JP5296701B2 - 線維性疾患および線維増殖性疾患を処置および診断するための方法 - Google Patents
線維性疾患および線維増殖性疾患を処置および診断するための方法 Download PDFInfo
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Description
この出願は、2006年11月30日に提出された米国仮出願番号60/872019号の優先権を主張するものである。なお、これらの開示内容は出典明示により本明細書の一部とする。
本発明は、国立衛生研究所により付与された承認番号HL73848、HL080206、AR055075、CA87879およびHL66027の下に一部助成されたものである。米国政府は本発明における所定の権利を有する。
本発明は、線維性疾患または線維増殖性疾患を有する被験体を処置および診断する方法に関する。
米国内の45%の死亡は、多くの組織および器官系に影響を与え得る線維増殖性疾患によると見積もられている。線維症は、ほぼ全ての組織および器官系に影響を与える。線維症が罹患率および死亡率の主な原因となる疾患には、慢性B型またはC型肝炎、腎臓疾患、心臓疾患および全身性硬化症によりもたらされる間質性肺疾患、肝硬変、肝線維症が挙げられる。また、線維増殖性疾患には、全身および局所強皮症、ケロイドおよび肥大型性心筋症、アテロ−ム性動脈硬化症、再狭窄および黄斑変性症、ならびに網膜および硝子体網膜症を含む眼疾患も包含される。他の線維症には、手術による過剰な瘢痕化、化学療法薬誘発性線維症、照射誘導性線維症、および損傷および熱傷が包含される。また、線維化した組織再構築により、癌転移に影響を与え、移植レシピエントにおける慢性移植片拒絶反応を加速させる[28]。
本願発明は、これに限定しないがヒトの線維化間質性肺疾患を含む線維性疾患および線維増殖性疾患への線維芽細胞の関与を含む。本出願において開示された試験は、線維芽細胞誘引性ケモカインであるCXCL−12の発現、循環する線維芽細胞の存在および数、ならびにCXCL−12受容体であるCXCR4のその発現について、UIPおよび線維性NSIP患者由来のヒト肺組織および末梢血液を、正常コントロールと比較したものである。いずれの特定の理論に縛られることなく、本明細書に開示したデータは、循環する線維芽細胞の数が、線維性疾患を有する患者における新規バイオマーカーであり得ることを示している。
略語および頭字語
αSMA-α-平滑筋アクチン
DAB−3,3'-ジアミノベンジジン
NSIP-非特異性間質性肺炎
UIP-通常の間質性肺炎
本発明の説明および特許請求の範囲において、以下の用語が下記の定義に従って使用さ
I.小分子脂肪族(small aliphatic)、非極性またはわずかに極性の残基:
Ala、Ser、Thr、Pro、GIy;
II.極性、陰性荷電残基およびそのアミド:
Asp、Asn、GIu、GIn;
III.極性、陽性荷電残基:
His、Arg、Lys;
IV.高分子(large)、脂肪族、非極性残基:
Met Leu、lie、VaI、Cys
V.高分子、芳香族残基:
Phe、Tyr、Trp。
本発明は、循環する線維芽細胞レベルおよびCXCL−12レベルが線維性疾患患者の末梢血液および線維化した組織中で、有意に上昇するという予想外の発見に基づいて、線維性疾患または線維増殖性疾患または線維増殖性障害を有する被験体を診断する方法に関する。
モノクローナル抗体を調製するために、培養中の連続細胞株により、抗体分子の産生のために提供するあらゆる技術を利用することができる。例えば、ハイブリドーマー技術は、KohlerおよびMilstein (1975、Nature 256:495-497)により初めて開発されたもので、トリオーマー技術、ヒトB細胞ハイブリドーマー技術(Kozbor et ah、1983、Immunology Today 4:72)、およびEBV−ハイブリドーマー技術(Cole et ah、1985、in Monoclonal Antibodies and Cancer Therapy、Alan R. Liss、Inc.、pp. 77-96)を用いて、ヒトモノクローナル抗体を生成することができる。他の実施態様において、モノクローナル抗体は、国際出願番号PCT/US90/02545に記載の技術を利用して無菌動物中で産生され、これらはその全ての文献を引用により本明細書に組み込まれる。
