JP2017114829A - インターロイキン36受容体アンタゴニスト欠損症の治療薬 - Google Patents
インターロイキン36受容体アンタゴニスト欠損症の治療薬 Download PDFInfo
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- JP2017114829A JP2017114829A JP2015254560A JP2015254560A JP2017114829A JP 2017114829 A JP2017114829 A JP 2017114829A JP 2015254560 A JP2015254560 A JP 2015254560A JP 2015254560 A JP2015254560 A JP 2015254560A JP 2017114829 A JP2017114829 A JP 2017114829A
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- psoriasis
- il36rn
- pustular
- therapeutic agent
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Abstract
Description
以下の発明は上記の成果及び考察に基づく。
[1]TAK-242又はその薬学的に許容される塩を有効成分として含有する、IL36RN遺伝子欠損症の治療薬。
[2]IL36RN遺伝子欠損症が膿疱性乾癬、関節症性乾癬、疱疹状膿痂疹、掌蹠膿疱症、アロポー稽留性指端皮膚炎、急性汎発性発疹性膿疱症、及び再発性環状紅斑様乾癬からなる群より選択される疾患である、[1]に記載の治療薬。
[3]IL36RN遺伝子欠損症が膿疱性乾癬又は関節症性乾癬である、[1]に記載の治療薬。
[4]TAK-242又はその薬学的に許容される塩を治療上有効量、IL36RN遺伝子欠損症の患者に投与するステップを含む、IL36RN遺伝子欠損症の治療法。
[5]IL36RN遺伝子欠損症の治療薬を製造するための、TAK-242又はその薬学的に許容される塩の使用。
関節症性乾癬の病態を再現するモデル動物(関節症性乾癬モデル)及び膿疱性乾癬の病態を再現するモデル動物(膿疱性乾癬モデル)の創出を試みた。
(1)IL36RN(Il1f5)遺伝子ノックアウトマウスの作製
ES細胞を用いてコンベンショナルなIl1f5(ヒトのIL36RN遺伝子に相当)遺伝子ノックアウトマウスを作製する。ES細胞にはHK3i細胞(C57BL/6N系統)を使用した。使用したプラスミド(ターゲティングベクター)の構成及び標的部位を図1に示す。Il1f5遺伝子のエクソン1(Ex1)の一部からエクソン3(Ex3)の一部にまたがる領域(配列番号1)をPr Neo pA(配列番号2)に置換した。
本実験ではリポ多糖(LPS)(製品名Lipopolysaccharides from Escherichia coli O111:B4、SIGMA-ALDRICH社)を使用した。
本実験ではC57BL/6N系統のマウスを使用した。
関節炎/膿疱の誘発のために、IL36RN(Il1f5)遺伝子ホモ欠損マウスの関節近傍又は後足の足裏にLPSを下記の通り投与する。
(投与量)
関節炎:2μg/ml〜2mg/mlの濃度で20μl
膿疱:2μg/ml〜2mg/mlの濃度で50μl
(投与スケジュール)
関節炎:1日1回、3日間
膿疱:1日1回、1〜5日間
(1)関節炎の誘導
複数のオスマウスを同ケージで飼育するとファイティングすることが多い。IL36RN遺伝子ホモ欠損マウス及びヘテロ欠損マウスではファイティングにより関節炎が起こった(WTマウスではこのような現象は認めていない)。この現象の機序として、外傷に伴う感染から自然免疫が賦活化し、関節症性乾癬と同様の関節炎が起こっている可能性を考え、TLR4アゴニストをIL36RN遺伝子ホモ欠損マウスの関節近傍に局所投与することにより関節炎を誘導することを試みた。まず、8〜12週齢、オスの野生型(WT)マウス及びIL36RN遺伝子ホモ欠損マウスの後足の関節近傍に、TLR4リガンド(アゴニスト)であるLPSを40ng〜40μg(容量20μl)の投与量で1日1回、3日間皮下注射した。そして、最終投与6時間後に後足の厚さを測定した。その結果、LPS 300ng以上で、IL36RN遺伝子ホモ欠損マウスにおいてWTマウスより優位に後足の腫脹・肥厚がみられた(図2、3)。
8〜12週齢、オスの野生型(WT)マウス及びIL36RN遺伝子ホモ欠損マウスの除毛した背部皮膚に、LPSを100ng〜100μg(容量50μl)の投与量で1日1回、1〜5日間皮下注射し、皮膚の状態を観察した。50μg投与した群では、5日間投与後においてWTマウス、IL36RN遺伝子ホモ欠損マウスいずれにおいても著しい紅斑・膿疱がみられた(図4)。尚、3μg投与した群においても、Il36RN遺伝子欠損マウスでは著しい紅斑・膿疱が、また野生型においても軽度ではあるものの、紅斑・膿疱が観察された。
