JP2017149745A - シータデフェンシンによる炎症性プロテアーゼの遮断 - Google Patents
シータデフェンシンによる炎症性プロテアーゼの遮断 Download PDFInfo
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- JP2017149745A JP2017149745A JP2017076042A JP2017076042A JP2017149745A JP 2017149745 A JP2017149745 A JP 2017149745A JP 2017076042 A JP2017076042 A JP 2017076042A JP 2017076042 A JP2017076042 A JP 2017076042A JP 2017149745 A JP2017149745 A JP 2017149745A
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- defensin
- rtd
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- defensins
- analog
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- Dispersion Chemistry (AREA)
Abstract
【解決手段】θデフェンシン、その類似体または誘導体がθデフェンシン−1、θデフェンシン−1類似体、θデフェンシン−1誘導体、θデフェンシン−2、θデフェンシン−2類似体、θデフェンシン−2誘導体、θデフェンシン−3、θデフェンシン−3類似体、θデフェンシン−3誘導体、θデフェンシン−4、θデフェンシン−4類似体、θデフェンシン−4誘導体、θデフェンシン−5、θデフェンシン−5類似体、θデフェンシン−5誘導体、およびRTD−1から選択される薬物組成物。TACE活性を阻外するのに有効量の前記薬物組成物を投与する方法。
【選択図】図1
Description
本明細書で引用される参考文献はすべて、その全体が完全に記載された場合と同様に参照により組み込まれるものとする。特に定義されない限り、本明細書で使用する技術用語および科学用語は、本発明の属する分野の当業者により一般に理解されるものと同じ意味を有する。Singletonら,Dictionary of Microbiology and Molecular biology第3版,J.Wiley & Sons(New York,NY 2001);March,Advanced Organic Chemistry Reactions,Mechanisms and Structure第5版,J.Wiley & Sons(New York,NY 2001);およびSambrookおよびRussel,Molecular Cloning:A Laboratory Manual第3版,Cold Spring Harbor Laboratory Press(Cold Spring Harbor,NY 2001)は、本願で使用される多くの用語に関する一般的な指針を当業者に提供するものである。
デフェンシンは、白血球および各種上皮によって産生され、陽イオン性でジスルフィドを3つ含む抗微生物ペプチドである。デフェンシンはさらにαデフェンシン、βデフェンシン、θデフェンシンのサブファミリーに分けられ、これらはペプチドの大きさおよびジスルフィドモチーフの違いによって区別される。ヒトでは、4種類のαデフェンシン(HNP−1〜HNP−4)が好中球から単離されており、また2種類の腸αデフェンシン(HD−5およびHD−6)が小腸陰窩のパネート細胞によって発現される。このほか、女性泌尿生殖管でHD−5の発現が検出されている。3種類のヒトβデフェンシン(hBD−1〜hBD−3)が各種器官の上皮細胞種および非上皮細胞種から単離されており、またcDNA解析によって、あるいはヒトゲノム解析から、ほかにも数種類のデフェンシンの発現が推定されている。皮膚、呼吸上皮、泌尿生殖管および各種白血球(すなわち、好中球、単球およびNK細胞)においてデフェンシンが抗微生物エフェクター機能を示すことが多数の証拠から示唆されている。さらにデフェンシンは、自然免疫応答および適応免疫応答に関与する細胞をともに活性化し、このことは、デフェンシンが2系統の免疫内で作用し、2つを結び付けることを示唆している。
