JPWO2021081026A5 - - Google Patents

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JPWO2021081026A5
JPWO2021081026A5 JP2022523709A JP2022523709A JPWO2021081026A5 JP WO2021081026 A5 JPWO2021081026 A5 JP WO2021081026A5 JP 2022523709 A JP2022523709 A JP 2022523709A JP 2022523709 A JP2022523709 A JP 2022523709A JP WO2021081026 A5 JPWO2021081026 A5 JP WO2021081026A5
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dsrna agent
pharmaceutical composition
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  1. 細胞における補体成分Ｃ３の発現を阻害するための二本鎖リボ核酸(ｄｓＲＮＡ)剤であって、ここで、
    ａ）該ｄｓＲＮＡ剤が、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、アンチセンス鎖がヌクレオチド配列５’－ＡＧＵＡＡＵＵＧＵＡＧＡＧＡＡＣＧＧＣＵＣＧＧ－３’（配列番号５０３）由来の少なくとも１７連続ヌクレオチドを含む；
    ｂ）該ｄｓＲＮＡ剤が、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、アンチセンス鎖が補体成分Ｃ３をコードするｍＲＮＡに相補性の領域を含み、該相補性領域が、表２～７、１５、１８、２０～２３、３０および３１のいずれか１つに示されるアンチセンスヌクレオチド配列の何れか１つと３以下のヌクレオチドが異なる少なくとも１５連続ヌクレオチドを含む；
    ｃ）該ｄｓＲＮＡ剤が、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、センス鎖が配列番号１のヌクレオチド配列のヌクレオチド４７５～４９７、４８７～５０９、４９０～５１２、４９１～５１３、７０５～７２７、８０９～８３１、８１３～８３５、１１４７～１１６９、１４３７～１４５９、１４３９～１４６１、１４４７～１４６９、２５９６～２６１８、２６３４～２６５６、３０１２～３０３４、３３３４～３３５６、３６１１～３６３３、３６１４～３６３６、３６２２～３６５５、３８０９～３８３１、３８４６～３８６８、３８４７～３８６９、３９２０～３９４２、４０４７～４０６９、４０６１～４０８３、４１５６～４１７８、４１５７～４１７７、４１６２～４１８４、４１７８～４２００、４２２６～４２４８、４３６９～４３９１、４３９２～４４１４、４５２１～４５４３、４５２２～４５４４、４５２３～４５４５、５０１２～５０３４のヌクレオチド配列と３以下のヌクレオチドが異なる少なくとも１５連続ヌクレオチドを含み、アンチセンス鎖が配列番号５の対応するヌクレオチド配列の少なくとも１９連続ヌクレオチドを含む；
