JP2021191768A - 腫瘍又は線維症の診断及び治療における使用のためのフィブロネクチン結合ペプチド - Google Patents
腫瘍又は線維症の診断及び治療における使用のためのフィブロネクチン結合ペプチド Download PDFInfo
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Abstract
Description
(i)少なくとも1つのフィブロネクチン結合ペプチド(FnBP)、及び
(ii)それと結合した少なくとも1つの診断薬又は治療薬
を含む組成物によって解決する。
(a)配列番号1から147、好ましくは配列番号117〜147、より好ましくは配列番号141、143及び145からなる群から選択されるアミノ酸配列を含むポリペプチド、
(b)配列番号1から147、好ましくは配列番号117〜147、より好ましくは配列番号141、143及び145からなる群から選択されるアミノ酸配列と少なくとも70%又は80%、好ましくは少なくとも90%又は95%のアミノ酸配列同一性を有するアミノ酸配列を含むポリペプチド、
(c)配列番号148から294、好ましくは配列番号264〜294、より好ましくは配列番号288、290及び292からなる群から選択される核酸配列を有する核酸によってコードされるアミノ酸配列を含むポリペプチド、
(d)配列番号148から294、好ましくは配列番号264〜294、より好ましくは配列番号288、290及び292からなる群から選択される核酸配列と少なくとも80%、好ましくは少なくとも90%又は95%の核酸配列同一性を有する核酸によってコードされるアミノ酸配列を含むポリペプチド、並びに
(e)(a)、(b)、(c)及び(d)のいずれかの機能的断片及び/又は機能的誘導体
からなる群から選択されるポリペプチドである組成物である。
(a)インテグリン阻害剤、好ましくは、WO2015/048819A1で開示されたインテグリン阻害剤、より好ましくは、図1で示したαvβ1インテグリン阻害剤及びWO2015/048819A1の表1に挙げたようなその他のインテグリンブロック化合物、
(b)骨形成タンパク質7(BMP-7)(例えば、Zhong等、Int. J. of Medical Sciences 2013年、10, 441〜450頁;Zhao X.-K.、World Journal of Gastroenterology 2014年、20, 14875〜14883頁参照)、
(c)レラキシン及びレラキシン様ペプチド、好ましくは、レラキシン-1又は2(例えば、Zhou等、Drug Design, Development and Therapy 2015年、9, 4599〜4611頁参照)、
(d)リシルオキシダーゼ(LOX)阻害剤ベータ-アミノプロピオニトリル(BAPN)(例えば、Erler等、Nature 2006年、440, 1222〜1226頁参照)、並びに
(e)リンパ節線維症を処置するためのインターロイキン-7(IL-7)(例えば、Fletcher等、(2015年 Nature Reviews Immunology, 15(6), 350〜361頁参照)
からなる群から選択される抗線維化剤である組成物を対象とする。
(a)免疫系を刺激するためのインターロイキン-12(Il-12)処置(例えば、Cicchelero, L.,等(2016)、Vet Comp Oncol.参照)
(b)がんを処置するためにEGFRシグナル伝達カスケードを標的とする阻害剤(例えば、Datta, J.,等(2015)、Breast Cancer Res 17: 71参照)
(c)多発性硬化症を処置するためのミエリンオリゴデンドロサイト糖タンパク質ペプチド配列35〜55(例えば、Getts, D. R.,等、Trends in Immunology, 2015年、36(7), 419〜427頁参照)
(d)(自己)免疫疾患の処置及び免疫調節のためのsiRNA(例えば、Katakowski, J. A.,等(2016)、Mol Ther 24(1): 146〜155頁参照)
(e)(自己)免疫疾患の処置及び免疫調節のためのmiRNA(例えば、Getts, D. R.,等、Trends in Immunology, 2015年、36(7),419〜427頁参照)
(f)免疫細胞機能を調節するための遺伝子編集機構(例えば、Getts, D. R.,等、Trends in Immunology, 2015年、36(7),419〜427頁参照)
(g)がん免疫療法のためのがんワクチン(例えば、Grivas, P.,等、(2017)、Ann Oncol 28(4): 680〜682頁参照)
(h)シプロイセル-T、がんを処置するための樹状細胞をベースにしたワクチン。その他の分子は、PSA-TRICOM、イピリムマブ及びキメラ抗原受容体T細胞療法を含むことができる(例えば、Yeku, O.及びS. F. Slovin (2016)、Cancer J 22(5):334〜341頁参照)
