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

• 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
• 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

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.

项目总结 肿瘤抗原的利用，即在癌细胞中表达的抗原肽，其结果是随机 体细胞突变，用于开发针对患者的治疗性癌症疫苗一直是一个领域 强烈的兴趣。然而，在安全和有效地提供亚单位疫苗方面仍然存在重大挑战。 激发强大的抗肿瘤免疫反应的成分。为了克服这些挑战，这 Proposal利用一种新的方法来保护活性多肽免受蛋白质分解的影响，以持续递送 肿瘤抗原与免疫调节化合物联合作为合理设计的癌症疫苗。这 Approach将多肽作为高密度刷状聚合物包装在一起，这导致了独特的 与利用多肽作为治疗药物的传统尝试相比，具有显著优势的特征。这些 包括增加对蛋白质降解的抵抗力和改善药代动力学曲线，同时保持强劲 生物活性和细胞摄取。这种多肽包装方法被称为类蛋白质聚合物(PLP)，因为它 聚集在疏水合成聚合物核心周围的球状多肽结构，显示出活性 以序列控制的方式识别和发挥功能的氨基酸。PLP在有效载荷方面是模块化的， 能够与特定比例的多肽、小分子和核酸结合。进一步 PLP的修饰可以赋予其他特性，包括组织靶向、特定部位的货物释放和 堆积密度的变化。PLP纳米平台表明，以独特的3- 空间结构显示出该构型所特有的性质，为生物分子提供了新的途径 送货。在这项提议中，PLP将被用来克服与利用肿瘤相关的固有困难 抗原作为癌症疫苗，即通过防止其降解，实现靶向递送，并允许 比例定义的不同抗原与免疫刺激化合物的多价展示。