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REVIEW

Tocilizumab, A Humanized Anti-IL-6R Antibody, as an Emerging Therapeutic Option for Rheumatoid Arthritis: Molecular and Cellular Mechanistic Insights

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Pages 265-279 | Accepted 17 Jun 2014, Published online: 06 Aug 2014

REFERENCES

  • McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365(23): 2205–2019.
  • Smolen JS, Aletaha D, Redlich K. The pathogenesis of rheumatoid arthritis: new insights from old clinical data? Nat Rev Rheumatol 2012;8(4):235–243.
  • Hallert E, Husberg M, Bernfort L. The incidence of permanent work disability in patients with rheumatoid arthritis in Sweden 1990–2010: before and after introduction of biologic agents. Rheumatology (Oxford) 2012;51(2):338–346.
  • Hashizume, Mihara The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis 2011;2011:765624.
  • Mihara M, Hashizume M, Yoshida H, et al. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 2012;122:143–159.
  • Hibi M, Murakami M, Saito M, et al. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 1990;63:1149–1157.
  • Rose-John S, Neurath M F. IL-6 trans-signaling: the heat is on. Immunity 2004;20:2–4.
  • Madhok R, Crilly A, Watson J, Capell H A. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993;52: 232–234.
  • Nishimoto N, Miyasaka N, Yamamoto K, et al. 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;19:12–19.
  • Ohshima S, Saeki Y, Mima T, et al. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA 1998;95:8222–8226.
  • Alonzi T, Fattori E, Lazzaro D, et al. Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998;187:461–468.
  • Nowell MA, Williams AS, Carty SA, et al. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol 2009;182:613–622.
  • Richards PJ, Nowell MA, Horiuchi S, et al. Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis Rheum 2006;54:1662–1672.
  • Paleolog EM. Angiogenesis in rheumatoid arthritis. Arthritis Res 2002;4(Suppl 3):S81–90.
  • Kume K, Amano K, Yamada S, et al. Very early improvements in the wrist and hand assessed by power Doppler sonography predicting later favorable responses in tocilizumab-treated patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2011;63(10):1477–1481.
  • Besada E, Nossent JC. Ultrasonographic resolution of the vessel wall oedema with modest clinical improvement in a large-vessel vasculitis patient treated with tocilizumab. Clin Rheumatol 2012;31(8):1263–1265.
  • Sone H, Sakauchi M, Takahashi A, et al. Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis correlation with disease activity. Life Sci 2001;69:1861–1869.
  • Ballara S, Taylor PC, Reusch P, et al. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 2001;44(9): 2055–2064.
  • Nakahara H, Song J, Sugimoto M, et al. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum 2003;48:1521–1529.
  • Hashizume M, Hayakawa N, Suzuki M, Mihara M. IL-6/sIL-6R trans-signalling, but not TNF-α induced angiogenesis in a HUVEC and synovial cell co-culture system. Rheumatol Int 2009;29:1449–1454.
  • Kayakabe K, Kuroiwa T, Sakurai N, et al. Interleukin-6 promotes destabilized angiogenesis by modulating angiopoietin expression in rheumatoid arthritis. Rheumatology (Oxford) 2012;51(9): 1571–1579.
  • Mihara M, Moriya Y, Kishimoto T, Ohsugi Y. Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol 1995;34(4):321–325.
  • Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-α and IL-17. Rheumatology (Oxford) 2008;47:1635–1640.
  • Chen Q, Wang WC, Bruce R, et al. Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity 2004;20:59–70.
  • Chen Q, Fisher DT, Clancy KA, et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat Immunol 2006;7:1299–1308.
  • Uchiyama Y, Yorozu K, Hashizume M, et al. Tocilizumab, a humanized anti-interleukin-6 receptorantibody, ameliorates joint swelling in established monkey collagen-induced arthritis. Biol Pharm Bull 2008;31:1159–1163.
  • Karsdal MA, Neutzsky-Wulff AV, Dziegiel MH, et al. Osteoclasts secrete non-bone derived signals that induce bone formation. Biochem Biophys Res Commun 2008;366(2):483–488.
  • Henriksen K, Bollerslev J, Everts V, Karsdal MA. Osteoclast activity and subtypes as a function of physiology and pathology — Implications for future treatments of osteoporosis. Endocr Rev 2011;32(1):31–63.
  • Bromley M, Woolley DE. Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum 1984;27(9):968–975.
  • Gravallese EM, Harada Y, Wang JT, et al. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol 1998;152(4): 943–951.
  • Sondergaard BC, Henriksen K, Wulf H, et al. Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation. Osteoarthritis Cartilage 2006;14(8):738–748.
  • Schett G, Hayer S, Zwerina J, et al. Mechanisms of disease: The link between RANKL and arthritic bone disease. Nat Clin Pract Rheumatol 2005;1(1):47–54.
  • Schett G, Teitelbaum SL. Osteoclasts and arthritis. J Bone Miner Res 2009;24(7):1142–1146.
  • Fujikawa Y, Shingu M, Torisu T, et al. Bone resorption by tartrate-resistant acid phosphatase-positive multinuclear cells isolated from rheumatoid synovium. Br J Rheumatol 1996;35(3):213–217.
  • Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 2000;43(2):250–258.
  • Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93(2):165–176.
  • Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999;397(6717):315–323.
  • Choe JY, Park KY, Park SH, et al. Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes. Arthritis Res Ther 2013;15(1):R26.
  • Silacci P, Dayer J M, Desgeorges A, et al. Interleukin (IL)-6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity. J Biol Chem 1998;273:13625–13629.
