JP2023519700A - NF-κB抑制剤のエキソソーム基盤伝達の使用 - Google Patents
NF-κB抑制剤のエキソソーム基盤伝達の使用 Download PDFInfo
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Abstract
Description
NF-κB信号伝達による免疫反応はAKIに関与することができ、エキソ-srIκBは敗血症による腎臓損傷で腎臓損傷を改善する効果を発揮できる。本願の一部の実施例では、抑制剤の投与が虚血性AKI過程を軽減させるかどうかを評価した。本願の実施例ではEXPLOR技術を用いてIRI手術前後にsrIκBをマウスに伝達し、その結果を対照群と比較した。その結果、エキソ-srIκB処理されたマウスは、対照群グループと比較し、より低水準の血清BUN及びクレアチニン数値を示し、これによりIR誘導されたAKIから予防及び治療効果を発揮することを確認した。一方、エキソ-srIκBの投与が腎臓のNF-κB信号に局所的に影響を及ぼすかどうかを確認した結果、エキソ-srIκBは、対照群グループと比較し、NF-κBの核転座及び核結合活性を著しく減少させることが明らかになった。NF-κB経路は、免疫反応プロセスで重要な役割をすることができる。エキソ-srIκB治療グループと対照群グループ、IL-1β、IL-6でPan炎症性サイトカイン/ケモカインの遺伝子発現を比較した結果、CCL2、CCL5、CXCL2及びTNF-αを含む多数の炎症媒介因子の顕著な減少が確認された。最後に、本願の実施例では、NF-κB抑制剤の処理が腎臓免疫細胞母集団に影響を及ぼすかどうかを比較するためにフローサイトメトリーを行い、好中球、単核球/マクロファージ及びT細胞を含む多重免疫細胞母集団の頻度が顕著に減少することが観察された。
MFQAAERPQEWAMEGPRDGLKKERLLDDRHDAGLDAMKDEEYEQMVKELQEIRLEPQEVPRGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVITNQPEIAEALLGAGCDPELRDFRGNTPLHLACEQGCLASVGVLTQSCTTPHLHSILKATNYNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCGADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTEDELPYDDCVFGGQRLTL
MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYEQMVKELQEIRLEPQEVPRGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVITNQPEIAEALLGAGCDPELRDFRGNTPLHLACEQGCLASVGVLTQSCTTPHLHSILKATNYNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCGADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTEDELPYDDCVFGGQRLTL
DRHDAGLDAMKDE
敗血症は、多数の臓器不全及び過多な炎症反応を伴い、複雑な病態生理学的特徴を有し、あらゆる症状を効果的に治療できる治療剤を開発することは容易ではない。敗血症は、先天性免疫系の強力な活性化を通じて開示され、病源体によるパターン認識受容体(PRR)の活性化により媒介され、補体システム、凝固システム及び血管内皮の活性化を誘導して正常な恒常性が困難である。