θデフェンシンは、76アミノ酸のαデフェンシン関連前駆体から生じる2つのノナペプチドの転写後スプライシングによって形成される環状オクタデカペプチドである。ヒトでは、進化の過程でオランウータンが出現した頃に、ペプチド前駆体に早期停止コドンをもたらした突然変異によってθデフェンシンが発現されなくなったため、θデフェンシンペプチドの発現はみられない。
典型的なθデフェンシンペプチドは、18アミノ酸大環状ペプチドのアカゲザルθデフェンシン−1(RTD−1)である(22)。記載されているように、成熟ペプチドは、短縮されたαデフェンシン様前駆体から生じる2つの9アミノ酸ペプチドが頭尾型のスプライシングを受け、3つのジスルフィドによって安定化された大環状分子を形成する固有の過程によって生成する(図1)。成熟大環状θデフェンシンが生じる生合成経路は新規なものである。アカゲザル(22、23、25)およびアヌビスヒヒ(9)ではそれぞれ、3つおよび4つのθデフェンシン前駆体が発現する。各前駆体から、すべて2要素の組合せで同一のナノペプチド(ホモ二量体スプライシング)または異なるノナペプチド(ヘテロ二量体スプライシング)と対になった固有のナノペプチドが生じる。これにより、6種類の固有のマカクθデフェンシンおよび10種類のヒヒθデフェンシンの生成が可能となる。本発明者らは、予測されるマカクペプチド全6種類を単離し(23)、ヒヒで予測されるペプチドのうち7種類を単離した(9)。
腫瘍壊死因子α(「TNF−α」、カヘキシンまたはカケクチンとしても知られる)は全身性炎症に関与するサイトカインであり、急性期反応を誘発するサイトカイン群のメンバーである。
記載したように、TNF−αシグナル伝達活性の重要な段階は、「シェディング」として知られる過程のTACEによる触媒作用を受けて、膜結合型のタンパク質が遊離し、可溶型の血中TNF−αになることである。TACEは824個のアミノ酸からなる70kDaのタンパク質で、ディスインテグリンおよびメタロプロテイナーゼからなるADAMタンパク質ファミリー(A Disintegrin And Metalloproteinase)に属する。ADAMタンパク質ファミリーのメンバーは、進化的に保存された構造および膜結合プロタンパク質から可溶性の外部ドメインを切断し解離する機能の両方を有する。炎症過程におけるTNF−αの強力で極めて重要なメディエーターとしての役割を考慮すれば、TACE阻害剤として機能する環状ペプチドが、現在用いられている抗体または可溶性受容体ベースの組成物などの抗TNF−α剤の極めて重要な代用になると考えられる。
θデフェンシンは、大腸菌(E.coli)細胞の取込みを媒介する細胞外膜に小孔を形成することによってその細胞を死滅させる(24)。この研究では、本発明者らは、θデフェンシンが多くのαデフェンシンおよびβデフェンシンとは異なり、宿主細胞に対して非毒性であり(24)、各種経路でマウスに投与することができる(29)という注目すべき事実を発見した。この点に関して、マウスは少なくとも用量80mg/kgの3種類の異なるθデフェンシンのi.v.投与を容易に許容する。さらに本発明者らは、成体チンパンジー2個体にi.v.用量を増加させて(最大3mg/kg)RTD−1を投与した。すべての注射の後、いずれの項目にも臨床毒性は認められず、また臨床化学検査値および血液学検査値がすべて正常範囲内にあった。いずれの動物種もRTD−1に対する抗体を産生しなかったことは、様々な哺乳動物種に対する毒性および免疫原性の著明な欠如を示している。ここに挙げたデータおよびその他のデータに基づき、盲腸結紮穿刺(CLP)により重度の敗血症を誘発したマウスモデルを用いて、RTD−1の有効性を試験した(12)。図2に示されるように、CLP手術の4時間後または24時間後にペプチドを投与した場合、RTD−1(5mg/kg)の単回注射によりBALB/cマウスの死亡率が著明に減少した(第4日および第7日でP<0.01)。