(i)免疫制御経路の標的化によって免疫系の抗腫瘍応答を増強する抗体、例えば、免疫チェックポイントを標的とする抗体、例えば、抗CTLA-4、抗PD1及び抗PD-L1抗体(例えば、Diesendruck, Y.及びI. Benhar (2017)、Drug Resist Updat 30: 39〜47頁;D'Errico, G.,等(2017)、Clin Transl Med 6(1): 3頁);Xia, B.及びR. S. Herbst (2016)、Immunotherapy 8(3): 279〜298頁; Topalian, S. L.,等(2016)、Nat Rev Cancer 16(5): 275〜287頁; Marrone, K. A.及びJ. R. Brahmer (2016)、Cancer J 22(2): 81〜91頁参照)、例えば、また細胞傷害性Tリンパ球抗原-4の免疫チェックポイント遮断及び抗腫瘍細胞傷害性T細胞応答を活性化するために有望な戦略として出現したプログラム死-1のための分子(例えば、Swart, M.,等(2016)、Front Oncol 6:233頁; Papaioannou, N. E.,等(2016)、Ann Transl Med 4(14):261頁)又はTAMファミリー受容体(例えば、Paolino, M.及びJ. M. Penninger (2016)、Cancers (Basel) 8(10))、また免疫チェックポイントのB7ファミリー(PD-L1、PD-L2、B7-H3、B7x及びHHLA2)を遮断する抗体(例えば、Janakiram, M.,等(2016)、Immunotherapy 8(7):809〜819頁参照)を含む
(k)免疫系のエピジェネティック制御を変化させるHDAC阻害剤(例えば、Hull, E. E.,等(2016)、Biomed Res Int 2016年:8797206参照)
からなる群から選択される免疫調節剤である組成物を対象とする。
(a)配列番号148から294、好ましくは配列番号264から294、より好ましくは配列番号288、290及び292からなる群から選択される核酸配列、
(b)配列番号148から294、好ましくは配列番号264から294、より好ましくは配列番号288、290及び292に挙げた核酸配列と、好ましくは全配列にわたって、少なくとも80%又は90%の同一性、好ましくは少なくとも95%の同一性、より好ましくは少なくとも98%の同一性を有する核酸配列、
(c)(a)又は(b)の核酸配列とストリンジェントな条件下でハイブリダイズする核酸配列、
(d)(a)又は(b)の核酸配列とストリンジェントな条件下でハイブリダイズする核酸配列(a)から(c)のいずれかの断片、並びに
(e)(a)又は(b)の核酸配列とストリンジェントな条件下でハイブリダイズする(a)から(d)の核酸の1つの置換、付加及び/又は欠失によって生じる核酸配列
からなる群から選択される核酸配列を含む核酸である。
ology, 72, 211, 2006年参照)、植物CaMV35S、ocs、nos、Adh-1、Tetプロモーター(例えば、Lau及びSun、Biotechnol Adv. 2009年、27, 1015〜22頁)又はSambrook及びRussell(2001)で記載された哺乳類細胞用の誘導性プロモーターからなる群から選択されるプロモーターに作動可能に結合する核酸である。
(a)治療薬及び任意選択で更に生理学的に許容される賦形剤及び希釈剤を生理学的に有効な量で含む本発明の組成物又はパーツキットを準備する工程、
(b)(a)の組成物又はパーツキットをそれらを必要とする対象に、好ましくは、静脈内投与によって投与する工程
を含む方法を対象とする。
(a)診断薬及び任意選択で更に生理学的に許容される賦形剤及び希釈剤を生理学的に有効な量で含む本発明による組成物又はパーツキットを準備する工程、
(b)(a)の組成物又はパーツキットをそれらを必要とする対象に、好ましくは、静脈内投与によって投与する工程、並びに、
(c)前記組成物中のフィブロネクチン結合ペプチド(FnBP)の蓄積によって病的フィブロネクチン蓄積を同定する工程
を含む方法を含む。
全般的な材料及び方法
Fnの単離及び標識化
