Novel therapeutic agents in clinical development for systemic lupus erythematosus

BMC Medicine

David P D’Cruz¹  Pamela MK Lutalo¹  Natasha Jordan¹ 

[1] Louise Coote Lupus Unit, St Thomas’ Hospital, Westminster Bridge Road,London, SE1 7EH, UK

关键词: Interferon-α, SLE;    T-cell co-stimulation;    BLys;    B-cell depletion;    Lupus nephritis;   

Others  :  857045
DOI  :  10.1186/1741-7015-11-120

 received in 2012-10-31, accepted in 2013-04-09,  发布年份 2013

【 摘 要 】

Conventional immunosuppressive therapies have radically transformed patient survival in systemic lupus erythematosus (SLE), but their use is associated with considerable toxicity and a substantial proportion of patients remain refractory to treatment. A more comprehensive understanding of the complexity of SLE immunopathogenesis has evolved over the past decade and has led to the testing of several biologic agents in clinical trials. There is a clear need for new therapeutic agents that overcome these issues, and biologic agents offer exciting prospects as future SLE therapies.

An array of promising new therapies are currently emerging or are under development including B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anti-cytokine therapies, such as monoclonal antibodies against interleukin-6 and interferon-α.

【 授权许可】

   
2013 Jordan et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Agmon-Levin N, Mosca M, Petri M, Shoenfeld Y: Systemic lupus erythematosus one disease or many? Autoimmun Rev 2012, 11:593-595.
• [2]Rahman A, Isenberg DA: Systemic lupus erythematosus. N Engl J Med 2008, 358:929-939.
• [3]Johnson AE, Gordon C, Hobbs FD, Bacon PA: Undiagnosed systemic lupus erythematosus in the community. Lancet 1996, 347:367-369.
• [4]Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, Urowitz M, Fortin PR, Petri M, Barr S, Gordon C, Bae SC, Isenberg D, Zoma A, Aranow C, Dooley MA, Nived O, Sturfelt G, Steinsson K, Alarcón G, Senécal JL, Zummer M, Hanly J, Ensworth S, Pope J, Edworthy S, Rahman A, Sibley J, El-Gabalawy H, McCarthy T: Mortality in systemic lupus erythematosus. Arthritis Rheum 2006, 54:2550-2557.
• [5]Mavragani CP, Moutsopoulos HM: Lupus nephritis: current issues. Ann Rheum Dis 2003, 62:795-798.
• [6]Korbet SM, Schwartz MM, Evans J, Lewis EJ: Severe lupus nephritis: racial differences in presentation and outcome. J Am Soc Nephrol 2007, 18:244-254.
• [7]Croca SC, Rodrigues T, Isenberg DA: Assessment of a lupus nephritis cohort over a 30-year period. Rheumatology (Oxford) 2011, 50:1424-1430.
• [8]Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, Chatham WW, Strand V, Weinstein A, Chevrier MR, Zhong ZJ, Freimuth WW: Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum 2009, 61:1143-1151.
• [9]Zonana-Nacach A, Barr SG, Magder LS, Petri M: Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 2000, 43:1801-1808.
• [10]Sanz I, Lee FE: B cells as therapeutic targets in SLE. Nat Rev Rheumatol 2010, 6:326-337.
• [11]Diaz-Lagares C, Croca S, Sangle S, Vital EM, Catapano F, Martinez-Berriotxoa A, Garcia-Hernandez F, Callejas-Rubio JL, Rascon J, D’Cruz D, Jayne D, Ruiz-Irastorza G, Emery P, Isenberg D, Ramos-Casals M, Khamashta MA, UK-BIOGEAS Registry: Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 2012, 11:357-364.
• [12]Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG: Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010, 62:222-233.
• [13]Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G, LUNAR Investigator Group: Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012, 64:1215-1226.
• [14]Diaz-Lagares C, Perez-Alvarez R, Garcia-Hernandez FJ, Ayala-Gutierrez MM, Callejas JL, Martinez-Berriotxoa A, Rascon J, Caminal-Montero L, Selva-O’Callaghan A, Oristrell J, Hidalgo C, Gómez-de-la-Torre R, Sáez L, Canora-Lebrato J, Camps MT, Ortego-Centeno N, Castillo-Palma MJ, Ramos-Casals M, BIOGEAS Study Group: Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label. Arthritis Res Ther 2011, 13:R112. BioMed Central Full Text