IL36RN遺伝子ホモ欠損マウスの関節近傍にTLR4リガンドを局所投与することによって、関節症性乾癬と同様の関節炎を誘導すること、即ち、関節症性乾癬モデルの作製に成功した。また、IL36RN遺伝子ホモ欠損マウスの皮膚にTLR4リガンドを局所投与することによって、膿疱の病変を再現すること、即ち膿疱性乾癬モデルの作製にも成功した。これらの乾癬モデルは、関節症性乾癬と膿疱性乾癬の病態解明、或いは治療薬の開発のための有用な実験動物となる。一方、上記の実験によって、従来の関節炎モデルで立証されてきた定説と異なり、関節症性乾癬の病態形成にIL-36が関与することが明らかとなった。この事実は、今後の治療戦略において重要な意義を持つ。また、作製に成功したモデル動物の活用を図る上でも重要である。
上記の通り、TLR4アゴニストをIL36RN遺伝子ホモ欠損マウスの関節近傍に局所投与することにより関節症性乾癬の病態を再現することに成功した(関節症性乾癬モデル)。また、皮膚にTLR4アゴニストを投与することにより、膿疱性乾癬で見られる膿疱病変も再現できた(膿疱性乾癬モデル)。これらの動物モデルを用い、関節症性乾癬/膿疱性乾癬に有効な治療薬を見出すべく、TLR4アンタゴニストとして知られるTAK-242による治療を試みた。
(1)実験の概要
8〜12週齢、オスの野生型(WT)マウス(コントロール)及びIL36RNホモ欠損マウスを用いて実験を行う。TLR4アゴニストを関節近傍に局所投与することにより、Il36RN欠損マウスに関節炎を誘導する(関節症性乾癬モデル)。同様にTLR4アゴニストをWTマウス及びIL36RN欠損マウスの皮膚に投与することにより、膿疱性乾癬の皮膚病変である膿疱を再現する(膿疱性乾癬モデル)。再現された関節炎及び皮膚病変に対して、TLR4アンタゴニストであるTAK-242による治療を行う。
TLR4アゴニストであるリポポリサッカリド(LPS) (Sigma: L-3024)を、マウスの後足の関節近傍に300ng(容量20μl)を1日1回、3日間皮下注射し、最終投与6時間後に後足の厚さを測定する。また、後足の検体を採取する。治療群にはTLR4アンタゴニストであるTAK-242 (Chemscene: CS-0408)をLPS投与前日より4日間、5mg/kg/日の用量で腹腔内投与する。コントロール群には、溶媒であるDMSO(1%)をLPS投与前日より4日間、同用量で腹腔内投与する。
(3)膿疱性乾癬モデル(皮膚病変)による評価
除毛したマウスの背部皮膚にLPS 3μg(容量50μl)を1日1回、1〜5日間皮下注射する。治療群にはTAK-242をLPS投与前日より最終投与日まで毎日、5mg/kg/日の用量で腹腔投与する。コントロール群は、溶媒であるDMSO(1%)をLPS投与前日より最終投与日まで毎日、同用量で腹腔投与する。2日目のLPS投与4時間後及び24時間後に皮膚、血液、肝臓の検体を採取する。
(1)関節症性乾癬モデル(関節炎)による評価
LPS投与2日目(LPS投与6時間後)に各マウスの後足の厚さを測定した。その結果、TAK-242による治療で腫脹・肥厚が有意に軽減し(図6)、関節症性乾癬の治療・予防に対するTAK-242の有効性が示された。尚、比較実験として、3μgのLPSの投与(1日1回、3日間皮下注射)によって病態を誘導したマウスにIL-1b抗体、IL-17a抗体又はCxcr2アンタゴニストを投与したが、いずれも効果は認められなかった。
LPS投与2日目(LPS投与4時間後)の皮膚の状態を観察した。未治療群(図7、8)では膿疱の形成が認められるのに対し、TAK-242による治療群では全ての個体(6/6)で膿疱が消失した(図9)。一方、2日目のLPS投与24時間後に肝臓を摘出し、観察した。未治療群(LPSのみ投与)では全個体(6/6)で肝臓の白色組織(壊死性血管炎)がみられた(図10左上、右上、右下)。TAK-242治療群では6匹中2匹(2/6)で肝臓に白色組織(壊死性血管炎)を認めた(図10左下)。LPSの代わりに水を皮下注した群では白色組織を認めた個体はなかった(0/4)。このように、膿疱性乾癬の病態の治療・予防にもTAK-242が有効であることが示された。尚、比較実験として、3μgのLPSの投与(1日1回、1〜5日間皮下注射)によって病態を誘導したマウスにIL-1b抗体、IL-17a抗体、IL-36a抗体又はCxcr2アンタゴニストの腹腔内投与、あるいはIL36rnの局所投与を行ったが、いずれも一定の治療効果は認められなかった。
Claims (5)
- TAK-242又はその薬学的に許容される塩を有効成分として含有する、IL36RN遺伝子欠損症の治療薬。
- IL36RN遺伝子欠損症が膿疱性乾癬、関節症性乾癬、疱疹状膿痂疹、掌蹠膿疱症、アロポー稽留性指端皮膚炎、急性汎発性発疹性膿疱症、及び再発性環状紅斑様乾癬からなる群より選択される疾患である、請求項1に記載の治療薬。
- IL36RN遺伝子欠損症が膿疱性乾癬又は関節症性乾癬である、請求項1に記載の治療薬。
- TAK-242又はその薬学的に許容される塩を治療上有効量、IL36RN遺伝子欠損症の患者に投与するステップを含む、IL36RN遺伝子欠損症の治療法。
- IL36RN遺伝子欠損症の治療薬を製造するための、TAK-242又はその薬学的に許容される塩の使用。
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