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Home , Pascolizumab, Pitrakinra, Ustekinumab

Published: 14 September 2009 © 2009 Biology Reports Ltd

Targeting in inflammatory diseases: focus on -1-mediated autoinflammation George D Kalliolias1 and Lionel B Ivashkiv1,2*

Addresses: 1Arthritis and Tissue Degeneration Program and Department of Medicine, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA; 2Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10065, USA * Corresponding author: Lionel B Ivashkiv ([email protected]) F1000 Biology Reports 2009, 1:70 (doi:10.3410/B1-70) The electronic version of this article is the complete one and can be found at: http://F1000.com/Reports/Biology/content/1/70

Abstract In this commentary, we summarize the most recent advances in the -targeting therapies. We focus on new aspects of interleukin-1 (IL-1)-mediated autoinflammation and novel strategies to target IL-1.

Introduction and context the IL-1 inhibitor appears to be only moder- The treatment of the broad and heterogeneous group ately effective in its FDA-approved indication for RA in of inflammatory diseases has been revolutionized with clinical practice [5]. the introduction of therapies that target cytokines [1]. Since 1998, the year that tumor necrosis factor-alpha Although anakinra did not fulfill all of the expectations (TNF-a) blockade was first approved for rheumatoid for managing RA, this therapeutic showed remarkable arthritis (RA), our cytokine-targeting armamentarium effectiveness in a heterogeneous group of heritable and has been enriched [1]. Table 1 summarizes all of the sporadic disorders now considered IL-1-mediated anti-cytokine regimens approved by the US Food and autoinflammatory diseases [10]. The prototype of Drug Administration (FDA), and Table 2 lists the these diseases is the cryopyrin-associated periodic cytokine-targeting therapies that are still under inves- syndrome (CAPS) [11]. CAPS is now considered a tigation [2]. Recent evidence suggests that interleukin-6 continuum of one disorder with varying severity and (IL-6) blockade using is effective in RA [3] includes the mild phenotype known as familial cold and that the p40 neutralizing autoinflammatory syndrome (FCAS), the intermediate (targeting both IL-12 and IL-23) is beneficial for Muckle-Wells syndrome (MWS), and the severe form [4]. of neonatal-onset multisystem inflammatory disorder (also called chronic infantile neurologic cutaneous and Despite all of these breakthroughs in targeting cyto- articular syndrome) [11]. kines, the treatment of inflammatory diseases is still imperfect and challenging. The high cost and the The discriminates self from nonself and treatment-related adverse events (mainly infections distinguishes pathogens from commensal organisms and and the reported, but controversial, increased risk for specifically eliminates pathogens. Regulation of immune malignancies) are major drawbacks of cytokine target- responses restrains concurrent tissue damage and ing [5-7]. In addition, the available cytokine blockade is orchestrates tissue repair. This balance between defense not always effective, as exemplified by the failure of the and protection of tissue integrity results from a tight anti-p40 to show a significant regulation of the innate and adaptive branches of benefit in patients with [8]. Further- the immune system. Failure of these regulatory mecha- more, approximately 30% of RA patients do not nisms causes an aberrant immune response ranging respond adequately to anti-TNF-a treatments [9] and from inadequate defense to uncontrolled/unprovoked