Fnは、以前に記載されたように(E. Engvall及びE. Ruoslahti、「Binding of soluble form of fibroblast surface protein, fibronectin, to collagen」、Int. J. Cancer、20巻、1号、1〜5頁、1977年7月)、ゼラチンセファロースクロマトグラフィーを使用してヒト血漿(Zurcher Blutspendedienst SRK社、Switzerland)から単離した。血漿を解凍し、PD-10カラム(GE Healthcare社、Little Chalfont, UK)を通過させて凝集物を除去した。溶出液を収集し、ゼラチンセファロースカラムを通過させた。カラムを洗浄後、Fnを6M尿素溶液でゼラチンカラムから溶出した。次に、非標識Fnを使用する前にPBSで再緩衝化した。単一標識のために、Fnをグアニジニウム塩酸塩(GdnHCl、Applichem社、Darmstadt, Germany)4M溶液中で変性させ、FnIII7及びFnIII15の潜在的システインを開裂させた。Fnを過剰なCy5マレイミド色素(GE Healthcare社、Little Chalfont, UK)でインキュベートし、PD-10カラムを使用して色素から分離した。
放射性リガンド又はフルオロフォアで更に標識するために、ペプチドはS.アウレウス(aureus)の元のペプチド配列のN末端の3つのグリシン及び1つのシステイン残基のスペーサーを用いて商業的に合成した(Pichem社、Graz, Austria)。FnBPA5は、更に111Inで放射標識するために、マレイミド残基に結合した、又はマレイミドNODAGA複合体単位とコンジュゲートしたフルオロフォアを使用して標識した。ペプチドは、残存する遊離の結合残基を除去するために、コンジュゲート後にHPLC精製した。スクランブル配列を有するFnBPA5の陰性対照は、FnBPA5のFnへの結合が配列特異的であるかどうかを調べるために考案した。全ペプチド配列を図1Cに示す(配列番号295及び296)。凍結乾燥したペプチドを10%DMFを含む水中に溶解し、更に使用するまで-20℃で保存した。
手動で引っ張ったFn線維を以前に記載されたような線維性Fnのモデル系として使用した(W. C. Little, M. L. Smith, U. Ebneter、及びV. Vogel、「Assay to mechanically tune and optically probe fibrillar fibronectin conformations from fully relaxed to breakage」、Matrix Biology、27巻、5号、451〜461頁、2008年6月)。5%の光標識Fn-Cy5を含有する線維を伸長可能なシリコーンシートに沈着させ、全部で7%の分子緊張に対応する元の長さの半分まで弛緩させ、PBSに溶かした4%ウシ血清アルブミンによるブロッキング工程の後、様々な濃度のAlexa488蛍光標識FnBPA5でインキュベートして結合曲線を得た。
手動で引っ張ったFn線維試料をOlympus FV1000共焦点顕微鏡で、開口数0.9の40×水浸レンズを用いて撮像した。Alexa488-FnBPA5及びFn-Cy5チャネルは、512×512ピクセルの分解能で撮像し、光電子倍増管電圧及びレーザー出力は実験内で一定に維持した。
画像は、Fiji-ImageJ及びMatlab(MathWorks社、Natick, MA, USA)を使用して解析した。Fn線維親和性研究のために、Fn-Cy5強度によって除したFnBPA5-Alexa488シグナル強度のピクセル毎の比は、カスタムメイドのMatlab scriptを使用して線維毎に計算した。暗電流値は、画像から差し引いて、カットオフ閾値を下回る強度のピクセル及び飽和時のピクセルを解析から除外した。約10本の線維を実験条件毎に撮像し、これらの条件それぞれを三連で実施した。FnBPA5-Alexa488濃度10μMの結合比を1に設定し、その他の点は全てこの参照点に正規化した。データ点は、Hillモデルを使用して当てはめ非協同的結合(以下の式を使用する)と仮定し、Originを使用してプロットした。
フィブロネクチン結合ペプチド(FnBPA5)及びそのスクランブル誘導体(scraFnBPA5)を、Peptide Specialty Laboratories GmbH社(Heidelberg, Germany)から購入し、マレイミドNODAGAとコンジュゲートした。化合物をTraceSELECT(登録商標)水(Sigma Aldrich社)に溶解して、最終濃度を0.25mMにした。標識化のために、各ペプチド14nmolを0.5M酢酸アンモニウムpH5.5中で、111InCl3(Mallincrodt社、Wollerau, Switzerland)80MBqを添加し、その後50℃で30分間のインキュベーション工程によって放射標識した。品質管理は、radio-HPLC(Varian Prostar社、Santa Clara, USA)によって実施した;カラムDr.Maisch社Reprospher(Ammerbuch, Germany)300C18-TN、4.6cm×150mm、5μm、15%アセトニトリルから開始して95%までのアセトニトリル/水勾配を用いて流速1mL/分で15分間。
PC-3細胞(ヒト前立腺癌細胞株、ACC-465、DSMZ、Braunschweig, Germany)をロズウェルパーク記念研究所1640培地(Amimed、Bioconcept社、Switzerland)中で培養した。細胞を単層で37℃で5%CO2を含有する湿潤な雰囲気中で培養した。
