JP2020534337A - オートファジーをモジュレーションするための方法及び医薬組成物 - Google Patents
オートファジーをモジュレーションするための方法及び医薬組成物 Download PDFInfo
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Abstract
Description
本発明は、オートファジーをモジュレーションするための方法及び医薬組成物に関する。
オートファジー(「自食」)は、細胞生物学における微妙に制御されているが最も壮観な現象の1つであり、細胞質構造のターンオーバーを促進し、栄養不足を含む変化するストレス条件への細胞の適応を可能にすることにより、細胞及び生物の恒常性の維持において重要な役割を果たす(1、2)。いくつかのリーダーレスタンパク質(これは、ゴルジを回避する非従来型経路を介してのみ放出され得る)の細胞分泌は、オートファジーと強く関連する(3〜7)。1つのこのようなタンパク質は、ジアゼパム結合タンパク質(DBI)又はアシル補酵素A(CoA)結合タンパク質(ACBP)として公知の系統発生学的に古い因子である(3、4)。ヒト又はマウスDBIは、すなわち、細胞内(それが長鎖アシルCoA分子に結合する場所)ではACBPとして、及び細胞外(タンパク質全体又はその分解生成物であるトリアコンタテトラニューロペプチド[TTN、残基17〜50]及びオクタデカニューロプチド[ODN、残基33〜50]が、γ−アミノ酪酸タイプAレセプターGABAARのベンゾジアゼピン結合部位と相互作用し、GTPタンパク質共役レセプターGPCRとしてその活性をモジュレーションし得る場所)ではDBIとして、2つの全く異なる機能を有する87アミノ酸の小さなタンパク質(10kDa)である(8〜10)。DBI及びそのタンパク質分解フラグメントはまた、末梢型ベンゾジアゼピンレセプター(PBR)(11〜13)及び未だ同定されていないGPCR(ODN−GPCR)(14〜17)に結合する。しかしながら、オートファジーのフィードバックレギュレーションにおけるDBI分泌の役割は調査されていない。
オートファジーは、典型的には、飢餓により活性化され、細胞及び生物がエネルギー貯蔵を動員することを可能にする。本明細書では、本発明者らは、非従来型のオートファジー非依存的な方法で細胞から放出されるタンパク質、すなわちアシル補酵素A結合タンパク質(ACBP)としても公知のジアゼパム結合インヒビター(DBI)が、3つのレベルでオートファジーをレギュレーションすることを報告する。第1に、オートファジーはDBI分泌を引き起こし、細胞からこのオートファジー促進因子を枯渇させる(オートクリンレギュレーション)。第2に、オートファジーは、細胞外空間におけるDBIの蓄積を引き起こし、DBIが他の細胞に対して作用してオートファジーを阻害することを可能にする(パラクリンレギュレーション)。第3に、循環DBIは摂食行動を刺激するので、オートファジー誘導の主な原因を除去する(エンドクリンレギュレーション)。ヒトでは、血漿DBIレベルは肥満で増加する。マウスへのリコンビナントDBIの追加供給は、解糖を増強し、脂質生成を増強し、脂肪酸酸化を阻害した。本発明者らはまた、自己抗体を誘発する免疫原性DBI誘導体により、DBIを中和するための3つの戦略、すなわち、誘導性全身ノックアウト、受動免疫及び能動免疫を設計した。これらの戦略は、飢餓誘導性体重減少を増加させ、再給餌による食物摂取を減少させる代謝変化を促す。
本明細書で使用される場合、「被験体」、「個体」又は「患者」という用語は互換的に使用され、診断、処置又は治療が望まれる任意の被験体、特にヒトを指す。他の被験体としては、ウシ、イヌ、ネコ、モルモット、ウサギ、ラット、マウス、ウマなどが挙げられ得る。いくつかの好ましい実施態様では、被験体はヒトである。
したがって、本発明の第1の目的は、それを必要とする被験体におけるオートファジーを阻害する方法であって、DBIの活性又は発現を促進する治療有効量の薬剤を前記被験体に投与することを含む方法に関する。
