JP2017527553A - 慢性腎疾患の治療のための医薬および装置 - Google Patents
慢性腎疾患の治療のための医薬および装置 Download PDFInfo
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Abstract
Description
本発明の目的は、血液、血漿または血清中のヒト骨シアロタンパク質(BSP)を認識する受容体分子の有効量を含む、細胞外組織および血管石灰化、アテローム性動脈硬化症、動脈硬化症および動脈石灰化、ならびにCKD、ESRDおよび腎代替療法に伴う心血管リスクを治療するための医薬により達成される。該医薬はヒトモノクローナル抗体またはヒト化モノクローナル抗体またはラットモノクローナル抗体でありうる。該医薬は、好ましくは、配列番号1、2、3、4、5および6のいずれかに開示されているタンパク質配列の機能的部分の1以上を含む抗体でありうる。これに関する機能的または必須部分は、血漿中のヒトBSPの検出および結合に関与する分子の部分を意味する。したがって、リンカー部分、タンパク質の成熟中に切断されるリーダー配列、または抗体の互換性部分は含まれない。したがって、受容体分子または抗体の必須部分は、配列番号1、2、3、4、5および6の配列のいずれかに含有される相補性決定領域(CDR)の1以上に関するものである。なぜなら、それらは血漿または血清中のヒトBSPの認識および結合に要求されるからである。保存的タンパク質置換および挿入は当業者に公知である。
本発明は、好ましくは血漿交換または血漿中のBSPに対する抗体の投与による、慢性腎疾患(CKD)を有する患者の血漿からの循環BSP(骨シアロタンパク質)の除去に基づく新規治療概念を提供する。本発明は更に、血漿交換用のBSP吸収物質、およびヒトにおいて生体適合性である直接投与用の医薬組成物を提供する。この治療の有益な効果は、CKD患者の死亡率と循環遊離BSPレベルとが対応することが観察されたことにより証明されている。
利用可能な実験モデルのうち、ラットの5/6腎摘出術(5/6Nx)が進行性腎疾患の研究に最もよく用いられている。これは、この実験手法の特徴が、ヒトにおいて観察されるCKDに一般的なものだからである[Kren Sら,The course of the remnant kidney model in mice.Kidney Int.1999;56:333−337]。5/6腎摘出術は、新規療法を試験するためにも確立されており、臨床的に意義があることが証明されている[Fujihara CKら,Losartan−hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long−term renal injury in the 5/6 ablation model.Am J Physiol Renal Physiol.2007;292:F1810−1818;Terzi Fら,Sodium restriction decreases AP−1 activation after nephron reduction in the rat:role in the progression of renal lesions.Exp Nephrol.2000;8:104−114;Waanders Fら,Effect of renin−angiotensin−aldosterone system inhibition,dietary sodium restriction,and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease:a post hoc analysis of a randomized controlled trial.Am J Kidney Dis.2009;53:16−25]。5/6腎摘出術は片側腎摘出術および残りの腎臓の極の部分的梗塞または切断により行われうる[Santos LSら,Surgical reduction of the renal mass in rats:morphologic and functional analysis on the remnant kidney.Acta Cir Bras.2006;21:252−257]。
大動脈および残存腎臓の目視検査
