JP2020525554A - アルファ−プロテインキナーゼ1を阻害することにより炎症ならびに関連した疾患および障害を処置するための方法 - Google Patents
アルファ−プロテインキナーゼ1を阻害することにより炎症ならびに関連した疾患および障害を処置するための方法 Download PDFInfo
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Abstract
Description
[15]実施形態において、ALPK1阻害剤は、ALPK1アンチセンスポリヌクレオチドである。実施形態において、ALPK1阻害剤は、マイクロRNA(miRNA)、低分子干渉RNA(siRNA)、および低分子ヘアピン型RNA(shRNA)からなる群から選択されるALPK1に方向付けられた干渉RNAである。
[19]方法が自己免疫疾患を処置するための方法である実施形態において、自己免疫疾患は、全身性血管炎、糸球体腎炎(連鎖球菌感染後糸球体腎炎)、シェーグレン症候群、乾癬性関節炎、痛風、痛風性関節炎、反応性関節炎、敗血症性ショック、グレーブス病、グッドパスチャー症候群、重症筋無力症、自己免疫性溶血性貧血、特発性血小板減少性紫斑病、自己免疫性筋炎、悪性貧血、セリアック病、湿疹、自己免疫性甲状腺炎、自己免疫性心筋炎、セリアック病、若年性特発性関節炎、グレーブス眼症、リウマチ性多発筋痛症、自己免疫性ぶどう膜炎(uveoitis)、円形脱毛症、ウェゲナー、白斑、原発性硬化性胆管炎、原発性胆汁性肝硬変、自己免疫性肝炎、ギラン・バレー症候群、抗リン脂質抗体症候群、サルコイドーシス疼痛、円形脱毛症、ランバート・イートン筋無力症症候群、自己免疫性溶血性貧血、寒冷凝集素症、温式自己免疫性溶血性貧血、多発性血管炎を伴う好酸球性肉芽腫症(チャーグ・シュトラウス症候群)、およびベーチェット病から選択され得る。
1〜92:MNNQKVVAVL...VIGAGLQQLL → MCRKRTRARTSAAE
[39]実施形態において、炎症性疾患または障害は、炎症促進性サイトカインの過剰産生による、炎症性腸疾患、関節炎、肥満症、痛風、放射線誘発性炎症、乾癬、心血管疾患、糖尿病、肺、結腸、および乳房の癌を含む上皮癌、T細胞媒介性過敏性疾患、アレルギー性疾患、ならびにアトピー性皮膚炎から選択される。
[67]本発明はさらに、以下の非限定的実施例により記載および例示される。
実施例1
不活化ALPK1変異は、DSS誘導性大腸炎に対する抵抗性を与える
[69]デキストラン硫酸ナトリウム(DSS)誘導性大腸炎のマウスモデルを用いて、ALPK1の不活化変異による阻害(エクソン13の前の1個およびエクソン13の後の1個である、イントロンにおける2個の部位をターゲットするCRISPRベクターを、マウス受精胚へ注射して、エクソン13が欠失したALPK1マウス変異体を作製した。ALPK1のキナーゼドメインの一部分をコードするエクソン13の欠失は、ALPKのキナーゼ活性を殺す)が、潰瘍性大腸炎およびクローン病などの炎症性腸疾患を改善することができるかどうかを評価した。DSS処理は、結腸上皮細胞の破壊を引き起こし、大腸炎を誘導し、それは、次に、体重減少を引き起こす。体重減少を、疾患進行の指標として用いた。このモデル系は、以前に、例えば、Okayasu Hら、1990に記載されている。簡単に述べれば、8〜9週齢の雌マウスを、オートクレーブされた飲料水中に溶解された2%DSS(MW 40K〜50K、MP BIOANALYTICAL)で、7日間、処理した。マウスの体重を毎日および試験期間の終わりに、計量した。全データを、平均値±平均値の標準誤差(SEM)として表した。実験群は、ALPK1野生型(WT)(n=3);ヘテロ接合性(HE)不活化ALPK1変異(n=2);およびホモ接合性(HO)不活化ALPK1変異(n=3)であった。
実施例2
不活化ALPK1変異は、放射線誘発性炎症に対する抵抗性を与える
[71]放射線誘発性炎症のマウスモデルを用いて、ALPK1の不活化変異による阻害が放射線誘発性炎症を改善することができるかどうかを評価した。放射線は、免疫系を刺激して、炎症応答を活性化する。このモデル系は、以前に、例えば、Biju Gら、2012に記載されている。簡単に述べれば、8〜9週齢雌マウスに、1日目に1回、マウスあたり9グレイ(Gy)全身照射(Co60からのガンマ線)を照射した。動物生存率および体重を毎日測定した。放射線は、胃腸系および造血系の損傷を引き起こした。免疫系不全と組み合わされた腸管内菌叢の移行は、敗血症および死をもたらし得る。
