JP2022130599A - 細胞傷害性免疫刺激性粒子及びその使用 - Google Patents
細胞傷害性免疫刺激性粒子及びその使用 Download PDFInfo
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- JP2022130599A JP2022130599A JP2022104427A JP2022104427A JP2022130599A JP 2022130599 A JP2022130599 A JP 2022130599A JP 2022104427 A JP2022104427 A JP 2022104427A JP 2022104427 A JP2022104427 A JP 2022104427A JP 2022130599 A JP2022130599 A JP 2022130599A
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Abstract
Description
外因性RNAは、感染の免疫センサー、例えばエンドソーム中に位置するToll様受容体(TLR)3、7、及び8、又は細胞質ゾル中に位置するRIG-Iなどを引き起こすことができる危険なシグナルである。その免疫刺激活性を発揮させるためには、外因性RNAを、例えば、粒子(例えばプロタミン-RNAナノ粒子など)中に製剤化しなければならない(Rettig L. et al., 2010, Blood 115(22):4533-41 and WO 2009/144230 A1)。
第1の態様では、本発明は、RNAがカチオン性ポリマーもしくは脂質と又はカチオン性ポリマー及び脂質の両方と会合したRNAを含む粒子に関し、RNAは細胞傷害性ヌクレオチドもしくは細胞傷害性ヌクレオチド類似体を含み、及び/又は RNAは細胞毒素に共有結合している。
以下において、本発明の全ての態様に適用される定義を提供する。
(a)RNAの水溶液を提供する;
(b)プロタミンの水溶液を提供する;並びに
(c)工程(a)及び(b)で得られた溶液を組み合わせる。
(a)純水中の5mg/ml未満のRNA水溶液を提供する;
(b)プロタミンの5000ヘパリン中和単位/mlを含む水性等張ストック溶液を純水で希釈することにより5mg/ml未満のプロタミン水溶液を提供する;
(c)工程(a)及び(b)で得られた溶液を組み合わせる。
式中、G、C、A、及びUは、特定のRNA分子又はRNA配列中の各々の残基の数を指し、U含量を提供する。
アザシチジン(4-アミノ-1-β-D-リボフラノシル-1,3,5-トリアジン-2(1H)-オン)、
クラドリビン(5-(6-アミノ-2-クロロ-プリン-9-イル)-2-(ヒドロキシメチル)オキソラン-3-オール)、
クロファラビン(5-(6-アミノ-2-クロロ-プリン-9-イル)-4-フルオロ-2-(ヒドロキシメチル)オキソラン-3-オール)、
シタラビン(4-アミノ-1-[(2R、3S、4R、5R)-3,4-ジヒドロキシ-5-(ヒドロキシメチル)オキソラン-2-イル]ピリミジン-2-オン)、
デシタビン(4-アミノ-1-(2-デオキシ-β-D-エリスロ-ペントフラノシル)-1,3,5-トリアジン-2(1H)-オン)、
フロクスウリジン(5-フルオロ-1-[4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロフラン-2-イル]-1H-ピリミジン-2,4-ジオン)、
フルダラビン([(2R、3R、4S、5R)-5-(6-アミノ-2-フルオロ-プリン-9-イル)-3,4-ジヒドロキシ-オキソラン-2-イル]メトキシホスホン酸)、
フルオロウリジン(例えば5-フルオロ-ウリジンなど)、
ゲムシタビン(4-アミノ-1-(2-デオキシ-2,2-ジフルオロ-β-D-エリスロ-ペントフラノシル)ピリミジン-2(1H)-オン)、
ネララビン((2R、3S、4S、5R)-2-(2-アミノ-6-メトキシ-プリン-9-イル)-5-(ヒドロキシメチル)オキソラン-3,4-ジオール)、
ペントスタチン((R)-3-((2R、4S、5R)-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロフラン-2-イル)-3,6,7,8-テトラヒドロイミダゾ[4,5-d][1,3]ジアゼピン-8-オール)、
アザチオプリン(6-[(1-メチル-4-ニトロ-1H-イミダゾール-5-イル)スルファニル]-7H-プリン)、
カルマフール(5-フルオロ-N-ヘキシル-2,4-ジオキソ-ピリミジン-1-カルボキサミド)、
メルカプトプリン(3,7-ジヒドロプリン-6-チオン)、