    ｄ）該ｄｓＲＮＡ剤が、ＡＤ－５６５５４１.２、ＡＤ－５６４７４２、ＡＤ－５６７３０４、ＡＤ－５６８９７８、ＡＤ－５６９１６４、ＡＤ－５６９２７２.２、ＡＤ－５６９７６５.２、ＡＤ－５６４７３０.２、ＡＤ－５６７３１５、ＡＤ－５６４７４５.２、ＡＤ－５７１７１５.２、ＡＤ－５７０７１４、ＡＤ－５７１８２６、ＡＤ－５７２０４１.２、ＡＤ－５７２０３９.２、ＡＤ－５７２３８７、ＡＤ－５６８５８６.２、ＡＤ－５６６８３７.２、ＡＤ－５６６４４４.２、ＡＤ－５６７７００.２、ＡＤ－５６７８１４.２、ＡＤ－５６８００３.２、ＡＤ－５６９１６４.２、ＡＤ－５６９７６３.２、ＡＤ－５６５２８１.２、ＡＤ－５７１５３９.２、ＡＤ－５７２３８９.２、ＡＤ－５６７３１５.２、ＡＤ－５７１７５２.２、ＡＤ－５６８０２６.２、ＡＤ－５７１２９８、ＡＤ－５７２１１０.２、ＡＤ－５７２０６２.２、ＡＤ－５７２３８８.２、ＡＤ－５７２０４０.２、ＡＤ－５６７７１３.２、ＡＤ－５６７５２１.２、ＡＤ－５６７０６６.２、ＡＤ－１１８１５１９、ＡＤ－５６９２６８またはＡＤ－５７０７１４からなる群から選択される；
    ｅ）該ｄｓＲＮＡ剤が、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、該センス鎖がヌクレオチド配列５’－ｇｓａｓｇｃｃｇＵｆｕＣｆＵｆＣｆｕａｃａａｕｕａｃｕ－３’（配列番号４１８８）と３以下のヌクレオチドが異なり、アンチセンス鎖がヌクレオチド配列５’－ａｓＧｆｓｕａａＵｆｕＧｆＵｆａｇａｇＡｆａＣｆｇｇｃｕｃｓｇｓｇ－３’（配列番号４３６７）と３以下のヌクレオチドが異なる；あるいは
    ｆ）該ｄｓＲＮＡ剤が、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、センス鎖がヌクレオチド配列５’－ｇｓａｓｇｃｃｇＵｆｕＣｆＵｆＣｆｕａｃａａｕｕａｃｕ－３’（配列番号４１８８）を含み、アンチセンス鎖がヌクレオチド配列５’－ａｓＧｆｓｕａａＵｆｕＧｆＵｆａｇａｇＡｆａＣｆｇｇｃｕｃｓｇｓｇ－３’（配列番号４３６７）を含む、
    ｄｓＲＮＡ剤。
  2. ｄｓＲＮＡ剤が少なくとも１個の修飾ヌクレオチドを含む、請求項１のｄｓＲＮＡ剤。
  3. センス鎖の全ヌクレオチドが修飾を含む；アンチセンス鎖の全ヌクレオチドが修飾を含む；またはセンス鎖の全ヌクレオチドおよびアンチセンス鎖の全ヌクレオチドが修飾を含む、請求項１または２のｄｓＲＮＡ剤。
  4. 修飾ヌクレオチドの少なくとも１個がデオキシ－ヌクレオチド、３'末端デオキシ－チミン(ｄＴ)ヌクレオチド、２'－Ｏ－メチル修飾ヌクレオチド、２'－フルオロ修飾ヌクレオチド、２'－デオキシ－修飾ヌクレオチド、ロックドヌクレオチド、非ロックドヌクレオチド、立体配座が制限されたヌクレオチド、拘束エチルヌクレオチド、脱塩基ヌクレオチド、２'－アミノ－修飾ヌクレオチド、２'－Ｏ－アリル－修飾ヌクレオチド、２'－Ｃ－アルキル－修飾ヌクレオチド、２'－ヒドロキシ－修飾ヌクレオチド、２'－メトキシエチル修飾ヌクレオチド、２'－Ｏ－アルキル－修飾ヌクレオチド、モルホリノヌクレオチド、ホスロアミデート、非天然塩基含有ヌクレオチド、テトラヒドロピラン修飾ヌクレオチド、１,５－アンヒドロヘキシトール修飾ヌクレオチド、シクロヘキセニル修飾ヌクレオチド、ホスホロチオエート基含有ヌクレオチド、メチルホスホネート基含有ヌクレオチド、５'－ホスフェート含有ヌクレオチド、５'－ホスフェート含有ヌクレオチド模倣体、熱不安定化ヌクレオチド、グリコール修飾ヌクレオチド(ＧＮＡ)および２－Ｏ－(Ｎ－メチルアセトアミド)修飾ヌクレオチド；およびそれらの組み合わせからなる群から選択される、請求項２または３のｄｓＲＮＡ剤。
  5. 二本鎖領域が１９～３０ヌクレオチドペア長である、請求項１～４の何れかのｄｓＲＮＡ剤。
  6. 各鎖が独立して３０ヌクレオチド長を超えない、請求項１～５の何れかのｄｓＲＮＡ剤。
  7. 少なくとも一方の鎖が少なくとも１ヌクレオチドの３'オーバーハングを含む、請求項１～６の何れかのｄｓＲＮＡ剤。
  8. さらにリガンドを含む、請求項１～７の何れかのｄｓＲＮＡ剤。
  9. リガンドがｄｓＲＮＡ剤のセンス鎖の３'末端にコンジュゲートされる、請求項８のｄｓＲＮＡ剤。