本発明のペプチドは、Stewartら(固体相ペプチド合成、2nd Edition、1984、Pierce Chemical Company、Rockford、Illinois);およびBodanszkyおよびBodanszky(The Practice of Peptide Synthesis、1984、Springer-Verlag、New York)らにより概説された標準的かつ十分確立された技術、例えば固体相ペプチド合成(SPPS)により容易に調製され得る。はじめに、好適に保護されたアミノ酸残基は、そのカルボキシル基により、架橋ポリスチレンまたはポリアミド樹脂のような誘導体化された不溶性ポリマー支持体に付着される。「好適に保護された」は、アミノ酸のα−アミノ基、および任意の側鎖官能基の両方における保護基の存在を指す。側鎖保護基は、一般に、合成全体を通して使用される溶媒、試薬および反応条件に対して安定であり、最終的なペプチド産物に影響を及ぼさない条件下で脱離可能である。オリゴペプチドの段階的合成は、最初のアミノ酸からのN保護基の脱離、所望されるペプチドの配列での次のアミノ酸のカルボキシル末端のそれへの結合によって行われる。このアミノ酸もまた好適に保護される。次に加わるアミノ酸のカルボキシルを活性化させて、反応基中の構造によって、例えば、カルボジイミド、対称酸無水物またはヒドロキシベンゾトリアゾールまたはペンタフルオロフェニルエステルなどの「活性エステル」基中の構造により、支持体結合アミノ酸のN末端と反応させることができる。
本発明は、本発明のペプチド、タンパク質、および抗体をコードする核酸を提供する。「核酸」とは、デオキシリボヌクレオシドまたはリボヌクレオシドから構成されるか、ホスホロジエステル結合または修飾結合(例えば、ホスホトリエステル、ホスホロアミデート、シロキサン、カルボネート、カルボキシメチルエステル、アセトアミデート、カルバメート、チオエーテル、架橋したホスホロアミデート、架橋メチレンホスホネート、架橋ホスホロアミデート、架橋ホスホロアミデート、架橋メチレンホスホネート、ホスホロチオエート、メチルホスホネート、ホスホロジチオエート、架橋ホスホロチオエートまたはスルホン架橋等)およびかかる結合の組合せ物から構成される、あらゆる核酸を意味する。用語「核酸」は、5つの生理学的に生じる塩基(アデニン、グアニン、チミン、シトシンおよびウラシル)以外の塩基から構成される核酸もまた特に包含し得る。
本発明は、本発明の方法を実施するための医薬組成物の使用も包含し、該組成物は、好適な化合物またはそのアナログ、誘導体または修飾物、および医薬的に許容し得る担体を含んでいる。
本発明はまた、本発明の組成物および哺乳動物の細胞または組織に該組成物を投与することを説明する取扱説明書を含んでなるキットを含む。別の実施形態では、このキットは、組成物を投与する前に本発明の組成物を溶解または懸濁するのに適切な(好ましくは無菌の)溶媒を含んでなる。
材料および方法
患者およびサンプル
患者はUCLAで間質性肺疾患の診療所から募集され、全て試験が治験審査委員会により認証された。線維性肺疾患患者由来の肺組織サンプルを、間質性肺疾患の診断のための肺生検の切開中に取得し、また正常サンプルを悪性腫瘍と離れた部位にある気管支癌のために肺葉切除をうけた患者から得た。サンプルを、ホモジネートし、先に記載したような完全緩衝液中で超音波処理した(Roche Diagnostics、Indianapolis、Indiana、USA) [14]。ホモジネートを、900xg、15分間で遠心分離し、1.2μm滅菌アクロディスク(Gelman Sciences、Ann Arbor、Michigan、USA)をとおして濾過した。また、我々は、5人の正常ボランティアおよび5人の線維化間質性肺疾患罹患患者からのヘパリン処理した静脈血液(10ml)を得た。線維化間質性肺疾患罹患患者のうちの4人の患者を、臨床的、X線写真的および組織学的特徴を根拠としてUIPと診断し、1人の患者を、組織的病変を根拠として線維性NSIPと診断した。前記したように[15、16]、サンプルを処理し、遠心分離によるFACS分析のために軟膜白血球細胞集団を単離した。夾雑物を含む赤血球細胞を除いて、次いで該細胞を洗浄し、0.1%FBSを含有するPBS中で1x107/mlの濃度とした。肺ホモジネートおよび血漿サンプルを、ELISAの為に処理されるまで−70℃で凍結した。サンプルを、前記したように[17]、CXCL−12レベルについてアッセイした。
