Development of a Novel Her2/neu Expressing Adenovirus for Treatment

开发用于治疗的新型 Her2/neu 表达腺病毒

• 批准号: 7669707
• 负责人: Frank R. Jones
• 金额: $ 12.36万
• 依托单位: ETUBICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669707
• 关键词: Address; Adenovirus Infections; Adenoviruses; Adverse reactions; Animals; Cell Line; Cellular Immunity; Cloning; Development; ERBB2 gene; Effectiveness; Funding; Gene Proteins; Generations; Genes; Goals; Human; Immune; Immunity; Immunization; Licensing; Longevity; Malignant Neoplasms; Memory; Monitor; Mus; Patients; Phase I Clinical Trials; Polymerase; Production; Proteins; Reporting; Research Design; Serotyping; System; Testing; Vaccines; Viral; Viral Genes; base; immunogenic; novel; particle; public health relevance; response; therapeutic vaccine; vaccine delivery; vaccine development; vector; vector vaccine

DESCRIPTION (provided by applicant): The objective of this project is to continue developing an adenoviral serotype 5 (Ad5) vector vaccine against Ad5[E1-, E2b]-Her2/neu that is effective in stimulating cell-mediated immunity (CMI) in animals previously immune to Ad5. The Ad5[E1-, E2b-]- Her2/neu vaccine endpoint is to treat patients with HER2 over expressing cancers. HER2 is a protein that has been reported to be useful as a vaccine treatment target. Evidence indicates that a broad CMI response is needed to treat certain HER2 expressing. Ad5 vector vaccines induce CMI responses and have emerged as a leading candidate to be used as a treatment vaccine as a treatment vaccine delivery platform. Current Generation Ad5 vaccines have proven less effective than anticipated and adverse reaction are in question. Furthermore, pre-existing Ad5 immunity of most humans causes decreased effectiveness. To address these issues, we have developed an advanced ad5 based vector that is devoid of early genes E1, E2b3, and E3. These "E2b-deleted" vectors, with deletions in the polymerase and preterminal protein genes, have an expanded cloning capacity greatly reduced expression of viral late genes as compared to current generation. The reduced expression of multiple Ad5 viral genes has been demonstrated to be advantageous for vaccine development for reasons such as reduced antigenic competition, greater longevity of advantages are important in the presence of pre-existing Ad5 immunity, and provide the E2b deleted vectors stealth-like attributes. The Company has exclusive license for the new Ad5 vector system and the E.C7 cell line that supports vector production. The proposed studies are designed to construct and test the effectiveness of HER2/neu vaccines based on the new E2b-deleted Ad5 platform, which will carry the HER2/neu gene. The Ad5 vaccine will be tested for its potential to induce HER2/neu memory CMI responses as a prime and for their re-immunization (boost) potential in Ad5- na¿ve and Ad5-immune mice. Mice will be monitored for any adverse easy effects of the vaccine. This project will result in an effective, safe, easy to produce, stable, and easy to use HER/2 neu therapeutic vaccine. Our goal is to initiate a Phase 1 clinical trial using the Ad5 vector Platform within a year of funding. PUBLIC HEALTH RELEVANCE: During this study, we will further develop an advanced vector delivery system for an Ad5[HER2/neu treatment vaccine. The vaccine platform is needed to break through the barrier presented by vaccines that have had prior adenovirus infections which include most humans.

描述（由适用提供）：该项目的目的是继续开发针对AD5 [E1-，E2B] -HER2/NEU的腺病毒血清型疫苗，该疫苗可有效地刺激细胞介导的免疫组织化学（CMI），以前以前对AD5进行免疫组织的动物。 AD5 [E1-，E2B-] - HER2/NEU疫苗终点是治疗HER2患者而不是表达癌症。 HER2是一种蛋白质，据报道可作为疫苗治疗靶标。证据表明，需要广泛的CMI响应来处理某些HER2表达。 AD5载体疫苗诱导CMI反应，并已成为主要候选者，以作为治疗疫苗作为治疗疫苗输送平台。事实证明，当前一代AD5疫苗的有效性低，而不良反应也有问题。此外，大多数人类的预先存在的AD5免疫学会导致有效性降低。为了解决这些问题，我们开发了一个基于AD5的高级向量，该向量没有早期基因E1，E2B3和E3。与当前一代相比，这些“ E2B剥落”载体在聚合酶和早产蛋白基因中具有缺失，其克隆能力大大降低了病毒后期基因的表达。由于抗原竞争的降低，更大的优势寿命寿命较高，因此在存在先前存在的AD5免疫力的情况下，多个AD5病毒基因的表达降低对疫苗的发育有利，并且提供了E2B已删除的矢量隐形属性。该公司拥有新的AD5矢量系统的独家许可证和支持向量生产的E.C7单元线。拟议的研究旨在基于新的E2B删除的AD5平台来构建和测试HER2/NEU疫苗的有效性，该平台将携带HER2/NEU基因。 AD5疫苗将通过其诱导HER​​2/NEU记忆CMI响应作为素数及其在AD5-NA¿VE和AD5-免疫小鼠中诱导HER​​2/NEU记忆响应的潜力进行测试。将监测小鼠的疫苗任何不利影响。该项目将导致有效，安全，易于生产，稳定且易于使用她/2 NEU治疗性疫苗。我们的目标是在资助一年内使用AD5矢量平台启动1阶段临床试验。 公共卫生相关性：在这项研究中，我们将进一步开发用于AD5 [HER2/NEU治疗疫苗的先进矢量输送系统。需要该疫苗平台突破疫苗所带来的屏障，这些疫苗先前腺病毒感染包括大多数人。

项目成果

An Ad5[E1-, E2b-]-HER2/neu vector induces immune responses and inhibits HER2/neu expressing tumor progression in Ad5 immune mice.

• DOI: 10.1038/cgt.2010.82
• 发表时间: 2011-05
• 期刊: Cancer gene therapy
• 影响因子: 6.4