JP2007538232A - B型肝炎のための治療薬、予防薬、および診断薬 - Google Patents
B型肝炎のための治療薬、予防薬、および診断薬 Download PDFInfo
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Abstract
Description
本発明は、動物種においてB型肝炎ウイルス(HBV)の感染の治療および予防に有用な化合物を提供する。本発明はさらに、HBVによる感染または他の疾患状態を診断するための方法および診断プロトコールに有用な薬剤を提供する。本発明はさらに、ヒトおよび動物モデルを含む他の動物種において病態をモニターするための方法、ならびにHBVによる感染または他の病的状態の進行に対する被験体の感受性の指標を提供するための方法を意図する。
本明細書において言及される刊行物の参考文献詳細もまた、本明細書の末尾に収載する。
本明細書を通じて、文脈上他の意味に解すべき場合を除き、「含む(comprise)」という単語、または「含む(comprises)」もしくは「含んでいる(comprising)」などの変化形は、明記した要素もしくは整数または要素もしくは整数の群を包含することを意味するが、任意の他の要素もしくは整数または要素もしくは整数の群の排除を意味するものではないと理解される。
本発明は、プレコアタンパク質もしくはHBeAgなどのその分泌された形態を産生するHBVによる感染は、肝細胞(肝実質細胞およびクッパー細胞を含む)およびPBMC(末梢単球を含む)においてTLR-2およびTLR-4のレベルを低下させるが、プレコア突然変異および/またはBCP突然変異を有するHBVによる感染は、TLR-2およびTLR-4を上方制御させ、さらにTLRシグナル伝達を調節する可能性もあるという決定に基づいて述べられている。TLR-2およびTLR-4のレベルの調節を、HBVに特定されるエフェクター分子、プレコアタンパク質もしくはHBeAgなどのその分泌された形態により判定した。プレコアタンパク質もしくはHBeAgなどのその分泌された形態の存在、非存在またはレベル、あるいはTLR-2およびTLR-4のレベル、ならびに/あるいはプレコアタンパク質もしくはHBeAgなどのその分泌された形態の機能または活性は、HBV感染または感染の原因となるHBVの種類またはHBV感染の素因もしくは持続の診断指標を提供する。さらに、プレコアタンパク質もしくはHBeAgなどのその分泌された形態、TLR-2およびTLR-4は、プレコアタンパク質もしくはHBeAgなどのその分泌された形態またはTLR-2および/もしくはTLR-4レベルまたはTLRシグナル伝達経路の成分を調節するワクチンを含む薬剤の治療標的となる。
(a)レポーター分子と抗体との直接結合;
(b)レポーター分子と抗体との間接結合;すなわち、レポーター分子と、その後に抗体と結合する別のアッセイ試薬との結合;および
(c)抗体のその後の反応生成物との結合。
TLR2およびTLR4レベルの測定
方法
HBVバキュロウイルス感染HepG2
HepG2細胞をHBV1:3野生型、HBV1:3プレコア突然変異株または偽感染バキュロウイルスで感染させ、7日間培養した後回収し、フローサイトメトリーのために染色した。RNeasyミニキット(Qiagen)を製造業者の仕様書に従って用いて全RNA抽出のためにいくつかの細胞を保存した。
TLR2-FITC(TL2.1; eBioscience)およびTLR4-PE(HTA125; eBioscience)抗体を用いてHepG2細胞の細胞表面染色を行った。適当なアイソタイプ対照(isotype control)を用いた。死細胞を散乱特性に基づいてゲートから排出した。FACSCaliburフローサイトメーター(BD)で実験を行った。各試料につき合計10000個の細胞を得た。FlowJoソフトウェア(Tree Star Inc.)を用いてデータを解析した。偽感染細胞の幾何平均蛍光強度を野生型またはプレコア突然変異株感染細胞の幾何平均蛍光強度から引くことにより相対蛍光強度を決定した。
cDNAのリアルタイムPCR解析の前にランダムヘキサマーを用いて全RNAを逆転写した。TaqMan Universal PCR Master MixならびにAssays-On-Demand Gene Expression Assayプローブおよびプライマー(Applied Biosystems)を用いて最終容量10μlでPCRを3通り行った。以下の通りにプログラムされたABI Prism 7700配列検出システムによってシグナル検出を行った:50℃,2分間;95℃,10分間;40サイクルの95℃,15秒間;60℃,1分間。各遺伝子のサイクル閾値(CT)、を18SのCT値(ΔCT)と比較し、相対発現単位(REU)を各試料について計算した。従って、REU=2^CT(関心対象遺伝子)−Ct(18S)=2^ΔCtである。
結果を図1および2ならびに表3に示す。TLR2およびTLR4のレベルをHBV野生型とプレコア突然変異HBV株の感染細胞において比較する。