該器官を最後に採取し、目視検査した。健常(偽処理)動物からの大動脈は大動脈石灰化の徴候、アテローム性動脈硬化内膜病変および「動脈硬化性」内膜/中膜病変を示さなかった。リンカルシウム食およびカルシトリオールを摂取していた5/6Nx腎臓残存ラットからの大動脈は大規模な大動脈石灰化および拡張した大動脈ブラケットを示した。Nxラットの大動脈の胸部および腹部領域は更に、拡張した石灰化ブラケットを示した。健常(偽処理)動物は腎疾患の症状を示さなかったが、5/6Nxラットの残存腎臓は尿毒症石灰化に典型的な浮腫状肥大および白っぽい色を示した。
健常(偽処理)ラットおよび5/6Nxラットの体重は5週間後に有意に異なっていた。健常動物の体重はその5週間で次第に増加したが、プラセボ処理5/6Nxラットの体重は最初は増加し、石灰化処理の進行につれて減少した。一方、抗BSP mAb処理5/6Nxラットの体重は5週間の全期間にわたって増加し、その結果、抗BSP mAb処理動物の体重は未処理動物の体重より有意に高かった。これらの結果は図1に要約されている。したがって、抗BSP mAb療法を受けた5/6Nxラットは5週間後に対照より有意に高い体重を有していた(*p<0.05;5/6Nx対照と比較した場合のプール化されたmAb−BSP療法)。
プラセボ処理5/6Nxラットの死亡率(4週間後に14匹中4匹)は、低用量、中等度用量もしくは高用量の抗BSP mAb処理を受けたラット(2/14および4/14および2/14)または偽処理のみを受けたラット(0/10)と比較して有意に高かった。
シスタチンCの血漿レベルは、糸球体濾過率(GFR)および腎機能を反映するパラメータである。図2は、抗BSP mAb療法を受けた5/6Nxラット(低用量、中等度用量および高用量療法に関してプール化されたもの)およびプラセボでの処理を受けた5/6Nxラットに関する血漿シスタチンCレベルを比較した柱状図である。該データのマン−ホイットニーU検定(MWU)は、抗BSP mAb療法を受けた5/6Nx動物(プール化されたもの)の場合には、未処理5/6 Nx対照と比較して有意に低いシスタチンC値を支持している(***p<0.0001)。
染色後に腎臓を組織学的に検査した。カルシウム産物に関するフォン・コッサ染色の後には、大きな相違は検出できなかった。抗BSP療法を受けた5/6Nxラットにおいては、シリウス・レッド染色は間質性線維症の低減の傾向を示し、PAS染色は糸球体硬化症の有意な低減(図4を参照されたい)および中膜対管腔比の有意な減少(図3 A/B)を示した。より厳密には、抗BSP mAb療法に付された5/6Nxラットは、未処理5/6Nx対照と比較して有意に低い糸球体硬化症を示し(***p<0.0001;*p<0.05)、抗BSP処理5/6Nxラットは、腎内血管において、未対照と比較して有意に低い中膜対管腔比、および低減した血管周囲線維症をも示した。
抗BSP mAb療法に付された5/6Nxラットは、ウエスタンブロット分析により分析された場合に、プラセボ処理ラットおよび偽処理体と比較してマトリックスタンパク質コラーゲンIおよびコラーゲンIIIの発現の低下の傾向を示した(図5)。しかし、該結果の標準偏差は高く、該結果はコラーゲンIIIに関して有意であるに過ぎない。腎ビタミンD受容体のRT−PCR発現分析は、抗BSP mAb療法が、プラセボ処理5/6Nxラットおよび偽処理体と比較して、ビタミンD受容体のアップレギュレーションをもたらすらしいことを示している(図4を参照されたい)。腎カルシウムリン産物の湿式化学分析は有意な相違を示さなかった。
心臓の組織学的検査は、抗BSP IDK1 mAb療法を受けた5/6Nxラットにおいて、有意に低減した間質性線維症を示した(図6)。該療法は心臓血管周囲線維症をも有意に低減した(図7を参照されたい)。該結果はプラセボ処理対照および偽処理体と比較して有意であった(*p<0.0001;*p<0.05)。タンパク質の分析は再び、記載されている療法が、プラセボ処理5/6Nx対照および偽処理体と比較して、線維症過程に通常関連しているマトリックスタンパク質コラーゲンIIIおよびTGFβ−1の心臓発現の低減を招きうることを示した。
BSPは血漿中で高いアフィニティで補体因子Hと結合する。BSPのペプチド部分構造体に対する抗体(Fisher,L.W.ら,Acta Orthop Scand Suppl.,1995,266,61−655)、組換えBSPに対する抗体(Stubbs JT 3rdら,J.Bone Miner.Res.1997 12(8),1210−22)、および骨から単離されたBSPに対する抗体(該抗体は血漿または血清中ではいずれのBSPにも結合しなかった)が製造されている。150kDaの、より大きな因子Hは、約65kDaの、より小さなBSPを遮蔽するらしく(Fedarko NSら,J.Biol.Chem.,200,275,16666−16672;WO 00/062065)、本発明者らは、血清または血漿中で、そして因子Hまたは内因性BSP受容体の存在下でさえも、BSP(ラットまたはヒト)またはそのBSP断片と交差反応する抗体をスクリーニングした。
