• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

抗体-寡核苷酸缀合物的结构-活性关系：评估用于药物开发的抗体-磷酰二胺吗啉寡聚物缀合物的生物缀合策略。

Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-Phosphorodiamidate Morpholino Oligomer Conjugates for Drug Development.

机构信息

Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125, San Diego, California 92121, United States.

CYTOO, 7 Parv. Louis Néel CS 20050, 38040 Grenoble, France.

出版信息

J Med Chem. 2024 Sep 12;67(17):14868-14884. doi: 10.1021/acs.jmedchem.4c00803. Epub 2024 Aug 28.

DOI:10.1021/acs.jmedchem.4c00803
PMID:39197837
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11403617/
Abstract

Antibody-oligonucleotide conjugates (AOCs) are promising treatments for Duchenne muscular dystrophy (DMD). They work via induction of exon skipping and restoration of dystrophin protein in skeletal and heart muscles. The structure-activity relationships (SARs) of AOCs comprising antibody-phosphorodiamidate morpholino oligomers (PMOs) depend on several aspects of their component parts. We evaluate the SAR of antimouse transferrin receptor 1 antibody (αmTfR1)-PMO conjugates: cleavable and noncleavable linkers, linker location on the PMO, and the impact of drug-to-antibody ratios (DARs) on plasma pharmacokinetics (PK), oligonucleotide delivery to tissues, and exon skipping. AOCs containing a stable linker with a DAR9.7 were the most effective PMO delivery vehicles in preclinical studies. We demonstrate that αmTfR1-PMO conjugates induce dystrophin protein restoration in the skeletal and heart muscles of mice. Our results show that αmTfR1-PMO conjugates are a potentially effective approach for the treatment of DMD.

摘要

抗体-寡核苷酸缀合物 (AOCs) 是治疗杜氏肌营养不良症 (DMD) 的有前途的方法。它们通过诱导外显子跳跃和恢复骨骼肌和心肌中的肌营养不良蛋白起作用。由抗体-磷酸二酰胺吗啉寡聚物 (PMO) 组成的 AOC 的结构-活性关系 (SAR) 取决于其组成部分的几个方面。我们评估了抗小鼠转铁蛋白受体 1 抗体 (αmTfR1)-PMO 缀合物的 SAR：可切割和不可切割的接头、PMO 上接头的位置，以及药物与抗体的比例 (DAR) 对血浆药代动力学 (PK)、寡核苷酸向组织的递送以及外显子跳跃的影响。在临床前研究中，含有稳定接头和 DAR9.7 的 AOC 是最有效的 PMO 递药载体。我们证明，αmTfR1-PMO 缀合物可诱导小鼠骨骼肌和心肌中的肌营养不良蛋白恢复。我们的结果表明，αmTfR1-PMO 缀合物是治疗 DMD 的一种潜在有效方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/f73725cad754/jm4c00803_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/071c8f7b3e27/jm4c00803_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/c53dca4c099c/jm4c00803_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/6a056ec1f16a/jm4c00803_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/18f754820a23/jm4c00803_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/a94472e10c88/jm4c00803_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/8ae7ddbbc66c/jm4c00803_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/53ee69d80fe2/jm4c00803_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/5e92fa457ebf/jm4c00803_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/3aaabada00b1/jm4c00803_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/f73725cad754/jm4c00803_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/071c8f7b3e27/jm4c00803_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/c53dca4c099c/jm4c00803_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/6a056ec1f16a/jm4c00803_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/18f754820a23/jm4c00803_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/a94472e10c88/jm4c00803_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/8ae7ddbbc66c/jm4c00803_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/53ee69d80fe2/jm4c00803_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/5e92fa457ebf/jm4c00803_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/3aaabada00b1/jm4c00803_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf33/11403617/f73725cad754/jm4c00803_0008.jpg

