JP2019524695A - ブルトン型チロシンキナーゼ(Btk)の阻害によるアテローム血栓症の治療および予防 - Google Patents
ブルトン型チロシンキナーゼ(Btk)の阻害によるアテローム血栓症の治療および予防 Download PDFInfo
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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Abstract
Description
試薬
イブルチニブ、アカラブルチニブ(ACP−196)およびONO/GS−4059をSelleckchem(Houston,USA)から入手した。ジメチルスルホキシド(DMSO)およびヒト血清からのアルブミン(脂肪酸不含)はSigma−Aldrich(Taufkirchen,Germany)製であった。コラーゲン(Horm)および希釈溶媒をTakeda(Linz,Austria)から購入した。トロンビン受容体活性化ペプチド(TRAP)をBachem AG(Bubendorf,Switzerland)から入手した。3’−ホスフェート5’−ホスフェート(ADP)は、Biopool(Wicklow,Ireland)製であった。DiOC6をLife Technologies(Eugene,Oregon,USA)から入手した。PBS(ダルベッコのリン酸緩衝生理食塩水)はGibco(Grand Island,New York,USA)製であった。組換えレピルジン(Refludan(登録商標))はCelgene(Windsor,UK)製であった。クライオトミー(cryotomy)用の包埋媒体としてのTissue−Tek(登録商標)は、Sakura(Alphen aan den Rijn,the Netherlands)製であった。
イブルチニブ、アカラブルチニブ(ACP−196)およびONO/GS−4059を、ジメチルスルホキシド(DMSO)中で20mMの濃度において溶解させた。アリコート(30μl)を−80℃において貯蔵した。それぞれのインビトロ実験前、希釈物をDMSO(0.1、0.2、0.5、1および2mM)中で作製してそれぞれ0.1μM、0.2μM、0.5μM、1μMおよび2μMの血中最終濃度を得た。血中のDMSOの最終濃度は0.1%であった。コラーゲン(1000μg/ml)を希釈溶媒中で、凝集測定実験のために1:10の比(100μg/ml)で、または流動実験のために1:50の比(20μg/ml)で希釈した。TRAPを0.9%のNaCl中で500μMの濃度において溶解させた。ADPを蒸留水中で500μMの濃度において溶解させた。血小板標識のためのDiOC6をDMSO中で5mMの濃度において溶解させた。アリコート(10μl)を−20℃において貯蔵した。それぞれの流動実験前、原液をヒト血清アルブミン(HSA、PBS中0.5%)中で100μMの濃度において溶解させて1μMの血液試料中の最終濃度を得た。
アテローム動脈硬化性プラーク検体が、既に記載のとおり(Brandl R.et al.,Circulation.1997;96:3360−3368;Reininger AJ.et al.,J Am Coll Cardiol.2010;55:1147−11585;Penz S.et al.Faseb J.2005;19:898−909)、高悪性度頸動脈狭窄のための動脈内膜切除を受けた患者から寄付された。Faculty of Medicine of the University of Munichの倫理委員会により承認されるとおり患者同意を得た。脂質リッチプラークを含有する検体を回収した。アテロームプラークを無菌条件下で、アテローム動脈硬化性組織検体の他の領域から慎重に切除した(Brandl R.et al.,Circulation.1997;96:3360−3368;Reininger AJ.et al.,J Am Coll Cardiol.2010;55:1147−11585;Penz S.et al.Faseb J.2005;19:898−909)。プラークを処理してホモジネートまたは連続組織切片のいずれかを得た。
インビトロでのイブルチニブ添加の実験のため、実験前少なくとも2週間、血小板機能に影響を与えるいかなる医薬品も服用していない健常成人から血液を得た。
血液中での血小板凝集を、Dynabyte(Munich,Germany)製のMultiplate(登録商標)装置を使用して複数の電極凝集測定(MEA)により計測した(Toth O.et al.Thromb Haemost.2006;96:781−8)。イブルチニブ、アカラブルチニブ(ACP−196)、またはONO/GS−4059(0.1、0.2、0.5、1または2μM)またはDMSO(0.1%、対照)をMEAキュベット中の0.3mlの生理食塩水に最初に添加してから0.3mlの血液を添加した。試料を撹拌の不存在下で試験キュベット中で15分間プレインキュベートした。患者の血液を用いるエクスビボ実験において、試料を撹拌の不存在下で37℃において3分間プレインキュベートした(Bampalis VG.et al.J Thromb Haemost.2012;10:1710−4)。続いて、プラークホモジネート(833μg/ml)またはコラーゲン(0.2〜0.4μg/ml;プラークホモジネートと同一の凝集値を誘導するために個々の血液ドナーにおいて試験)、TRAP(5μM)またはADP(5μM)を添加し、撹拌を開始し、デュプリケート試料においてインピーダンス変化を10分間継続して記録した。10分間の時間にわたる累積凝集値をAU*min(AU、凝集単位)として表現する。