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Table 1. Cytokine-targeting therapies approved by the US Food of autoantibodies [11,13,14]. To distinguish this group and Drug Administration for the treatment of inflammatory of diseases from autoimmune diseases, emphasizing the diseases primary role of innate immunity in driving their Targeted cytokine Description FDA-approved ‘ ’ indications pathogenesis, the term autoinflammatory diseases has been proposed [11,13,14]. The new aspects in the a TNF- concept of IL-1-mediated autoinflammation and the 1. (Enbrel®; Dimeric • RA , Thousand Oaks, consisting of the • JIA recent advances in targeting IL-1 will be the focus of this CA, USA, and Wyeth, ligand-binding portion of • ASp commentary. Madison, NJ, USA) human p75TNFR linked • Psoriasis to the Fc of human IgG1 • PsA 2. Chimeric (human and • RA Major recent advances (Remicade®; Johnson & mouse) IgG1k • ASp Understanding Horror autoinflammaticus a • Johnson, New anti-TNF- Mab Psoriasis More than 60 mutations in the CIAS1 gene are responsible Brunswick, NJ, USA) • PsA • CD for a hyperactive NALP3 (cryopyrin) leading to CAPS [11]. • UC NALP3 functions as a sensor of pathogens and danger • 3. Recombinant human IgG1 RA signals and is expressed mainly in immune cells, (Humira®; Abbott anti-TNF-a Mab • JIA Laboratories, Abbott • ASp chondrocytes, and epithelial cells [15]. Upon activation, Park, IL, USA) • Psoriasis NALP3 recruits ASC (apoptosis-associated speck-like • PsA protein containing caspase-recruitment domain), Cardi- • CD 4. Humanized Fab fragment • RA nal, and pro-caspase-1, assembling a multimeric complex (Cimzia®; UCB, of anti-TNF-a Mab • CD called the inflammasome. NALP3 inflammasomes acti- Brussels, Beglium) conjugated to PEG vate the downstream caspase-1, the protease that cleaves 5. Human IgG1k • RA pro-IL-1, releasing the potent pyrogen IL-1b [15,16]. The (Simponi™; Centocor anti-TNF-a Mab • ASp understanding of the direct role of NALP3 in IL-1b • Ortho Biotech, Inc., PsA processing led to the concept that CAPS (a result of Horsham, PA, USA) hyperactive inflammasome due to mutated NALP3) is an IL-1 IL-1-mediated autoinflammatory disease, justifying the 1. Anakinra (Kineret®; Recombinant human • RA Amgen) IL-1Ra that inhibits IL-1 by use of IL-1 blockade to control disease activity [11]. binding IL-1RI 2. Consisting of the • CAPS Targeting IL-1b to treat autoinflammation (Arcalyst™; Regeneron ligand-binding domains of Pharmaceuticals, Inc, human IL-1RI and IL-1AcP The recombinant human IL-1 receptor antagonist ana- Tarrytown, NY, USA) fused in line with Fc of kinra was the first IL-1-targeting intervention used in human IgG1 (IL-1 trap) patients with CAPS with impressive effectiveness ASp, ankylosing spondylitis; CAPS, cryopyrin-associated periodic [17-19]. The short half-life of anakinra necessitates syndrome; CD, Crohn' s disease; Fab, fragment -binding; FDA, US daily injections for efficient responses, and injection Food and Drug Administration; IgG, immunoglobulin G; IL-1, interleukin-1; site reactions are commonly observed [5,17-19]. To IL-1AcP, interleukin-1 accessory protein; IL-1Ra, interleukin-1 receptor overcome these limitations, sophisticated investigation antagonist; JIA, juvenile idiopathic arthritis; Mab, monoclonal antibody; resulted in new efficient strategies to target IL-1 with PEG, polyethylene glycol; PsA, ; RA, rheumatoid arthritis; improved and thus better compliance TNF-a, tumor necrosis factor-alpha; TNFR, tumor necrosis factor and tolerance [20,21]. receptor; UC, . Rilonacept is a new IL-1 blocker that functions as an . Generation of pathogenic autoantibodies IL-1 trap, binding IL-1 with an affinity at least 100-fold or autoreactive T-cell clones or both, due to deregulated higher than that of the native IL-1 cell surface receptor adaptive immunity, leads to ‘autoimmunity’ [12]. complex [22]. Normally, IL-1b binds first to IL-1RI on Systemic lupus erythematosus exemplifies systemic the surface of target cells and subsequently IL-1 autoimmunity, whereas autoimmune thyroiditis and accessory protein (IL-1AcP) is recruited, thus forming diabetes mellitus type I reflect some facets of tissue- a trimolecular signaling complex [16]. Rilonacept is an specific autoimmunity [12]. artificial molecule that contains the ligand-binding portions of both IL-1RI and IL-1AcP fused to a dimeric Now it is well established that genetic defects in molecule containing the Fc segment of hIgG1 (human molecules regulating the function of the innate immune immunoglobulin G1) [22]. In contrast to the system are the cause of several diseases characterized by daily injected anakinra, rilonacept has a half-life of systemic or localized inflammation in the absence of approximately 7 days and thus is administered once infection, autoreactive lymphocytes, and high titers weekly [20].

