TN-LAMP-vax: a Multi-Valent Tree Nut Allergy Immunotherapy

TN-LAMP-vax：多价树坚果过敏免疫疗法

基本信息

批准号：
8777024
负责人：
Therese L Heiland
金额：
$ 25.52万
依托单位：
IMMUNOMIC THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777024
关键词：
Address Affect Allergen Immunotherapy Allergens Allergic Allergic Disease Almond Nut American Anaphylaxis Animal Model Antibodies Antibody Formation Antigen Presentation Antigens Applications Grants Biodistribution Biological Assay CD4 Positive T Lymphocytes Cashew nut Cells Cessation of life Chimera organism Chimeric Proteins Clinical Research Clinical Trials Computer Simulation Control Groups Crying DNA DNA Vaccines Development Dose Drug Formulations Enzyme-Linked Immunosorbent Assay Evaluation Exposure to Extravasation Food Food Hypersensitivity Future Gene Expression Goals Grant Hazelnuts Health Helper-Inducer T-Lymphocyte Human Hypersensitivity Hypersensitivity skin testing IL2RA gene IgE IgG1 Immune response Immunization Immunoglobulin G Immunologic Memory Immunotherapeutic agent Immunotherapy Inbred BALB C Mice Inbred C3H Mice Individual Ingestion Injection of therapeutic agent Intramuscular Injections Japanese Population Juglans Measures Mediating Medical Membrane Proteins Modeling Molecular Weight Mus Nut Hypersensitivity Nuts Oral Pathway interactions Patients Peanuts - dietary Phase Phase I Clinical Trials Plasmids Pollen Preparation Quality of life Reaction Regulatory T-Lymphocyte Reporting Research Risk Safety Saline Serum Severe Adverse Event Small Business Innovation Research Grant Symptoms Testing Therapeutic Time Toxicology Treatment Efficacy Trees Vaccination Vaccines Validation Work base cashew Ana o 2 allergen cell type cost effective cytokine design experience food allergen immunogenic immunogenicity innovation novel novel therapeutics pre-clinical prevent protein expression public health relevance response therapeutic evaluation vector vector control

项目摘要

DESCRIPTION (provided by applicant): Extreme reactions to food results in over 30,000 incidents of anaphylaxis and between 100 - 200 deaths in the US each year. Allergies to tree nuts (TN), such as almond, cashew, hazelnut and walnut, are collectively the second most common triggers of anaphylaxis behind peanut. An estimated million Americans are allergic to TNs with many impacted by exposure to trace amounts and no recourse but to stringently avoid ingestion or risk a potentially fatal anaphylactic episode. In response to NIAID's commitment to address the health challenge posed by food allergies, , Immunomic Therapeutics, Inc. ("ITI") proposes innovative SBIR Phase I research to design a novel multivalent TN immunotherapy that utilizes a lysosomal associated membrane protein ("LAMP") chimeric construct to direct the major TN allergens of almond, hazelnut, cashew, and walnut into the MHC II / endosomal pathway. ITI envisions a novel therapeutic product consisting of 4 plasmids, each encoding the major TN allergens as a LAMP chimera. When administered, this product, TN-LAMP-vax, is expected to rapidly desensitize subjects to the encoded allergens and cross reactive allergens by inducing a helper T-cell type 1 (Th1) response. The proposed therapeutic product is anticipated to be a safe, hypoallergenic, and cost-effective immunotherapy that significantly reduces or eliminates sensitivity to TN allergens. ITI has successfully designed, tested and validated multiple antigen-LAMP-vax DNA formulations, including multivalent peanut and cedar allergy vaccines. Recently, ITI completed a Phase I clinical study of JRC-LAMP-vax, an immunotherapeutic for treating Japanese red cedar allergy through administration of the major cedar allergen Cry j 2. When administered intramuscularly as naked DNA in saline four times, biweekly, no severe adverse events were reported and skin test conversion from Japanese red cedar positive to negative was observed in 14 out of 16 patients at the end of the trial at day 132. The putative mechanism of action behind this result is suggested by previous work with LAMP that shows immunization initiates a Th 1 response, high titers of immunoglobulin (Ig) G, and immunological memory. The Th1 and IgG immune response provides a compelling argument in support of LAMP vaccines to treat IgE-mediated allergic diseases. The LAMP vaccine immune response follows the accepted medical paradigm for allergy de-sensitization and establishes a new level of safety by eliminating exposure to free allergen as required in traditional immunotherapy. This Phase I research draws on ITI's experience in commercializing LAMP-based allergy vaccines and completion of the Aims will clearly provide a rationale for commercializing the therapeutic TN vaccine for allergic patients. Phase I Aims are to: (1) design and synthesize TN allergen-encoding plasmids; (2) evaluate and optimize immunogenicity of TN-LAMP-vax; and (3) evaluate TN-LAMP-vax in single TN and multi-nut anaphylaxis animal model and optimize dosing and delivery. During Phase II, ITI will prepare TN-LAMP-vax, under current Good Manufacturing Practices (cGMP) and conduct biodistribution & toxicology studies in support of an IND filing. The goal of this project is to commercialize TN-LAMP-vax. ITI strongly believes that this proposal supports NIAID's commitment to address the health challenge posed by food allergy and TN-induced anaphylaxis, for which there is no treatment.

