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: 8424948
• 负责人: PAUL WENTWORTH
• 金额: $ 23.69万
• 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/8424948
• 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.

描述（由申请人提供）：尽管癌症筛查计划取得了显着进展，公众对吸烟和饮食等生活方式风险因素的认识不断提高，并且基于肿瘤的治疗方法取得了里程碑式的进展，但我们仍然面临着癌症净增长的问题。在可预见的未来，癌症对人口老龄化的影响。因此，保持对新治疗策略的研究重点仍然至关重要，该策略是旨在降低全球人口癌症发病率和患病率的总体方法的综合体。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难以实现的长期焦点。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长且复杂的问题中的第一个问题。具体来说，这个 R21 提案利用了 PI 最近的发现 补体蛋白 C3 可以进行位点特异性化学修饰，生成 C3 癌症碳水化合物生物缀合物，该生物缀合物也可以掺入 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 细胞依赖性免疫的已知能力，如果完全实现 C3 癌症碳水化合物生物结合物（例如本提案中设计和合成的生物结合物），可能会具有成为针对癌症相关碳水化合物抗原的新型癌症免疫疗法核心成分的潜力。应该强调的是，全面实现这一目标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业知识进行综合研究，这远远超出了本初步提案的范围，然而，这个初步的 R21 项目旨在产生关键的使用化学合成的 C3 癌症碳水化合物抗原对小鼠进行免疫的初步数据有望支持这样的假设：此类 C3 生物缀合物可以在小鼠中触发抗癌碳水化合物 B 和 T 细胞免疫反应，以及因此需要更加综合和深入的建议。