Development of Rationally Designed Cancer Vaccines Using Protein-like Polymers (PLPs)

使用类蛋白聚合物 (PLP) 开发合理设计的癌症疫苗

基本信息

批准号：
10457246
负责人：
Max Wang
金额：
$ 5.03万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457246
关键词：
Address Adjuvant Affect Agonist Amides Amino Acids Antigen-Presenting Cells Antigens Antitumor Response Architecture Area Autoimmunity CT26 Cancer Vaccines Cell Proliferation Cells Characteristics Chemistry Clinical Colon Carcinoma Combination immunotherapy Complex Cross Presentation Data Development Disulfide Linkage Drug Kinetics Esters Exhibits Formulation Generations Harvest Heterophile Antigens High Pressure Liquid Chromatography Human papillomavirus 16 Hydrophobicity Immune Immune response Immunity Incubated Kinetics Label Length Libraries Malignant Neoplasms Mediating Methodology Methods Modeling Molecular Weight Mus Neoplasm Transplantation Nucleic Acids Oncoproteins Ovalbumin Patients Peptides Polymers Post-Translational Protein Processing Production Property Proteins Proteolysis Reaction Resistance Risk SILV gene STING agonists Side Signal Transduction Site Somatic Mutation Structure Structure-Activity Relationship Subunit Vaccines System T-Lymphocyte Testing Therapeutic Time Tissues Transgenic Organisms Treatment Protocols Tumor Antigens Tumor Burden Tumor Immunity Vaccination Vaccines Vertebral column anti-PD-1/PD-L1 anti-PD-L1 antibodies anti-cancer anti-tumor immune response base cancer cell cancer immunotherapy central tolerance combinatorial copolymer cytokine density design disulfide bond early phase clinical trial effective therapy effectiveness evaluation efficacy testing experimental study gp100 Antigen immunogenic immunoregulation improved in vitro Assay in vivo insight interest melanoma melanoma-associated antigen nanoparticle nanotechnology platform neoantigens novel peripheral tolerance physical property polymerization preservation prevent rational design small molecule spatiotemporal synergism targeted delivery three dimensional structure treatment optimization tumor uptake vaccine efficacy vaccine formulation

项目摘要

PROJECT SUMMARY The utilization of tumor antigens, which are antigenic peptides expressed in cancer cells as a result of random somatic mutations, for the development of patient-specific therapeutic cancer vaccines has been an area of intense interest. However, significant challenges remain in safely and efficiently delivering subunit vaccine components for the elicitation of robust antitumor immune responses. To overcome these challenges, this proposal utilizes a new methodology for protecting active peptides from proteolysis for the sustained delivery of tumor antigens in conjunction with immunomodulatory compounds as rationally designed cancer vaccines. This approach packages peptides together as high-density brush polymers, which results in the introduction of unique characteristics with significant advantages over conventional attempts to utilize peptides as therapeutics. These include increased resistance to proteolysis and improved pharmacokinetic profiles, while maintaining strong bioactivity and cell uptake. This peptide packaging method is termed Protein-Like Polymers (PLPs) due to its globular, peptide-based structure assembled around a hydrophobic synthetic polymer core, displaying active amino acids for recognition and function in a sequence-controlled manner. PLPs are modular in terms of payload, able to be conjugated with defined proportions of peptides, small molecules, and nucleic acids. Further modifications of PLPs can confer additional properties including tissue targeting, site-specific cargo release, and changes in packing density. The PLP nanoplatform demonstrates that compounds arranged in unique 3- dimensional structures exhibit properties exclusive to that configuration, providing new avenues for biomolecule delivery. For this proposal, PLPs will be used to overcome inherent difficulties associated with utilizing tumor antigens as cancer vaccines, namely by preventing their degradation, enabling targeted delivery, and allowing proportion-defined multivalent display of dissimilar antigens with immunostimulatory compounds.

项目摘要肿瘤抗原的利用，它们是随机在癌细胞中表达的抗原肽体细胞突变，用于发育患者特异性治疗性癌症疫苗一直是强烈的兴趣。但是，在安全有效地输送亚基疫苗中仍然存在重大挑战启发鲁棒抗肿瘤免疫反应的成分。为了克服这些挑战，提案利用一种新方法来保护活性肽免受蛋白水解的持续递送肿瘤抗原与免疫调节化合物作为合理设计的癌症疫苗。这接近肽作为高密度刷聚合物一起包装，这导致引入独特与传统尝试使用肽作为治疗剂相比，具有显着优势的特征。这些包括对蛋白水解的耐药性增加和改善的药代动力学特征，同时保持强大生物活性和细胞摄取。这种肽包装方法称为蛋白质样聚合物（PLP）球状基于肽的结构围绕疏水合成聚合物核心组装，显示活性氨基酸以序列控制的方式识别和功能。 PLP在有效载荷方面是模块化的，能够与定义的肽，小分子和核酸相结合。更远 PLP的修改可以赋予其他特性，包括组织靶向，特定地点的货物释放和包装密度的变化。 PLP纳米平台表明，以独特的3-排列的化合物尺寸结构表现出该配置独有的属性，为生物分子提供了新的途径送货。对于此提案，PLP将用于克服与使用肿瘤有关的固有困难抗原作为癌症疫苗，即防止其降解，实现靶向输送并允许具有免疫刺激化合物的不同抗原的比例定义的多价显示。