JP2013540770A - 慢性又は非慢性の炎症性眼疾患を治療するためのjnkシグナル伝達経路の細胞透過性ペプチド阻害剤の使用 - Google Patents
慢性又は非慢性の炎症性眼疾患を治療するためのjnkシグナル伝達経路の細胞透過性ペプチド阻害剤の使用 Download PDFInfo
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Abstract
【選択図】なし
Description
(i)放射活性標識、即ち、放射活性リン酸化又は硫黄、水素、炭素、窒素等による放射活性標識;
(ii)着色色素(例えば、ジゴキシゲニン等);
(iii)蛍光基(例えば、フルオレセイン等);
(iv)化学発光基;
(v)固相に固定するための基(例えば、His−タグ、ビオチン、strep−タグ、flag−タグ、抗体、抗原等);及び
(vi)(i)〜(v)に記載した標識のうちの2以上の標識の組み合わせ。
溶液及び生成物
配列番号11の全てのD−レトロ−インベルソ型JNK阻害剤(ポリ)ペプチドをPolypeptide Laboratories(フランス)において作製し、高速液体クロマトグラフィー(HPLC)によって精製した。それを、アイデンティティについては質量分析法によって、純度についてはRP−HPLCによって分析した(Polypeptide Laboratories、フランス)。凍結乾燥した時点で、粉末を2℃〜8℃で保存した。実験の1日間前、配列番号11のJNK阻害剤(ポリ)ペプチド粉末を、無菌条件下で、National Scientific(NSC)不活性ガラスバイアル(NSC−C4015−S1)内にて10μMの濃度になるように生理食塩水(NaCl 0.9%、Versol(登録商標)、Aguettant)に溶解させ、使用まで4℃で保存した。
各実験について、配列番号11のJNK阻害剤(ポリ)ペプチドを新たに溶解させた画分を−20℃で保存し、高速液体クロマトグラフィー(HPLC)分析によってその濃度を確認した。
デキサメタゾンナトリウムリン酸塩(4mg/mL)(Soludecadron;Laboratoire Roussel,Paris、フランス)を、EIU.10における抗炎症活性のポジティブコントロールとして用いた。
体重175gの7週齢の雌Lewisラット(Elevage Janvier,Le Genest Saint Isle、フランス)を用い、Use of Animals in Ophthalmic and Vision ResearchのARVO Statementに従って取り扱った。ケタミン(88mg/kg)(Virbac、フランス)及びラルガクチル(0.6mg/kg)(Sanofi−Aventis、フランス)を筋肉内注射することによってラットに麻酔した後、静脈内注射又は眼内注射を行った。
静脈内(IV)注射については、生理食塩水(NaCl 0.9%)又は配列番号11のJNK阻害剤(ポリ)ペプチド(生理食塩水中20μg/kg)100μLを、1mLのシリンジ(Becton Dickinson、フランス)に取り付けられている25Gの針を用いて尾静脈に注射した。硝子体内(IVT)注射については、生理食塩水又は配列番号11のJNK阻害剤(ポリ)ペプチド(生理食塩水中0.2μg/注射)5μLを、30Gの使い捨て針(BD−microfine syringe、nm Medical、Asniere、フランス)を用いて両目に注射した。他のモデルにおいて配列番号11のJNK阻害剤(ポリ)ペプチドが非常に低用量で活性を有することを示す研究に従って、20μg/kg(即ち、体重175gのラットにおいて3.5μg/ラット)のIV用量を選択した。硝子体内注射については、本発明者らは、患者において急性騒音外傷後に直接耳に適用される最低用量を用いた。これは、静脈内に注射される用量の5%に相当する。静脈内処理又は硝子体内処理の直後、200μgのLPS(ネズミチフス菌由来のリポ多糖類、Sigma−Aldrich、Saint−Quentin Fallavier、フランス)を含有する滅菌発熱物質不含水100μLを片方の足蹠に注射することによって、エンドトキシン誘導性ブドウ膜炎(EIU)を誘導した。実験の最後、即ち、LPSチャレンジの6時間、24時間、又は48時間後に、ペントバルビタール(30mg/kg)(Sanofi−Aventis、フランス)を腹腔内注射することによってラットに麻酔した後、心臓穿刺によって血液を回収した。次いで、致死量のペントバルビタールでラットを屠殺し、両眼を摘出した。