• [15]Calabrese LH, Molloy ES: Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risks of biological immunosuppressive therapies. Ann Rheum Dis 2008, 67:iii64-iii65.
• [16]Pepper R, Griffith M, Kirwan C, Levy J, Taube D, Pusey C, Lightstone L, Cairns T: Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant 2009, 24:3717-3723.
• [17]Lightstone L: The landscape after LUNAR: rituximab’s crater-filled path. Arthritis Rheum 2012, 64:962-965.
• [18]Traczewski P, Rudnicka L: Treatment of systemic lupus erythematosus with epratuzumab. Br J Clin Pharmacol 2011, 71:175-182.
• [19]Jacobi AM, Goldenberg DM, Hiepe F, Radbruch A, Burmester GR, Dorner T: Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann Rheum Dis 2008, 67:450-457.
• [20]Gregersen JW, Jayne DR: B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol 2012, 8:505-514.
• [21]Pisetsky DS, Grammer AC, Ning TC, Lipsky PE: Are autoantibodies the targets of B-cell-directed therapy? Nat Rev Rheumatol 2011, 7:551-556.
• [22]Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J: BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 1999, 189:1747-1756.
• [23]Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, Leon MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA, BLISS-52 Study Group: Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011, 377:721-731.
• [24]van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, Zhong ZJ, Freimuth W: Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 2012, 71:1343-1349.
• [25]Fried AJ, Bonilla FA: Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev 2009, 22:396-414.
• [26]Dennis GJ: Belimumab: a BLyS-specific inhibitor for the treatment of systemic lupus erythematosus. Clin Pharmacol Ther 2012, 91:143-149.
• [27]Gunnarsson I, van Vollenhoven RF: Biologicals for the treatment of systemic lupus erythematosus? Ann Med 2012, 44:225-232.
• [28]Ginzler EM, Wax S, Rajeswaran A, Copt S, Hillson J, Ramos E, Singer NG: Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther 2012, 14:R33. BioMed Central Full Text
• [29]Genovese MC, Kinnman N, de La Bourdonnaye G, Pena Rossi C, Tak PP: Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. Arthritis Rheum 2011, 63:1793-1803.
• [30]Scheipers P, Reiser H: Role of the CTLA-4 receptor in T cell activation and immunity. Physiologic function of the CTLA-4 receptor. Immunol Res 1998, 18:103-115.
• [31]Reiser H, Stadecker MJ: Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases. N Engl J Med 1996, 335:1369-1377.
• [32]Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P: A new member of the immunoglobulin superfamily–CTLA-4. Nature 1987, 328:267-270.
• [33]Daikh DI, Wofsy D: Cutting edge: reversal of murine lupus nephritis with CTLA4Ig and cyclophosphamide. J Immunol 2001, 166:2913-2916.
• [34]Cunnane G, Chan OT, Cassafer G, Brindis S, Kaufman E, Yen TS, Daikh DI: Prevention of renal damage in murine lupus nephritis by CTLA-4Ig and cyclophosphamide. Arthritis Rheum 2004, 50:1539-1548.
• [35]Finck BK, Linsley PS, Wofsy D: Treatment of murine lupus with CTLA4Ig. Science 1994, 265:1225-1227.
• [36]Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace DJ, Bae SC, Sigal L, Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P: The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010, 62:3077-3087.
• [37]Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL: Efficacy and safety of abatacept over 12 months in patients with lupus nephritis: results from a multicenter, random- ized, double-blind, placebo-controlled phase II/III study [abstract]. Arthritis Rheum 2011, 63(Suppl):S962-3.
