JP2020511148A - 血管新生阻害剤としてのc型レクチンであるレベセチン - Google Patents
血管新生阻害剤としてのc型レクチンであるレベセチン Download PDFInfo
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Abstract
Description
1)α鎖とβ鎖との間の鎖内又は鎖間ジスルフィド架橋に関連するシステイン残基、すなわち、配列番号1のCys27、Cys38、Cys55、Cys106、Cys129、Cys149及びCys154と、配列番号3のCys27、Cys38、Cys55、Cys100、Cys123、Cys136及びCys144(Jebali et al. 2009)、並びに/又は、
2)HCYドメインの残基、すなわち、配列番号1のHis37、Cys38、Tyr39と、配列番号3のHis37、Cys38、Tyr39(Jebali et al. 2009)、並びに/又は、
3)DAEKドメインの残基、すなわち、配列番号1のAsp50、Ala51、Glu52及びlys53と、配列番号3のAsp50、Ala51、Glu52及びlys53(Jebali et al. 2009)、並びに/又は、
4)WIGLモチーフの残基、すなわち、配列番号1のTrp94からLeu96と、配列番号3のTrp94からLeu96(Zelensky et al., 2005)、に一致する。
(動物)
3週齢及び11週齢のC57BL/6JRj雄マウス並びに4日齢のLewisラットをJanvier Labs (Le Genest- Saint-Isle, France)から購入した。11週齢のCX3CR1+/GFP雄マウスをJackson Laboratory (Bar Harbor, USA)から購入した。動物を特定の病原体がいない、12時間毎の明暗サイクルで水及び通常の規定食を自由にとれる条件下で動物施設に収容した。
Lewisラットの断頭後、胸部大動脈を1mm厚に切断し、48well組織培養プレートにおいて15μlの増殖因子低減フェノールレッドフリーマトリゲル(Corning, Boulogne Billancourt, France)で覆った。大動脈リングを、10%ウシ胎児血清、1%ペニシリン/ストレプトマイシン及び0.2%ファンギゾンを添加したダルベッコ改変イーグル培地(DMEM)(Thermo Fisher Scientific, Villebon-sur-Yvette, France)で3日間培養した(Lavalette, S. et al. 2011)。培養組織を、M. lebetina毒から単離されたLCTに、異なる用量(30nM、300nM、1.5μM)で3日目(D3)から6日目(D6)まで曝露した。対照培養組織は、LCTの添加無しのDMEM中で培養した。それぞれの培養組織の写真を、D3からD6までで撮影した。D3におけるそれぞれの大動脈リング及びインキュベーション前の発芽の表面を、D6における表面から差し引いて、LCTの有無で起こる血管発芽を算出した。発芽領域を、Fijiソフトウェア(Schindelin, J. et al. 2012)で定量した。データはD6とD3との間の割合の増加で示される。
C57BL/6JRjマウスから眼を摘出し、解剖前に氷冷内皮細胞用培地(EGM−2)(Lonza, Levallois-Perret, France)で維持した。他の眼組織から脈絡膜を分離し、約1mm×1mmに切断した。脈絡膜断片を単離し、48wellプレートに播かれた増殖因子減少フェノールレッドフリーマトリゲル(Corning, Boulogne Billancourt, France)に置いた。
瞳孔をトロピカミド(ミドリアティカム)(Thea, Clermont-Ferrand, France)及びフェニレフリン(ネオシネフリン)(Europhta,Monaco)で拡張した。マウスを、イソフルラン(2%)(Axience, Pantin, France)の吸入で麻酔し、スペクトラルドメイン光干渉断層撮影(SD−OCT)イメージング装置(Bioptigen 840 nm HHP; Bioptigen, North Carolina, USA)の前に載置した。上網膜の約0.1又は1.4mmにおける視神経円板から画像を得た。SD−OCTを、以前に説明されるように(Dominguez, E. et al. 2015)較正した(1ピクセル=1.6μm)。網膜層、内顆粒層(INL)、外顆粒層(ONL)及び視細胞外節(OS)の厚さを、Fijiソフトウェア(Schindelin, J. et al. 2012)によって、7日目の視神経の中心から500μmの箇所で測定した。
