JP2019532962A - 皮膚疾患における治療標的としてのfabp4 - Google Patents
皮膚疾患における治療標的としてのfabp4 Download PDFInfo
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- JP2019532962A JP2019532962A JP2019520695A JP2019520695A JP2019532962A JP 2019532962 A JP2019532962 A JP 2019532962A JP 2019520695 A JP2019520695 A JP 2019520695A JP 2019520695 A JP2019520695 A JP 2019520695A JP 2019532962 A JP2019532962 A JP 2019532962A
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Abstract
Description
[1]Furuhashi et al.,Nat Rev Drug Discov 2008,7(6),489−503
[2]Coe et al.,Biochim Biophys Acta 1998,1391(3),287−306
[3]Hotamisligil et al.,Science 1996,274(5291),1377−1379
[4]Maeda et al.,Cell Metab 2005,1(2),107−119
[5]Furuhashi et al.,Nature 2007,447(7147),959−965
[6]Tuncman et al.,PNAS 2006,103(18),6970−6975
[7]Garin−Shkolnik et al.,Diabetes 2014,63(3),900−911
[8]Bolognia et al.,Dermatology 2012,Sounders,3rd ed.
[9]Krueger et al.,Annals of the Rheumatic Diseases 2005(64),30−36
[10]Siegenthaler et al.,Biochem Biophys Res Commun 1990,3,190,482−487
[II]Floresta et al.,Eur J Med Chem 2017,138,854−873
[12]Cao et al.,Cell Metab 2013,17,768−778
[13]Burak et a.,Sci Transl Med 2015,7,319ra205
[14]Miao et al.,Mol Cell Endocrinol 2015,403,1−9
[15]Won et al.,Nat Mater 2014,13,1157−1164
[16]Madsen et al.,J Invest Dermatol 1992,99(3),299−305
[17]Guttman−Yassky et al.,J Allergy Immunol 2011,127(5),1110−1118
[18]Yuspa et al.,J Cell Biol 1989,109,1207−1217
[19]Wu et al.,Australasian Journal of Dermatology 2004,45(1),47−50
[20]Van der Fits et al.,The Journal of Immunology 2009,182(9),5836−5845
センス3’ guagguaccuggaaacuuguu(配列番号2)
アンチセンス5’ caaguuuccagguaccuacuu(配列番号3)
センス3’ gaaaugggauggaaaaucauu(配列番号4)
アンチセンス5’ ugauuuuccaucccauuucuu(配列番号5)