いくつかの実施態様では、DBIの活性を促進する薬剤は、配列番号1の配列又はそのフラグメントと少なくとも80%の同一性を有するポリペプチドである。
−配列番号1と少なくとも80%の同一性を有するアミノ酸配列、又は
−配列番号1の17位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列、又は
−配列番号1の33位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列、又は
−配列番号1の43位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列
を含むポリペプチドからなる。
したがって、本発明の第1の目的は、それを必要とする被験体におけるオートファジーを刺激する方法であって、DBIの活性又は発現を阻害する治療有効量の薬剤を前記被験体に投与することを含む方法に関する。
いくつかの実施態様では、DBIの活性を阻害する薬剤は、DBIに対する抗体である。
DBIの活性又は発現をモジュレーションする(すなわち、促進又は阻害する)薬剤は、医薬組成物の形態で被験体に投与される。典型的には、治療用組成物を形成するために、本発明の薬剤は、薬学的に許容し得る賦形剤及び場合により持続放出マトリックス、例えば生分解性ポリマーと組み合わされ得る。「薬学的に」又は「薬学的に許容し得る」は、哺乳動物に、特に必要に応じてヒトに投与された場合に、有害な、アレルギー性の又は他の望まれない反応を生成しない分子実体及び組成物を指す。薬学的に許容し得る担体又は賦形剤は、任意の種類の非毒性固体、半固体又は液体充填剤、希釈剤、封入材料又は製剤助剤を指す。経口投与、舌下投与、皮下投与、筋肉内投与、静脈内投与、経皮投与、局所投与又は直腸投与のための本発明の医薬組成物では、有効成分は単独で、又は別の有効成分と組み合わせて、従来の医薬支持体との混合物として、単位投与形態で被験体に投与され得る。適切な単位投与形態は、錠剤、ゲルカプセル剤、粉末剤、顆粒剤及び経口懸濁剤又は溶液などの経口経路形態、舌下及び口腔内投与形態、エアロゾル、インプラント、皮下、経皮、局所、腹腔内、筋肉内、静脈内、皮下、経皮、髄腔内及び鼻腔内投与形態並びに直腸投与形態を含む。典型的には、医薬組成物は、注射されることができる製剤のための薬学的に許容し得るビヒクルを含有する。これらは特に、等張性滅菌生理食塩水溶液(一ナトリウム若しくは二ナトリウムのリン酸塩、ナトリウム、カリウム、カルシウム若しくはマグネシウムの塩化物など、又はこのような塩の混合物)、又は場合に応じて、滅菌水又は生理食塩水の添加により注射液の構成を可能にする乾燥組成物、特に凍結乾燥組成物であり得る。注射用途に適切な医薬形態としては、滅菌水溶溶液又は分散液;ゴマ油、落花生油又は水性プロピレングリコールを含む製剤;及び滅菌注射液又は分散液の即時調製のための滅菌粉末が挙げられる。全ての場合において、前記形態は滅菌されてなければならず、容易な注射可能性が存在する程度に流動性でなければならない。それは、製造及び保存の条件下で安定でなければならず、細菌及び真菌などの微生物の汚染作用に対して保全されなければならない。遊離塩基又は薬理学的に許容し得る塩として本発明の化合物を含む溶液は、ヒドロキシプロピルセルロースなどの界面活性剤と適切に混合された水中で調製され得る。分散液はまた、グリセロール、液体ポリエチレングリコール及びこれらの混合物中、並びに油中で調製され得る。保存及び使用の通常の条件下では、微生物の成長を防止するために、これらの調製剤は保存剤を含有する。本発明の薬剤は、中性又は塩形態の組成物に製剤化され得る。(タンパク質の遊離アミノ基で形成される)薬学的に許容し得る塩は、例えば塩酸若しくはリン酸などの無機酸と、又は酢酸、シュウ酸、酒石酸、マンデル酸などの有機酸と形成される酸付加塩を含む。遊離カルボキシル基で形成される塩はまた、例えばナトリウム、カリウム、アンモニウム、カルシウム又は第2鉄の水酸化物などの無機塩基、及びイソプロピルアミン、トリメチルアミン、ヒスチジン、プロカインなどの有機塩基に由来するものであり得る。