JP2010065057A - 眼の状態を処置するための光力学的治療 - Google Patents
眼の状態を処置するための光力学的治療 Download PDFInfo
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Abstract
眼の状態を処置するための光力学的治療において、処置の有効性および選択性を増大させる改善されたPDTベースの方法を提供すること。
【解決手段】
望ましくない脈絡膜新血管構造により特徴づけられる哺乳類の眼球状態、例えば、血管新生AMD、眼ヒストプラズマ症候群、病的近視、網膜色素線条、突発性障害、脈絡膜炎、脈絡膜破裂、被覆する脈絡膜の母斑、および特定の炎症性の疾患の処置における、同時の、別々の、または連続した使用のためのアポトーシス調節因子および光増感剤の組合せ剤を提供することにより上記課題を解決する。
【選択図】なし
Description
実験を、PDTから生じる細胞毒性が、抗血管新生因子の添加によって増強され得るかどうかを決定するために実施した。目的の細胞を、PDT単独でか、または抗血管新生因子と組み合わせて処置し、そしてPDTの細胞毒性に及ぼす影響を、細胞増殖アッセイによって評価した。
実験を、PDTが、BRCEおよびRPE細胞の細胞形態にどのように影響を与えるかを確立するために実施した。細胞を、処置しそして実施例1で記載したように、PDT単独で、またはアンギオスタチンと組み合わせて曝露した。細胞は、PDT直後に激しく損傷されたようだが、特定の状況下で、引き続いて回復した。PDTの1週間後に、いくらかの細胞が消滅したが、残った細胞は、紡錘形状およびそれらの接着能力を回復した。
BRCEおよびRPE中でのLu−Tex/PDT媒介細胞死におけるアポトーシスの役割を調査するために、カスパーゼ3様(DEVDアーゼ)プロテアーゼの活性化、アポトーシスの特徴(Nicholson(1997)TIBS 22:299−309)をモニタリングした。活性化の動態学を、カスパーゼ3様プロテアーゼファミリーメンバーによってのみ切断され得る基質の加水分解をアッセイすることによって、分光蛍光分析学的に測定した。
Lu−Tex/PDT後のBRCEおよびRPE細胞中でのBcl−2ファミリーメンバーの発現を評価するために、BRCEおよびRPE細胞を、Lu−Tex/PDTに供し、そして得られた細胞溶解物を、抗アポトーシスBcl−2、Bcl−XLマーカー、およびプロアポトーシスのBaxおよびBakマーカーの検出のためのウエスタンブロット分析に供した。
Lu−Tex/PDTは、用量および時間依存性様式で、BRCEおよびRPE細胞の両方においてカスパーゼ3様活性化を誘導し、これは、アポトーシスがこれらの細胞株中のLu−Tex/PDTの細胞毒性のメディエータであることを示唆する。さらに、このデータは、Lu−Tex/PDTが、用量および時間依存性様式でBcl−2およびBaxの転形を通じて、BRCE細胞中でアポトーシスを誘導し、そしてBcl−xLおよびBakの転形を通じてRPE細胞中でアポトーシスを誘導したことを示す。結果として、Lu−Tex/PDTは、異なる細胞型の各々において、異なるモードの死を引き起こす。
れた活性化の閾値によって益を得てアポトーシス応答を迅速に増幅することに基づいて説明され得る。しかし、このことは、1つより多いのアポトーシス経路の関係の可能性を排除しない。なぜならば、特に、PDTは、活性酸素種の発生を介して細胞毒性を惹起することで公知であるが(Weishaupら(1976)前出)、アンギオスタチンは、細胞表面に存在するアデノシントリホスフェートシンターゼのα−サブユニットに結合することによって、ヒト内皮細胞において作用することが最近示された(Moserら(1999)PROC NATL ACAD SCI USA 96:2811−2816)、さらに、アンギオスタチン/Lu−Tex/PDT(20J/cm2)は、Lu−Tex/PDT(40J/cm2)単独で実施したのと同様に、BRCE細胞の100%の死亡率を生じたが、DEVDアーゼ活性化のレベルは、上述のレジメンにおいて顕著により高かった。このことは、Lu−Tex/PDTおよびアンギオスタチン/Lu−Tex/PDTが、BRCE細胞中で異なるアポトーシス経路を介して作用するという理論を支持する。
効果を上げそしてPDTの毒性を下げるために、光増感剤を新血管内皮結合部分に結合することによって、この光増感剤がCNV内皮に指向され得ることが企図される。いくつかの標的分子は、新血管内皮に光増感剤を標的化するために使用され得る。α−vインテグリン、特に、α−v β−3およびα−v β−5インテグリンは、臨床標本および実験モデルの両方において、眼の新血管組織で発現されるようである(Corjayら(1997)前出;Friedladerら(1995)前出)。これらのインテグリンの環状ペプチドアンタゴニストは、実験モデルにおいて、新血管形成を阻害するために使用されている(Friedlanderら、(1996)、PROC.NATL.ACAD.SCI.USA 93:9764−9769)。ヒトα−vインテグリンに選択的に結合し、そして他の新脈管形成標的ペプチドより効率的に腫瘍新血管構造内に蓄積する、ペプチドモチーフのACDCRGDCFC(配列番号2)(RGD−4Cとも呼ばれる)が同定された(Arapら(1998)、NATURE 279:377−380)。