JP7127988B2 - 新規な組成物ならびに慢性閉塞性肺疾患を処置および/または予防する方法 - Google Patents
新規な組成物ならびに慢性閉塞性肺疾患を処置および/または予防する方法 Download PDFInfo
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Description
本発明は、したがって、COPDおよびAECOPDを予防および/または処置するための方法における使用のための組成物であって、ケモカイン受容体CXCR4、CCR2および/またはCCR3、そのバリアントおよび/またはアイソフォーム、リガンド、それらのバリアントおよび/またはアイソフォームに対する少なくとも1種のアンタゴニストまたは阻害剤の治療有効量を含む前記組成物を提供する。CCR2/CCL2、CCR2/CCL7、CCR2/CCL13、CXCR4/CXCL12および/またはCCR3/CCL11の受容体/リガンド対のアンタゴニストは、小有機分子または合成分子、天然産物、ペプチド、タンパク質、ペプチド模倣薬、ポリクローナルまたはモノクローナル抗体、抗体フラグメント、核酸剤、例えばRNAi、siRNA、shRNA、アンチセンス、リボザイム、またはDNAザイムの中から選択してもよい。
における、気管支肺胞洗浄(BAL)後の細胞回収(103/ml)を、特に以下によって示したグラフである:(A)細胞総数、(B)マクロファージ細胞の回収、(C)好中球の回収および(D)リンパ球の回収。
出願人らは、トランスレーショナル臨床研究において、増悪期間中の、および増悪の2月後の安定状態のCOPD患者における末梢血線維細胞濃度を、対照対象および非増悪COPDを有する患者と比較して調査した。さらにまた、ケモカイン受容体を特徴づけし、COPDを有する患者、および対照対象からの、これらの線維細胞の遊走特性を調査した。
シクロ[2-Nal-Gly-D-Tyr-Arg-Arg](配列番号10)
式中、Nalは2-ナフチルアラニン、Argはアルギニン、Tyrはチロシン、およびGlyはグリシンである。これは、とりわけYoshikawa Y et al.(Bioorg Med Chem Lett. 2012 Mar 15;22(6):2146-50)により記載されており、強力であり経口で活性なペプチド模倣薬CXCR4阻害剤であり、Tocris Bioscience社により販売されている。FC122もまた、FC131の類似体であって、アルギニン残基がエピマーのN-メチル-D-アルギニンによって置き換えられたものとして記載されている。さらなるF131およびFC122の(E)-アルケンおよび(Z)-フルオロアルケン類似体が、CXCR4アンタゴニストとして記載されている(Narumi T, et al., Org Biomol Chem. 2010;8:616-21)。
例1-対象の登録
40歳を超える対象を、彼らがGOLDガイドライン(Gold 1998、Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention for Chronic Obstructive Pulmonary Disease. NIH出版- 2011年改訂)によるCOPD増悪の臨床診断を有する場合に、登録対象者とした。増悪のあるCOPD患者を、集中治療室での入院中に、またはCHU de Bordeauxの臨床研究センターにおける外来患者として採用している。48名の、いかなる肺疾患の病歴もなく肺機能検査が正常である健康な志願被験者を採用した。対象を喫煙歴(喫煙未経験者、元または現喫煙者)によって2つのサブ群に分け、年齢および性別によって患者と対にした。
研究は、センターの共同臨床試験において3年間行われた。研究の概要を図1に提示する。研究は、ClinicalTrials.govにて番号NCT01196832(すなわち「Firebrob」研究)で登録されている。
「非増悪COPD患者」については、1回の来院があり、その間にインフォームドコンセントへの署名をもらい、臨床および機能評価を行い(プレチスモグラフィー、TLCO、動脈血圧)、線維細胞分析のために血液サンプルを取った。
