C3 Tumor Associated Carbohydrate Antigen Bioconjugates

描述(申请人提供)：尽管癌症筛查计划取得了显著进展，公众对吸烟和饮食等生活方式风险因素的认识也有所提高，基于肿瘤学的治疗方法也取得了里程碑式的进步，但在可预见的未来，我们仍然面临癌症对老龄化人口的影响净增加的问题。因此，继续把研究重点放在新的治疗战略上，将其作为旨在减少全球人口中癌症发病率和患病率的总体方法的组合，仍然至关重要。在这方面，生产能够使免疫系统识别癌症碳水化合物抗原的有效疫苗的能力仍然是癌症治疗的一个难以实现和长期关注的问题。这个R21项目旨在回答可能导致这一重要目标的一系列非常长和复杂的问题中的第一个问题。具体地说，这项R21提案利用了PI最近的发现 补体蛋白C3可以被定点化学修饰，以产生C3-癌症碳水化合物生物结合物，这种生物结合物也可以结合B细胞和/或T细胞表位。鉴于C3片段在体内激活B细胞和T细胞依赖免疫的已知能力，如果完全实现C3-癌症碳水化合物生物结合物(如本提案中设计和合成的生物结合物)，则有可能成为针对癌症相关碳水化合物抗原的新癌症免疫疗法的核心成分。应该强调的是，全面实现这一目标将需要综合研究，利用肿瘤免疫学、互补学、自身免疫学和基础免疫学的专业知识，这远远超出了本初步提案的范围，然而，这个初步的R21项目旨在生成用化学合成的C3癌症碳水化合物抗原进行小鼠免疫的关键初步数据，有望支持这样的C3生物结合物可以在小鼠中引发抗癌碳水化合物B细胞和T细胞免疫反应的假设，因此需要提出更综合和更深入的建议。 公共卫生相关性：生产有效的疫苗，使免疫系统能够识别癌症碳水化合物抗原，这仍然是癌症治疗的一个困难和长期关注的问题。此项目旨在仅回答第一个问题 针对这一重要目标提出了一系列非常长的问题，具体地说，这项R21建议利用了PI最近的发现，即补体蛋白C3可以被多肽和小分子特异性地修饰，以产生C3-癌症碳水化合物生物结合物。鉴于已知的C3片段激活B细胞和T细胞依赖免疫的能力，如果完全实现(需要进行超出本初步研究范围的更多研究)，这是合理的 C3-癌症碳水化合物生物结合物(如本提案中正在设计和合成的那些)可能成为新的癌症免疫疗法的核心成分。

DESCRIPTION (provided by applicant): Even with the remarkable advances seen with cancer screening programs and increased public awareness of lifestyle risk factors, such as smoking and diet, and the landmark progress in oncology-based therapeutics we are still facing a net increase in the impact of cancer on the aging population for the foreseeable future. Therefore it remains of critical importance to maintain research focus on new therapeutic strategies as a composite of the overall approaches aimed at reducing the incidence and prevalence of cancer in the global population. In this regard the ability to produce effective vaccines that allow immune system recognition of cancer carbohydrate antigens continues to be a difficult to achieve and long term focus for cancer therapy. This R21 project is designed to answer just the first question in a very long and complex series of questions that may lead toward this important goal. Specifically, this R21 proposal exploits the recent discovery by the PI that complement protein C3 can be site-specifically chemically modified to generate C3-cancer carbohydrate bioconjugates that can also incorporate B-cell and/or T-cell epitopes. Given the known ability of C3-fragments to activate both B-cell and T-cell dependent immunity in vivo, it is plausible that if fully realized C3-cancer carbohydrate bioconjugates (such as the ones being designed and synthesized in this proposal), may offer the potential of being core components of new cancer immunotherapies directed against cancer-related carbohydrate antigens. It should be stressed that the full realization of this goal will require integrated research exploiting expertise in tumor immunology, complementology, autoimmunity and fundamental immunology which is way beyond the remit of this preliminary proposal, However, this preliminary R21 project is designed to generate the critical preliminary data from murine immunization with chemically-synthesized C3-cancer carbohydrate antigens that will hopefully support the hypothesis that such C3-bioconjugates can trigger anti-cancer carbohydrate B- and T-cell immune responses in mice, and as such warrant more integrated and in-depth proposals. PUBLIC HEALTH RELEVANCE: The ability to produce effective vaccines that allow immune system recognition of cancer carbohydrate antigens continues to be a difficult to achieve and long term focus for cancer therapy. This project is designed to answer just the first question in a very long series of questions toward this important goal Specifically, this R21 proposal exploits the recent discovery by the PI that complement protein C3 can be site-specifically modified with peptides and small molecules to generate C3-cancer carbohydrate bioconjugates. Given the known ability of C3-fragments to activate both B-cell and T-cell dependent immunity, it is plausible that if fully realized (requiring much more research beyond the remit of this preliminary proposal), C3-cancer carbohydrate bioconjugates (such as the ones being designed and synthesized in this proposal), could offer the potential of being core components of new cancer immunotherapies.