CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Allergology International (2003) 52: 53–63 Review Article Cytokine-directed therapies in asthma Peter J Barnes National Heart and Lung Institute, Imperial College, London, UK ABSTRACT Multiple cytokines and chemokines have been impli- cated in the pathophysiology of asthma.1 There is now Multiple cytokines play a critical role in orchestrating an intensive search for more specific therapies in and perpetuating inflammation in asthma and several asthma. Inhibitors of cytokines and chemokines figure specific cytokine and chemokine inhibitors are now in prominently in these novel therapeutic approaches2 development as future therapy. Anti-interleukin (IL)-5 (Table 1). antibodies markedly reduce peripheral blood and airway eosinophils, but do not appear to be effective in symptomatic asthma. Inhibition of IL-4, despite prom- STRATEGIES FOR INHIBITING CYTOKINES ising early results in asthma, has been discontinued There are several possible approaches to inhibiting and blocking IL-13 may be more effective. Inhibitory specific cytokines. These range from drugs that inhibit cytokines, such as IL-10, interferons and IL-12 are less cytokine synthesis (glucocorticoids, cyclosporine A, promising, because systemic delivery produces side- tacrolimus, rapamycin, mycophenolate, T helper 2 effects. Inhibition of tumor necrosis factor (TNF)-α may (Th2)-selective inhibitors), humanized blocking anti- be useful in severe asthma. Many chemokines are bodies to cytokines or their receptors, soluble receptors involved in the inflammatory response of asthma and to mop up secreted cytokines, small molecule receptor several small molecule inhibitors of chemokine recep- antagonists or drugs that block the signal transduction tors are in development. The CCR3 antagonists (which pathways activated by cytokine receptors. In contrast, block eosinophil chemotaxis) are in clinical develop- there are cytokines that themselves suppress the allergic ment for asthma. Because so many cytokines are inflammatory process and these may have therapeutic involved in asthma, drugs that inhibit the synthesis of potential in asthma.3 multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side-effects with these non-specific INHIBITION OF TH2 CYTOKINES inhibitors may be reduced by the inhaled route. The Th2 lymphocytes play a key role in orchestrating the eosinophilic inflammatory response in asthma, suggest- Key words: chemokines, interleukin-4, interleukin-5, ing that blocking the release or effects of these cytokines interleukin-10, interleukin-12, interleukin-13, tumor may have therapeutic potential. This has been strongly necrosis factor-α. supported by studies in experimental animals, including mice with deletion of the specific Th2 cytokine genes. INTRODUCTION Anti-interleukin-5 Cytokines play a critical role in the orchestration of chronic inflammation in all diseases, including asthma. Interleukin (IL)-5 plays an essential role in orchestrating the eosinophilic inflammation of asthma.4 In IL-5 gene knock-out mice, the eosinophilic response to allergen Correspondence: Professor PJ Barnes, Department of Thoracic and the subsequent airway hyperresponsiveness (AHR) Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. are markedly suppressed and yet animals have a normal Email: [email protected] survival, validating the strategy to inhibit IL-5. This has Received 18 February 2003. also been achieved using blocking antibodies to IL-5. 54 PJ BARNES Blocking antibodies to IL-5 inhibit eosinophilic inflam- several weeks and prevents eosinophil recruitment into mation and AHR in animal models of asthma, including the airways after allergen challenge in patients with mild primates.5 This blocking effect may last for up to asthma6 (Fig. 1). However, this treatment has no signifi- 3 months after a single intravenous injection of antibody cant effect on the early or late response to allergen in primates, making treatment of chronic asthma with challenge or on baseline AHR, suggesting that eosin- such a therapy a feasible proposition. Humanized mono- ophils may not be of critical importance for these clonal antibodies to IL-5 have been developed and a responses in humans (Fig. 2). A clinical study in patients single intravenous infusion of one of these antibodies with moderate to severe asthma who had not been (mepolizulab) markedly reduces blood eosinophils for controlled on inhaled corticosteroid therapy confirmed a Table 1 Cytokine modulators for asthma Anti-cytokines Inhibitory cytokines Chemokine inhibitors Cytokine synthesis inhibitors Anti-IL-5 IL-1 receptor antagonist CCR3 antagonists Corticosteroids Anti-IL-4 IL-10 CCR2 