JP2019521963A - Cd47を活性化する作用物質およびその炎症治療における使用 - Google Patents
Cd47を活性化する作用物質およびその炎症治療における使用 Download PDFInfo
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Abstract
Description
本発明では、下記の用語は以下のような意味を有する:
(1)ローリー法により求める場合、タンパク質の80重量%、85重量%、90重量%、95重量%超、最も好ましくは96重量%、97重量%、98重量%もしくは99重量%超まで、
(2)スピニングカップ配列決定装置の使用によりN末端または内部のアミノ酸配列のうち少なくとも15残基を得るのに十分な程度まで、または
(3)還元もしくは非還元条件下、クーマシーブルーもしくは好ましくは銀染色を用いて、SDS−PAGEにより均質になるまで
精製する。
本発明は、互いに連結された少なくとも2つのペプチド単量体を含む多量体ペプチドまたはポリペプチドであって前記少なくとも2つのペプチド単量体がCD47を活性化する多量体ペプチドまたはポリペプチドに関する。
ウエスタンブロット、逆転写およびリアルタイムポリメラーゼ連鎖反応ならびにELISA
既に記載されている(Houssierら,PLoS Med.2008,5:e39)通りに、モノクローナル抗TSP1抗体(Abcam社)を用いてWB解析を実施した。RT−PCRプライマーをTaqman、照会:Hs01016151_m1から注文した。
PBS灌流マウスからミクログリア細胞を調製した。Neural Dissociation Kit Papain(miltenyi Biotech社)を用いて脳または網膜を分離した後、70μmでろ過した細胞懸濁物を洗浄し、75%等張Percoll(Percoll Plus、GE Healthcare社)に再懸濁させ、25%PercollおよびPBSを重層した。細胞を4℃、1000gで30分間遠心分離した。75%と25%の境界面にあるリングを収集し、PBSで洗浄し、遠心分離した。
単球
ヘルシンキ宣言に従い、国立キャンズ・ヴァン病院眼科センター(パリ、フランス)倫理委員会による承認(第913572号)を受けたヒト単球発現に関する試験の書面および説明による同意を志願者から得た。健常被験者のヘパリン処置静脈血からFicoll Paque層(GE Healthcare社)での1段階の遠心分離によりPBMCを単離し、CD16 Depletion Kit(StemCells Technology社)を用いずにEasySep Human Monocyte Enrichment Cocktailで選別した。マウス腹膜マクロファージ、骨髄由来単球および光受容細胞外節(POS)の単離(いずれも無血清X−Vivo 15培地中)を、既に記載されている(Sennlaubら,EMBO Mol Med.2013,5:1775−1793)通りに実施した。共培養実験に関して、単核単球を、CellTrace(商標)CFSE(Life technologies(登録商標))を用いて染色した後3回洗浄するか、またはPU1免疫組織化学でRPEにMP特異的転写因子が発現していないことにより同定した。
食肉処理場から眼球摘出後2〜3時間の新鮮なブタ眼球を入手した。眼球から周辺組織を取り除き、消毒液(Pursept(登録商標))に短時間浸漬した。前眼部の水晶体、硝子体および硝子体を除去した。後眼部をPBS(リン酸緩衝生理食塩水)で2回洗浄し、次いで0.25%トリプシンの存在下、37℃でインキュベートしてRPE細胞を剥離させた。1時間のインキュベーション後、トリプシン溶液を除去し、非動化した20%ウシ胎児血清(FCS)を添加したダルベッコ変法イーグル培地(DMEM)中、抗生物質(1%ペニシリン/ストレプトマイシン)の存在下で細胞を回復させた。細胞を数回洗浄し、次いで培養皿中、37℃でインキュベートした。培養3日後、この細胞を0.25%トリプシンと再びインキュベートし、洗浄し、48ウェル培養プレート(Grenier(登録商標))に150,000細胞/培養ウェルの密度(300,000細胞/Lまたは500μL/ウェル)で播種した。37℃で4日間インキュベートした後、細胞がコンフルエンスに達し、最適な細胞特性(色素沈着が十分な扁平細胞)が得られた。この初代細胞培養物の加齢を避けるため、全ての実験を培養プレートに播種後第5日〜第7日の間に実施した。
