Published: 14 September 2009 © 2009 Biology Reports Ltd Targeting cytokines in inflammatory diseases: focus on interleukin-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 cytokine-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 anakinra 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 tocilizumab is effective in RA [3] includes the mild phenotype known as familial cold and that the p40 neutralizing antibody ustekinumab autoinflammatory syndrome (FCAS), the intermediate (targeting both IL-12 and IL-23) is beneficial for Muckle-Wells syndrome (MWS), and the severe form psoriasis [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 immune system 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 monoclonal antibody to show a significant regulation of the innate and adaptive branches of benefit in patients with multiple sclerosis [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 Page 1 of 5 (page number not for citation purposes) F1000 Biology Reports 2009, 1:70 http://F1000.com/Reports/Biology/content/1/70 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. Etanercept (Enbrel®; Dimeric fusion protein • RA Amgen, 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. Infliximab 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. Adalimumab 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. Certolizumab pegol 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. Golimumab 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. Rilonacept 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 antigen-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, psoriatic arthritis; RA, rheumatoid arthritis; improved pharmacokinetics and thus better compliance TNF-a, tumor necrosis factor-alpha; TNFR, tumor necrosis factor and tolerance [20,21]. receptor; UC, ulcerative colitis. Rilonacept is a new IL-1 blocker that functions as an inflammation. 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]. Page 2 of 5 (page number not for citation purposes) F1000 Biology Reports 2009, 1:70 http://F1000.com/Reports/Biology/content/1/70 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 Canakinumab Anti-IL-1 Mab CAPS/SoJIA/RA/Gout/DM II/COPD IL-4 and IL-13 Pascolizumab Anti-IL-4 Mab Asthma Pitrakinra (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 Mepolizumab 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 Belimumab Anti-BLyS Mab SLE/RA 2. LTa1b2 and LIGHT Baminercept Ligand-binding portion of LT-b R fused with hIgG1 Fc RA 3.