各摘出した眼から房水及び硝子体を回収し、プールした。眼水を直ちに遠心分離し、細胞を含まない画分を回収し、−20℃で凍結させた後、マルチプレックスアッセイによって分析した。先ず、血液サンプルを室温で2時間、次いで、4℃で一晩凝固させた。血清を回収し、遠心分離し、透明な上清を回収し、−20℃で凍結させた後、マルチプレックスアッセイを行った。
実験の第1のセットでは、70匹のラットを各群5匹の14の実験群に無作為に割付けた。各群においてブドウ膜炎を誘導し、LPSチャレンジの6時間後(4群)、24時間後(6群)、及び48時間後(4群)にラットを屠殺した。試験した各時点(即ち、6時間、24時間、及び48時間)について、ビヒクル(NaCl 0.9%)又は配列番号11のJNK阻害剤(ポリ)ペプチドの静脈内注射又は硝子体内注射によって処理したラットを、未処理の対照ブドウ膜炎ラットと比較した。ビヒクルの静脈内注射及びデキサメタゾンの硝子体内注射によって処理した2つの更なる群を24時間で用いた。24時間においてのみ臨床的な眼の炎症を記録した(エンドトキシン誘導性ブドウ膜炎(EIU)の採点の章を参照されたい)。各時点において、各眼(1群当たりn=10)に由来する眼内液及び各動物(1群当たりn=5)に由来する血清をケモカイン/サイトカインマルチプレックスアッセイで用いた。
本実験における疾患の臨床ピークである24時間において、スリットランプによって動物を検査した。臨床的な眼の炎症の強度を、上記10の通り各眼について0点〜5点で採点した:0点は、炎症無しを示し;1点は、最小限の虹彩及び結膜の血管拡張が存在するが、前房(AC)におけるフレア又は細胞はみられないことを示し;2点は、中程度の虹彩及び結膜の血管拡張が存在するが、ACにおける明らかなフレア又は細胞はみられないことを示し;3点は、強度の虹彩の血管拡張が存在し、ACにおいてフレア及びスリットランプ視野当たり10個未満の細胞がみられることを示し;4点は、3点よりも重篤な臨床徴候が存在し、前房蓄膿が形成されているか又は形成されていないACにおいて10個超の細胞がみられることを示し;5点は、強度の炎症反応、ACにおけるフィブリン形成、及び瞳孔の完全な閉鎖が存在することを示す。マスキングした状態で臨床評価を実施した。
RPE/脈絡膜/強膜複合体及び神経網膜(実験群当たり2個)を切開後直ちに瞬間凍結させ、使用まで−80℃で保存した。プロテアーゼ阻害剤カクテル(Roche Diagnostics、Meylan、フランス)(50mLにつき1錠)を添加した溶解バッファ(MOPS SDS Running Buffer、Invitrogen、Cergy−Pontoise、フランス)500μL中で組織をホモジナイズした。LDSサンプルバッファ(Invitrogen)を添加し、100℃で5分間加熱した後、MOPS SDSランニングバッファを用いてNuPAGE 4−12% Bis−Trisゲル(Invitrogen)で等量のタンパク質を電気泳動した。次いで、得られたバンドをニトロセルロースメンブレン(Schleicher&Schuell BioScience、Dassel、ドイツ)に電気転写した。
