1 Effect of pascolizumab binding of IL-4 inhibits IL-4 interaction with the alpha chain of the IL-4 receptor. and no adverse clinical responses occurred NBD-557 after up to 9 months of treatment. Three monkeys developed an anti-idiotypic response that resulted in rapid pascolizumab clearance. However, in the chronic dosing study the antibody response was transient and not associated with clinical events. In conclusion, pascolizumab is a humanized anti-IL-4 monoclonal antibody that can inhibit upstream and downstream events associated with asthma, including TH2 cell activation and immunoglobulin E production. Clinical trials are under way to test the clinical efficacy of pascolizumab for asthma. Keywords: asthma, interleukin-4, monoclonal antibody, preclinical safety, toxicology INTRODUCTION Although the cause of asthma has not been defined completely, it is clear that asthma is the result of a series of cellular and cytokine-mediated events that induce chronic airway inflammation. Interleukin (IL)-4 is thought to be a key cytokine in the early stages of asthma because of its role in regulating B-cell isotype switching to immunoglobulin (Ig)E production, eosinophil chemotaxis and the development of effector T-cell responses [1,2], Interleukin-4 is produced by T lymphocytes, activated mast cells and basophils. Along with other cytokines (including IL-5 and IL-13), IL-4 can induce the development of allergic inflammatory diseases and can promote the differentiation of undifferentiated helper T cells (TH0) into type 2 helper T cells (TH2) [3,4]. These TH2 cells, in turn, secrete a pattern of cytokines including IL-3, IL-4, IL-5, IL-13 and granulocyte-macrophage colony-stimulating factor [5] that initiate and perpetuate the asthmatic inflammatory response leading to airway inflammation, obstruction and hyperresponsiveness characteristic of chronic asthma [6]. Both IL-4 and IL-5 mRNA and protein are elevated in asthmatic airway tissues [7,8]. Inhibition of IL-4 activity could potentially reduce the pulmonary inflammation and remodelling that define chronic persistent asthma. Because TH2 differentiation is IL-4-dependent, IL-4 neutralization may inhibit the development of TH2 cells and the subsequent events that lead to allergic inflammation [9]. Also, as IL-4 induces IL-5 synthesis, IL-4 neutralization NBD-557 may also block IL-5-dependent pulmonary eosinophilia. Inhibition of IL-4 may also reduce aberrant IgE production and subsequent IgE-mediated, mast cell-dependent inflammation. Furthermore, because IL-4 up-regulates collagen and fibronectin synthesis in subepithelial fibroblasts (leading to airway remodelling), inhibiting IL-4 may prevent long-term reduction in pulmonary function [10]. Finally, animal studies have revealed that IL-4 knockout mice sensitized to antigen were unable to develop allergic eosinophilic airway infiltration and did not produce antigen-specific IgE following exposure to aerosolized antigen [11]. Additionally, these mice failed to develop airway hyperresponsiveness following chronic aerosol exposure to antigen. Interleukin-13 is related closely to IL-4 and has similar downstream functions. Produced by activated TH2 cells, TH0 cells, mast cells and dendritic cells, IL-13 can also stimulate IgE production by B cells NBD-557 [12]. However, because T cells do not express IL-13 receptors, IL-13 does not promote TH2 responses or suppress TH1 cell differentiation as does IL-4 [13]. Because of this difference in function, it is possible that suppressing IL-4 will prevent IL-13 up-regulation. Thus, although other cytokines are involved in the development of asthma, the neutralization of IL-4 alone may be sufficient to decrease eosinophil accumulation in the airways and to reduce lung airway remodeling in asthmatic patients. Research NBD-557 in murine types of asthma possess proven that both anti-IL-4 antibodies and soluble IL-4 receptors can stop the downstream occasions connected with asthma. The administration of the aerosolized, soluble, murine recombinant IL-4 receptor inhibited IL-4 activity in mice and prevented the introduction of allergen-induced and allergen-dependent instant hypersensitivity reactions [14]. Similarly, inside a murine style of atopic asthma, mice Rabbit Polyclonal to Cytochrome P450 8B1 treated with anti-IL-4 monoclonal antibody (MoAb) ahead of energetic sensitization with ovalbumin demonstrated lower serum IgE amounts weighed against saline-treated settings [15]. Pascolizumab (SB 240683) can be a humanized anti-IL-4 MoAb created originally by GlaxoSmithKline (Philadelphia, PA, USA) and presently in advancement at Protein Style Laboratories, Inc. (Fremont, CA, USA). Pascolizumab blocks the discussion of IL-4 using its receptor (Fig. 1), inhibiting the first occasions of asthma including TH2 cell differentiation therefore, igE and eosinophilia up-regulation. Preclinical data indicate that blocking these events might prevent airway.
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