非接着非T(NANT)細胞の精製を行った。手短にいうと、末梢血単核細胞(PBMC)を全血からFicoll-Hypaque密度勾配遠心分離法により分離した。最初の遠心分離を150gで15分間行った後、上部の血漿層を採取し、さらなる分析のために-80℃で保管した。界面の単核細胞を採取し、1×PBSで一回洗浄した。赤血球の溶解を、30秒間の間に、20mlの低張の0.2% NaCl溶液を加えることにより行い、続いて20mlの1.6% NaCl溶液を加えて最終的に等張溶液が得られた。単核細胞を再び1×PBSで洗浄し、ダルベッコ改変イーグル培地(DMEM)、4.5/l グルコース、L-グルタミン中に再懸濁させ、20%ウシ胎児血清(FBS)、ペニシリン/ストレプトマイシンおよびMEM非必須アミノ酸を補い、37℃で1時間インキュベートした。非接着単核細胞画分を取り、冷1×PBS 0.5% BSA、2mM EDTA中で洗浄した。抗CD3モノクローナル抗体(Miltenyi Biotech)を用いてT細胞をさらに除去した。少なくとも0.2×106個の非接着非T(NANT)細胞を各FACSチューブ中に分配し、Cytofix/Cytoperm(eBioscience)を用いて終夜固定した。
線維細胞を、表面マーカーCD45および細胞内マーカーコラーゲンIについての二重陽性として、フローサイトメトリーにより同定した。固定された血液NANT細胞を、易透化緩衝液(eBioscience)中で洗浄し、マウス抗ヒトコラーゲンI抗体(Millipore Cat# MAB3391, RRID:AB_94839)と共にまたはマッチドIgG1アイソタイプ対照(Santa Cruz Biotechnology Cat# sc-3877, RRID:AB_737222)と共にインキュベートし、イソチオシアン酸フルオレセイン(FITC)コンジュゲート抗マウス抗体(Beckman Coulter Cat# IM0819)がこれに続いた。次に、細胞ペレットを、アロフィコシアニン(APC)コンジュゲート抗CD45抗体(BD Biosciences Cat# 555485, RRID:AB_398600)と共にまたはマッチドAPCコンジュゲートIgG1アイソタイプ対照(BD Biosciences Cat# 555751, RRID:AB_398613)と共にインキュベートした。細胞懸濁液を、BD FACSCanto IIフローサイトメーター(BD Biosciences, San Jose, CA)で分析した。オフライン分析を、FACSDivaソフトウェアで行った。CD45についての陰性閾値を、マッチドAPCコンジュゲートIgG1アイソタイプ対照を使用して設定し、全てのそれに続くサンプルを、CD45陽性リージョンのためにゲートした。CD45のためにゲートしたサンプルのコラーゲンIの発現についての分析を、設定した陰性対照閾値を用いて、FITC染色細胞を使用して行った。コラーゲンIについての特異的な染色を、この閾値を上回る陽性事象の増加として決定した。線維細胞の数を、PBMCのカウント総数の割合として表現した。
改変されたBoydenチャンバアッセイを使用して線維細胞遊走を評価した。細胞接着を防止するため、transwellのインサート(孔サイズ8μM)およびウェルを室温にて1時間、ポリリジンエチレングリコール(PEG-PLL、Susos)で被覆した。インサートおよびウェルを、PBSですすいだ。0.2mlのDMEM、4.5/l グルコース、L-グルタミン、supp DMEM、4.5/l グルコース、L-グルタミン中に再懸濁し、ITS、ペニシリン/ストレプトマイシンおよびMEM非必須アミノ酸を補った、0.3×106個の非接着非T(NANT)細胞を、各ウェルの上部の区画に加えた。表示されている場合、NANT細胞には、25μg/mlのプレリキサフォル(Sigma-Aldrich)または10μMのSB 328437(R&D Systems)によって37℃で1時間、上部の区画に加える前に前処理を行った。組換えヒトCXCL12(25ng/ml~200ng/ml;R&D Systems)、組換えヒトCCL11(25ng/ml~200ng/ml;R&D Systems)、またはCOPD V1患者もしくは対照対象に由来する血液から抽出した血漿(50%希釈)を、各ウェルの下部の区画に加えた。約12時間後、下部の区画の内容物を取り除き、2重標識CD45-コラーゲンIを使用したフローサイトメトリーによって線維細胞遊走を評価した。遊走細胞の絶対数を得るために、一定の予め決定された期間(1分間)の間、各条件についてのフローサイトメトリーカウント数を得た。遊走線維細胞の割合を、下部のチャンバ内でカウントされたCD45+coll I+細胞数を上部の区画に加えたCD45+coll I+細胞数で除した比率によって定義づけた。これらの値を、基本条件(媒体のみ)にて得られた遊走線維細胞の割合に対して正規化した。