• [38]Wofsy D, Hillson JL, Diamond B: Comparison of alternative primary outcome measures for use in a lupus nephritis trial. Arthritis Rheum 2013. [Epub ahead of print]
• [39]Davidson A, Wang X, Mihara M, Ramanujam M, Huang W, Schiffer L, Sinha J: Co-stimulatory blockade in the treatment of murine systemic lupus erythematosus (SLE). Ann N Y Acad Sci 2003, 987:188-198.
• [40]Early GS, Zhao W, Burns CM: Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice. Response correlates with the absence of an anti-antibody response. J Immunol 1996, 157:3159-3164.
• [41]Kalunian KC, Davis JC Jr, Merrill JT, Totoritis MC, Wofsy D: Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002, 46:3251-3258.
• [42]Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A: A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003, 48:719-727.
• [43]Ryffel B, Car BD, Gunn H, Roman D, Hiestand P, Mihatsch MJ: Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice. Am J Pathol 1994, 144:927-937.
• [44]Yang G, Liu H, Jiang M, Jiang X, Li S, Yuan Y, Ma D: Experimental study on intramuscular injection of eukaryotic expression vector pcDNA3- IL-6 on BXSB mice. Chin Med J (Engl) 1998, 111:38-42.
• [45]Liang B, Gardner DB, Griswold DE, Bugelski PJ, Song XY: Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 2006, 119:296-305.
• [46]Mihara M, Takagi N, Takeda Y, Ohsugi Y: IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol 1998, 112:397-402.
• [47]Chun HY, Chung JW, Kim HA, Yun JM, Jeon JY, Ye YM, Kim SH, Park HS, Suh CH: Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol 2007, 27:461-466.
• [48]Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T, Klinenberg JR: Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 1991, 147:117-123.
• [49]Peterson E, Robertson AD, Emlen W: Serum and urinary interleukin-6 in systemic lupus erythematosus. Lupus 1996, 5:571-575.
• [50]Tsai CY, Wu TH, Yu CL, Lu JY, Tsai YY: Increased excretions of beta2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis. Nephron 2000, 85:207-214.
• [51]Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, Fleisher T, Balow JE, Lipsky PE: 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 2010, 62:542-552.
• [52]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW: Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 2003, 100:2610-2615.
• [53]Crow MK, Wohlgemuth J: Microarray analysis of gene expression in lupus. Arthritis Res Ther 2003, 5:279-287. BioMed Central Full Text
• [54]Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK: Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 2005, 52:1491-1503.
• [55]Merrill JT, Wallace DJ, Petri M, Kirou KA, Yao Y, White WI, Robbie G, Levin R, Berney SM, Chindalore V, Olsen N, Richman L, Le C, Jallal B, White B, Lupus Interferon Skin Activity (LISA) Study Investigators: Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann Rheum Dis 2011, 70:1905-1913.
• [56]Cordeiro AC, Isenberg DA: Novel therapies in lupus - focus on nephritis. Acta Reumatol Port 2008, 33:157-169.
• [57]Wang Y, Hu Q, Madri JA, Rollins SA, Chodera A, Matis LA: Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc Natl Acad Sci U S A 1996, 93:8563-8568.
• [58]Rother RP, Mojcik CF, McCroskery EW: Inhibition of terminal complement: a novel therapeutic approach for the treatment of systemic lupus erythematosus. Lupus 2004, 13:328-334.
• [59]van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, Cardiel MH, Cohen S, Nash P, Song YW, Tegzová D, Wyman BT, Gruben D, Benda B, Wallenstein G, Krishnaswami S, Zwillich SH, Bradley JD, Connell CA, ORAL Scan Investigators: Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 2013, 65:559-570.
• [60]Morales-Torres J: The status of fostamatinib in the treatment of rheumatoid arthritis. Expert Rev Clin Immunol 2012, 8:609-615.