Immunoglobulin E: Allergy’s Antibody, Therapy’s Target

BOSTON – In the last three decades allergy has gone from a discipline based on poorly defined principles to an immunological disease as described by Bob Q. Lanier, M.D., Fort Worth, Texas, moderator of the session titled ‘Affecting the Antibody’ presented at the 62nd Annual Meeting of the American College of Allergy, Asthma and Immunology (ACAAI).

The session included two pioneers in the field of allergy, the discoverer of the Immunoglobulin E (IgE) antibody, S.G.O. Johannson, M.D, Ph.D., of the Karolinska Institute in Stockholm, Sweden, and the man who saw the value in inhibiting the antibody to treat severe allergies, Tse Wen Chang, Ph.D., of Tsing Hua University, in Hsinchu, Taiwan.

Immunoglobulin E was unknown to researchers before Dr. Johannson defined a fifth immunoglobulin class in the late 1960s. His discovery explained the nature of reagins fifty years after M.A. Ramirez documented their existence in 1919. Ramirez noticed that a patient he was treating for aplastic anemia developed asthma following a horse carriage ride a few days after receiving a transfusion. The blood donor had suffered from asthma due to horse allergy. During the session, Johannson introduced a new nomenclature system (www.eaaci.org/taskforce) recently put in place to augment further research in the field of allergy.

Over the course of the past 17 years, IgE’s role in the manifestation of allergic systems has had to overcome skepticism to become one of the fruits of rational drug discovery. The development of an anti-IgE therapy is largely due to Dr. Chang’s research. Allergic reactions, allergic asthma, rhinoconjuctivitis and gastrointestinal allergy are all primarily mediated by IgE antibodies produced in response to external allergens – a fact that was not widely accepted when Dr. Chang first started publishing research papers on the topic.

IgE triggers immune system cells known as mast cells and basophils. These cells initiate an inflammatory reaction. The inflammatory reaction leads to symptoms that affect 20 to 40 million allergy sufferers in America. The rationale for specifically targeting IgE is based on its being unique to the IgE-mediated allergic pathway. Such an approach is independent of allergens and early in the allergic pathway, and it seems to be dispensable.

Omalizumab, a therapeutic anti-IgE antibody, was approved by the Food and Drug Administration in 2003 for patients who are age 12 and older, who have moderate-to-severe allergic asthma – asthma triggered by allergic reactions to inhaled allergens such as dust mites, pollens, pet dander and mold. Since approval, more than 5,000 physicians have written prescription for 30,000 patients. The therapy is also currently involved in 15 clinical trials, including one for peanut allergies.

The clinical development of an anti-IgE antibody opens up a new direction of therapeutic innovation for allergic diseases. Although pharmacologic agents are often effective for many patients because they treat the symptoms and not the root cause, relief is often not complete.

According to Thomas Casale, M.D., of Creighton University in Omaha, Neb., current therapies for allergic rhinitis include allergen avoidance, pharmacological interventions such as anti-histamines, sympathomimetics, topical and systemic corticosteroids, chromones and immunotherapy. Although pharmacologic agents are often effective for many patients, their role is sometimes limited by their inability to completely relieve symptoms and in some cases induce deleterious effects.

Immunotherapy regimens can be highly effective in controlling symptoms of allergic rhinitis and can offer advantages over pharmacotherapy for patients refractory to medication or those who cannot tolerate the side effects. Ironically, immunotherapy is associated with a risk of allergic reaction to the extract injections.

Dr, Casale explained the need for safer and more effective therapies capable of inducing an immune tolerant state and the promise of the combination of anti-IgE and allergen immunotherapy in fulfilling this unmet clinical need. He presented results of a NIH/Immune Tolerance Network sponsored study examining the effects of pre-treatment of ragweed allergic rhinitis patients with omalizumab prior to immunotherapy.

The study included 159 patient randomised to receive omalizumab or placebo for nine weeks. This was followed by a five-hour rush or placebo immunotherapy day. Rush immunotherapy is a rapid take on conventional immunotherapy or allergy shots designed to desensitize people to allergens. Normally, the allergy shots take four to six months for a patient to build up to a maintenance dose, which is a dose at which they will begin to show clinical benefits. The shots are usually given once a week, with each dose increased for the patient to build up a tolerance over time. With rush immunotherapy, the process is sped up, so a patient can receive a full maintenance dose of shots in one day. After nine weeks of therapy with omalizumab or placebo, patients received omalizumab or placebo with rush immunotherapy or placebo immunotherapy for twelve weeks.

Preliminary analysis of the data indicated the average daily allergy severity scores were significantly better for patients receiving omalizumab plus immunotherapy versus immunotherapy alone. Omalizumab also had a protective effect on allergic type reactions. This effect was manifested by a reduction in serious adverse events, anaphylactic reactions and the use of epinephrine and prednisone to treat reactions. Patients are being followed over a second ragweed season off immunotherapy and omalizumab to determine whether there are long-lasting effects of the therapy.

The ACAAI is a professional medical organization, headquartered in Arlington Heights, Ill., comprising nearly 5,000 qualified allergists-immunologists and related health care professionals. The College is dedicated to the clinical practice of allergy, asthma and immunology through education and research to promote the highest quality of patient care.