最近、エキソソームは、遺伝子/薬物伝達のための新規なバイオ担体として重要な注目を受けた。エキソソームは、生物活性物質を受容者細胞に伝達したり、標的細胞の信号伝達経路に影響を及ぼすことにより細胞間の通信で重要な役割をする細胞外小胞(EV)である。エキソソームは貯蔵がより容易であり、より大きい安定性を示す。エキソソームは、生物学的障壁を克服できる高用量を有し、特定の細胞類型を標的化する表面分子を運搬でき、従って、オフ標的効果がより少ない。しかし、エキソソームの臨床的適用において、多量の純粋なエキソソームを得、可溶性タンパク質をエキソソームにローディングすることは重大な課題であった。イムら(Yim et al.)により開発された新規な、光遺伝学的に操作されたエキソソーム技術である「光可逆的タンパク質-タンパク質相互作用を通じたタンパク質ローディングのためのエキソソーム」(EXPLOR)を使用し、エキソソームの生産効率及び生物学的互換性で顕著な発展がなされた。このEXPLOR技術は、最近、チェら(Choi et al.)により実験的敗血症モデルに採択され;これらはスーパーリプレッサーIκB(srIκB)を含有するエキソソームをマウスに伝達した。これは、NF-κBの核転座を防止するカッパーB(IκB)抑制剤の非分解性形態であった。これらの研究は、エキソ-srIκB処理がマウス敗血症モデルにおいて全身炎症反応及び後続する臓器機能障害を改善させることを示した。
動物:雄性C57BL/6Jマウスを、延世医療センターの中央動物施設で特定の病源体非含有条件(specific pathogen-free condition)で飼育させた。全ての実験に6-7週齢の雄マウスを用いた。また、C56BL/6、C57BL/6N、BALB/cマウスは、オリエントバイオ(Orientbio)(大韓民国城南)から購入した。好中球及びマクロファージにおいてGFPを本質的に発現するLysMGFP/+マウスは、Dr.M.Kim(University of Rochester, Rochester, NY, USA)により寛大に提供された。
エキソソーム製造、回収及び精製は、図13に示された通り、以前の研究で完全に記載されている。粒子の大きさは大部分30~120nmであり、平均サイズは101nmである。透過電子顕微鏡(TEM)は、ナノ粒子追跡分析(NTA)結果に応じて大きさを有する無損傷のカップ状の膜小胞を示した(図1、B及びC)。エキソ-srIκBに対するイムノブロッティング分析結果は、CD63、TSG101、Alix及びGAPDHなどの陽性エキソソームマーカーを有するsrIκB、mCherry、CD9及びGFPを含む標的タンパク質の強力な発現を示した。エキソ-srIκBは、プロヒビチン、カルネキシン、GM130及びヌクレオポリン62を含む細胞小器官マーカーの発現が欠如した。エキソ-ナイーブはエキソソームマーカーを除いた如何なるマーカーも発現しなかった(図1D)。
まず、腎臓IRI過程でエキソ-srIκBの役割を調査した。各実験グループを3×109pnのエキソ-srIκBまたは、腎臓IRIの前後に、エキソ-ナイーブを1時間間隔(合計9×109pn)で3回腹腔内注射した。(前処理:IRI手術前に3、2及び1時間、後処理:IRI手術後に1、2及び3時間)。マウスを手術24または48時間後に犠牲にした(図2A)。
全身エキソ-srIκB処理がIR誘導されたAKI過程に影響を及ぼす根本的メカニズムを理解するために、エキソ-srIκBの全身伝達をまず研究し、腎臓において局所NF-κB信号伝達を抑制するかどうかを決定した。それぞれ相違する実験グループの腎臓核抽出物中のNF-κB p65タンパク質の発現はウェスタンブロッティングを通じて測定した。9×109pnのエキソ-srIκBを用いた全身処理は、エキソ-ナイーブ処理グループで発見されたものと比較し、IRI前(IRI 24時間後、P<0.05;48時間、P<0.01)及びIRI後(IRI 24-/48時間後、P<0.01)(図3A)処理モデルにおいてIR誘導されたNF-κB核転座を減少させた。この発見は、各実験グループの腎臓核抽出物を用いてp65のDNA結合活性を測定することにより再確認された。エキソ-srIκB処理は、処理時点(前処理:IRI 24-/48-時間後、P<0.05;後処理:IRI 2-/48時間、P<0.01)と関係なく、エキソ-ナイーブグループと比較し、腎臓IRI後にNF-κBのDNA結合活性を有意に下向調節した(図3B)。NF-κB免疫組織化学(IHC)染色を通じた追加検証は、対照群処理グループと比較し、エキソ-srIκB処理グループでNF-κBの発現が有意に減少したことが示された(前処理:IRI 24時間後、P<0.05;48-h、P<0.001及び後処理:IRI 24-/48-h後、P<0.05)(図3C)。従って、全身エキソ-srIκB処理はIR後の腎臓で腎臓NF-κB信号伝達を減少させることができる。
