JP2023052387A - リウマチ関節炎治療用ペプチド及びその用途 - Google Patents
リウマチ関節炎治療用ペプチド及びその用途 Download PDFInfo
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Abstract
Description
反応が慢性的に示され、それにより、滑膜が増殖され、滑液の量が増加し、関節の腫れと疼痛とをもたらす疾患である。リウマチ関節炎は、全身性炎症反応であり、人体内の多くの組織及び器官(皮膚、血管、心臓肺、筋肉)に影響を与えて、特に、関節に非可逆的な増殖性滑膜炎を起こし、関節軟骨の破壊と関節の硬直とに進む。リウマチ関節炎の原因は、まだ明らかにされていないが、自家免疫反応が、本疾患の慢性化と進行とに重要な役割を行うと知られている。さらに具体的には、炎症性媒介体またはサトカインの局所的な放出と共に、T細胞が重要な役割を行い、関節を破壊させる持続的な自家免疫反応が起こる。主要症状としては、疲れ、無力感、疼痛などであり、関節炎が進みながら、発熱及び体力衰弱を伴う。また、炎症が起こった関節近辺に、筋肉硬直と筋肉萎縮とが示され、関節の動きに影響を与える。
溶性受容体、TNFやインターロイキン(IL)6受容体に対する抗体、またはCD20に対する抗体などを遺伝子組み換え技術で生産し、それらを治療剤として開発し、疾病経過をかなり好転させているが、それもまた、重症感染、結核または腫瘍のような予期せぬ副作用が発生する問題点がある。
そのような技術的背景下で、リウマチ関節炎と係わる核心的な炎症メカニズムを調節することにより、リウマチ関節炎の諸般の症状である炎症、骨及び軟骨組織の浸食などを緩和させることができる新たな治療剤の発掘が必要な実情である。
白質B100(apoB100)を、候補物質と共に接触させる段階と、(b)前記候補物質と接触された試料において測定されたアポリポ蛋白質B100とENO1との結合レベルを、候補物質が投与されていない対照群と比較する段階と、を含む、リウマチ関節炎治療剤をスクリーニングする方法を提供するものである。
的のために製造されたアミノ酸配列を追加して含んでもよい。
白質B100(apoB100)を、候補物質と共に接触させる段階と、(b)前記候補物質と接触された試料において測定されたアポリポ蛋白質B100とENO1との結合レベルを、候補物質が投与されていない対照群と比較する段階と、を含む、リウマチ関節炎治療剤をスクリーニングする方法を提供する。
(container)において、2個以上の製剤を結合させるか、あるいは試験製剤及び細胞、
または細胞溶解物及び試験製剤を結合させることができる。また、該接触は、細胞またはインサイチュ(in situ)においても起こる。例えば、2個のポリペプチドを暗号化する組み換えポリヌクレオチドを、細胞内で共同発現(coexpression)させることにより、細胞または細胞溶解物において、2個のポリペプチドを接触させることができる。また、テストする蛋白質が、固定相表面に配列された蛋白質チップ(protein chip)や蛋白質ア
レイ(protein array)を利用することもできる
元素(element)、化合物(compound)、実在物(entity)、またはそれらの組み合わせ
を含んでもよい。例えば、蛋白質、ポリペプチド、低分子有機化合物、ポリサッカライド、ポリヌクレオチドなどを含んでもよい。また、自然産物(natural product)、合成化合物または化学化合物、あるいはそれら2個以上物質の組み合わせでもある。
)からなる群から選択されるいずれか1以上でもある。
本実施例においては、リウマチ関節炎と、末梢血液内単核球細胞のENO1発現との関連性を確認し、それらの発現を観察した。また、リウマチ関節炎患者から、IP(immunoprecipitation)/MS(mass spectroscopy)法を利用したプロテオミクス分析を介し
、ENO1(α-enolase)の結合リガンドとして選定されたアポリポ蛋白質B100(
apoB100)との結合が、リウマチ関節炎患者の末梢血液内炎症性サトカイン分泌に及ぼす影響を確認しようとした。具体的には、リウマチ関節炎患者から得た単核球細胞を対象にENO1免疫染色が施された末梢血液単核球細胞にapoB100を処理した後、IL-1β、IL-6、TNF-αの分泌量変化を比較した。なお、対照群としては、正常人から分離された細胞を利用した群(HC:healthy control)を設定した。
本実施例においては、前記実施例1の実験結果に基づき、末梢血液内ENO1とapoB100との結合を阻害することにより、炎症性サトカインの分泌を抑制させることができるペプチドを導き出そうとするものである。具体的には、図7に示されているように、ペプチドマイクロアレイを利用し、ENO1と結合するapoB100のモチーフを確認し、総5種のペプチドを得た。前記ペプチドの具体的な情報は、下記表1の通りである。
3-1.リウマチ関節炎患者由来の末梢血液における炎症性サトカイン分泌低減
3-2.リウマチ関節炎動物モデルでの治療効果確認
立した後、前記動物モデルを対象に、炎症性サトカイン分泌抑制用ペプチドを病変部位に皮下注射した。その後、前記ペプチド注射による足首厚(ankle thickness)及び関節炎指数(arthritis score)の変化を確認した。併せて、前述のところと同一条件で、関節液炎症、骨浸食、軟骨損傷、白血球浸潤の変化を比較した。一方、対照群として、K/BxN血清及びapoBのみを処理した、比較群としては、K/BxN血清、apoB及び非結合ペプチド処理群(NP)を設定した。
本発明はまた、以下の項目を提供する。
(項目1)
