、文献、例えばC. G. A Thomas, Medical Microbiology, Bailliere Tindall, Great Britain 1983に広く記載されており、その全内容は参照により本明細書に組み込まれる。
動物:6〜12週齢C57BL6/Jマウス(B6マウス)、B6。ヒトHLA−A2遺伝子(AADマウス)を発現するCg−Tg(HLA−A/H2−D)2Enge/Jトランスジェニックブリーダーマウス、及びJackson研究所(Bar港、ME)から得たIFNAR−/−(B6.129S2−Ifnar1tm1Agt/Mmjax)遺伝子ノックアウトブリーダーマウスを、特異的病原体フリー条件下で飼育した。DLARにより承認されたIACUCプロトコールに従って、動物の飼育、繁殖及び実験手順を実施した。
R−DOTAPは流入領域リンパ節におけるI型インターフェロン遺伝子発現を誘導する
カチオン性ナノ粒子誘導遺伝子発現を評価するために、C57BL/6Jマウスに頸部後方の皮下に100μlの12mM R−DOTAPナノ粒子を注射し、流入リンパ節における炎症性遺伝子発現をワクチン接種後4又は24時間で分析した。PBS及びLPS(50μg/マウス)を注射したマウス(24時間時点)を、それぞれ陰性及び陽性対照として用いた。注射の4時間後又は24時間後に、各マウスからの腋窩リンパ節及び上腕リンパ節をプールし、コラゲナーゼ消化により処理した。リンパ節細胞懸濁液中の活性化樹状細胞(CD11c+)細胞を選別精製し、RLT緩衝液中で溶解し、nCounter(登録商標)マウス炎症キット及びナノストリング技術を用いて相対遺伝子発現解析のために処理した。R−DOTAP注射は、両方の時点でいくつかの炎症性遺伝子の発現を有意に変化させることが分かった。IFN−1α及びIFN−1βを含むいくつかの遺伝子は、陽性対照として使用したLPSよりも5倍以上高い増加を示した。Cxcl10を含む他の遺伝子の発現も有意に増加し、LPSによって誘導されるレベルと同程度であった(図1)。
R−DOTAPとS−DOTAPはいずれも流入領域リンパ節におけるインターフェロンαとインターフェロンβ遺伝子発現を誘導する
R−DOTAP及びS−DOTAPはT細胞におけるI型インターフェロン関連CD69発現をアップレギュレートする
I型インターフェロンを活性化するカチオン性脂質の効果及び能力をさらに理解するために、C57BL/6Jマウス又はIFNAR−/−マウスに、足パッドに50μlの6mM R−DOTAPナノ粒子又は6mM S−DOTAP又は280mMスクロースを皮下注射した。注射24時間後、各マウスから膝窩リンパ節流出リンパ節を単離し、リンパ節の単細胞懸濁液を蛍光色素結合CD3及びCD69で染色した。R−DOTAP単独(抗原なし)はDLNサイズの目に見える増加をもたらし、これは7日間にわたる総細胞数の着実な増加によるものであった(図3A)。百日咳毒素を用いたDLNへのT細胞流入の研究は、R−DOTAPに構造的に関連する脂質がリンパ節ホーミングケモカインを誘導することを示唆しており、おそらくI型IFNシグナル伝達の直接的な結果であると思われる。この総細胞数の増加は、IFNαRノックアウトマウスで大幅に減少したことから、I型IFNシグナル伝達に依存していることが確認された(図3B)。I型IFNは、CD69のアップレギュレーションを介してリンパ器官からのリンパ球排出を阻害することが知られており、CD69は、次に、リンパ球排出に必要なスフィンゴシン1リン酸受容体を阻害する。従って、S−DOTAPとR−DOTAPの両方の注射はDLNにおけるCD69のアップレギュレーションをもたらすと仮定した。実際、野生型マウスに両カチオン性脂質を皮下注射すると、T細胞で最も強くCD69のアップレギュレーションが生じた。対照的に、IFNαRノックアウトマウスのR−DOTAP注射後にはCD69のアップレギュレーションは認められず、R−DOTAPが誘導するCD69のアップレギュレーションがI型IFN依存性であることが示された(図3C)。データは、各所属リンパ節におけるCD69+CD3+T細胞%を表す。
種々のカチオン性脂質はI型インターフェロンをアップレギュレートする