全身性エキソソームsrIκB処理が腎臓IRI誘導された炎症を局所軽減させるかどうかを追加で調査するために、定量的リアルタイムポリメラーゼ連鎖反応(qRT-PCR)を通じてIL-1α、IL-1β、IL-2、IL-4、IL-6、Il-10、Il-17α、Ccl2、Ccl3、Ccl5、Cxcl2、Ifn-γ及びTnf-αを含む中枢炎症性媒介因子の遺伝子発現水準を決定した。IRI前にエキソ-TIκBの9×109pnを用いた処理は、IR損傷した腎臓でEx-ナイーブ処理されたグループのものと比較し、Il-1β、Il-6、Tnf-α、Ccl2、Ccl5及びCxc12の発現水準を有意に抑制させた(図4A)。多重サイトカイン分析は、また、相違する実験グループの血清を用いて行った。結果は、腎臓転写データより有意ではなかったが、対照群グループでのものと比較し、エキソ-srIκB処理グループでIL-6、TNF-α、CCL2、CCL5及びCXCL2を含む炎症性サイトカインの発現が減少する明白な傾向があった(図4B)。
プログラム細胞致死を調節する時にNF-κBの公知となった役割に基づいて、エキソ-srIκBが虚血後の腎臓でアポトーシスにいかに影響を及ぼしたかを調査した。腎臓IRI手術は腎臓細胞で有意なアポトーシスを誘導し、これはウェスタンブロット分析で切断されたカスパーゼ-3及び切断されたポリ(ADP-リボース)ポリメラーゼ(PARP)水準の急激な増加を示した。損傷の前/後にエキソ-srIκBの全身伝達は、切断されたカスパーゼ-3及び切断されたPARPの発現水準を実質的に下向調節でき、これはエキソ-srIκBが虚血後の腎臓でアポトーシスに対する保護効果を奏することを示唆する(図5A)。末端デオキシヌクレオチジルトランスフェラーゼdUTPニック末端標識(TUNEL)染色を用いて腎臓細胞損傷の程度を決定した。対照群と比較し、エキソ-srIκB処理された腎臓は前/後処理モデルにおいて有意に少ない数のTUNEL陽性細胞を示した(図5B)。
腎臓IRIモデルにおいてエキソ-srIκBの生体分布は、細胞類型が虚血後の腎臓でエキソ-srIκBの保護効果を調整することをより十分に理解するために調査した。マウスに、IRI手術1時間前にフルオロクロム標識されたLy6G及びF4/80抗体を静脈内注射し、再灌流1時間後に9×109pnのエキソ-srIκBを静脈内注射した。生体内イメージングは再灌流後10分、5時間及び24時間に行った(図6A)。好中球を可視化するための抗Ly6G抗体(Fluor 555)及びマクロファージを可視化するための抗F4/80抗体(Fluor 488)だけでなく、DiD標識されたエキソソーム注射後の生体内イメージングはエキソ-srIκB及びエキソ-ナイーブのいずれも虚血後の腎臓で好中球(Ly6G+)及びマクロファージ(F4/80+)により吸収されるということを確認した(図6B)。本発明者らは、IRI後の細尿管でDiD(緑色)信号の軽微な増加を観察し、細尿管細胞によるエキソソーム吸収可能性を高めたが、信号強度はDiD標識されたエキソソーム注射前のものと有意に相違しなかった(データは提示されない)。脾臓は同時に観察され、これは、外部実質領域の好中球及びマクロファージでエキソソームの吸収を示した(図6C)。内部実質領域は有意な吸収を示さなかった(データは提示されない)。
免疫細胞は、虚血性AKIの過程で重要な役割を提供することが公知となっており;従って、IRI手術前にエキソソームsrIκB処理を提供することが各免疫細胞類型の母集団に影響を及ぼすかを評価した。虚血性AKIの24時間後、実験グループ間の機械的破壊、酵素分解及びパーコール密度勾配方法の複数の段階を通じて単離された腎臓細胞の総数に対する差異はなかったが、エキソ-srIκB処理グループは、エキソ-Niave処理されたグループのものより腎臓単核細胞(KMNC)の有意な低頻度を有した(P<0.05)(図7、A及びB)。追加分析は、エキソ-srIκB注射グループがエキソ-ナイーブ注射グループのものより総KMNC中の好中球(CD45+Ly6G+)(P<0.01)プロ/抗炎症性単核食細胞(CD45+Ly6C+/CD45+F4/80+)(それぞれP<0.01/P<0.05)、及びT細胞(CD45+CD3+)(P<0.05)の有意な低頻度を有することを示した(図7C)。