担体はまた、例えば、水、エタノール、ポリオール(例えば、グリセロール、プロピレングリコール及び液体ポリエチレングリコールなど)、これらの適切な混合物、及び植物油を含有する溶媒又は分散媒体であり得る。適切な流動性は、例えば、レシチンなどのコーティングの使用により、分散液の場合には必要な粒度の保持により、及び界面活性剤の使用により維持され得る。微生物作用の防止は、様々な抗菌剤及び抗真菌剤、例えばパラベン、クロロブタノール、フェノール、ソルビン酸、チメロサールなどによりもたらされ得る。多くの場合に応じて、等張剤、例えば糖又は塩化ナトリウムを含めることが好ましいであろう。注射用組成物の持続吸収は、吸収を遅延させる薬剤、例えばモノステアリン酸アルミニウム及びゼラチンを組成物で使用することによりもたらされ得る。滅菌注射液は、必要に応じて前掲のいくつかの他の成分と共に適切な溶媒中に、必要量の活性化合物を取り込ませ、その後、濾過滅菌することにより調製される。一般に、分散液は、基本分散媒体及び前掲のものからの他の必要成分を含有する滅菌のビヒクル中に、様々な滅菌された有効成分を取り込ませることにより調製される。滅菌注射液の調製のための滅菌粉末の場合、好ましい調製方法は、有効成分プラス任意のさらなる所望の成分の粉末を、予め滅菌濾過されたその溶液から生成する真空乾燥及び凍結乾燥技術である。直接注射のためのより濃縮された又は高度に濃縮された溶液の調製も企図され、この場合、極めて迅速な浸透をもたらして、高濃度の活性薬剤を小さな腫瘍領域に送達するために、溶媒としてのDMSOの使用が想定される。製剤化により、溶液は、投与製剤に適合する方法で、治療上有効である量で投与されるであろう。製剤は、上記注射液のタイプなどの様々な剤形で容易に投与されるが、薬物放出カプセルなども用いられ得る。水溶液による非経口投与のために、例えば、溶液は、必要に応じて適切に緩衝化されるべきであり、最初に、十分な生理食塩水又はグルコースで液体希釈剤は等張にされる。これらの特定の水溶液は、静脈内投与、筋肉内投与、皮下投与及び腹腔内投与に特に適切である。これに関して、用いられ得る滅菌水性媒体は、本開示を考慮して当業者には公知であるであろう。投与量の変動は、処置されている被験体の状態に応じて必ず生じるであろう。投与責任者は、いずれにせよ、個々の被験体のための適切な用量を決定するであろう。
本発明のさらなる目的は、オートファジーをモジュレーションするために適切な化合物をスクリーニングする方法であって、i)候補化合物を提供すること、ii)前記候補化合物がDBIの活性又は発現をモジュレーションすることができるかを決定すること、及びiii)DBIの活性又は発現をモジュレーションすることができる前記候補化合物をポジティブ選択することを含む方法に関する。
本発明のさらなる目的は、被験体が体重モジュレーションのリスクがあるかを決定する方法であって、i)前記被験体から得られた血液サンプル中のDBIのレベルを決定すること、ii)工程i)において決定した前記レベルを所定の基準値と比較すること、及びiii)工程i)において決定した前記レベルと前記所定の基準値との間の差が決定された場合、前記被験体が体重モジュレーションのリスクがあると結論することを含む方法に関する。
化学物質、細胞株及び培養条件。
特に指定がない限り、細胞培養のための培地及びサプリメントはGibco-Invitrogen (Carlsbad, CA, USA)から購入し、プラスチックはCorning B.V. Life Sciences (Schiphol-Rijk, The Netherlands)から購入し、化学物質はSigma-Aldrich (St Louis, MO, USA)から購入した。全ての細胞株を、10%ウシ胎仔血清、100mg/Lピルビン酸ナトリウム、10mM HEPESバッファー、100単位/mLペニシリンGナトリウム及び100μg/mL硫酸ストレプトマイシンを含有する培地中、5%CO2下、37℃で培養した。加えて、ヒト子宮頸ガンHeLa細胞及びヒト脳神経膠腫H4細胞並びにそれらのGFP−LC3発現誘導体の場合には、細胞型特異的培養条件はダルベッコ改変イーグル培地(DMEM)を含む。ヒト肝細胞ガンHepG2細胞の場合には、最小必須培地イーグル(EMEM)を上記のように補充し、2mMグルタミン及び1%非必須アミノ酸(NEAA)を加えた。細胞を、6ウェルプレート、94ウェルプレートに播種し、24時間成長させてから、指定の期間にわたって単独で及び/又は50nMバフィロマイシンA1(BafA1、Tocris)、100nMラパマイシン(Rapa)、DBIに対する抗体(antiDBI)、リコンビナントタンパク質DBI(recDBI)と組み合わせて処理した。血清及び栄養枯渇(NF)では、細胞を、無血清ハンクス平衡塩溶液(HBSS)中で培養した。
