Li YY, Zhang WT. IL-6: the next key target for rheumatoid arthritis after TNF-α. Chin J Biotech, 2017, 33(1):

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1 36 生物工程学报 Chinese Journal of Biotechnology DOI: /j.cjb 李岩异等 /IL-6: TNF-α 之后的类风湿关节炎治疗关键靶点 January 25, 2017, 33(1): Chin J Biotech, All rights reserved 综述 IL-6: TNF-α 李岩异, 张卫婷 ,. IL-6:TNF-α., 2017, 33(1): Li YY, Zhang WT. IL-6: the next key target for rheumatoid arthritis after TNF-α. Chin J Biotech, 2017, 33(1): 摘要 : IL-6 是一种重要的细胞因子, 在类风湿关节炎发病过程中发挥重要作用 本文对已上市的 IL-6 受体单克隆抗体 tocilizumab 对类风湿关节炎的临床疗效和安全性进行了总结, 并和 TNF-α 阻断药物进行了对比, 证明 tocilizumab 在药物疗效和副作用方面与 TNF-α 阻断药物相比各有优劣 另外也对在研的 IL-6 通路阻断单抗的临床试验结果进行了总结 结合本中心近年的研究和总结,IL-6 是继 TNF-α 之后的另一个重要的类风湿关节炎治疗关键靶点, 该类药物的上市为以后类风湿关节炎的个性化治疗提供了更多的选择 : IL-6, 单克隆抗体, 类风湿关节炎 IL-6: the next key target for rheumatoid arthritis after TNF-α Yanyi Li, and Weiting Zhang North China Pharmaceutical Group Corporation Genetech Biotechnology Co. Ltd., Shijiazhuang , Hebei, China Abstract: IL-6 is an important cytokine that plays an important role in the pathogenesis of rheumatoid arthritis. We summarized the clinical efficacy and safety of tocilizumab, the IL-6 receptor monoclonal antibody in rheumatoid arthritis, and compared tocilizumab with TNF-α blocking mabs. The efficiency of tocilizuamb is equivalent to that of TNF-α blockers, and each of the drugs has its advantages and disadvantages. We also summarized the clinical trials of the mabs blocking IL-6 pathway in development. According to the results of recent studies by several research teams including our research group, IL-6 is another key target for the treatment of rheumatoid arthritis after TNF-α. The listing of the IL-6 blockers provides more choices for personalized treatment of rheumatoid arthritis in the future. Keywords: IL-6, monoclonal antibodies, rheumatoid arthritis Received: June 20, 2016; Accepted: October 31, 2016 Corresponding author: Weiting Zhang. Tel/Fax: ; weentingzh@163.com

2 李岩异等 /IL-6: TNF-α 之后的类风湿关节炎治疗关键靶点 37 (Non-steroidal antiinflammatory drugs NSAIDs) (Disease-modifying antirheumatic drugs DMARDs) 21 (bdmards) TNF-α bdmards TNF-α MTX (Methotrexate ) MTX 20% 50% 6 [1 2] TNF-α [3] IL kda 4 - IL-6 IL-6R IL-6 2 (mil-6r) (sil-6r) [4] IL-6 IL-6R ( mil-6r sil-6r) IL-6/IL-6R gp130 JAK/STAT ERK PI3K IL-6 IL-6 3 site 1 site 2 site3 site 1 IL-6R site 2 gp site 3 gp130 1 Ig-like [5] IL-6 B Th17 IL-1 (MMPs) [6 8] IL-6 DMARDs IL-6 IL-6 [9] IL-6 (IL-6R) tocilizumab (ACTEMRA Roche) IL-6 [10] 1 IL-6 通路抑制药物的临床应用 tocilizumab 1 IL-6R tocilizumab 2009 DMARD TNF-α tocilizumab 7 Ⅲ tocilizumab DMARD tocilizumab 24 TNF-α MTX 8 mg/kg tocilizumab ACR20 (ACR20 ACR50 ACR70 (ACR) ) [11] 70% 80% MTX 25% 53% [12 13] 8 mg/kg tocilizumab MTX 24 TNF-α MTX ACR20 50% 59% MTX ACR20 10% 26% [14 15] 8 mg/kg tocilizumab MTX 52 MTX cjb@im.ac.cn

