JP2011505843A - 線維症および肝疾患の治療 - Google Patents
線維症および肝疾患の治療 Download PDFInfo
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Abstract
【選択図】なし
Description
その場合オートロガス・シグナル配列(下線を付す)が宿主細胞によって除去のために切断される。従って本発明に基づくACE2タンパク質は好ましくは配列番号1の18位以下に相当するACE2配列を含む。別の実施形態ではACE2ポリペプチドは膜貫通ドメインをもたない。この膜貫通ドメインは配列番号1のC末端にある。従ってその場合は可溶性ACE2となる。特に好ましい実施形態は、アミノ酸からなるポリペプチド鎖がアミノ酸740位までの配列番号1またはその酵素活性フラグメントを含む可溶性ACE2ポリペプチドを包含する。別の可溶性ACE2タンパク質は配列番号1のアミノ酸18〜615からなる。
ACE2ノックアウトマウスおよびACE2野生型マウスを胆管結紮(Bile Duct Ligation,BDL)の21日後に評価し、偽処置対照群と比較した。肝臓の病理学的研究は、BDLを施した動物でコラーゲン沈着の著しい増加を示した(図1)。肝組織のコラーゲン沈着はシリウスレッドによる特異的染色で調べたが、驚くべきことにACE2ノックアウト動物では野生型群の2.5倍であった(図1)。肝臓のコラーゲン産生細胞の数はSMA(活性化星細胞のマーカー)の測定であるウエスタンブロット法およびmRNA測定により決定した。図2はACE2活性の欠如と肝障害の関連を表し、コラーゲン産生細胞の数が著しく高くなっていることをはっきり示す。
第2の試験では野生型マウスにBDLを行った後、組換えACE2を2mg/kgのボーラス注射として毎日、14日にわたり静脈内に投与した。これらの動物もやはり処置の終了後に、生理食塩液だけを投与された対照群と比較した。図3は、野生型動物の組織のSMA濃度および損傷した肝組織のコラーゲン産生細胞の数が極めて著しく増加するが、ACE2処置マウスの肝臓のSMAはウエスタンブロット法で検出不能であったことを非常に明瞭に示している。SMAのmRNAの分析はこの結果を確認する。図4に調べた各群の実験終了時のALT血清濃度を示す。この場合もACE2処置群のALTが低い濃度になっていることを示すことができた。
腎細胞株(Ceropithecus aethiops)Vero E6は通常の培養条件でACE2を膜結合糖タンパク質として発現する。Vero E6細胞を10ng/mlのIL−4、IFN−γまたはTNF−αと共に24時間インキュベートし、ポリクロナールACE2特異的ヤギ抗体およびヤギ特異的FITC標識抗体を使用してACE2表面発現に関する変化をFACS分析法により分析した。図6にそれぞれのヒストグラムを示す。当該分析を表1にまとめた。IL−4、IFN−γまたはTNF−αとのインキュベートでACE2発現が著しく低減された。刺激しない細胞で51±3%のACE2陽性が測定されたが、IL−4、IFN−γおよびTNF−α刺激の後にACE2陽性がそれぞれ28±2、22±1および39±2%に引き下げられた(図6)。
本実施例では、刺激したPBMC(末梢血単核細胞)のサイトカイン発現に対するACE2の効果を示す。種々のリンパ球の協動を可能にするために、PBMC調製物およびドナーの全リンパ球スペクトルを試験に使用した。健康なドナーから全血を採取し、それに含まれるPBMCを遠心して分離した。この細胞をその後、強力な免疫原性物質、例えばリポ多糖(LPS、100ng/ml)および植物性血球凝集素(PHA、20μg/ml)ならびに両物質の組合せを用いて、AngII、ACE2およびACE2+AngIIの存在下で刺激し、37℃で16時間インキュベートした。上清をTNF−αについて調べ、ACE2およびRASのペプチドの不在で行なった対照試験と比較した。この試験の結果を図7にグラフで示す。すなわちLPSおよびPHAとのインキュベーションはすべての場合にTNF−αの分泌を誘導した。ACE2なしで共インキュベートした各対照試験は、それぞれLPS、PHAおよび組み合わせによる刺激の後に極めて高いTNF−α濃度を示した(203、352および278mOD)。