パラフィン埋包組織を、前記したように[18]、CXCL−12の免疫組織化学的局在性のために処理した。要するに、組織セクションを、キシレンで脱ワックスし、エタノールの段階的濃度をとおして再水和した。スライドを、1:1の完全メタノールと3%H2O2で30分間固定し、PBSですすぎ、次いで非特異的結合部位を、室温で30分間のインキュベーションにより、ユニバーサルブロッキング試薬を用いてブロッキングした(Biogenex、San Ramon、CA)。ブロッキング工程の後に、1:500希釈のコントロール(ヤギ)またはヤギ抗hCXCL−12血清のいずれかを一次抗体として加え、スライドを、30分間室温でインキュベートした。次いで、スライドをPBSですすぎ、ビオチン化抗ヤギIgG(Vector ABC Elite Kit、Vector Laboratories、Burlingame、CA)を用いて重層し、さらに30分間インキュベートした。スライドを、2回PBSですすぎ流し、次いで30分間室温にてストレプトアビジン結合ペルオキシダーゼで処理した。次に、PBSを用いて3回洗浄し、スライドを基質色原体3,3'-ジアミノベンジジン(DAB、Vector Laboratories)を用いて比色分析の検出に供した。スライドを、DAB溶液中に室温で5-10分間インキュベートし、発色させ、蒸留水ですすぎ流し、反応を停止させた。マイヤーズヘマトキシリンを対比染色液として使用した。
循環する線維芽細胞を、以前に公開された方法[17]に従って、フローサイトメトリーにより同定した。要するに、白血球を、抗CXCR4-FITC(R&D Systems)および抗CD45-PerCP(BD Biosciences)により染色した。つぎに、該細胞を、コラーゲン-I(Col I、Rockland)およびαSMA(R&D Systems)の細胞内染色の前にcytofix/cytoperm(BD Biosciences)を使用して透過させた。次いで、CoI-IおよびαSMAを、非結合ウサギ抗ヒトCoI-Iおよびマウス抗ヒトαSMA Absに続いて、Alexa Fluor 610-R-フィコエリトリンヤギ抗ウサギまたはマウス(Molecular Probes)を用いて染色した。サンプルを、Cellquest softwareを用いるFACS Calibur flow cytometer 上で処理した。
データを、Statview 統計パッケージ(Abacus Concepts、Berkeley、California、USA)を用いて、Dell PC(Dell、Round Rock、Texas、USA)コンピューターにて分析した。比較を、対応のないスチューデントt-検定により評価した。該結果を、p値が0.05未満であれば統計的に有意とみなした。
肺線維症の動物モデルにおいて該肺へ線維芽細胞を動員する際に、ケモカインリガンド、CXCL−12の役割が示されたので、線維性肺疾患罹患患者から得た保管サンプル中の生検組織中のCXCL−12の肺発現を比較することにより開始した。免疫組織化学により検出されたとおり(図1a)、臨床的および組織学的診断UIPを有する患者由来の肺組織中でCXCL−12の大量の蓄積を見出した。定量的にこの知見を評価するために、UIPおよび線維性NSIPを有する患者からの肺組織におけるCXCL−12のタンパク質レベルを比較し、それらを正常な肺組織(図Ib)中のレベルについて比較した。64%および77%が、正常な肺と比較して、線維性NSIPおよびUIP各々を有する患者の肺中のCXCL−12レベルで各々増加することに注目されたい。興味深いことに、CXCL−12のレベルは、NSIPおよびUIPとの間で差違はなかった。
線維芽細胞は、造血細胞および線維芽細胞両方に対するマーカーを発現する骨髄誘導性循環細胞の近年同定された集団である。先の証拠は、循環する線維芽細胞と、線維芽細胞および筋線維芽細胞へのその分化による、創傷修復、強皮症および喘息の生物学的特徴とを関連づけている(文献[11、12]を参照されたい)。線維芽細胞は、さらに含脂肪細胞および抗原提示細胞を含めた異なる細胞型へ分化することができる[13、24]。
本明細書および後記の全体を通じて引用した文献は、その出典明示により、その全体において本明細書の一部とする。
[2] S. American Thoracic、and S. European Respiratory、American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.、American Journal of Respiratory & Critical Care Medicine 165 (2002)277-304.