統計解析は、両側t検定タイプ3(Microsoft Excel)を使用して実施した。p値が0.05より小さい場合に統計学的有意と見なした。
FnBPA又はその他のFnBPの結合特異性及び結合親和性を評価するための手動で引っ張ったFn線維系
Alexa488-FnBPA5及びそのスクランブル類似体のFn線維に対する結合定数を評価するために、上記及び下記のような線維伸長アッセイ(Little等、Matrix Biology、27巻、5号、451〜461頁、2008年6月)を使用した。Fn線維を、5%フルオロフォア標識Fnを含有するFn溶液から手動で引っ張り、シリコーン膜上に沈着させた。次に、所望の機械的緊張状態までシリコーン膜を伸長又は弛緩させることができる。溶液中のFnBPA5ペプチドに曝露した手動で引っ張ったFn線維の共焦点顕微鏡画像を図2Aに示す。FnBPA5ペプチドは、シグナルがバックグラウンド雑音内であるスクランブル対照誘導体よりもずっと強くFnに結合することを示した(図2A)。この結果は、いくつかの視野からの多数の線維の分析及び定量によって裏付けられる(図2B)。
FnBPA5又はその他のFnBPの細胞培養マトリクス中の線維性Fnへの結合の評価
このような固い結合が天然の細胞外マトリクス中でも観察できることを確認するために、線維芽細胞によって2日間アセンブルされた、Fnの豊富なECMを、固定前に天然の、又はスクランブルFnBPA5で1時間インキュベートし、FnBPA5は線維性Fnに特異的に結合するが、スクランブル誘導体は結合しないことを示した(図2C)。これを実現するために、正常なヒト皮膚線維芽細胞(PromoCell社、Heidelberg, Germany)をBioWest社、Nuaille, Franceの10%牛胎児血清(FBS)を含むアルファ最小必須培地(α-MEM)中で培養し、コンフルエントに達する前に分割した。細胞を、Fnをコーティングした8ウェルチャンバーカバーガラス(Lab-Tek, Nalgene Nunc、Thermo Scientific社、Waltham, MA, USA)にcm2当たり30×103細胞の密度で播種し、表面に結合させてから未標識Fn50μg/mlを含有する培地に培地交換した。細胞を48時間培養した。次に、フィブロネクチンをウサギポリクローナル抗フィブロネクチン抗体(ab23750、abcam社、Cambridge, UK)及びFnBPA5-Alexa488、scr-FnBPA5-Alexa488ペプチド5μg/mlそれぞれを使用して1時間染色してからPBSに溶かした4%パラホルムアルデヒド溶液で固定した。固定後、細胞を0.01%トリトンX-100を含有するPBSで10分間透過処理した。洗浄工程後、試料を4%BSA及び4%ロバ血清で1時間室温でブロックした。次に、試料をロバ抗ウサギAlexa546(Invitrogen社)第2抗体及びPhalloidin-633(Invitrogen社、Carlsbad, CA, USA)で1時間インキュベートした。画像処理する前に、DAPIを使用して細胞核を染色した。線維芽細胞ECM試料(図2C)は、Olympus FV1000共焦点顕微鏡で、油浸1.45NA 60×レンズを用いて1024×1024のピクセル分解能で取得した。次に、特異的結合はペプチドとFnとの共存によって、陰性対照としてスクランブルペプチド誘導体を用いて評価することができる(図2C)。
FnBPA5の血漿安定性
インビトロにおける血漿安定性を評価するために、111In-[FnBPA5-NODAGA]及び111In-[scraFnBPA5-NODAGA]12MBqをヒト血漿400μLで37℃でインキュベートした。様々な時点で(0、0.25、0.5、1、2、48及び72時間)、血漿40μLを採取し、EtOH、アセトニトリル、0.1%TFA200μLを添加することによって沈殿させた。試料を濾過後(MiniPrep, Qiagen社、Valencia, CA, USA)、上清をradio-HPLC(Varian Prostar社、USA)で分析した;カラムD-Bio Discovery C18、25×4.6、5μm、5%アセトニトリルから開始して95%までのアセトニトリル/水勾配を用いて、流速1mL/分で30分間。72時間後でも111In-FnBPA5ペプチドは依然としてインタクトで(図5)、したがってFnBPA5ペプチドはインビボにおける適用に使用するために十分な血漿安定性を有することが立証された。
蛍光偏光実験