ACE2の存在下では、すべてのグループで、測定されたシグナルが著しく小さく、各グループで181、266、223のmOD値にしかならなかった。ところがACE2とAngIIの存在下では、測定されたTNF−α濃度が最小であり、mOD144、247および187にしかならなかった。これらの結果が示すところでは、ACE2の存在は、刺激のために特に免疫原性の物質、例えばLPSまたはPHAを使用しても、炎症性サイトカインの著しく弱められた産生をもたらす。このことはACE2の抗炎症効果を実証する。意外なことにこのメカニズムはAngIIの存在なしですでに機能し、その存在下で強化される。このことは二重因子を示唆している。効果の一部分はAngIIおよびその分解産物Ang1−7によってもたらされ、別の一部分は明らかに他のACE2基質の1つの分解によって機能し、現存するAngIIには無関係である(図7)。
本実施例では、外因性ACE2投与がいかにして脱調節RASを再び制御のもとに置くかを示した。そのためにAPN01(組換え可溶性ヒトACE2)をLPS投与により誘導された敗血症モデルに投与した。−120分の時点から動物にLPSを連続的に輸液し、それが広範囲な炎症とその結果敗血症をもたらした。炎症性サイトカインの大量の放出に基づき、ACE2発現の遮断が起こり、その結果炎症性ペプチドAngIIの蓄積が生じた(図8を参照)。
以下の実施例では、ブタの敗血症モデルで炎症性サイトカインの濃度が急激に増加し、ACE2投与の後に再び健康な動物のレベルに逆戻りすることを示す。−120分の時点から動物に高用量のLPSを連続的に輸液した。このため広範囲な炎症とその結果敗血症が生じた。炎症性サイトカインの大量の放出に基づきACE2発現の遮断が起こり、その結果炎症性ペプチドAngIIだけでなく、炎症性サイトカインTNF−αの蓄積も生じた(図10)。0分の時点から動物(処置群の6頭、対照群の5頭)に0.4mg/kgの用量のACE2または緩衝溶液をボーラスとして静脈内に投与した。LPSを引き続き同じ高用量で連続的に投与する一方で、その後の3時間にわたり動物を観察し、血清試料を採取し、TNF−αについて分析した。対照群ではTNF−α濃度が実験の終りまで引き続き高かったが、ACE2処置群では連続的なLPS投与のもとで1回のACE2投与の後にすでにTNF−α濃度の著しい低下(p<0.001)が起こることを示すことができた。広範囲な敗血症にかかわらず、健康な動物で測定されたのとほぼ同じ値に再び到達した。従って非常に侵襲的な敗血症モデルでもACE2投与によってTNF−α発現を健常者のレベルに急速に引き下げ、さらに増強する炎症に歯止めを掛けることができた(図10)。
本実施例ではブタの肺障害モデルにおいて炎症性サイトカインの発現に対する全身投与したACE2の影響を示した。このプラセボ対照盲験試験で14頭の動物が検討された。実験の第1段階ですべての動物に20%胎便溶液の3回の吸引を施し、その際高い血行動態パラメーターに基づきすべての動物に同等な障害が誘導された。実験の第2段階、すなわち処置段階で動物の半数に組換え可溶性ヒトACE2を0.4mg/kgの用量のボーラスとして静脈内に投与した。他方の半数には生理食塩液を与えた。−30、0、30、60、90および150分の時点で血清試料を採取し、この血清試料で最重要の炎症性サイトカインの濃度を測定した。この場合、時点0は処置の開始点であり、このときすべての動物はすでにARDS(急性呼吸窮迫症候群)の症状を示していた。図11で明かなように、TNF−αの血清濃度に対してACE2投与の非常に顕著な影響がある。これはプラセボ群で230ng/ml超から大幅に上昇するが、処置群では投与後30分以内に40ng/ml以下に低下し、投与後90分で25ng/mlに近づく。
Claims (14)
- 線維症および/もしくは肝疾患の治療または予防のためのACE2タンパク質またはACE2コード核酸、好ましくはACE2タンパク質。
- 線維症が組織または器官の局所的線維症である、請求項1に記載のACE2または核酸。
- 線維症が肝線維症、肺線維症、結合組織線維症、皮膚の線維症または腎線維症、好ましくは肝線維症を含む、請求項1または2に記載のACE2または核酸。