製造者(R&D Systems)の説明書に従ってELISAによって、血漿CXCL12およびCCL11を測定した。
登録およびベースライン特性
58名の増悪COPD患者および48名の対照対象を登録した(図1)。48名の増悪COPD患者(V1)、9名の非増悪COPD患者、および38名の対照対象における線維細胞のレベルを次に定量した。27名の安定状態(V2)のCOPD患者における線維細胞のレベルを次に定量した。
血液線維細胞(CD45+ColI+細胞)の割合は、増悪期間中のCOPDを有する患者において(「V1」、中央値=PBMCの9.6(95%信頼区間[CI]、9.5~15.7)、n=48)、「非増悪COPD患者」(「Nex」、中央値=PBMCの2.4(95%CI、0.3~6.8)、n=9、p<0.05)および対照対象における(中央値=PBMCの3.0(95%CI、3.1~5.3)、n=38、p<0.001)と比較して高かった(図2A)。血液のミリリットルあたりの絶対的カウント数として表現したときの線維細胞レベルにも、類似の結果が得られた(図2B)。循環CD34陽性線維細胞の割合(図2C)および絶対数(図2D)の両方が、増悪COPD患者においては、対照対象におけるそれらと比較して増加した。しかしながら、増悪COPD患者のサブ群を、彼らのCOPDの増悪に対する処置(抗生剤、経口コルチコイド)、換気モード(自発換気、非侵襲的換気または挿管)、入院の有無に基づいて分けたところ、異なるサブ群間の線維細胞における有意な相違は観察されなかった(データ示さず)。
COPD患者における生存率データを、V1後1.4年の中央値期間、および3年までの期間、収集した。V1で評価した線維細胞の割合に基づいた患者の2つのサブ群においてKaplan-Meier生存分析を行った。28%を超える線維細胞を有する患者は、28%未満の線維細胞を有する患者のと比較して、有意に減少した平均余命を有していた(図3A)。男女比、年齢、FEV1、FVC、PaO2に関しては、2つのサブ群間に統計的相違がなかった(データ示さず)。28%を超える線維細胞を有する患者のサブ群は、急性増悪があり全員が入院を要する6名の患者で構成されたが、一方、28%未満の線維細胞を有する患者のサブ群は、急性増悪がある36名の患者(20名は入院を要し、16名は入院なし)で構成された。
ケモカイン受容体の発現を、線維細胞において、フローサイトメトリーによってさらに評価した。CXCR4、CCR2およびCCR3が、高い割合の線維細胞にて発現し(図4A、C、E)、一方、CCR5およびCCR7は、少ない割合のCD45+ColI+細胞上にのみ見出された(図4GおよびH)。CR4+およびCCR3+線維細胞のレベルは、COPD患者において、対照対象よりも高かった(図4B、DおよびF)。
より多くのCXCR4+およびCCR3+線維細胞が増悪COPD患者の血液中で見出されたので、血漿誘発性線維細胞遊走におけるCXCR4とCCR3の両方の役割を、in vitroのアッセイにて調査した。CXCR4のアンタゴニストであるプレリキサフォル(De Clercq, E. 2003. The bicyclam AMD3100 story. Nat Rev Drug Discov 2(7):581-7)は、増悪COPD患者から得た線維細胞の血漿誘発性動員の有意な減少を誘発したが、正常な対象から得た線維細胞の遊走には有意な減少を誘発しなかった(図5A)。対照的に、増悪COPD患者または対照対象からの線維細胞の血漿誘発性遊走は、CCR3のアンタゴニストであるSB 328437による影響を受けなかった(White, J. R., et al. 2000. J Biol Chem 275(47):36626-31)(図E3A)。
タバコ煙(CS)にさらされたマウスモデルを、ウイルス性増悪と組み合わせた。該ウイルス性増悪を、ウイルス感染により誘発される反応と類似した反応を誘発させる二本鎖RNA、つまりポリ(I:C)を注射することにより引き起こした。
