Recent Patents on Inflammation & Allergy Drug Discovery - Volume 3, Issue 2, 2009

Co-stimulatory molecules are antigen-independent generators of secondary signals which aid in maintaining the homeostasis of the immune system. CTLA-4 is one among extensively studied co-stimulatory molecules which downregulate immune response. The attributes of immunosuppressive qualities and capacity to induce tolerance have made its recognition as a potential immuno-therapeutic agent for autoimmune mediated inflammatory disorders. In 2007, European Medical Drug Agency (EMEA) has approved administration of CTLA-4Ig (commercial name: Orencia® ; generic name: Abatacept), as a mean for co-stimulation blockade, for treating patients with rheumatoid arthritis. This review is focused on working mechanism of CTLA-4 from its recognition (bench) to its usage as a potential therapeutic agent (bedside) for several inflammatory diseases. The efficacious aspects of chimeric CTLA-4 in phase I, II and III clinical trials for rheumatoid arthritis, psoriasis, multiple sclerosis are concisely described. This article highlights recent patents and the future usage of co-stimulatory molecules as a therapeutic agent providing a promising immuno-modulatory approach in regulating inflammation.

Sepsis is currently the 10th leading cause of death overall and accounts for significant healthcare expenditures in the developed world. There are now more deaths attributable to sepsis than coronary artery disease, stroke, or cancer, and it is widely believed that the incidence of sepsis and sepsis-related mortality will continue to rise. Based on these sobering statistics, there is great interest in identifying novel treatments for managing critically ill children and adults with sepsis. Unfortunately, to date, there have been very few successful therapeutic agents employed in the clinical setting. Despite these disappointing results, new therapeutic agents continue to be identified, and there is reason for optimism and hope for the future. Herein, we will briefly review several novel therapeutic adjuncts for the management of critically ill patients with sepsis. We will largely focus on those therapies that directly target the host inflammatory response, specifically those that result in activation of the transcription factor, nuclear factor (NF)-κB. We will also reference some of the patents recently filed that pertain to the host innate immune response and sepsis.

Specific immunotherapy is the only treatment targeting the causes, and not only the symptoms, of allergic diseases. Sublingual immunotherapy (SLIT) was introduced and developed to solve the problem of the adverse reactions, uncommon but possibly severe and rarely fatal, to the traditional subcutaneous immunotherapy (SCIT). The evidence of SLIT efficacy concerns rhinitis and asthma caused by sensitization to pollens and to house dust mites, but there are increasing data suggesting that SLIT could be applied in forms of allergy hardly feasible for SCIT because of its poor safety (this is true for food allergy and latex allergy) or could be considered for new applications, such as atopic dermatitis or baker's asthma. In particular, there are placebo-controlled trials indicating good efficacy and safety of SLIT in patients allergic to latex and to foods and in children with atopic dermatitis, that indicate SLIT as a real treatment option in such clinical entities. This article also discusses some patent related to the field.

Seasonal and perennial allergic conjunctivitis are IgE-mediated, hypersensitivity ophthalmic conditions characterized by ocular pruritus, epiphora, and hyperemia. Proper diagnosis is usually made clinically based on history and physical examination. Diagnostic procedures are rarely necessary. Non-pharmacological measures, such as environmental modification and proper eye care, should be considered for all patients with allergic conjunctivitis. Pharmacological interventions may also be required. Milder cases can be treated with short-term topical ophthalmic therapy such as a decongestant/antihistamine combination, a mast cell stabilizer, or a multi-action agent. Moderate to severe cases may require longer usage of the above agents or the addition of an oral antihistamine. Refractory cases may necessitate the use of topical ophthalmic corticosteroids and/or immunotherapy. Despite all the available therapeutic agents, there continues to be a constant need to discover more effective ways to treat seasonal and perennial allergic conjunctivitis. This review article also discusses recent patents related to the field.

CD86 is a well-known costimulatory molecule in its interaction with CD28 and/or CTLA present on T cells, and is essential for full activation of naive T-cell and subsequent differentiation. Usually the B7 molecules are expressed mainly on APCs and B cells and in specific conditions on other activated cells. These costimulatory molecules are involved in the development of allergic inflammation and airways hyperreactivity (AHR) in allergen-challenged mice. Activated T cells, CD4+CD25+, express CD86 in the first 60 minutes after the specific inhalatory exposure. These T cells can be relevant in IgE mediated allergic reaction possibly by an autocrine costimulation via CD28/CTLA activation pathway. The blockage of the expression of CD86 could be a potential therapeutical target to reduce the magnitude or the progression of the allergic reaction. The review article also discussed relevant patents.

Cytotoxic lymphocyte-associated molecule-4 (CTLA-4, CD152) is a member of the CD28 receptor family. Blocking CD28 interaction with its ligands through the use of CTLA-4Ig might contribute to better control of dysregulated immune response processes. The ligands binding to CTLA-4 are the B7 family members, B7-1 (CD80) and B7-2 (CD86). CTLA-4Ig is now a Food and Drug Administration-approved drug for use treating patients with Rheumatoid arthritis (RA) but its use is explored also in other autoimmune diseases, transplantation as well as allergic diseases. Patents related to CTLA-4 function as well as possible clinical applications are discussed in this paper.

Asthma is the most common pulmonary disease in children worldwide. As its prevalence significantly increases from 30% to 50% every 10 years it seems that finding the exact form of treatment is crucial to achieve a longterm- benefit effect. Sometimes it appears hard, especially in case of difficult and severe asthma when a standard therapy is not sufficient. The success of omalizumab inspired further studies which turned the spotlight on other pro-inflammatory cytokines such as TNF-α. After the success of anti-TNF-α therapy in many other inflammatory diseases such as for instance Crohn's Disease and Rheumatoid Arthritis, there appeared several trials discussing the usage of anti-TNF agents in asthma. The first wave of enthusiasm over positive results in treating asthma patients was blunted by other researches which challenged the benefit of anti-TNF- α in asthma. What is more, they warned about serious problems and adverse events related to that kind of treatment. These results hindered further investigation, especially in case of children's population, because of the ambiguity as far as the risks and benefits of the treatment were concerned. Nevertheless, the research on anti-TNF-α and asthma underlined a significant polymorphism in asthma phenotypes. It seems likely that a therapy with anti-TNF-α should be limited to a small subgroup of patients with a specific phenotype manifested by an increased TNF axis. The purpose of this review article is to discuss some recent patents in anti-TNF- α therapy.

Recently, a third subset of Th17 cells has been described. This T helper subset induces the release of chemokines and growth factors and causes neutrophil accumulation in several mammalian organs. Pharmacological intervention blocking Th17 generation as well as IL-17 signaling might prove useful in a variety of diseases including asthma, chronic obstructive pulmonary disease, Crohn's disease, cystic fibrosis, multiple sclerosis, psoriatic disease and rheumatoid arthritis. Here, we describe the patents that address a potential pharmacological use of promoting or targeting IL-17.

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