FnのFnBPA5に対する結合親和性は、3つの独立した測定において、自動偏光子を装備したCary Eclipse蛍光分光光度計(Agilent Technologies社)における異方性滴定によって判定した。N末端Alexa-488色素を有するFnBPA5及びそのスクランブル誘導体を合成した。Alexa-488標識ペプチド100nMの異方性は、PBS中において、Fn濃度0から1.4μMの範囲で測定した。励起はλex480nm、放出はλem520nmで、いずれもスリットは10nm、20℃、シグナル取得5s及びg=1.4であった。Kd値は、Origin7(OriginLab社 Northampton, MA, USA)を使用してデータを1部位結合モデルに当てはめることによって判定した。
生きたマウスに注射した111In-FnBPA5の放射線トレース
SPECT/CT実験は、4台の多重マルチピンホールカメラ(NanoSPECT/CTplus、Bioscan Inc.社、Washington DC, USA)を使用して実施した。CTスキャンは、管電圧45kV及び管電流145μAを用いて実施した。注射して24、72及び96時間後のSPECTスキャンは視野当たりの取得時間20〜90秒で、マウス当たりの全スキャニング時間は20〜45分で得た。
生きたマウスに注射した111In-FnBPA5の薬物動態は、マウス前立腺腫瘍異種移植における長期蓄積を示す。
特にがん間質における組織特異的ペプチドの薬物動態は、111In-FnBPA5及び111In-scraFnBPA5約150kBq(2.4nmol/PBS100μL)それぞれを尾静脈に注射した4匹のPC-3を有するマウスの群において評価し、ペプチドの体内分布は、様々な時点(注射して1、4、24及び96時間後(p.i.及び殺処分後))において組織グラム当たりの注射した活性の割合(%IA/g)によって分析した。両ペプチドの等しい蓄積が腎臓において認められ(図4A、図B)、SPECT/CT画像による発見が裏付けられた(図5参照)。両方の場合において、p.i.の1時間後に最大に達するのが認められた(111In-FnBPA5では140.58±18.10%IA/g及び111In-scra FnBPA5では163.70±18.90%IA/g)。111In-FnBPA5はその他の試験した器官全てにおいて蓄積を示し(図4A)、そのスクランブル誘導体とはまた対照的であった。特に腫瘍、肝臓及び脾臓において、FnBPA5取込みはスクランブル誘導体と比較して著しく高い。腫瘍による取込みは、全時点で著しく高く、最大は1h p.i.(4.74±0.77%IA/g)であった。腫瘍組織中における111In-FnBPA5の保持は、その他の器官と比較して長かった(図4A)。実際に、腫瘍対血液比は、1h p.i.の3.05±1.66から96h p.i.の34.03±18.36に増加した(図4D及び図7(例えば、補足表1))。体内分布の結果は、図3で示したSPECT/CT分析と一致し、111In-FnBPA5の器官による取込みが腎臓は別として細胞外マトリクスタンパク質フィブロネクチンに特異的でそれに関連していることを例示する。111In-FnBPA5のFn特異的結合を更に裏付けるために、インビボのブロッキング実験を実施し、非標識FnBPA5の約10倍過剰(PBS100μLに溶かした100μg)を111In-FnBPA5の直前に予備注射して、結合部位をブロックした(図4C)。非標識FnBPA5の予備注射は、腎臓及び膵臓は除外して試験した器官全てにおいて111In-FnBPA5蓄積の有意な低下(p<0.05)を引き起こす。それによって、ブロッキング効果は、肝臓(58.2%)と比較して腫瘍組織(35.6%の取込み減少)ではあまり大きくなかった。対照的に、有意差は111In-scraFnBPA5で認められなかった。
Claims (25)
- (i)少なくとも1つのフィブロネクチン結合ペプチド(FnBP)、及び
(ii)それと結合した少なくとも1つの診断薬又は治療薬
を含む組成物。 - 少なくとも1つのフィブロネクチン結合ポリペプチド(FnBP)が、
(a)配列番号1〜147、好ましくは配列番号117〜147、より好ましくは配列番号141、143、及び145からなる群から選択されるアミノ酸配列を含むポリペプチド、
(b)配列番号1〜147、好ましくは配列番号117〜147、より好ましくは配列番号141、143、及び145からなる群から選択されるアミノ酸配列と少なくとも70%又は80%、好ましくは少なくとも90%又は95%のアミノ酸配列同一性を有するアミノ酸配列を含むポリペプチド、
(c)配列番号148〜294、好ましくは配列番号264〜294、より好ましくは配列番号288、290、及び292からなる群から選択される核酸配列を有する核酸によってコードされるアミノ酸配列を含むポリペプチド、
(d)配列番号148〜294、好ましくは配列番号264〜294、より好ましくは配列番号288、290、及び292からなる群から選択される核酸配列と少なくとも80%、好ましくは少なくとも90%又は95%の核酸配列同一性を有する核酸によってコードされるアミノ酸配列を含むポリペプチド、並びに
