The Application of Monoclonal Therapies and Therapeutics to Asthma and Allergy
The Future Application of Monoclonal Antibodies to Asthma and Allergy
Stephen T. Holgate
Infection, Inflammation and Repair Division
Southampton General Hospital
Southampton, United Kingdom
Allergic diseases have reached epidemic proportions worldwide. An understanding of the cellular and soluble mediators that are involved in allergic inflammatory responses not only helps in understanding the mechanisms of current treatments, but is also important for the identification of new targets that are amenable to both small-molecule and biological interventions. It is the introduction of monoclonal antibodies and soluble cytokine receptors that is revolutionising approaches to the treatment of asthma and allergy however, when compared to other areas of chronic inflammation; development of biologics in our field has been slow with the exception of immunotherapy. The successful introduction of omalizumab for severe allergic asthma has stimulated great interest in this approach, but even with this humanised monoclonal antibody, cost effectiveness analyses are restricting its use even though it has passed scrutiny by such agents as the National Institute of Health & Clinical Excellence in the UK. The need for 16 weeks therapy before a decision can be made to separate responders from non responders emphasises the need for biomarkers of response since patients vary greatly in their response to this treatment. Understanding the underlying mechanisms of allergic disease has stimulated the further development of a series of biologics targeted towards critical cells and molecules in the allergic cascade presented below. Because of the sentinel role that Th2 cytokines have in orchestrating allergic inflammation, they and their receptors are key therapeutic targets. Both IL-4 and IL-13 have a crucial role in the immunoglobulin isotype switching of B cells to produce IgE, whereas IL-4 alone is crucial for maintaining the Th2-cell phenotype, which makes both cytokines attractive therapeutic targets. A large number of animal studies have shown that blocking production or inhibiting the effects of IL-4 has profound effects on the allergic phenotype. A soluble, recombinant, human IL-4 receptor (altrakincept) consists of the extracellular portion of human IL-4Rα and is nonimmunogenic. A small proof-of-concept trial of nebulized inhaled altrakincept for 12 weeks in patients with mild to moderate asthma indicated efficacy by allowing withdrawal from treatment with inhaled corticosteroids without relapse, and this result was subsequently confirmed in a larger trial. However, a Phase III trial failed to confirm the efficacy of altrakincept for the treatment of asthma. This trial does not invalidate IL-4 as a target for the treatment of allergy and asthma, as there were concerns over the bioavailability of altrakincept in this study. Further Phase II studies are in progress using humanized IL-4-specific and IL-4Rα-blocking antibodies such as pascolizumab (SB240, 683). Two vaccines against IL-4 have been tested in mice, one in which IL-4 is chemically coupled to limpet haemocyanin and the other in which a 14 -amino-acid peptide from IL-4 is inserted into variant hepatitis B virus core antigen. Both vaccines induced high antibody titres specific for mouse IL-4 and inhibited antigen-induced lung inflammation. However, using co-stimulation blockade in a mouse model of allergy to grass pollen, it was reported that the secondary IgE response is not T-cell dependent, thereby raising doubts over the usefulness of IL.4 blockade for treating established allergic disease. The numerous functions of IL-13 in regulating IgE production, eosinophilic inflammation, airway smooth-muscle hyperplasia, the induction of goblet-cell hyperplasia with mucus production, and the recruitment of monocytes, macrophages and T cells into the airway spaces make it a key therapeutic target in allergy and asthma. IL-13 binds to a low-affinity IL-13Rα1 subunit and a high-affinity complex comprised of IL-13Rα1 and IL-4Rα. Binding to this high-affinity complex leads to the phosphorylation-dependent activation of Janus kinase 1 (JAK1), JAK2 and STAT6. IL-4Rα also stabilizes the binding of IL-13 to its receptor to augment IL-13 -mediated responses. However, a non-signalling, high-affinity IL-13 -binding chain, IL-13 Rα2, strongly inhibits the activity of IL-13. Selective blockade of IL-13 has been achieved in mice using a soluble form of IL-13Rα2, which competes for binding to IL-13 but not to IL4, and this led to the reversal of airway hyperresponsiveness and mucus production in allergen exposed sensitized mice. A soluble form of IL-13Rα2 that binds IL-13 with 100-fold greater affinity than does IL-13Rα1 is present in mouse but not human serum. Antagonizing the effects of IL-13 could also be achieved by administering soluble IL-13 receptors or IL-13R-specific monoclonal antibodies. In cynomolgus monkeys sensitized to Ascaris suum and then challenged with antigen from this nematode, a mouse antibody specific for human IL-13 (mAb13.2) and the humanized counterpart (IMA-638) inhibited eosinophil and neutrophil influx into the lungs as assessed by bronchoalveolar lavage. Phase I trials of the IL-13-specific monoclonal antibody CAT-354 in 34 mildly asthmatic patients have been successfully completed and Phase II trials are in progress. Subcutaneous or inhaled pitrakinra, a mutant IL-4 protein that inhibits the binding of IL-4 and IL-13 to IL-4Rα complexes, has recently shown efficacy in the treatment of allergen-induced asthma. A novel, recombinant IL-13 peptide-based vaccine has also been shown to reduce allergic inflammatory responses in mice. Rodent and non-human primate studies have indicated an important role for IL-5 in various models of asthma. Inhaled IL-5 modulates the number of eosinophil progenitors in both the airways and bone marrow of asthmatic individuals and induces local eosinophilia in non-asthmatic individuals. Two humanized, human-IL-5-specific monoclonal antibodies, Sch-55,700 and mepolizumab (SB-240,563), have been developed for the treatment of asthma. In a small double-blind trial, mepolizumab produced a rapid dose-dependent reduction in the number of circulating and sputum eosinophils that persisted for 3 months but, surprisingly, this had no effect on either the late asthmatic response or on airway hyper-responsiveness. In a group of patients with severe persistent asthma, treatment with Sch-55,700 resulted in a decrease in the number of blood eosinophils, but over the course of 10 weeks it had no effect on any measures of asthma outcome, an observation that has recently been confirmed in a large trial with mepolizumab. A further study using mepolizumab confirmed the persistent suppression of eosinophilia in blood, bone marrow and airway lavage, but in airway biopsies, there was only a 55% reduction in the number of tissue eosinophils. As a proportion of eosinophils in the airways of patients with asthma lack IL-5R, it was suggested that this might explain the apparent lack of clinical efficacy of targeting IL-5. IL-5 could have more subtle effects on asthmatic airways - for example, mepolizumab treatment decreases immunostaining for tenascin, lumican and procollagen III in the bronchial mucosal subepithelial basal lamina and in allergen challenged skin. In addition, IL-5-specific treatment resulted in a parallel decrease in the number of airway eosinophils expressing mRNA for TGFβ1 and of TGFβ1 levels in bronchoalveolar-lavage fluid, which indicates a possible role for IL-5 in airway remodelling. In contrast to asthma, mepolizumab is highly efficacious in the treatment of hypereosinophilic syndrome and eosinophilic oesophagitis, but not atopic dermatitis. A therapeutic DNA-based vaccine against IL-5 is also being developed. As asthma becomes more severe and aggressive it adopts a Th2 cytokine profile with enhanced production of IFN-β and TNFα. Both in mouse models and in 3 small clinical trials in severe asthma anti-TNF therapies (etanercept, infliximab) were reported to be efficacious. However in a large RCT involving over 300 patients with severe asthma, treated with golimumab (CNTO 148) for 52 weeks efficacy for baseline lung function and asthma exacerbations was not apparent. However, a subgroup analysis indicated that reversibility of lung function, late onset disease and concurrent sinusitis were predictors of efficacy and further trials in this subpopulation are now being undertaken. Blocking the actions of IL-9 reduces allergen-induced airway inflammation and airway hyper-responsiveness in mouse models. Two Phase I dose-escalation studies of an IL-9-specific monoclonal antibody (MEDI-528) in healthy volunteers have been completed without problems. Phase II trials are in progress for treating symptomatic, moderate to severe, persistent asthma. IL-2 is intimately involved in T cell activation and its α receptor (CD25) has been targeted with a monoclonal antibody Daclizumab that is efficacious in preventing renal transplant rejection. A phase IIa clinical trial in moderate-severe asthma has also revealed efficacy on the basis that activated T cells contribute to ongoing disease activity. As new targets for immunologics are discovered it is important that appropriate trial designs are used to test them taking account of markers of response and surrogate endpoints that include the identification of biomarkers. Some examples of novel targets that have been largely identified in mouse models of antigen driven allergic type inflammation include IL-15, IL-17A, IL-17E (or IL-25), IL-33, IL-31, IL-21 and thymic stromal lymphopoietin (TSLP) which are all proposed to enhance inflammatory responses. The engineering of monoclonal antibodies to include fully humanised molecules as well as antibody engineering to enhance certain properties such as antibody dependant cell cytotoxicity involving activation of NK cells created when the fucose-linked carbohydrate chain of the Fc portion of the antibody is removed, greatly enhances the potential of these agents as therapeutics so that whole cell populations can be eliminated rather than simply blunting their function.
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