オートファジー(「自食」)は、細胞生物学における微妙にレギュレーションされているが最も壮観な現象の1つであり、細胞質構造のターンオーバーを促進し、栄養不足を含む変化するストレス条件への細胞の適応を可能にすることにより、細胞及び生物の恒常性の維持において重要な役割を果たす(1、2)。いくつかのリーダーレスタンパク質(これは、ゴルジを回避する非従来型経路を介してのみ放出され得る)の細胞分泌は、オートファジーと強く関連する(3〜7)。1つのこのようなタンパク質は、ジアゼパム結合タンパク質(DBI)又はアシル補酵素A(CoA)結合タンパク質(ACBP)として公知の系統発生学的に古い因子である(3、4)。ヒト又はマウスDBIは、すなわち、細胞内(それが長鎖アシルCoA分子に結合する場所)ではACBPとして、及び細胞外(タンパク質全体又はその分解生成物であるトリアコンタテトラニューロペプチド[TTN、残基17〜50]及びオクタデカニューロプチド[ODN、残基33〜50]が、γ−アミノ酪酸タイプAレセプターGABAARのベンゾジアゼピン結合部位と相互作用し、GTPタンパク質共役レセプターGPCRとしてその活性をモジュレーションし得る場所)ではDBIとして、2つの全く異なる機能を有する87アミノ酸の小さなタンパク質(10kDa)である(8〜10)。DBI及びそのタンパク質分解フラグメントはまた、末梢型ベンゾジアゼピンレセプター(PBR)(11〜13)及び未だ同定されていないGPCR(ODN−GPCR)(14〜17)に結合する。今回、本発明者らは、DBI分泌がオートファジーのフィードバックレギュレーションに関与し得るかという問題に取り組んだ。
Claims (27)
- それを必要とする被験体におけるオートファジーを阻害する方法であって、DBIの活性又は発現を促進する治療有効量の薬剤を前記被験体に投与することを含む、方法。
- 前記被験体が低体重である、請求項1に記載の方法。
- 前記被験体が消耗障害を患っている、請求項2に記載の方法。
- 前記被験体が、食欲不振悪液質、高齢食欲不振、神経性食欲不振、ガンに関連する悪液質、AIDSに関連する悪液質、心不全に関連する悪液質、嚢胞性線維症に関連する悪液質、関節リウマチに関連する悪液質、腎疾患に関連する悪液質、慢性閉塞性肺疾患(COPD)に関連する悪液質、ALSに関連する悪液質、腎不全に関連する悪液質又は関連悪液質、並びに異常な食欲、体脂肪、エネルギーバランス及び/又は意図的ではない体重減少に関連する他の障害を患っている、請求項2に記載の方法。
- 前記被験体が、ガン疾患、神経変性疾患、心血管疾患、感染性疾患、自己免疫疾患及び/又は炎症性疾患からなる群より選択される疾患を患っている、請求項1に記載の方法。
- DBIの活性を促進する前記薬剤が、i)配列番号1と少なくとも80%の同一性を有するアミノ酸配列、又はii)配列番号1の17位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列、又はiii)配列番号1の33位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列、又はiv)配列番号1の43位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列を含むポリペプチドからなる、請求項1に記載の方法。
- DBIの発現を促進する前記薬剤が、請求項6の前記ポリペプチドをコードする核酸分子である、請求項1に記載の方法。