(e)(a)、(b)、(c)、及び(d)のいずれかの機能的断片及び/又は機能的誘導体
からなる群から選択されるポリペプチドである、請求項1に記載の組成物。 - ポリペプチドが、フィブロネクチンサブユニットFnI1〜6、FnII1〜2、FnI7〜9、又はFnIII7〜15、好ましくはサブユニットFnI1〜5、FnII1〜2、FnIII7〜11、より好ましくはサブユニットFnI2〜5の少なくとも1つに特異的に結合する、請求項1又は2に記載の組成物。
- 診断薬が、放射性核種、MRI活性化合物、超音波造影剤、フルオロフォア、PET及びSPECT用マーカー、好ましくは44Sc、64Cu、67Ga、99mTc、111In、遠赤色/近赤外スペクトル領域のフルオロフォア、Gdをベースにした、及びFeオキシド粒子をベースにしたMRI造影剤、より好ましくはSPECTマーカー99mTc、111In及びPETマーカー44Sc及び64Cuからなる群から選択される、請求項1から3のいずれか一項に記載の組成物。
- 治療薬が細胞分裂阻害剤、細胞傷害性剤、サイトカイン、転写因子阻害剤、プロテアソーム及びプロテアーゼ阻害剤、アポトーシス調節剤、細胞周期調節剤、血管新生阻害剤、ホルモン又はホルモン誘導体、光線力学的治療分子、熱焼灼療法用のナノ粒子及びマイクロ粒子、放射性核種、miRNA、siRNA、並びに免疫調節抗原分子、好ましくは、
- 細胞分裂阻害剤:ドキソルビシン、パクリタキセル、クロラムブシル、トポテカン、及びビンクリスチン、
- サイトカイン:インターロイキン-2、インターロイキン-7、インターフェロン-γ、及び腫瘍壊死因子、
- 転写因子阻害剤:クルクミン、リバビリン、及びゲニステイン、
- アポトーシス調節剤:イマチニブ、エルロチニブ、及びブリオスタチン、
- 細胞周期調節剤:フラボピリドール及びロスコビチン、
- 血管新生阻害剤:エンドスタチン、セレコキシブ、ADH-1(エキセリン)、及びスニチニブ、
- ホルモン及びホルモン誘導体:フルタミド、ホスフェストロール、タモキシフェン、及びレラキシン、
- 放射性核種:64Cu、90Y、111In、131I、161Tb、169Er、及び177Lu、
- CD40、CD80、及びCD86に特異的なmiRNA及びsiRNA、並びに
- 免疫調節抗原分子:インスリン関連抗原、P31、全グリアジン、全ラッカセイ抽出物、ミエリンオリゴデンドロサイト糖タンパク質、好ましくはミエリンオリゴデンドロサイト糖タンパク質のアミノ酸35〜55、プロテオリピドタンパク質1、好ましくはプロテオリピドタンパク質1のアミノ酸139〜151及び178〜191、第V因子、好ましくは第V因子のアミノ酸75〜89、1723〜1737、及び2191〜2210、
最も好ましくは、パクリタキセル、クロラムブシル、エンドスタチン、スニチニブ、インターロイキン-7、90Y、及びミエリンオリゴデンドロサイト糖タンパク質アミノ酸35〜55
からなる群から選択される、請求項1から3のいずれか一項に記載の組成物。 - 治療薬が、
(a)インテグリン阻害剤、
(b)骨形成タンパク質7(BMP-7)、
(c)レラキシン及びレラキシン様ペプチド、好ましくはレラキシン-1又はレラキシン-2、
(d)リシルオキシダーゼ(LOX)阻害剤ベータ-アミノプロピオニトリル(BAPN)、並びに
(e)インターロイキン-7(IL-7)
からなる群から好ましくは選択される抗線維化剤である、請求項1から3及び5のいずれか一項に記載の組成物。 - 治療薬が、
(a)インターロイキン12(IL-12)、
(b)EGFRシグナル伝達カスケードを標的とする阻害剤、
(c)ミエリンオリゴデンドロサイト糖タンパク質ペプチド配列35〜55、
(d)好ましくはCD40、CD80、及びCD86に特異的なmiRNA、
(e)好ましくはCD40、CD80、及びCD86に特異的なsiRNA、
(f)PSA-TRICOM、
(g)イピリムマブ、
(h)抗体、好ましくは抗CTLA-4、抗PD1、及び抗PD-L1抗体、並びに
(i)HDAC阻害剤
からなる群から好ましくは選択される免疫調節剤である、請求項1から3及び5のいずれか一項に記載の組成物。 - (i)少なくとも1つのフィブロネクチン結合ポリペプチド(FnBP)と(ii)それと結合した少なくとも1つの診断又は治療ペプチド薬とを含む融合ポリペプチドをコードする核酸。
- 少なくとも1つのフィブロネクチン結合ポリペプチド(FnBP)をコードする核酸配列が、
(a)配列番号148〜294、好ましくは配列番号264〜294、より好ましくは配列番号288、290、及び292からなる群から選択される核酸配列、
(b)配列番号148〜294、好ましくは配列番号264〜294、より好ましくは配列番号288、290、及び292に挙げた核酸配列と、好ましくは全配列にわたって、少なくとも80%又は90%の同一性、好ましくは少なくとも95%の同一性、より好ましくは少なくとも98%の同一性を有する核酸配列、