配列番号1、配列番号3または配列番号5のアミノ酸配列からなる、ペプチド。
(項目2)
配列番号1、配列番号3または配列番号5のアミノ酸配列からなるペプチド、またはそれをコーディングするポリヌクレオチドを有効成分として含む、リウマチ関節炎の予防用または治療用の薬学的組成物。
(項目3)
上記組成物は、炎症性サトカインの分泌を抑制させるものである、項目2に記載の薬学的組成物。
(項目4)
上記サトカインはIL-1β(interleukin-1β)、IL-6、TNF-α(tumor necrosis factor-α)、それらの組み合わせから選択されるいずれか一つである、項目2に記載の薬学的組成物。
(項目5)
上記ペプチドのN末端は、アセチル基、フルオレニルメトキシカルボニル基、ホルミル基、パルミトイル基、ミリスチル基、ステアリル基及びポリエチレングリコール(PEG)からなる群から選択されるいずれか1つの保護基と結合されるか、
上記ペプチドのC末端は、アミノ基(-NH 2 )及びアジド基(-NHNH 2 )からなる群から選択されるいずれか1つの保護基と結合されるものである、項目2に記載の薬学的組成物。
(項目6)
上記組成物は、上記ペプチド以外の他の抗炎症剤と同時、別途、または順に併用投与されるものである、項目2に記載の薬学的組成物。
(項目7)
上記組成物は、薬学的に許容可能な担体をさらに含むものである、項目2に記載の薬学的組成物。
(項目8)
配列番号1、配列番号3または配列番号5のアミノ酸配列からなるペプチドを有効成分として含む、リウマチ関節炎の予防用または改善用の健康機能性食品組成物。
(項目9)
(a)ENO1(α-enolase)を含む個体の試料に、アポリポ蛋白質B100(apo
B100)を、候補物質と共に接触させる段階と、
(b)上記候補物質と接触された試料において測定されたアポリポ蛋白質B100とENO1との結合レベルを、候補物質が投与されていない対照群と比較する段階と、を含む、リウマチ関節炎治療剤をスクリーニングする方法。
(項目10)
上記試料は、血液試料である、項目9に記載の方法。
(項目11)
上記アポリポ蛋白質B100とENO1との結合レベルは、ツーハイブリッド方法、共同免疫沈降方法、共同局所化分析、閃光近接測定法(SPA)、UV架橋結合方法または化学的架橋結合方法、異分子相互作用分析(BIA)、質量分析法(MS)、NMR(nuclear magnetic resonance)、蛍光偏光分析法(FPA)及び試験管内プルダウンアッセイからなる群で選択されるいずれか1以上の方法によって測定されるものである、項目9に記載の方法。
(項目12)
上記候補物質と接触された試料において測定されたアポリポ蛋白質B100とENO1との結合レベルが、対照群に比べて低下された場合、リウマチ関節炎治療剤として決定する段階をさらに含む、項目9に記載の方法。
Claims (12)
- 配列番号1、配列番号3または配列番号5のアミノ酸配列からなる、ペプチド。
- 配列番号1、配列番号3または配列番号5のアミノ酸配列からなるペプチド、またはそれをコーディングするポリヌクレオチドを有効成分として含む、リウマチ関節炎の予防用または治療用の薬学的組成物。
- 前記組成物は、炎症性サトカインの分泌を抑制させるものである、請求項2に記載の薬学的組成物。
- 前記サトカインはIL-1β(interleukin-1β)、IL-6、TNF-α(tumor necrosis factor-α)、それらの組み合わせから選択されるいずれか一つである、請求項2に記載の薬学的組成物。
- 前記ペプチドのN末端は、アセチル基、フルオレニルメトキシカルボニル基、ホルミル基、パルミトイル基、ミリスチル基、ステアリル基及びポリエチレングリコール(PEG)からなる群から選択されるいずれか1つの保護基と結合されるか、
前記ペプチドのC末端は、アミノ基(-NH2)及びアジド基(-NHNH2)からなる群から選択されるいずれか1つの保護基と結合されるものである、請求項2に記載の薬学的組成物。 - 前記組成物は、前記ペプチド以外の他の抗炎症剤と同時、別途、または順に併用投与されるものである、請求項2に記載の薬学的組成物。
- 前記組成物は、薬学的に許容可能な担体をさらに含むものである、請求項2に記載の薬学的組成物。
- 配列番号1、配列番号3または配列番号5のアミノ酸配列からなるペプチドを有効成分として含む、リウマチ関節炎の予防用または改善用の健康機能性食品組成物。
- (a)ENO1(α-enolase)を含む個体の試料に、アポリポ蛋白質B100(apo
B100)を、候補物質と共に接触させる段階と、
(b)前記候補物質と接触された試料において測定されたアポリポ蛋白質B100とENO1との結合レベルを、候補物質が投与されていない対照群と比較する段階と、を含む、リウマチ関節炎治療剤をスクリーニングする方法。 - 前記試料は、血液試料である、請求項9に記載の方法。
- 前記アポリポ蛋白質B100とENO1との結合レベルは、ツーハイブリッド方法、共同免疫沈降方法、共同局所化分析、閃光近接測定法(SPA)、UV架橋結合方法または化学的架橋結合方法、異分子相互作用分析(BIA)、質量分析法(MS)、NMR(nuclear magnetic resonance)、蛍光偏光分析法(FPA)及び試験管内プルダウンアッセイからなる群で選択されるいずれか1以上の方法によって測定されるものである、請求項9に記載の方法。
- 前記候補物質と接触された試料において測定されたアポリポ蛋白質B100とENO1との結合レベルが、対照群に比べて低下された場合、リウマチ関節炎治療剤として決定する段階をさらに含む、請求項9に記載の方法。
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