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

食物过敏(FA)是一种潜在威胁生命的疾病，20年来迅速增加，影响32 百万美国人，每年花费250亿美元。治疗选择极其有限。避免进食 意外暴露后的抢救药物是FA管理的主要内容。花生过敏(PNA)原因 严重的反应，通常与树坚果过敏(TNA)共存。贝类过敏(SHA)是引起 成人过敏反应。多种食物过敏和多种食物之间的交叉反应，如坚果和 贝类使避免进食变得更加复杂。FA主要由异常升高的食物蛋白质介导- 特异性免疫球蛋白E(SIgE)。无法抑制持久性食物sIgE是FA的一个重大障碍 治疗学。因此，对包括多个和严重的FA在内的所有FA有效的非食物限制治疗， 逆转升高的sIgE的能力将缩小治疗差距，具有重大的市场价值。 总部位于纽约的生物技术初创公司General Nutreutical Technology LLC(GNT)正在 突破性的FA研究始于西奈山的伊坎医学院。我们第一次被孤立 并鉴定了茜草中的IgE抑制化合物黄嘌呤(XPP，一种小分子蒽醌 紫草属。我们的初步数据表明，XPP具有良好的生物利用度，并具有较高的稳定性 临床前安全性简介(每日剂量10倍时无不良反应)。引人注目的是，一天一次、为期4周的低剂量XPP口服 (0.4 mg/只小鼠，相当于成人每天0.1g的体表面积44)诱导率为100% 抑制过敏反应，80-100%降低血清花生(PN)-sIgE和血浆组胺水平 PNA的小鼠模型，没有全面的免疫抑制免疫球蛋白或免疫球蛋白A。其作用机制初步探讨 作用(MOA)包括XPP抑制IgE+B细胞，通过增加IL-4的DNA甲基化来降低IL-4 启动子，不影响IL-10或干扰素-γ，并诱导不同的B细胞转录模式。为了确保 药品采购的可持续性和环境保护，我们通过生产 合成XPP(SXPP)及其类似物。我们发现其中一个类似物(命名为XPP1a)是一种优越的IgE 并表现出良好的体外安全性。因此，为FA开发XPP1a产品将是 这是STTR第一阶段拨款申请的重点。我们假设XPPIa将对PNA和其他 Fas，如TNA和SHA，以及严重FAs。因此，这一为期1年的第一阶段STTR应用的目标是 生成XPP1a有效性、安全性和PK配置文件的可行性，并以常规方式探索/验证MOA 和人性化的FA模特。我们将追求两个具体目标：目标1：确定XPP1a对IgE的保护- 常规和人源化FA小鼠模型的介导性过敏反应；目的2.确定XPPIa的安全性 和PK配置文件。该项目的完成将导致IND备案的下一阶段研究(第二阶段STTR) 走向商业化的XPP1a治疗多发性严重FA。

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.