JP7370252B2 - 神経炎症性疾患の治療 - Google Patents
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Description
神経性炎症性疾患。用語「炎症性」応答は、体液性(抗体媒介性)及び/または細胞(抗原特異的T細胞またはその分泌産物により媒介される)応答の進行である。中枢神経系の炎症性脱髄性疾患は特に関心対象であり、これには、多発性硬化症(MS)、視神経脊髄炎(NO)、及び実験的後天性脳炎(EAE)が含まれるが、これに限定されない。末梢神経系の脱髄性炎症性疾患には、ギラン-バレー症候群(GBS)ならびにそのサブタイプである急性炎症性脱髄性多発根ニューロパチー、急性運動性軸索型ニューロパチー、急性運動感覚性軸索型ニューロパチー、ミラーフィッシャー症候群、及び急性汎自律神経異常症、慢性炎症性脱髄性多発神経炎(CIDP)ならびにそのサブタイプである古典的CIDP、糖尿病を伴うCIDP、CIDP/意義不明の単クローン性ガンマグロブリン血症(MGUS)、感覚性CIDP、多巣性運動ニューロパチー(MMN)、多巣性後天性脱髄性感覚運動性ニューロパチーまたはルイス・サムナー症候群、多巣性後天性感覚運動性ニューロパチー、及び遠位型後天性脱髄性感覚ニューロパチーが含まれる。従来、炎症性疾患に分類されていないが、ALSは、CD49eマクロファージ数が増加していることがわかっており、本明細書に記載する方法により治療され得る。
スタチンは、HMG-CoAレダクターゼ酵素の阻害剤であり、抗α5 剤との併用療法で、例えば、MSまたはNMOの治療のために提供され得る。スタチンには詳しい記載があり、例えば、米国特許第3,983,140号に開示のメバスタチン及び関連化合物、米国特許第4,231,938号に開示のロバスタチン(メビノリン)及び関連化合物、米国特許第4,346,227号に開示のようなプラバスタチン及び関連化合物、米国特許第4,448,784号及び第4,450,171号に開示のシンバスタチン及び関連化合物、米国特許第5,354,772号に開示のフルバスタチン及び関連化合物、米国特許第4,681,893号、第5,273,995号及び第5,969,156号に開示のアトルバスタチン及び関連化合物、ならびに米国特許第5,006,530号及び第5,177,080号に開示のセリバスタチン及び関連化合物がある。さらなる化合物は米国特許第5,208,258号、第5,130,306号、第5,116,870号、第5,049,696号、RE36,481号、及びRE36,520号に開示されている。
本開示は、多発性硬化症などの脱髄性自己免疫疾患であり得る神経性炎症性疾患を治療するための方法を提供する。方法は、対象に対し、有効量の、抗α5 剤である薬剤を単剤として、または1つ以上の追加薬剤(複数可)と組み合わせて投与することを含む。
上記で考察した化合物は、任意の好都合な添加剤、試薬及び方法を使用して製剤化することができる。組成物は、薬理学的に許容される添加剤(複数可)との製剤で提供される。多種多様な薬理学的に許容される添加剤が当該技術分野で公知であり、本明細書での詳細な考察を要しない。薬理学的に許容される添加剤はさまざまな刊行物に十分に記載されており、それらには、例えば、A.Gennaro(2000)“Remington:The Science and Practice of Pharmacy,” 20th edition,Lippincott,Williams, & Wilkins、Pharmaceutical Dosage Forms and Drug Delivery Systems(1999) H.C.Ansel et al.,eds.,7th ed.,Lippincott,Williams, & Wilkins、及びHandbook of Pharmaceutical Excipients(2000) A.H.Kibbe et al.,eds.,3rd ed.Amer.Pharmaceutical Assocなどがある。
単一細胞解析により、神経炎症対神経変性の対比モデルから骨髄細胞の鑑別的分子シグネチャーが明らかになる。