PBS及びM.lebetina毒から単離されたLCT(500μM)の注射後7日間ERGを行った。C57BL/6JRjマウスを一晩中、暗順応させ、その後にケタミン(100 mg/kg, Virbac, Carros, France)及びキシラジン(10mg/kg, Bayer HealthCare, Berlin,Germany)の腹腔内注射により麻酔した。瞳孔をフェニレフリン(ネオシネフリン)(Europhta, Monaco)及びトロピカミド(ミドリアティカム)(Thea,Clermont-Ferrand, France)で拡張した。角膜をオキシブプロカイン塩酸塩(Thea,Clermont-Ferrand, France)で麻痺させた。体温を温熱パッドを用いて37℃に維持した。上眼瞼及び下眼瞼を引き込ませて、眼を開き、膨らんだ状態で維持した。金ループ電極を、各角膜の表面に接触させて置き、ルブリタル(Zubial, Auros, France)で保持して、ERGを記録した(Espion,Diagnosys LLC, Lowell, MA, USA)。参照電極及び接地電極を、それぞれ動物の額及び背中に配置した。ガンツフェルト刺激装置(Espion, Diagnosys LLC, Lowell, MA, USA)により光刺激を提供した。1チャンネルDC/AC増幅器により反応を増幅及びフィルタリング(1 Hz−low及び 300 Hz−high カットオフフィルター)した。5つのレベルの刺激強度(0.003cd.s/m2;0.03cd.s/m2;0.3cd.s/m2;3cd.s/m2;10cd.s/m2)を、暗順応ERG記録のために用いた。各暗順応ERG反応は、5つのフラッシュの刺激の1セットから5つの反応の平均を示す。
C57BL/6JRjマウスをケタミン(100 mg/kg, Virbac, Carros, France)及びキシラジン(10mg/kg, Bayer HealthCare, Berlin,Germany)の腹腔内注射により麻酔した。瞳孔を拡張し、slit lamp (BQ 900, Hagg-Streitt, Chambery, France)に搭載されたLaser Yag 532 Eyelite(Alcon, Rueil-Malmaison, France)で4回のレーザ凝固(400 mW,50 ms, スポットの大きさ100 μm)を行った。レーザ凝固及びブルッフ膜の裂傷を、泡の迅速な観察により確認した(Lavalette, S. et al. 2011, Berger, A. et al. 2014)。レーザ処理の後すぐに又は3日後に、マウスに対して1μlのPBS、M. lebetina毒から単離したLCT(500μM)、組換えLCT(500μM)又はアフリベルセプト(25μM)を注射した。
乳母と共にC57BL/6JRj仔マウスを、以前の報告(Connor, K. M. et al. 2009)のように生後7日目(P7)に連続5日間75%酸素に曝露した。P12において、マウスを室内気に戻し、PBS、M. lebetina毒から単離したLCT(500μM)、組換えLCT(500μM)又はアフリベルセプト(25μM)を注射した。P17において、マウスをCO2吸入により屠殺し、網膜を解剖した。虚血(VO)及び血管新生(NV)領域を、MetaMorphソフトウェア(Molecular Devices, Saint-Gregoire, France)により、免疫染色されたフラットマウント網膜で算出した。