(c)(a)又は(b)の核酸配列とストリンジェントな条件下でハイブリダイズする核酸配列、
(d)(a)又は(b)の核酸配列とストリンジェントな条件下でハイブリダイズする核酸配列(a)〜(c)のいずれかの断片、並びに
(e)(a)又は(b)の核酸配列とストリンジェントな条件下でハイブリダイズする(a)〜(d)の核酸の1つの置換、付加、及び/又は欠失によって生じる核酸配列
からなる群から選択される核酸配列を含む、請求項8に記載の核酸。 - DNA、RNA、又はPNAであり、好ましくはDNA又はPNAであり、より好ましくはDNAである、請求項8又は9に記載の核酸。
- フィブロネクチンサブユニットFnI1〜6、FnII1〜2、FnI7〜9、又はFnIII7〜15、好ましくはサブユニットFnI1〜5、FnII1〜2、FnIII7〜11、より好ましくはサブユニットFnI2〜5の少なくとも1つに特異的に結合するフィブロネクチン結合ポリペプチドをコードする、請求項8から10のいずれか一項に記載の核酸。
- 診断ポリペプチド薬が、蛍光タンパク質、好ましくは蛍光タンパク質eGFP、YFP、RFP、mOrange、mCherry、フラビンをベースにした蛍光タンパク質(FbFP)、より好ましくはRFP及びmCherryからなる群から選択される、請求項8から11のいずれか一項に記載の核酸。
- 治療ポリペプチド薬が、骨形成タンパク質、インターロイキン、インターフェロン、レラキシン、プロサポシン由来のトロンボスポンジン-1誘導ペプチド、好ましくは骨形成タンパク質-7(BMP-7)、インターロイキン-2(IL-2)、インターロイキン-7(IL-7)、インターフェロン-γ、腫瘍壊死因子(TNF)、レラキシン-1、レラキシン-2、並びにDWLPK及びDWLPプロサポシン由来ペプチド、より好ましくはBMP-7、IL-7、IL-2、及びTNFからなる群から選択される、請求項8から11のいずれか一項に記載の核酸。
- 請求項8から13のいずれか一項に記載の核酸を含む組換えベクター、好ましくはウイルスベクター又はエピソーマルベクター、好ましくはバキュロウイルスベクター、レンチウイルスベクター、アデノウイルスベクター、ワクシニア又はレトロウイルスベクター、酵母又は細菌エピソーマルベクター。
- 請求項8から13のいずれか一項に記載の核酸を含む宿主細胞又は請求項14に記載のベクター、好ましくは酵母細胞、好ましくはサッカロマイセス・セレビシエ、ピキア・パストリス細胞、細菌性の大腸菌又は枯草菌細胞、植物細胞、好ましくはタバコ又はニセツリガネゴケ細胞、NIH-3T3、HEK293、HEK293T、CHO、及びCOS哺乳類細胞、並びに昆虫細胞、好ましくはsf9昆虫細胞からなる群から選択される宿主細胞。
- 少なくとも1つのフィブロネクチン結合ポリペプチド(FnBP)、少なくとも1つの診断薬又は治療薬、及び任意選択でフィブロネクチン結合ポリペプチド(FnBP)を診断薬又は治療薬に結合させるための1つ又は複数の化学物質を含むパーツキット。
- 少なくとも1つのフィブロネクチン結合ポリペプチド(FnBP)及び少なくとも1つの診断薬又は治療薬を含み、フィブロネクチン結合ポリペプチド(FnBP)及び少なくとも1つの診断薬又は治療薬が、それぞれ、生理学的条件下でフィブロネクチン結合ポリペプチド(FnBP)を少なくとも1つの診断薬又は治療薬に結合させる少なくとも1つの部分を含む、請求項16に記載のパーツキット。
- 疾患、好ましくは病的フィブロネクチン蓄積に関連する疾患の治療的又は予防的処置における使用のための、請求項1から3及び5から7のいずれか一項に記載の組成物又は請求項16若しくは17に記載のパーツキット。
- 疾患が、線維症、がん、リンパ浮腫、免疫疾患、自己免疫疾患、動脈硬化プラーク、好ましくは全身性硬化症、肺線維症、肝線維症、腎線維症、乳がん、頭頸部扁平上皮癌、前立腺がん、腎がん、膵臓がん、及び肺がん、より好ましくは非小細胞肺がんからなる群から選択される、請求項18に記載の組成物又はパーツキット。
- 疾患、好ましくは病的フィブロネクチン蓄積に関連する疾患、より好ましくは線維症、がん、リンパ浮腫、動脈硬化プラーク、免疫疾患、及び自己免疫疾患、好ましくは全身性硬化症、肺線維症、肝線維症、腎線維症、乳がん、頭頸部扁平上皮癌、前立腺がん、腎がん、膵臓がん、肺がん、及び自己免疫疾患、より好ましくは非小細胞肺がん、1型糖尿病、グレーブス病、多発性硬化症、及び関節リウマチからなる群から選択される疾患の処置又は予防のための医薬の製造における、請求項1から3及び5から7のいずれか一項に記載の組成物又は請求項16若しくは17に記載のパーツキットの使用。
- 疾患、好ましくは病的フィブロネクチン蓄積に関連する疾患の診断で使用するための、請求項1から4のいずれか一項に記載の組成物又は請求項16若しくは17に記載のパーツキット。