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[10] R. J. Phillips et al.、Journal of Clinical Investigation 114 (2004) 438-446.
[11] C. N. Metz、Cell Mol Life Sci 60 (2003) 1342-1350.
[12] T. E. Quan et al.、Int J Biochem Cell Biol 36 (2004) 598-606.
[13] K. M. Hong et al.、FASEB Journal 19 (2005) 2029-2031.
[14] M. P. Keane et al.、J Immunol 163 (1999) 5686-5692.
[15] J. M. Ham et al.、Chemotactic cytokine (IL-8 and MCP-I) gene expression by human whole blood、Immunol Invest 20 (1991) 387-394.
[16] R. M. Strieter et al.、J Leukoc Biol 47 (1990) 366-370.
[17] R. J. Phillips et al.、J Clin Invest 114 (2004) 438-446.
[18] D. A. Arenberg et al.、J Clin Invest 97 (1996) 2792-2802.
[19] R. M. Strieter et al.、Am J Respir Crit Care Med 170 (2004) 133-140.
[20] S. H. Phan、The myofibroblast in plumonary fibrosis、Chest 122 (2002) 286S-289S.
[21] Z. Xing et al.、Am J Pathol 150 (1997) 59-66.
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[29] Bucala、et al. 、MoI. Med. 1 (1994) 71-81
Claims (28)
- 被験体中の循環する線維芽細胞の数をインビトロで決定することを含む、肺の線維性疾患または肺の線維性障害を有する被験体を検査する方法であって、ここでコントロール被験体中の循環する線維芽細胞の数と比較した該被験体中の循環する線維芽細胞の数の増加が線維性疾患または線維性障害の指標である、方法。
- 肺の線維性障害が、特発性肺線維症、線維化間質性肺疾患、間質性肺炎、非特異的間質性肺炎の線維化した亜型、嚢胞性線維症、肺線維症、珪肺症、石綿症、喘息、慢性閉塞性肺疾患(COPD)、および肺動脈性肺高血圧からなる線維性障害の群から選択される、請求項1の方法。
- 被験体中の循環する線維芽細胞の数が、コントロール被験体中の循環する線維芽細胞の数よりも、少なくとも10%多く、少なくとも20%多く、少なくとも30%多く、少なくとも40%多いか、または少なくとも50%多い、請求項1または2の方法。
- 被験体中の循環する線維芽細胞の数が、コントロール被験体中の循環する線維芽細胞の数よりも少なくとも2倍多いか、少なくとも3倍多いか、少なくとも4倍多いか、または少なくとも5倍多い、請求項1または2の方法。
- 循環する線維芽細胞が、末梢血液線維芽細胞である、請求項1〜4いずれかの方法。
- 循環する線維芽細胞が、コラーゲン-1発現CD45+細胞である、請求項1〜4いずれかの方法。
- 循環する線維芽細胞が、フローサイトメトリーにより同定される、請求項1または6の方法。
- 被験体中のα-SMAを発現する循環する線維芽細胞のパーセンテージをインビトロで決定することをさらに含んでおり、ここでコントロール被験体中のα-SMAを発現する循環する線維芽細胞のパーセンテージと比較して、被験体中のα-SMAを発現する循環する線維芽細胞のパーセンテージにおける増加が、線維性疾患または線維性障害の指標である、請求項1〜7いずれかの方法。
- α-SMAの発現の増加が、循環する線維芽細胞の筋線維芽細胞への分化の増加に関する指標である、請求項8の方法。