種々のカチオン性脂質がI型インターフェロンを誘導する可能性を評価するために、インビトロで研究を行った。本研究では、カチオン性脂質DOTAP、DOEPC及びDOTMAを研究した。中性脂質DOPCも評価し、カチオン性脂質に対するインターフェロンアップレギュレーションの特異性を確認した。ある研究では、IFNAR−Koマウス由来の骨髄由来樹状細胞(BMDC)を、示された(6〜400μM)濃度のカチオン性脂質又はLPS陽性対照(1〜500ng/ml)で24時間刺激した(図4A)。第2の研究では、FLT3誘導BMDC(pDC)及びGM−CSF/IL−4誘導BMDC(cBMDC)を、R−DOTAP又はLPS陽性対照(1〜500ng/ml)の所定濃度(6〜400μM)で24時間刺激した(図4B)。I型インターフェロン産生を測定するために、細胞上清(100μl)をレポーター細胞(米国インビボゲンのB16.Blue−IFNα/β細胞)に添加し、18時間インキュベートして、レポーター細胞によるI型インターフェロン誘導性の分泌アルカリホスファターゼ(SEAP)産生を刺激した。レポーター細胞上清中のSEAP活性を、製造プロトコールに従って比色SEAPアッセイキットを用いて定量した。BMDC分泌I型インターフェロンを、レポーター細胞株において組換えマウスIFN−β刺激SEAP活性を用いて標準曲線を用いて定量した。これらの研究は、I型インターフェロンをアップレギュレートする能力がDOTAPに特異的ではなく、複数のカチオン性脂質によって活性化され得ることを確認している。また、中性脂質がI型インターフェロン経路を活性化できないことも確認されている。
カチオン性脂質を介したCD8+T細胞応答の低下がI型IFN欠損マウスにおいて観察される
カチオン性脂質によるI型IFN遺伝子のアップレギュレーションが実証されたことは、カチオン性脂質がI型IFN経路を標的とし、強固なCD8+T細胞応答を誘導することを示唆している。この仮説をさらに確認するために、ニワトリ卵白アルブミン又はHPV16−E7蛋白由来CD8 T細胞エピトープ(RF9:RAHYNIVTF(配列番号2))の十分に特徴付けられたマウスCD8+T細胞エピトープ(SIINFEKL(配列番号1))を含むR−DOTAP製剤を、野生型C57BL/6Jマウス及びI型インターフェロンシグナル欠損IFNAR-/-マウスに、0日目及び7日目に投与した。マウスにも完全フロイントアジュバント(CFA)+SIINFEKLを接種した。陽性対照としてペプチドのみのワクチンを用いた。14日目に、R−DOTAP又はCFAによって誘導された抗原特異的(SIINFEKL)CD8+T細胞応答を、IFN−γELISPOTアッセイを用いて評価した。図5Aに示されるように、DOTAP製剤で野生型マウスにワクチン接種すると、CFAアジュバント製剤よりも大きさが高い強力な抗原特異的CD8+T細胞応答が誘導された。対照的に、R−DOTAPによって誘導されるCD8+ T細胞応答は、IFNAR−/−マウスにおいて劇的に減少するが、CFA−アジュバント製剤ではそのような差は認められない。HPV16陽性腫瘍で発現した腫瘍関連抗原でも同様の結果が認められた(図5B)。CFAアジュバントは、複数のTLR経路を標的とし、したがって、抗原特異的CD8+T細胞応答を誘導するためのI型IFNシグナル伝達の必要性を回避することができることは十分に立証されている。
Claims (25)
- 哺乳動物へのカチオン性脂質の投与を含む対象におけるI型IFNシグナル伝達経路を修飾するための方法。
- カチオン性脂質が、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)、N−1−(2,3−ジオレオイルオキシ)−プロピル−N,N,N−トリメチルアンモニウムクロリド(DOTMA)、1,2−ジオレオイル−sn−グリセロ−3−エチルホスホコリン(DOEPC)、及びそれらの組み合わせを含む、請求項1に記載の方法。
- カチオン性脂質が、カチオン性脂質の鏡像異性体を含む、請求項2に記載の方法。
- カチオン性脂質が、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)である、請求項3に記載の方法。
- 鏡像異性体が、(R)−1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(R−DOTAP)又は(S)−1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(S−DOTAP)である、請求項4に記載の方法。