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Table 2. Cytokine-targeting therapies that are under investigation in clinical trials Targeted cytokine Description Investigational trials

IL-1 Rilonacept IL-1 trap (Table 1) FMF/AOSD/SoJIA/Gout Anti-IL-1 Mab CAPS/SoJIA/RA/Gout/DM II/COPD IL-4 and IL-13 Anti-IL-4 Mab (blocks IL-4 and IL-13) Mutated IL-4 Asthma CAT-354, IMA-638, QAX576 Anti-IL-13 Mabs Asthma/IPF/Allergic rhinitis/SSc IL-5 Anti-IL-5 Mab Asthma/CSS/HES MEDI-563 Anti-IL-5R Mab Asthma IL-6 Tocilizumab Anti-IL-6R Mab RA/SoJIA IL-9 MEDI-528 Anti-IL-9 Mab Asthma p40 (IL-12 and IL-23) Ustekinumab (CNTO 1275) hIgG1 anti-p40 Mab Psoriasis/PsA/CD ABT-874/J695 hIgG1l anti-p40 Mab Psoriasis/CD IL-15 HuMax-IL-15 (AMG 714) Anti-IL-15 Mab RA/Psoriasis IL-17A AIN457 Anti-IL-17A Mab RA/Psoriasis/PsA/ASp/CD/Uveitis IL-23 Anti-p19 Mab Clinical trials in preliminary stage. No further information available. TGF-b CAT-192 Anti-TGF-beta1 Mab SSc TNF superfamily 1. BAFF(BLyS)/APRIL Atacicept (blocks BLyS and APRIL) Ligand-binding portion of TACI fused with hIgG1 Fc SLE/RA/MS/Optic neuritis Anti-BLyS Mab SLE/RA 2. LTa1b2 and LIGHT Baminercept Ligand-binding portion of LT-b R fused with hIgG1 Fc RA 3. RANKL Denosumab Anti-RANKL Mab RA IFN-a MEDI-545 Anti-IFN-a Mab SLE/Psoriasis

For further information, see [2]. AOSD, adult-onset Still’s disease; APRIL, a proliferation-inducing ligand; ASp, ankylosing spondylitis; BAFF, B-cell activating factor of tumor necrosis factor family; BLyS, B lymphocyte stimulator; CAPS, cryopyrin-associated periodic syndrome; CD, Crohn' s disease; COPD, chronic obstructive pulmonary disease; CSS, Churg-Strauss syndrome; DM II, diabetes mellitus type II; FMF, familial Mediterranean fever; HES, hyper-eosinophilic syndromes; hIgG1, human immunoglobulin G1; IFN-a, -alpha; IL, interleukin; IPF, idiopathic pulmonary fibrosis; LIGHT, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells; LT, lymphotoxin; Mab, monoclonal antibody; MS, multiple sclerosis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor-kappa B ligand; SLE, systemic lupus erythematosus; SoJIA, systemic onset juvenile idiopathic arthritis; SSc, systemic scleroderma; TACI, transmembrane activator and CAML (calcium modulator and ligand) interactor; TGF-b, transforming growth factor-beta; TNF-a,tumor necrosis factor-alpha.

In February 2008, rilonacept (Arcalyst™; Regeneron two most commonly observed adverse events in patients Pharmaceuticals, Inc, Tarrytown, NY, USA) was approved treated with rilonacept [20]. by the FDA for the treatment of CAPS. IL-1 trap was proven very effective and safe in a small open-label pilot A third IL-1 blocker, the monoclonal human anti-IL-1b study [23] and in a larger two-part phase III canakinumab (ACZ885), was used in patients with [24] which included patients with FCAS and MWS. CAPS in one small study [26] and a second recently Rilonacept not only rapidly improved patients’ symp- reported randomized placebo-control clinical trial [27]. toms, but also reduced serum levels of serum amyloid A Canakinumab was administered subcutaneously once (SAA) [20,24]. The latter is of great importance given that every 8 weeks and induced a remarkable clinical high serum levels of SAA are directly related to the risk of response with normalization of SAA and C-reactive developing secondary amyloidosis [25], the main cause of protein levels [27]. During the treatment period, only renal insufficiency in these patients. Injection site two serious adverse events were observed: one case of reactions and upper respiratory tract infections were the urosepsis and an episode of vertigo [27].