- コントロール被験体が、線維性疾患または線維性障害を示さない被験体である、請求項1〜9いずれかの方法。
- 被験体中の循環するCXCL−12の量をインビトロで決定することを含む、肺の線維性疾患または肺の線維性障害を有する被験体を検査する方法であって、ここでコントロール被験体中の循環するCXCL−12の量と比較して、被験体中の循環するCXCL−12の量における増加が、肺の線維性疾患または肺の線維性障害の指標である、方法。
- 肺の線維性障害が、特発性肺線維症、線維化間質性肺疾患、間質性肺炎、非特異的間質性肺炎の線維化した亜型、嚢胞性線維症、肺線維症、珪肺症、石綿症、喘息、慢性閉塞性肺疾患(COPD)、および肺動脈性肺高血圧からなる線維性障害の群から選択される、請求項11の方法。
- 被験体中の循環するCXCL−12の量が、コントロール被験体中の循環するCXCL−12の量よりも少なくとも10%多いか、少なくとも20%多いか、少なくとも30%多いか、または少なくとも50%多い、請求項11または12の方法。
- 被験体中の循環するCXCL−12の量が、コントロール被験体中の循環するCXCL−12の量よりも、少なくとも2倍多いか、少なくとも3倍多いか、少なくとも4倍多いか、または少なくとも5倍多い、請求項11または12の方法。
- 循環するCXCL−12が血漿CXCL−12である、請求項11〜14いずれかの方法。
- コントロール被験体が、線維性疾患または線維性障害を示さない被験体である、請求項11〜15いずれかの方法。
- 被験体中の循環する線維芽細胞の数をインビトロで決定することを含む肺の繊維増殖性障害に罹患している被験体中の肺の繊維増殖性疾患の進行を検査する方法であって、ここで該被験体中の循環する線維芽細胞の数が時間と共に増加することが、肺の繊維増殖疾患または障害の進行の指標である、方法。
- 肺の繊維増殖性障害が、特発性肺線維症、線維化間質性肺疾患、間質性肺炎、非特異的間質性肺炎の線維化した亜型、嚢胞性線維症、肺線維症、珪肺症、石綿症、喘息、慢性閉塞性肺疾患(COPD)、および肺動脈性肺高血圧からなる繊維増殖性疾患の群から選択される、請求項17記載の方法。
- 被験体中の循環する線維芽細胞の数が、繊維増殖性障害を有さないコントロール被験体のものより、少なくとも10%多いか、少なくとも20%多いか、少なくとも30%多いか、少なくとも40%多いか、または少なくとも50%多い、請求項17または18記載の方法。
- 被験体中の循環する線維芽細胞の数が、繊維増殖性障害を持たないコントロール被験体の循環する線維芽細胞の数よりも少なくとも2倍多いか、少なくとも3倍多いか、少なくとも4倍多いか、または少なくとも5倍多い、請求項17または18記載の方法。
- 循環する線維芽細胞が、末梢血液線維芽細胞である、請求項17〜20いずれか記載の方法。
- 循環する線維芽細胞が、コラーゲン-1発現CD45+細胞である、請求項17〜20いずれか記載の方法。
- 循環する線維芽細胞がフローサイトメトリーにより同定される、請求項17または22記載の方法。
- 被験体中のα-SMAを発現する循環する線維芽細胞のパーセンテージをインビトロで決定することをさらに含んでおり、ここで被験体中のα-SMAを発現する循環する線維芽細胞のパーセンテージにおける増加および被験体中の循環する線維芽細胞の数における増加が、線維増殖性疾患または障害の進行の指標である、請求項17記載の方法。
- α-SMAの発現の増加が、循環する線維芽細胞の筋線維芽細胞への分化の増加に関する指標である、請求項24の方法。
- 被験体中の循環するCXCL−12の量をインビトロで決定することをさらに含んでおり、ここで被験体中の循環するCXCL−12の量における増加および循環する線維芽細胞の数における増加が、肺の線維増殖性疾患または障害の進行の指標である、請求項17記載の方法。
- 被験体中の循環する線維芽細胞の数を、コントロール被験体中の循環する線維芽細胞の数とインビトロで比較することをさらに含む、請求項17記載の方法。
- コントロール被験体が、肺の線維増殖性疾患の既知の段階を有する、請求項27の方法。
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