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雑誌文献

臨床検査54巻6号

2010年06月発行

文献概要

今月の主題 注目されるサイトカイン 話題

抗IL-6受容体抗体療法

著者: 西本憲弘1

所属機関: 1和歌山県立医科大学免疫制御学講座

ページ範囲:P.659 - P.664

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1.はじめに

 インターロイキン6(interleukin-6;IL-6)は,免疫応答や炎症反応の調節など多彩な生理作用を有する生体防御にとって重要なサイトカインである.しかし,多彩な作用を有するために,もしIL-6が持続的かつ過剰に産生されると様々な病態を引き起こす.関節リウマチ(rheumatoid arthritis;RA)をはじめとする多くの炎症性免疫疾患や血液疾患の根本的な原因はいまだ明らかではないが,その病態形成においてIL-6の過剰産生が重要な役割を果たしている.したがって,IL-6のシグナル伝達を阻害することにより,治療効果が得られる可能性が考えられる.そのようなコンセプトにより開発されたのがヒト化抗IL-6受容体抗体であるトシリズマブ(商品名:アクテムラ®)である.

 トシリズマブは本邦オリジナルの初の治療用ヒト化モノクローナル抗体である.IL-6がIL-6受容体に結合するのを特異的に阻害することで効果を発揮する.トシリズマブは2005年に希少疾患であるキャッスルマン病に,2008年にはRAと若年性特発性関節炎(juvenile idiopathic arthritis;JIA)の治療薬として世界に先駆けて本邦で承認された.さらに日本から世界に発信し,2009年に欧州連合で,2010年1月には米国食品医薬品局(Food and Drug Administration;FDA)によりRAに対し承認された.

 本稿ではサイトカイン研究の疾患治療への応用として,トシリズマブによる抗IL-6受容体抗体療法について紹介したい.

参考文献

1) Hirano T, Yasukawa K, Harada H, et al:Complementary DNA for a novel human interleukin(BSF-2)that induces B lymphocytes to produce immunoglobulin. Nature 324:73-76, 1986
2) Kishimoto T:Interleukin-6:from basic science to medicine-40 years in immunology. Annu Rev Immunol 23:1-21, 2005
3) Mangan PR, Harrington LE, O'Quinn DB, et al:Transforming growth factor-βinduces development of the TH17 lineage. Nature 441:231-234, 2006
4) Bettelli E, Carrier Y, Gao W, et al:Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235-238, 2006
5) Nemeth E, Rivera S, Gabayan V, et al:IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest 113:1271-1276, 2004
6) Mima T, Nishimoto N:Clinical value of blocking IL-6 receptor. Curr Opin Rheumatol 21:224-230, 2009
7) Nishimoto N:Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin Pharmacol Ther 87:483-487, 2010
8) 西本憲弘:IL-6受容体をターゲットにした免疫療法 日本離床免疫学会会報 31:399-404, 2008
9) Sato K, Tsuchiya M, Saldanha J, et al:Reshaping a human antibody to inhibit the interleukin-6-dependent tumor cell growth. Cancer Res 53:851-856, 1993
10) Nishimoto N, Yoshizaki K, Maeda K, et al:Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis-Phase Ⅰ/Ⅱ clinical study―. J Rheumatol 30:1426-1435, 2003
11) Kawano M, Hirano T, Matsuda T, et al:Autocrine generation and requirement of BSF-2/IL-6 for human multiple myeloma. Nature 322:83-85, 1988
12) Yoshizaki K, Matsuda T, Nishimoto N, et al:Pathogenic significance of interleukin 6(IL-6/BSF-2)in Castleman's disease. Blood 74:1360-1367, 1989
13) Nishimoto N, Sasai M, Shima Y, et al:Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95:56-61, 2000
14) Nishimoto N, Kanakura Y, Aozasa K, et al:Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman' s disease. Blood 106:2627-2632, 2005
15) Choy EH, Isenberg DA, Garrood T, et al:Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin 6 receptor monoclonal antibody in rheumatoid arthritis:a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46:3143-3150, 2002
16) Nishimoto N, Hashimoto J, Miyasaka N, et al:Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor(SAMURAI):evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 66:1162-1167, 2007
17) Nishimoto N, Miyasaka N, Yamamoto K, et al:Long-term safety and efficacy of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis(the STREAM study):evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis 68:1580-1584, 2009
18) Smolen JS, Beaulieu A, Rubbert-Roth A, et al:Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis(OPTION study):a double-blind, placebo-controlled, randomised trial. Lancet 371:987-997, 2008
19) Genovese MC, McKay JD, Nasonov EL, et al:Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs:the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 58:2968-2980, 2008
20) Emery P, Keystone E, Tony HP, et al:IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals:results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 67:1516-1523, 2008
21) De Benedetti F:Targeting interleukin-6 in pediatric rheumatic diseases. Curr Opin Rheumatol 21:533-537, 2009
22) Yokota S. Interleukin 6 as a therapeutic target in systemic-onset juvenile idiopathic arthritis. Curr Opin Rheumatol 15:581-586, 2003
23) Yokota S, Miyamae T, Imagawa T, et al:Phase II trial of anti-IL-6 receptor antibody(MRA)for children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 52:818-825, 2005
24) Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis:a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371:998-1006, 2008
25) Imagawa T, Miyamae T, Mori M, et al:Efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in patients with polyarticular or oligoarticular onset juvenile idiopathic arthritis. Arthritis Rheum 54:S168, 2006
26) Fujiwara H, Nishimoto N, Hamano Y, et al:Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment:A report of two cases. Mod Rheumatol 19:64-68, 2009
27) Illei GG, Shirota Y, Yarboro CH, et al:Tocilizumab in systemic lupus erythematosus:data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 62:542-552, 2010
28) Nishimoto N, Nakahara H, Yoshio-Hoshino N, et al:Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor monoclonal antibody, tocilizumab. Arthritis Rheum 58:1197-1200, 2008

掲載誌情報

出版社:株式会社医学書院

電子版ISSN:1882-1367

印刷版ISSN:0485-1420

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