C3 Tumor Associated Carbohydrate Antigen Bioconjugates

C3 肿瘤相关碳水化合物抗原生物缀合物

• 批准号: 8301502
• 负责人: PAUL WENTWORTH
• 金额: $ 28.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301502
• 关键词: Active Immunization; Adjuvant; Affinity; Alkynes; Antibody Formation; Antigens; Autoimmunity; Awareness; Azides; B-Lymphocytes; Binding; Carbohydrates; Complement; Complement 3a; Complex; Data; Development; Diet; Fee-for-Service Plans; Female; Future; Goals; Imaging technology; Immune response; Immune system; Immunity; Immunization; Immunoglobulin G; Immunology; Incidence; Lead; Life Style; Malignant Neoplasms; Measures; Mono-S; Mus; Ohio; Parents; Peptides; Population; Preparation; Prevalence; Proteins; Protocols documentation; Research; Research Project Grants; Risk Factors; Screening for cancer; Series; Serum; Site; Smoking; Specificity; Stress; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Therapeutic; Tumor-Associated Carbohydrate Antigens; United States National Institutes of Health; Vaccines; Validation; aging population; base; cancer immunotherapy; cancer therapy; chemical synthesis; cytokine; design; enzyme linked immunospot assay; in vivo; novel; novel strategies; novel therapeutics; oncology; programs; response; small molecule; thioester; tumor immunology

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.

描述（由申请人提供）：即使癌症筛查项目取得了显着进展，公众对生活方式风险因素（如吸烟和饮食）的认识提高，以及基于肿瘤学的治疗取得了里程碑式的进展，在可预见的未来，我们仍然面临癌症对老龄化人口影响的净增加。因此，保持对新的治疗策略的研究重点，作为旨在降低全球人口癌症发病率和流行率的总体方法的一个组成部分，仍然至关重要。在这方面，生产允许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焦点。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漫长而复杂的问题中的第一个问题。具体而言，R21提案利用了PI最近的发现， 该补体蛋白C3可以被位点特异性化学修饰以产生C3-癌症碳水化合物生物缀合物，其也可以掺入B细胞和/或T细胞表位。考虑到C3片段在体内激活B细胞和T细胞依赖性免疫的已知能力，如果完全实现C3-癌症碳水化合物生物缀合物（例如在本提案中设计和合成的那些），则可能提供作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组分的潜力。应该强调的是，这一目标的充分实现将需要利用肿瘤免疫学、补体学、自身免疫学和基础免疫学方面的专门知识进行综合研究，这远远超出了本初步提案的范围。这个初步的R21项目旨在从化学合成的C3-癌症碳水化合物抗原有望支持这样的C3-生物缀合物可以在小鼠中触发抗癌碳水化合物B-和T-细胞免疫应答的假设，并且因此保证更综合和深入的提议。 公共卫生相关性：生产允许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难以实现和长期关注的焦点。这个项目的目的是回答第一个问题， 具体地说，R21方案利用了PI最近的发现，即补体蛋白C3可以用肽和小分子进行位点特异性修饰，以产生C3-癌症碳水化合物生物缀合物。考虑到C3片段激活B细胞和T细胞依赖性免疫的已知能力，如果完全实现（需要超出本初步研究范围的更多研究）， C3-癌症碳水化合物生物缀合物（例如在该提案中设计和合成的那些）可以提供成为新癌症免疫疗法的核心组分的潜力。