センス3’ gaugugaucaccauuaaauuu(配列番号6)
アンチセンス5’ auuuaauggugaucacaucuu(配列番号7)
センス3’ gaaagucaagagcaccauauu(配列番号8)
アンチセンス5’ uauggugcucuugacuuucuu(配列番号9)
被験体由来のケラチノサイト又は炎症性細胞を含有する試料中のFABP4の発現を検出するステップと、
FABP4発現が所定の塩基レベルを上回るか下回るかを決定するステップと;
試料中のFABP4発現が所定の塩基レベルを上回る場合、治療有効量の少なくとも1つのFABP4阻害剤又はそれを含む医薬組成物を対象に投与するステップと;
を具える。
本明細書と共に提供される核酸配列(以下の表2)は、37C.F.R1.822に規定されるヌクレオチド塩基の標準的な略語を用いて示されている。各核酸配列の一方の鎖のみが示されているが、相補鎖は表示されている鎖への言及によって含まれると理解される。
乾癬を発症している患者の皮膚からパンチ生検(直径4mm)を得た(n=10)。さらに慢性皮膚炎を発症している患者の皮膚から生検を得た(n=5)。余分な皮膚を外科的に取り除いた後、患者から正常な皮膚を得た(n=10)。組織をホルマリンで固定し、パラフィンに包埋した。光学顕微鏡による組織病理学的検査用に、切片をヘマトキシリン及びエオシン(H&E)で染色し、そして診断を確認した病理学者が観察した。さらに、免疫組織化学的分析用に、切片を以下の抗体で染色した:FABP4(ウサギポリクローナル抗FABP4抗体、PAB 12276、Abnova社製)、FABP5(ウサギポリクローナル抗FABP5の抗体、SC−50379、Santa Crus社製)とPPARγ(マウスモノクローナル抗PPARvγ抗体、E−8、Santa Crus社制)、すべて1:50に希釈した。ラフィン包埋組織及び凍結保存組織を標準的なプロトコルに従って処理した。
CTCLは皮膚ホーミングT細胞の一群の新生物である。菌状息肉腫(MF)はCTCLの最も一般的なタイプを表し、全原発性皮膚リンパ腫の約50%を占めている。本来悪性ではあるが、MFは炎症性の皮膚炎様症状を呈する長期の臨床経過をたどっている[8]。
乾癬に見られるように、ケラチノサイトへのFABP4の導入が、分化が損なわれた過剰増殖状態を作り出すことが示唆された。2つのケラチノサイト分化マーカーK1及びK5の発現を測定することによって分化を評価した。K5は、レベルがケラチノサイト分化の間に変化せず、したがってローディングコントロールとして働くケラチンであり、一方K1は通常のケラチノサイト分化の間に誘発される。
上述したように、乾癬は慢性炎症性皮膚疾患である。免疫系が皮膚細胞を病原体と間違えて、皮膚細胞の増殖を加速させる誤ったシグナルを送り出すときに起こる。イミキモド(IMQ)は、局所投与すると乾癬を誘発し、悪化させる強力な免疫活性化剤である。マウスの背部の皮膚にIMQを毎日塗布すると、プラーク型乾癬に似た炎症性のうろこ状の皮膚病変が誘発される[19、20]。マウスにおけるIMQ誘発乾癬は、ヒト乾癬のモデルとして長い間使用されている。
− ナイーブマウスのグループ(IMQなし)
− 1のビヒクル対照群。ビヒクル配合物は注射用水(WFI)中の10%の1−メチル−2−ピロリドンと、5%のクレモフォールELである。
−陽性対照として酢酸コルチゾンを投与した1処置群−1の錠剤(各25mg、Rekah Pharm)を乳鉢で粉砕した。粉末を2.5mlのWFIに溶解させて10mg/mlを得た。化合物を、IMQ適用の初日(1日目)から6日間、1日1回、12.5mg/kg体重(体重)マウスで、経口投与した。
− 5、15及び30mg/kgの3つの投与量で、BMS(すなわち試験項目)を受けた3つの治療群。BMS粉末(Cayman Chemical)をエタノールに溶解させて30mg/mlの溶液を作った。この原液をビヒクルで希釈して、0.5、1.5及び3mg/mlの3つの異なる濃度とした。新しい水溶液を毎日調製した。IMQを適用した初日(1日目)から6日間、1日1回BMSを経口投与した。