第7日に生存していた個体は、第15日に屠殺されるまで臨床的に正常であった。θデフェンシンのCLP敗血症に対するこの治療効果は再現性が高いものであった(N=5の実験)。しかし、多菌性敗血症のミクロビオームがきわめて大きいことから、θデフェンシンのこの有効性の高さは、このモデルでのRTD−1の有効性が主として抗菌作用によって媒介されたものではないことを示唆していた。むしろ、示された治療効果の高さは、さらに抗炎症機序により媒介されると考えられた。この可能性を検証するため、本発明者らは新たな実験を実施し、CLPマウスをRTD−1で治療したところ、TNF−α、IL−6およびMIFを含めた多種多様な血清炎症性サイトカインの著明な減少がみられた。
典型的なθデフェンシンRTD−1が、抗微生物作用を介してではなく、宿主細胞との相互作用によってその抗炎症効果を発揮することが、複数のデータにより示されている(29)。これらの知見をもとに、大腸菌(E.coli)または黄色ブドウ球菌(S.aureus)で刺激したヒト全血によるTNF−α産生に及ぼすRTDの効果を評価するさらなる実験を実施した。図4(BおよびC)に示した代表的な実験では、RTD1〜5(図4A)が大腸菌(E.coli)によって誘発されるTNF−α放出を阻害することが示されている;異なるθデフェンシンの間にも阻害能力の著しい差がみられることに留意されたい。黄色ブドウ球菌(S.aureus)を用いた実験でもほぼ同じ結果が得られた。対照実験では、本発明者らは、θデフェンシンがELISA標準曲線を変化させないこと、またイムノアッセイでは活性な三量体TNF−αのみが検出されることを示す結果に基づき、θデフェンシンは他の多くのデフェンシンとは異なり、TNF−αタンパク質と直接相互作用しないということを発見した。ここに挙げた実験およびその他の実験の結果は、RTD−1のCLP敗血症における防御作用(図3)が、抗微生物作用ではなく免疫調節活性によるものであることを示唆していた。この結果を受けて、本発明者らは、10μg/mlのRTD−1を同時に加えて、あるいは加えずに、ヒト末梢血白血球(PBL)をTLR1〜9のアゴニストで4時間刺激した。図5に示されるように、PBLとRTD−1を共インキュベートしたところ、TLR2、4、5および8のアゴニストによって誘発されるTNF−α放出が著明に減少した。さらに、RTD−1は、各アゴニストによって刺激されるIL−1βおよび1L−6の放出も阻害し、IL−8は、TLR2アゴニストの存在下を除くすべての誘発において強力に阻害された。RTD−1は、無刺激細胞には実質的にいかなる効果も示さなかった(図5、左上のパネル)。RTD−1治療のMCP−1レベルに対する効果には差がみられた。本発明者らは、マウスSARS間質性肺炎でRTD−1が肺MCP−1レベルを著明に減少させたことから(29)、このケモカインを分析に含めた。これは、ウイルスssRNAで刺激したPBLに及ぼすRTD−1の効果と一致している(図5)。最後に、本発明者らはさらに、RTD−1が、ex vivoでエンテロトキシン産生黄色ブドウ菌(S.aureus)により刺激したヒトPBMCによる1L−17Aの発現を用量依存性に抑制する(85%を上回る減少)ことを発見した。
ここに挙げた結果は、θデフェンシンが細菌(図4)、各種TLRアゴニスト(図5)および動物で測定されたもの(上を参照)によって誘発されたTNF−αの阻害を媒介することを示していることから、TNF−α変換酵素の活性がθデフェンシンによって打ち消されるという1つの作用機序が考えられた。このTNF−α変換酵素(「TACE」、ADAM(a disintegrin and metalloproteinase)ファミリー)のメンバー、ADAM17としても知られる)は、膜結合TNF−αの放出に関与するシェダーゼである。驚くべきことに、本発明者らは、RTD−1が、IC50約0.1μg/ml(48nM)の強力な組換えTACE(rTACE)の阻害剤であることを発見した。