IgE-suppressing small molecule compound Xanthopurpurin analog for multiple food allergies

General Nutraceutical Technology, Llc, Briarcliff Manor NY

Investigators

Abstract

Food allergy (FA), a potentially life-threatening condition, has rapidly increased for 2 decades, affecting 32 million Americans with annual costs of $25 billion. Treatment options are extremely limited. Food avoidance and rescue medication after accidental exposure are primary to FA management. Peanut allergy (PNA) causes severe reactions, often co-existing with tree nut allergies (TNA). Shellfish allergy (ShA) is the main cause of adult anaphylaxis. Multiple food allergies and cross-reactivity among groups of foods such as tree nuts and shellfish further complicate food avoidance. FA is primarily mediated by abnormally elevated food protein- specific immunoglobulin E (sIgE). The inability to curb persistent food sIgE is a significant barrier to FA therapeutics. Thus, a non-food restricted treatment working for “all” FA including multiple and severe FAs, with the ability to reverse elevated sIgE, will narrow treatment gaps and have significant market value. General Nutraceutical Technology LLC (GNT), a NY-based biotechnology startup, is building on groundbreaking FA research started at Icahn School of Medicine at Mount Sinai. We for the first time isolated and identified IgE inhibitory compound xanthopurpurin (XPP, a small molecule anthraquinone) from Rubia Cordifolia. Our preliminary data show that XPP exhibits favorable bioavailability and is stable with a high preclinical safety profile (no AEs at 10X daily dose). Strikingly, a 4-week once-a-day oral low dose of XPP (0.4mg /mouse, equivalent to a human adult dose of 0.1g/day based on body surface area44) induced 100% suppression of anaphylaxis, 80-100% of reduction of serum peanut (PN)-sIgE and plasma histamine levels in a murine model of PNA, with no overall immune suppression of IgG or IgA. The preliminary mechanisms of action (MOA) include XPP suppressing IgE+ B cells, reducing IL-4 by increased DNA methylation at IL-4 promoter, without affecting IL-10 or IFN-γ, and inducing a distinct B cell transcriptomic profile. To ensure medicinal sourcing sustainability and environmental conservation, we advanced XPP production by generating synthetic XPP (sXPP) and its analogs. We found that one of the analogs (named XPP1a) is a superior IgE inhibitor and showed excellent in vitro safety. Therefore, developing an XPP1a product for FA will be the focus of this STTR phase I grant application. We hypothesize XPPIa will be effective for PNA and for other FAs such as TNA and ShA, and for severe FAs. Thus, the goal of this 1-year phase I STTR application is to generate the feasibility of XPP1a efficacy, safety, and PK profile and explore/validate the MOA in conventional and humanized FA models. We will pursue 2 Specific Aims: Aim # 1: Determine XPP1a protection against IgE- mediated anaphylaxis in conventional and humanized murine models of FA; Aim #2. Determine XPPIa safety and PK profiles. Completion of this project will lead to the next phase study (Phase II STTR) for IND filing towards commercialization of XPP1a to treat multiple and severe FA.