マウスを、5週間の間、タバコ煙(CS)または室内気(RA)に曝露させた。プロトコルの最後の2週間、ポリ(I:C)またはビヒクル(PBC)を週2回注射した。図9に示したとおり、CSおよびポリ(I:C)への曝露は、気管支肺胞洗浄(BAL)における全細胞およびマクロファージの回収を軽度に増加させた。しかしながら、好中球およびリンパ球の回収には大幅な増加が観察された(図9)。
Claims (8)
- ケモカイン受容体CXCR4に対する、少なくとも1種のアンタゴニストの治療有効量を含む、AECOPDを予防および/または処置する方法における使用のための組成物であって、AECOPDが、気管支および/または気管支周囲線維症によって特徴付けられ、アンタゴニストが、インドールベースのCXCR4アンタゴニスト、ビシクラムCXCR4アンタゴニスト、シクラム模倣薬CXCR4アンタゴニスト、グアニジンベースのCXCR4アンタゴニスト、テトラヒドロキノリンベースのCXCR4アンタゴニスト、パラ-キシリル-エンジアミンベースのCXCR4アンタゴニスト、1,4-フェニレンビス(メチレン)CXCR4アンタゴニスト、ピリミジンベースのCXCR4アンタゴニスト、および、修飾ペプチドCXCR4アンタゴニストから選択される、前記組成物。
- アンタゴニストが、プレリキサフォル(AMD3100)、またはプレリキサフォルのテトラフルオロ誘導体、ブリキサフォア(TG-0054)、JM1657、AMD3329、AMD3465、AMD070、MSX-122、CTCE-9908、WZ811、およびBKT-140から選択される小分子である、請求項1に記載の組成物。
- CXCR4アンタゴニストがプレリキサフォルである、請求項1または2に記載の組成物。
- 請求項1~3のいずれか一項に記載の組成物および薬学的に許容し得るビヒクルを含む、AECOPDを予防および/または処置する方法における使用のための医薬組成物。
- 気管支拡張薬、コルチコイド、および/またはホスホジエステラーゼ阻害剤をさらに含む、請求項4に記載の医薬組成物。
- 該組成物が、経口、口腔または舌下に投与され、即時放出、遅延放出、調節放出、持続放出、二重放出、制御放出または拍動送達用途のための、香味剤または着色剤を含有し得る、錠剤、カプセル(ソフトゲルカプセルを含む)、多粒子剤、ゲル、フィルム、エリキシル、溶液または懸濁液の形態である、請求項4または5に記載の医薬組成物。
- 該組成物が、吸入により投与され、乾燥粉末吸入器、または、圧力容器、ポンプ、スプレーもしくはネブライザーからのエアロゾルスプレー提示の形態である、請求項6に記載の医薬組成物。
- 請求項4~7のいずれか一項に記載の医薬組成物の1以上の用量を含む、AECOPDを予防および/または処置する方法における使用のためのキットまたは医薬パッケージ。
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EP3050574B1 (en) | 2019-10-09 |
CN107405405A (zh) | 2017-11-28 |
WO2016120369A1 (en) | 2016-08-04 |
DK3050574T3 (da) | 2020-01-20 |
EP3613435A1 (en) | 2020-02-26 |
EP3050574A1 (en) | 2016-08-03 |
BR112017016347A2 (pt) | 2018-03-27 |
IL253688B1 (en) | 2023-01-01 |
CA2972319A1 (en) | 2016-08-04 |
AU2016212067A1 (en) | 2017-09-14 |
US20180271831A1 (en) | 2018-09-27 |
JP2018505187A (ja) | 2018-02-22 |
CN107405405B (zh) | 2021-05-11 |
IL253688A (en) | 2017-09-28 |
US10813911B2 (en) | 2020-10-27 |
ES2764840T3 (es) | 2020-06-04 |
IL253688B2 (en) | 2023-05-01 |
CA2972319C (en) | 2023-08-01 |
EA201791689A1 (ru) | 2017-11-30 |
AU2016212067B2 (en) | 2020-10-08 |
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