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: 10841112
• 负责人: Emil Khisamutdinov
• 金额: $ 3.97万
• 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/10841112
• 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; Immunoglobulin M; 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; cancer therapy; cancer type; career; chemical stability; cost; cross reactivity; design; dimer; experience; graduate student; immunogenicity; in vivo; in vivo Model; innovation; large scale production; meetings; men; monomer; nano; nanoparticle; novel therapeutics; 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.

抽象的 治疗性单克隆抗体 (mAb) 是增长最快的一类新治疗药物。 对于治疗包括前列腺癌（PC）在内的各种类型的癌症具有广阔的前景。 结构复杂、选择困难、生产成本高、交叉反应性、免疫原性和相关性 不稳定是现代医学快速发展和苛刻需求的主要限制。 与 mAb 相比，核酸 (NA) 适体与其表位结合具有相似的高亲和力和特异性 最近已成为诊断、治疗、成像和靶向领域中单克隆抗体的有吸引力的替代品 应用程序。 在此，我们建议生成一组创新的基于核酸的纳米颗粒（NANP），模仿 mAb（NANP-mAb）利用了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核酸多边形将作为 支架在精确位置容纳一个或多个 PC 结合适体 编程的目的。 设计旨在模仿 mAb 的结构同种型，包括单体（IgD、IgE、IgG）、二聚体（IgA）和五聚体 (IgM)，酶稳定的 2'F 修饰的 RNA 适体，已知具有很强的结合亲和力。 PC 细胞的前列腺特异性膜抗原 (PSMA) 被选为主要的适体候选者。 mAb，产生的 NANP-mAb 不需要任何动物用于其生产，并且由于可编程 NANP 是在体外合成和组装的，它们具有出色的批次间一致性。 经济、高精度、大规模生产所提出的 NANP-mAb，用于 PC 检测和 治疗。 本科院校学术研究增强奖（AREA）的目标 R15提案是开发一个强大的NANP-mAbs系统，可用于治疗应用 短期目标是构建一组能够适应多种疾病的 NANP-mAb。 多个人 PSMA 结合适体和成像染料可产生协同和增强的 PC 特异性 所有 NANP-mAb 的结合亲和力和细胞内化都将受到影响。 必须并排比较并筛选体内模型的候选者，最终得出结果。 这个创新项目产生的成果将导致强大的纳米支架平台的开发 生物医学应用。

项目成果

Bioconjugation of Functionalized Oligodeoxynucleotides with Fluorescence Reporters for Nanoparticle Assembly.

功能化寡脱氧核苷酸与荧光报告基因的生物共轭用于纳米颗粒组装。

• 发表时间: 2023
• 作者: Doe, Erwin;Hayth, Hannah L;Khisamutdinov, Emil F
• 通讯作者: Khisamutdinov, Emil F

Effective, Rapid, and Small-Scale Bioconjugation and Purification of "Clicked" Small-Molecule DNA Oligonucleotide for Nucleic Acid Nanoparticle Functionalization.

有效、快速、小规模的“点击”小分子 DNA 寡核苷酸生物共轭和纯化，用于核酸纳米颗粒功能化。

• 发表时间: 2023-03-02
• 影响因子: 5.6
• 作者: Doe, Erwin;Hayth, Hannah L;Brumett, Ross;Khisamutdinov, Emil F
• 通讯作者: Khisamutdinov, Emil F

Thermodynamic Characterization of Nucleic Acid Nanoparticles Hybridization by UV Melting.

紫外熔融核酸纳米颗粒杂交的热力学表征。

• 发表时间: 2023
• 作者: Teter, Megan;Brumett, Ross;Coffman, Abigail;Khisamutdinov, Emil F
• 通讯作者: Khisamutdinov, Emil F

Toehold-Mediated Shape Transition of Nucleic Acid Nanoparticles.

核酸纳米粒子的立足点介导的形状转变。

• 发表时间: 2023-05-31
• 影响因子: 9.5
• 作者: Hartung, Jordan;McCann, Nathan;Doe, Erwin;Hayth, Hannah;Benkato, Kheiria;Johnson, M Brittany;Viard, Mathias;Afonin, Kirill A;Khisamutdinov, Emil F
• 通讯作者: Khisamutdinov, Emil F

Design and Characterization of Compact, Programmable, Multistranded Nonimmunostimulatory Nucleic Acid Nanoparticles Suitable for Biomedical Applications.

适用于生物医学应用的紧凑、可编程、多链非免疫刺激核酸纳米颗粒的设计和表征。

• 发表时间: 2024-02-06
• 影响因子: 2.9
• 作者: Brumett, Ross;Danai, Leyla;Coffman, Abigail;Radwan, Yasmine;Teter, Megan;Hayth, Hannah;Doe, Erwin;Pranger, Katelynn;Thornburgh, Sable;Dittmer, Allison;Li, Zhihai;Kim, Tae Jin;Afonin, Kirill A;Khisamutdinov, Emil F
• 通讯作者: Khisamutdinov, Emil F