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Future directions 2. ClinicalTrials.gov homepage. [http://www.clinicaltrials.gov] Recently, it was shown that MSU (monosodium urate 3. Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R; OPTION Investigators: Effect of monohydrate) and CPPD (calcium pyrophosphate interleukin-6 receptor inhibition with tocilizumab in patients dihydrate) crystals activate NALP3 inflammasome and with rheumatoid arthritis (OPTION study): a double-blind, that IL-1 plays a central role in driving acute inflamma- placebo-controlled, randomised trial. Lancet 2008, 371:987-97. tion during gout and pseudo-gout attacks [28]. In a small F1000 Factor 3.0 Recommended uncontrolled study and in case reports, anakinra has Evaluated by Johanne Martel-Pelletier 21 May 2008 been proven to be very effective in controlling disease 4. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB; PHOENIX 1 study investigators: flares in patients with gout and pseudo-gout [29-31]. Efficacy and safety of ustekinumab, a human interleukin-12/ Rilonacept and canakinumab are under investigation in 23 monoclonal antibody, in patients with psoriasis: 76-week crystal-induced arthritides, and the preliminary results results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008, 371:1665-74. have been promising (Table 2 and [2]). In this context, 5. Clark W, Jobanputra P, Barton P, Burls A: The clinical and cost- targeting IL-1 could be a therapeutic alternative, at least effectiveness of anakinra for the treatment of rheumatoid for the cases of crystal-induced arthritis with refractori- arthritis in adults: a systematic review and economic analysis. ness or intolerance to the standard treatment with Health Technol Assess 2004, 8:1-105. 6. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: nonsteroidal anti-inflammatory drugs, steroids, and Anti-TNF antibody therapy in rheumatoid arthritis and the colchicine. risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006, 295:2275-85. The group of IL-1-mediated autoinflammatory diseases F1000 Factor 6.5 Must Read has been broadened with the addition of TNF receptor- Evaluated by Michael Ward 30 May 2006, Peter Taylor 15 Jun 2006, associated periodic syndrome, familial Mediterranean Joel Gelfand 12 Jul 2006 fever, hyper-IgD syndrome, PAPA (pyogenic arthritis, 7. Askling J, Baecklund E, Granath F, Geborek P, Fored M, Backlin C, pyoderma gangrenosum, and acne) syndrome, Schnit- Bertilsson L, Cöster L, Jacobsson LT, Lindblad S, Lysholm J, zler syndrome, systemic onset juvenile idiopathic arthri- Rantapää-Dahlqvist S, Saxne T, van Vollenhoven R, Klareskog L, Feltelius N: Anti-tumour necrosis factor therapy in rheuma- tis, and adult-onset Still’s disease [11,16]. In the above toid arthritis and risk of malignant lymphomas: relative risks inflammatory disorders, anakinra was remarkably effec- and time trends in the Swedish Biologics Register. Ann Rheum Dis 2009, 68:648-53. tive [10] and, in the near future, it is expected that the novel IL-1-targeting therapeutics rilonacept and canaki- F1000 Factor 3.0 Recommended Evaluated by Zoltán Szekanecz 22 May 2009 numab will be useful treatment choices for these diseases. 8. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH: Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relap- Abbreviations sing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet ASC, apoptosis-associated speck-like protein containing Neurol 2008, 7:796-804. caspase-recruitment domain; CAPS, cryopyrin-associated F1000 Factor 6.0 Must Read periodic syndrome; CPPD, calcium pyrophosphate Evaluated by Roland Martin 14 Nov 2008 dehydrate; FCAS, familial cold autoinflammatory syn- 9. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, drome; FDA, US Food and Drug Administration; hIgG1, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, human immunoglobulin G1; IL, interleukin; IL-1AcP, Harriman GR, Maini RN; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group: interleukin-1 accessory protein; MSU, monosodium Infliximab and in the treatment of rheumatoid urate monohydrate; MWS, Muckle-Wells syndrome; arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J PAPA, pyogenic arthritis, pyoderma gangrenosum, and Med 2000, 343:1594-602. acne; RA, rheumatoid arthritis; SAA, serum amyloid A; 10. Kalliolias GD, Liossis SN: The future of the IL-1 receptor TNF, tumor necrosis factor. antagonist anakinra: from rheumatoid arthritis to adult- onset Still’s disease and systemic-onset juvenile idiopathic arthritis. Expert Opin Investig Drugs 2008, 17:349-59. 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