Novel Adjuvant Discovery in Vaccine Therapy

疫苗治疗中新佐剂的发现

基本信息

批准号：
8298167
负责人：
SAMUEL J DANISHEFSKY
金额：
$ 87.17万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298167
关键词：
Acute Address Adjuvant Advanced Malignant Neoplasm Affinity Chromatography Animals Antigens Antiviral Agents Applications Grants Attenuated Behavior Biochemical Biodistribution Biological Biological Factors Cancer Vaccine Related Development Cancer Vaccines Centers for Disease Control and Prevention (U.S.)Chemicals Chemosensitization Clinical Communicable Diseases Complex Development Discipline Dose Dose-Limiting Drug Formulations Drug Kinetics Enzyme-Linked Immunosorbent Assay Epidemic Evaluation Generations Glycolipids Goals Harvest Image Imaging technology Immune Immune response Immunization Immunologic Adjuvants Immunologics Impotence In Vitro Investigation Keyhole Limpet Hemocyanin Laboratories Lead Malignant Neoplasms Methodology Molecular Mucin-1 Staining Method Mus Organ Patients Peptides Pharmacodynamics Positron-Emission Tomography Preparation QS21 Radio Radiochemistry Radiolabeled Research Resistance Role Safety Saponin Saponins Screening procedure Structure Technology Time Tissues Toxic effect Vaccine Adjuvant Vaccine Clinical Trial Vaccine Therapy Vaccines Variant analog authority cellular targeting chemical synthesis combat cytokine design functional group immunogenic improved in vivo insight interest novel novel therapeutics pre-clinical preclinical evaluation preclinical study programs public health relevance radiotracer response success sugar tumor immunology vaccine development vaccinology

项目摘要

DESCRIPTION (provided by applicant): The development of vaccines to combat vaccine resistant cancers and infectious diseases has relied significantly on constructs employing subunit antigens. While the use of defined molecular antigens offers advantages in terms of safety and precision in immune response targeting, they are typically less immunogenic. Often, these vaccine formulations require an adjuvant, a substance that potentiates immune response. The critical roles of vaccine adjuvants lie in their ability to (1) enable the use of otherwise impotent antigens, (2) extend the benefits of vaccines to poor responders (e.g., older or immune-compromised patients), and (3) effect "dose-sparing" of rare and expensive antigens in short supply (e.g., in an epidemic). The natural product saponin QS-21 is the adjuvant of choice in numerous promising antitumor and antiviral vaccine clinical trials, despite liabilities associated with toxicity, chemical instability, and lack of availability in pure form. This grant application comprises a unique multi-disciplinary approach toward the preparation, discovery, evaluation, and understanding of potent adjuvant molecules essential in the development of vaccines for cancer and infectious diseases. The Specific Aims of this research program will involve: (1) the development of novel and efficient strategies for the chemical synthesis of designed non-natural structural variants of the saponin QS-21 possessing improved activity and stability with attenuated toxicity; (2) the evaluation of these novel compounds in mice to assess their ability to potentiate immune response, as well as their specific toxicity profiles; and (3) to employ small animal radio-imaging technologies, immunohistology, cytokine profiling, and affinity chromatography to gain insight into the adjuvant's as yet unknown mechanism of action. These efforts will address fundamental chemical and immunological questions associated with this extremely complex class of adjuvants, and holds the promise of yielding novel therapeutics in the vaccine arena. PUBLIC HEALTH RELEVANCE: The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that is itself not necessarily immunogenic, but significantly enhances the immune response of a patient to a co- administered antigen. This grant application comprises a unique multi-disciplinary approach toward the preparation, discovery, evaluation, and understanding of potent adjuvant molecules essential in the development of vaccines for cancer and infectious diseases. These efforts will address fundamental chemical and immunological questions central to immune response potentiation, and holds the promise of yielding novel therapeutics in the vaccine arena.

描述（由申请人提供）：开发疫苗以打击抗疫苗的抗药性癌和传染病，这取决于采用亚基抗原的结构。虽然使用定义的分子抗原在免疫反应靶向方面具有优势，但它们的免疫原性通常较低。通常，这些疫苗制剂需要一种辅助物质，这是一种增强免疫反应的物质。疫苗佐剂的关键作用在于它们的能力（1）实现原本无能的抗原，（2）将疫苗的益处扩展到较差的响应者（例如，年龄较大或免疫功能低下的患者），以及（3）效果“稀有和昂贵的抗原的剂量 - 比剂量”（例如，在供应中（例如，在epecticmecy中）。天然产物Saponin QS-21是许多有前途的抗肿瘤和抗病毒疫苗临床试验的辅助剂，尽管与毒性，化学不稳定性以及纯净形式缺乏可用性有关。该赠款的应用包括一种独特的多学科方法，用于制备，发现，评估和理解对癌症和传染病疫苗开发必不可少的有效辅助分子。该研究计划的具体目的将涉及：（1）开发新颖有效的策略，用于化学合成皂苷QS-21的设计非天然结构变体，具有改善的活性和稳定性，并减弱毒性；（2）评估小鼠中这些新化合物的评估，以评估它们增强免疫反应的能力及其特定毒性谱；（3）采用小型动物射线射击技术，免疫组织学，细胞因子分析和亲和色谱法，以深入了解辅助者的作用机理。这些努力将解决与这种非常复杂的佐剂类别相关的基本化学和免疫学问题，并有望在疫苗领域产生新的治疗疗法。公共卫生相关性：抗肿瘤和抗病毒疫苗的成功通常需要使用佐剂，佐剂本身不一定是免疫原性的，但会显着增强患者对辅助抗原的免疫反应。该赠款的应用包括一种独特的多学科方法，用于制备，发现，评估和理解对癌症和传染病疫苗开发必不可少的有效辅助分子。这些努力将解决免疫反应增强的基本化学和免疫学问题，并有望在疫苗领域产生新的治疗疗法。