JP2019214575A - 無毒性神経毒誘導体を用いる治療方法 - Google Patents
無毒性神経毒誘導体を用いる治療方法 Download PDFInfo
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Abstract
Description
本発明は、無毒性神経毒誘導体を用いる治療方法に関する。
クロストリジウム神経毒は、シナプス小胞の開口分泌のための神経細胞の仕組みを標的とする、構造的に類似のタンパク質の群である。クロストリジウム(Clostridium)属の嫌気性細菌によって生成されたボツリヌス神経毒(「BoNT」、7種の免疫学的に異なる亜型、A〜G)及び破傷風神経毒(「TeNT」)は、静脈あるいは筋肉注入で投与されると、0.5〜2.5ng/kgの範囲内でLD50を有する、重量当たり最も毒性の強い物質であることが知られている(National Institute of Occupational Safety and Health, "Registry of Toxic Effects of Chemical Substances(R−TECS)," Cincinnati,Ohio:National Institute of Occupational Safety and Health(1996)(非特許文献1))。BoNTは、神経筋接合部のコリン作動性神経を標的とし、アセチルコリン放出を阻害し、そして末梢神経筋遮断を引き起こす(Simpson, "Identification of the Major Steps in Botulinum Toxin Action," Annu.Rev.Pharmacol.Toxicol.44:167−193(2004)(非特許文献2))。
[本発明1001]
クロストリジウム神経毒の、単離された、生理学的に活性な無毒誘導体を対象に接触させる段階を含み、クロストリジウム神経毒の前記誘導体が、そのN末端にカーゴ付着ペプチド配列を持たないという条件で、前記接触させる段階が、前記対象を治療するために実行される、治療方法。
[本発明1002]
前記神経毒誘導体が、クロストリジウムボツリナム(Clostridium botulinum)神経毒誘導体である、本発明1001の方法。
[本発明1003]
クロストリジウムボツリナム神経毒誘導体が、クロストリジウムボツリナムセロタイプA、クロストリジウムボツリナムセロタイプB、クロストリジウムボツリナムセロタイプC、クロストリジウムボツリナムセロタイプD、クロストリジウムボツリナムセロタイプE、クロストリジウムボツリナムセロタイプF、及びクロストリジウムボツリナムセロタイプGからなる群より選択されるセロタイプを持つ、本発明1001または本発明1002の方法。
[本発明1004]
前記神経毒誘導体が、メタロプロテアーゼ無効化変異を持つ、本発明1001〜1003のいずれかの方法。
[本発明1005]
前記神経毒誘導体が、組換えタンパク質である、本発明1001〜1004のいずれかの方法。
[本発明1006]
前記対象が、しわ、肥大性咬筋、及び局所多汗症からなる群より選択される皮膚科的あるいは美容的な状態に対して治療される、本発明1001〜1005のいずれかの方法。
[本発明1007]
前記対象が、食道運動障害、咽頭食道痙攣、及び裂肛からなる群より選択される胃腸病学的な状態に対して治療される、本発明1001〜1006のいずれかの方法。
[本発明1008]
前記対象が、尿路神経原性機能障害、過活動膀胱、及び切迫性尿失禁の神経調節からなる群より選択される尿生殖器学的な状態に対して治療される、本発明1001〜1007のいずれかの方法。
[本発明1009]
前記対象が、トゥーレット症候群、局所の筋痙縮またはジストニア、痙性斜頚、原発性眼瞼痙攣、片側顔面痙攣、痙攣性発声障害、顔面神経障害、ラスムッセン症候群、切断痛、声の震え、ワニの涙症候群、辺縁性下顎神経麻痺、疼痛、食道由来の胸痛、頭痛、脳性麻痺、多発性硬化症の臀部内転筋機能障害、神経痛及び炎症、関節炎、医原性耳下腺唾液腺粘液腫、ならびに慢性TMJ疼痛及び転位からなる群より選択される神経学的な状態に対して治療される、本発明1001〜1008のいずれかの方法。
[本発明1010]
前記神経毒誘導体が、野生型クロストリジウム神経毒のLD50よりも少なくとも1,000倍高いLD50を持つ、本発明1001〜1009のいずれかの方法。
[本発明1011]
前記神経毒誘導体が、神経細胞の細胞質ゾル内に、野生型クロストリジウム神経毒に比べ、より多量に蓄積する、本発明1001〜1010のいずれかの方法。
[本発明1012]