インテグリンサブユニットαV、α5、β3及びβ5遺伝子の発現を、レーザ損傷後0、1、3及び7日目におけるCNVモデルにおいて、逆転写定量ポリメラーゼ連鎖反応(RT−qPCR)により定量した。脈絡膜をRNaseフリー条件で解剖した。総RNAをNucleospin RNAII(Macherey Nagel, Hoerdt, France)で単離した。一本鎖cDNA、プライマーとしてのオリゴdT及びsuperscript II逆転写酵素(Thermo Fisher Scientific, Villebon-sur-Yvette, France)を用いて、(DNaseIの増幅グレード(Thermo Fisher Scientific, Villebon-sur-Yvette, France)で前処理された)総RNAから合成した。リアルタイムポリメラーゼ連鎖反応を、cDNAと、SYBR Green Gene Expression Master Mix (Thermo Fisher Scientific, Villebon-sur-Yvette, France)と、以下のプライマー(0.5 pmol/μl) (Life Technologies, Saint-Aubin, France):GAPDHセンス:5’−ACG GCC GCA TCT TCT TGT GCA−3’(配列番号5) ; GAPDHアンチセンス:5’−CAG GCG CCC AAT ACG GCC AA−3’(配列番号6); ITGAV センス:5’−CAC CCT CAG AGA GGG AGA TG−3’(配列番号7);ITGAVアンチセンス:5’−ACG TAC AGG ATT GCG CTC TT−3’(配列番号8);ITGA5センス:5’−AGT ACG CAC CTT GCC GCT CA−3’(配列番号9); ITGA5アンチセンス:5’−ACA CGG CCA GTC TTG GTG AAC−3’(配列番号10);ITGB3 センス:5’−AAC CGG GGA ACG CTC CAT GA−3’(配列番号11);ITGB3アンチセンス:5’−CGG CGT TTT TGC CAG TAT CCG−3’(配列番号12);ITGB5センス:5’−AGC CTT TGG GGA GAC GTG TGA−3’(配列番号13);ITGB5アンチセンス:5’−TGG TGG TGG CAG GTC TGG TT−3’(配列番号14)とを用いて行った。
LCTを以前に説明されるように入手した(Sarray, S. et al. 2003)。簡潔に説明すると、M.lebetinaの毒をSephadex G−75カラムを用いてゲルろ過した。まず、LCTをMono S (HR5/5)カラムでFPLCにより精製し、0〜1Mの線形勾配NaClで溶出した。LCTを凍結乾燥し、次にPBSで溶解した。LCTの調製品質を、アセトニトリルの線形勾配を用いたC8逆相HPLCカラムで試験した(Sarray, S. et al. 2003)。アフリベルセプト(Eylea; Bayer,Lyon, France)は、Chiara Eandi博士(University of Torino)及びAudrey Giocanti−Auregan博士(Hopital Avicenne Paris)により親切に提供された。インビボ研究のために、1μlの以下の溶液を硝子体に注射した:500μMのLCT(15μg/μl)又は25μMのアフリベルセプト(2.5μg/μl)。いくつかの実施例において、2μlのPBS又は標識化LCT、標識化アフリベルセプト又は標識化BSAを右目に注射した。
α(配列番号15)及びβ(配列番号16)LCTサブユニット(ペプチドシグナルMACPGFLWALVISTCLEFSMAを含む(配列番号17))をコードする2つの核酸配列は、2つのpCDNA3.1(+)プラスミドにクローニングした。α及びβLCTサブユニットの成熟配列は、それぞれ配列番号2及び18である。βLCT配列は、C末端ドメインに6ヒスチジンタグを含む。HEK expi293細胞に2つのコンストラクトをコトランスフェクションした。その4日後に上清を500g、4℃で15分間の遠心分離により回収し、その後、−20℃で保管する前に15900g、4℃で30分間の遠心分離及び0.22μmのフィルタでろ過した。上清を、室温でエンドトキシンフリーの条件で精製した。上清を解凍し、300mLにまで濃縮し、リン酸緩衝液(NaPO420mM;NaCl 300mM;pH7.2)を用いてタンジェンシャルフロー・フィルトレーション(TFF)5kDa−0.1m2カセット(Centramate serie T, PALL)で完全にろ過した。