  • Garnero P, Thompson E, Woodworth T, Smolen J S. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum 2010;62:33–43.
  • Kirwan JR, Minnock P, Adebajo A, et al. Patient perspective: fatigue as a recommended patient centered outcome measure in rheumatoid arthritis. J Rheumatol 2007;34:1174–1177.
  • Moreland LW, Curtis JR. Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms. Semin Arthritis Rheum 2009;39(2):132–143.
  • Davis MC, Zautra AJ, Younger J, et al. Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue. Brain Behav Immun 2008;22:24–32.
  • 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 (Oxford). 2012;51(10):1860–1869.
  • Weeiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352(10):1011–1023.
  • Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783–788.
  • Rivera S, Nemeth E, Gabayan V, et al. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood 2005;106:2196–2199.
  • 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 2004;113:1271–1276.
  • Hashizume M, Uchiyama Y, Horai N, et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production. Rheumatol Int 2010;30:917–923.
  • Song SN, Tomosugi N, Kawabata H, et al. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood 2010;116:3627–3634.
  • Wilson PW. Evidence of systemic inflammation and estimation of coronary artery disease risk: a population perspective. Am J Med 2008;121:S15–S20.
  • Kaplan MJ. Management of cardiovascular disease risk in chronic inflammatory disorders. Nat Rev Rheumatol 2009;5:208–217.
  • Kaplan MJ. Cardiovascular disease in rheumatoid arthritis. Curr Opin Rheumatol 2006;18: 289–297.
  • Bessant R, Duncan R, Ambler G, et al. Prevalence of conventional and lupus-specific risk factors for cardiovascular disease in patients with systemic lupus erythematosus: a case-control study. Arthritis Rheum 2006;55:892–899.
  • Gonzalez-Gay MA, Gonzalez-Juanatey C, Miranda-Filloy JA, et al. Cardiovascular disease in rheumatoid arthritis. Biomed Pharmacother 2006;60:673–677.
  • Kremers HM, Gabriel SE. Rheumatoid arthritis and the heart. Curr Heart Fail Rep 2006;3:57–63.
  • Gonzalez A, Maradit Kremers H, Crowson CS, et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann Rheum Dis 2008;7:64–69.
  • Boekholdt SM, Stroes ES. The interleukin-6 pathway and atherosclerosis. Lancet 2012;379(9822): 1176–1178.
  • Stamatelopoulos KS, Kitas GD, Papamichael CM, et al. Atherosclerosis in rheumatoid arthritis versus diabetes: a comparative study. Arterioscler Thromb Vasc Biol 2009;29(10):1702–1708.
  • Protogerou AD, Zampeli E, Fragiadaki K, et al. A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis. Atherosclerosis 2011;219(2):734–736.
  • Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 1983;52:223–261.
  • Jessup W, Kritharides L. Metabolism of oxidized LDL by macrophages. Curr Opin Lipidol 2000;11(5):473–481.
  • Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Hingorani AD, Casas JP. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379(9822):1214–1224.
  • Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011;121:3375–3383.
  • Tan SL, O'Mahony A, Berg E, et al. Primary human cell BioMAP® profiling of Methotrexate, Tocilizumab, Adalimumab, and Tofacitinib Reveals Different Mechanisms of action with distinct phenotypic signatures. Arthritis Rheum 2013;65(10) (supplement).
  • Gabay C, Emery P, van Vollenhoven R, et al. ADACTA Study Investigators. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013;381(9877):1541–1550.
  • Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69(1):88–96.
  • van Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 2013;9(3):164–172.
  • Roche Registration Limited. RoActemra 20 mg/ml concentrate for solution for infusion [Summary of Product Characteristics]. Welwyn Garden City, UK: Roche Registration Limited; 2011.
  • Atzeni F, Sarzi-Puttini P. Autoantibody production in patients treated with anti-TNF-alpha. Expert Rev Clin Immunol 2008;4:275–280.
  • Atzeni F, Sarzi-Puttini P. Anti-cytokine antibodies for rheumatic diseases. Curr Opin Investig Drugs 2009;10:1204–1211.
  • Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 2006;54:3782–3789.
  • Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 2012;71:1914–1915.
  • Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 2002;24:1720–1740.
  • Chirmule N, Jawa V, Meibohm B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J 2012;14:296–302.
  • Clark M. Antibody humanization: a case of the ‘Emperor's new clothes’? Immunol Today 2000;21:397–402.
  • Rojas JR, Taylor RP, Cunningham MR, et al. Formation, distribution, and elimination of infliximab and anti-infliximab immune complexes in cynomolgus monkeys. J Pharmacol Exp Ther 2005;313(2):578–585.
  • Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552–1563.
  • Chirino A J, Mire-Sluis A. Characterizing biological products and assessing comparability following manufacturing changes. Nat Biotechnol 2004;22:1383–1391.
  • Hermeling S, Schellekens H, Maas C, et al. Antibody response to aggregated human interferon α2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J Pharm Sci 2006;95:1084–1096.
  • Carpenter J, Cherney B, Lubinecki A, et al. Meeting report on protein particles and immunogenicity of therapeutic proteins: filling in the gaps in risk evaluation and mitigation. Biologicals 2010;38:602–611.
  • Cronstein BN. Interleukin-6—a key mediator of systemic and local symptoms in rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007;65(Suppl 1):S11–S15.

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