- 疾患が、線維症、がん、リンパ浮腫、免疫疾患、自己免疫疾患、及び動脈硬化プラーク、好ましくは全身性硬化症、肺線維症、肝線維症、腎線維症、乳がん、頭頸部扁平上皮癌、前立腺がん、腎がん、膵臓がん、及び肺がん、より好ましくは非小細胞肺がん、1型糖尿病、グレーブス病、多発性硬化症、及び関節リウマチからなる群から選択される、請求項21に記載の組成物又はパーツキット。
- 疾患、好ましくは病的フィブロネクチン蓄積に関連する疾患、より好ましくは、線維症、がん、リンパ浮腫、免疫疾患、自己免疫疾患、及び動脈硬化プラーク、好ましくは全身性硬化症、肺線維症、肝線維症、腎線維症、乳がん、頭頸部扁平上皮癌、前立腺がん、腎がん、膵臓がん、及び肺がん、より好ましくは非小細胞肺がん、1型糖尿病、グレーブス病、多発性硬化症、及び関節リウマチからなる群から選択される疾患の診断のための診断用組成物の製造における、請求項1から4のいずれか一項に記載の組成物又は請求項16若しくは17に記載のパーツキットの使用。
- 病的フィブロネクチン蓄積に関連する疾患に罹患している、好ましくは線維症、がん、リンパ浮腫、免疫疾患、自己免疫疾患、及び動脈硬化プラーク、好ましくは全身性硬化症、肺線維症、肝線維症、腎線維症、乳がん、頭頸部扁平上皮癌、前立腺がん、腎がん、膵臓がん、及び肺がん、より好ましくは非小細胞肺がん、1型糖尿病、グレーブス病、多発性硬化症、及び関節リウマチからなる群から選択される疾患に罹患している対象を処置するための方法であって、
(a)治療薬と、任意選択で更に生理学的に許容される賦形剤及び希釈剤とを生理学的に有効な量で含む請求項1から3及び5から7のいずれか一項に記載の組成物、又は請求項16若しくは17に記載のパーツキットを準備する工程、
(b)(a)の組成物又はパーツキットをそれらを必要とする対象に、好ましくは静脈内投与によって投与する工程
を含む、方法。 - 対象における病的フィブロネクチン蓄積に関連する疾患、好ましくは線維症、がん、リンパ浮腫、免疫疾患、自己免疫疾患、及び動脈硬化プラーク、好ましくは全身性硬化症、肺線維症、肝線維症、腎線維症、乳がん、頭頸部扁平上皮癌、前立腺がん、腎がん、膵臓がん、及び肺がん、より好ましくは非小細胞肺がん、1型糖尿病、グレーブス病、多発性硬化症、及び関節リウマチからなる群から選択される疾患の診断のための方法であって、
(a)診断薬と、任意選択で更に生理学的に許容される賦形剤及び希釈剤とを生理学的に有効な量で含む請求項1から4のいずれか一項に記載の組成物又は請求項16若しくは17に記載のパーツキットを準備する工程、
(b)(a)の組成物又はパーツキットをそれらを必要とする対象に、好ましくは静脈内投与によって投与する工程、並びに、
(c)前記組成物中のフィブロネクチン結合ペプチド(FnBP)の蓄積によって病的フィブロネクチン蓄積を同定する工程
を含む、方法。
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EP16174824.9A EP3257862A1 (en) | 2016-06-16 | 2016-06-16 | Fibronectin-binding peptides for use in tumor or fibrosis diagnosis and therapy |
EP16174824.9 | 2016-06-16 | ||
JP2018566287A JP7258559B2 (ja) | 2016-06-16 | 2017-06-14 | 腫瘍又は線維症の診断及び治療における使用のためのフィブロネクチン結合ペプチド |
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JP2021138041A Pending JP2021191768A (ja) | 2016-06-16 | 2021-08-26 | 腫瘍又は線維症の診断及び治療における使用のためのフィブロネクチン結合ペプチド |
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WO2023057034A1 (en) | 2021-10-05 | 2023-04-13 | ETH Zürich | Fibronectin-binding peptides for use in tumor or fibrosis diagnosis and therapy |
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US6565880B2 (en) | 2000-07-24 | 2003-05-20 | Boehringer Ingelheim Pharmaceuticals, Inc. | Oral dosage formulations of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea |
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