Nucleic Acid Nanoparticle-based Monoclonal Antibody Mimics

基于核酸纳米颗粒的单克隆抗体模拟物

• 批准号: 10201231
• 负责人: Emil Khisamutdinov
• 金额: $ 41.74万
• 依托单位: BALL STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201231
• 关键词: 3-Dimensional; Academic Research Enhancement Awards; Affect; Affinity; American Cancer Society; Animals; Antigens; Avidity; Award; Binding; Biological Sciences; Cancer Etiology; Cell Survival; Cells; Cessation of life; Chemicals; Chemistry; Complex; DNA; Detection; Development; Diagnosis; Diagnostic; Discipline; Disease; Dyes; Epitopes; Excision; Exhibits; FOLH1 gene; Goals; Human; IgE; Image; Immune; Immunoglobulin A; Immunoglobulin D; Immunoglobulin G; Immunologics; In Vitro; Institution; Interdisciplinary Study; LNCaP; Laboratory Research; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Modern Medicine; Monoclonal Antibodies; Monoclonal Antibody Therapy; Nanotechnology; Nucleic Acids; Oligonucleotides; Pharmaceutical Preparations; Population; Positioning Attribute; Production; Property; Prostate; Prostate Cancer therapy; RNA; Reporting; Research; Resistance; Screening for Prostate Cancer; Serum; Shapes; Side; Specificity; Structure; Surface Plasmon Resonance; System; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Thermodynamics; Variant; Work; antigen binding; aptamer; base; cancer therapy; cancer type; career; cost; cross reactivity; design; dimer; experience; graduate student; immunogenicity; in vivo; in vivo Model; innovation; large scale production; meetings; men; monomer; nanoparticle; novel therapeutics; programs; prostate cancer cell; scaffold; student participation; undergraduate student

ABSTRACT Therapeutic monoclonal antibodies (mAbs) are the fastest growing class of new therapeutic agents. They hold great promise for the treatment of various types of cancer including prostate cancer (PC). However, their complex structure, selection difficulties, high costs of production, cross reactivity, immunogenicity, and relative instability are the major limitations in the rapidly evolving and demanding needs of modern medicine. Frequently compared to mAbs, Nucleic Acid (NA) aptamers bind with similarly high affinity and specificity to their epitopes and have recently emerged as attractive alternatives to mAbs in diagnostic, therapeutic, imaging and targeting applications. Herein, we propose to generate a panel of innovative nucleic acid-based nanoparticles (NANPs) that mimic mAbs (NANP-mAbs) by utilizing advantages of aptamers. Our recently developed modular, enzymatically stable, and non-immunogenic chemically modified nucleic acid polygons of different sizes and shapes will serve as scaffolds to harbor one or multiple PC binding aptamers at a precise position. The purpose of the programmed design is to mimic structural isotypes of mAbs including monomers (IgD, IgE, IgG), dimers (IgA), and pentamers (IgM). The enzymatically stable 2’F-modified RNA aptamer that is known to have strong binding affinity to Prostate Specific Membrane Antigen (PSMA) of PC cells is selected as primarily aptamer candidate. Unlike mAbs, the resulting NANP-mAbs do not require any animal use for their production and since programmable NANPs are synthesized and assembled in vitro, they offer a great batch-to-batch consistency. This all allows for an economical, highly accurate, large-scale production of the proposed NANP-mAbs for PC detection and treatment. The goal of this Academic Research Enhancement Award for Undergraduate-Focused Institutions (AREA) R15 proposal is to develop a robust NANP-mAbs system that can be used for therapeutic applications towards a broad range of diseases. The short-term objective is to construct a panel of NANP-mAbs that will accommodate multiple human PSMA binding aptamers and an imaging dye to generate synergistic and enhanced PC-specific binding and therapeutic effects. Binding affinities and cellular internalization of all NANP-mAbs will be systematically compared side-by-side and screen candidates for the in vivo models. Ultimately, the results generated from this innovative project will lead to the development of robust nanoscaffold platforms for biomedical applications.

摘要 治疗性单克隆抗体（mAb）是增长最快的一类新的治疗剂。他们 在治疗包括前列腺癌（PC）在内的各种癌症方面前景广阔。但他们的 结构复杂、选择困难、生产成本高、交叉反应性、免疫原性和相对生物学特性。 不稳定性是现代医学快速发展和苛刻需求的主要限制。频繁 与单克隆抗体相比，核酸（NA）适体以类似的高亲和力和特异性结合其表位 并且最近在诊断、治疗、成像和靶向方面成为单克隆抗体的有吸引力的替代品 应用. 在此，我们建议产生一组创新的基于核酸的纳米颗粒（NANP）， 单克隆抗体（NANP-单克隆抗体）。我们最近开发的模块化，酶稳定， 不同大小和形状的非免疫原性化学修饰的核酸多边形将用作 支架以在精确位置处容纳一个或多个PC结合适体。程序的目的 设计旨在模拟mAb的结构同种型，包括单体（IgD、IgE、IgG）、二聚体（伊加）和五聚体 （IgM）。已知酶促稳定的2 'F-修饰的RNA适体具有强结合亲和力， 选择PC细胞的前列腺特异性膜抗原（PSMA）作为主要的适体候选物。不像 由于NANP-mAb是可编程的，因此所得NANP-mAb的生产不需要任何动物使用， NANP是在体外合成和组装的，它们提供了很好的批次间一致性。这一切都考虑到 用于PC检测的所提出的NANP-mAb的经济、高准确度、大规模生产，以及 治疗 本届本科院校学术研究提升奖（AREA）的目标 R15的建议是开发一种稳健的NANP-单克隆抗体系统，可用于治疗应用， 一系列的疾病。短期目标是构建一组NANP-mAb， 多种人PSMA结合适体和成像染料以产生协同和增强的PC特异性 结合和治疗效果。所有NANP-单抗的结合亲和力和细胞内化将被评估。 系统地比较了体内模型的并排和筛选候选物。最终，结果 从这个创新项目产生的将导致强大的nanoscaffold平台的发展， 生物医学应用