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

抑制 IgE 的小分子化合物黄紫嘌呤类似物，用于治疗多种食物过敏

• 批准号: 10761370
• 负责人: Xiu-Min Li
• 金额: $ 28.96万
• 依托单位: GENERAL NUTRACEUTICAL TECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761370
• 关键词: Abbreviations; Accidents; Adult; Affect; Allergy to peanuts; American; Anaphylaxis; Anthraquinones; Antibodies; Applications Grants; Area Under Curve; B-Lymphocytes; Biochemistry; Biological Availability; Biotechnology; Body Surface Area; C3H/HeJ Mouse; Cashew nut; Categories; Chemicals; Chronic; DNA Methylation; Data; Dose; Ensure; Exhibits; FDA approved; Feedback; Fishes; Food; Food Hypersensitivity; Genetic Transcription; Goals; Health; Histamine; Histology; Hypersensitivity; IgE; Immunoglobulin A; Immunoglobulin G; Immunosuppression; In Vitro; Inflammation; Interferon Type II; Interleukin-10; Interleukin-4; Life; Marketing; Measures; Mediating; Medicine; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Names; Normal Range; Nut Hypersensitivity; Nutraceutical; Nuts; Oral; Outcome; Pharmaceutical Preparations; Phase; Plants; Plasma; Production; Proteins; Rattus; Reaction; Regulation; Regulator Genes; Research; Rubia cordifolia; Safety; Schedule; Serum; Shellfish; Shrimp; Small Business Technology Transfer Research; Source; Symptoms; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toxicology; Trees; analog; anti-IgE; commercialization; cost; cross reactivity; cytokine; feeding; food avoidance; immunoreaction; inhibitor; manufacture; medical schools; mortality; mouse model; natural hypothermia; novel; omalizumab; oral immunotherapy; phase 1 designs; phase I trial; preclinical efficacy; preclinical safety; promoter; safety outcomes; shellfish hypersensitivity; small molecule; transcription factor; transcriptomics

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.

食物过敏（FA）是一种潜在的危及生命的疾病，20年来迅速增加，影响32 每年花费250亿美元。治疗选择非常有限。食物回避 和意外暴露后的补救药物是FA管理的主要内容。花生过敏（PNA） 严重的反应，通常与树坚果过敏（TNA）共存。贝类过敏（ShA）是导致 成人过敏反应多种食物过敏和交叉反应之间的食物组，如树坚果和 贝类进一步使避免进食复杂化。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）。无法抑制持续的食物sIgE是FA的一个重要障碍 治疗学因此，非食物限制治疗对“所有”FA都有效，包括多重和重度FA， 逆转sIgE升高的能力将缩小治疗差距，并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 Nutraceutical Technology LLC（GNT）正在建立 开创性的FA研究始于西奈山伊坎医学院。我们第一次分离出 并从茜草中鉴定出IgE抑制化合物黄紫嘌呤（XPP，一种小分子蒽醌） 心叶我们的初步数据表明，XPP具有良好的生物利用度， 临床前安全性特征（10倍日剂量下无AE）。引人注目的是，为期4周的每日一次口服低剂量XPP （0.4mg /小鼠，相当于基于体表面积的成人剂量0.1g/天44）诱导100% 抑制过敏反应，使血清花生（PN）-sIgE和血浆组胺水平降低80-100%， PNA的鼠模型，没有IgG或伊加的总体免疫抑制。初步机制 作用（MOA）包括XPP抑制IgE+ B细胞，通过增加IL-4上的DNA甲基化来减少IL-4， 启动子，而不影响IL-10或IFN-γ，并诱导不同的B细胞转录组学谱。确保 医药采购的可持续性和环境保护，我们通过产生 合成XPP（sXPP）及其类似物。我们发现其中一种类似物（命名为XPP 1a）是一种上级IgE 抑制剂，并显示出优异的体外安全性。因此，为FA开发XPP 1a产品将是 这是STTR第一阶段拨款申请的重点。我们假设XPPIa对PNA和其他 如TNA和ShA，以及严重的FA。因此，这一为期一年的第一阶段STTR申请的目标是 生成XPP 1a疗效、安全性和PK特征的可行性，并探索/验证常规治疗中的MOA 和人源化FA模型。我们将追求2个具体目标：目标1：确定XPP 1a对IgE的保护作用- 在FA的常规和人源化鼠模型中介导的过敏反应;目的#2。确定XPPIa安全性 和PK图谱。本项目完成后，将进入下一阶段研究（II期STTR）进行IND申报 将XPP 1a商业化以治疗多发性和重度FA。