IR損傷腎臓の免疫蛍光の結果は、また、エキソ-srIκB注射腎臓で好中球及び単核食細胞頻度の減少を示した(図7D)。しかし、エキソ-srIκB処理は、虚血性AKI後の脾臓の総免疫細胞数または頻度に有意な影響を及ぼさなかった。エキソ-srIκB及びエキソ-ナイーブ処理グループとの間でT細胞(CD45+CD3+)を除いて、総免疫細胞(CD45+)、好中球(CD45+Ly6G+)、プロ/抗炎症単核食細胞(CD45+Ly6C+/CD45+F4/80+)の総細胞数及び頻度の差はなかった。これは、虚血性AKIの前に全身エキソ-srIκB処理が腎臓免疫細胞の増殖/輸送に顕著な局所的影響を及ぼすが、脾臓免疫細胞には顕著な局所的影響を有さないことを確認する。
腹腔内エキソソーム伝達において類似の保護効果が静脈内伝達で発見されるかどうかを検証するために、静脈内注射方式を用いて一部実験を繰り返した。改善された生化学的結果、その上、エキソ-srIκBの静脈内伝達によるNF-κB信号伝達及びICAM-1発現の減少した水準は図8に示されたように再現された。従って、エキソ-srIκB結果の静脈内伝達も虚血性AKIモデルで腹腔内伝達と比較して類似の生物学的効果をもたらす。
十分なエキソソームを生産するために、それぞれの細胞類型から培養培地を収集した。
エキソ-srIκBの腹腔内(i.p.)注射がエンドトキシン衝撃(endotoxic shock)から保護する効果があるかどうかを調査した。動物に致死量のLPS(C57BL/6の場合、40mg/kgの体重、BALB/cの場合、20mg/kgの体重)で単一i.p注射後、エキソ-srIκBを単一i.p.注射した(6時間間隔)。LPS誘導された敗血症による死亡率が100%である対照群C57BL/6マウスと比較し、エキソ-srIκBで処理されたマウスはLPS誘導死亡率に顕著に耐性を示し;マウスの大部分は敗血症から治癒(rescue)され、生存が延長された(図10A、上部)。エキソ-srIκB-媒介効果はLPS誘導された温度降下から適当な保護と関連があった(図14A)。BALB/cマウスを用いてLPS誘導された敗血症のマウスモデルを開発した。エキソ-srIκB処理はBALB/cマウスにおいてLPS誘導された敗血症の生存率を有意に改善させた(図10A、中間)。続けて、腹部敗血症の標準化したマウスモデルにおいてCLP誘導された敗血症モデルを用いて、生存においてエキソ-srIκBの役割を調査した。動物は7日のモニタリング期間生存し、これはエキソ-srIκBが敗血症死亡率に対して持続的保護を提供することを示す(図10A、下部)。エキソ-srIκB処理が敗血症により誘導された炎症を緩和させるかどうかをさらに調査するために、酵素結合免疫吸着検定(ELISA)を使用して血清で主要炎症因子の濃度を決定した。LPS誘導された敗血症を有するエキソ-srIκB処理グループにおいて炎症誘発性サイトカインTNFα、IL-1β及びIL-6及びケモカイン四塩化炭素(CCL4)の発現水準が有意に減少することが観察された(図10B、上部)。また、CLPグループにおいてTNF-α及びCCL4の血清水準が虚偽操作対照群マウスの血清水準より有意に高く観察されたが、CLP及びエキソ-srIκBがいずれも処理されたマウスでは上昇しなかった(図10B、下部)。このような結果はエキソ-srIκBがLPSまたはCLPにより誘導された炎症を緩和させ、急性炎症プロセスから敗血症マウスを保護することを示唆する。
LPS注射された敗血症マウスモデルにおいてエキソソーム生体分布の変化を調査した。生体内生体分布は、注文製作された生体内ビデオレートレーザースキャニング共焦点顕微鏡システム(custom-made intravital video-rate laser scanning confocal microscopy system)を用いて分析した。好中球(緑色蛍光タンパク質[GFP]及びAlexa 555)及びマクロファージ(GFP)を可視化するために抗Ly6G抗体が既に注射されたLysMgfp/+トランスジェニックC57BL/6マウスにmCLING蛍光染料標識されたエキソソームを静脈内注射した。大部分のエキソソームが速やかに、即ち、静脈内エキソソーム注射後、数分間以内に好中球及びマクロファージにより吸収されることを観察した(図11A)。