慢性HBV感染におけるTLR発現の低下
患者
肝生検
シングルパス肝生検を5名のCHB患者に行った。これらは大学病院の肝臓専門外来に通院する臨床的に安定な患者であった。患者らのトランスアミナーゼは正常または軽度に上昇していた(平均ALT 87.8 U/L(N<45);平均AST 32.2 U/L(N<45)。Ishak改変組織活動性指標のスコアは1/6〜3/6の間の病期で1/18〜7/18まで変化した。5名の患者のうちの4名はHBeAg陽性でウイルス複製が進行していた(HBV DNA 200〜1.1×108コピー数/ml中央値1500コピー/ml)。生検試料を、実験室へ輸送するためにRPMI-1640(Gibco-BRL)に入れ、そこで単細胞浮遊液を調製した。半分の生検(1.5×8mm)を、他の細胞と混ざり合った約6×104個の肝細胞を分離するため、緩いピストルの付いた、ワイヤーメッシュまたはガラスホモジナイザーのいずれかに供した。受容体の損傷を防ぐため、このプロセスにはコラゲナーゼもデオキシリボヌクレアーゼも用いなかった。次に、この単細胞浮遊液を適当な抗体で染色し、フローサイトメトリーにより解析した(下記参照)。
細胞培養
ヒト肝芽腫細胞株HepG2を、ペニシリンおよびストレプトマイシン、L-グルタミンおよび10%v/v熱不活性化ウシ胎児血清(FCS)(Invitrogen)を補充したMinimum Essential Medium(MEM; Invitrogen/Gibco)で維持した。全ての細胞株を週毎に継代し、3日毎に培地を交換して5%v/v C02中、37℃にて維持した。
HepG2細胞にFugene 6試薬(Roche, IN)を用いてHBVの感染性cDNAクローンをトランスフェクトして組換え型HBVを作製し(Chen et al, Hepatology 27(1):27-35, 2003)、5日後、細胞培養上清を回収した。分泌されたウイルスを含有する上清を回収し、プールし、遠心分離してペレット状の細胞片を得た。次に、SW28ローター(Beckman)を用いて、20%スクロースクッション(20% w/vスクロース、1mM EDTA、30mM Tris pH7.4、150mM NaCl)による、12℃で25,000rpmにて16時間の上清の超遠心分離によりHBVを濃縮した。
HBVプレコアおよびコアタンパク質の緊密な誘導発現をもつHuh-7細胞を、遺伝子型DのcDNA(Chen 2003前記)からのHBVコア遺伝子またはプレコア遺伝子をテトラサイクリン応答性発現系(pTRE-2; Clontech, Palo Alto, CA)へクローニングすることにより作製した。これらの3種類の細胞株PC47(プレコア産生細胞株)、C4B(コア産生細胞株)および親株(対照細胞株)の樹立および特徴付けは、詳細に公開されている(Locarnini et al., J Clin Virol. 32:113-21, 2005)。テトラサイクリンの存在下(タンパク質発現抑止)または非存在下(タンパク質発現誘導)での10日間の培養の後、細胞培養上清を回収した。
既に記載したように(Chen 2003 前記)、1.3ゲノム長の野生型(WT)HBV鋳型(遺伝子型D、サブタイプayw)(Invitrogen, Stratagene, CA)を用いる位置指定突然変異誘発および同時トランスフェクションにより組換え型HBVバキュロウイルス構築物を作製した。次に、HepG2細胞に、対照、WTおよびプレコア突然変異組換え型HBVバキュロウイルスを50プラーク形成単位(PFU)/細胞の感染多重度(MOI)で平行して形質導入した(22、23)。細胞培養の培地を形質導入後1、3、および5日目に交換し、7日目に回収した。
500μlのリチウム-ヘパリン全血を、抗生物質および5%v/v熱不活性化ウシ胎児血清を補充した500μlのRPMI-1640に希釈し、しっかりと蓋をした5mlポリスチレン管(Becton Dickinson, San Jose, CA)中で緩やかに回転させながら37℃でインキュベートした。細胞を、濃度1、10、および50×106ウイルスゲノムコピー/mlのHBV野生型1.5(遺伝子型A)、1μg/mlラミブジン、PLC/PRF/5細胞の細胞上清(HBsAg)またはHBVプレコアの上清(pC47:HBeAg陽性)またはコアタンパク質(C4B)産生細胞株ならびに適当な対照細胞株で刺激した。20時間後、培養上清を回収し、サイトカイン解析まで-20℃で保存した。残りの細胞をフローサイトメトリー用に染色した。
TNF-αを、OptEIAセット(Becton Dickinson, San Jose, CA)を製造業者の仕様書に従って用いて捕捉ELISAにより測定した。ELISAの感受性は8pg/mlであった。
肝細胞懸濁液
