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）是一种潜在的威胁生命的状况，已迅速增加了20年，影响32 百万美国人的年费用为250亿美元。治疗选择极为有限。避免食物 意外暴露后的救援药物是FA管理的主要因素。花生过敏（PNA）原因 严重的反应，通常与树坚果过敏（TNA）并存。贝类过敏（SHA）是 成人过敏反应。多种食物过敏和在树坚果等食物组之间的交叉反应性 贝类进一步避免食物复杂。 FA是由绝对升高的食物蛋白介导的。 特异性免疫球蛋白E（SIGE）。无法遏制持续食品sige是FA的重大障碍 疗法。这是针对“所有” FA工作的非食品限制治疗，包括多个和重度FA， 扭转SIGE，将缩小治疗差距并具有巨大的市场价值的能力。 一般性营养技术有限责任公司（GNT）是一家基于纽约的生物技术创业公司，正在建立 开创性的足总研究在西奈山的伊坎医学院开始。我们第一次孤立 并从rubia鉴定出IgE抑制性化合物Xanthopurin（XPP，一个小分子蒽醌） 山脉。我们的初步数据表明，XPP表现出有利的生物利用度，并且稳定很高 临床前安全性（每日10倍无AE）。令人惊讶的是，每天为期4周的口服低剂量XPP （0.4mg/鼠标，基于身体表面积44的人类成人剂量为0.1g/天）诱导100％ 过敏反应的抑制作用，降低血清花生（PN） - sige和血浆组胺水平的80-100％ PNA的鼠模型，没有IgG或IgA的总体免疫抑制。初步机制 动作（MOA）包括XPP抑制IgE+ B细胞，通过在IL-4处增加DNA甲基化来降低IL-4 启动子，不影响IL-10或IFN-γ，并诱导不同的B细胞转录组谱。确保 药用采购可持续性和环境保护，我们通过生成XPP生产来提高XPP的生产 合成XPP（SXPP）及其类似物。我们发现其中一个类似物（命名为XPP1A）是上级IgE 抑制剂并显示出极好的体外安全性。因此，开发FA的XPP1A产品将是 此STTR I阶段授予应用程序的重点。我们假设XPPIA对PNA和其他 FAS，例如TNA和SHA，以及严重的FAS。那是这1年I阶段sttr应用程序的目标是 产生XPP1A效率，安全性和PK曲线的可行性，并探索/验证传统中的MOA 和人性化的FA模型。我们将追求2个具体目标：目标＃1：确定XPP1A防止IgE的保护 FA的常规和人源化鼠模型中介导的过敏反应；目标＃2。确定XPPIA安全 和PK配置文件。该项目的完成将导致下一个阶段研究（II阶段STTR）用于IND归档 致力于XPP1A的商业化以治疗多重和重度FA。