- 線維症および/または肝疾患への予防的適用のための請求項1〜4のいずれか1項に記載のACE2または核酸。
- 肝疾患が肝障害または肝細胞障害をもたらすものである、請求項1〜4のいずれか1項に記載のACE2または核酸。
- 線維症または肝疾患が炎症、好ましくは肝炎を併発している、請求項1〜5のいずれか1項に記載のACE2または核酸。
- 線維症、肝疾患もしくは炎症が感染または創傷を原因とするものである、請求項1〜6のいずれか1項に記載のACE2または核酸。
- ACE2タンパク質が組換えACE2である、請求項1〜7のいずれか1項に記載のACE2または核酸。
- ACE2タンパク質が特に膜ドメインのない水溶性ACE2である、請求項1〜8のいずれか1項に記載のACE2または核酸。
- ACE2タンパク質が哺乳動物、好ましくはヒト、マウス、ラット、ハムスター、ブタ、霊長類またはウシのものである、請求項1〜9のいずれか1項に記載のACE2または核酸。
- 線維症、好ましくは請求項2、4および6〜10のいずれか1項で規定された線維症の治療または予防のためのACE2タンパク質。
- 線維症が肝線維症、肺線維症、結合組織線維症、筋線維症、皮膚線維症または腎線維症から選択される、請求項11に記載のACE2。
- 線維症および/または肝疾患の治療のための医薬組成物の製造のためのACE2またはACE2コード核酸の使用。
- 線維症および/または肝疾患およびACE2ならびにそのコード核酸が請求項1〜12のいずれか1項に記載のものである、請求項13に記載の使用。
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- 2008-12-22 WO PCT/AT2008/000472 patent/WO2009086572A1/de active Application Filing
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Also Published As
Publication number | Publication date |
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AU2008347208B9 (en) | 2014-06-19 |
TR201807891T4 (tr) | 2018-06-21 |
DK2227246T3 (da) | 2014-08-25 |
ES2671556T3 (es) | 2018-06-07 |
NO2572724T3 (ja) | 2018-08-11 |
US20100316624A1 (en) | 2010-12-16 |
NZ586265A (en) | 2012-06-29 |
JP5706163B2 (ja) | 2015-04-22 |
PT2227246E (pt) | 2014-09-02 |
EP2572724B1 (de) | 2018-03-14 |
WO2009086572A1 (de) | 2009-07-16 |
DK2572724T3 (en) | 2018-06-06 |
CA2709895A1 (en) | 2009-07-16 |
AU2008347208A1 (en) | 2009-07-16 |
EP2227246A1 (de) | 2010-09-15 |
EP2572724A1 (de) | 2013-03-27 |
PT2572724T (pt) | 2018-06-14 |
PL2227246T3 (pl) | 2014-10-31 |
ES2481645T3 (es) | 2014-07-31 |
EP2077119A1 (de) | 2009-07-08 |
CA2709895C (en) | 2017-10-31 |
PL2572724T3 (pl) | 2018-08-31 |
AU2008347208B2 (en) | 2014-05-22 |
EP2227246B1 (de) | 2014-06-04 |
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