Recent Patents on Inflammation & Allergy Drug Discovery - Volume 4, Issue 3, 2010

Asthma is a chronic inflammatory disorder of the airway in which many cells play a role. The inflammation results in recurrent coughing, breathless, chest tightness and airway obstruction often reversible [1].The use of inhaled corticosteroids, short and long acting beta2-adrenoceptor agonists and inhibitors of leukotrienes provide most asthmatic patients with good disease control. However, none of these therapies are specifically directed to the underlying causal pathways of asthma. Further, almost 10%of asthma patients have severe asthma that is often steroid-resistant [2-4]. These patients are responsible for more than 50% of health care expenditure for all asthma due to the lack of appropriate pharmacological therapy[5]. Recent studies suggest that asthma is a heterogeneous disorder presenting with many phenotypes. These phenotypes are likely the result of specific gene- environment interactions and are defined by many interacting factors including: age of patients, age of disease onset, corticosteroid resistance, chronic airflow obstruction, and evidence for eosinophilic airway inflammation on biopsy [6,7]. Therapies based on phenotypic and genotypic characteristics may be useful in asthma management and contribute to better asthma control potentially also in those that are relatively treatment resistant [8,9]. It is also possible that while current asthma treatments were not shown to affect the natural course of asthma, treatment tailored to a specific phenotype may have such an effect. Indeed, monoclonal antibodies affect specific immunologic pathways involved in asthma pathogenesis and recent studies suggest specific benefits of certain monoclonal antibodies in different asthma phenotypes. Thus, monoclonal antibodies tailored therapies to asthma may well provide the future biologic modifiers of asthma and be used as second or even first line of personalized asthma treatment. In this monothematic issue we sought to describe monoclonal antibodies with potential role in asthma treatment and to highlight key issues related to their mechanisms of action, potential contribution to asthma treatment as well as side effects and future directions related to pertinent patents. Monoclonal antibodies discussed include: anti-IgE, anti-Tumor Necrosis Factor (TNF) anti-Interleukin 5 (IL5), anti-integrins, anti-CD25 and anti-Th2 cytokines. Omalizumab is currently the only IgE-targeted therapy approved by the United States Food and Drug Administration for asthma treatment. It is used in patients with inadequately controlled moderate-to-severe persistent allergic asthma that is not controlled with high-dose inhaled corticosteroids [10]. The PERSIST study as well as other recent studies suggest that under real-life conditions, omalizumab is effective as add-on therapy in the treatment of patients with persistent severe allergic asthma including steroid-resistant asthma [11,12]. Further, as discussed in this issue, its potential off label use in asthma e.g. in children and in asthma related diseases suggests future broader applications. Although current studies suggest acceptable safety profile future studies exploring the long term consequences of omalizumab treatment are still required. Another family of monoclonal antibodies with a possible role in asthma treatment targets the TNF axis. Preliminary studies have demonstrated an improvement in asthma quality of life, lung function, airway hyperresponsiveness and a reduction in exacerbation frequency in patients treated with anti-TNF-alpha therapy. However, there is marked heterogeneity in response and anti-TNF treatment may benefit mainly a specific subset of asthma in which TNF may play a crucial pathogenic role [13]. As discussed in this issue by Dr. Desai and Prof. Brightling this subgroup may consist mainly of those with late onset disease. Given the risk for severe infections and malignancy risk associated with anti-TNF treatment, the safety profile of anti-TNF treatment remains at this point unacceptable in a clinical setting.

Omalizumab is a recombinant humanized monoclonal antibody. Use of omalizumab is reported to benefit significantly a subset of asthmatics patients with inadequately controlled moderate-to-severe persistent allergic asthma that is not controlled with high-dose inhaled corticosteroids. However, recent reports and patents suggest wider applications in asthma and related diseases. In this review unmet needs and future directions regarding the use of omalizumab in asthma are discussed. Better understanding of omalizumab's mechanisms of action on one hand and asthma and related pathogenesis on the other hand might contribute to the development of better future guidelines of omalizumab use in asthma patients.

A small minority of patients with asthma have severe disease that is refractory or poorly responsive and remain persistently symptomatic despite maximal inhaled therapy. These patients represent an important unmet clinical need as they suffer considerable morbidity and mortality and consume a disproportionately large amount of health care resource. Tumour necrosis factor- alpha (TNF-α) is a pro-inflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. Evidence is emerging to suggest that it may play an important role in severe, refractory disease. The development of novel TNF-α antagonist has allowed us to test the role of this cytokine in vivo. Early studies demonstrated an improvement in asthma quality-of-life, lung function, airway hyperresponsiveness (AHR) and a reduction in exacerbation frequency, in patients treated with anti-TNF-α therapy. However, there is marked heterogeneity in response suggesting that benefit is likely to be reserved to a small sub-group. This view is supported by the lack of efficacy in later large clinical trials, although subgroups of responders were identified. Importantly, concerns have been raised about the safety of anti-TNF-α therapies in severe asthma. Therefore, current evidence suggests that the risk of anti- TNF-α therapies outweighs benefit in severe asthma. In this review, we will discuss the role of TNF-α biology and its role in severe asthma, the clinical trials conducted so far and summarize the patents related to TNF-α and the antagonist drug therapies.