相似文献

1
Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-Phosphorodiamidate Morpholino Oligomer Conjugates for Drug Development.抗体-寡核苷酸缀合物的结构-活性关系：评估用于药物开发的抗体-磷酰二胺吗啉寡聚物缀合物的生物缀合策略。
J Med Chem. 2024 Sep 12;67(17):14868-14884. doi: 10.1021/acs.jmedchem.4c00803. Epub 2024 Aug 28.
2
Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice.利用 TfR1 靶向递送反义寡核苷酸并通过 FORCE 缀合在 mdx 小鼠中实现增强的外显子跳跃和延长的肌营养不良蛋白恢复。
Nucleic Acids Res. 2022 Nov 11;50(20):11401-11414. doi: 10.1093/nar/gkac641.
3
Bubble liposomes and ultrasound exposure improve localized morpholino oligomer delivery into the skeletal muscles of dystrophic mdx mice.气泡脂质体和超声照射可改善吗啉代寡聚物在营养不良性mdx小鼠骨骼肌中的局部递送。
Mol Pharm. 2014 Mar 3;11(3):1053-61. doi: 10.1021/mp4004755. Epub 2014 Jan 27.
4
Morpholino-induced exon skipping stimulates cell-mediated and humoral responses to dystrophin in mdx mice.Morpholino 诱导的外显子跳跃刺激 mdx 小鼠中的细胞介导和体液反应对肌营养不良蛋白。
J Pathol. 2019 Jul;248(3):339-351. doi: 10.1002/path.5263. Epub 2019 Apr 16.
5
Effects of Chronic, Maximal Phosphorodiamidate Morpholino Oligomer (PMO) Dosing on Muscle Function and Dystrophin Restoration in a Mouse Model of Duchenne Muscular Dystrophy.慢性最大剂量磷酰二胺吗啉代寡聚物（PMO）给药对杜氏肌营养不良症小鼠模型肌肉功能和肌营养不良蛋白恢复的影响。
J Neuromuscul Dis. 2021;8(s2):S369-S381. doi: 10.3233/JND-210701.
6
Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice.己糖可增强抗肌萎缩蛋白缺陷的mdx小鼠的寡核苷酸递送和外显子跳跃。
Nat Commun. 2016 Mar 11;7:10981. doi: 10.1038/ncomms10981.
7
Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the mdx52 Mouse Model of Duchenne Muscular Dystrophy.在杜氏肌营养不良症的mdx52小鼠模型中使用磷酰二胺吗啉代寡聚物进行外显子跳跃疗法
Methods Mol Biol. 2018;1687:123-141. doi: 10.1007/978-1-4939-7374-3_9.
8
Dosing regimen has a significant impact on the efficiency of morpholino oligomer-induced exon skipping in mdx mice.给药方案对吗啉代寡聚物诱导mdx小鼠外显子跳跃的效率有显著影响。
Hum Gene Ther. 2009 Sep;20(9):955-65. doi: 10.1089/hum.2008.157.
9
Antisense Oligonucleotide Treatment in a Humanized Mouse Model of Duchenne Muscular Dystrophy and Highly Sensitive Detection of Dystrophin Using Western Blotting.反义寡核苷酸治疗杜氏肌营养不良症的人源化小鼠模型及利用 Western blot 高度敏感检测肌营养不良蛋白
Methods Mol Biol. 2021;2224:203-214. doi: 10.1007/978-1-0716-1008-4_15.
10
Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy.吗啉代寡核苷酸及其肽缀合物：杜氏肌营养不良症的治疗前景与挑战
Biochim Biophys Acta. 2010 Dec;1798(12):2296-303. doi: 10.1016/j.bbamem.2010.02.012. Epub 2010 Feb 17.

