Anti-IgE Monoclonal Antibodies - Drugs in the Treatment of Asthma

OTHER DRUGS IN THE TREATMENT OF ASTHMA

Anti-IgE Monoclonal Antibodies

An entirely new approach to the treatment of asthma exploits advances in molecular biology to target IgE antibody. From a col-lection of monoclonal antibodies raised in mice against IgE anti-body itself, a monoclonal antibody was selected that is targeted against the portion of IgE that binds to its receptors (FCε-R1 and FCε-R2 receptors) on mast cells and other inflammatory cells. Omalizumab (an anti-IgE monoclonal antibody) inhibits thebinding of IgE to mast cells but does not activate IgE already bound to these cells and thus does not provoke mast cell degranu-lation. The murine antibody has been genetically humanized by replacing all but a small fraction of its amino acids with those found in human proteins, and it does not appear to cause sensiti-zation when given to human subjects.

Administration of omalizumab to asthmatic patients for 10 weeks lowers plasma IgE to undetectable levels and significantly reduces the magnitude of both early and late bronchospastic responses to antigen challenge. Repeated administration lessens asthma severity and reduces the corticosteroid requirement in patients with moderate to severe disease, especially those with a clear environmental antigen precipitating factor, and improves nasal and conjunctival symptoms in patients with perennial or seasonal allergic rhinitis. Omalizumab’s most important effect is reduction of the frequency and severity of asthma exacerbations, even while enabling a reduction in corticosteroid requirements. Combined analysis of several clinical trials has shown that the patients most likely to respond are, fortunately, those with the greatest need: those with a history of repeated exacerbations, a high requirement for corticosteroid treatment, and poor pulmo-nary function. Similarly, the exacerbations most prevented are the ones most important to prevent: Omalizumab treatment reduced exacerbations requiring hospitalization by 88%. These benefits justify the high cost of this treatment in selected individuals with severe disease characterized by frequent exacerbations.

POSSIBLE FUTURE THERAPIES

The rapid advance in the scientific description of the immuno-pathogenesis of asthma has spurred the development of many new therapies targeting different sites in the immune cascade. These include monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13), antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lym-phocytes from the TH2 to the TH1 phenotype or at selective inhibi-tion of the subset of TH2 lymphocytes directed against particular antigens. There is evidence that asthma may be aggravated—or even caused—by chronic airway infection with Chlamydia pneu-moniae or Mycoplasma pneumoniae. This may explain the reportsof benefit to some patients from treatment with macrolide antibi-otics, but a recent trial of prolonged treatment with clarithromy-cin (500 mg twice daily for weeks) failed to improve asthma control in patients with moderately severe asthma.