JP4961559B2 - インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 - Google Patents
インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 Download PDFInfo
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Description
(2)(1)のうち、ポリペプチドであるもののアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18阻害活性を有するタンパク質
(3)(1)のうち、ポリペプチドであるものをコードする遺伝子
(4)(2)をコードする遺伝子
プロテアーゼとは、蛋白質分解酵素のことであるが、例えば、メタロプロテアーゼ,システインプロテアーゼ,セリンプロテアーゼ,アスパラギン酸プロテアーゼ(酸性プロテアーゼ)等が挙げられる。
MMPとは、動物細胞の細胞間の接着性マトリックス・タンパク質を加水分解し、細胞分裂や形態形成、さらにはガン転移に関与している亜鉛含有プロテアーゼである。MMPとしては、MMP−1,2,・・・28等30種類近くが同定されている。
本発明のCOPDの予防又は治療剤の有効成分として用いられるものとしては、下記(1)乃至(4)単独の他、これらの組み合わせ等が挙げられる。
(1)インターロイキン18阻害剤(レドックス活性蛋白質を除く)
(2)インターロイキン18阻害剤(レドックス活性蛋白質を除く)のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18阻害活性を有するタンパク質
(3)(1)をコードする遺伝子
(4)(2)をコードする遺伝子
尚、上記(1)および(2)に於けるインターロイキン18阻害剤のアミノ酸配列は、後述するIL−18阻害剤として、一般に知られるアミノ酸配列であれば、特に限定されるものではないが、レドックス活性蛋白質は除くものとする。
阻害剤である、I-κBinhibitor,I-κBαgene transfer(American Journal of Respiratory and Critical Care Medicine vol.160 pp S72-S79, 1999)やPS-341(Proc.Natl.Acad.Sci.USA vol.95 PP.15671-15676, December 1998 Medical Sciences)等が挙げられる。
例えば、LTB4 antagonists (例えばLY29311, SC-53228, CP-105,696, SB201146, BIIL284)、5'-Lipxygenase inhibitors (例えばzileutin, Bayx1005)、Chemokine inhibitors、IL-8 antagonists (例えばSB225002; CXCR2 antagonists)、TNF inhibitors (例えばmonoclonal Ab, soluble receptors, MMP inhibitors)、Antioxydants (例えばNAC, NAL, グルタチオン,スーパーオキシドジスムターゼ等)、Prostanoid inhibitors (例えばCOX-2 inhibitors, thromboxane antagonists、isoprostane receptor antagonists)、iNOS inhibitor 等
例えば、Phosphodiesterase 4 inhibitors (例えばSB207499, CP80633, CDP-840)、Adhesion inhibitors (例えばanti-CD11/CD18, anti-ICAM1, E-selectin inhibitors)、Prostaglandin E analogs (例えばmisoprostil, butaprost)、サイトカイン(例えばIL-10)、Colchicine、Macrolide antibiotics (例えばerythromycin, clarithromycin, roxithromycin)等
例えば、Neutrophil elastase inhibitors (例えばICI200355, ONO-5046, MR-889, L658,758)、Cathepsin inhibitors (例えばsuramin)、Matrix metalloprotease inhibitors (例えばbatimastat, marimastat、KBR7785)、alpha1-antitrypsin (例えばpurified, human recombinant, gene transfer)、Secretory leukoprotease inhibitor、Elafin等
例えば免疫抑制剤FK506等
テオフィリン等のキサンチン誘導体,β2受容体刺激剤,抗コリン剤,抗アレルギー用剤,副腎皮質ホルモン剤及び吸入ステロイド等のステロイド剤等。
ウイルスの中では、レトロウイルス、アデノウイルス、アデノ関連ウイルス、ワクシニアウイルス等が好ましく、特にアデノウイルスが好ましい。
本発明のプロテアーゼ阻害剤やCOPD又は免疫不全症候群の予防又は治療剤を、上記のような様々な形態で投与すること、あるいは、本発明のプロテアーゼ阻害剤やCOPD、免疫不全症候群の予防又は治療剤である遺伝子を、遺伝子治療によって用いることによって、予防又は治療することができる。
