Development of Nanoplasmid LAMP-based Peanut Allergy Immunotherapy

基于纳米质粒LAMP的花生过敏免疫疗法的开发

• 批准号: 8902553
• 负责人: Therese L Heiland
• 金额: $ 20.03万
• 依托单位: IMMUNOMIC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902553
• 关键词: Address; Affect; Allergen Immunotherapy; Allergens; Allergic; Allergic Disease; Allergic Reaction; Allergy to peanuts; American; Anaphylaxis; Antibiotic Resistance; Antibodies; Antigen Presentation; Antigens; Applications Grants; Biodistribution; Cells; Cessation of life; Child; Chimera organism; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Computer Simulation; Control Groups; DNA; Data; Development; Disease; Dose; Drug Formulations; Ensure; Equilibrium; Exposure to; FDA approved; Food Hypersensitivity; Future; Gene Expression; Goals; Grant; Health; Human; Hypersensitivity; Hypersensitivity skin testing; IgE; Immune response; Immunization; Immunoglobulin G; Immunotherapy; Inbred BALB C Mice; Inbred C3H Mice; Individual; Intramuscular Injections; Japanese Population; Mediating; Medical; Membrane Proteins; Memory; Modeling; Mus; Nature; Oral; Outpatients; Patients; Phase; Phase I Clinical Trials; Plasmids; Preparation; Production; Protocols documentation; Reporting; Research; Research Proposals; Risk; Safety; Saline; Severe Adverse Event; Small Business Innovation Research Grant; Symptoms; Technology; Testing; Therapeutic; Time; Toxicology; Translating; Transmembrane Domain; Treatment Efficacy; Vaccination; Vaccines; Validation; Western Blotting; Work; base; cytokine; desensitization; design; effective therapy; experience; expression vector; immunogenic; immunogenicity; innovation; mouse model; novel; pre-clinical; prevent; prophylactic; protein expression; public health relevance; response; vector control

 DESCRIPTION (provided by applicant): Development of Nanoplasmid LAMP-based Peanut Allergy Immunotherapy. An estimated million Americans are allergic to peanut, which is the most common trigger of anaphylaxis resulting in over 30,000 incidents and between 100 - 200 deaths in the US each year. There are no FDA approved treatments for peanut allergy. In response to NIAID's commitment to address the health challenge posed by peanut allergies, Immunomic Therapeutics, Inc. ("ITI") proposes novel and innovative SBIR Phase I research to develop ARA-LAMP-vax by encoding the three major peanut allergens as a single lysosomal associated membrane protein ("LAMP") chimera to desensitize peanut allergic patients through a Th1-based mechanism, delivered using a recently developed Nanoplasmid with greatly enhanced gene expression and immunogenicity. ARA-LAMP-vax is a safe, short treatment course with long-lasting anaphylactic protection. ITI has successfully designed, tested and validated multiple antigen-LAMP-vax DNA formulations, with a therapeutic focus on treating IgE-mediated allergic diseases. Recently, ITI completed a Phase I clinical study of JRC-LAMP-vax, a plasmid-based immunotherapy for Japanese red cedar. When administered intramuscularly (IM) 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 and maintained in 14 out of 16 patients out through day 400. It is hypothesized that the observed desensitization is due to re-balancing of the allergic Th2 / immunoglobulin (Ig) E response by inducing a Th1 central memory response and high titers of allergen-specific IgG. The use of LAMP-vax in treating serious IgE-mediated diseases establishes a new level of safety by eliminating the risky exposure to free allergen as required in traditional immunotherapy. This Phase I research draws on ITI's experience in commercializing LAMP-based allergy vaccines, the innovations in plasmid design executed by ITI's long-time collaborators at Nature Technologies that led to the breakthrough in minimal plasmid design realized in the Nanoplasmid expression vector, and previous work that showed that a DNA-based multivalent peanut vaccine could provide therapeutic and prophylactic benefits in peanut allergic mice. Completion of the Aims herein will provide a clear rationale for commercializing the Nanoplasmid-based peanut allergy vaccine ARA-LAMP-vax. Phase I Aims are to: (1) design and synthesize peanut allergen-encoding Nanoplasmids; (2) Test ARA- LAMP-vax formulations in a prophylactic model of peanut allergy; and (3) Evaluate therapeutic efficacy in a mouse model of peanut anaphylaxis. During Phase II, ITI will prepare ARA-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 ARA-LAMP-vax. ITI strongly believes that this proposal supports NIAID's commitment to address the health challenge posed by food allergy and peanut-induced anaphylaxis, for which there is no FDA approved treatment.

 描述(申请人提供)：基于纳米质粒LAMP的花生过敏免疫疗法的发展。据估计，有100万美国人对花生过敏，花生是最常见的过敏反应触发物，每年在美国导致3万多起事件和100-200人死亡。目前还没有FDA批准的花生过敏治疗方法。为了响应NIAID解决花生过敏带来的健康挑战的承诺，免疫组学治疗公司(ITI)提出了新颖和创新的SBIR第一阶段研究，通过将三种主要花生过敏原编码为单一溶酶体相关膜蛋白(LAMP)嵌合体来开发ARA-LAMP-VAX，通过基于Th1的机制使花生过敏患者脱敏，该嵌合体使用最近开发的一种基因表达和免疫原性大大增强的纳米质粒。ARA-LAMP-VAX是一种安全、疗程短、具有长期过敏保护作用的药物。ITI已经成功地设计、测试和验证了多种抗原-LAMP-VAX DNA配方，重点是治疗IgE介导的过敏性疾病。最近，ITI完成了JRC-LAMP-VAX的I期临床研究，JRC-LAMP-VAX是一种基于日本红柏的质粒型免疫疗法。当在生理盐水中肌肉注射(IM)裸露DNA四次，每两周一次，没有严重不良反应的报道，在16名患者中有14名患者在400天内观察到并保持了皮肤试验从日本红柏阳性到阴性。据推测，观察到的脱敏是由于Th2/免疫球蛋白(Ig)E过敏反应的重新平衡，诱导了Th1中央记忆反应和高滴度的过敏原特异性IgG。LAMP-VAX用于治疗严重的IgE介导性疾病，通过消除传统免疫疗法所要求的暴露于游离变应原的危险，建立了一个新的安全水平。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，ITI在自然技术公司的长期合作者在质粒设计方面的创新，导致在纳米质粒表达载体中实现的最小质粒设计的突破，以及之前的工作，表明基于DNA的多价花生疫苗可以在花生过敏小鼠中提供治疗和预防益处。本文目标的完成将为以纳米质粒为基础的花生过敏疫苗ARA-LAMP-VAX的商业化提供明确的理论基础。第一阶段的目标是：(1)设计和合成花生过敏原编码纳米质粒；(2)在花生过敏的预防模型中测试ARA-LAMP-VAX配方；以及(3)在花生过敏的小鼠模型中评估治疗效果。在第二阶段，ITI将根据当前的良好制造规范(CGMP)准备ARA-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ARA-LAMP-VAX商业化。ITI强烈认为，这项建议支持NIAID的承诺，即解决食品过敏和花生引起的过敏反应带来的健康挑战，而FDA没有批准对这些过敏反应进行治疗。