JP2023057328A - 自己免疫性疾患治療効果を有するオリゴヌクレオチドおよびそのオリゴヌクレオチドを含有する自己免疫性疾患治療薬 - Google Patents
自己免疫性疾患治療効果を有するオリゴヌクレオチドおよびそのオリゴヌクレオチドを含有する自己免疫性疾患治療薬 Download PDFInfo
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Abstract
Description
アプタマー1およびアプタマー2については、国際公開第2013/073602号および国際公開第2016/143700号に記載されている方法で化学合成した。
国際公開第2013/073602号および国際公開第2016/143700号に記載の方法を用い、配列番号3の配列のXの位置に、Amino-Modifier C6-dT Amiditeを導入して、アプタマー3を合成した。その他のX置換体に関しては、市販の人工塩基または修飾塩基のアミダイトを用いることにより合成できる。
実施例2で製造した、Xの塩基部分に1級アミン側鎖を有するアプタマー3(1eq)と、市販のNHS-PEG(40000)(1.5eq)とをpH7~8のリン酸バッファー中で混合し、室温下1日撹拌した。反応液を濃縮し、生成した修飾体を逆相HPLCで精製し、アプタマー3のPEG修飾体を得た。得られたアプタマー3のPEG修飾体については、SPR(Surface Plasmon Resonance)にてIFN-γとの結合能を保持していることを確認した。
工程1 ヒト化モデルマウスの作製
A.Gilhar, et.al.,Journal of Investigative Dermatology,2013(133),844-847に記載の方法に従い、ヒト活性化リンパ球の移植皮内注射により誘発される円形脱毛症のヒト化モデルマウスを作製した。
作製したヒト化モデルマウスを3群に分け、それぞれに、Vehicle(PBS)、Dexamethasone+Minoxidil (Positive control)、アプタマー2を投与した。Vehicle群に対しては、PBS15μLを2日に1回移植皮膚に投与した。アプタマー2を投与する群(以下、「アプタマー投与群」という)に対しては、アプタマーのPBS溶液15μLを2日に1回移植皮膚に投与し、アプタマー2の溶液の濃度を12nMから300nMまで143日間で徐々に増加させた。Dexamethasone+Minoxidilを投与する群に対しては、Dexamethasone2mgと5%Minoxidil40μLを、1日1回、移植皮膚に塗布した。
Claims (24)
- 配列番号1に記載の塩基配列を有し、IFN-γへ選択的に結合することで自己免疫性疾患治療効果を有するDNAオリゴヌクレオチド。
- 配列番号1に記載の塩基配列の3′末端に9残基の天然型塩基からなるオリゴヌクレオチドを付加した配列である配列番号2に記載の塩基配列を有し、IFN-γへ選択的に結合することで自己免疫性疾患治療効果を有するDNAオリゴヌクレオチド。
- 配列番号2に記載の塩基配列の5′末端から53番目の塩基を任意の塩基Xに置換した配列である配列番号3に記載の塩基配列を有し、
前記塩基Xが任意の天然型塩基または人工的に製造された塩基である、IFN-γへ選択的に結合することで自己免疫性疾患治療効果を有するDNAオリゴヌクレオチド。 - 前記塩基Xが人工的に製造された塩基であり、前記人工的に製造された塩基が、低分子化合物で化学修飾された、請求項3に記載の自己免疫性疾患治療効果を有するDNAオリゴヌクレオチド。
- 前記低分子化合物が、グルココルチコイド、タクロリムス、シロリムス、サイクロスポリン、メトトレキサート、レフルノミドから選択される抗炎症化合物であるか、または、エリスロマイシン、アジズスロマイシン、カナマイシン、オフロキサシン、ガチフロキサシン、テトラサイクリン、バンコマイシンから選択される抗生物質である、請求項4に記載の自己免疫性疾患治療効果を有するDNAオリゴヌクレオチド。
- 前記塩基Xが人工的に製造された塩基であり、前記人工的に製造された塩基が、中分子化合物、高分子化合物、生体高分子、または生体親和性のあるポリマーで化学修飾された、請求項3に記載の自己免疫性疾患治療効果を有するDNAオリゴヌクレオチド。
- 前記人工的に製造された塩基を修飾する前記高分子化合物が、分子量20000以上のポリエチレングリコール(PEG)、または、分子量20000以上の生体親和性のある任意の高分子である、請求項6に記載の自己免疫性疾患治療効果を有するDNAオリゴヌクレオチド。
- 配列番号1に記載の塩基配列を有するDNAオリゴヌクレオチドを有効成分として含有する自己免疫性疾患治療薬。
- 配列番号1に記載の塩基配列の3′末端に9残基の天然型塩基からなるオリゴヌクレオチドを付加した配列である配列番号2に記載の塩基配列を有するDNAオリゴヌクレオチドを有効成分として含有する自己免疫性疾患治療薬。
- 配列番号2に記載の塩基配列の5′末端から53番目の塩基を任意の塩基Xに変化させた配列である配列番号3に記載の塩基配列を有し、前記塩基Xが任意の天然型塩基または人工的に製造された塩基であるDNAオリゴヌクレオチドを有効成分として含有する、自己免疫性疾患治療薬。