別の強力な標的分子は、血管内皮増殖因子レセプター(VEGF−2R)に対する抗体である。臨床的証拠および実験的証拠は、眼の新血管形成、特に、虚血関連性新血管形成におけるVEGFの役割を強く支持する(Adamisら、(1996)、ARCH.OPHTHALMOL.114:66−71;Tolentinoら、(1996)、ARCH.OPHTHALMOL.114:964−970;Tolentinoら、(1996)、OPHTHALMOLOGY 103:1820−1828)。VEGFレセプター(KDRとしてもまた公知のVEGFR−2)に対する抗体は、新血管内皮に優勢に結合することが予測され得る。
光増感剤のVerteporfin(QLT Phototherapeutics,Inc.,Vancouver BC)またはLutetium Texaphyrin(Alcon Laboratories,Fort Worth,TX)を、標準的なカップリング化学を使用して、標的部分(例えば、RGD−4Cペプチドまたは抗VEGFレセプター抗体)にカップリングする。得られる光増感剤複合体のスペクトル特性(発光および励起)をインビトロで測定し得る。続いて、BRCEおよびRPE細胞を使用して、インビトロ研究を行って、PDT後の細胞の取込みおよび光毒性を評価し得る。実験は、インビトロにおける選択的光毒性に対する最適なタイミング、ならびに薬物および光線量を含むPDT処置パラメーターをアドレスし得る。次いで、CNVのラットモデルにおける、結合光増感剤をインビボで使用して、PDTの有効性および選択性を試験し得る。次いで、標的分子を含む光増感剤を用いるPDTの結果を、標的分子を欠く同じ光増感剤を用いるPDTの結果と比較し得る。
(a)CNV閉塞の有効性。CNVの効果的な閉塞は、PDTの24時間後のフルオレセイン血管造影法により、CNVからの漏出がないことによって評価され得る。この方法論は、サルにおけるレーザー損傷において十分に確立されている。組織病理学は光学顕微鏡を使用して実施され得る。
(b)効果の選択性。このモデルにおけるCNVは、レーザー損傷の領域において発生するため、CNVの領域が処置される場合、網膜および脈絡膜に対するP
DTの効果を評価することは困難である。従って、CNVに対するPDTの選択性を証明するために、PDTをまた、正常な網膜および脈絡膜の領域に適用し得、そして公表された組織病理学的類別スキームを使用して、RPE、光受容体、網膜および脈絡膜血管に対する損傷を定量する(Kramerら(1996)、OPHTHALMOLOGY 103:427−438)。
(c)PDT 対 組み合わせPDTレジメンの効果の比較。PDTの効果を、光増感剤のみを用いるPDTで処置したCNV動物の群と、改変したPDT(すなわち、標的化光増感剤)を受けた群との間で比較し得る。PDTを、CNVおよび正常な領域に適用し得る。初めに、CNV閉塞が、改変PDTを使用するPDTのみを用いる場合と同じ光用量(フルエンスJ/cm2)において生じるか否かが決定され得る。次いで、特定された光用量において、改変PDTおよびPDTのみの、正常な網膜に対する効果が比較され得る。例として、標的化光増感剤を使用して、未結合の光増感剤を用いる場合より低いフルエンスで、CNVの閉塞を達成することが可能であり、そしてこのフルエンスにおいて、標的光増感剤を使用するPDTで処置された正常な領域におけるRPEに対するかなり少ない損傷を見出し得る。
実験により、PDTは、アポトーシスにより内皮細胞において細胞死を引き起こし、そしてそのRPEに対する毒性はまた、プログラムされた細胞死によって進行することが示された。異なるアポトーシス経路は、BRCEおよびRPE細胞において、PDTによって誘引されるようである。PDTの前に新血管毛細管内皮細胞のアポトーシス機構(machinery)を特異的にプライムすることによって、PDTに対するそれらの感受性を増加することが可能となり得る。このアプローチは、CNV閉塞を達成するのに必要な光用量(フルエンス)を減少し得、それにより、RPE細胞のような周辺細胞に対する影響を軽減し得る。
目的のペプチドを、初めに、BRCEおよびRPE細胞においてインビトロで試験して、特異性および有効性を確認する。次いで、プロアポトーシスペプチド/PDTレジメンをインビトロで評価し得、次いで、BRCEおよびRPE細胞の両方において、PDTのみおよびペプチドのみと比較する。BRCEおよびRPE細胞を、標準的な組織培養技術を使用して増殖させ得る。ApoAlertアッセイキット(Clonetech)を使用して、処置後の細胞におけるカスパーゼ−3様活性についてアッセイし得る。この比色アッセイは、基質のDEVD−pNAの切断から生じる発色団のp−ニトロアニリド(pNA)を追跡する。DEVD−pNAは、活性なカスパーゼ−3に対する公知の基質であり、そして処置後の異なる時点で調製された細胞抽出物に添加され得、そしてサンプルは、カスパーゼ−3活性を評価するために分析され得る。
Claims (14)
- 望ましくない脈絡膜新血管構造により特徴づけられる哺乳類の眼球状態の処置における、同時の、別々の、または連続した使用のためのアポトーシス調節因子および光増感剤の組合せ剤。
- 光増感剤が、ルテチウムテキサフィリン、ベンゾポルフィリン、ベンゾポルフィリン誘導体、ヘマトポルフィリンまたはヘマトポルフィリン誘導体を含む、前記使用のための請求項1に記載の組合せ剤。
- アポトーシス調節因子が、アポトーシス促進因子、アポトーシス刺激因子またはアポトーシス抑制因子である、請求項1に記載の使用のための請求項1または2に記載の組合せ剤。
- アポトーシス調節因子が、アポトーシス抑制因子である、請求項1に記載の使用のための請求項3に記載の組合せ剤。
- 望ましくない脈絡膜新血管構造により特徴づけられる眼球状態の処置における、組合せでの使用のための、第1および第2医薬の製造でのアポトーシス調節因子および光増感剤、各々の使用であって、アポトーシス調節因子が、請求項1、3または4のいずれか1項に記載したものであり、光増感剤が、請求項1または2に記載したものである、使用。
- 望ましくない脈絡膜新血管構造により特徴づけられる眼球状態の処置用医薬の製造でのアポトーシス調節因子および光増感剤の使用であって、アポトーシス調節因子が、請求項1、3または4のいずれか1項に記載したものであり、光増感剤が、請求項1または2に記載したものである、使用。
- 望ましくない脈絡膜新血管構造により特徴づけられる眼球状態の処置における、光力学的治療と組合せた使用のための医薬の製造でのアポトーシス調節因子の使用であって、アポトーシス調節因子が、請求項1、3または4のいずれか1項に記載したものである、使用。
- 望ましくない脈絡膜新血管構造により特徴づけられる眼球状態の処置における、アポトーシス調節因子と組合せた光力学的治療での使用のための医薬の製造での光増感剤の使用であって、光増感剤が、請求項1または2に記載したものである、使用。
- アポトーシス調節因子および光増感剤を含むキットであって、アポトーシス調節因子が、請求項1、3または4のいずれか1項に記載したものであり、光増感剤が、請求項1または2に記載したものであって、所望により、使用のための指示書を含む、キット。
- アポトーシス調節因子および光増感剤を含む組成物であって、アポトーシス調節因子が、請求項1、3または4のいずれか1項に記載したものであり、光増感剤が、請求項1または2に記載したものである、組成物。
- アポトーシス調節因子および光増感剤が、望ましくない脈絡膜新血管構造の処置において相乗的な効果を有する、請求項1から4のいずれか1項に記載の組合せ剤。
- アポトーシス調節因子および光増感剤が、望ましくない脈絡膜新血管構造の処置において相乗的な効果を有する、請求項5から8のいずれか1項に記載の使用。
- アポトーシス調節因子および光増感剤が、望ましくない脈絡膜新血管構造の処置において相乗的な効果を有する、請求項9に記載のキット。
- アポトーシス調節因子および光増感剤が、望ましくない脈絡膜新血管構造の処置において相乗的な効果を有する、請求項10に記載の組成物。
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JP2013082746A (ja) | 2013-05-09 |
US20120323162A1 (en) | 2012-12-20 |
US20140163451A1 (en) | 2014-06-12 |
ATE552855T1 (de) | 2012-04-15 |
EP1253943B1 (en) | 2008-09-03 |
EP1997513A1 (en) | 2008-12-03 |
AU2001234979B2 (en) | 2006-07-27 |
CA2714081C (en) | 2013-08-06 |
JP5749750B2 (ja) | 2015-07-15 |
US7125542B2 (en) | 2006-10-24 |
US20030185834A1 (en) | 2003-10-02 |
EP1253943A2 (en) | 2002-11-06 |
US20030175282A1 (en) | 2003-09-18 |
CA2714081A1 (en) | 2001-08-16 |
WO2001058240A2 (en) | 2001-08-16 |
EP1997513B1 (en) | 2012-04-11 |
US20110144035A1 (en) | 2011-06-16 |
AU3497901A (en) | 2001-08-20 |
CA2398901C (en) | 2010-11-16 |
WO2001058240A3 (en) | 2002-04-11 |
ATE406914T1 (de) | 2008-09-15 |
US20020040015A1 (en) | 2002-04-04 |
US20090286743A1 (en) | 2009-11-19 |
DE60135633D1 (de) | 2008-10-16 |
CA2398901A1 (en) | 2001-08-16 |
ES2311507T3 (es) | 2009-02-16 |
JP2003530146A (ja) | 2003-10-14 |
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