細胞浸潤の特性評価を行うために、切片をED1及びiNOSで二重染色した。簡潔に述べると、30分間リン酸緩衝生理食塩水(PBS)中0.1%Triton−X100を用いて透過処理した後、試料をすすぎ、PBS中5%スキムミルクを30分間浸透させた。これらを、以下の2つの一次抗体と共に4℃で一晩インキュベートした:ラットの単球、マクロファージ、及び樹状細胞における細胞質抗原に対する1:50マウスモノクローナル抗マクロシアリンCD68(クローンED1)(Serotec Ltd.(Oxford、UK)から購入)、及びポリクローナルウサギ抗−iNOS(1/75e;Transduction Laboratories、Lexinton、FY)。洗浄後、それぞれ1:250で希釈した二次Alexa Fluor 594(赤)コンジュゲートロバ抗マウスモノクローナル抗体(mAb)及び二次Alexa Fluor 488(緑)コンジュゲートヤギ抗ウサギmAb(Invitrogen、Cergy Pontoise、フランス)と共に室温で1時間切片をインキュベートした。各工程について、抗体をPBS−1%スキムミルク−0.1%TritonX100で希釈した。全ての染色操作は異なる対照を含んでいた:一次抗体を含まないネガティブコントロール、及び一次抗体の代わりに正常マウス又はウサギの血清免疫グロブリン(Ig)と共にインキュベートすることによるアイソタイプコントロール。DAPI(Sigma−Aldrich、Saint−Quentin Fallavier、フランス)で核を染色した後、切片をPBS/グリセロール(1/1)中に置き、蛍光顕微鏡写真機(FXA、Microphot、Nikon、Melville、USA)によって観察した。デジタルカメラ(Spot、BFI Optilas、Evry、フランス)を用いてデジタル化された顕微鏡写真を得た。DAPIで染色した核の形状によって識別したED1陽性細胞及び多形核細胞を、組織学的切片上で定量した。視神経乳頭レベルにおいて眼1個当たり2枚の異なる切片を用いて、実験群当たり3個の眼について分析を実施した。結果を、平均±平均の標準誤差(SEM)として表した。
1群当たり2個の眼をこの分析に用いた。切開後直ちに、各眼から抽出した網膜を別々に瞬間凍結させ、使用まで−80℃で保存した。製造業者の指示書に従って全RNAを組織から抽出した(RNeasy minikit、Qiagen、Courtaboeuf、フランス)。製造業者の指示書に従って、Superscript II逆転写酵素(Invitrogen、Cergy−Pontoise、フランス)を用いて総体積20μLで全RNA1μgに対して逆転写を実施した。GAPDH及びiNOSのcDNAを増幅させるために、第1の連鎖反応産物2μL、0.4μMのフォワードプライマー、0.4μMのリバースプライマー、0.4μMのdNTPミックス、1.5mMのMgCl2、1×PCRバッファ、及び2.5UのTaq DNAポリメラーゼ(Invitrogen、Cergy Pontoise、フランス)を含有する総体積25μLでポリメラーゼ連鎖反応(PCR)を実施した。GAPDH(フォワード:5’−ATGCCCCCATGTTTGTGATG−3’;リバース:5’−ATGGCATGGACTGTGGTCAT−3’)及びiNOS(フォワード:5’−TTTCTCTTCAAAGTCAAATCCTACCA−3’;リバース:5’−TGTGTCTGCAGATGTGCTGAAAC−3’)に特異的なプライマーをInvitrogenから入手した。Crocodile III(Appligene Oncor)において、初期変性(94℃で3分間)後、変性(30秒間、94℃)、アニーリング(1分間、58℃(GAPDH)及び52℃(iNOS))、及び伸長(1分間〜2分間、72℃)を30サイクル〜32サイクル実施した。72℃で5分間の伸長によって最後のサイクルを完了した。PCR断片(GAPDHについては162bp、及びiNOSについては657bp)を2.5%アガロースゲル電気泳動によって分析し、紫外光下でエチジウムブロマイド染色によって可視化した。濃度測定分析(ImageJソフトウェア)後にGAPDHと比較してiNOSの相対バンド強度を計算した。