引用本文的文献

1
Exploring Experimental and In Silico Approaches for Antibody-Drug Conjugates in Oncology Therapies.探索肿瘤治疗中抗体药物偶联物的实验方法和计算机模拟方法。
Pharmaceuticals (Basel). 2025 Aug 14;18(8):1198. doi: 10.3390/ph18081198.
2
Brogidirsen and Exon 44 Skipping for Duchenne Muscular Dystrophy: Advances and Challenges in RNA-Based Therapy.用于杜氏肌营养不良症的Brogidirsen与外显子44跳跃：基于RNA疗法的进展与挑战
Genes (Basel). 2025 Jun 30;16(7):777. doi: 10.3390/genes16070777.
3
AOC 1044 induces exon 44 skipping and restores dystrophin protein in preclinical models of Duchenne muscular dystrophy.

本文引用的文献

1
Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-siRNA Conjugates for Drug Development.抗体-寡核苷酸缀合物的结构-活性关系：评估用于药物开发的抗体-siRNA 缀合物的生物缀合策略。
J Med Chem. 2024 Sep 12;67(17):14852-14867. doi: 10.1021/acs.jmedchem.4c00802. Epub 2024 Aug 28.
2
Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties.勤勉设计使抗体-ASO 缀合物具有最佳的药代动力学性质。
Bioconjug Chem. 2023 Nov 15;34(11):2096-2111. doi: 10.1021/acs.bioconjchem.3c00393. Epub 2023 Nov 2.
3
A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy.
AOC 1044在杜氏肌营养不良症的临床前模型中诱导外显子44跳跃并恢复肌营养不良蛋白。
Nucleic Acids Res. 2025 Mar 20;53(6). doi: 10.1093/nar/gkaf241.
4
Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-siRNA Conjugates for Drug Development.抗体-寡核苷酸缀合物的结构-活性关系：评估用于药物开发的抗体-siRNA 缀合物的生物缀合策略。
J Med Chem. 2024 Sep 12;67(17):14852-14867. doi: 10.1021/acs.jmedchem.4c00802. Epub 2024 Aug 28.
抗体药物偶联物综述：从概念形成到癌症治疗
Front Pharmacol. 2023 Sep 18;14:1274088. doi: 10.3389/fphar.2023.1274088. eCollection 2023.
4
Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs).利用抗体-寡核苷酸缀合物（AOCs）实现 RNA 治疗药物的靶向组织递送。
Nucleic Acids Res. 2023 Jul 7;51(12):5901-5910. doi: 10.1093/nar/gkad415.
5
Noncompetitive immunoassay optimized for pharmacokinetic assessments of biologically active efruxifermin.优化用于生物活性 efruxifermin 的药代动力学评估的非竞争免疫测定法。
J Pharm Biomed Anal. 2023 Aug 5;232:115402. doi: 10.1016/j.jpba.2023.115402. Epub 2023 Apr 18.
6
Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy.杜氏肌营养不良症反义疗法的最新趋势
Pharmaceutics. 2023 Feb 26;15(3):778. doi: 10.3390/pharmaceutics15030778.
7
The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction.肌细胞力学转导中 dystrophin 糖蛋白复合物的作用。
Commun Biol. 2022 Sep 27;5(1):1022. doi: 10.1038/s42003-022-03980-y.
8
Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice.利用 TfR1 靶向递送反义寡核苷酸并通过 FORCE 缀合在 mdx 小鼠中实现增强的外显子跳跃和延长的肌营养不良蛋白恢复。
Nucleic Acids Res. 2022 Nov 11;50(20):11401-11414. doi: 10.1093/nar/gkac641.
9
Incidence of Duchenne muscular dystrophy in the modern era; an Australian study.杜氏肌营养不良症在现代的发病率：一项澳大利亚的研究。
Eur J Hum Genet. 2022 Dec;30(12):1398-1404. doi: 10.1038/s41431-022-01138-2. Epub 2022 Jun 27.
10
Development of Therapeutic RNA Manipulation for Muscular Dystrophy.用于治疗肌肉萎缩症的RNA操控技术的发展
Front Genome Ed. 2022 May 10;4:863651. doi: 10.3389/fgeed.2022.863651. eCollection 2022.