10mMのイミダゾールを加え、ヒスチジンタグ化タンパク質をHitrap IMACセファロースFF5mL(GE healthcare Life Sciences)カラムで精製した。前平衡化及び洗浄ステップを、20mMのNaPO4緩衝液;pH7.2;300mMのNaCl、10mMのイミダゾールで行った。40mMのイミダゾールの段階で、ほとんどの汚染物質(他の細胞のタンパク質)を除去させた。80〜500mMのイミダゾールの勾配で溶出を行った。LCTを溶出するために最適なイミダゾールの濃度は165mMである。溶出された分画をプールし、その後に、イミダゾールの除去のために濃縮及びVivaspin(登録商標)3kDa(GE healthcare Life Sciences)でろ過した。タンパク質をTBS緩衝液(tris−HCl20mM;NaCl 150mM;pH7.5)に再懸濁し、0.22μmの膜でろ過した。
LCT(500μM)、アフリベルセプト(25μM)及びウシ血清アルブミン(BSA、15.4μM)を標識するためにAlexa Fluor 647 microscale protein labeling Kit(Thermo Fisher Scientific, Villebon-sur-Yvette, France)を用いた。タンパク質を1Mの重炭酸ナトリウムで溶解し、タンパク質の第一級アミンと反応するAlexaFluor 647スクシンイミドエステルと混合し、4℃で1時間インキュベートした。室温でコンジュゲートタンパク質を供給されたスピンカラムを用いて未反応の色素から分離した。最終濃度を、製造者の忠告に従って最初の濃度の1/4に見積もった。
CNVの7日後に、PBS、又は647−LCT、ケタミン(100 mg/kg, Virbac, Carros, France)及びキシラジン(10mg/kg, Bayer HealthCare, Berlin,Germany)の混合液300μLを、深い麻酔をかけられた動物に腹腔内注射した。マウスに対して5mLの0.9%NaCl溶液、続いて30mLの4%パラホルムアルデヒド溶液により上行大動脈を介して灌流した。固定後、脳を注意深く解剖し、同一の固定剤で後固定を48時間行った。フリーフローティング切片(40μm)をビブラトーム(Leica Microsystems, Wetzlar, Germany)を用いて行った。
マウスをCO2の吸入により安楽死させた。眼を摘出し、4%パラホルムアルデヒドにより室温で30分間固定した。PBSで数回洗浄した後、角膜及びレンズを除去し、網膜を注意深くRPE/脈絡膜/強膜から分離した。
データ分析及びグラフィック表示のために、GraphPad Prism(GraphPad Software, San Diego, USA)を用いた。すべての値を平均値±SEMで示した。データをマン−ホイットニーのU検定、一元配置分散分析に続くボンフェローニ又はダネットのポストテストで分析した。P<0.05を統計的に有意とみなした。
(実施例1:LCTが大動脈及び脈絡膜外植片からの血管発芽を阻害する)
LCTは、インビトロにおける内皮細胞の増殖及び血管形成を阻害する(Pilorget, A. et al. 2007)。LCTがエクスビボで血管新生を阻害するか否かを試験するために、我々はマトリゲルにてマウスの大動脈リングを培養した(Lavalette, S. et al. 2011)。大動脈リングを3日間培養して血管発芽させ、その後に漸増用量のLCTで処理した。LCTを加えた後の3日間に、血管発芽領域を定量し、D3とD6との間での発芽領域の(割合の)増加を示した(図1A及びB)。参照条件において、D3とD6との間で血管発芽が259%増大した。30nMの最小濃度で加えたLCTは血管発芽に影響せず、300nMのLCTはD3からD6までで血管発芽を85%減少させた。1.5μMの用量のLCTは発芽を完全に阻害し、既存のD3における血管発芽の退縮を引き起こした(図1B)。LCTの用量の増大は、外植片から生じ、プラスチックディッシュの表面で増殖する線維芽細胞に特に影響はなかった。