注目すべきことは、ヒトαデフェンシン(HNP−2、HNP−4)がいずれもrTACEを阻害しないという点で(図6A)、θデフェンシンの活性がデフェンシンのなかでも独特なものであったということである。天然のθデフェンシン(RTD1〜5;図4Aの構造)の相対的阻害活性を試験したところ、IC50値に約10倍の範囲にわたる差がみられた(図6B)。注目すべきことは、RTD1〜5によるTACE阻害の序列とヒト血液中のペプチドによるTNF−α阻害との間に強い相関がみられるということである(図4C)。RTD−1によるTACE阻害がTACEとの15分間のプレインキュベーションによって増強されなかったという結果は、迅速な結合および競合阻害を示唆するものである。このことは酵素反応速度データの二重逆数プロット解析によって確認され(図6C)、RTD−1がTACEの偽基質として作用することを示している。RTD−1の開鎖類似体(S−7;図6D)をTACE阻害について試験し、活性がRTD−1の20%未満であることがわかったが、このことは、効果的なTACE阻害に環状構造が必要であることを示している(図6E)。
各種ADAMが、膜に固定された増殖因子、サイトカインおよび受容体を解離する調節シェダーゼに関係があるとされている(3)。ADAMは、炎症および癌の調節を含めた多数の重要な生物学的過程に関与することから、ADAM阻害剤の同定は研究の盛んな分野となっている。本発明者らは、天然のθデフェンシンRTD1〜3が、TACEの阻害で観察されたものとほぼ同じIC50(図6を参照)でADAM10を阻害する(図7)ことを確認した。したがって、θデフェンシンは少なくとも2種類のADAMのメタロプロテアーゼ阻害剤である。
天然θデフェンシンおよび修飾θデフェンシンの構造活性解析から、これらのペプチドの抗炎症作用を媒介すると予測される特定の配列特性が示唆された。一例をあげると、天然θデフェンシンの抗炎症作用に重要であると考えられる特性をもつよう3種類のテトラデカペプチド(ミニθデフェンシン)を設計した。これらを図8Aに示すペプチドの配列中に組み込んだ。各ペプチドをマウスCLP敗血症に対する有効性について評価した。図8Bに示されるように、ミニθデフェンシン3種類ともPBS偽治療よりマウスの致死率を低下させた。本発明者らはさらに、刺激したヒト血液からのTNF−α放出に及ぼす効果(図8C)およびTACEに対する阻害活性(図8D)について各ミニθデフェンシンを評価した。図8のデータに示されるように、ミニθデフェンシンは、CLPアッセイ(図3と比較)、TNF−α阻害アッセイ(図8C)またはTACE阻害アッセイ(図8D)でRTD−1とほぼ同じか、これを上回る活性を示した。
本発明者らは、in vivoまたはex vivoでのθデフェンシンによるTNF−αの遮断がこのペプチドの抗炎症作用の中心的な役割を担っているとすれば、TNF−αによって進むことが知られている疾患の経過を調節するはずであると考えた。本発明者らは次に、確立されたPIAを有するラットに及ぼすRTD−1の効果を試験した。代表的な実験(N=3)では、Vingsboら(26)に記載されている通りに、第0日にプリスタン0.3mlを成体Dark Agouti(DA;OlaHsd系統)ラット(N=21)に皮下注射した。臨床疾患の最初の徴候がみられた時点(第14〜21日;肉眼的病理スケールに基づく参考文献(4))で、ラットを生理食塩水群(N=10)またはRTD−1治療群(N=11)に交互に割り付けた。関節炎の重症度(3人の観察者によって最大36日間、毎日盲検的に採点)が以前のゼロに戻るまで(生理食塩水群ではN=1;RTD−1群ではN=8)最大14日間、毎日、尾静脈注射によって生理食塩水(0.2〜0.25ml)またはRTD−1(0.2〜0.25ml生理食塩水中5mg/kg)の盲検投与を実施した。第7日からRTD−1治療個体に関節病理の統計的に有意な(*=不対両側StudentT検定によりp≦0.05)減少がみられた。このモデルではこのほか、同じRTD=Tの用量および製剤の皮下注射によって効果が示された。治療中止後少なくとも45日間、疾患再発の証拠はみられなかった。