  10. リガンドがＮ－アセチルガラクトサミン(ＧａｌＮＡｃ)誘導体である、請求項８または９のｄｓＲＮＡ剤。
  11. リガンドが単価、二価または三価分岐リンカーを介して結合した１以上のＧａｌＮＡｃ誘導体である、請求項８～１０の何れかのｄｓＲＮＡ剤。
  12. リガンドが
    Figure 2021081026000001
     である、請求項１０または１１のｄｓＲＮＡ剤。
  13. ｄｓＲＮＡ剤が下の図に示すリガンドにコンジュゲートされる、請求項１２のｄｓＲＮＡ剤。
    Figure 2021081026000002
    〔式中、ＸがＯまたはＳである。〕
  14. ＸがＯである、請求項１３のｄｓＲＮＡ剤。
  15. ｄｓＲＮＡ剤がさらに少なくとも１個のホスホロチオエートまたはメチルホスホネートヌクレオチド間結合を含む、請求項１～１４の何れかのｄｓＲＮＡ剤。
  16. 請求項１～１５の何れかのｄｓＲＮＡ剤を含む、細胞。
  17. 請求項１～１５の何れかのｄｓＲＮＡ剤を含む、補体成分Ｃ３をコードする遺伝子の発現を阻害するための医薬組成物。
  18. 細胞における補体成分Ｃ３遺伝子の発現を阻害するインビトロでの方法であって、細胞と請求項１～１５の何れかのｄｓＲＮＡ剤または請求項１７の医薬組成物を接触させ、それにより細胞における補体成分Ｃ３遺伝子の発現を阻害することを含む、方法。
  19. 補体成分Ｃ３発現の減少により利益を受ける障害を有する対象を処置するための医薬組成物であって、請求項１～１５の何れかのｄｓＲＮＡ剤または請求項１７の医薬組成物を含む、医薬組成物。
  20. 補体成分Ｃ３発現の減少により利益を受ける障害を有する対象における少なくとも１個の症状を予防するための医薬組成物であって、請求項１～１５の何れかのｄｓＲＮＡ剤または請求項１７の医薬組成物を含み、それにより補体成分Ｃ３発現の減少により利益を受ける障害を有する対象における少なくとも１個の症状を予防するものである、医薬組成物。
  21. 障害が補体成分Ｃ３関連障害である、請求項１９または２０の医薬組成物。
  22. 補体成分Ｃ３関連障害が寒冷凝集素疾患(ＣＡＤ)、温自己免疫性溶血性貧血および発作性夜間ヘモグロビン尿症(ＰＮＨ)、ループス腎炎(ＬＮ)、類天疱瘡、天疱瘡、尋常性天疱瘡(ＰＶ)および落葉状天疱瘡(ＰＦ)およびＣ３糸球体症からなる群から選択される、請求項２１の医薬組成物。
  23. 対象がヒトである、請求項２１の医薬組成物。
  24. ｄｓＲＮＡ剤が約０.０１mg／kg～約５０mg／kgの用量での投与に適したものである、請求項１９～２３の何れかの医薬組成物。
  25. ｄｓＲＮＡ剤が対象に皮下投与される、請求項１９～２４の何れかの医薬組成物。
  26. さらに溶血の処置のための付加的治療剤を含む、請求項１９～２５の何れかの医薬組成物。
  27. 請求項１～１５の何れかのｄｓＲＮＡ剤または請求項１７の医薬組成物を含む、キット、バイアルまたはシリンジ。
JP2022523709A 2019-10-22 2020-10-21 補体成分Ｃ３ ｉＲＮＡ組成物およびその使用方法 Pending JP2022553348A (ja)

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TW202333749A (zh) 2021-10-29 2023-09-01 美商艾拉倫製藥股份有限公司 補體因子ｂ（ｃｆｂ）ｉｒｎａ組成物及其使用方法
WO2023088455A1 (zh) * 2021-11-22 2023-05-25 苏州瑞博生物技术股份有限公司 一种核酸、含有该核酸的药物组合物与siRNA缀合物及制备方法和用途
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