次に、LCT活性について、脈絡膜−毛細血管床からの血管の形成を厳密に再現したマウスの脈絡膜外植片モデル(Shao, Z. et al. 2013)で試験した。脈絡膜は以前に説明されるように培養組織として培養した(Shao, Z. et al. 2013)。大動脈リングの場合のように、培養組織をD3のときにLCTで処理し、D6で分析した(図1C及びD)。まず、我々は、大動脈リングにおいて血管退縮が生じた用量を用いた。参照条件と比較して1.5μMのLCTで血管発芽を78%阻害したが、D3と比較して未だ286%の増大が見られた。5μMにおいて、LCTは血管の成長を有効に阻害したが、既存のD3における血管発芽を退縮できなかった。最後に、15μMにおいて、LCTはD3の発芽を退縮した(図1D)。従って、LCTは血管新生の2つの独立したエクスビボモデルにおける血管発芽を有効に抑制した。
エクスビボの試験は、血管新生の阻害に必要な用量における変動性を示した。従って、我々は、レーザ誘発脈絡膜血管新生(CNV)のモデルにおける血管新生を抑制するのに必要な濃度を決めるための予備実験を行った。硝子体の体積が5.3μlとして(Remtulla, S. Et al. 1985)、1μlのLCTを硝子体注射に用い、LCTの初期濃度はその初期濃度の1/5に見積もられ得る。その薬物動態に依存して、LCTは全ての眼のコンパートメント(10μl)に達し、その濃度は、初期濃度の1/10に低減し得る。従って、動物に対して、概算で15μM(脈絡膜外植片の発芽を退縮する濃度)又は50μM(我々が毒から生成できる最も高い濃度)の最終濃度になるように1μlの150又は500μMのLCTを硝子体内注射した。我々は、150μMのLCTを1μl硝子体内注射することはCNVを抑制するのに十分でなく、500μlのLCTを1μl注射することは血管新生領域を低減することを判定した。500μMのLCTの単回注射が網膜構造を変更するか否かを試験するために、我々は、参照の生体マウスにLCTを注射し、7日後にそれらの網膜を試験した。網膜構造をSD−OCTにより分析した。OCTは、網膜の全体構造において顕著な汎化を示さなかった(図2A)。内及び外顆粒層並びに外側の領域の全体の網膜の厚さは、参照とLCTを注射した眼との間で統計的な差は無かった(図2B)。ERG反応を、注射から7日後の参照動物及び処理動物から記録した。LCTの硝子体内注射は、参照又はPBS注射動物と比較して、0.003から10cds/m2の範囲の強度において記録された暗順応EGRを変更しなかった(図2C;D)。同様に、明順応反応(図2E)及びフリッカー反応(図2F;G)は、参照動物と比較してLCT注射後に変更されなかった。
我々は、LCTがインビトロでのHBMECの増殖及び管形成(Pilorget, S. et al. 2007)、並びに血管新生のエクスビボモデルでの血管発芽(図1)を血管完全性に影響なく(図3)阻害することを示した。LCTがインビボで血管新生を阻害するか否かを試験するために、LCT活性をCNVマウスモデルで評価した。インテグリンサブユニットαv及びα5は、ラットCNVモデルにおいてD3からD7まで増大されることが最近に示された(Nakajima, T. et al. 2014)。我々は、レーザ誘発脈絡膜損傷後の異なる時点でのマウス脈絡膜におけるインテグリンサブユニットαv、α5、β3及びβ5の発現を定量した。D0において脈絡膜損傷を眼科用レーザで誘発し、D1、D3及びD7で脈絡膜を回収した。これらのサブユニットの発現をRT−qPCRにより分析し、非損傷脈絡膜(D0)と比較した。全てのサブユニットの発現は、損傷後24時間以内に増大が見られ、D3でピークとなった。D7において、αvは基底レベルに戻ったが、α5、β3及びβ5は高いレベルを維持した(図4A)。硝子体内注射後のLCT結合特異性を決定するために、次に我々は、レーザ損傷された眼の硝子体内に標識分子を注射した。ウシ血清アルブミン(BSA)、LCT及びアフリベルセプトに、マイクロスケールタンパク質標識キットを用いてAlexaFluor647色素を共有結合的にコンジュゲートし、その後に精製し、屠殺(D7)の3日前(D4)に右眼に注射した。左眼にはPBSを注射した。Alexa Fluor647にコンジュゲートされたBSA(647−BSA)は、CD102陽性CNV損傷を標識しなかった。