θデフェンシン RTD−1をヒト血漿、ヒト血清中50μg/mlまたはヒト血清アルブミン中50mg/ml、室温で72時間インキュベートした。定量HPLC分析を実施したところ、各試験条件下でペプチドの95%超が変化しなかった。さらにθデフェンシンは、低pH(約pH2.5)または中性pH(pH7.4)条件下での長期間保管に対しても安定である。
本発明による組成物は経口経路、非経口経路、吸入による経路、局所経路、直腸内経路、経鼻経路または埋め込みリザーバーを介した経路を含めた各種経路を用いて投与することができ、ここでは、本明細書で使用される「非経口」という用語は、皮下、静脈内、筋肉内、関節内、滑膜内、髄腔内、肝内、病巣内および頭蓋内への各投与(通常は注射または注入)を包含する。好ましくは、組成物を経口的に、皮下に、腹腔内にまたは静脈内に投与する。
上記の各種方法および技術は、本発明に関連する方法を実施する方法を多数提供するものである。当然のことながら、記載されている目的または利点が、本明細書に記載の任意の特定の実施形態に従えば必ずしも達成されるわけではないということを理解するべきである。したがって、例えば、本明細書で教示または示唆され得る他の目的または利点の達成を必ずしも必要とすることなく、本明細書で教示されるような1つの利点または一群の利点を達成する、または最大限に活用する方法でこれらの方法を実施することができることを当業者は認識するであろう。本明細書では、様々な有利な代替物および不利な代替物が挙げられている。好ましい実施形態にも、1つの、別のまたは複数の有利な特徴を特に含むものがあり、1つの、別のまたは複数の不利な特徴を特に除外するものがあり、さらには1つの、別のまたは複数の有利な特徴を含むことによって既存の不利な特徴を軽減するものもあることを理解するべきである。
(1)
薬物組成物を販売する方法であって、
前記薬物組成物がθデフェンシン、その類似体または誘導体を含み、
前記方法が、
前記薬物組成物の有効性をヒトにおける抗炎症性効果に関して判定することと、
炎症性病態を治療するために前記薬物組成物を市場に提供することと
を含む方法。
(2)
前記薬物組成物がRTD−1−27である、(1)に記載の方法。
(3)
前記薬物組成物がRTD−1−28である、(1)に記載の方法。
(4)
前記薬物組成物がRTD−1−29である、(1)に記載の方法。
(5)
前記有効性を判定する段階が、前記薬物組成物に関する毒性試験、有効性試験および用量反応試験のうちの少なくとも1つを依頼することを含む、(1)に記載の方法。
(6)
前記有効性を判定する段階が、前記薬物組成物に関する毒性実験、有効性試験および用量反応試験のうちの少なくとも1つに関して別の者によって得られたデータを利用することを含む、(1)に記載の方法。
(7)
前記炎症性効果が、臨床的に意義のある炎症誘発性プロテアーゼの阻害を含む、(1)に記載の方法。
(8)
前記炎症誘発性プロテアーゼが腫瘍壊死因子α(TNF−α)変換酵素(TACE)である、(7)に記載の方法。
(9)
前記炎症性効果が、臨床的に意義のある炎症誘発性プロテアーゼの阻害を含む、(1)に記載の方法。
(10)
前記炎症性効果が、臨床的に意義のあるシェダーゼの阻害を含む、(1)(1)に記載の方法。
(11)
前記炎症性効果が、臨床的に意義のあるカテプシンCの阻害を含む、(1)に記載の方法。
(12)
前記薬物組成物を市場に提供する段階が、販売のために前記薬物組成物を少なくとも1キログラム生産することを含む、(1)に記載の方法。
(13)
前記生産する段階が、前記薬物組成物を少なくとも1キログラム製造することを含む、(12)に記載の方法。
(14)
前記薬物組成物を経口製剤として包装することをさらに含む、(1)に記載の方法。
(15)
前記炎症性病態がタンパク質分解による疾患である、(1)に記載の方法。
(16)
前記炎症性病態が関節リウマチを含む、(1)に記載の方法。
(17)
前記炎症性病態が自己免疫疾患を含む、(1)に記載の方法。
(18)
前記薬物組成物を癌の治療薬として販売することをさらに含む、(1)に記載の方法。
(19)
前記薬物組成物を神経変性疾患の治療薬として販売することをさらに含む、(1)に記載の方法。
(20)
前記薬物組成物を炎症性腸疾患の治療薬として販売することをさらに含む、(1)に記載の方法。
