World Allergy Forum: Immune Intervention
Monoclonal Antibody Treatment of IgE Mediated Disease
Paula M. Jardieu
Monoclonal antibodies are potentially useful therapeutic agents in a variety of immunologically mediated diseases since they offer the theoretical advantage of selectively targeting the mediators of the immunopathogenesis. It has been well established that IgE antibody synthesized by the immune system plays a pivotal role in the cascade of biochemical events leading to the allergic reaction. When cell-bound IgE on mast cells or basophils is crosslinked by an antigen, the cell degranulates releasing the mediators of immediate hypersensitivity such as histamine, leukotrienes, and platelet-activating factor. These inflammatory mediators are responsible for the swelling, erythema, and smooth muscle contraction characteristic of the asthmatic reaction.
Numerous studies show that direct interference with the IgE response leads to a decrease or elimination of the allergic symptoms of rhinitis, asthma and atopic dermatitis. The aim of these studies was to design a monoclonal antibody which targeted IgE as a means to ameliorate atopic disease. To this end a murine monoclonal antibody (MAE11) directed against IgE was identified which had all of the properties necessary to interfere with IgE responses, but lacked the harmful side-effects of inducing receptor crosslinking. The antibody was selected based on its ability to bind circulating IgE at the same site as the high affinity receptor, thus block binding of IgE to mast cells and basophils. To avoid the problems of antigenicity associated with chronic administration of murine antibodies MAE11 was humanized. The critical amino acids responsible for the binding of the murine anti-IgE Mab were engrafted into a human IgG1, such that less than 5% of the resulting antibody remain murine in origin. The best of several humanized variants, version 25 (rhuMAb-E25) was selected since it possessed biological activity comparable to MAE11.
To determine the clinical efficacy of rhuMAb-E25, clinical trials have been undertaken in both allergic and allergic rhinitis. In initial safety studies, rhuMAb-E25 given by single or multidose administrations was very well tolerated. Decreases in free IgE concentrations indicative of pharmacodynamic activity were seen as early as 5 minutes following IV doses of rhuMAb-E25 and within 24 hours after SC doses.
Phase II studies were designed to determine if elimination of serum IgE, as a result of rhuMAb-E25 administration, had significant impact on allergic symptoms. Given the well established role of IgE in allergic rhinitis, it is not surprising that treatment of rhinitis with anti-IgE attenuated both nasal and cutaneous responses to allergen challenge.
To examine the effect of neutralizing IgE on allergic airway responses, the effects of treatment with rhuMAb-E25 was assessed in a series of randomized, double blind placebo controlled trials in moderate to severe allergic asthmatics. Treatment with rhuMAb-E25 caused an average reduction in free serum IgE levels of greater than 90% of baseline values. This reduction in IgE correlated with a significant decrease in both symptom scores and steroid use in these patients.
Anti-IgE antibodies permit interruption of the allergic cascade at an early and central level by efficiently and selectively blocking IgE effector functions mediated by Fc>eRI. Preclinical animal studies and clinical trials in patients with allergic rhinitis and allergic asthma revealed that selective neutralization and inhibition of IgE is associated with inhibition of IgE mediated allergic reactions. These findings establish the involvement of IgE in the pathophysiology of rhinitis and asthma and suggest E25 is a novel treatment for these diseases.