これに対して、647−LCT及び647−アフリベルセプトは、脈絡膜フラットマウントにおいてCD102陽性CNVを標識した(図4D;E)。その後、網膜フラットマウントをコラーゲンIVで標識して、血管基底膜及び沈着物を検出した。強い647−LCTの標識は、CNV損傷に面する網膜の外側部分に見られ、弱い標識はLCT注射された眼の大きい血管で観察された。反対側のPBSが注射された眼では標識は見られなかった。次に、我々は、647−LCTが注射された動物における視神経、三叉神経及び脳の異なる領域における647−LCTの標識を分析し、PBSのみが注射された動物の標識と比較した。LCTは、視神経及び三叉神経において検出されず(図示せず)、海馬、梨状皮質、前帯状皮質、視床下部、腹側視索前核(VMPO)及び尾状核被殻(線条体)においても検出されなかった。さらに、我々は神経細胞障害を示すATF3標識を検出しなかった(Launay, P. S. et al. 2016; Tsujino, H. et al. 2000)。
次に我々は、OIRモデルにおいて、いくつかの静脈うっ血性網膜症の特徴である網膜血管新生におけるLCTの効果を試験した。このモデルは、網膜の血管損失、血管再生、血管新生及び新生血管の退縮を理解するために広く用いられている(Connor, K. M. et al. 2009)。げっ歯類の新生児に対してP7からP12に高酸素を与えることにより網膜の血管新生を誘導して、生理学的な血管発生を阻害する。動物が室内気に戻されると、相対的な網膜の低酸素がP12からP17の間で重度の網膜血管新生を引き起こす(Smith, L. E. et al. 1994)。LCTの結合特異性を決定するために、まず我々は、OIRを受けた動物に対して、P17での屠殺の3日前にAlexaFluor647コンジュゲートLCT(647−LCT)を硝子体内に注射した。647−LCTは、BS−1レクチン陽性新生血管房を強く標識したが、網膜血管系は標識しなかった(図7A)。OIRモデルにおけるLCTの抗血管新生特性を評価するために、P7マウスに対してOIRを受けさせて、12日目に1μlのPBS又は500μMのLCTを注射し、室内気に戻した。マウスをP17で屠殺し、虚血(VO)及び血管新生領域(NV)を、以前に説明されるように(Stahl, A. et al. 2009)BS−1を用いて染色された網膜フラットマウントで決定した。LCTは、PBS注射と比較してVOの比率を変更しなかった(図7B;D)。対照的に、P12でのLCTの単回注射は、P17において網膜血管新生で覆われる領域を48.1%低減した(図7B;E)。LCT処理を抗VEGF治療と比較するために、網膜形成に影響なくNVの低減を示す用量( Stahl, A. et al. 2009)である25μMのアフリベルセプトをP12において注射し、NV及びVOをLCT動物と比較した。LCT処理とアフリベルセプト処理との間でVO及びNVの差は見られなかった。
次に我々は、OIRモデルの網膜血管新生に対するLCT及びアフリベルセプトの同時注射の効果を試験した。OIRモデルへのLCT及びアフリベルセプトの同時注射の抗血管新生特性を評価するために、P7マウスに対してOIRを受けさせ、12日目に1μlのPBS、500μMのLCT、25μMのアフリベルセプト、又は500μMのLCT及び25μMのアフリベルセプトを注射し、室内気に戻した。マウスをP17で屠殺し、虚血(VO)及び血管新生領域(NV)を、BS−1レクチンで染色された網膜フラットマウントにおいて決定した。LCT及びアフリベルセプトの同時注射は、PBSと比較してVOの比率を変更しなかった(図8)。対照的に、LCT及びアフリベルセプトの同時注射は、アフリベルセプト又はLCTの単独よりも強い血管新生阻害を起こした。
脈絡膜の毛細血管床からの血管の形成を厳密に再現するマウス脈絡膜培養組織モデル(Shao, Z. et al. 2013)において、組換えLCT活性を試験した。脈絡膜を以前に説明された培養組織と同様に(Shao, Z. et al. 2013)、培養した。培養組織をD3において組換えLCT(rLCT)で処理し、D6において分析した(図9)。参照条件と比較して、1.5μMのrLCTは血管発芽を65.0%阻害した。