Claims (52)
- 皮膚疾患の治療又は予防に使用する少なくとも1つのFABP4阻害剤を含むことを特徴とする医薬組成物。
- 前記少なくとも1つのFABP4阻害剤が、ペプチド、抗体、抗体断片、低分子、低分子干渉RNA(siRNA)、低分子ヘアピン型RNA(shRNA)、及びそれらの混合物から選択されることを特徴とする、請求項1に記載の医薬組成物。
- 前記少なくとも1つのFABP4阻害剤が、最大約1000Da乃至500Daの分子量を有する低分子であることを特徴とする医薬組成物。
- 前記低分子が、カルバゾールブタン酸、アリールスルホンアミド、スルホニルチオフェン 又はスルホニルチオフェン誘導体、4−ヒドロキシピリミジン、2−ヒドロキシピリミジン、カルバゾール又はカルバゾール誘導体、テトラヒドロカルバゾール又はテトラヒドロカルバゾール誘導体、2,3−ジメチルインドール又は2,3−ジメチルインドール誘導体、ベンゾイルベンゼン、ビフェニルアルカン酸又はビフェニルアルカン酸誘導体、2−オキサゾールアルカン酸又は2−オキサゾールアルカン酸誘導体、テトラヒドロピリミジン又はテトラヒドロピリミジン誘導体、ピリジン又はピリジン誘導体、ピラジン又はピラジノン誘導体、キノロン又はキノロン誘導体、アリールカルボン酸又はアリールカルボン酸誘導体、テトラゾール、トリアゾロピリミジン又はトリアゾロピリミジン誘導体、インドール又はインドール誘導体、フラボノイド(フラバノール、フラバノン、イソフラボン、ピラゾール又はピラゾール誘導体など)、(2−(2’−(5−エチル−3,4−ジフェニル−1H−ピラゾール−1−イル)(1,1’−ビフェニル)−3−イル)オキシ)−酢酸(BMS309403)及び4−{[2−メトキシカルボニル)−5−(2−チエニル)−3−チエニル]アミノ}−4−オキソ−2−ブタン酸(BMS480404)、ならびにこれらの塩、立体異性体、水和物及び混合物からなる群から選択されることを特徴とする、請求項2又は3に記載の医薬組成物。
- 前記少なくとも1つのFABP4阻害剤が、FABP4に特異的に結合してその活性を阻害する抗体であることを特徴とする、請求項2に記載の医薬組成物。
- 前記FABP4阻害剤が、配列番号2乃至9の核酸配列を含むsiRNAであることを特徴とする、請求項2に記載の医薬組成物。
- 前記FABP4阻害剤がFABP5阻害剤でもあることを特徴とする、請求項1乃至6のいずれか1項に記載の医薬組成物。
- 前記皮膚疾患が乾癬、皮膚炎(アトピー性、脂漏性、接触性)、湿疹、類乾癬、扁平苔癬、扁平毛孔性苔癬、急性痘瘡状苔癬状粃糠疹、慢性苔癬状粃糠疹、毛孔性紅色批糠疹、ジベルばら色粃糠疹、移植片対宿主病、組織球増殖症、薬剤誘発性発疹、自己免疫結合組織の疾患(例えば、狼瘡)、酒さ、毛嚢炎、にきび、いぼ、魚鱗癬、白斑、瘢痕性脱毛症、CTCL、光線性角化症、扁平上皮癌、基底細胞癌、母斑、慢性単純性苔癬、乾癬、角化症、角膜皮膚炎、そう痒症、やけど、瘢痕、カルス、及びケロイドから成る群から選択されることを特徴とする、請求項1乃至7のいずれかに記載の医薬組成物。
- 前記皮膚疾患がCTCLであることを特徴とする、請求項8に記載の医薬組成物。
- 前記皮膚疾患が炎症性皮膚疾患であることを特徴とする、請求項1乃至7のいずれか一項に記載の医薬組成物。
- 前記炎症性皮膚疾患が、乾癬、皮膚炎(アトピー性、脂漏性、接触性)、湿疹、類乾癬、扁平苔癬、扁平毛孔性苔癬、急性痘瘡状苔癬状粃糠疹、慢性苔癬状粃糠疹、毛孔性紅色批糠疹、ジベルばら色粃糠疹、移植片対宿主病、組織球増殖症、薬剤誘発性発疹、自己免疫結合組織の疾患(例えば、狼瘡)、酒さ、毛嚢炎、にきび、いぼ、魚鱗癬、白斑、瘢痕性脱毛症、及びCTCLから成る群から選択されることを特徴とする、請求項10に記載の医薬組成物。
- 前記炎症性皮膚疾患が、乾癬であることを特徴とする、請求項11に記載の医薬組成物。
