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

描述（由申请人提供）：在美国，对食物的极端反应每年导致超过30，000起过敏反应事件和100 - 200人死亡。对树坚果（TN），如杏仁，腰果，榛子和核桃过敏，是仅次于花生的第二大常见过敏反应。据估计，有100万美国人对TN过敏，其中许多人受到痕量接触的影响，没有追索权，只能严格避免摄入或冒着潜在致命的过敏性发作的风险。 为了响应NIAID致力于解决食物过敏带来的健康挑战，免疫治疗公司。（“ITI”）提出创新的SBIR I期研究以设计新颖的多价TN免疫疗法，其利用溶酶体相关膜蛋白（“LAMP”）嵌合构建体将杏仁、榛子、腰果和核桃的主要TN过敏原引导到MHC II /内体途径中。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LAMP嵌合体。当给药时，该产品TN-LAMP-vax预期通过诱导辅助T细胞1型（Th 1）应答，使受试者对编码的过敏原和交叉反应性过敏原快速脱敏。预计拟议的治疗产品是一种安全、低过敏性和具有成本效益的免疫疗法，可显著降低或消除对TN过敏原的敏感性。 ITI已经成功设计、测试和验证了多种抗原-LAMP-vax DNA制剂，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是一种通过施用主要的雪松过敏原Cry j 2来治疗日本红雪松过敏的免疫制剂。当以裸DNA的盐水溶液肌内给药4次，每两周一次时，没有报告严重的不良事件，并且在试验结束时的第132天，在16名患者中的14名中观察到皮肤试验从日本红杉阳性转化为阴性。该结果背后的假定作用机制由先前的LAMP工作提出，其显示免疫启动Th 1应答、高滴度的免疫球蛋白（IG）G和免疫记忆。Th 1和IgG免疫应答为支持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疫苗免疫应答遵循公认的过敏脱敏医学范式，并通过消除传统免疫疗法中所需的游离过敏原暴露来建立新的安全水平。 这项I期研究借鉴了ITI在将基于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的治疗性TN疫苗商业化提供明确的依据。 第一阶段的目标是：（1）设计和合成TN变应原编码质粒;（2）评估和优化TN-LAMP-vax的免疫原性;和（3）评估TN-LAMP-vax在单一TN和多坚果过敏反应动物模型中的作用并优化给药和递送。 在第二阶段，ITI将根据现行的良好生产规范（cGMP）制备TN-LAMP-vax，并进行生物分布和毒理学研究，以支持IND申请。本项目的目标是将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诱导的过敏反应所带来的健康挑战，对此没有治疗方法。

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.