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

基本信息

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
项目类别：
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

项目摘要

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) 是一种可能危及生命的疾病，20 年来迅速增加，影响了 32 人每年花费 250 亿美元的治疗方案极其有限。意外接触后的急救药物是花生过敏 (PNA) 管理的主要原因。严重反应，通常与树坚果过敏（TNA）共存，是贝类过敏（ShA）的主要原因。成人过敏反应。多种食物过敏以及多种食物之间的交叉反应，例如坚果和坚果。贝类使食物回避变得更加复杂，FA 主要是由异常升高的食物蛋白介导的。特异性免疫球蛋白 E (sIgE) 无法抑制持久性食物 sIgE 是 FA 的一个重要障碍。因此，非食物限制治疗适用于“所有”FA，包括多种和严重的 FA。逆转升高的 sIgE 的能力将缩小治疗差距并具有巨大的市场价值。 General Nutraceutical Technology LLC (GNT) 是一家总部位于纽约的生物技术初创公司，其基础是突破性的 FA 研究在西奈山伊坎医学院启动，我们首次进行了隔离。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）我们的初步数据表明，XPP 具有良好的生物利用度，并且稳定且具有较高的生物利用度。临床前安全性概况（每日 10 倍剂量时无 AE），为期 4 周、每日一次的口服低剂量 XPP。（0.4毫克/小鼠，相当于成人剂量0.1克/天，基于体表面积44）诱导100% 抑制过敏反应，血清花生 (PN)-sIgE 和血浆组胺水平降低 80-100% PNA 小鼠模型，没有 IgG 或 IgA 的整体免疫抑制。作用 (MOA) 包括 XPP 抑制 IgE+ B 细胞，通过增加 IL-4 的 DNA 甲基化来减少 IL-4 启动子，不影响 IL-10 或 IFN-γ，并诱导独特的 B 细胞转录组谱。为了实现药物采购的可持续性和环境保护，我们通过发电来推进 XPP 生产合成 XPP (sXPP) 及其类似物我们发现其中一种类似物（名为 XPP1a）是一种优异的 IgE。抑制剂并表现出优异的体外安全性，因此，开发用于 FA 的 XPP1a 产品将是当务之急。我们相信 XPPIa 将对 PNA 和其他项目有效。 TNA 和 ShA 等 FA 以及严重 FA 因此，这一为期 1 年的第一阶段 STTR 申请的目标是：生成 XPP1a 功效、安全性和 PK 概况的可行性，并探索/验证传统药物中的 MOA 我们将追求 2 个具体目标：目标#1：确定 XPP1a 对 IgE- 的保护作用。 FA 的传统和人源化小鼠模型中介导的过敏反应；确定 XPPIa 的安全性。该项目的完成将导致下一阶段研究（第二阶段 STTR）的 IND 备案。 XPP1a 的商业化用于治疗多发性和严重的 FA。