antagonists Immunomodulators Anti-IL-13 IL-12 CCR4 antagonists Phosphodiesterase-4 inhibitors Anti-IL-9 Interferons (IFN-α, IFN-γ) CCR8 antagonists NF-κB inhibitors (IKK2 inhibitors) Anti-IL-25 IL-18 CXCR2 antagonists p38 MAPK inhibitors Anti-IL-1 IL-23 CXCR4 antagonists Anti-TNF-α IL, interleukin; TNF-α, tumor necrosis factor-α; IFN, interferon; NF-κB, nuclear factor-κB; IKK, inhibitor of NF-κB kinase; MAPK, mitogen- activated protein kinase. Fig. 1 Effect of a humanized monoclonal antibody against interleukin-5 (mepolizumab) on circulating eosinophils in patients with mild asthma, demonstrating a profound and very prolonged inhibitory effect. (᭡), placebo (n = 8); ( ), 2.5 mg/kg mepolizumab (n = 8); (᭿), 10 mg/kg mepolizumab (n = 8). B/L, baseline; D, day; Wk, week. Adapted from Leckie et al.6 CYTOKINE-DIRECTED THERAPIES IN ASTHMA 55 Fig. 2 Effect of a humanized monoclonal antibody against interleukin (IL)-5 (mepomizulab) on (a) the early and late response to allergen (–––, IL-5 antibody; -----, placebo) and (b) airway hyperresponsiveness (ᮀ, placebo; ᭿, IL-5 antibody). FEV1, forced expiratory volume in 1 s. Adapted from Leckie et al.6 profound reduction in circulating eosinophils, but no α-chain and through large-scale throughput screening. significant improvement in either asthma symptoms or One such molecule, YM-90709, appears to be a rela- lung function.7 In both these studies, it would be tively selective inhibitor of IL-5-receptors.10 However, the expected that high doses of corticosteroids would lack of clinical benefit of anti-IL-5 antibodies has made improve these functional parameters.6,7 These surprising this a less attractive approach. It is possible that eosin- results question the critical role of eosinophils in asthma ophils are associated with more chronic aspects of and indicate that other strategies aimed at inhibiting asthma, such as airway remodeling, and, in mice, a eosinophilic inflammation may not be effective. More blocking anti-IL-5 antibody prevents the increased colla- recently, a biopsy study has demonstrated that anti-IL-5 gen deposition in airways associated with repeated aller- antibody, while profoundly reducing eosinophils in the gen exposure. circulation (by over 95%), is less effective at reducing eosinophils in bronchial biopsies (by approximately Anti-IL-4 50%), which may explain why this treatment is not clinically effective.8 Nevertheless, this suggests that Interleukin-4 is critical for the synthesis of IgE by blocking IL-5 is not likely to be a useful approach to B lymphocytes and is also involved in eosinophil recruit- asthma therapy. ment to the airways.11 A unique function of IL-4 is Somewhat similar findings have been reported previ- to promote differentiation of Th2 cells and, there- ously in some studies in mice, where anti-IL-5 antibodies fore, it acts at a proximal and critical site in the allergic reduced eosinophilic responses to allergen, but not AHR, response, making IL-4 an attractive target for inhibition. whereas AHR was reduced by anti-CD4 antibody, which Interleukin-4 blocking antibodies inhibit allergen- depletes Th cells9 and suggests that T cell-derived induced AHR, goblet cell metaplasia and pulmonary cytokines other than IL-5 must be playing a more impor- eosinophilia in a murine model.11 Therefore, inhibition of tant role in AHR. IL-4 may be effective in inhibiting allergic diseases and Non-peptidic IL-5 receptor antagonists would be an soluble humanized IL-4 receptors (sIL-4R) have been alternative strategy and there is a search for such com- tested in clinical trials. A single nebulized dose of sIL-4R pounds using molecular modeling of the IL-5 receptor prevents the fall in lung function induced by withdrawal of 56 PJ BARNES inhaled corticosteroids in patients with moderately severe where concentrations of IL-13 are much higher than asthma.12 Subsequent studies have demonstrated that those of IL-4. Humanized IL-13Rα2 is now in clinical weekly nebulization of sIL-4R improves asthma control development as a therapeutic approach for asthma. over a 12 week period.13 However, subsequent studies in patients with milder asthma proved disappointing Anti-IL-9 and this treatment has now been withdrawn. Another Interleukin-9 is a Th2 cytokine that may enhance approach is blockade of IL-4 receptors with a mutated Th2-driven inflammation and amplify mast cell mediator form of IL-4 (BAY 36-1677), which binds to and blocks release and IgE production.18 Interleukin-9 may also IL-4Rα and IL-13Rα1, thus blocking both IL-4 and enhance mucus hypersecretion. Interleukin-9 and its IL-13.14 This treatment has also been withdrawn. receptors show an increased expression in asthmatic Interleukin-4