JP2016506956A - 多発性硬化症を治療するためのPPARγアゴニスト - Google Patents
多発性硬化症を治療するためのPPARγアゴニスト Download PDFInfo
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Abstract
Description
本願は、2013年1月30日に出願された米国特許仮出願第61/758,641号の優先権を主張し、この開示は、参照により本明細書中に援用される。
再発寛解型MS(「RRMS」):「増悪」と呼ばれる予測不可能な急性の発作によって特徴付けられ、症状の悪化の後、いくらかの機能が完全に回復するか、部分的に回復するかまたは回復しない。これらの発作は、数日間から数週間にわたって展開すると見られる。発作からの回復には、数週間、時折、数ヶ月間を要する。この疾患は、発作の間の期間は悪化しない。このパターンは、通常、ほとんどの人において、MSの経過の初期に起きる。
本明細書中で使用される省略形は、別段定義されない限り、従来のものである。
PPARγを調節する公知の化合物の新しい用途がここに発見された。
INT131は、EAEの進行の強力な阻害剤である
INT131は、マウスモデルにおいて再発を減少させる
EAEは、十分に特徴付けられ、広く使用されているMSのモデルである。EAEは、このモデルにおける薬物治療活性が、ヒトの疾患における薬物の作用をしばしば模倣し、予想する数少ない動物モデルのうちの1つである。このモデルでは、中枢神経系ミエリンの詳細に明らかにされた抗原性フラグメント、例えば、プロテオリピドタンパク質(PLP)のフラグメントでマウスを免疫する。2から3週間の間に、免疫された動物は、再発/寛解型MS(RRMS)に非常によく似ている、T細胞媒介性の脳自己免疫の臨床的および病理組織学的な症候群を発症する。EAEとRRMSとの間の類似点としては、浸潤された脳の炎症応答および両方の疾患を惹起するミエリンPLPペプチドに対する付随するTh1/Th17応答ならびに疾患の再発において見られるこの後のエピトープ拡大が挙げられる。
寛解中にINT131治療を開始すると、ビヒクル/プラセボ治療と比べて、被験体が再発しないままである時間が延長される。しかしながら、寛解中は活発な神経炎症が少ないので、このパラダイムは、急性神経炎症に対するINT131の効果に関して情報価値がない。急性炎症反応に対するINT131の効果をより理解するために、本発明者らは、EAEを有するマウスをこの臨床疾患の最盛期に治療した。上で論じたように、これにより、臨床症状が迅速に改善される。疾患のピーク時にINT131で治療されたマウス由来の神経組織の検査から、ビヒクルで治療された動物由来の神経組織において観察される豊富な白血球浸潤と比べて、INT131で治療された組織における、浸潤しているCD45陽性白血球の欠乏が証明される(図1および2)。
中枢神経系におけるバイオアベイラビリティ
背景
血液脳関門(「BBB」)は、ほとんどの高分子および血液由来細胞の流入が脳に入るのを妨げる拡散バリアおよび物理的な篩として作用する物理的/生化学的な障害物である。BBBは、内皮細胞、アストロサイトエンドフィートおよび周皮細胞を含む、BBBを構成する3つの異なる細胞成分の物理的相互作用によって形成される。BBBの拡散バリア機能は、脳内皮細胞の間に形成しているタイトジャンクションに依存し、ほとんどの血液由来物質が脳に入るのを選択的に遮断する。Ballabh,P.et al.,The blood−brain barrier:an overview:structure,regulation,and clinical implications,Neurobiol Dis,2004,June,16(1),1−13。MSの再発中に起きる急性炎症の状況では、病変の近くのBBBは分解し、免疫調節性高分子と白血球の両方が病変部位に流入し、炎症過程がさらに推進される。Minagar A.et al.,Blood−brain barrier disruption in multiple sclerosis,Multi Scler,2003,Dec.,9(6),540−549。
INT131が、インタクトなBBBを貫通することができるかを試験するために、INT131をトリチウムで放射標識した後(「[3H]INT131」)、成体のSprague−Dawleyラットに腹腔内注射した。放射標識されたINT131の純度を、注射の前および実験の終了時に再度、高速液体クロマトグラフィー(HPLC)分画によって測定した。両方の時点において、放射標識された材料の実質的にすべてが、単一のピークで見られたことから、この研究の経過にわたる[3H]INT131の安定性が証明された。50mg/kgのINT131の注射によって、1000μCi/kgの標識された薬物が各動物に投与されるように、試験動物に注射するときに、標識されたINT131を、標識されていないINT131と混合した。これらの試験動物を、注射の1、6および24時間後に屠殺し、液体シンチグラフィー(scintillography)による[3H]INT131含有量の測定のために、血液、脳、脳脊髄液(「CSF」)、脊髄、腎臓、肝臓および小腸を回収した。
表1には、解析されたすべての組織におけるINT131の濃度が列挙されている。約50mg/kgの[3H]INT131の単回投与の1時間後、神経コンパートメントにおけるINT131の平均量は、脳組織1グラムあたり0.5μg未満であり、これは、循環中に見られる量よりもおよそ10倍少なかった。対照的に、6および24時間後、神経組織におけるINT131の量は、およそ10倍増加した。この神経組織における薬物蓄積の遅延は、BBBを横断する薬物の能動輸送と矛盾がない。
神経保護
皮質および皮質下の灰白質の萎縮が、MSの全ステージにおいて見られるが、しかしながら、最近になって、MSの初期段階におけるこの疾患の進行の高感度で信頼できるマーカーとして、視床の減少が登場した。1または3mgのINT131の添加により、さらなる萎縮から視床が残ると予想される。この結果、INT131は、MSにおける灰白質萎縮に対して臨床的に証明された最初の薬物になるだろう。
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JP2019531286A (ja) * | 2016-09-13 | 2019-10-31 | インテクリン セラピューティクス インコーポレイテッド | Chs−131による多発性硬化症の治療 |
JP2020515639A (ja) * | 2017-04-03 | 2020-05-28 | コヒラス・バイオサイエンシズ・インコーポレイテッド | 進行性核上性麻痺の処置のためのPPARγアゴニスト |
US11400072B2 (en) | 2015-03-09 | 2022-08-02 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
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KR20190064573A (ko) * | 2016-08-18 | 2019-06-10 | 인테크린 테라퓨틱스, 아이엔씨. | 혈액 암 치료용 PPARγ 작용제 |
CA3033971A1 (en) * | 2016-08-18 | 2018-02-22 | Intekrin Therapeutics, Inc. | Ppar.gamma. agonist for treatment of bone disorders |
EA201992364A1 (ru) * | 2018-04-02 | 2020-03-23 | Кохерус Байосайенсис Инк. | АГОНИСТ PPARγ ДЛЯ ЛЕЧЕНИЯ ПРОГРЕССИРУЮЩЕГО НАДЪЯДЕРНОГО ПАРАЛИЧА |
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US11400072B2 (en) | 2015-03-09 | 2022-08-02 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
JP2019531286A (ja) * | 2016-09-13 | 2019-10-31 | インテクリン セラピューティクス インコーポレイテッド | Chs−131による多発性硬化症の治療 |
CN110461318A (zh) * | 2016-09-13 | 2019-11-15 | 因特克林治疗股份有限公司 | 用chs-131治疗多发性硬化 |
JP2020515639A (ja) * | 2017-04-03 | 2020-05-28 | コヒラス・バイオサイエンシズ・インコーポレイテッド | 進行性核上性麻痺の処置のためのPPARγアゴニスト |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
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