不活化ALPK1変異は、高脂肪食誘導性肥満に対する抵抗性を与える
[73]高脂肪食誘導性肥満のマウスモデルを用いて、ALPK1の不活性化変異による阻害が、このモデル系において炎症を改善することができるかどうかを評価した。肥満は、代謝性疾患の発生の原因となる炎症性成分の存在を多くの慢性疾患と共有する。この炎症状態は、炎症促進性タンパク質の循環レベルの増加に反映される。高脂肪食(HFD)摂食は、ヒトメタボリックシンドロームに似ている、げっ歯類における肥満および代謝障害を誘導し得る。このモデル系は、以前に、例えば、Bourgeois Aら、1983;Takahashi Iら、1999に記載されている。簡単に述べれば、8〜9週齢雄マウスを、0日目からHFD(60%脂肪、Research Diets Inc.、New Brunswick、NJ)で処理した。体重を、HFD後1日目から84日目まで毎週、測定した。パーセンテージ体重増加(%g)を、平均値±標準偏差(SD)として表した。
不活化ALPK1変異は、コラーゲン誘導性関節炎に対する抵抗性を与える
[75]コラーゲン誘導性関節炎のマウスモデルを用いて、ALPK1の不活性化変異による阻害が、このモデル系において炎症を改善することができるかどうかを評価した。関節リウマチは、身体の過敏な免疫系が、関節内層および軟骨などの身体自体の組織を攻撃する、炎症性免疫過程として認識されている。炎症は、関節リウマチによく見られる疼痛および腫脹を引き起こし得る。このモデル系は、以前に、例えば、Campbell Hら、2000に記載されている。簡単に述べれば、8週齢雄マウスを、1つの後足の足蹠上での皮下注射による、20μlウシII型コラーゲン(免疫化グレード ウシII型コラーゲン、溶液(Chondrex、カタログ番号20022)および完全フロイントアジュバント(CFA、4mg/mlにおける不活性化Mycobacterium tuberculosis H37Ra(Chondrex、カタログ番号7001))(両方について1mg/ml最終濃度)で処理し、その他の足に、対照の20μl PBSを注射した。ウシII型コラーゲンは、炎症による足腫脹を誘導する。マウスを、関節リウマチスコアについて評価し、足腫脹についての足厚さを、コラーゲン注射から25日後まで1日おきに測定した。関節リウマチ(RA)スコアは、0〜16のスケール上での全ての4つの足スコアの合計であり、各足は、以下のようにスコアリングされる:
スコア0 − 正常な足;
スコア1 − 1つの爪先が炎症かつ腫大している;
スコア2 − 1つより多い爪先が、足全体ではないが、炎症かつ腫大している、または足全体の軽度の腫脹;
スコア3 − 足全体が炎症かつ腫大している;および
スコア4 − 非常に炎症かつ腫大した、または強直した(硬直した、または運動不能の)足。
ALPK1ノックダウンは、様々なヒトおよびマウス細胞において炎症促進性サイトカインの発現を阻害する
[77]結果は、表1に要約されており、下記でより詳細に記載されている。
[78]Lipofectamine(登録商標)RNAiMAX試薬(Life Technologies Corporation、Grand Island、NY)を用いて、HEK293T細胞にsiRNA(ALPK1−siRNA−1、ALPK1−siRNA−2、スクランブルsiRNA)をトランスフェクションした。トランスフェクション後42時間目において、HEK293T細胞を、Trizol試薬(Life Technologies Corporation)を用いて、RNA抽出のために収集した。PrimeScript(商標)RT試薬キット(Takara Bio Inc.、#RR037A)を用いて、RNAをcDNAに逆転写し、Applied Biosystems(商標)QuantStudio(商標)7 FlexリアルタイムPCRシステム(Life Technologies Corporation)においてSYBR Green I試薬を用いてqPCRにより測定した。ALPK1、IL−10、IL−1β、IL−6、IL−8、およびTNF−αのそれぞれの遺伝子発現を、GAPDHに対して標準化した。これらの炎症促進性サイトカインの全ての5つの発現は、ALPK1ノックダウンにより減少した(図5)。
