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 治疗性单抗是目前发展最快的一类新型治疗药物。他们 对包括前列腺癌(PC)在内的各种癌症的治疗大有可为。然而，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 不稳定是现代医学快速发展和要求苛刻的需求的主要限制。频繁 与单抗相比，核酸适配子与其表位具有同样高的亲和力和特异性 最近在诊断、治疗、成像和靶向方面成为mAbb的有吸引力的替代品 申请。 在这里，我们建议生成一组创新的基于核酸的纳米颗粒(NANP)，以模拟 利用适配子的优势进行单抗(NANP-mAbs)的研究。我们最近开发的模块化的，酶稳定的， 和不同大小和形状的非免疫原性化学修饰的核酸多边形将作为 支架在一个精确的位置放置一个或多个PC结合适配子。编程的目的 设计是模仿单抗的结构同型，包括单体(IgD、IgE、Ig G)、二聚体(Ig A)和五聚体 (IGM)。酶稳定的2‘F-修饰的RNA适配子，已知与 PC细胞的前列腺特异性膜抗原(PSMA)被选为第一适配子候选。不像 单抗，得到的NANP-单抗不需要任何动物用途来生产，因为是可编程的 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。这一切都允许 经济、高精度、大规模生产用于PC检测和检测的NANP-mAb 治疗。 这项面向本科重点院校(地区)的学术研究提升奖的目标 R15建议开发一种强大的NANP-mAbbs系统，可用于以下治疗应用 各种各样的疾病。短期目标是构建一组NANP-mAb，以适应 多个人PSMA结合适配子和一种成像染料产生协同和增强的PC特异性 具有约束性和治疗性。所有NANP-mAb的结合亲和力和细胞内化将是 系统地比较了体内模型的并排和筛选候选模型。最终，结果是 这一创新项目产生的纳米支架将为以下领域带来强大的发展 生物医学应用。