FCSを含まないDMEM(DMEM+1%ペニシリン/ストレプトマイシンのみ)で共培養する前日、RPE細胞の培地を交換した。単球を48ウェルプレートにRPE細胞の存在下または非存在下、200,000細胞/培養ウェルの濃度で播いた。
PBS−0.1%Triton−クエン酸0.1%の溶液で4%PAFを洗浄した後、RPE細胞を透過処理した。非特異的免疫原部位をPBS−0.1%Triton−5%ウマ血清でブロックした。1時間後、ブロッキング溶液を除去し、細胞をPBS triton0.1%および1%ウマ血清で希釈した一次抗体(ポリクローナルウサギ抗ヒトPU.1、1/200、LifeTechnologies社;ポリクローナルヤギ抗ヒトOTX2、1/500、R&D社)の存在下に置き、4℃で12時間インキュベートした。PBSで3回洗浄した後、蛍光色素と結合させPBS−0.1%Triton−1%ウマ血清で希釈した二次抗体をDAPI(核染色)とともに加え、周囲温度で1時間放置した後、PBSで数回洗浄した。
1ウェル当たり25視野をArrayscan(登録商標)により解析し、次いで、各培養条件の細胞数をコンピュータプロトコルにより直接カウントした。核はいずれもDAPIで標識され、単球が緑色の488nm(CellTrace(商標)CFSE)で、または/およびRPE細胞が遠赤色の647nm(抗OTX2一次抗体による認識)で示された。複数のプレートの定量化をプールしたグラフについては(図4Dおよび4E)、結果をHTRA1処理条件に対して正規化したPU.1またはOTX2陽性細胞の数の百分率で表した。
トリプシン消化
50mM炭酸水素アンモニウムに溶かした5mMジチオトレイトール(dithiotreitol)(AmBic)と37℃で30分間インキュベートすることによりタンパク質を還元し、次いで、50mM AmBicに溶かした15mMヨードアセトアミドと室温で30分間インキュベートすることによりアルキル化した。トリプシン消化を50mM AmBic中、37℃、タンパク質/酵素比25/1で一晩実施した。
ペプチド混合物に最終濃度が0.1%となるようにギ酸を添加し、HCTultraイントラップ(Bruker社)と連動したU3000 nanoLC(Thermo社)で解析した。ペプチドを、プレカラムRP−C18(5mm、300μm i.d.、100Å、Thermo社)で移動相A(2%ACN/0.1%ギ酸)を用いて流速20μL/分で5分間、濃縮および脱塩し、次いで、分析カラムRP−C18(15cm、75μm i.d.、100Å、Dionex社)で流速300nL/分にて分離した。溶離勾配として、2%〜10%の溶媒B(95%ACN/0.1%ギ酸)を10分間、次いで10%〜35%のBを60分間、35%〜50%のBを10分間流した。イオントラップを、衝突誘起解離(CID)による断片化のために各MSスペクトルから8つの前駆体イオンを選択してポジティブモードで使用した。キャピラリー電圧を2kVに設定し、フルスキャンスペクトルを取得し、100〜2800m/zのMSMSスペクトルを一価イオン排除、ダイナミックエクスクルージョン30秒間および単離幅4Daで取得した。ICCスマートターゲットを250000に設定し、ターゲット質量を622m/zに設定した。
LC−MS/MSデータの解析には、Data Analysis 3.4(Bruker社)を用いて生データを処理した。シグナル強度閾値100000(AU)およびスペクトルデコンボリューションを用いて、最大5000の化合物についてMgfファイルを作成した。SwissProtデータベース(01/04/2015)、Homos sapiens taxonomy(登録数20203)にMascotを用いてProteinScape 2.1(Bruker社)でタンパク質同定を実施した。トリプシンを、切れ残り2の酵素として選択した。Cysのカルバミドメチル化を固定修飾、Metの酸化を可変修飾としてそれぞれ設定し;MS許容誤差およびMS/MS許容誤差を0.5Daに設定した。ペプチドのバリデーションにはp値<0.05であることが必要であった。さらに、酵素としてセミトリプシンを使用し、同じパラメータを用いて解析を実施した。