眼内液(最終体積が25μLになるように希釈)及び血清(25μL、1:5希釈)をマルチプレックスビーズアッセイに供した。この方法は、イムノアッセイ12の固相としてミクロスフィアを使用し、ELISA13よりも高感度で多数のサイトカインを滴定することができる。各サンプルについて、製造業者の指示書に従ってラットサイトカイン/ケモカイン−17plexキット(Milliplex Map Kit、Millipore、Saint−Quentin−en−Yvelines、フランス)を用いて17個のアナライトを同時に定量した:ケモカイン MCP−1/CCL2、MIP−1α/CCL3、RANTES/CCL5、IP−10/CXCL10(IFN−誘導性タンパク質−10)及びGRO/KC;炎症促進性メディエータIL−1 、IL−18及びTNF− ;Th1/Th2/Th17サイトカインIL−2及びIFN− /IL−4、IL−5、IL−6、IL−10及びIL−13/IL−17。96ウェルのフィルタープレートでアッセイを実施し、キットに提供されているラットサイトカイン標準を用いて各サイトカインについての検量線を作成した。全てのインキュベート工程は、培地を軌道撹拌しながら、光からビーズを保護するために暗条件下で実施した。検量線につき4個又は5個のロジスティックパラメータを用いてmanagerソフトウェアバージョン4.1(Bioplex;Bio−Rad)を用いてデータの取得及び分析を行った。全てのアナライトの検出閾値は、約1pg/mL〜約10pg/mLであると推定された。
数値結果を平均±平均の標準誤差(SEM)として表した。ノンパラメトリックなMann−Whitney U−検定を用いてデータを比較した。p<0.05を統計的に有意であるとみなした。
配列番号11の全てのD−レトロ−インベルソ型JNK阻害剤(ポリ)ペプチドは、エンドトキシン誘導性ブドウ膜炎(EIU)を有意に低減した。配列番号11のJNK阻害剤(ポリ)ペプチドは、未処理のブドウ膜炎の眼(3.2±0.1、p<0.001)及びビヒクルのIV(3.2±0.1、p<0.001)と比べて、20μg/kgの静脈内(IV)注射(2.0±0.1)後のEIU臨床スコアを有意に低下させた(図1A)。同様に、未処理のブドウ膜炎の眼(3.2±0.1、p<0.001)及びビヒクルIVT(3.0±0.1、p<0.01)と比べて、配列番号11のJNK阻害剤(ポリ)ペプチドの0.2μg/硝子体内注射(IVT)投与後の臨床スコア(2.2±0.2)は有意に低下した(図1B)。EIUの臨床徴候に対する配列番号11のJNK阻害剤(ポリ)ペプチドのIVT注射の効果は、デキサメタゾンのIVT後にみられた効果(1.8±0.4)とは統計的に差はなく、これは、配列番号11のJNK阻害剤(ポリ)ペプチドが、この時点で投与したときEIUの低減においてデキサメタゾンと同程度有効であったことを示唆する(図1B)。
配列番号11のJNK阻害剤(ポリ)ペプチドの臨床効果がその作用機序、即ち、JNKシグナル伝達に干渉する能力に関連しているかどうかを判定するために、6つのc−Junリン酸化状態をウエスタンブロットによって眼組織において分析した。Ser63(図2A)及びSer73残基におけるc−Junのリン酸化は、配列番号11のJNK阻害剤(ポリ)ペプチドを静脈内又は硝子体内に注射した24時間後のRPE/脈絡膜抽出物において低下した。神経網膜では、ホスホc−Junは、微かにしか検出することができなかった。配列番号11のJNK阻害剤(ポリ)ペプチドのIV(ビヒクルのIVにおける0.77±0.26に対して0.28±0.01)又はIVT(ビヒクルのIVTにおける0.79±0.25に対して0.35±0.08)投与後のいずれにおいても、RPE/脈絡膜においてc−Junのリン酸化が約3分の1に減少したことが観察された(図2B)。配列番号11のJNK阻害剤(ポリ)ペプチドが眼組織においてc−Jun NH2末端キナーゼ(JNK)活性をブロックする能力により、配列番号11のJNK阻害剤(ポリ)ペプチドの特定の眼内活性が実証された。