テガフール((RS)-5-フルオロ-1-(テトラヒドロフラン-2-イル)ピリミジン-2,4(1H、3H)-ジオン)、及び
チオグアニン(2-アミノ-1H-プリン-6(7H)-チオン)。
A.G.U(5F).G.U(5F).U(5F).A.U(5F).U(5F).C.U(5F).U(5F).G.U(5F).A.U(5F).G.G.U(5F).U(5F).G(配列中U(5F)は5-フルオロウリジン(配列番号1)である)。
配列5’
A.G.U(5F).G.U(5F).U(5F).A.U(5F).U(5F).C.U(5F).U(5F).G.U(5F).A.U(5F).G.G.U(5F).U(5F).G 3’(配列中U(5F)は5フルオロウリジンである)を伴う約21残基のmtRNAオリゴリボヌクレオチドを合成及び精製する。産物を次に凍結乾燥し、純水中に0.5mg/mlで再懸濁する。プロタミンIPEX 5000を純水で28倍希釈し、低塩中で約0.5mg/mlのプロタミン溶液を提供する。等量のRNA及びプロタミンを一緒に混合する。即時及び集中的な混合は、例えば上下のピペッティング及びボルテックスにより実施する。製剤をベンチ上に数分間放置し、次に注射溶液(例えば、5%グルコース)でさらに希釈することができる。約100nmの粒子は、光散乱分光法を使用して検出することができる(図1)。プロタミン/mtiRNA粒子溶液を希釈しすぎた場合、粒子を、遠心分離又は凍結乾燥により回収し、処置製剤のために使用する前に、適当な容量の所望の溶液中に再懸濁することができる。
配列5’
A.G.U(5F).G.U(5F).U(5F).A.U(5F).U(5F).C.U(5F).U(5F).G.U(5F).A.U(5F).G.G.U(5F).U(5F).G 3’(配列中U(5F)は5フルオロウリジンである)を伴う約21残基のmtRNAオリゴリボヌクレオチドを合成し、精製する。産物を次に凍結乾燥し、純水中に0.5mg/mlで再懸濁する。プロタミンIPEX 5000を純水で28倍希釈し、低塩中で約0.5mg/mlのプロタミン溶液を提供する。等容量のRNA及びプロタミンを一緒に混合する。即時及び集中的な混合は、例えば上下のピペッティング及びボルテックスにより実施する。製剤をベンチ上に数分間放置し、次に注射溶液(例えば、5%グルコース)でさらに希釈することができる。インビトロの腫瘍細胞上で数時間パルスされた粒子により、細胞成長の阻害が誘導され(図2)、新鮮なヒトPBMCとインキュベートされた、又は動物において静脈注射された同じ粒子により、免疫刺激が誘導される(アルファインターフェロンの産生:図3及び4)。
Claims (20)
- RNAが細胞傷害性ヌクレオチドもしくは細胞傷害性ヌクレオチド類似体を含み、及び/又はRNAが細胞毒素に共有結合しており、RNAがカチオン性ポリマーもしくは脂質と又はカチオン性ポリマー及び脂質の両方と会合したRNAを含む粒子。
- RNAが、少なくとも1つのUヌクレオチド、少なくとも1つのGヌクレオチド、少なくとも1つの修飾Uヌクレオチド、少なくとも1つの修飾Gヌクレオチド、又はそれらの組み合わせを含む、請求項1記載の粒子。
- 少なくとも1つの修飾Uヌクレオチド及び/又は少なくとも1つの修飾Gヌクレオチドが、細胞傷害性ヌクレオチド又は細胞傷害性ヌクレオチド類似体である、請求項2記載の粒子。
- 細胞傷害性ヌクレオチド又は細胞傷害性ヌクレオチド類似体が、アザシチジン、カペシタビン、クラドリビン、クロファラビン、シタラビン、デシタビン、フロクスウリジン、フルダラビン、フルオロウリジン、ゲムシタビン、ネララビン、ペントスタチン、アザチオプリン、カルモフール、メルカプトプリン、テガフール、及びチオグアニンからなる群より選択される部分を含む、請求項1~3のいずれか一項記載の粒子。
- 細胞毒素が、アルキル化剤、シアン化物基、代謝拮抗剤、抗微小管剤、トポイソメラーゼ阻害剤、チロシンキナーゼ阻害剤、及び細胞傷害性抗原特異的構造物、例えば細胞傷害性抗体からなる群より選択される、請求項1~4のいずれか一項記載の粒子。
- 細胞傷害性抗体が、アレムツズマブ、ベバシズマブ、セツキシマブ、デノスマブ、ゲムツズマブ、オゾガマイシン、イブリツモマブチウキセタン、イピリムマブ、オファツムマブ、パニツムマブ、ペルツズマブ、リツキシマブ、トシツモマブ、及びトラスツズマブからなる群より選択される、請求項5記載の粒子。
