Engineering bacteriophage Qβ conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines

工程噬菌体 Qβ 与肿瘤相关碳水化合物抗原缀合物作为多组分抗癌疫苗

基本信息

批准号：
10358502
负责人：
Xuefei Huang
金额：
$ 44.74万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358502
关键词：
Abbreviations Address Adjuvant Alkynes Animal Model Antibodies Antibody Response Antigen-Presenting Cells Antigens Apoptosis Azides B-Lymphocytes Bacteriophages Biological Assay CD22 gene Caliber Cancer Patient Cancer Vaccines Canis familiaris Capsid Carbohydrates Cause of Death Centers for Disease Control and Prevention (U.S.)Cessation of life Characteristics Clinical Clinical Trials Complement-Dependent Cytotoxicity Copper Crystallization Cyclophosphamide Cytotoxic T-Lymphocytes Dendritic Cells Development Dreams Engineering Enzyme-Linked Immunosorbent Assay Enzymes Esters Future Ganglioside GD2 Glycopeptides Helper-Inducer T-Lymphocyte Human Immune Immune response Immunity Immunize Immunoglobulin G Immunoglobulins Immunologic Surveillance Keyhole Limpet Hemocyanin Ligands Link Lipid A Major Histocompatibility Complex Malignant Neoplasms Molecular Weight Monoclonal Antibodies Mucin 1 protein Mus Natural Killer Cells Normal Cell Passive Immunity Patients Polysaccharides Population Prevention therapy Proteins Resistance Resolution Risk Scheme Structure T cell response T-Lymphocyte Epitopes Testing Tn antigen Toll-like receptors Transgenic Mice Transgenic Organisms Translations Tumor Antibodies Tumor Escape Tumor Immunity Tumor-Associated Carbohydrate Antigens United States Food and Drug Administration Vaccine Design Vaccines Variant Virus-like particle aldehyde dehydrogenases anti-cancer anti-tumor immune response antibody-dependent cell cytotoxicity base cancer biomarkers cancer cell cancer stem cell cancer therapy cancer type carboxyfluorescein chemotherapy clinically relevant cycloaddition density design human disease human model immunogenic immunogenicity innovation liquid chromatography mass spectrometry mouse model mutant neoplastic cell novel osteosarcoma polymerization preservation pressure prevent programmed cell death protein 1 response stem cells success tumor tumor growth vaccine efficacy vaccine platform vaccine safety

项目摘要

Project Summary Targeting tumor-associated carbohydrate antigens (TACAs) for anticancer vaccines is exceptionally attractive because many TACAs are highly expressed on multiple types of cancer cells with no or negligible expression on normal cells. While passive immunity utilizing anti-TACA monoclonal antibodies has achieved clinical success, developing a TACA based immunogen to elicit effective anti-cancer immunity has been extremely difficult due to the notoriously low immunogenicity of TACAs. To address this challenge, exciting preliminary results have been obtained showing that TACA-based vaccines can significantly reduce cancer induced death by delivering a prototypical TACA, the Tn antigen, using virus like particle bacteriophage Qβ. In this proposal, new ground in TACA based cancer vaccine design will continue to be broken by engineering Qβ to generate powerful anti-cancer immune responses. Building on the exciting preliminary results, in Aim 1, an important tumor associated glycopeptide antigen human MUC-1 bearing Tn glycan will be targeted. Using Qβ as the carrier, super-high titers of IgG antibodies were elicited against MUC1-Tn, which significantly reduced tumor growth in mice, even in transgenic mice tolerant to human MUC1. Besides Tn and tumor associated MUC1 glycopeptides, other TACAs including GD2 and SSEA-3 will be investigated as vaccine targets to reduce the risk of tumor escape from immune surveillance and to kill purported cancer stem cells, a possible cause for resistance to traditional treatments such as chemotherapy. In addition, guided by the crystal structure of Qβ, Qβ mutants will be developed to reduce undesirable anti-Qβ antibodies and further boost desired anti- TACA responses. Cytotoxic T cells can also kill cancer cells. In Aim 2, Qβ will be engineered to deliver cytotoxic T cell epitopes and built-in adjuvants in addition to generating anti-TACA IgG antibodies. The comprehensive antibody and cytotoxic T cell immune responses induced by Qβ-TACA-cytotoxic T cell epitope conjugate should provide superior protection to immunized host against tumor development. To lay the groundwork for future translation, in Aim 3, the vaccine efficacy in treating canine cancer patients will be established. Canines can naturally develop cancer, which are clinically relevant large animal models for human diseases due to their high similarities to human cancer. This will be the first of its kind trial of such TACA based vaccine constructs in canine patients. Overall impacts: This project will establish a Qβ vaccine platform vastly superior to currently available carriers to deliver both TACAs and cytotoxic T cell epitopes, which will elicit long-lasting anti-TACA IgG antibodies and cytotoxic T cells for cancer treatment. Deeper understanding of the connections between structural features of Qβ-TACA conjugates and anti-tumor immunity will exert a sustained impact on cancer vaccine design and is essential for successful TACA-based anti-cancer vaccines.

