Up to 30% of the US population are now affected by nasal allergy, resulting in a total (direct and indirect) cost of approximately $14.6 billion per year. Seasonal allergic rhinitis (AR), due to exposure to airborne pollen and molds is a major component of this problem in the US and worldwide. The limitations of current pharmaceutical and specific immunotherapy for AR include their side-effects and the time, effort and cost associated with their use. The goal of this Phase I project is to explore an entirely new paradigm for preventing seasonal AR, employing an antibody-based, nasal prophylactic to be used only when patients know they will be exposed to large quantities of specific allergens. This project builds upon our NIAID-funded experimental model system of mountain cedar allergy. Using this model, we discovered that ~90% of patients'IgE against mountain cedar pollen binds to conformational epitopes of a single allergen Jun a 1 and that a unique monoclonal antibody (E58) causes extensive loss of these conformation epitopes on Jun a 1. Further, the binding of E58 extensively reduces of the release of allergic mediators from mast cells sensitized with human IgE and challenged with Jun a 1. We have therefore developed a multidisciplinary, academic-corporate team of clinical and basic investigators with expertise to determine the feasibility of developing E58 as a novel therapeutic to benefit seasonal pollinosis sufferers. This project is within an NIAID STTR Area of Interest. The goal of this Phase 1 Project is to determine whether nasal instillation of bioengineered, recombinant E58 (rE58) will prevent the acute nasal airway obstruction and other signs of allergic inflammation.
The Specific Aims are to: 1) Complete the optimization of a recombinant E58 antibody (rE58) for enhanced avidity and expression level and down-modulatory activity on Jun a1 reactivity and express rE58 as a univalent, partially humanized antibody. 2) Test in our mouse model of cedar pollinosis the efficacy of intranasal instillations of varying doses of rE58 antibody in preventing or substantially reducing the allergic response to subsequent nasal exposure of mountain cedar pollen. Positive Phase I results will provide """"""""proof of concept"""""""" that nasal instillation of optimized antibodies can provide an effective """"""""barrier"""""""" between an inhaled allergen and patient's IgE antibodies in the nasal mucosa. Further, these results will lay the ground work for Phase II studies, in which we will;a) produce and test potential commercial formulations and methods of delivery of rE58 antibody to optimize rapid onset and prolonged duration of the effect;b) validate efficacy and safety studies in GLP compliant facilities;and c) initiate FDA discussions and submission of an IND application to initiate clinical trials. The ultimate success of this product may lead to similar anti-allergen based therapeutics for other causes of seasonal AR.
Allergic rhinitis (AR) has become one of the most common chronic diseases in industrialized countries, yet despite the billions of dollars spent each year on therapeutics, many symptoms are not fully relieved. We have discovered that a specific monoclonal antibody rE58 reduces allergen-IgE interactions and propose that instillation of this antibody to the nasal mucosa may prevent seasonal pollinosis-induced AR. This project will test the feasibility of this new paradigm for treating seasonal nasal allergy and if successful may lead to a new class of anti-allergy antibody drugs.
|Goldblum, Randall M; Ning, Bo; Judy, Barbara M et al. (2016) A single mouse monoclonal antibody, E58 modulates multiple IgE epitopes on group 1 cedar pollen allergens. Mol Immunol 74:106-12|
|Goldblum, Randall M; Ning, Bo; Endsley, Mark A et al. (2014) IgE antibodies to mountain cedar pollen predominantly recognize multiple conformational epitopes on Jun a 1. J Allergy Clin Immunol 134:967-9.e7|