患者の肝生検から得た肝細胞懸濁液の細胞表面染色を、CD14-PerCP(MφP9; Becton Dickinson, San Jose, CA)、TLR2-FITC(TL2.1; eBioscience, San Diego, CA)およびTLR4-PE(HTA125; eBioscience, San Diego, CA)を用いて行った。適当なアイソタイプ対照を用いた。細胞をCD14表面発現の量;CD14が高度であるかまたはCD14が低度であるか、に応じてゲートした。これはその散乱特性と相互に関連した。CD14の高い細胞(肝細胞)は、CD14の低い細胞(クッパー細胞)よりもさらに大きく、より粒状であった。
新鮮なリチウム-ヘパリン血の細胞表面染色を、既に記載したように(Riordan et al., Hepatology 37:1154-64, 2003)、CD14-PerCP(MφP9; Becton Dickinson, San Jose, CA)、TLR2-FITC(TL2.1; eBioscience, San Diego, CA)およびTLR4-PE(HTA125; eBioscience, San Diego, CA)を用いて行った。適当なアイソタイプ対照を用いた。それらの散乱特性に基づいて、FACSCaliburフローサイトメーター(Becton Dickinson, San Jose, CA)で単球をゲートしてリンパ球の尾部を捕捉した。合計8000個のCD14+単球を各試料から得た。FlowJoソフトウェア(Tree Star Inc., Ashland, OR)を用いてデータを解析した。相対蛍光強度を、そのアイソタイプの合致する対照を越える、試料の幾何平均蛍光強度の比として決定した。結果はTLRの変化率(%)として表した。
患者の培養全血の細胞表面染色を、CD14-PerCP(MφP9; Becton Dickinson, San Jose, CA)、TLR2-FITC(TL2.1; eBioscience, San Diego, CA)およびTLR4-PE(HTA125; eBioscience, San Diego, CA)を用いて行った。適当なアイソタイプ対照を用いた。それらの散乱特性に基づいて、FACSCaliburフローサイトメーター(Becton Dickinson, San Jose, CA)で単球をゲートしてリンパ球の尾部を捕捉した。合計8000個のCD14+単球を各試料から得た。FlowJoソフトウェア(Tree Star Inc., Ashland, OR)を用いてデータを解析した。相対蛍光強度を、非刺激または親刺激対照と比較して、そのアイソタイプの合致する対照を越える試料の幾何平均蛍光強度の比として決定した。結果はTLRの変化率(%)で表した。
その後のフローサイトメトリーのために細胞の状態および受容体の完全性を最適化するため、全てのヒト肝臓細胞株単層をハンクス平衡塩類溶液(カルシウム、マグネシウムを含まない)中で5回洗浄してから、Versene溶液(ハンクス平衡塩類溶液と1:1で混合した0.02% w/v EDTA.4Na)中で培養して細胞単層を剥離した。次に無血清のMEMを用いて単細胞浮遊液を作製してからフローサイトメトリーのために染色した。次に、細胞を室温にて回収した後、直ちに細胞をTLR2-FITC(TL2.1; eBioscience, San Diego, CA)およびTLR4-APC(HTA125; eBioscience, San Diego, CA)で染色した。細胞を1%v/vホルマリンを加えたPBSで固定し、染色後直ちに行った。
RNAを、RNeasy MiniKit(Qiagen)を製造業者の仕様書に従って用いて細胞株から単離した。RNAをカラムから溶出してヌクレアーゼを含まない水50ulに入れ、-70℃で保存した。OD 260nmでの分光測定によりRNAの濃度を推定した。
末梢血および肝細胞の示す類似したTLR2の下方制御
4名のHBeAg陽性CH-B患者、3名のHBeAg陰性CH-B患者および脂肪肝対照の5つの肝生検試料からの末梢血および肝細胞を調べた。これらの肝生検試料の肝細胞を、方法セクションに記載されるように単細胞浮遊液へ分離し、図3に示すようにフローサイトメトリーにより2つの別個のCD14+ve細胞集団をゲートした。これらの2つの集団、(1つは肝細胞に代表され、1つはクッパー細胞に代表される)において、TLR2およびTLR4を測定した(図4および5)。TLR2も肝細胞上に検出され、さらに、その発現レベルが、HBeAg陰性CHBおよび脂肪肝患者の幹細胞と比較してHBeAg陽性CHBの肝細胞で下方制御された(図5)。このTLR2の下方制御は、末梢血での以前の実証がHBV感染患者の肝細胞とクッパー細胞の双方でも明白であることを確信させる(図5)(Visvanathan et al, GUT 52:130, 2003)。TLR4発現のレベルは3つの集団間で有意に異なることはなかった。
臨床的に観察したプレコアタンパク質とTLR経路の相互作用をさらに調査するため、HepG2細胞の組換え型HBVバキュロウイルス形質導入系をインビトロで用いた。HepG2細胞に、対照、野生型またはプレコア突然変異組換え型HBVバキュロウイルスを平行して形質導入し、7日後に処理し、既に概説したようにフローサイトメトリーによるTLR2およびTLR4の発現のために染色した(図4)。
