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World Allergy Organization
WAO's mission: To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

Novel Approaches to Food Allergy

3.5-Novel Approaches to Food Allergy: Treatment of Food Allergy

Hugh A. Sampson, M.D.
Prof. of Pediatrics & Immunobiology
Mount Sinai School of Medicine
New York, NY

Food allergy is a major problem in westernized countries, e.g, it affects about 3.5% of the U.S. population, and is the leading single cause of anaphylaxis treated in hospital emergency departments in many "westernized" countries. The "standard of care" for food allergy consists of educating patients and caregivers how to avoid food allergens and arming them with medications to treat accidental ingestions. Food allergic patients with asthma or a history of a previous severe reaction or a reaction to peanuts, nuts, seeds or seafood should be given self-injectable epinephrine in addition to a written emergency plan for treatment of an accidental ingestion. However, given the continued high rate of severe food allergic reactions, it is clear that the current "standard of care" is inadequate. An attempt to "desensitize" peanut-allergic patients utilizing a traditional "desensitization" protocol demonstrated a limited rate of response and a high rate of adverse reactions, leading most investigators to conclude that alternative immunotherapeutic approaches are necessary for this potentially fatal allergy.

Three of seven novel immunotherapeutic approaches being investigated as treatment modalities for food allergy will be reviewed: (1) humanized anti-IgE monoclonal antibody therapy, (2) "engineered" [mutated] allergen protein immunotherapy, (3) a Chinese herbal medication, (4) plasmid DNA-based immunotherapy, (5) antigen-immunostimulatory sequence [ISS]-modulated immunotherapy, (6) peptide immunotherapy, and (7) an Fcγ-antigen chimeric fusion protein vaccine.

1) Anti-IgE Therapy: Two humanized, recombinant monoclonal anti-IgE antibody preparations were available for clinical trials in food allergic patients, HU-901 [Tanox Inc, Houston, TX] and omalizumab [Genentec/Novartis/Tanox]. Both bind to the third domain of the Fc region of IgE molecules, thus preventing the molecule from binding to FcεRIs. A phase I/II double-blind placebo-controlled trial of HU-901 in 82 peanut allergic patients, compared monthly injections of placebo, 150, 300, and 450 mg of HU-901. The median sensitivity threshold obtained in the 450 mg HU-901 dose group, 2,805 mg, is equivalent to approximately 8 peanuts and is likely to provide protection from accidental ingestions in most patients. Currently a similar Phase II multi-center clinical trial is underway to evaluate the efficacy of omalizumab in treating peanut-allergic patients.

2) "Engineered" [mutated] Allergen Protein Immunotherapy: The immunodominant epitopes of the three major peanut proteins, Ara h1-3, were altered by a single amino acid substitution, which dramatically reduced IgE binding to individual epitopes and left T-cell epitopes intact. In vivo efficacy of the engineered recombinant proteins were tested in the murine model of peanut anaphylaxis, which demonstrated suppressed synthesis of Ara h2-IgE and significantly decreased symptoms following oral peanut challenge compared to a sham-treated group. In order to potentiate the immuno-modulatory effect and increase efficacy of modified peanut vaccines, heat-killed E coli (HKE) producing mutated proteins Ara h1, 2 and 3 (HKE-MP123) were administered rectally (pr) in a murine model of peanut anaphylaxis. HKE-MP123-treated mice remained protected for up to 10 weeks post-therapy. IgE levels were significantly lower in all HKE-MP123-treated groups (P <0.001), and in vitro IL-4, IL-13, IL-5 and IL-10 production by peanut-stimulated splenocytes of high-dose HKE-MP123-treated mice were significantly decreased and IFN-γ and TGF-β production were significantly increased compared with sham-treated mice at the time of the last challenge. An IND is being filed with the FDA to begin clinical trials.

3) Traditional Chinese Medicine: Traditional Chinese Medicine (TCM) is based on herbal remedies, which have been used successfully in Asia for centuries for treatment of diverse diseases, including asthma and environmental allergies. A 9-herb formulation, FAHF-2, was developed and tested in peanut-allergic mice. It prevented allergic reactions following peanut challenge and induced significantly reduced peanut-specific IgE for up to 24 weeks post-therapy. Splenocytes from FAHF-2-treated mice showed significantly reduced IL-4, IL-5 and IL-13 production and enhanced IFN- g production to recall peanut-stimulation in vitro. An IND is being submitted to investigate FAHF-2 in a Phase I/II clinical trial to determine whether it will be effective and safe for treating peanut-allergic patients.

 

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