Tsp1−/−マウス、CD47−/−マウス、CD36−/−−マウスおよびCx3cr1GFP/GFPマウスは購入したものである(Charles River Laboratories社、Jackson laboratories社)。マウスは全て、Crb1rd8、Pde6brd1およびGnat2cpfl3変異が陰性(Tsp1−/−)であったが、または陰性となるように戻し交配した。マウスを動物施設内で特定の病原微生物が存在しない条件下、12/12時間の明/暗(100〜500ルクス)周期で飼育し、水および通常の飼料を自由摂取させた。実験のプロトコルおよび手順はいずれも、地元の動物管理倫理委員会「Comite d’ethique en experimentation animale Charles Darwin」による承認(第Ce5/2010/011号、第Ce5/2010/044号、第Ce5/2011/033号)を受けた。
固相/液相混合法を用いてPKT16を合成した。簡潔に述べれば、2−クロロトリチルクロリド樹脂を予め完全無水CH2Cl2中で2時間膨張させた。Fmoc−Aa−OH(0.32mmol)をCH2Cl2(4mL)中、ジイソプロピエチルアミン(diisopropyethylamine)(DIPEA、4eq.)の存在下で2−CTC樹脂(400mg、充填量=1.6mmol/g)とカップリングさせた。CH2Cl2/MeOH/DIPEA(7:2:1)の混合物、次いでMeOHで洗浄することにより、樹脂上の未反応部位をキャップした。N,N−ジメチルホルムアミド(DMF)中20%のピペリジンを用いてFmoc基を除去した後、Fmoc脱保護のために20%ピペリジン/DMF、活性化のために2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスファート/1−ヒドロキシベンゾトリアゾール(HBTU/HOBt)、塩基としてDIPEAおよび溶媒としてN−メチル−2−ピロリジノン(NMP)を用い、標準的なFmoc保護アミノ酸(Bachem社、スイス)により鎖伸長を実施した。直鎖状ペプチド鎖の組立てが完了したとき、樹脂を収縮させるため、最終洗浄段階としてさらにMeOH洗浄を実施した(1×1分、1×15分)。
手術用顕微鏡に装着した532nm眼科用レーザー(Vitra Laser、532nm、450mW、50ミリ秒および250μm)でレーザー凝固を実施した。ガラスキャピラリー(Eppendorf社)および微量注入器を用いて、2μlのHTRA1および/またはTSP1の硝子体内注射を実施した。注射溶液2μlは、50μg/mlTSP1およびHTRA1を含み、この濃度は、各タンパク質が眼内体積で約10分の1に希釈されると仮定した眼内濃度5μg/mlに相当する。一連の実験では、光刺激後およびレーザー損傷後に加齢に伴い過度の網膜下炎症を発症するCx3cr1GFP/GFPマウス(Combadiereら,J Clin Invest.2007,117:2920−2928;Levyら,EMBO Mol Med.2015,7:211−226)にレーザー損傷を実施した。損傷後第4日(MP浸潤が最大になるとき)および第7日に、PBS、組換えTSP1(10μg/ml)、4NGG対照ペプチドまたはCD47活性化ペプチドPKT16(200μM)のいずれかの100μM溶液を2μlの体積で注射し、第10日、フラットマウントしたRPE/脈絡膜フラットマウントで網膜下炎症を評価した。
既に記載されている(Sennlaubら,EMBO Mol Med.2013,5:1775−1793)通りに、2〜3か月齢のマウスを6時間暗順応させ、瞳孔を散大させ、緑色LED光に4日間曝露し(午前2時開始、4500ルクス、JP Vezon equipements社)、次いで12時間/12時間周期の通常の施設条件下で飼育した。光曝露終了時または10日後(第14日)にMPカウントを評価した。
眼球を摘出し、4%PFAで30分間固定し、輪部で切開し;角膜および水晶体を廃棄した。網膜をRPE/脈絡膜/強膜から慎重に剥がした。網膜および脈絡膜を抗IBA−1(Wako chemicals社)、次いで二次抗体の抗ウサギAlexa 488(Molecular Probes社)とインキュベートし、ヘキスト染色を実施した。脈絡膜および網膜をフラットマウントし、蛍光顕微鏡DM5500B(Leica社)で観察した。RPE/脈絡膜フラットマウント全体および網膜の外節側のIBA−1+細胞をカウントした。