クロストリジウム神経毒の前記誘導体が、以下のプロペプチドを切断することによって生成される、本発明1001〜1011のいずれかの方法であって:
前記プロペプチドが、
軽鎖領域と、
重鎖領域と
前記軽鎖及び重鎖領域を結合し、高度に特異的なプロテアーゼ切断部位を含む中間領域と
を含み、
前記軽鎖及び重鎖領域がジスルフィド結合によって連結され、
前記高度に特異的なプロテアーゼ切断部位が、切断を可能にするために、高度に特異的なプロテアーゼによって認識される三つ以上の特異的近接アミノ酸残基を持つ、方法。
[本発明1013]
前記高度に特異的なプロテアーゼ切断部位が、エンテロキナーゼ切断部位及びタバコエッチ病ウイルスプロテアーゼ認識(TEV)配列から選択される、本発明1012の方法。
[本発明1014]
前記プロペプチドが、前記中間領域内に低度に特異的なプロテアーゼ切断部位を持たず、前記低度に特異的なプロテアーゼ切断部位が、切断を許容するために、プロテアーゼによって認識される二つ以下の近接アミノ酸残基を持つ、本発明1012または本発明1013の方法。
[本発明1015]
前記軽鎖及び重鎖領域が切断されていない、本発明1012〜1014のいずれかの方法。
[本発明1016]
前記プロペプチドが、前記軽鎖領域に結合されたシグナルペプチドをさらに含み、前記シグナルペプチドが、真核細胞から培地への前記神経毒プロペプチドの分泌を可能にするのに適切である、本発明1012〜1015のいずれかの方法。
[本発明1017]
前記シグナルペプチドが、gp64シグナルペプチドである、本発明1016の方法。
[本発明1018]
前記プロペプチドが、前記シグナルペプチドと前記軽鎖領域との間に位置する親和性タグをさらに含む、本発明1016または本発明1017の方法。
[本発明1019]
前記親和性タグが配列番号10の配列を持つ、本発明1018の方法。
[本発明1020]
前記重鎖がトリプシン感受性の認識配列を持たない、本発明1001〜1019のいずれかの方法。
本発明は治療方法に関する。本方法は、対象に、クロストリジウム神経毒の、単離された生理学的に活性な無毒誘導体を接触させることを伴う。この接触は、神経毒誘導体がそのN末端にカーゴ付着ペプチド配列を持ないという条件で、対象を治療するために実行される。
である。カーゴ付着ペプチド配列を持つ適切なクロストリジウム神経毒プロペプチドの構造バリエーションは、参照によりその全体を本明細書に援用するIchtchenko及びBand U.S.Patent Application Publication No.2011/0206616に説明されている。本発明の方法に用いるのに適切なクロストリジウム神経毒の無毒性誘導体をコードするプロペプチドは、N末端でのカーゴ付着ペプチド配列以外の、参照によりその全体を本明細書に援用するIchtchenko及びBand U.S.Patent Application Publication No.2011/0206616に説明があるプロペプチドの構造的特徴のいずれを含んでもよい。参照によりその全体を本明細書に援用するIchtchenko及びBand U.S.Patent Application Publication No.2011/0206616で説明されているように、親和性タグの活性化及び除去のために、単一のプロテアーゼ切断ステップを用いることができる。
物質及び方法
(参照によりその全体を本明細書に援用する)Ichtchenko及びBand U.S.Patent No.7,785,606に説明のクロストリジウムボツリナムセロタイプA(「BoNT A/ad」)の無毒性誘導体を、説明に従い、発現させた。この神経毒誘導体は無毒であり、そのN末端にカーゴ付着ペプチド配列を有しないため、「BoNT A/ad−0」と呼ぶことにした。この場合、本明細書で説明するように、「ad−0」は、カーゴ部位なし(0)の無毒性誘導体を意味する。BoNT A/ad−0は、参照によりその全体を本明細書に援用するBand et al.,"Recombinant Derivatives of Botulinum Neurotoxin A Engingeered for Trafficking Studies and Neuronal Delivery," Protein Expression&Purification 71:62(2010)に説明されているように、電気泳動で均一になるよう精製し、特異的プロテアーゼ切断によって活性化させた。精製タンパク質は、安定化のための40%グリセリンを含むPBS内に10mg/mlの濃度のストックとして調製した。下記に説明の試験は、組換え分子の毒性と薬理学的活性を評価するものである。