発明者らは次に、HBVの種々の希釈液およびその個々の抗原成分による全血のインビトロ刺激を調べた。培養の20時間後、フローサイトメトリーによりCD14陽性単球でのTLR2およびTLR4の発現について血液を解析した(図5)。さらにこれらの刺激から上清を回収し、TNF-αをELISAにより測定した(図6)。CD14+細胞をHBVに曝露した結果、TLR2の抑制が顕著となったが、TLR4ではそうではなく、慢性HBeAg陽性HBV感染患者において得られた臨床データがさらに確かめられた。TNF-α抑制はTLR2の減少と平行し、これらの刺激実験においてTLRの減少と機能的な相関があったことを示す。また、プレコアタンパク質刺激も、野生型ウイルスで示された同様のTNF-αの平行抑制を実証し、CHBにおいてTLR2を下方制御する因子である可能性を示している。
Claims (19)
- TLRシグナル伝達のレベルを調節するHBV特定エフェクター分子の存在もしくは非存在を判定する段階を含む、HBVによる感染または疾患状態もしくはその素因の存在を検出するための方法であって、該エフェクター分子の存在もしくは非存在、またはTLRのレベルの高低、またはTLRシグナル伝達経路内の成分が、HBVによる感染または関連する疾患状態もしくはその素因の存在の指標となる、方法。
- プレコア発現産物が細胞内型である、請求項1記載の方法。
- プレコア発現産物が細胞外型である、請求項1記載の方法。
- TLRがTLR-2またはそのホモログである、請求項1または2または3記載の方法。
- TLRシグナル伝達のレベルがTLRまたはTLR-2のレベルで判定され、次にそれがコードするmRNAの量で判定される、請求項1または4記載の方法。
- 細胞内もしくは細胞外のプレコア発現産物のレベルまたはTLRのレベルがタンパク質レベルで判定される、請求項4記載の方法。
- TLRシグナル伝達を調節するHBV特定エフェクター分子のレベルまたは活性を判定する段階を含む、HBVによる感染または疾患状態の進行に対する治療プロトコールへの応答をモニターするための方法であって、該エフェクター分子の存在もしくは非存在、またはTLRのレベルの高低、またはTLRシグナル伝達経路内の成分が、HBVによる感染または関連する疾患状態もしくはその素因の存在の指標となる、方法。
- HBVがプレコアおよび/またはBCP突然変異体である、請求項7記載の方法。
- HBVに特定されるエフェクター分子が細胞内または細胞外のプレコア発現産物である、請求項8記載の方法。
- TLRがTLR-2またはそのホモログである、請求項7記載の方法。
- TLRシグナル伝達のレベルがTLRまたはTLR-2のレベルで判定され、次にそれがコードするmRNAの量で判定される、請求項7または10記載の方法。
- 細胞内もしくは細胞外のプレコア発現産物のレベルまたはTLRもしくはそのホモログのレベルがタンパク質レベルで判定される、請求項10記載の方法。
- 細胞内もしくは細胞外のプレコア発現産物のレベルを下方制御するまたはTLRのレベルを上方制御もしくは下方制御するワクチンを含む有効量の薬剤を被験体へ投与する段階を含む、HBVに感染したまたは疾患状態を有するもしくはその素因を有する被験体を治療するための方法。
- HBVがプレコアおよび/またはBCP突然変異体である、請求項13記載の方法。
- HBVに特定されるエフェクター分子が細胞内もしくは細胞外のプレコア発現産物である、請求項13記載の方法。
- TLRがTLR-2またはそのホモログである、請求項13記載の方法。
- 細胞内もしくは細胞外のプレコア発現産物のレベルまたはTLRのレベルが、それをコードするmRNAの量で判定される、請求項13または16記載の方法。
- 細胞内もしくは細胞外のプレコア発現産物のレベルまたはTLRのレベルがタンパク質レベルで判定される、請求項13または16記載の方法。
- 細胞内もしくは細胞外のプレコア発現産物の調節因子および任意でTLRまたはそのホモログの調節因子と、1つまたは複数の薬学的に許容される担体および/または希釈液とを含む、HBVによる感染または疾患状態もしくはその素因の治療に用いるための薬学的組成物またはワクチン。
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WO2017015175A1 (en) | 2015-07-17 | 2017-01-26 | Arcturus Therapeutics, Inc. | Compositions and agents against hepatitis b virus and uses thereof |
US20170137821A1 (en) | 2015-07-17 | 2017-05-18 | Arcturus Therapeutics, Inc. | Molecules and agents for treating hepatitis b virus |
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