・N末端において1*Flagでタグ付けされたALPK1(Flag−ALPK1)
・マウスC末端HA−タグ付けALPK1(マウスALPK1)
・N末端において6*Hisタグで、およびC末端において3*Flagでタグ付けされたALPK1(6*His−ALPK1−3*Flag)
・N末端において6*Hisタグでタグ付けされたALPK1(6*His−ALPK1)
・6*His−ALPK1のE1190A変異体(6*His−ALPK1−E変異体)。
[81]CRISPR HEK293T細胞を、ALPK1のエクソン3へのターゲティング配列およびALPK1のエクソン14へのターゲティング配列を含有するCRISPRv1.0のトランスフェクションにより作製した。トランスフェクションから1日後、HEK293T細胞を、2.5μg/mlピューロマイシン上で3日間、選択した。単一コロニーを増殖して、安定発現株を作製した。NF−κβシグナル伝達を、HEK293T細胞のS.flexneri細胞可溶化物での処理により活性化した。1%S.flexneri細胞可溶化物の4時間の処理後、293T細胞を、mRNA発現の分析のために、Trizol試薬(LIFE)を用いて、収集した。ALPK1、IL−10、IL−1β、IL−6、IL−8、およびTNF−αのmRNAレベルを、GAPDH発現に対して標準化した(図7A)。上清HEK293T細胞培養物におけるIL−8分泌を、ヒトIL−8 ELISAキット(BD Biosciences)を用いて測定した(図7B)。
[82]S.flexneri細胞可溶化物(SFL)およびS.typhimurium細胞可溶化物(STL)は、HEK293細胞において、炎症促進性サイトカインIL6、IL8、およびTNFαの発現を誘導し得る。ALPK1のsiRNAによるノックダウンは、これらのサイトカインの全ての3つの発現を減少させる(図8)。siRNAは、上記の5Aにおいて記載されている通りであった。
[83]THP−1細胞を、ALPK1に方向付けられたshRNA−1190、ALPK1に方向付けられたshRNA−2027、またはヌルベクター(Neg)を有するレンチウイルスに5日間、感染させ、ピューロマイシンを用いることにより選択した。PMA(50ng/ml)を加えて、マクロファージ分化を2日間、誘導し、LPS(10ng/ml)を加えて、NFκβ経路を誘導した。LPSで刺激された細胞(図9A)と刺激されていない細胞(図9B)のどちらにおいても、IL1β、IL−8、およびTNFαの発現は、ALPK1のshRNAノックダウンにより低下した。アクチン(actb)およびGADPH(gadph)の発現もまた、示されている。
[84]THP−1細胞を、PMA(50ng/ml)により2〜6日間、分化型マクロファージへ誘導した時、THP−1マクロファージにおけるALPK1のshRNAによるノックダウンは、LPS(10ng/ml)誘導によるTNFα(図10A)およびIL1β(図10B)の分泌の阻害をもたらす。
[85]乳癌細胞株MDA−MB−468におけるsiRNAによるALPK1ノックダウンは、IL1β、IL8、およびTNFαの発現の減少を生じた(図11)。
[86]マウスマクロファージ細胞株RAW264.7におけるshRNAによるALPK1ノックダウンは、LPS(100ng/ml)刺激の有り(図12A)無し(図12B)に関わらず、サイトカイン発現の減少をもたらす。
[87]マウス骨髄由来マクロファージ細胞(BMDM)を、上記の実施例1に記載された野生型(WT)マウスならびにホモ接合性(HO)およびヘテロ接合性(HE)ALPK1マウスから採取した。成熟BMDMを、100ng/ml LPSで処理して、サイトカイン発現を誘導した。サイトカインIL1β、TNFα、TGFβ1、IL6、IFNα、IL15、IL10、およびTNFβのmRNA発現は、ホモ接合性(HO)ALPK1ノックアウトマウスとヘテロ接合性(HE)ALPK1ノックアウトマウスの両方由来の細胞において低下した(図13)。
低分子キナーゼ阻害剤、MI6は、DSS大腸炎モデルにおいて回復を向上させる