Levyら(EMBO Mol Med.2015,7:211−226)に従い、図のマウス系統の脳ミクログリアを上記の通りに選別し、10μM CFSE(Life Technologies社)で標識し、洗浄し、PBSに再懸濁させた。麻酔をかけた10〜14週齢の野生型マウスの網膜下腔にガラスマイクロキャピラリー(Eppendorf社)および微量注入器を用いて細胞12000個(4μL)を注射した。眼圧上昇を回避し、4μLの溶液で網膜が剥離するよう網膜下注射の前にガラスキャピラリーで孔を開けた。眼底検査により網膜下注射を確認した。特定の実験では、細胞に組換えヒトTSP1(10μg/ml、R&D Systems社)を同時に注射し、24時間後に眼球を摘出し、4%PFAで30分間固定し、DAPIで標識した。出血のみられる眼球は廃棄した。フラットマウントで網膜下腔内の網膜のRPE側およびRPEの頂端側のCFSE+細胞を定量化した。
10週齢の雄C57BL/6JマウスおよびCd47−/−マウスに3%チオグリコラート(T9032、Sigma社)0.5mlをi.p.注射することによりマウス腹腔滲出細胞(PEC)を誘発した。1日後、氷冷PBSで腹膜を洗い流すことによりPECを単離した。製造業者のプロトコルに従い磁気ソーティング(EasySep Mouse Monocyte Enrichment Kit、Stemcell Technologies社)によりMφを陰性選択し、X−VIVO 15培地(Lonza社)に再懸濁させ、Lab−Tek(登録商標)Chamber Slide(商標)(Nunc(登録商標))に播いた。
Graph Pad 6(GraphPad Software社)をデータ解析およびグラフ表示に用いた。数値はいずれも平均+/−SEMで報告する。実験計画に応じて平均値間の一元配置ANOVA、次いでボンフェローニの事後検定(多重比較)またはマン・ホイットニーのU検定(2グループ間比較)により統計解析を実施した。n値およびP値は図の説明文に示す。
Tsp1−/−マウスには、実験的に誘導した脈絡網膜炎、光誘導損傷およびレーザー誘導損傷後に網膜下炎症の増大および長期化がみられることから、TSP1は網膜下単核単球除去に関与する(Wangら,Arch Ophthalmol.2012,130:615−620;Ngら,Invest Ophthalmol Vis Sci.2009,50:5472−5478;Chenら,Am J Pathol.2012,180:235−245)。この作用を媒介するTSP1受容体は明らかにされていない。2〜3か月齢および12か月齢のマウスの網膜およびRPE/脈絡膜のフラットマウントにおいて網膜下IBA−1+単核単球を定量化したところ、同じ条件で飼育した野生型個体と比較して、Tsp1−/−マウスおよびCd47−/−マウスには加齢による網膜下単核単球の有意な増加がみられたが、Cd36−/−マウスにはみられなかった(図1A、マウスは全て、Crb1rd8遺伝子を排除するように戻し交配し、ほかにケージを覆うものがない状態で、ケージレベルで100〜500ルクス、12時間ずつの明/暗周期の下で育てた)。
遺伝子に関連する多数の研究から、染色体10q26はAMDに関連する領域の主要な候補であることがわかっている。リスクハプロタイプは、高温要求性Aセリンペプチダーゼ1(HTRA1)プロモーターの保存されたCpGアイランド(DNAメチル化部位)のCGパターンを破壊するSNP rs11200638を含む(Yangら,Science.2006,314:992−993)。このSNPは、リンパ球でのHTRA1転写のエピジェネティックな阻害を取り除くことがわかっている(Yangら,Science.2006,314:992−993)。HTRA1を発現することができるマクロファージ(Houら,Arthritis and rheumatism.2013,65:2835−2846)とは対照的に、リンパ球はAMD患者の網膜にはあまり存在しない。単球由来マクロファージのHTRA1発現を評価するため、最初に、健常ドナーから新たに精製し様々な長さの時間培養したCD14+末梢血単球(PBMC)でのHTRA1発現を解析した。