Development of a Novel Her2/neu Expressing Adenovirus for Treatment

描述（由申请人提供）：该项目的目标是继续开发针对Ad5[E1-， E2b]- her2 /neu的腺病毒血清型5 （Ad5）载体疫苗，该疫苗可有效刺激先前对Ad5免疫的动物的细胞介导免疫（CMI）。Ad5[E1-， E2b-]- Her2/neu疫苗终点是治疗Her2过表达的癌症患者。据报道，HER2是一种可作为疫苗治疗靶点的蛋白质。有证据表明，治疗某些HER2表达需要广泛的CMI反应。Ad5载体疫苗可诱导CMI反应，并已成为治疗疫苗作为治疗疫苗递送平台的主要候选疫苗。目前的第5代Ad5疫苗已被证明不如预期有效，不良反应值得怀疑。此外，大多数人已有的Ad5免疫导致有效性降低。为了解决这些问题，我们开发了一种先进的基于ad5的载体，它不含早期基因E1， E2b3和E3。这些“e2b缺失”的载体，在聚合酶和前端蛋白基因中缺失，与当前一代相比，具有扩展的克隆能力，大大降低了病毒晚期基因的表达。多个Ad5病毒基因表达的减少已被证明对疫苗开发有利，原因包括抗原竞争减少，在存在预先存在的Ad5免疫的情况下，更长的优势是重要的，并且提供了E2b缺失载体的隐身性。该公司拥有新的Ad5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e2b缺失Ad5平台的HER2/neu疫苗的有效性，该平台将携带HER2/neu基因。Ad5疫苗将被测试其诱导HER2/新记忆CMI反应的潜力，以及它们在Ad5- na和Ad5免疫小鼠中的再免疫（增强）潜力。将对小鼠进行监测，看疫苗是否有任何不良影响。该项目将产生一种有效、安全、易生产、稳定、易于使用的HER/2新型治疗性疫苗。我们的目标是在一年内利用Ad5载体平台启动一期临床试验。

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.