マウス:雌のBalb/Cマウス、5〜7週齢、体重約19±3グラム。
筋肉虚弱効果によって測定される、筋肉における局所薬理学的活性を測定するために、古典的なマウス指外転評価(「DAS」)アッセイの改変を、参照によりその全体が本明細書に援用されるAoki,"Preclinical Update on BOTOX(登録商標)(Botulinum Toxin Type A)−Purified Neurotoxin Complex Relative to Other Botulinum Neurotoxin Preparations," European Journal of Neurology(1999)に説明されているように用いた。DASアッセイにおいては、特徴的驚愕反応を引き出すために短時間、マウスは尾でつるされる。その反応では、マウスは後足を伸ばして後指を外転させる。DASアッセイは、異なるBoNT製剤の筋肉虚弱効果を比較するために、特に有用である(参照によりその全体が本明細書に援用されるAoki,"Preclinical Update on BOTOX(登録商標)(Botulinum Toxin Type A)−Purified Neurotoxin Complex Relative to Other Botulinum Neurotoxin Preparations," European Journal of Neurology(1999)及びAoki,"A Comparison of the Safety Margins of Botulinum Neurotoxin Serotypes A,B,and F In Mice," Toxicon 39:1815−1820(2001))。
明確な麻痺を、二つの独立変数を使って表す。第一は、歩くのに注入された脚を使うことができない(麻痺)。第二は、注入された脚の足指を広げること(指の外転)ができない。
上記説明のBoNT A/ad−0製剤は、次の毒性試験のために使用した。試験は、野生型BoNT A(「wt BoNT A」)のための標準的なマウスLD50テストに近似するようデザインされた。
BoNT A/ad−0が、そのLD50をかなり下回る用量で薬理活性を持つかどうか、また、典型的な用量反応活性を示すかどうかを判定するために、上記説明のBoNT A/ad−0を、マウスDASでテストした。マウスの腓腹筋に、25μlハミルトンシリンジを使用して、3μlの、BoNT A/ad−0を含む0.9%NaClを注入した。投与用量は、マウスにつき投与されるμg、あるいはマウスにつき投与されるBoNT A/ad−0活性の単位で表す(表2)。
先行研究は、組換えBoNT A/adの軽鎖に導入された変異(参照によりその全体が本明細書に援用されるIchtchenko及びBand U.S.Patent Application Publication No.2011/0206616に説明されたカーゴ付着ペプチドを含む分子)が、毒素のLD50を100,000倍上昇させることを発見した。特に、各動物に繰り返し用量投与を行う2ヵ月前に、(治療薬を含まない)BoNT A/adの0.5μg(n=25)または1μg(n=15)を、脛骨筋に注射した。示した量のBoNT A/adを含む3μlからなる繰り返し用量、1μg(n=18)または2μg(n=20)を、脛骨筋に同じように注入した。これらのデータ(表4及び表5)は、繰り返し治療でBoNT A/adへの免疫耐性が発達しないことを示唆する。
Claims (20)
- クロストリジウム神経毒の、単離された、生理学的に活性な無毒誘導体を対象に接触させる段階を含み、クロストリジウム神経毒の前記誘導体が、そのN末端にカーゴ付着ペプチド配列を持たないという条件で、前記接触させる段階が、前記対象を治療するために実行される、治療方法。
- 前記神経毒誘導体が、クロストリジウムボツリナム(Clostridium botulinum)神経毒誘導体である、請求項1に記載の方法。
- クロストリジウムボツリナム神経毒誘導体が、クロストリジウムボツリナムセロタイプA、クロストリジウムボツリナムセロタイプB、クロストリジウムボツリナムセロタイプC、クロストリジウムボツリナムセロタイプD、クロストリジウムボツリナムセロタイプE、クロストリジウムボツリナムセロタイプF、及びクロストリジウムボツリナムセロタイプGからなる群より選択されるセロタイプを持つ、請求項1または請求項2に記載の方法。
- 前記神経毒誘導体が、メタロプロテアーゼ無効化変異を持つ、請求項1〜3のいずれか一項に記載の方法。