- 薬学的に許容される担体をさらに含むことを特徴とする、請求項1乃至12いずれか一項に記載の医薬組成物。
- 前記少なくとも1つのFABP阻害剤を、局所的に、経口的に、吸入により、経鼻的に、経皮的に、眼球内に、又は非経口的に対象の循環系に送達するように適合させたことを特徴とする、請求項1乃至13のいずれか一項に記載の医薬組成物。
- 前記少なくとも1つのFABP4阻害剤を経皮投与するように適合させたことを特徴とする、請求項14に記載の医薬組成物。
- 前記少なくとも1つのFABP4阻害剤を皮膚層にわたって局所投与するように適合させたことを特徴とする、請求項15に記載の医薬組成物。
- 前記少なくとも1つのFABP4阻害剤を角質層にわたって送達するように適合させたことを特徴とする、請求項15又は16に記載の医薬組成物。
- 前記少なくとも1つのFABP4阻害剤を注射による投与に適合させたことを特徴とする、請求項17に記載の医薬組成物。
- 前記少なくとも1つのFABP4阻害剤を経口投与に適合させたことを特徴とする、請求項18に記載の医薬組成物。
- PPARγアゴニストと共に使用するように適合させたことを特徴とする、請求項1乃至19のいずれか一項に記載の医薬組成物。
- PPARγアゴニストをさらに含むことを特徴とする、請求項1乃至19のいずれか一項に記載の医薬組成物。
- 前記PPARγアゴニストが、チアゾリジンジオン、ピオグリタゾン(アクトス)、ロシグリタゾン(アバンディア)、ロベグリタゾン(商品名Duvie)、シグリタゾン、ダルグリタゾン、エングリタゾン、ネトグリタゾン、リボグリタゾン、トログリタゾン(商品名Rezulin)、及びローダミンから選択されることを特徴とする請求項20又は21に記載の医薬組成物。
- 少なくとも1つのFABP4阻害剤の経皮送達用の局所製剤において、前記組成物が少なくとも1つのFABP4阻害剤及び少なくとも1つの薬学的に許容される担体を含むことを特徴とする、局所製剤。
- 少なくとも1つのPPARγアゴニストをさらに含むことを特徴とする、請求項23に記載の局所製剤。
- 必要とする対象に治療有効量の少なくとも1つのFABP4阻害剤又はそれを含む医薬組成物を投与するステップを具えることを特徴とする、対象の皮膚疾患を治療又は予防する方法。
- PPARγアゴニストを前記対象に投与するステップをさらに具えることを特徴とする、請求項25に記載の方法。
- 前記PPARγアゴニストが、前記少なくとも1つのFABP4阻害剤と同時に投与されることを特徴とする、請求項26に記載の方法。
- 前記FABP阻害剤及び前記PPARγアゴニストが逐次的に投与されることを特徴とする、請求項26に記載の方法。
- 前記少なくとも1つのFABP4阻害剤が、ペプチド、抗体、低分子、低分子干渉RNA(siRNA)、低分子ヘアピン型RNA(shRNA)、及びこれらの混合物から選択されることを特徴とする、請求項25から28のいずれか1項に記載の方法。
- 前記少なくとも1つのFABP4阻害剤が、最大約1000Da乃至500Daの分子量を有する低分子であることを特徴とする、請求項29に記載の方法。
- 前記低分子が、カルバゾールブタン酸、アリールスルホンアミド、スルホニルチオフェン又はスルホニルチオフェン誘導体、4−ヒドロキシピリミジン、2−ヒドロキシピリミジン、カルバゾール又はカルバゾール誘導体、テトラヒドロカルバゾール又はテトラヒドロカルバゾール誘導体、2,3−ジメチルインドール又は2,3−ジメチルインドール誘導体、ベンゾイルベンゼン、ビフェニルアルカン酸又はビフェニルアルカン酸誘導体、2−オキサゾールアルカン酸又は2−オキサゾールアルカン酸誘導体、テトラヒドロピリミジン又はテトラヒドロピリミジン誘導体、ピリジン又はピリジン誘導体、ピラジン又はピラジノン誘導体、キノロン又はキノロン誘導体、アリールカルボン酸又はアリールカルボン酸誘導体、テトラゾール、トリアゾロピリミジン又はトリアゾロピリミジン誘導体、インドール又はインドール誘導体、フラボノイド(フラバノール、フラバノン、イソフラボン、ピラゾール又はピラゾール誘導体など)、(2−(2’−(5−エチル−3,4−ジフェニル−1H−ピラゾール−1−イル)(1,1’−ビフェニル)−3−イル)オキシ)−酢酸(BMS309403)及び4−{[2−メトキシカルボニル)−5−(2−チエニル)−3−チエニル]アミノ}−4−オキソ−2−ブタン酸(BMS480404)、ならびにこれらの塩、立体異性体、水和物及び混合物からなる群から選択されることを特徴とする、請求項29又は30に記載の方法。
- 前記少なくとも1つのFABP4阻害剤が、FABP4に特異的に結合してその活性を阻害する抗体であることを特徴とする、請求項29に記載の方法。
- 前記FABP4阻害剤が、配列番号2乃至9の核酸配列を含むsiRNAであることを特徴とする、請求項29に記載の方法。
- 前記FABP4阻害剤がFABP5阻害剤でもあることを特徴とする、請求項25乃至33のいずれか1項に記載の方法。
- 前記皮膚疾患が乾癬、皮膚炎(アトピー性、脂漏性、接触性)、湿疹、類乾癬、扁平苔癬、扁平毛孔性苔癬、急性痘瘡状苔癬状粃糠疹、慢性苔癬状粃糠疹、毛孔性紅色批糠疹、ジベルばら色粃糠疹、移植片対宿主病、組織球増殖症、薬剤誘発性発疹、自己免疫結合組織の疾患(例えば、狼瘡)、酒さ、毛嚢炎、にきび、いぼ、魚鱗癬、白斑、瘢痕性脱毛症、CTCL、光線性角化症、扁平上皮癌、基底細胞癌、母斑、慢性単純性苔癬、乾癬、角化症、角膜皮膚炎、そう痒症、やけど、瘢痕、カルス、及びケロイドから成る群から選択されることを特徴とする、請求項25乃至34のいずれかに記載の方法。
- 前記皮膚疾患がCTCLであることを特徴とする、請求項35に記載の方法。
- 前記皮膚疾患が炎症性皮膚疾患であることを特徴とする、請求項25乃至34のいずれか一項に記載の方法。
- 前記炎症性皮膚疾患が、乾癬、皮膚炎(アトピー性、脂漏性、接触性)、湿疹、類乾癬、扁平苔癬、扁平毛孔性苔癬、急性痘瘡状苔癬状粃糠疹、慢性苔癬状粃糠疹、毛孔性紅色批糠疹、ジベルばら色粃糠疹、移植片対宿主病、組織球増殖症、薬剤誘発性発疹、自己免疫結合組織の疾患(例えば、狼瘡)、酒さ、毛嚢炎、にきび、いぼ、魚鱗癬、白斑、瘢痕性脱毛症、及びCTCL地衣類から成る群から選択されることを特徴とする、請求項37に記載の方法。
- 前記炎症性皮膚疾患が、乾癬であることを特徴とする、請求項38に記載の方法。
- 対象の乾癬を治療又は予防する方法において、必要とする対象に治療有効量の少なくとも1つのFABP4阻害剤又はそれを含む医薬組成物を投与するステップを具えることを特徴とする方法。
- 対象のCTCLを治療又は予防する方法において、必要とする対象に治療有効量の少なくとも1つのFABP4阻害剤又はそれを含む医薬組成物を投与するステップを具えることを特徴とする方法。
- 皮膚疾患又は状態を発症している対象における素因を検出する方法において:
前記対象由来のケラチノサイト又は炎症性細胞を含む試料中のFABP4の発現を検出するステップであって、所定の塩基レベルを超える前記試料中のFABP4の存在が、皮膚疾患又は状態を発症する素因を表す、ステップを具えることを特徴とする方法。 - 前記試料が皮膚試料であることを特徴とする、請求項42に記載の方法。
- 前記所定の塩基レベルが、正常な皮膚サンプル中のFABP4のレベルであることを特徴とする、請求項42又は43に記載の方法。
- 前記検出するステップが、FABP4核酸の発現の検出を具えることを特徴とする、請求項42乃至44のいずれか1項に記載の方法。
- 前記検出するステップが、FABP4タンパク質又はその断片の発現を検出するステップを具えることを特徴とする、請求項42乃至45のいずれか1項に記載の方法。