組織学的切片に対して免疫組織化学試験を実施して、健常な眼及びブドウ膜炎状態における、全身(IV)又は局所(IVT)投与の24時間後の眼組織における配列番号11のJNK阻害剤(ポリ)ペプチドの生体分布を評価した(図4)。配列番号11のJNK阻害剤(ポリ)ペプチド又はビヒクルのIV又はIVT投与後の健常な眼において炎症細胞の浸潤はみられなかった。配列番号11のJNK阻害剤(ポリ)ペプチドに対する免疫反応性は、未処理の対照眼又はビヒクルによって処理された眼では検出されなかった。これは、配列番号11のJNK阻害剤(ポリ)ペプチドで処理された眼においてみられるシグナルの特異性を示す。用いた用量では全身(IV)注射後の正常な眼においてシグナルは観察されなかった(図4A〜4C)が、配列番号11のJNK阻害剤(ポリ)ペプチドは、IVT投与後に正常ラットの殆ど全ての眼組織に分布していた(図4D〜4L)。興味深いことに、配列番号11のJNK阻害剤(ポリ)ペプチドの蓄積は、虹彩/毛様体上皮(パネルG及びJ)及び網膜色素上皮(パネルL)で主に検出された。また、配列番号11のJNK阻害剤(ポリ)ペプチドの浸透は、虹彩支質(パネルG)、並びに神経節細胞層の神経網膜(GCL、パネルH)、内顆粒層(INL、パネルK)、及び視細胞(PR)の内節(IS、パネルI)においても検出された。全ての細胞種において、配列番号11のJNK阻害剤(ポリ)ペプチドは、細胞質に蓄積していた。角膜内皮及び水晶体嚢においては、疎らな染色がみられた。
ブドウ膜炎における配列番号11のJNK阻害剤(ポリ)ペプチドの効果を更に特性評価するために、ED1及びiNOSの抗体で免疫染色した組織学的切片(図6)に対する計算によって、眼組織における浸潤炎症細胞を定量した(図5)。LPSチャレンジの24時間後、ED1陽性細胞の数は、未処理のブドウ膜炎の眼(LPS)(187±13、p<0.005)(図5A、図6A、6D、6G、6J)又はビヒクルを注射した眼と比較して、配列番号11のJNK阻害剤(ポリ)ペプチドのIV注射で処理した眼において有意に減少した(137±7)(図5A、図6M、6P、6S)。同様に、配列番号11のJNK阻害剤(ポリ)ペプチドのIVTは、ビヒクルをIVT注射した眼(175±15、p<0.009)及び未処理のブドウ膜炎の眼(p<0.005)と比べて、ED1陽性浸潤細胞を著しく減少させた(93±8)(図5A)。ED1陽性細胞の浸潤に対する配列番号11のJNK阻害剤(ポリ)ペプチドの低減効果(93±8)は、デキサメタゾン(79±15)によって誘導される効果と差がなかった。これは、両処理が、このパラメータに対して同様の効果を有することを示唆する。
iNOS(誘導性一酸化窒素合成酵素)は、ブドウ膜炎、14、15の病因における重要なメディエータであることが報告されているので、iNOSの発現に対する配列番号11のJNK阻害剤(ポリ)ペプチドの効果をタンパク質及びmRNAの両方のレベルで調べた。
炎症促進性及び抗炎症性のメディエータの産生に対する処理の効果を評価するために、透光体(図8及び9)及び血清に対してマルチプレックス分析によってケモカイン及びサイトカインを投与した。
Claims (26)
- 被験体における慢性又は非慢性の炎症性眼疾患を治療する医薬組成物を調製するための、150未満のアミノ酸長を有することを特徴とするJNK阻害剤(ポリ)ペプチドの使用。
- JNK阻害剤(ポリ)ペプチドが、5アミノ酸残基〜150アミノ酸残基、より好ましくは10アミノ酸残基〜100アミノ酸残基、更により好ましくは10アミノ酸残基〜75アミノ酸残基、最も好ましくは10アミノ酸残基〜50アミノ酸残基を含む請求項1に記載のJNK阻害剤(ポリ)ペプチドの使用。
- JNK阻害剤(ポリ)ペプチドが、c−junアミノ末端キナーゼ(JNK)に結合する請求項1又は2に記載のJNK阻害剤(ポリ)ペプチドの使用。
- JNK阻害剤(ポリ)ペプチドがJNK発現細胞に存在するとき、前記JNK阻害剤(ポリ)ペプチドが、少なくとも1つのJNKを標的とする転写因子の活性化を阻害する請求項1から3のいずれかに記載のJNK阻害剤(ポリ)ペプチドの使用。
- JNKを標的とする転写因子が、c−Jun、ATF2、及びElklからなる群より選択される請求項1から4のいずれかに記載のJNK阻害剤(ポリ)ペプチドの使用。
- JNK阻害剤(ポリ)ペプチドがJNK発現細胞に存在するとき、前記JNK阻害剤(ポリ)ペプチドが、JNKの効果を変化させる請求項1から5のいずれかに記載のJNK阻害剤(ポリ)ペプチドの使用。