- 前記神経毒誘導体が、組換えタンパク質である、請求項1〜4のいずれか一項に記載の方法。
- 前記対象が、しわ、肥大性咬筋、及び局所多汗症からなる群より選択される皮膚科的あるいは美容的な状態に対して治療される、請求項1〜5のいずれか一項に記載の方法。
- 前記対象が、食道運動障害、咽頭食道痙攣、及び裂肛からなる群より選択される胃腸病学的な状態に対して治療される、請求項1〜6のいずれか一項に記載の方法。
- 前記対象が、尿路神経原性機能障害、過活動膀胱、及び切迫性尿失禁の神経調節からなる群より選択される尿生殖器学的な状態に対して治療される、請求項1〜7のいずれか一項に記載の方法。
- 前記対象が、トゥーレット症候群、局所の筋痙縮またはジストニア、痙性斜頚、原発性眼瞼痙攣、片側顔面痙攣、痙攣性発声障害、顔面神経障害、ラスムッセン症候群、切断痛、声の震え、ワニの涙症候群、辺縁性下顎神経麻痺、疼痛、食道由来の胸痛、頭痛、脳性麻痺、多発性硬化症の臀部内転筋機能障害、神経痛及び炎症、関節炎、医原性耳下腺唾液腺粘液腫、ならびに慢性TMJ疼痛及び転位からなる群より選択される神経学的な状態に対して治療される、請求項1〜8のいずれか一項に記載の方法。
- 前記神経毒誘導体が、野生型クロストリジウム神経毒のLD50よりも少なくとも1,000倍高いLD50を持つ、請求項1〜9のいずれか一項に記載の方法。
- 前記神経毒誘導体が、神経細胞の細胞質ゾル内に、野生型クロストリジウム神経毒に比べ、より多量に蓄積する、請求項1〜10のいずれか一項に記載の方法。
- クロストリジウム神経毒の前記誘導体が、以下のプロペプチドを切断することによって生成される、請求項1〜11のいずれか一項に記載の方法であって:
前記プロペプチドが、
軽鎖領域と、
重鎖領域と
前記軽鎖及び重鎖領域を結合し、高度に特異的なプロテアーゼ切断部位を含む中間領域と
を含み、
前記軽鎖及び重鎖領域がジスルフィド結合によって連結され、
前記高度に特異的なプロテアーゼ切断部位が、切断を可能にするために、高度に特異的なプロテアーゼによって認識される三つ以上の特異的近接アミノ酸残基を持つ、方法。 - 前記高度に特異的なプロテアーゼ切断部位が、エンテロキナーゼ切断部位及びタバコエッチ病ウイルスプロテアーゼ認識(TEV)配列から選択される、請求項12に記載の方法。
- 前記プロペプチドが、前記中間領域内に低度に特異的なプロテアーゼ切断部位を持たず、前記低度に特異的なプロテアーゼ切断部位が、切断を許容するために、プロテアーゼによって認識される二つ以下の近接アミノ酸残基を持つ、請求項12または請求項13に記載の方法。
- 前記軽鎖及び重鎖領域が切断されていない、請求項12〜14のいずれか一項に記載の方法。
- 前記プロペプチドが、前記軽鎖領域に結合されたシグナルペプチドをさらに含み、前記シグナルペプチドが、真核細胞から培地への前記神経毒プロペプチドの分泌を可能にするのに適切である、請求項12〜15のいずれか一項に記載の方法。
- 前記シグナルペプチドが、gp64シグナルペプチドである、請求項16に記載の方法。
- 前記プロペプチドが、前記シグナルペプチドと前記軽鎖領域との間に位置する親和性タグをさらに含む、請求項16または請求項17に記載の方法。
- 前記親和性タグが配列番号10の配列を持つ、請求項18に記載の方法。
- 前記重鎖がトリプシン感受性の認識配列を持たない、請求項1〜19のいずれか一項に記載の方法。
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JP2016513082A (ja) * | 2013-01-28 | 2016-05-12 | ニューヨーク・ユニバーシティ | 無毒性神経毒誘導体を用いる治療方法 |
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JP2016513082A (ja) | 2016-05-12 |
US20160296608A1 (en) | 2016-10-13 |
EP2948174A4 (en) | 2016-08-31 |
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WO2014117148A1 (en) | 2014-07-31 |
DK2948174T3 (da) | 2019-12-02 |
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JP6877780B2 (ja) | 2021-05-26 |
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