次に我々は、OIRモデルにおいて、重度の静脈うっ血性網膜症の特徴である網膜の血管新生における組換えLCTの効果を試験した。網膜の血管新生は、生理学的血管形成を阻害するために、げっ歯類の新生児にP7からP12において高酸素を与えることにより誘導される。動物が室内気に戻された際に、相対的な低酸素がP12からP17において重度の網膜血管新生を引き起こす(Smith, L. E. et al. 1994)。OIRモデルにおけるrLCTの抗血管新生特性を評価するために、P7マウスに対してOIRを受けさせ、12日目に1μlのPBS又は500μMのrLCTを注射し、室内気に戻した。マウスをP17において屠殺し、虚血(VO)及び血管新生領域(NV)を、以前に説明されるように(Stahl, A. et al. 2009)BS−1レクチンで染色された網膜フラットマウントにおいて決定した(図10A)。rLCTは、PBS注射と比較してVOの比率を変更しなかった(図10B)。対照的に、P12におけるrLCTの単回注射は、P17における網膜血管新生により覆われた領域を22.1%低減した(図10C)。
組換えLCTがインビボにおける血管新生を阻害するか否かを試験するために、rLCT活性をCNVマウスモデルにおいて評価した。D0において眼科用レーザを用いて脈絡膜損傷を誘発し、D7で脈絡膜を回収した。インビボにおけるrLCTの抗血管新生特性を決定するために、我々は、D7においてCD102で染色された脈絡膜フラットマウントにおける新生血管により覆われた領域を定量した(図11A)。CNV領域は、rLCT注射の7日後に顕著に29.8%低減した(図11B)。
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Claims (20)
- 血管新生疾患の治療に用いるための、レベセチン及びその機能的変異体又は断片から選択されるタンパク質。
- レベセチンである請求項1に記載のタンパク質。
- 配列番号1又は配列番号2のアミノ酸配列からなる又は含む第1サブユニットと、
配列番号3又は配列番号4のアミノ酸配列からなる又は含む第2サブユニットと、を含む請求項2に記載のタンパク質。 - 配列番号2のアミノ酸配列からなる又は含む第1サブユニットと、
配列番号4のアミノ酸配列からなる又は含む第2サブユニットと、を含む請求項2に記載のタンパク質。 - 配列番号1又は配列番号2の配列と少なくとも75%の同一性を有するアミノ酸配列からなる又は含む第1のサブユニットと、
配列番号3又は配列番号4の配列と少なくとも75%の同一性を有するアミノ酸配列からなる又は含む第2のサブユニットと、を含むレベセチンの機能的変異体である請求項1に記載のタンパク質。 - 配列番号1又は配列番号2の配列と少なくとも90%の同一性を有するアミノ酸配列からなる又は含む第1サブユニットと、
配列番号3又は配列番号4の配列と少なくとも90%の同一性を有するアミノ酸配列からなる又は含む第2サブユニットと、を含むレベセチンの機能的変異体である請求項1又は5に記載のタンパク質。 - 配列番号2の配列と少なくとも90%の同一性を有するアミノ酸配列からなる又は含む第1サブユニットと、
配列番号4の配列と少なくとも90%の同一性を有するアミノ酸配列からなる又は含む第2サブユニットと、を含むレベセチンの機能的変異体である請求項1、5及び6のいずれか1項に記載のタンパク質。 - 配列番号2の配列と比較して1〜10、好ましくは1〜5の変異アミノ酸残基を有する配列からなる又は含む第1サブユニット、及び/又は、
配列番号4の配列と比較して1〜10、好ましくは1〜5の変異アミノ酸残基を有する配列からなる又は含む第2サブユニットを含むレベセチンの機能的変異体である請求項1及び5〜7のいずれか1項に記載のタンパク質。 - 配列番号1又は配列番号2に由来し、1〜30のアミノ酸配列の保存的置換を含む配列からなる又は含む第1サブユニット、及び/又は、