- JNK阻害剤(ポリ)ペプチドが、L−アミノ酸及びD−アミノ酸の少なくともいずれかを含み、好ましくは、少なくとも1又は更には2、好ましくは少なくとも3、4、又は5、より好ましくは少なくとも6、7、8、又は9、更により好ましくは少なくとも10以上の前記D−アミノ酸及びL−アミノ酸の少なくともいずれかを含み、前記D−アミノ酸及びL−アミノ酸の少なくともいずれかが、ブロック状、非ブロック状、又は交互に前記JNK阻害剤(ポリ)ペプチド中に配置されていてよい請求項1から6のいずれかに記載のJNK阻害剤(ポリ)ペプチドの使用。
- JNK阻害剤(ポリ)ペプチドが、配列番号102、配列番号103、配列番号104、又は配列番号105に係る配列のいずれかによって定義又はコードされているヒト又はラットのIB1(ポリ)ペプチドの断片、変異体、又は前記断片の変異体を含む請求項1から7のいずれかに記載の使用。
- 阻害剤の配列が、配列番号1〜4、13〜20、及び33〜100に係る少なくとも1つのアミノ酸配列、又はその断片、誘導体、若しくは変異体を含むか、或いは配列番号1〜4、13〜20、及び33〜100に係る少なくとも1つのアミノ酸配列、又はその断片、誘導体、若しくは変異体からなる請求項1から8のいずれかに記載のJNK阻害剤(ポリ)ペプチドの使用。
- 被験体における慢性又は非慢性の炎症性眼疾患を治療する医薬組成物を調製するための、共有結合によって結合されている少なくとも1つの第1のドメインと少なくとも1つの第2のドメインとを含むキメラ(ポリ)ペプチドの使用であって、前記第1のドメインが、輸送(ポリ)ペプチドを含み、前記第2のドメインが、請求項1から9のいずれかに記載のJNK阻害剤(ポリ)ペプチドを含むことを特徴とする使用。
- キメラ(ポリ)ペプチドが、L−アミノ酸及びD−アミノ酸の少なくともいずれかを含み、好ましくは、少なくとも1又は更には2、好ましくは少なくとも3、4、又は5、より好ましくは少なくとも6、7、8、又は9、更により好ましくは少なくとも10以上のD−アミノ酸及びL−アミノ酸の少なくともいずれかを含み、前記D−アミノ酸及びL−アミノ酸の少なくともいずれかが、ブロック状、非ブロック状、又は交互に前記キメラ(ポリ)ペプチド中に配置されていてよい請求項10に記載のキメラ(ポリ)ペプチドの使用。
- 輸送(ポリ)ペプチドが、ヒト免疫不全ウイルスTATポリペプチドのアミノ酸配列を含む請求項10又は11に記載のキメラ(ポリ)ペプチドの使用。
- 輸送配列が、配列番号5、6、7、8、21、若しくは22のアミノ酸配列からなるか、又は配列番号5、6、7、8、21、若しくは22のアミノ酸配列を含む請求項10から12のいずれかに記載のキメラ(ポリ)ペプチドの使用。
- 輸送(ポリ)ペプチドが、ペプチドの細胞内取り込みを増加させる請求項10から13のいずれかに記載のキメラ(ポリ)ペプチドの使用。
- 輸送(ポリ)ペプチドが、ペプチドを核に局在させる請求項10から14のいずれかに記載のキメラ(ポリ)ペプチドの使用。
- キメラ(ポリ)ペプチドが、配列番号9〜12及び23〜32のいずれかのアミノ酸配列、又はこれらの断片若しくは変異体からなるか、或いは配列番号9〜12及び23〜32のいずれかのアミノ酸配列、又はこれらの断片若しくは変異体を含む請求項10から15のいずれかに記載のキメラ(ポリ)ペプチドの使用。
- キメラ(ポリ)ペプチドが、配列番号9又は11のアミノ酸配列からなるか又は配列番号9又は11のアミノ酸配列を含む請求項10から15のいずれかに記載のキメラ(ポリ)ペプチドの使用。
- 被験体における慢性又は非慢性の炎症性眼疾患を治療する医薬組成物を調製するための、請求項1から9のいずれかに記載のJNK阻害剤(ポリ)ペプチド又は請求項10から17のいずれかに記載のキメラ(ポリ)ペプチドをコードすることを特徴とする単離核酸の使用。
- 被験体における慢性又は非慢性の炎症性眼疾患を治療する医薬組成物を調製するための請求項18に記載の核酸を含むことを特徴とするベクターの使用。