描述（由申请人提供）：在美国，每年对食物的极端反应会导致超过 30,000 起过敏反应事件和 100 - 200 人死亡。对杏仁、腰果、榛子和核桃等坚果 (TN) 过敏是仅次于花生的第二大常见过敏反应诱因。据估计，有数百万美国人对 TN 过敏，其中许多人受到微量接触的影响，除了严格避免摄入之外别无选择，否则可能会导致致命的过敏发作。为了响应 NIAID 解决食物过敏带来的健康挑战的承诺，Immunomic Therapeutics, Inc.（“ITI”）提出了创新的 SBIR I 期研究，以设计一种利用溶酶体相关膜蛋白（“LAMP”）的新型多价 TN 免疫疗法) 嵌合构建体可将杏仁、榛子、腰果和核桃的主要 TN 过敏原引导至 MHC II/内体途径。 ITI 设想了一种由 4 个质粒组成的新型治疗产品，每个质粒都将主要 TN 过敏原编码为 LAMP 嵌合体。施用后，该产品 TN-LAMP-vax 有望通过诱导 1 型辅助 T 细胞 (Th1) 反应，快速使受试者对编码的过敏原和交叉反应性过敏原脱敏。所提出的治疗产品预计将是一种安全、低过敏性且具有成本效益的免疫疗法，可显着降低或消除对 TN 过敏原的敏感性。 ITI 已成功设计、测试和验证了多种抗原-LAMP-vax DNA 配方，包括多价花生和雪松过敏疫苗。最近，ITI 完成了 JRC-LAMP-vax 的 I 期临床研究，这是一种通过施用主要雪松过敏原 Cry j 2 治疗日本红雪松过敏的免疫疗法。当以盐水中的裸 DNA 肌肉注射四次、每两周一次时，没有出现严重的症状报告了不良事件，并且在第 132 天试验结束时，16 名患者中有 14 名观察到皮试从阳性转为阴性。先前对 LAMP 的研究表明了这一结果背后的假定作用机制，该研究表明免疫启动了 Th 1 反应、高滴度的免疫球蛋白 (Ig) G 和免疫记忆。 Th1 和 IgG 免疫反应为支持 LAMP 疫苗治疗 IgE 介导的过敏性疾病提供了令人信服的论据。 LAMP 疫苗免疫反应遵循公认的过敏脱敏医学范例，并通过消除传统免疫疗法所需的游离过敏原暴露，建立了新的安全水平。这项第一期研究借鉴了 ITI 在基于 LAMP 的过敏疫苗商业化方面的经验，目标的完成将为过敏患者治疗性 TN 疫苗的商业化提供明确的理由。第一阶段的目标是：（1）设计并合成TN过敏原编码质粒； (2)评估并优化TN-LAMP-vax的免疫原性； (3) 在单一 TN 和多坚果过敏反应动物模型中评估 TN-LAMP-vax，并优化剂量和给药。在第二阶段，ITI 将根据现行良好生产规范 (cGMP) 制备 TN-LAMP-vax，并进行生物分布和毒理学研究以支持 IND 备案。该项目的目标是将 TN-LAMP-vax 商业化。 ITI 坚信，该提案支持 NIAID 致力于解决食物过敏和 TN 引起的过敏反应带来的健康挑战，而目前尚无治疗方法。