A fully synthetic carbohydrate-based cancer vaccine

一种全合成的基于碳水化合物的癌症疫苗

基本信息

批准号：
7909448
负责人：
Geert-Jan Boons
金额：
$ 15.15万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7909448
关键词：
Adjuvant Affect Antibodies Antibody Formation Antigen-Presenting Cells Antigens Appearance Architecture B-Lymphocytes CD4 Positive T Lymphocytes Cancer Patient Cancer Vaccine Related Development Cancer Vaccines Carbohydrates Carrier Proteins Cell surface Cells Characteristics Clinical Research Complex Conjugate Vaccines Cysteine Cytolysis Development Drug Formulations Epitopes Flow Cytometry Foundations Funding Glycopeptides Goals Helper-Inducer T-Lymphocyte Immune Sera Immune response Immune system Immunization Immunoglobulin Class Switching Immunoglobulin G Inbred BALB C Mice Keyhole Limpet Hemocyanin Knowledge Lead Ligands Lipid A Liposomes Malignant Neoplasms Mediating Mono-S Mus Neoplasm Metastasis Operative Surgical Procedures Patients Pattern Peptide T Phase I Clinical Trials Preparation Production Property Proteins QS21 Relapse Research Personnel Residual Neoplasm Role Signal Transduction Subunit Vaccines Surface Antigens Survival Rate Synthetic Vaccines T-Lymphocyte TLR2 gene Time Toll-Like Receptor 2 Tumor-Associated Carbohydrate Antigens Vaccines Viral base cancer cell chemotherapy cytokine expectation glycolipopeptide immunogenicity improved neoplastic cell novel novel strategies pre-clinical programs response tumor tumor progression uptake vaccine candidate

项目摘要

Tumor progression is intimately associated with the appearance of unusual carbohydrates on the surface of cells. A broad and expanding body of preclinical and clinical studies demonstrates that naturally acquired, passively administered or actively induced antibodies against these carbohydrate-associated tumor antigens are able to eliminate tumor cells. Carbohydrate-based cancer vaccine developmenthas, however, been complicated by the difficulty of eliciting high titers of IgG antibodies in most patients. The successful development of a carbohydrate-based cancer vaccine requires a novel strategy for a more efficient presentation of tumor associated carbohydrate epitopes to the immune system resulting in a more efficient class switch to IgG antibodies. We have shown that a full-synthetic vaccine candidate composed of a tumor-associated carbohydrate-antigen, a promiscuous peptide T-helper epitope and the lipopeptide adjuvant S-[(R)-2,3- dipalmitoyloxy-propyl]-N-palmitoyl-(R)-cysteine (Pam3Cys) can successfully elicit high titers of IgG antibodies. The objective of this application is to investigate in detail the optimum architecture of a three- component cancer-vaccine for eliciting a strong and relevant anti-tumor immune response. Furthermore, the role of the TLR ligand (adjuvant) to polarize the immune response will be investigated. Thus, three- component cancer vaccines will be synthesized that differ in B- and T-epitopes, TLR ligands and topology The antigenicity of the synthetic compounds and ability of the antisera to recognize and neutralize cancer cells will be determined. Finally, the ability of the synthetic vaccine candidates to induce a range of cytokines relevant to adaptive immune response will be examined. At the completion of our studies, we will be able to make correlations between the architecture of the glycolipopeptides and innate and adaptive immune responses and the ability of antisera to recognize and eliminate cancer cells. These correlations will provide a firm scientific foundation for murine tumor-challenge studies or a phase I clinical trial.

肿瘤进展与异常碳水化合物的出现密切相关细胞表面。广泛且不断扩大的临床前和临床研究表明，自然获得的、被动施用或主动诱导的针对这些碳水化合物相关的抗体肿瘤抗原能够消灭肿瘤细胞。基于碳水化合物的癌症疫苗的开发，然而，由于在大多数患者中难以引发高滴度 IgG 抗体，使情况变得复杂。这成功开发基于碳水化合物的癌症疫苗需要一种新的策略有效地将肿瘤相关碳水化合物表位呈递给免疫系统，从而产生更多高效切换至 IgG 抗体。我们已经证明，一种由肿瘤相关蛋白组成的全合成候选疫苗碳水化合物抗原、混杂的肽 T 辅助表位和脂肽佐剂 S-[(R)-2,3- 二棕榈酰氧基-丙基]-N-棕榈酰-(R)-半胱氨酸 (Pam3Cys) 可成功引发高滴度 IgG 抗体。此应用程序的目的是详细研究三层的最佳架构组成癌症疫苗，用于引发强烈且相关的抗肿瘤免疫反应。此外，将研究 TLR 配体（佐剂）极化免疫反应的作用。因此，三- 将合成 B 和 T 表位、TLR 配体和拓扑结构不同的癌症疫苗成分合成化合物的抗原性以及抗血清识别和中和癌症的能力细胞将被确定。最后，合成候选疫苗诱导一系列细胞因子的能力将检查与适应性免疫反应相关的问题。完成我们的研究后，我们将能够在架构之间建立关联糖脂肽和先天性和适应性免疫反应以及抗血清识别和识别的能力消除癌细胞。这些相关性将为小鼠肿瘤挑战提供坚实的科学基础研究或 I 期临床试验。