[88]小分子のライブラリーをALPK1に対する阻害活性についてスクリーニングすることにより、ALPK1阻害剤を同定した。そのライブラリーをスクリーニングするために、結合アッセイ、キナーゼアッセイ、およびサイトカイン分泌についての細胞に基づいたアッセイを含む様々なアッセイを用いた。結合アッセイおよびキナーゼアッセイ、加えて少なくとも2つの細胞に基づいたアッセイにおけるそれのパフォーマンスに基づいて、MI6をALPK1阻害剤として同定した。
ALPK1変異は、乳癌モデルにおいて腫瘍増殖および転移を低下させる
[90]MMTV−PyVTトランスジェニック腫瘍モデルにおいて、ポリオーマウイルスミドルT抗原(PyVT)は、マウス乳腺腫瘍ウイルス(MMTV)プロモーター下で発現し、そのプロモーターは、PyVTの乳腺組織特異的発現を作動させる。PyVTは、srcおよびホスファチジルイノシトール−3−キナーゼを含む複数の発癌経路を活性化し、侵襲性腫瘍表現型を生じる、癌遺伝子である。その導入遺伝子を有する未交尾の雌は、10〜12週齢までに、多巣性で、低分化で、高浸潤性腺管癌を発生し、その原発性乳腺腫瘍に由来した肺転移の高い発生率を有する。5週齢において、雌は、以下の4つの群へ分類される非侵襲性局所的病変を発生する:単純、固形、嚢胞性、および混合型(固形および嚢胞性)。固形病変は、結節性シートにおける異型細胞の高密度腫瘤を有する大きな病巣からなる。嚢胞性病変は、サイズおよび複雑度が様々であり、著しい量の透明液を含む多層上皮により裏打ちされている。
[93]当業者は、本明細書に記載されているような本発明の特定の実施形態の多くの等価物を認識し、または単なる日常的な実験を用いて、確かめることができるだろう。そのような等価物は、以下の特許請求の範囲により包含されることを意図される。
Claims (26)
- 炎症の処置を必要としている対象において炎症を処置するための方法であって、アルファ−キナーゼ1(ALPK1)阻害剤を前記対象に投与するステップを含む、方法。
- 炎症性疾患、障害、または状態を処置するための方法であって、そのような処置を必要としている対象にアルファ−キナーゼ1(ALPK1)阻害剤を投与するステップを含む、方法。
- 炎症性疾患または障害が、炎症促進性サイトカインの過剰産生による、炎症性腸疾患、関節炎、肥満症、放射線誘発性炎症、乾癬、T細胞媒介性過敏性疾患、アレルギー性疾患、アトピー性皮膚炎、非アルコール性脂肪性肝炎(NASH)、アルツハイマー病、全身性エリテマトーデス(SLE)、自己免疫性甲状腺炎(グレーブス病)、多発性硬化症、強直性脊椎炎、および水疱症から選択される、請求項2に記載の方法。
- 炎症性疾患または障害が、炎症性腸疾患、関節炎、肥満症、および放射線誘発性炎症から選択される、請求項3に記載の方法。
- 炎症性腸疾患がクローン病および潰瘍性大腸炎から選択される、請求項4に記載の方法。
- ALPK1阻害剤がキナーゼ阻害剤である、請求項1〜5のいずれか一項に記載の方法。
- キナーゼ阻害剤が、1−ベンジル−3−ヘキサデシル−2−メチル−1H−イミダゾール−3−イウム ヨウ素化塩または他のそのハロゲン塩である、請求項6に記載の方法。
- ALPK1阻害剤が、ALPK1に方向付けられた抗体または抗ALPK1−Fc融合タンパク質である、請求項1〜5のいずれか一項に記載の方法。
- ALPK1阻害剤がALPK1アンチセンスポリヌクレオチドである、請求項1〜5のいずれか一項に記載の方法。
- ALPK1阻害剤が、マイクロRNA(miRNA)、低分子干渉RNA(siRNA)、および低分子ヘアピン型RNA(shRNA)からなる群から選択されるALPK1に方向付けられた干渉RNAである、請求項1〜5のいずれか一項に記載の方法。
- 請求項7に記載のキナーゼ阻害剤、および担体または賦形剤を含む、薬学的組成物。
- 炎症の処置を必要としている対象において炎症を処置する方法における使用のためのALPK1の阻害剤。
- 炎症促進性サイトカインの過剰産生による、炎症性腸疾患、関節炎、肥満症、放射線誘発性炎症、乾癬、T細胞媒介性過敏性疾患、アレルギー性疾患、およびアトピー性皮膚炎からなる群から選択される炎症性疾患、障害、または状態を処置する方法における使用のためのALPK1の阻害剤。