神経炎症対神経変性という2つの極性は、脳病理において非常に注目する対象である。ここでは、ハンチントン病(HD)、神経変性病態のR6/2マウスモデル、それに対する、脳の典型的炎症性疾患である多発性硬化症(MS)の実験的自己免疫性脳脊髄炎(EAE)マウスモデルにおける免疫応答の系全体にわたる分析を実施するため、不偏データ分析を行う単一細胞マスサイトメトリー(CyToF)を使用する。中枢神経系(CNS)に限定され、神経炎症性(EAE)病態及び神経変性(HD)病態のどちらにも存在する3つの骨髄細胞集団を同定した。CNSに常在する骨髄細胞由来の単球の比較対照となる血液由来単球は5つの亜集団からなり、EAEでは検出されたがHDでは検出されなかった。単一細胞分析により、EAEでは、HDと比較して、同様の骨髄系集団内部でのシグナル伝達活性及びサイトカイン産生が非常に不均衡であることが明らかにされた。神経炎症性病態では、しっかりと組織化されたシグナル伝達イベントが段階的に出現するが、神経変性病態ではこれらの同じシグナル伝達イベントが出現しない。さらに、これら2つの神経病理間には、単一細胞レベルでサイトカインプロファイルに顕著な相違があり、多機能性細胞は複数のサイトカインを同時に分泌し、EAEの神経炎症と相関した。これらの知見は、炎症性脳疾患と変性脳疾患との神経病理における相違を強調しており、これらの特定の脳病理についての選択的治療標的を明らかにしている。
異種性CNS常在骨髄系集団。神経炎症性病態及び神経変性病態での免疫応答を調べるため、これら2極の神経病理病態の例における中枢神経系(脳及び脊髄)及び末梢血に由来する単一細胞懸濁液で、細胞表現型、シグナル伝達特性、及びサイトカイン産生を分析した。マウスが振戦、不規則歩行、異常運動及び痙攣を示した時点で、MSに似た神経炎症性疾患のモデルである実験的自己免疫性脳脊髄炎(EAE)の異なる臨床病期と、ハンチントン病(HD)のモデルであるR6/2トランスジェニックマウスとを、単一細胞マスサイトメトリー(CyTOF)を用いて比較した(図1)。
マウス。雌C57BL/6JマウスをJackson Laboratory(Sacramento,CA)から7週齢で購入した。動物をStanford Universityの研究動物施設で2週間休ませ、9週齢でEAEを誘導した。雌R6/2マウスをJackson Laboratoryから7~8週齢で購入し、マウスが重度の振戦、不規則歩行、異常運動及び痙攣を発症した13週齢で回収した。動物実験は、Stanford UniversityのInstitutional Animal Care and Use CommitteeのNational Institute of Healthガイドラインにより承認されている実験であり、それらに従って実施された。全動物を12時間の明周期で飼育した。ケージあたりの最大飼育動物数はマウス5匹であった。動物を無作為に選択し、本試験で使用した。
骨髄細胞集団の概要
本明細書で論じる骨髄細胞集団の表現型は表4にまとめられている。集団A、集団B及び集団Cはミクログリア細胞に対応する。これらの集団は、ヒトの脳のCD45中間体、CD11b+細胞と同等である。
筋萎縮性側索硬化症
我々の先の試験及び他の試験から、ミクログリアは、ALS疾患のマウスモデルであり末梢血からの骨髄細胞の浸潤がないmSOD1マウスの脳及び脊髄における唯一の骨髄細胞であることが実証された(Ajami et al(2007) Nature Neuroscience 10:1538-1543、Chiu et al.(2013) Cell Reports 4(2):385-401)。さらに、いくつかの研究から、ミクログリアは、ALSの病因に関与し、ミクログリアにおける変異SODの発現を制限することで変性を遅らせ、運動mSOD発現運動ニューロンの生存を延長することが示された(Clement et al(2003) Science 302:113-117、Lino et al(2002) The Journal of Neuroscience 22(12):4825-4832)。
刺青除去
刺青除去を高めるには、100マイクログラムの抗CD49eを週3回、全身、IM、IP、皮内、またはIVで6週間投与することによって達成される。レジメンは、1週間から開始し、その後各6週間ラウンドで、複数のラウンドの治療を継続してよい。
本出願は、2017年5月30日に出願された米国仮特許出願第62/512,457号の利益を主張するものであり、その出願は参照によりその全体が本明細書に組み込まれる。
本発明は、例えば、以下の項目も提供する。
(項目1)
患者の炎症性の疾患または病態を治療するための医薬組成物であって、
治療的有効用量の抗インテグリン-α 5 剤
を含む、医薬組成物。
(項目2)
前記患者はヒトである、項目1に記載の医薬組成物。
(項目3)
前記炎症性の疾患は多発性硬化症である、項目1または2に記載の医薬組成物。
(項目4)
患者の筋萎縮性側索硬化症を治療するための医薬組成物であって、