- 前記皮膚疾患が乾癬、皮膚炎(アトピー性、脂漏性、接触性)、湿疹、類乾癬、扁平苔癬、扁平毛孔性苔癬、急性痘瘡状苔癬状粃糠疹、慢性苔癬状粃糠疹、毛孔性紅色批糠疹、ジベルばら色粃糠疹、移植片対宿主病、組織球増殖症、薬剤誘発性発疹、自己免疫結合組織の疾患(例えば、狼瘡)、酒さ、毛嚢炎、にきび、いぼ、魚鱗癬、白斑、瘢痕性脱毛症、CTCL、光線性角化症、扁平上皮癌、基底細胞癌、母斑、慢性単純性苔癬、乾癬、角化症、角膜皮膚炎、そう痒症、やけど、瘢痕、カルス、及びケロイドから成る群から選択されることを特徴とする、請求項42乃至46のいずれか1項に記載の方法。
- 前記皮膚疾患がCTCLであることを特徴とする、請求項47に記載の方法。
- 前記皮膚疾患が炎症性皮膚疾患であることを特徴とする、請求項42乃至46のいずれか1項に記載の方法。
- 前記炎症性皮膚疾患が、乾癬、皮膚炎(アトピー性、脂漏性、接触性)、湿疹、類乾癬、扁平苔癬、扁平毛孔性苔癬、急性痘瘡状苔癬状粃糠疹、慢性苔癬状粃糠疹、毛孔性紅色批糠疹、ジベルばら色粃糠疹、移植片対宿主病、組織球増殖症、薬剤誘発性発疹、自己免疫結合組織の疾患(例えば、狼瘡)、酒さ、毛嚢炎、にきび、いぼ、魚鱗癬、白斑、瘢痕性脱毛症、及びCTCLから成る群から選択されることを特徴とする、請求項49に記載の方法。
- 前記炎症性皮膚疾患が乾癬であることを特徴とする、請求項50に記載の方法。
- 対象からのケラチノサイト又は炎症性細胞を含む試料中のFABP4の発現を検出するステップと、当該FABP4の発現が所定の塩基レベルより上又は下であるかどうかを決定するステップと、前記試料中のFABP4発現が前記所定の塩基レベルを上回る場合、被験体に、治療有効量の少なくとも1つのFABP4阻害剤又はそれを含む医薬組成物を投与するステップを具えることを特徴とする、対象における皮膚疾患の治療又は予防方法。
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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, JPN6021037000, 2007, pages 3511 - 3515, ISSN: 0004601238 * |
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 24, JPN6021037001, July 2016 (2016-07-01), pages 4310 - 4317, ISSN: 0004601237 * |
INTERNATIONAL JOURNAL OF INFLAMMATION, vol. Vol.2011, Article ID 642612, JPN6021037004, 2011, pages 1 - 12, ISSN: 0004601235 * |
JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 134, JPN6021037003, 2014, pages 1001 - 1011, ISSN: 0004601236 * |
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WO2018078624A1 (en) | 2018-05-03 |
JP7199096B2 (ja) | 2023-01-05 |
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US20220096435A1 (en) | 2022-03-31 |
CN115998871A (zh) | 2023-04-25 |
US20200138779A1 (en) | 2020-05-07 |
IL265719A (en) | 2019-05-30 |
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CN110035749B (zh) | 2022-11-15 |
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