HTRA1のRT−PCR解析から、単球からマクロファージへの分化の初期にHTRA1が迅速かつ有意に誘導され、それが少なくとも168時間にわたって高レベルで持続することがわかった(7日間;図2A)。RT−PCR解析では、新鮮なPBMCにはHtra1 mRNAが新鮮な血液リンパ球の10倍発現し、この発現は、24時間のPBMC培養の後にさらにその10倍増加することが明らかになった(図2B)。rs11200638がホモ接合型のウェット型AMDの患者および年齢をマッチさせた遺伝子多型のない対照被験者の定量的RT−PCRにより、rs11200638がリンパ球において有意に高いHtra1 mRNAレベルと関係があるのみならず、さらに重要なことに、PBMCおよび初期PBMC由来マクロファージが、AMDでは多量のHtra1を発現し、蓄積することから、PBMCおよび初期PBMC由来マクロファージでも有意に高いHtra1 mRNAレベルに関連することが確認された(図2C)。
HTRA1はどちらかといえば非選択性のプロテアーゼであり、複数種のタンパク質を分解することがわかっている(Anら,Invest Ophthalmol Vis Sci.2010,51:3379−3386)。興味深いことに、組換えHTRA1(rHTRA1)と37℃で24時間共インキュベートした組換えTSP1(rTSP1)の電気泳動ゲルのクーマシー染色から、HTRA1がTSP1を分解することが明らかになった(図3A)。タンパク質のウエスタンブロット解析では、共インキュベートした条件下で完全な大きさのTSP1が消失し、これより小さいバンドが複数現れることが確認された(図3A)。組換えTSP2/rHTRA1と共インキュベートしたタンパク質の電気泳動ゲルのクーマシー染色では、そのような分解はみられなかった(図3B)。次に、in vivoのレーザー誘導網膜下炎症におけるrTSP1およびHTRA1消化TSP1の機能性を解析した。第3日にPBS、rHTRA1、rTSP1およびrHTRA1消化rTSP1を硝子体内注射した野生型マウスおよびTsp1−/−マウスの第7日のレーザー誘導網膜下炎症の定量化により、(i)野生型マウスではrHTRA1が網膜下炎症を悪化させるが、Tsp1−/−マウスでは悪化させないこと、および(ii)rTSP1は、この炎症を有意に減少させるが、rHTRA1消化rTSP1は減少させないことが明らかになった(図3C)。その結果、脈絡膜フラットマウントでCD102+CNVによって覆われた表面として第7日に測定した関連する脈絡膜血管新生にも同様の差がみられた(図3D)。
TSP1のHTRA1切断部位を明らかにするため、TSP1の消化後フラグメントを液体クロマトグラフィー−タンデムマススペクトロメトリーに供した。この解析から、HTRA1はTSP1を(i)インテグリンα3β1との結合能があることがわかっている部位で、(ii)「2型」ドメインの間にある2つの部位で、および(iii)それぞれがCD47受容体と相互作用することが可能であり、その効率の高いCD47活性化に関与する2つのバリン−バリン−メチオニン(VVM)配列の間にある2つの部位で切断することが明らかになった。TSP1のCD36またはLAP結合ドメインは直接影響を受けなかった。
網膜下免疫抑制に対するHTRA1の作用を評価するため、CFSE標識ヒト単球とブタRPEの共培養モデルを開発した。このモデルでは、網膜下腔への単核単球のin vivo養子移植(Levyら,EMBO Mol Med.2015,7:211−226)と同様に、CFSE+単球の少なくとも50%が24時間以内に迅速に除去されるが、RPE細胞数(OTX−2+核のカウントにより示される)は影響を受けない(図4Aおよび4B)。共培養物に組換えHTRA1(5μg/mL)を添加すると、このRPEの免疫抑制が極めて有意に阻害され、24時間後のhMo数は対照条件より3〜4倍多かった(共培養対照群と比較してp<0.0001)。核RPEマーカー(下を参照されたい)があまり減少しなかったため、共培養物中のRPE細胞数はOTX2を用いて自動的にカウントした(Arrayscan)。transwellを用いた実験では、Mo細胞死を誘導するにはRPE細胞との間の物理的接触が必要であり、HTRA1の熱不活化によりその作用が消失することが示された(不掲載)。