- 被験体における慢性又は非慢性の炎症性眼疾患を治療する医薬組成物を調製するための請求項19に記載のベクターを含むことを特徴とする細胞の使用。
- 被験体における慢性又は非慢性の炎症性眼疾患を治療する医薬組成物を調製するための、請求項1から9のいずれかに記載のJNK阻害剤(ポリ)ペプチド又は請求項10から17のいずれかに記載のキメラ(ポリ)ペプチドに対して免疫特異的に結合することを特徴とする抗体の使用。
- 医薬組成物が、静脈内、筋肉内、皮下、皮内、経皮を含む非経口経路;経口、直腸内を含む経腸経路;経鼻、鼻腔内を含む局所経路;表皮又は貼付送達を含む他の経路;並びに眼への局所投与、特に、硝子体内投与、結膜下投与、及び点眼の少なくともいずれか;からなる群より選択される投与経路によって投与される請求項1から21のいずれかに記載の使用。
- 非慢性又は慢性の炎症性眼疾患が、眼瞼、結膜、角膜、強膜、硝子体、ブドウ膜、毛様体、脈絡膜、眼窩骨、涙腺、又は虹彩の炎症性疾患から選択され、特に、前記炎症性疾患が、麦粒腫、霰粒腫、結膜炎、角膜炎、強膜炎、上強膜炎、眼内炎、汎眼球炎、虹彩炎、ブドウ膜炎、毛様体炎、脈絡膜炎、眼窩蜂巣炎、及び眼筋炎から選択される請求項1から22のいずれかに記載の使用。
- JNK阻害剤(ポリ)ペプチド及びキメラ(ポリ)ペプチドの少なくともいずれかの(体重1kg当たりの)用量が、10mmol/kg以下、好ましくは1mmol/kg以下、より好ましくは100μmol/kg以下、更により好ましくは10μmol/kg以下、更により好ましくは1μmol/kg以下、更により好ましくは100nmol/kg以下、最も好ましくは50nmol/kg以下である請求項1から23のいずれかに記載の使用。
- JNK阻害剤(ポリ)ペプチド及びキメラ(ポリ)ペプチドの少なくともいずれかの用量が、約1pmol/kg〜約1mmol/kg、約10pmol/kg〜約0.1mmol/kg、約10pmol/kg〜約0.01mmol/kg、約50pmol/kg〜約1μmol/kg、約100pmol/kg〜約500nmol/kg、約200pmol/kg〜約300nmol/kg、約300pmol/kg〜約100nmol/kg、約500pmol/kg〜約50nmol/kg、約750pmol/kg〜約30nmol/kg、約250pmol/kg〜約5nmol/kg、約1nmol/kg〜約10nmol/kg、又は前記値のうちの任意の2つの組み合わせである請求項1から24に記載の使用。
- 炎症性眼疾患が、ブドウ膜炎であり、(ポリ)ペプチドが、配列番号11のアミノ酸配列からなる又は配列番号11のアミノ酸配列を含むか、或いは配列番号11と少なくとも約30%、50%、70%、80%、90%、92%、若しくは更には95%の配列同一性を共有するアミノ酸配列からなる又は配列番号11と少なくとも約30%、50%、70%、80%、90%、92%、若しくは更には95%の配列同一性を共有するアミノ酸配列を含む請求項1から25のいずれかに記載の使用。
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US9150618B2 (en) | 2015-10-06 |
JP5857056B2 (ja) | 2016-02-10 |
US20130337557A1 (en) | 2013-12-19 |
AU2010362444B2 (en) | 2015-08-06 |
US20160089413A1 (en) | 2016-03-31 |
AU2010362444A1 (en) | 2013-02-28 |
WO2012048721A1 (en) | 2012-04-19 |
US20190060392A1 (en) | 2019-02-28 |
CA2807036A1 (en) | 2012-04-19 |
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US10967038B2 (en) | 2021-04-06 |
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