- 細胞毒素が、メトトレキサート、ペメトレキセド、ラルチトレキセド、ヒドロキシカルバミド、イリノテカン、トポテカン、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ミトキサントロン、バルルビシン、エトポシド、テニポシド、カバジタキセル、ドセタキセル、パクリタキセル、ビンブラスチン、ビンクリスチン、ビンデシン、ビンフルニン、ビノレルビン、アムサクリン、ベンダムスチン、ブスルファン、カルムスチン、クロラムブシル、クロルメチン、シクロホスファミド、ダカルバジン、フォテムスチン、イホスファミド、ロムスチン、メクロレタミン、メルファラン、ミトソロマイド、ストレプトゾトシン、テモゾロミド、チオテパ、ウラミンチン、カルボプラチン、シスプラチン、ネダプラチン、オキサリプラチン、アルトレタミン、ブレオマイシン、ボルテゾミブ、ダクチノマイシン、エストラムスチン、イクサベピロン、マイトマイシン、プロカルバジン、サトラプラチン、トリプラチン四硝酸塩、アファチニブ、アフリバーセプト、アキシチニブ、ボスチニブ、クリゾチニブ、ダサチニブ、エロチニブ、ゲフィチニブ、イマチニブ、ラパチニブ、ニロチニブ、パゾパニブ、ポナチニブ、レゴラフェニブ、ルキソリチニブ、ソラフェニブ、スニチニブ、バンデタニブ、エベロリムス、テムシロリムス、アリトレチノイン、ベキサロテン、イソトレチノイン、タミバロテン、トレチノイン、レナリドマイド、ポマリドマイド、サリドマイド、ロミデプシン、バルプロエート、ボリノスタット、アナグレリド、三酸化ヒ素、アスパラギナーゼ、デニロイキン・ジフチトックス、及びベムラフェニブからなる群より選択される、請求項1~4のいずれか一項記載の粒子。
- RNAがオリゴヌクレオチドであるか、又はメッセンジャーRNA(mRNA)である、請求項1~7のいずれか一項記載の粒子。
- カチオン性ポリマーが、プロタミン、ポリエチレンイミン、ポリ-L-リジン、ポリ-L-アルギニン、及びヒストンからなる群より選択される、請求項1~8のいずれか一項記載の粒子。
- 粒子がRNA及びプロタミンを含む、請求項9記載の粒子。
- プロタミン-RNA粒子が、約10nm~約990nm、約10nm~約750nm、約10nm~約450nm、約 50nm~約450nm、約50nm~約100nm、又は約90nm~約110nmの範囲内のサイズを有するプロタミン-RNAナノ粒子である、請求項10記載の粒子。
- プロタミン-RNAナノ粒子が、約16:1~約1:2、約8:1~約1:2、又は約4:1~約1:2の範囲内のプロタミン:RNA質量比 を有する、請求項11記載の粒子。
- RNAが、細胞中にトランスフェクトされた場合に、又は細胞により取り込まれた場合に免疫応答を誘導し、及び/又は細胞傷害性を誘導する、請求項1~12のいずれか一項記載の粒子。
- 請求項1~13のいずれか一項記載の粒子及び医薬的に許容可能な担体を含む医薬組成物。
- 抗原及び/又はアジュバントをさらに含む、請求項14記載の医薬組成物。
- 医薬としての使用のための請求項14又は15記載の医薬組成物。
- 免疫応答を誘導する際での使用のための、及び/又は細胞傷害性を誘導する際での使用のための、請求項14又は15記載の医薬組成物。
- 治療における使用のための請求項14又は15記載の医薬組成物。
- 治療が、免疫応答を誘導すること、及び/又は細胞傷害性を誘導することを含む、請求項18記載の医薬組成物。
- 治療により癌が処置又は予防される、請求項18記載の医薬組成物。
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JP2018520152A JP7098520B2 (ja) | 2015-10-21 | 2016-10-20 | 細胞傷害性免疫刺激性粒子及びその使用 |
PCT/EP2016/075146 WO2017068013A1 (en) | 2015-10-21 | 2016-10-20 | Cytotoxic immunostimulating particles and uses thereof |
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US10980875B2 (en) | 2021-04-20 |
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JP7098520B2 (ja) | 2022-07-11 |
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CA3002288A1 (en) | 2017-04-27 |
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EP3365010B1 (en) | 2024-01-03 |
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