Although glucocorticosteroids are still the first line of treatment for chronic asthma, over the last two decades great advances have been made in understanding the pathogenesis of asthma that enabled the identification of new therapeutic targets for asthma treatment. The interleukin (IL) 5: eosinophil axis is a hallmark pathway of allergic inflammation that has received much attention. Indeed, IL-5 is known to regulate eosinophil differentiation, proliferation, priming and activation. Therefore, therapeutic agents targeting IL-5 have been generated. In this review we will discuss the effects of IL-5 on eosinophils and outline the signaling mechanism involved in IL-5-mediated effects. Furthermore, recent results from clinical trials targeting IL-5 in asthma and hypereosinophilic syndrome will be discussed and an overview of newly developed patents aimed to target IL-5 will be reviewed.

There is considerable evidence that implicates eosinophils as important effector cells and immunomodulators in the inflammation characteristic of asthma. Numerous in vitro and animal studies have demonstrated essential roles for cell adhesion molecules in eosinophil adhesion and transendothelial migration including the selectins, ICAM-1, VCAM-1 together with many of the β1 and β2 integrins. A large body of evidence has also implicated several cytokines and chemokines in the selective recruitment of eosinophils to sites of asthmatic inflammation. Biopharmaceutical approaches have been used to identify inhibitory molecules that target key elements in the processes controlling eosinophil accumulation in asthma. This review will summarise, the problems and successes regarding recent patents and developments in adhesion-based therapeutic strategies aimed at reducing eosinophil-mediated inflammation in the asthmatic lung.

Airways inflammation in asthma is triggered and maintained by CD4+ (Th2) cells which are activated by IL-2 and stimulate the eosinophilic inflammation, IgE secretion and mucus hyperproduction. Current anti-inflammatory therapies include inhaled corticosteroids, and leukotriene modifiers but they are not universally effective. IL-2 pathway inhibition might represent a potent anti-inflammatory therapy in asthma given the cytokine early role in the asthma complex inflammatory cascade and daclizumab which is a IL-2R blocker currently used as an immunsupressor in organ transplantation might be a potential asthma therapy. This is a review on the pathogenic role of IL-2, on the therapeutic potential of daclizumab and on its related patents.

While the incidence of allergy and allergic diseases continues to increase, new drugs to treat these disorders have not been forthcoming. The mainstay of therapy continues to be inhaled steroids, leukotriene receptor antagonists, antihistamines and immunotherapy. Even though these drugs work for many patients there remains a group of individuals who fail to improve with these treatments. With the exception of immunotherapy, these drugs improve symptoms, but do not do anything to alter the course of disease. This review will cover recent patents and new drugs that target IL-4, IL-13 and IL-9, molecules involved not only in inflammation associated with disease, but also with the development of the immune repertoire necessary for the perpetuation of disease. Inhibition of these cytokines may lead to true immunomodulation of disease and finally give us drugs that cure the disease rather than just treat symptoms.

Since their initial discovery in the 1970s and their subsequent resurgence in the mid 1990s, regulatory T (Treg) cells have become one of the most studied cell subsets. Treg cells prevent autoimmunity and limit aggressive immune responses directed against either pathogen or foreign antigen that might serve to damage host tissue. In contrast, tumour cells have been shown to recruit and/or induce Treg cells, which can impair tumour immunity. The immunoregulatory function of these cells makes them ideal therapeutic candidates for the treatment of autoimmune disease and in the prevention of transplant rejection. Likewise, depletion of Treg cells remains an additional option in the treatment of cancer. Despite significant advances in the treatment of murine models of disease with Treg cells, it has been difficult to transfer this success into the clinic. In this review, we will discuss relevant patents and the most recent advances in the use of Treg cells to treat autoimmunity, prevent graft rejection as well as the use of anti-bodies to deplete these cells in cancer.

Atopic dermatitis is one of the most prevalent chronic eczematous inflammatory skin diseases in westernized populations. It is caused by both skin barrier dysfunction and abnormal immunologic response. An imbalance of effector T cells and regulatory T cells is a crucial factor in the initiation of allergic diseases. Recent advances in immunology have revealed the role of regulatory T cells in atopic dermatitis. Treatment of atopic dermatitis consists of restoring and maintaining a sufficient skin barrier and inducing a balanced systemic immune response.

Regulatory T cells (Tregs) are essential for maintaining self-tolerance and also play a pivotal role in diminishing anti-tumor immunoresponse. The frequency and activity of CD4+CD25+FoxP3+ Tregs in the circulation and tumor microenvironment is increased in patients with various cancers. Although, the exact role of Tregs in cutaneous tumors remains unclear, Tregs contribute to tumor progression of skin cancers, explaining, in part, why immunotherapy with dendritic cell-based vaccination for melanoma patients has not been satisfactory. Therefore, there has been considerable interest in determining their function in order to treat skin cancers such as malignant melanoma. However, clinical trials with specific antibodies designed to overcome Treg-associated immunosuppression resulted in limited clinical efficacy with some adverse effects. A better understanding of the role of Tregs in the tumor environment might contribute to the development of novel approaches for treating various cutaneous tumors. In this review, we focus on clinical and basic research on Tregs in relation to skin tumors and describe some important patents for the treatment of skin cancers.

The balance between apoptosis and cell proliferation is the key determinant in the pathogenesis of many diseases including autoimmune thyroiditis. In recent years, many studies have strengthened the concept that pro- and antiapoptotic molecules expressed in thyroid epithelial cells as well as in thyroid infiltrating lymphocytes play a pivotal role in the pathogenesis and/or progression of autoimmune thyroiditis. In this review, the role of apoptosis in the pathogenesis in the two well-defined murine models of autoimmune thyroiditis, experimental autoimmune thyroiditis (EAT) and iodine-induced autoimmune thyroiditis (IAT) is discussed. Recent important patents focusing on apoptosis as novel therapeutic targets are also discussed in this review. Further clinical trials are needed to evaluate the efficacy and safety of these agents.

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