- 前記核酸分子が、配列番号2と少なくとも50%の同一性を有する核酸配列を含む、請求項7に記載の方法。
- DBIの活性を促進する前記薬剤が、DBIの活性を模倣する小有機分子又はペプチド模倣物である、請求項1に記載の方法。
- それを必要とする被験体におけるオートファジーを刺激する方法であって、DBIの活性又は発現を阻害する治療有効量の薬剤を前記被験体に投与することを含む、方法。
- 前記被験体が過体重である、請求項10に記載の方法。
- 前記被験体が肥満を患っている、請求項11に記載の方法。
- 前記被験体が2型糖尿病又はメタボリックシンドロームを患っている、請求項10に記載の方法。
- 前記被験体が、ガン、神経変性疾患、感染性疾患、肺気腫といった肺疾患、嚢胞性線維症、肝疾患、膵炎又はタンパク質症を患っている、請求項10に記載の方法。
- DBIの活性又は発現を阻害する治療有効量の前記薬剤及び治療有効量の化学療法剤を、ガンを患っている前記被験体に投与することを含み、前記化学療法剤の前に、DBIの活性又は発現を阻害する前記薬剤を投与する、請求項14に記載の方法。
- DBIの活性を阻害する前記薬剤が、DBIに対する抗体又はアプタマーである、請求項10に記載の方法。
- 前記抗体が、43位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列からなるフラグメントに対するものである、請求項16に記載の方法。
- 前記抗体が、モノクローナルキメラ抗体、モノクローナルヒト化抗体又はモノクローナルヒト抗体である、請求項16に記載の方法。
- DBIの発現を阻害する前記薬剤が、siRNA、エンドヌクレアーゼ、アンチセンスオリゴヌクレオチド又はリボザイムといった発現の阻害剤である、請求項10に記載の方法。
- DBIの活性を阻害する前記薬剤が、前記被験体に投与された場合に、DBIに対する自己抗体の中和を誘発するために適切なワクチン組成物からなる、請求項10に記載の方法。
- 前記ワクチン組成物が、i)配列番号1と少なくとも80%の同一性を有するアミノ酸配列、又はii)配列番号1の17位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列、又はiii)配列番号1の33位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列、又はiv)配列番号1の43位のアミノ酸残基から50位のアミノ酸残基の範囲のアミノ酸配列と少なくとも80%の同一性を有するアミノ酸配列を含むポリペプチドからなる抗原を含む、請求項10に記載の方法。
- 前記ポリペプチドが、前記ワクチンに対する強力な免疫反応を誘発するために一般に十分に外来性である担体タンパク質にコンジュゲートされている、請求項10に記載の方法。
- 前記ワクチン組成物がアジュバントを含む、請求項10に記載の方法。
- オートファジーをモジュレーションするために適切な化合物をスクリーニングする方法であって、i)候補化合物を提供すること、ii)前記候補化合物がDBIの活性又は発現をモジュレーションすることができるかを決定すること、及びiii)DBIの活性又は発現をモジュレーションすることができる前記候補化合物をポジティブ選択することを含む、方法。
- 被験体が体重モジュレーションのリスクがあるかを決定する方法であって、i)前記被験体から得られた血液サンプル中のDBIのレベルを決定すること、ii)工程i)において決定した前記レベルを所定の基準値と比較すること、及びiii)工程i)において決定した前記レベルと前記所定の基準値との間の差が決定された場合、前記被験体が体重モジュレーションのリスクがあると結論することを含む、方法。
- それを必要とする被験体における非アルコール性脂肪肝疾患(NAFLD)を処置する方法であって、DBIの活性又は発現を阻害する治療有効量の薬剤を前記被験体に投与することを含む、方法。
- 前記NAFLDが非アルコール性脂肪性肝炎(NASH)である、請求項26に記載の方法。
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