(21)
前記薬物組成物をアルツハイマー病の治療薬として販売することをさらに含む、(1)に記載の方法。
(22)
前記薬物組成物を変形性関節症の治療薬として販売することをさらに含む、(1)に記載の方法。
(23)
抗TNF−α療法に奏効しない患者を治療するために前記薬物組成物を販売することをさらに含む、(1)に記載の方法。
(24)
動物に投与して炎症性病態を治療するための薬剤を製造する方法であって、前記薬剤が、θデフェンシン、その類似体または誘導体のうちの少なくとも1つを含む方法。
(25)
前記薬剤が、RTD−1−27、RTD−1−28およびRTD−1−29のうちの少なくとも1つを含む、(24)に記載の方法。
(26)
前記薬剤が、臨床的に意義のある炎症誘発性プロテアーゼの阻害をもたらすのに有効である、(24)に記載の方法。
(27)
前記炎症誘発性プロテアーゼが腫瘍壊死因子α(TNF−α)変換酵素(TACE)である、(26)に記載の方法。
(28)
前記薬剤が、臨床的に意義のある炎症誘発性プロテアーゼの阻害をもたらすのに有効である、(25)に記載の方法。
(29)
前記薬剤が、臨床的に意義のあるシェダーゼの阻害をもたらすのに有効である、(24)に記載の方法。
(30)
前記炎症性病態が関節リウマチを含む、(24)に記載の方法。
(31)
前記炎症性病態が自己免疫疾患を含む、(24)に記載の方法。
(32)
前記薬物組成物を癌の治療薬として販売することをさらに含む、(24)に記載の方法。
(33)
前記薬物組成物を神経変性疾患の治療薬として販売することをさらに含む、(24)に記載の方法。
Claims (11)
- 必要とする対象において腫瘍壊死因子α(TNF−α)変換酵素(TACE)活性を阻害するために使用する薬剤組成物であって、
θデフェンシン、その類似体または誘導体を含み、
θデフェンシン、その類似体または誘導体が、必要とする対象においてTACE活性を阻害するのに有効な量で提供される、
薬物組成物。 - θデフェンシン、その類似体または誘導体がθデフェンシン−1、θデフェンシン−1類似体、θデフェンシン−1誘導体、θデフェンシン−2、θデフェンシン−2類似体、θデフェンシン−2誘導体、θデフェンシン−3、θデフェンシン−3類似体、θデフェンシン−3誘導体、θデフェンシン−4、θデフェンシン−4類似体、θデフェンシン−4誘導体、θデフェンシン−5、θデフェンシン−5類似体、θデフェンシン−5誘導体、およびRTD−1からなる群より選択される、請求項1に記載の薬物組成物。
- θデフェンシン−1類似体がRTD−1−28である、請求項1に記載の薬物組成物。
- θデフェンシン−1類似体がRTD−1−28である、請求項1に記載の薬物組成物。
- θデフェンシン−−1類似体がRTD−1−29である、請求項1に記載の薬物組成物。
- 前記TACE活性がシェダーゼ活性である、請求項1に記載の薬物組成物。
- 前記薬物組成物が経口製剤である、請求項1から6のいずれかに記載の薬物組成物。
- 過剰なTNF−α活性に関連する疾患を治療するための動物への投与のための医薬の製造方法であって、
前記医薬が、θデフェンシン、その類似体または誘導体の少なくとも1つをTACE活性を阻害するのに有効な量で含む、
方法。 - θデフェンシン、その類似体または誘導体がθデフェンシン−1、θデフェンシン−1類似体、θデフェンシン−1誘導体、θデフェンシン−2、θデフェンシン−2類似体、θデフェンシン−2誘導体、θデフェンシン−3、θデフェンシン−3類似体、θデフェンシン−3誘導体、θデフェンシン−4、θデフェンシン−4類似体、θデフェンシン−4誘導体、θデフェンシン−5、θデフェンシン−5類似体、θデフェンシン−5誘導体、およびRTD−1からなる群より選択される、請求項8に記載の方法。
- 前記医薬がRTD−1−27、RTD−1−28およびRTD−1−29の少なくとも1つを含む、請求項8に記載の方法。
- 前記TACE活性がシェダーゼ活性である、請求項8に記載の方法。
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