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）：即使随着癌症筛查计划的显着进步，公众对生活方式危险因素的认识，例如吸烟和饮食，以及基于肿瘤学的治疗剂的里程碑进步，我们仍面临净增长在可预见的未来，癌症对衰老人口的影响。因此，将研究重点保持在新的治疗策略上是旨在降低全球人群癌症发病率和患病率的整体方法的综合，这仍然至关重要。在这方面，生产有效疫苗的能力可以使癌症抗原的免疫系统识别持续很难实现，并且长期重点是癌症治疗。这个R21项目旨在仅回答一个非常复杂的问题中的第一个问题，这些问题可能导致这一重要目标。具体而言，该R21提案利用了PI的最新发现 该补体蛋白C3可以特定于化学修饰，以产生C3-癌碳水化合物生物缀合物，该偶联物也可以掺入B细胞和/或T细胞表位。鉴于C3-Fragments在体内激活B细胞和T细胞依赖性免疫的已知能力，如果完全实现的C3-癌碳水化合物生物偶联物（例如，在此提案中设计和合成），则可能是合理的，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成分的潜力。应该强调的是，该目标的全面实现将需要综合研究利用肿瘤免疫学，补充学，自身免疫性和基本免疫学方面的专业知识，这远远超出了该初步建议的良好性，但是，该初步R21项目旨在产生关键通过化学合成的C3-结合C碳水化合物抗原的鼠免疫的初步数据，有望支持这样的假设：这种C3-双缀合物可以触发小鼠中的抗癌碳水化合物B-和T-T-细胞免疫反应，并因此在此类认可中进行了更大的整合以及更具整合的整合和。 - 深度提案。 公共卫生相关性：生产有效疫苗的能力，可以使癌症抗原的免疫系统识别仍然很难实现，并且长期重点是癌症治疗。该项目旨在仅回答一个问题 特别是针对这个重要目标的一系列问题，该R21提案利用了PI的最新发现，即补充蛋白C3可以用肽和小分子特异性地修饰，以生成C3-Cancer碳水化合物生物缀合物。鉴于C3-Fragments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（需要更多的研究），则是合理的 提案），C3-癌碳水化合物生物缀合物（例如在本提案中设计和合成的碳水化合物）可能会提供成为新癌症免疫疗法的核心组成部分的潜力。