项目概要针对肿瘤相关碳水化合物抗原（TACA）的抗癌疫苗是非常特殊的之所以有吸引力，是因为许多 TACA 在多种类型的癌细胞中高度表达，而没有或可以忽略不计。同时利用抗 TACA 单克隆抗体实现了被动免疫。临床成功，开发基于 TACA 的免疫原以引发有效的抗癌免疫由于 TACA 的免疫原性非常低，因此解决这一挑战非常困难，令人兴奋。初步结果显示基于 TACA 的疫苗可显着减少癌症通过使用病毒样颗粒噬菌体 Qβ 传递原型 TACA（Tn 抗原）来诱导死亡。在此提案中，基于 TACA 的癌症疫苗设计的新领域将继续被打破在令人兴奋的初步结果的基础上，对 Qβ 进行改造以产生强大的抗癌免疫反应。在目标1中，将靶向具有Tn聚糖的重要肿瘤相关糖肽抗原人MUC-1。以Qβ为载体，诱导产生超高滴度的针对MUC1-Tn的IgG抗体，显着减少小鼠的肿瘤生长，甚至在对人类 MUC1 和肿瘤以外具有耐受性的转基因小鼠中也是如此。相关的 MUC1 糖肽、GD2 和 SSEA-3 等其他 TACA 将作为疫苗靶点进行研究降低肿瘤逃避免疫监视的风险并杀死所谓的癌症干细胞，一种可能的方法此外，还受晶体结构的影响，导致对化疗等传统治疗产生耐药性。 Qβ、Qβ突变体将被开发以减少不需要的抗Qβ抗体并进一步增强所需的抗- TACA 反应也可以杀死癌细胞。在目标 2 中，Qβ 将被设计为提供细胞毒性。除了生成抗 TACA IgG 抗体外，还包含 T 细胞表位和内置佐剂。 Qβ-TACA-细胞毒性 T 细胞表位缀合物诱导的抗体和细胞毒性 T 细胞免疫反应应为免疫宿主提供卓越的保护，防止肿瘤的发展，为未来奠定基础。换句话说，在目标 3 中，将确定疫苗对治疗犬类癌症患者的功效。自然发展为癌症，由于其高水平，它们是人类疾病临床相关的大型动物模型这将是此类基于 TACA 的疫苗结构的首次试验。犬类患者。总体影响：该项目将建立一个远远优于目前可用的 Qβ 疫苗平台载体递送 TACA 和细胞毒性 T 细胞表位，这将引发持久的抗 TACA IgG 更深入地了解用于癌症治疗的抗体和细胞毒性 T 细胞之间的联系。 Qβ-TACA缀合物的结构特征和抗肿瘤免疫将对癌症产生持续影响疫苗设计对于基于 TACA 的抗癌疫苗的成功至关重要。