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

TN-LAMP-vax：多价树坚果过敏免疫疗法

• 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
• 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

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(由申请者提供)：在美国，对食物的极端反应每年导致3万多起过敏反应事件和100-200人死亡。对坚果(TN)过敏，如杏仁、腰果、榛子和核桃，是仅次于花生的第二大过敏诱因。据估计，有100万美国人对TNS过敏，其中许多人受到接触微量药物的影响，没有办法，但严格避免摄入，否则有可能发生致命的过敏事件。 为了响应NIAID解决食物过敏带来的健康挑战的承诺，免疫组学治疗公司(ITI)提出了创新的SBIR第一阶段研究，以设计一种新型的多价TN免疫疗法，该疗法利用溶酶体相关膜蛋白(LAMP)嵌合构建，将杏仁、榛子、腰果和核桃等主要TN过敏原引导到MHC II/内体途径。ITI设想了一种新的治疗产品，由4个质粒组成，每个质粒编码主要的TN过敏原作为灯的嵌合体。在使用时，这种名为TN-LAMP-VAX的产品有望通过诱导辅助性T细胞1型(Th1)反应，迅速使受试者对编码的过敏原和交叉反应性过敏原脱敏。拟议的治疗产品有望成为一种安全、低过敏和成本效益高的免疫疗法，显著降低或消除对TN过敏原的敏感性。 ITI已经成功地设计、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，JRC-LAMP-VAX是一种通过注射主要雪松变应原Cry j 2来治疗日本红柏过敏的免疫疗法。在试验结束的第132天，16名患者中有14名患者在试验结束时以裸DNA的形式在生理盐水中肌肉注射四次，每两周一次，没有严重的不良反应发生，14名患者的皮肤试验从日本红柏阳性转为阴性。这一结果背后的可能作用机制是通过先前对LAMP的工作提出的，该工作表明免疫可启动Th1反应、高滴度免疫球蛋白(Ig)G和免疫记忆。Th1和Ig G免疫应答为LAMP疫苗治疗IgE介导的变态反应性疾病提供了有力的论据。LAMP疫苗免疫反应遵循公认的变态反应脱敏医学范例，并通过消除传统免疫疗法所要求的暴露于游离过敏原而建立了新的安全水平。 这项第一阶段的研究借鉴了ITI在将基于LAMP的过敏疫苗商业化方面的经验，AIMS的完成将明显为针对过敏患者的治疗性TN疫苗的商业化提供理论基础。 第一阶段的目的是：(1)设计和合成TN变应原编码载体；(2)评价和优化TN-LAMP-VAX的免疫原性；(3)评价TN-LAMP-VAX在单一TN和多坚果过敏动物模型中的作用，并优化给药和给药。 在第二阶段，ITI将根据当前的良好制造规范(CGMP)准备TN-LAMP-VAX，并进行生物分布和毒理学研究，以支持IND申请。该项目的目标是将TN-LAMP-VAX商业化。ITI强烈认为，这项建议支持NIAID的承诺，即解决食物过敏和TN引起的过敏反应带来的健康挑战，而这些过敏反应没有治疗方法。