In vivoでのCD47活性化の効果を評価するため、光刺激後およびレーザー損傷後に加齢に伴い過度の網膜下炎症を発症するCx3cr1GFP/GFPマウス(Combadiereら,JCI.2007;Levyら,EMBO Mol Med.2015)にレーザー損傷を実施した。損傷後第4日(MP浸潤が最大になるとき)および第7日に、PBS、TSP1、対照ペプチド4NGGまたはCD47活性化ペプチドPKT16の溶液(100μM)を2μlの体積で注射し、第10日、フラットマウントにしたRPE/脈絡膜フラットマウントで網膜下炎症を評価した。
CD47が他の病的状況下で炎症解消に影響を及ぼすかどうかを試験するため、ともに異なる速度論でアポトーシス促進性の除去を受ける初期の好中球蓄積とそれに続く動員された単球由来炎症性マクロファージ(recMφ)を特徴とする急性チオグリコラート誘導腹膜炎のモデルを用いた(Gautierら,Blood.2013,122:2714−2722)。
Claims (30)
- リンカーを介して連結された少なくとも2つのペプチド単量体を含む多量体ペプチドまたはポリペプチドであって、前記少なくとも2つのペプチド単量体がCD47を活性化する、多量体ペプチドまたはポリペプチド。
- 前記少なくとも2つのペプチド単量体が、4N1K、PKHB1およびPKT16を含む群から選択される、請求項1に記載の多量体ペプチドまたはポリペプチド。
- 前記リンカーがペプチドリンカー、好ましくはGlyリッチリンカーである、請求項1または2に記載の多量体ペプチドまたはポリペプチド。
- 二量体である、請求項1〜3のいずれか1項に記載の多量体ペプチドまたはポリペプチド。
- 配列番号7を含む、または配列番号7からなる、請求項1〜4のいずれか1項に記載の多量体ペプチドまたはポリペプチド。
- プロテアーゼHTRA1に耐性を示すものが、プロテアーゼHTRA1に対する耐性である、修飾TSP1タンパク質またはそのフラグメント。
- 少なくとも1つのHTRA1切断配列の少なくとも1個のアミノ酸が、欠失している、置換されている、または付加されている、請求項6に記載の修飾TSP1タンパク質。
- 配列番号8の242〜243位の残基VTおよび/または配列番号8の288〜289位の残基QVが欠失している、請求項6または7に記載の修飾TSP1タンパク質。
- 配列番号8の242位および/または289位の残基Vが置換されている、請求項6または7に記載の修飾TSP1タンパク質。
- 炎症の治療に使用するための作用物質であって、CD47を活性化する作用物質。
- CD47を直接活性化する、請求項10に記載の作用物質。
- CD47アゴニスト、好ましくはTSP1ペプチド模倣物である、請求項11に記載の作用物質。
- 請求項6〜9のいずれか1項に記載の修飾TSP1タンパク質またはそのフラグメントである、請求項11に記載の作用物質。
- 4N1K、PKHB1およびPKT16を含む群から選択される活性化ペプチドである、請求項11に記載の作用物質。
- 請求項1〜5のいずれか1項に記載の多量体ペプチドまたはポリペプチドである、請求項11に記載の作用物質。
- CD47を間接的に活性化する、請求項10に記載の作用物質。
- TSP1活性化因子、HTRA1阻害剤およびFas活性化因子を含む群から選択される、請求項16に記載の作用物質。
- 前記炎症が、急性炎症または慢性炎症である、10〜17のいずれか1項に記載の作用物質。
- 前記炎症が治療抵抗性炎症、好ましくは治療抵抗性低悪性度慢性炎症である、請求項10〜18のいずれか1項に記載の作用物質。
- 前記炎症が、単核食細胞蓄積に関連する炎症である、請求項10〜19のいずれか1項に記載の作用物質。
- 前記炎症が、加齢黄斑変性;加齢黄斑症;網膜色素変性;パーキンソン病、多発性硬化症またはアルツハイマー病などの神経変性疾患;肥満またはアテローム性動脈硬化症などの代謝障害、および関節症などの加齢関連慢性変性疾患を含む群から選択される、請求項10〜20のいずれか1項に記載の作用物質。
- 前記炎症が、加齢黄斑変性;加齢黄斑症;網膜色素変性;および神経変性疾患を含む群から選択される加齢性疾患である、請求項10〜21のいずれか1項に記載の作用物質。
- 前記炎症が、加齢黄斑変性;加齢黄斑症および網膜色素変性を含む群から選択される眼の炎症である、請求項10〜22のいずれか1項に記載の作用物質。
- 前記炎症が加齢黄斑変性である、請求項10〜23のいずれか1項に記載の作用物質。