- 炎症性腸疾患、関節炎、肥満症、または放射線誘発性炎症を処置するための方法における請求項12に記載のALPK1の阻害剤。
- クローン病または潰瘍性大腸炎を処置するための方法における請求項13に記載のALPK1の阻害剤。
- 炎症促進性サイトカインの過剰産生による、炎症性腸疾患、関節炎、肥満症、放射線誘発性炎症、乾癬、T細胞媒介性過敏性疾患、アレルギー性疾患、およびアトピー性皮膚炎からなる群から選択される炎症性疾患、障害、または状態を処置する方法における使用のための請求項11に記載の薬学的組成物。
- クローン病または潰瘍性大腸炎を処置する方法における使用のための請求項11に記載の薬学的組成物。
- 処置を必要としている対象において、自己免疫疾患、細菌感染により引き起こされる疾患もしくは障害、または癌を処置するための方法であって、アルファ−キナーゼ1(ALPK1)阻害剤を前記対象に投与するステップを含む、方法。
- 癌を処置する方法である、請求項18に記載の方法。
- 癌が、軟部組織肉腫、乳癌、頭頚部癌、メラノーマ、子宮頚癌、膀胱癌、血液悪性腫瘍、神経膠芽腫、膵臓癌、前立腺癌、結腸癌、乳癌、腎癌、肺癌、メルケル細胞癌、小腸癌、甲状腺癌、急性骨髄性白血病(AML)、急性リンパ性白血病(ALL)、慢性リンパ性白血病(CLL)、慢性骨髄性白血病(CML)、胃癌、胃腸間質性腫瘍、非ホジキンリンパ腫、ホジキンリンパ腫、肝臓癌、白血病、リンパ腫、T細胞リンパ腫、脳癌、および多発性骨髄腫から選択される、請求項19に記載の方法。
- 癌が乳癌である、請求項20に記載の方法。
- 自己免疫疾患を処置するための方法である、請求項18に記載の方法。
- 自己免疫疾患が、全身性血管炎、糸球体腎炎(連鎖球菌感染後糸球体腎炎)、シェーグレン症候群、乾癬性関節炎、痛風、痛風性関節炎、反応性関節炎、敗血症性ショック、グレーブス病、グッドパスチャー症候群、重症筋無力症、自己免疫性溶血性貧血、特発性血小板減少性紫斑病、自己免疫性筋炎、悪性貧血、セリアック病、湿疹、自己免疫性甲状腺炎、自己免疫性心筋炎、セリアック病、若年性特発性関節炎、グレーブス眼症、リウマチ性多発筋痛症、自己免疫性ぶどう膜炎(uveoitis)、円形脱毛症、ウェゲナー、白斑、原発性硬化性胆管炎、原発性胆汁性肝硬変、自己免疫性肝炎、ギラン・バレー症候群、抗リン脂質抗体症候群、サルコイドーシス疼痛、円形脱毛症、ランバート・イートン筋無力症症候群、自己免疫性溶血性貧血、寒冷凝集素症、温式自己免疫性溶血性貧血、多発性血管炎を伴う好酸球性肉芽腫症(チャーグ・シュトラウス症候群)、およびベーチェット病から選択される、請求項22に記載の方法。
- 細菌感染により引き起こされる疾患または障害を処置するための方法である、請求項18に記載の方法。
- 疾患または障害が、慢性感染症、敗血症、およびサイトカインストームから選択される、請求項24に記載の方法。
- 疾患または障害が、Neisseria、Escherichia、Klebsiella、Salmonella、Shigella、Vibrio、Helicobacter、Pseudomonas、Burkholderia、Haemophilus、Moraxella、Bordetella、Francisella、Pasteurella、Borrelia、Campylobacter、Yersinia、Rickettsia、Treponema、Chlamydia、およびBrucellaから選択される細菌により引き起こされる、請求項24に記載の方法。
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Publication number | Publication date |
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EP3649256A1 (en) | 2020-05-13 |
EP3649256A4 (en) | 2021-07-21 |
US20200207872A1 (en) | 2020-07-02 |
WO2019007362A1 (en) | 2019-01-10 |
CN110891606A (zh) | 2020-03-17 |
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