3 38 ISSN CN /Q Chin J Biotech January 25, 2017 Vol.33 No.1 ACR20 56% MTX ACR20 25% [16] Ⅲ Ⅲb Ⅳ MTX ACT-RAY 24 tocilizumab tocilizumab+mtx ACR20 ACR50 ACR70 70% vs 72% 40% vs 46% 25% vs 25% tocilizumab tocilizumab+mtx [17] tocilizumab adalimumab ACR20 ACR50 ACR70 65% vs 49% 33% vs 18% 47% vs 28% tocilizumab adalimumab [18] tocilizumab MTX sdmard [19] (EULAR) 2013 (DMARD) (RA) tocilizumab DMARD tocilizumab TNF-α [20] tocilizumab IL-6 2 在研 IL-6 抑制药物 IL-6 IL-6R sarilumab sirukumab bolokizumab clazakizumab sarilumab Sanofi Regeneron 1 IL-6R (tocilizumab ) IL-6R IL-6 IL-6 Sanofi Regeneron SARIL-RA-MOBILITY sarilumab Ⅲ sarilumab MTX MTX (150 mg sarilumab+mtx 200 mg sarilumab+mtx placebo+mtx q2w) 3 (P< ) 150 mg 200 mg sarilumab vs 24 ACR20 58% 66% vs 33% 16 HAQ-DI ( ) vs mtss vs 2.78 sarilumab 150 mg 2.6% 200 mg 4.0% 2.3% 3 sarilumab DAS28-ESR (DAS28 ESR ) (P< ) ACR20 ACR50 ACR70 (HAQ-DI P<0.01) adalimumab adalimumab FDA sarilumab sirukumab IL-6 Ⅲ FDA

4 李岩异等 / IL-6: TNF-α 之后的类风湿关节炎治疗关键靶点 39 Smolen 4 sirukumab MTX [21] 100 mg sirukumab 12 ACR % 3.3% (P=0.026) 12 DAS28-CRP (CRP C- CRP ) 6 sirukumab DMARDs mg (4 1 ) 100 mg (2 1 ) SHS (Sharp-van der Heijde ) mg 100 mg ACR % 53.5% 26.4% (P<0.001) olokizumab UCB IL-6 IL-6 site 3 IL-6 gp130 IL-6 [22] Genovese olokizumab TNF Ⅱb [23] mg olokizumab MTX olokizumab 12 olokizumab DAS28-CRP 60 mg olokizumab P= mg 240 mg olokizumab P< olokizumab tocilizumab ACR20 ACR50 (ACR20: olokizumab =32.5% 60.7% =17.1% 29.9% ACR50: olokizumab =11.5% 33.2% =1.3% 4.9%) olokizumab tocilizumab IL-6R UCB olokizumab R-Phram 2015 R-Phram olokizumab Ⅲ clazakizumab IL clazakizumab Ⅱb mg clazakizumab MTX MTX adalimumab 12 clazakizumab MTX MTX (ACR20) adalimumab (clazakizumab+mtx: 55.0% 78.0% adalimumab+ MTX 76.3%) 24 ACR70 adalimumab (clazakizumab+mtx: 27.1% 38.3% adalimumab+mtx 18.6%) adalimumab cjb@im.ac.cn

5 40 ISSN CN /Q Chin J Biotech January 25, 2017 Vol.33 No.1 3 IL-6 通路抑制药物与 TNF 抑制药物的比较 IL-6 tocilizumab IL-6 IL-6R TNF tocilizumab Ⅲ TNF tocilizumab [15,24 25] FDA tocilizumab olokizumab TNF-α [23] IL-6 TNF-α TNF-α IL-6 MTX MTX MTX tocilizumab MTX tocilizumab adalimumab tocilizumab TNF-α MTX [20] TNF-α tocilizumab [26 27] tocilizumab RA [28 29] TNF IL-6 Koike tocilizumab % 9.64% [30] tocilizumab 11.06% 3.77% (0.05%) (0.89%) (0.48%) (0.16%) TNF tocilizumab TNF-α tocilizumab ( /1 000 PYs) TNF-α (1.3/1 000 PYs) [31] tocilizumab TNF-α TNF-α [32] tocilizumab tocilizumab tocilizumab infliximab etanercept adalimumab 1 89% 73% 86% 78% % 47% 78% 55% tocilizumab etanercept infliximab adalimumab [33] tocilizumab

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7 42 ISSN CN /Q Chin J Biotech January 25, 2017 Vol.33 No.1 Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol, 2009, 19(1): [14] 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, 2008, 371(9617): [15] 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, 2008, 67(11): [16] Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum, 2011, 63(3): [17] Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis, 2013, 72(1): [18] Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet, 2013, 381(9877): [19] Kaneko A. Tocilizumab in rheumatoid arthritis: efficacy, safety and its place in therapy. Ther Adv Chronic Dis, 2013, 4(1): [20] Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis, 2014, 73(3): [21] Smolen JS, Weinblatt ME, Sheng SH, et al. Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis, 2014, 73(9): [22] Shaw S, Bourne T, Meier C, et al. Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130- signaling. MAbs, 2014, 6(3): [23] Genovese MC, Fleischmann R, Furst D, et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised phase IIb study. Ann Rheum Dis, 2014, 73(9): [24] Strand V, Burmester GR, Ogale S, et al. Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology, 2012, 51(10): [25] Tanaka Y, Takeuchi T, Amano K, et al. Effect of interleukin-6 receptor inhibitor, tocilizumab, in preventing joint destruction in patients with rheumatoid arthritis showing inadequate response to TNF inhibitors. Mod Rheumatol, 2014, 24(3): [26] 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, 2008, 371(9617): [27] Yokota S, Imagawa T, Mori M, et al. Long-term treatment of systemic juvenile idiopathic arthritis

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