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（由申请方提供）：本项目的目的是继续开发针对Ad 5 [E1-，E2 b]-Her 2/neu的腺病毒血清型5（Ad 5）载体疫苗，该疫苗可有效刺激先前对Ad 5免疫的动物的细胞介导免疫（CMI）。Ad 5 [E1-，E2 b-]-Her 2/neu疫苗终点是治疗HER 2过表达癌症患者。HER 2是已报道可用作疫苗治疗靶标的蛋白质。证据表明，需要广泛的CMI反应来治疗某些HER 2表达。Ad 5载体疫苗诱导CMI应答，并且已经成为用作治疗疫苗的主要候选者，作为治疗疫苗递送平台。目前一代Ad 5疫苗已被证明不如预期有效，不良反应也存在疑问。此外，大多数人预先存在的Ad 5免疫力导致有效性降低。为了解决这些问题，我们开发了一种先进的基于ad 5的载体，该载体缺乏早期基因E1，E2 b3和E3。这些“E2 b-缺失”载体在聚合酶和前末端蛋白基因中具有缺失，与当前一代相比，具有扩大的克隆能力，大大降低了病毒晚期基因的表达。已证明多种Ad 5病毒基因的表达减少对疫苗开发有利，原因包括抗原竞争减少、在存在预先存在的Ad 5免疫力的情况下更长的优势寿命很重要，并提供E2 b缺失载体隐形样属性。公司拥有新的Ad 5载体系统和支持载体生产的E.C7细胞系的独家许可。拟议的研究旨在构建和测试基于新的E2 b缺失的Ad 5平台的HER 2/neu疫苗的有效性，该平台将携带HER 2/neu基因。将检测Ad 5疫苗作为初免诱导HER 2/neu记忆CMI应答的潜力，以及在Ad 5初治和Ad 5免疫小鼠中再次免疫（加强）的潜力。将监测小鼠疫苗的任何不良反应。该项目将产生有效、安全、易于生产、稳定和易于使用的HER/2 neu治疗性疫苗。我们的目标是在一年内启动使用Ad 5载体平台的1期临床试验。 公共卫生相关性：在本研究期间，我们将进一步开发用于Ad 5 [HER 2/neu]治疗疫苗的先进载体递送系统。需要疫苗平台来突破由先前具有腺病毒感染（包括大多数人）的疫苗所呈现的障碍。

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