試験管内エキソ-srIκBの標的特異性及び効率を確認した。エキソ-srIκBはNF-κBルシフェラーゼリポーター遺伝子を安定的に発現するHEK293細胞においてTNF-α誘導されたNF-κB活性化を有意に遮断したが、エキソ-ナイーブは遮断しなかった(図12A)。エキソ-srIκBの量を増加させることは容量依存的方式でNF-κBリポーター活性を減少させ、これはエキソソームから放出されたsrIκBがNF-κB転写活性を防止することを示す(図12B)。
動物は、致死量のLPS(30mg/kgの体重)で30分間単一腹腔内注射、続いて、10時間エキソ-srIκB(1×1010)の単一静脈内注射の提供を受けた。肺組織を図17に提示された通りH&E染色で分析した。10時間LPSを注射したグループは、好中球浸潤及び肺胞マクロファージの増殖、肺胞内及び肺胞外充血を示し、出血が進行された。肺胞内皮細胞の損傷、その上、歯槽骨壊死が観察される。エキソソーム投与は、鬱血が若干観察される場合にも、肺胞壁拡張、好中球浸潤及び肺胞マクロファージ増殖を軽減させた。
実施形態1.これを必要とする対象体において急性腎障害(AKI)を治療するための方法であって、NF-κB抑制剤を含むエキソソームを含む組成物の有効量を前記対象体に投与する、方法。
実施形態1.これを必要とする対象体において敗血症により誘発された疾患を治療する方法であって、NF-κB抑制剤を含むエキソソームを含む組成物の有効量を前記対象体に投与することを含む、方法。
Claims (10)
- 急性腎障害(acute kidney injury;AKI)の治療を必要とする対象体で急性腎障害を治療する方法であって、
NF-κB抑制剤を含むエキソソーム(exosome)を含む組成物の有効量を前記対象体に投与することを含む、方法。 - NF-κB抑制剤がNF-κB抑制タンパク質、この断片及びこれらの混合物からなるグループから選択される、請求項1に記載の方法。
- NF-κB抑制剤がスーパーリプレッサー(super-repressor;SR)-IκB(srIκB)、IκB-α、IκB-β、IκB-ε、BCL-3、これらの突然変異体(mutant)及びこれらの混合物からなるグループから選択される、請求項1または2に記載の方法。
- 組成物が経口、経皮、腹腔内、静脈内、筋肉内、皮下または混合経路を通じて投与される、請求項1~3のいずれか一項に記載の方法。
- 対象体に抗炎症剤を投与することをさらに含む、請求項1~4のいずれか一項に記載の方法。
- NF-κB抑制剤を含むエキソソームが光特異的結合タンパク質(photo-specific binding protein)をさらに含む、請求項1~5のいずれか一項に記載の方法。
- NF-κB抑制剤が配列番号1または配列番号2に対して少なくとも85%の配列同一性(sequence identity)を有するアミノ酸配列を含む、請求項1~6のいずれか一項に記載の方法。
- NF-κB抑制剤を含むエキソソームが第1光特異的結合タンパク質及び/又は第2光特異的結合タンパク質をさらに含み、
第1光特異的結合タンパク質がエキソソーム特異的マーカーに接合されて融合タンパク質Iを形成し;
第2光特異的結合タンパク質がNF-κB抑制剤に接合されて融合タンパク質IIを形成する、請求項1~7のいずれか一項に記載の方法。 - 敗血症(sepsis)により誘発された疾患の治療を必要とする対象体において敗血症により誘発された疾患を治療する方法であって、
NF-κB抑制剤を含むエキソソームを含む組成物の有効量を対象体に投与することを含む、方法。 - 疾患が肺炎(pneumonia)、サイトカインストーム症候群(cytokine storm syndrome)、呼吸困難症候群(respiratory distress syndrome)及び臓器不全(organ failure)からなるグループから選択される、請求項9に記載の方法。
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