MONOCLONAL ANTIBODIES:
A NEW TREATMENT FOR SEVERE
ALLERGIC ASTHMA

DENVER--Patients with moderate to severe allergic asthma may soon be able to reduce symptoms and exacerbations, improve quality of life, and possibly decrease the need for corticosteroids. According to a new study published in the New England Journal of Medicine,[1] an investigational anti-IgE (immunoglobulin E) monoclonal antibody called rhuMAb-E25 holds promise as a treatment for patients with allergic asthma.

Researchers have long known that IgE is an essential factor in allergic diseases; it binds to mast cells and basophils, a significant step in the pathogenesis of asthma. IgE ultimately triggers the release of histamines, prostaglandins, and leukotrienes, which produce airway inflammation and obstruction. Anti-IgE therapy is designed to block IgE at the beginning of its cascade.

OF MICE AND MEN

The anti-IgE molecule itself is interesting: rhuMAb-E25 is a recombinant humanized monoclonal antibody developed by immunizing mice with human IgE. According to the researchers, led by Henry Milgrom, MD, who is a pediatric asthma specialist at the National Jewish Medical and Research Center in Denver, "A monoclonal antibody was selected that recognizes IgE at the same site as the high-affinity receptor for IgE (Fc[epsilon]RI). For clinical use, the amino acid residues of the variable immunoglobulin region of mouse origin implicated in binding to IgE were grafted onto the constant region of human IgG1, resulting in an immunoglobulin protein that is more than 95% human." The antibody forms complexes with IgE, thereby preventing it from binding with cell-membrane receptors. Thus, the "allergy cascade" is (theoretically) short-circuited.

The researchers randomized 317 patients into one of three groups: placebo, high-dose rhuMAb-E25 (5.8 µg/kg body weight per nanogram of IgE per milliliter), or low-dose rhuMAb-E25 (2.5 µg/kg per nanogram of IgE per milliliter). The drug (or placebo) was given intravenously on days 0 (half dose), 4 (half dose), and 7 (full dose), and then once every two weeks for 20 weeks. Subjects were between age 11 and 50 years; all were taking oral and/or inhaled corticosteroids for moderate to severe persistent allergic asthma. There were 106 subjects in the high-dose group, 106 subjects in the low-dose group, and 105 in the placebo cohort.

In addition, all patients received care in accordance with international recommendations for the optimum treatment of asthma. Thus, all three groups experienced symptomatic improvement, but the extent of the improvement was significantly greater in the patients given rhuMAb-E25.

LABORATORY RESULTS

In the two groups given rhuMAb-E25, serum concentrations of free IgE dropped rapidly and immediately. Within one hour after the first dose, serum free IgE concentrations fell from a mean of 1,000 ng/mL to 7.3 ng/mL in the high-dose group and from 1,060 ng/mL to 13.9 ng/mL in the low-dose group. By the end of the 20-week study period, serum free IgE concentrations averaged 10.2 ng/mL in the high-dose group and 18.0 ng/mL in the low-dose group; the mean decrease was 97.1% and 95.5%, respectively.

Although serum levels of free IgE decreased, total serum IgE concentrations (which include both free IgE and small complexes) increased over time in both of the rhuMAb-E25 groups. The researchers found that the complexes were easily disposed of--cleared by low-avidity interaction with Fc[gamma] receptors of leukocytes and the reticuloendothelial system. "[T]he immune complexes formed by the interaction of rhuMAb-E25 with IgE appear to be removed by the reticuloendothelial system, with no evidence of damage to the kidney or other organs or tissues," wrote Peter J. Barnes, DM, DSc, FRCP, of the National Heart and Lung Institute, London, United Kingdom, in an editorial accompanying the paper by Milgrom et al.[2]

CLINICAL OUTCOMES

At baseline, the mean asthma symptom score for all patients was 4.0, indicating that patients were experiencing a "good deal" of symptoms. After 12 weeks' treatment, the mean symptom score was 3.1 in the placebo cohort, 2.8 in the high-dose group, and 2.8 in the low-dose group. The differences in the scores between the placebo and active-treatment groups were highly statistically significant (P = .008 for the high-dose group and P = .005 for the low-dose group).

Quality of life (as measured by questionnaire) revealed significant improvement for all three groups; but again, the extent of the improvement was greater in the two groups given rhuMAb-E25. The mean increases in the quality-of-life score were 1.4 in the high-dose group, 1.2 in the low-dose group, and 0.8 in the placebo cohort. The differences between the two groups given active treatment and the placebo cohort were also highly significant (P < .001 and P = .007, respectively). The rhuMAb-E25 groups also experienced fewer asthma exacerbations than did the placebo group.

The monoclonal antibody appeared to reduce the need for corticosteroids. Among the 35 patients who had needed oral corticosteroids at baseline, three (33%) of the nine in the high-dose group and six (43%) of the 14 in the low-dose group were able to discontinue use of the oral medications, compared with only two (17%) of the 12 taking placebo. Additionally, among the 282 patients who used inhaled corticosteroids, 17 (18%) of the 97 patients in the high-dose group and 21 (23%) of 92 patients in the low-dose group were able to discontinue use of those agents, compared with only 11 (12%) of the 93 patients taking placebo. Most of these differences did not reach statistical significance, however, the study authors pointed out.

"This completely new approach to therapy [rhuMAb-E25] may greatly improve the treatment outlook for people with allergic asthma," Dr. Milgrom said. Of special significance is the antibody's ability to attenuate not only early-phase reactions to inhaled allergens, but also late-phase reactions. It is the latter set of reactions that has been associated with bronchial inflammation and subsequent bronchoconstriction. If the antibody can inhibit the late-phase reaction, the result should be a beneficial effect upon asthma pathogenesis.

In addition, anti-IgE antibody may have a role in the treatment of other atopic diseases, including allergic rhinitis and atopic dermatitis, suggested Dr. Milgrom. It is important to note, however, that rhuMAb-E25 is still investigational. The Milgrom paper recorded results from a phase 2 clinical trial; the drug is now reportedly at the end of phase 3 clinical development. Moreover, when and if the drug is approved, "it is likely to be very expensive," Dr. Barnes noted.

--Robert McCarthy

References
1. Milgrom H, Fick RB Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med. 1999;341:1966-1973.
2. Barnes PJ. Anti-IgE antibody therapy for asthma. N Engl J Med. 1999;341:2006-2008.

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