流動血液中での実験のため、ヒト血清アルブミン(HSA;PBS中4%)により既にブロッキングされた粘着スライド(0.1Luer粘着スライド、ibidi(登録商標)、Martinsried,Germany)を使用してコラーゲン(20μg/ml)、プラークホモジネートまたはプラーク組織切片によりコートされたガラスカバースリップ(Menzel、24×60mm、#1.5)を並行プレート流動チャンバ中に集めた。次いで、流動チャンバを、インキュベーションチャンバ(37℃)を備える蛍光顕微鏡(TE2000−E、Nikon,Tokyo,Japan)のステージ上にマウントした。流動チャンバをPBSにより灌流させ、続いて4%のHSAを含有するPBSにより2分間ブロッキングしてガラスカバースリップへの血小板の非特異的結合を防止した。
PFA100(登録商標)およびPFA200(登録商標)装置(Siemens Healthcare,Erlangen,Germany)は、一次止血をシミュレートし、インビトロで出血時間を計測するために使用されるThrombostatシステムのさらなる発展である(Kratzer MA.et al.Semin Thromb Hemost.1995;21 Suppl 2:25−31;Kundu SK,et al.Semin Thromb Hemost.1995;21 Suppl 2:106−12)。この機器は、一定真空下でクエン酸抗凝固血液(0.8ml)を容器からキャピラリーならびにコラーゲンおよびADP(コラーゲン/ADP試験カートリッジ)、またはコラーゲンおよびエピネフリン(コラーゲン/EPI試験カートリッジ)によりコートされた膜フィルター中の小穴に通して吸引する。開口部の完全閉塞を得るために要求される時間を「インビトロ閉止時間」として記録した。閉止時間を2人の健常ドナー、イブルチニブ処理を受けたまたは受けていない5人の患者において計測した。5人のイブルチニブ患者は、静的および流動実験において上記で試験された患者と同一であった。
2つの並行実験条件の平均を、対応のあるスチューデントのt検定により比較した(*:p<0.05;**:p<0.01、***:p<0.001)。3つ以上の同時実験条件を、反復計測についてANOVAにより検定し、次いでボンフェローニ検定により一対比較した(§:p<0.05;§§:p<0.01、§§§:p<0.001)。
血液とイブルチニブ(1μM)とのプレインキュベーションは、インピーダンス凝集測定により測定されるとおり、プラークおよびコラーゲンによる刺激時に血小板凝集をほぼ完全に阻害した(図1A)。イブルチニブによるプラークおよびコラーゲンにより刺激される血小板凝集の阻害は、類似の用量応答曲線を示した。プラークおよびコラーゲン刺激血小板凝集の阻害についてのイブルチニブのIC50値は、それぞれ0.18±0.05μM、および0.12±0.04μMであり、最大抑制は0.5μMにおいて達した(図1B、C)。対照的に、イブルチニブは、PAR−1受容体を活性化させるTRAPおよびADPにより刺激される血小板凝集をやや低減させたにすぎなかった(それぞれ−31%、および−13%だけ;図1A、D)。刺激の不存在下での自然最小血小板凝集も、イブルチニブにより停止した(図1A、下段、D)。
プラーク破裂による血小板活性化をシミュレートするため、ヒト血液を並行プレート流動チャンバ中で、ヒトプラークホモジネートまたはプラーク組織切片によりコートされたカバースリップ上で、健常頸動脈および冠動脈の生理学的壁剪断速度(600/s)ならびに軽度に狭窄の冠動脈病変上での速度(1500/s)において灌流させた。
次に、5人のCLL患者における進行中のイブルチニブ療法(420mg/日)の効果を分析した。イブルチニブを服用していない5人の合致患者が対照として機能した。血液血小板数は、イブルチニブ患者(174±19G/l)および対照(186±37G/l)において類似であった。イブルチニブ中の患者からの血液において、血小板凝集は、静的条件下でプラーク(−89±7%)またはコラーゲン(−84±8%)によりインビトロで刺激された場合に阻害され、非刺激自然血小板凝集も遮断された(図4)。注目すべきことに、イブルチニブ処理は、動脈流条件下でプラークホモジネート上への血小板血栓形成を停止させた一方、血小板粘着を保存した(図5A)。プラーク組織上への血小板血栓形成も、大幅に予防された(−83±24%だけ;図5B)。対照的に、イブルチニブは、コラーゲン線維上への流動血液からの初期血小板凝集を最小限に減速させたにすぎなかったが、対照と同一の最大応答に達した(図5C)。