- 請求項10〜24のいずれか1項に記載の作用物質を少なくとも1種含む、組成物。
- CD47アゴニストとFas活性化因子とを含む、請求項25に記載の組成物。
- 炎症、好ましくは加齢黄斑変性の治療に使用するための、CD47を活性化する少なくとも1種の作用物質と、少なくとも1種の薬学的に許容される担体と、を含む医薬組成物。
- 炎症、好ましくは加齢黄斑変性の治療に使用するための、CD47を活性化する少なくとも1種の作用物質を含む医薬。
- 好ましくは硝子体内注射により眼内に投与される、または局所眼内投与により適用されることを特徴とする、請求項10〜24のいずれか1項に記載の作用物質、請求項27に記載の医薬組成物または請求項28に記載の医薬。
- 請求項10〜24のいずれか1項に記載の作用物質、請求項27に記載の医薬組成物または請求項28に記載の医薬を少なくとも1種含む、キット。
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JP2023180474A JP2023179752A (ja) | 2016-05-10 | 2023-10-19 | Cd47を活性化する作用物質およびその炎症治療における使用 |
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PCT/EP2017/061151 WO2017194586A1 (en) | 2016-05-10 | 2017-05-10 | Agents that activate cd47 and their use in the treatment of inflammation |
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JP2023180474A Division JP2023179752A (ja) | 2016-05-10 | 2023-10-19 | Cd47を活性化する作用物質およびその炎症治療における使用 |
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JP2022035726A Pending JP2022078244A (ja) | 2016-05-10 | 2022-03-08 | Cd47を活性化する作用物質およびその炎症治療における使用 |
JP2023180474A Pending JP2023179752A (ja) | 2016-05-10 | 2023-10-19 | Cd47を活性化する作用物質およびその炎症治療における使用 |
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JP2023180474A Pending JP2023179752A (ja) | 2016-05-10 | 2023-10-19 | Cd47を活性化する作用物質およびその炎症治療における使用 |
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WO2022113887A1 (ja) * | 2020-11-27 | 2022-06-02 | 京都府公立大学法人 | 炎症性網膜疾患の判定方法、炎症性網膜疾患治療剤、及び炎症性網膜疾患治療剤のスクリーニング方法 |
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AU2019206468A1 (en) * | 2018-01-09 | 2020-08-06 | Brigham Young University | Compositions and methods for treating pain with wogonin |
WO2022232001A1 (en) * | 2021-04-26 | 2022-11-03 | President And Fellows Of Harvard College | Cd47 compositions and methods for the treatment of degenerative ocular diseases |
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