[伝統的COPD動物モデル]
本発明において、COPD抑制効果の確認のために用いる肺気腫動物モデルは、文献記載の方法を用いることができるが(Shapiro, S. D. Animal models for COPD. Chest, 117: 223S-227S, 2000)、具体的には、例えば清潔PBSに懸濁した豚エラスターゼを、シリンジで気管内投与すること等によって作製することができる。
本発明において、COPD抑制効果の確認のために用いる疾患動物モデルとしては、本発明者(星野,特願2004−069835)によって開発された、新たなCOPD動物モデルも用いることができる。この動物モデルは、COPDの他、肺胞蛋白症や循環器疾患の動物モデルとしても使用可能であるが、下記の説明におていは、便宜上、COPD動物モデルと記載することがある。その作製方法を以下に記載する。
(X1)インターロイキン−18遺伝子
(X2)インターロイキン−18のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18と同等の活性を有するタンパク質をコードする遺伝子
(Y1)カスパーゼ−1遺伝子
(Y2)カスパーゼ−1のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつカスパーゼ−1と同等の活性を有するタンパク質をコードする遺伝子
この動物モデルに導入する組換遺伝子は、下記(X1)又は(X2)遺伝子(以下、併せて「IL-18遺伝子類」と記載することがある。),あるいは下記(Y1)又は(Y2)遺伝子(以下、併せて「カスパーゼ1遺伝子類」と記載することがある。)を、肺特異的に発現するプロモーターの制御下に置くことによって、得ることができる。肺特異的に発現するプロモーターとしては、肺構成細胞由来プロモーター等が挙げられ、例えば肺サーファクタントプロモーター又はクララ細胞プロモーター等が挙げられる。
(X2)IL-18のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつIL-18と同等の活性を有するタンパク質をコードする遺伝子
(Y1)カスパーゼ−1遺伝子
(Y2)カスパーゼ−1のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつカスパーゼ−1と同等の活性を有するタンパク質をコードする遺伝子
シグナルペプチドとしては、例えばマウスの免疫グロブリン(以下「Ig」と記載する。)κ−チェーン・シグナルペプチド等が挙げられる。
マウスのIgκ−チェーン・シグナルペプチドは、例えば、Carroll, W. L., E. Mendel, S. Levy. 1985. Hybridoma fusion cell lines contain an aberrant kappa transcript. Mol. Immunol. 25:991.等に記載されている。
例えば、Nucleic Acids Res. 1984 Jan 25;12(2):857-72. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. に記載されている。
ポリA配列としては、牛由来のポリA配列等が挙げられる。例えば、Goldman, L. A., E. C. Cutrone, S. V. Kotenko, C. D. Krause, J. A. Langer. 1996. Modifications of vectors pEF-BOS, pcDNA1 and pcDNA3 result in improved convenience and expression. BioTechniques 21:1013.等に記載されている。
疾患動物モデルは、例えば次のような方法で、作成することができる。
COPD患者10人の外科手術で得た組織及び交通事故等で亡くなった人等の6人の肺組織をホルマリン固定し、パラフィン切片を作製した。抗ヒトIL-18抗体(clone8)で免疫組織染色を行った。
「Kitasato, Y., Hoshino, T., Okamoto, M., Kato, S., Koda, Y., Nagata, N., Kinoshita, M., Koga, H., Yoon, D. Y., Asao, H., Ohmoto, H., Koga, T., Rikimaru, T., and Aizawa, H. Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol, 31: 619-625, 2004.」に報告してあるように、健常人の肺にはほとんど発現していない(図1)。
このことは、肺でのIL-18の過剰発現が、COPDの病因であることを裏付けるものである。
Claims (1)
- 下記(1)乃至(4)から選択される、少なくとも一種以上を含むことを特徴とする、慢性閉塞性肺疾患の予防又は治療剤。
(1)レドックス活性タンパク質を除く、抗IL−18抗体
(2)(1)のうち、ポリペプチドであるもののアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18阻害活性を有するタンパク質
(3)(1)のうち、ポリペプチドであるものをコードする遺伝子
(4)(2)をコードする遺伝子
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