イブルチニブ摂取が出血時間を増加させ得るか否かを試験するため、計測を、上記で試験された患者と同一のイブルチニブを服用する5人の患者において血小板機能分析装置PFA−100により実施した。この装置は、インビトロでの一次止血をシミュレートする。しかしながら、PFA−100またはPFA−200装置により見出される異常値がインビボでの潜在的な出血リスクを反映するか否かは、依然として論争の主題である(Kundu SK.et al.,Semin Thromb Hemost.1995;21 Suppl 2:106−112;Paniccia R.et al.,Vascular health and risk management.2015;11:133−148)。イブルチニブ療法中の患者における平均閉止時間は、有意に増加しなかったが、5人の患者のうち2人は、コラーゲン/エピネフリン試験カートリッジについて閉止時間の延長を示した(図6A、C)。コラーゲン/ADPカートリッジについて、閉止時間は両方の患者群において正常範囲であった(図6B、C)。血液血小板数は、両方の患者群において類似であった(図6D)。
動脈流下で、インテグリンα2β1遮断抗体6F1は可溶性I型コラーゲン上への血小板粘着を遮断したが、イブルチニブは遮断しなかった(図7)。これは、インテグリンα2β1が可溶性コラーゲンへの血小板粘着に重要であることを裏付け(Jung and Moroi J Biol Chem(1998)273(24):14827−37)、イブルチニブが生理学的止血において天然コラーゲンへのインテグリンα2β1媒介血小板粘着を干渉しないことを実証する。
血液とアカラブルチニブ(ACP−196)およびONO/GS−4059とのプレインキュベーションは、インピーダンス凝集測定により計測されたとおり血中でプラーク誘導血小板凝集を用量依存的に阻害した(図9A;図10A)。ACP−196およびONO/GS−4059のIC50値はそれぞれ0.4μM、および1μMであり、最大抑制(それぞれ80%および82%)はそれぞれ1および2μMにおいて達した。コラーゲン誘導血小板凝集は、同等に十分阻害された(図9B、図10B)。対照的に、ACP−196(2μM)およびONO/GS−4059(2μM)は、TRAP、ADPまたはAAにより刺激される血小板凝集をわずかに低減させたにすぎなかった(図9B、図10B)。刺激の不存在下での自然最小血小板凝集は、イブルチニブにより停止した(図1A、下段、D)。
ACP−196は、600/sの剪断速度を有する動脈流においてプラークホモジネート上への血小板凝集を用量依存的に阻害し、2μMは、血小板凝集を96%だけ阻害した(図11)。ONO/GS−4059も用量依存的阻害を示し、2μMにおいて、プラークホモジネート上への血小板血栓形成を−76%だけ強力に阻害した;図12)。両方のBtk阻害剤は試験された最大濃度においてコラーゲン線維上への最終血小板凝集物形成をわずかに遅延させたが、減弱させなかった(図11、12)。DMSO溶媒は血小板凝集に影響を与えなかった(図13)。
イブルチニブの抗血小板療法としての可能性を試験するため、2人の健常医師(男性、61および66歳)は、負荷用量のImbruvica(3回のカプセル剤×140mg=420mg)を服用し、次いで1週間の140mg/日の低用量(ドナーA)または1週間の隔日140mgの極低用量(ドナーB)を服用した。このレジメンは、2人のドナーにおいていかなる有害な副作用も有さなかった。
Claims (8)
- アテローム血栓症の治療および/または予防における使用のためのブルトン型チロシンキナーゼ(Btk)の阻害剤。
- 医薬有効量のブルトン型チロシンキナーゼ(Btk)の阻害剤をアテローム血栓症の治療および/または予防を必要とする対象に投与することを含む、アテローム血栓症を治療および/または予防する方法。
- 前記阻害剤が、小分子、抗体または抗体模倣体、アプタマー、siRNA、shRNA、miRNA、リボザイム、またはアンチセンス核酸分子である、請求項1に記載の阻害剤または請求項2に記載の方法。
- 前記阻害剤が、アゾールモチーフおよび/またはアジンモチーフを含む小分子である、請求項3に記載の阻害剤または方法。
- 前記阻害剤が、Btkに不可逆的に結合する、請求項1〜4のいずれか一項に記載の阻害剤または方法。
- 前記阻害剤が、イブルチニブ、アカラブルチニブ(ACP−196)、ONO/GS−4059、BGB−3111、またはそれらのアナログである、請求項1〜5のいずれか一項に記載の阻害剤または方法。
- 前記阻害剤が、場合により、薬学的に許容可能な担体、賦形剤および/または希釈剤をさらに含む医薬組成物に含まれる、請求項1〜5のいずれか一項に記載の阻害剤または方法。
- 前記阻害剤が、280〜560mgの負荷用量、および1日当たり10〜140mgまたは隔日40〜280mgの維持投与量において使用/投与される、請求項5または6に記載の阻害剤または方法。
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