- I型IFNシグナル伝達経路が、アップレギュレート/活性化される、請求項1に記載の方法。
- I型IFNシグナル伝達経路が、ダウンレギュレート/不活性化される、請求項1に記載の方法。
- カチオン性脂質が、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)、N−1−(2,3−ジオレオイルオキシ)−プロピル−N,N,N−トリメチルアンモニウムクロリド(DOTMA)、1,2−ジオレオイル−sn−グリセロ−3−エチルホスホコリン(DOEPC)、及びそれらの組み合わせを含む、請求項6に記載の方法。
- カチオン性脂質が、カチオン性脂質の鏡像異性体を含む、請求項6に記載の方法。
- 鏡像異性体が、(R)−1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(R−DOTAP)又は(S)−1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(S−DOTAP)である、請求項9記載の方法。
- 抗原をさらに含む、請求項1に記載の方法。
- 抗原をさらに含む、請求項10に記載の方法。
- T細胞応答が上昇している、請求項10に記載の方法。
- 抗原特異的CD8+T細胞応答が上昇している、請求項11に記載の方法。
- カチオン性脂質を含む組成物の投与を含む対象において免疫原性応答を誘導するための方法であって、カチオン性脂質の投与は、I型IFNシグナル伝達経路の刺激をもたらす方法。
- カチオン性脂質が、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)、N−1−(2,3−ジオレオイルオキシ)−プロピル−N,N,N−トリメチルアンモニウムクロリド(DOTMA)、1,2−ジオレオイル−sn−グリセロ−3−エチルホスホコリン(DOEPC)、及びそれらの組み合わせを含む、請求項15に記載の方法。
- カチオン性脂質が、(R)−1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(R−DOTAP)を含む、請求項16に記載の方法。
- T細胞応答が上昇している、請求項17に記載の方法。
- 抗原特異的CD8+T細胞応答が上昇している、請求項18に記載の方法。
- カチオン性脂質を含む組成物の投与を含み、カチオン性脂質の投与がI型IFNシグナル伝達経路の刺激をもたらす、対象における癌を治療するための方法。
- カチオン性脂質が、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)、N−1−(2,3−ジオレオイルオキシ)−プロピル−N,N,N−トリメチルアンモニウムクロリド(DOTMA)、1,2−ジオレオイル−sn−グリセロ−3−エチルホスホコリン(DOEPC)、及びそれらの組み合わせを含む、請求項20に記載の方法。
- カチオン性脂質が、(R)−1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(R−DOTAP)を含む、請求項21に記載の方法。
- 抗原の投与をさらに含む、請求項20に記載の方法。
- 抗原が腫瘍抗原である、請求項23に記載の方法。
- 腫瘍抗原がHPVである、請求項24に記載の方法。
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IL275145A (en) | 2020-07-30 |
BR112020011265A2 (pt) | 2020-11-17 |
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CN111655238A (zh) | 2020-09-11 |
EP3720423A4 (en) | 2021-09-08 |
CA3084957A1 (en) | 2019-06-13 |
TW201924722A (zh) | 2019-07-01 |
EP3720423A1 (en) | 2020-10-14 |
JP2024036364A (ja) | 2024-03-15 |
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