治療的有効用量の抗インテグリン-α 5 剤
を含む、医薬組成物。
(項目5)
前記抗インテグリン-α 5 剤は、マクロファージ活性を低下させて刺青の除去を高める、項目1に記載の医薬組成物。
(項目6)
前記抗インテグリン-α 5 剤は、インテグリンα 5 のフィブロネクチンへの結合を遮断する、項目1~5のいずれか一つに記載の医薬組成物。
(項目7)
前記抗インテグリン-α 5 剤は、インテグリンα 5 、インテグリンβ 1 、またはヘテロ二量体インテグリンα 5 β 1 に特異的に結合する抗体である、項目6に記載の医薬組成物。
(項目8)
前記抗体は、インテグリンα 5 に対して特異的なキメラ型抗体もしくはヒト化抗体、またはその特異的結合断片である、項目7に記載の医薬組成物。
(項目9)
前記抗体はヒトIgG 4 Fc領域を含む、項目8に記載の医薬組成物。
(項目10)
多発性硬化症を治療するための追加の治療剤をさらに含む、項目3に記載の医薬組成物。
(項目11)
前記追加の治療剤は、スタチン、サイトカイン、フィンゴリモド、及びコパキソンからなる群から選択される、項目10に記載の医薬組成物。
(項目12)
前記サイトカインはインターフェロンベータ(IFNβ)である、項目11に記載の医薬組成物。
(項目13)
前記患者は、サイトカイン治療に対する反応性について分析され、治療剤の選択は、そのような分析に基づく、項目1に記載の医薬組成物。
(項目14)
抗α 5 剤と、前記抗α 5 剤が神経炎症性疾患または筋萎縮性側索硬化症(ALS)の治療のために患者に投与するものであることを示す添付文書またはラベルとを含む、包装体を有する、組成物。
(項目15)
患者における中枢神経系のCD49e + 骨髄細胞の活性を低下させることにより筋萎縮性側索硬化症(ALS)の臨床症状を安定化または低減させるための方法に使用するための医薬組成物であって、
前記方法は、ヒトインテグリンα 5 に特異的に結合してCD49e + 骨髄細胞の活性を低下させる遮断抗体の治療的有効用量を前記患者に投与することを含む、
使用するための医薬組成物。
(項目16)
前記患者はヒトである、項目15に記載の使用するための医薬組成物。
(項目17)
前記遮断抗体は、インテグリンα 5 に対して特異的なキメラ型抗体もしくはヒト化抗体、またはその特異的結合断片である、項目16に記載の使用するための医薬組成物。
(項目18)
前記遮断抗体はヒトIgG 4 Fc領域を含む、項目17に記載の使用するための医薬組成物。
(項目19)
前記方法は、ALSの治療のための追加の治療剤を投与することをさらに含む、項目15に記載の使用するための医薬組成物。
(項目20)
前記追加の治療剤は、リルゾールまたはエダラボンである、項目19に記載の使用するための医薬組成物。
Claims (11)
- 患者の中枢神経系の炎症性脱髄性疾患または病態を治療するための医薬組成物であって、
治療的有効用量のインテグリンα5またはヘテロ二量体インテグリンα5 β1 に特異的に結合する抗体を含み、
前記抗体は中枢神経系のCD49e+の単球系細胞の活性を低下させる
医薬組成物。 - 前記患者はヒトである、請求項1に記載の医薬組成物。
- 前記炎症性脱髄性疾患は多発性硬化症である、請求項1または2に記載の医薬組成物。
- 前記抗体は、インテグリンα5 のフィブロネクチンへの結合を遮断する、請求項1~3のいずれか一項に記載の医薬組成物。
- 前記抗体は、インテグリンα5 に対して特異的なキメラ型抗体もしくはヒト化抗体、またはその特異的結合断片である、請求項1に記載の医薬組成物。
- 前記抗体はヒトIgG4 Fc領域を含む、請求項1に記載の医薬組成物。
- 多発性硬化症を治療するための追加の治療剤をさらに含む、請求項3に記載の医薬組成物。
- 前記追加の治療剤は、スタチン、サイトカイン、フィンゴリモド、及びコパキソンからなる群から選択される、請求項7に記載の医薬組成物。
- 前記サイトカインはインターフェロンベータ(IFNβ)である、請求項8に記載の医薬組成物。
- 前記患者は、サイトカイン治療に対する反応性について分析され、治療剤の選択は、そのような分析に基づく、請求項1に記載の医薬組成物。
- インテグリンα5またはヘテロ二量体インテグリンα5 β1に特異的に結合する抗体を含み、前記抗体は中枢神経系のCD49e + の単球系細胞の活性を低下させ、中枢神経系の炎症性脱髄性疾患または病態の治療に用いるための、包装体。
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