配列番号3又は配列番号4に由来し、1〜30のアミノ酸配列の保存的置換を含む配列からなる又は含む第2サブユニットを含むレベセチンの機能的変異体である請求項1及び5〜7のいずれか1項に記載のタンパク質。 - 1)α鎖とβ鎖との間の鎖内又は鎖間ジスルフィド架橋に関与するシステイン残基、すなわち配列番号1のCys27、Cys38、Cys55、Cys106、Cys129、Cys149及びCys154、並びに、配列番号3のCys27、Cys38、Cys55、Cys100、Cys123、Cys136及びCys144;
2)HCYドメインの残基、すなわち配列番号1のHis37、Cys38及びTyr39、並びに、配列番号3のHis37、Cys38及びTyr39;
3)DAEKドメインの残基、すなわち配列番号1のAsp50、Ala51、Glu52及びlys53、並びに、配列番号3のAsp50、Ala51、Glu52及びlys53;及び/又は
4)WIGLモチーフの残基、すなわち配列番号1のTrp94〜Leu96、及び配列番号3のTrp94〜Leu96、
に対応する残基が保存されているレベセチンの機能的変異体である請求項1及び5〜9のいずれか1項に記載のタンパク質。 - M. lebetinaの毒から単離された請求項1〜4のいずれか1項に記載のタンパク質。
- 組換えタンパク質である請求項1〜10のいずれか1項に記載のタンパク質。
- 血管新生疾患の治療に用いるための、請求項1〜12のいずれか1項に記載のタンパク質をコードする核酸配列、又は該核酸配列を含む発現ベクター。
- 血管新生疾患の治療に用いるための、請求項1〜12のいずれか1項に記載のタンパク質又は請求項13に記載の核酸配列若しくはベクターと、医薬的に許容可能な賦形剤とを含む医薬組成物。
- 少なくとも1つの追加の有効成分、好ましくは血管新生阻害剤をさらに含む請求項14に記載の医薬組成物。
- 少なくとも1つの血管新生阻害剤と組み合わせて用いられる請求項14又は15に記載の医薬組成物。
- 前記血管新生阻害剤は、VEGF経路の阻害剤、好ましくはアフリベルセプトである請求項15又は16に記載の医薬組成物。
- 前記血管新生疾患は、眼の血管新生疾患及び血管新生要素を含む癌、好ましくは肺癌、乳癌、胃癌、大腸癌、膵臓癌及び脳癌からなる群から選択される請求項1〜12のいずれか1項に記載のタンパク質、請求項13に記載の核酸配列若しくはベクター、又は請求項14〜17のいずれか1項に記載の医薬組成物。
- 前記血管新生疾患は、眼の血管新生疾患、好ましくは加齢黄斑変性、糖尿病網膜虚血又は増殖性糖尿病網膜症等の糖尿病網膜変性症、虹彩血管新生、眼内血管新生、角膜血管新生、網膜血管新生、脈絡膜血管新生及び角膜炎からなる群から選択される請求項1〜12のいずれか1項に記載のタンパク質、請求項13に記載の核酸配列若しくはベクター、又は請求項14〜17のいずれか1項に記載の医薬組成物。
- 治療される対象は、血管新生阻害剤、好ましくはVEGF経路の阻害剤、より好ましくはアフリベルセプトによる治療に反応しない又は耐性となった対象である請求項1〜12、18及び19のいずれか1項に記載のタンパク質、請求項13、18及び19に記載の核酸配列若しくはベクター、又は請求項14〜19のいずれか1項に記載の医薬組成物。
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JP7179010B2 (ja) | 2022-11-28 |
US20190298797A1 (en) | 2019-10-03 |
KR20240025713A (ko) | 2024-02-27 |
WO2018108945A1 (en) | 2018-06-21 |
ES2901613T3 (es) | 2022-03-23 |
IL267298B1 (en) | 2023-07-01 |
EP3551211A1 (en) | 2019-10-16 |
CA3046283A1 (en) | 2018-06-21 |
JP2022119955A (ja) | 2022-08-17 |
EP3551211B1 (en) | 2021-09-01 |
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US11191807B2 (en) | 2021-12-07 |
IL267298B2 (en) | 2023-11-01 |
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