- 前記DNAオリゴヌクレオチドの配列中の前記塩基Xが人工的に製造された塩基であり、前記人工的に製造された塩基が、低分子化合物で化学修飾されている、請求項10に記載の自己免疫性疾患治療薬。
- 前記低分子化合物が、グルココルチコイド、タクロリムス、シロリムス、サイクロスポリン、メトトレキサート、レフルノミドから選択される抗炎症化合物であるか、または、エリスロマイシン、アジズスロマイシン、カナマイシン、オフロキサシン、ガチフロキサシン、テトラサイクリン、バンコマイシンから選択される抗生物質である、請求項11に記載の自己免疫性疾患治療薬。
- 前記DNAオリゴヌクレオチドの配列中の前記塩基Xが人工的に製造された塩基であり、前記人工的に製造された塩基が中分子化合物、高分子化合物、生体高分子、または生体親和性のあるポリマーで化学修飾されている、請求項10に記載の自己免疫性疾患治療薬。
- 前記高分子化合物が、分子量20000以上のポリエチレングリコール(PEG)、または、分子量20000以上の生体親和性のある任意の高分子である、請求項13に記載の自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、円形脱毛症、尋常性白斑、乾癬、強皮症、皮膚筋炎、アトピー性皮膚炎、皮膚エリテマトーデス、IgA性皮膚炎から選択される自己免疫性皮膚疾患である、請求項1乃至7のいずれか1項に記載のDNAオリゴヌクレオチドを有効成分として含有する自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、間質性膀胱炎および膀胱痛症候群からなる群から選択される、膀胱における自己免疫性疾患である、請求項1乃至7のいずれか1項に記載のDNAオリゴヌクレオチドを有効成分として含有する自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、ぶどう膜炎、ドライアイ、乾性角膜炎、上強膜炎、強膜炎からなる群から選択される、目における自己免疫性疾患である、請求項1乃至7のいずれか1項に記載のDNAオリゴヌクレオチドを有効成分として含有する自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、多発性硬化症、全身性エリテマトーデス、子宮内膜症、心筋炎、I型糖尿病、甲状腺炎、早期卵巣不全、シェーングレン症候群、レイノー症候群、関節リウマチ、重症筋無力症、高安動脈炎、アジソン病、ギラン・バレー症候群、甲状腺機能低下症、サルコイドーシス、血球貪食性リンパ組織球症、血栓性血小板減少性紫斑病、自己免疫性肝炎からなる群から選択される、全身性の自己免疫性疾患である、請求項1乃至7のいずれか1項に記載のDNAオリゴヌクレオチドを有効成分として含有する自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、クローン病、潰瘍性大腸炎、自己免疫性膵炎、胆汁性胆道炎、自己免疫性萎縮性胃炎からなる群から選択される消化器の自己免疫性疾患である、請求項1乃至7のいずれか1項に記載のDNAオリゴヌクレオチドを有効成分として含有する自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、円形脱毛症、尋常性白斑、乾癬、強皮症、皮膚筋炎、アトピー性皮膚炎、皮膚エリテマトーデス、IgA性皮膚炎からなる群から選択される自己免疫性皮膚疾患である、請求項8乃至14のいずれか1項に記載の自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、間質性膀胱炎および膀胱痛症候群からなる群から選択される、膀胱における自己免疫性疾患である、請求項8乃至14のいずれか1項に記載の自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、ぶどう膜炎、ドライアイ、乾性角膜炎、上強膜炎・強膜炎からなる群から選択される、目における自己免疫性疾患である、請求項8乃至14のいずれか1項に記載の自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、多発性硬化症、全身性エリテマトーデス、子宮内膜症、心筋炎、I型糖尿病、甲状腺炎、早期卵巣不全、シェーングレン症候群、レイノー症候群、関節リウマチ、重症筋無力症、高安動脈炎、アジソン病、ギラン・バレー症候群、甲状腺機能低下症、サルコイドーシス、血球貪食性リンパ組織球症、血栓性血小板減少性紫斑病、自己免疫性肝炎からなる群から選択される、全身性の自己免疫性疾患である、請求項8乃至14のいずれか1項に記載の自己免疫性疾患治療薬。
- 治療対象とする自己免疫性疾患が、クローン病、潰瘍性大腸炎、自己免疫性膵炎、胆汁性胆道炎、自己免疫性萎縮性胃炎からなる群から選択される消化器の自己免疫性疾患である、請求項8乃至14のいずれか1項に記載の自己免疫性疾患治療薬。
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