Immune-Based, Targeted Therapy for Allergic Diseases

Allergic rhinitis is an inflammatory disorder characterized by upper airway symptoms, including nasal congestion, rhinorrhea, sneezing, and itching of the palate, and, in some patients, by conjunctivitis, otitis media with effusion, sinusitis, or asthma.¹ The prevalence of allergic rhinitis, a common disease that affects approximately 9% to 22% of the US population,^{2 - 3} has increased substantially in the past 20 years.⁴ Symptoms of seasonal allergic rhinitis recur at times of the year corresponding to the appearance of airborne allergens such as pollens and mold spores. Some patients are symptomatic only during the pollen season while many others are allergic to multiple allergens or have a nonallergic component to their rhinitis so that they are symptomatic through much of the year.

One of the common causes of allergic rhinitis in the United States is ragweed.^{5 - 6} Ragweed is found east of the Rocky Mountains and typically produces pollen in August and September. Allergens—antigens that induce allergic responses—are released from ragweed pollen grains that reach the mucosa of the upper airways. Ragweed allergic rhinitis occurs only in individuals who are predisposed to produce IgE antibody in response to these allergens. Immunoglobulin E antibody production is the proximate cause of allergic rhinitis. The tendency to make IgE typically correlates with a family history of allergic diseases.⁷ The IgE antibody circulates and binds to high-affinity IgE receptors on mast cells and basophils. Once IgE antibody is bound to receptors on these cells, allergen cross-links bound antibody, initiating secretion of allergic inflammatory mediators, including histamine, leukotrienes, and cytokines. These mediators then induce both the acute and chronic inflammatory changes that result in symptoms of allergy.⁸

Allergic rhinitis is considered a minor illness by some patients and physicians, and individuals with mild disease often obtain adequate symptom relief with over-the-counter antihistamines. However, allergic rhinitis is associated with serious morbidity for many other patients.^{9 - 10} Even those with mild disease may lose days from work or school and have reduced productivity and quality of life.¹¹ Patients with moderate or severe disease usually require anti-inflammatory medications to control symptoms. Moreover, allergic rhinitis is a risk factor for the exacerbation of, and perhaps the development of, both chronic sinusitis and asthma.¹²

Many therapies are approved for the treatment of allergic rhinitis.^{1 ,10 ,13} One expert panel¹³ recommends using either oral antihistamines (with or without decongestants) or intranasal corticosteroids as the first line of therapy for moderate allergic rhinitis, and intranasal corticosteroids as the preferred therapy for severe rhinitis. Patients with severe symptoms may require a short course of oral corticosteroids followed by intranasal corticosteroids. Intranasal sodium cromoglycate is valuable in some patients, particularly when initiated before seasonal pollen exposure.¹³ Allergen-specific immunotherapy is also effective in many patients with seasonal allergic rhinitis.¹³

In this issue of THE JOURNAL, Casale et al¹⁴ report the results of a randomized trial evaluating a novel therapy for ragweed-induced seasonal allergic rhinitis, omalizumab (formerly called rhuMAb-E25), a humanized monoclonal anti–human IgE antibody. Omalizumab is molecularly engineered to possess a number of therapeutically useful features. It binds specifically to that region of the IgE molecule that binds to the IgE receptor on mast cells or basophils. Because omalizumab cannot bind to IgE molecules that are already bound to surface receptors on mast cells and basophils, it does not stimulate secretion of mediators from these cells. Omalizumab was originally derived from mouse B lymphocytes but has been humanized so that nearly the entire molecule, except for the IgE-binding regions, expresses human amino acid sequences. It does not appear to stimulate an immune response against itself.¹⁵

The actions of omalizumab are mediated by 2 effects on IgE pathways. First, it can bind more than 95% of free serum IgE when administered at an appropriate dose. Second, the decrease in free serum IgE induces a rapid and marked (>90%) reduction in IgE receptors on basophils and mast cells.¹⁶ The combined effects of reduction of both free IgE and IgE receptor numbers result in a substantial decrease in allergen-stimulated mediator release from inflammatory cells.¹⁶

The study by Casale et al demonstrates that omalizumab reduces the symptoms of allergic rhinitis during the ragweed allergy season. Among patients who received the highest dose of omalizumab, treatment was particularly effective in that nasal symptom severity scores did not increase above baseline during the pollen season. These results are strong evidence that IgE is central to the pathogenesis of allergic rhinitis. Indeed, omalizumab is a powerful tool for analyzing the role of IgE in other diseases. The function of IgE in asthma has been controversial, but recent studies have demonstrated that omalizumab reduces asthma symptoms in patients with moderate and severe allergic asthma, establishing the importance of IgE pathways in asthma.^{17 - 19}

Omalizumab is 1 of the first monoclonal antibodies to be used chronically and for a non–life-threatening disease. New immunologic treatments may be most beneficial when doses are adjusted in individual patients based on markers of their biological effect. Biomarkers may be used to follow the course of disease or the effects of certain treatments and may have important clinical value.²⁰ Patients in the study by Casale et al whose dosage of omalizumab resulted in the lowest levels of free IgE had the fewest symptoms. It is likely that biomarkers will facilitate less expensive and safer use of new agents rather than simply using the highest dose.

To establish the position of omalizumab among treatments of allergic rhinitis, it will be important to compare its efficacy with that of other therapies, as well as their relative costs (unknown at present for omalizumab) and their routes of administration (subcutaneous for omalizumab). The short- and long-term safety profile of omalizumab, including the effects of intermittent therapy, also must be investigated further.

Recent studies suggest that some treatments of allergic rhinitis may have a beneficial effect that has not been widely appreciated—prevention of asthma onset. Preliminary data from an ongoing European study indicate that a high proportion of children aged 6 to 14 years with allergic rhinitis will develop asthma within 2 to 5 years and that treating allergic rhinitis with 3 years of allergen-specific immunotherapy will substantially reduce the development of asthma.²¹ These results extend those of an earlier study.²² If additional data confirm that immunotherapy for allergic rhinitis decreases the incidence of new-onset asthma, then an important new criterion will be added to the evaluation of the efficacy of rhinitis therapy. It will be important for future research to evaluate whether omalizumab blocks the onset of asthma.

Omalizumab is the first of several new, immune-based, specifically targeted molecules that may change the face of allergy and asthma therapy. Other sets of agents that are currently undergoing evaluation are DNA-based therapeutics, including immunostimulatory sequences of DNA containing CpG motifs, either alone or conjugated to allergen.^{23 - 25} Such molecules block IgE antibody production in mice and are being tested for comparable effects in humans. Several cytokine antagonists (such as soluble interleukin 4 [IL-4] receptor²⁶ and anti-IL-5²⁷ ) have been evaluated as anti-asthma treatments, although their clinical efficacy is uncertain. It is anticipated that, as the result of basic and clinical research studies with these and other new, immune-based agents, some of them will become first-line therapies for allergic diseases.