The overall goal of this SBIR Phase II application is to develop and set for commercialization a next generation biologic for the treatment of allergic disease. This therapeutic, a low affinity anti-IgE monoclonal antibody targets surface-bound IgE on allergic effector cells and functionally blocks allergic reactivity by a novel mechanism(s). Allergic disorders have increased to the point where they are now a major worldwide public health issue and particularly so in developed countries such as the US. Novel effective treatment options for allergies remain a major unmet need; no effective therapy is available for severe food allergies such as peanut allergy and no new platforms for inhalant allergy have been licensed since Xolair(r)-based anti-IgE therapy in 2003. Herein we propose a new approach whereby a low affinity anti-IgE mAb, p6.2, blocks allergic reactivity. The rationale behind this therapeutic approach is based on results from the Phase I project that showed that p6.2 binding to IgE bound to FceRI on allergic effector cells drives rapid down-regulation of FceRI expression and loss of allergic reactivity. By binding with low affinity to a conformational epitope of IgE, p6.2 induces non- allergic piecemeal degranulation while failing to trigger anaphylactic degranulation. Additionally, p6.2 bound to circulating IgE remains active, functioning as a drug reservoir rather than a pathway for drug removal. The objectives of this application are to produce a genetically engineered humanized version of murine p6.2, better understand the mechanisms of its therapeutic effect to enhance drug development, design/select a limited number of final clinical candidates, and move these into development (established cell lines, purification methods and potency assays) for future IND enabling studies.
In Aim 1, we will identify the final clinical candidates from the humanized p6.2 mAb variants. This will be accomplished by determining the allergic therapeutic index (ratio of inhibition to potential release) for the humanized p6.2 variants and identifying those with the best index. The therapeutic index will be determined using our established models of basophil activation, passive cutaneous anaphylaxis, and murine systemic anaphylaxis.
In Aim 2, we will further explore the mechanisms by which humanized p6.2 mediates its anti-allergic therapeutic effects. Better understanding of the basis for p6.2s novel therapeutic effects will position us to use rational drug design to develop future improved/second generation therapeutics.
In Aim 3, we will establish stable research CHO cell banks from several optimal humanized p6.2 mAb clones defined in Aim 1. The antibodies produced from these cell lines will be used in future pre-IND studies (e.g. toxicology, manufacturing), that will define the final clinical candidate for Master Cell Bank production. We will simultaneously develop a panel of potency bioassays for analysis of the drug's efficacy and safety profile.
This aim will put us squarely on the road to commercialization.
Targeting surface-bound IgE as a novel allergy therapeutic Allergic diseases involving both inhalants and foods have significantly increased in both prevalence and incidence over the past decades in the United States and other developed countries and now have become a major worldwide public health issue. The goal of this project is to develop and ultimately commercialize a novel allergy biologic therapeutic for the effective prevention/treatment of severe allergic reactivity such as allergic asthma and food allergy. A therapy as is proposed is urgently needed and would be highly important for the public health.