血漿交換による循環BSPの排除が骨粗鬆症または骨疾患を引き起こしうるといういずれかの臨床的証拠が存在する。これに関して、本発明者らは、骨粗鬆症に罹患している閉経後の女性が、閉経期前後の健常対照と比較して上昇した血清BSPレベルを示すことさえあることに注目している。更に、確立された骨粗鬆症治療法であるアレンドロン酸(R)(INN)での治療およびホルモン補充療法は全て、閉経後の女性における血清BSPレベルの低下をもたらす。したがって、血漿交換による血清または血漿からのBSPの排除が、CKDまたはESRDに罹患した患者に対する受け入れられる療法となりうると考える正当な理由が存在する。
Claims (14)
- 血液、血漿または血清中のヒト骨シアロタンパク質(BSP)に特異的に結合する受容体分子の有効量を含む、細胞外組織および血管石灰化、アテローム性動脈硬化症、動脈硬化症ならびに動脈石灰化を治療するための医薬。
- 受容体分子がヒトモノクローナル抗体またはヒト化モノクローナル抗体またはラットモノクローナル抗体である、請求項1記載の医薬。
- 抗体が、配列番号4、5、6、7、8および9のいずれかに開示されているタンパク質配列の機能的部分の1以上を含む、請求項2記載の医薬。
- 受容体分子または抗体が、配列番号4、5、6、7、8および9のタンパク質配列のいずれかに含有される機能的相補性決定領域(CDR)の1以上を含む、請求項2または3記載の医薬。
- 受容体分子が、配列番号4、5、6、7、8および9のタンパク質配列のいずれかを有する抗体により結合され、血漿中で接近可能である、BSPの抗原決定基またはエピトープを認識する、請求項1記載の細胞外組織および血管石灰化を治療するための医薬。
- ビーズ、アガロース、アフェレーシスに使用される物質、血漿交換に使用される物質、マイクロタイタープレート、容器壁から選択されるいずれかの固相物質に結合している又は含有されている、請求項2〜5のいずれか1項記載の受容体分子または抗体。
- 診断系またはキット、好ましくは、腎代替療法、透析、CKD、ESRD、組織および血管石灰化、アテローム性動脈硬化症、動脈硬化症、動脈石灰化のコンパニオン診断のためのキット内に含まれる、請求項2〜5のいずれか1項記載の受容体分子または抗体。
- 患者から血液を採取するための手段、
血液細胞および血漿を分離するための手段、
可溶性BSP用のトラップを介して血漿を輸送するための手段、ここで、BSPトラップは、固定化種を有する基質を含み、固定化種は、血管および組織石灰化を妨げる濃度まで血中の可溶性BSP濃度を低下させてBSP枯渇血漿を得るのに適合している、および
処理された血漿および血液細胞を患者に戻すための手段
を含む体外血液処理系。 - 血液および/または血漿を、カルシウムトラップを介して輸送するための手段、ここで、カルシウムトラップは、固定化種を有する基質を含み、固定化種は、体外血液処理系におけるカルシウムおよびBSPの沈殿物の形成を妨げる濃度まで血中のカルシウム濃度を低下させてカルシウム枯渇血液を得るのに適合している、
骨シアロタンパク質用のトラップをも含み得る体外血漿処理装置によりカルシウムトラップの下流のカルシウム枯渇血液または血漿を処理するための手段、および
体外血液処理装置の下流の処理されたカルシウム枯渇血液中にカルシウムを注入して、処理されたカルシウム枯渇血液にカルシウムを添加するための手段
をさらに含む、請求項8記載の体外血液処理系。 - 可溶性BSP用のトラップの使用を含む血漿交換のための方法。
- 過剰なBSPを循環から排除する血漿交換介入を含む、血管および軟部組織石灰化を低減する方法。
- 血液透析法において循環から過剰物を排除する、請求項11記載の方法。
- BSPに対する治療用抗体の使用を含む、動脈および血管石灰化を低減する方法。
- CKDまたはESRDを有する腎障害患者の全体的な結果が改善する、請求項11または12記載の方法。
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