Structure–Activity Relationship of Antibody–Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody–Phosphorodiamidate Morpholino Oligomer Conjugates for Drug Development,Journal of Medicinal Chemistry

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Structure–Activity Relationship of Antibody–Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody–Phosphorodiamidate Morpholino Oligomer Conjugates for Drug Development
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-28 , DOI: 10.1021/acs.jmedchem.4c00803
Michael Cochran ₁ , Isaac Marks ₁ , Tyler Albin ₁ , Danny Arias ₁ , Philip Kovach ₁ , Beatrice Darimont ₂ , Hanhua Huang ₁ , Usue Etxaniz ₁ , Hae Won Kwon ₁ , Yunyu Shi ₁ , Matthew Diaz ₁ , Olecya Tyaglo ₁ , Arthur Levin ₁ , Venkata Ramana Doppalapudi ₁

Affiliation

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 mdx mice. Our results show that αmTfR1-PMO conjugates are a potentially effective approach for the treatment of DMD.

中文翻译：

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-磷酸二酰胺吗啉代寡聚物缀合物的生物缀合策略

抗体-寡核苷酸缀合物 (AOC) 是治疗杜氏肌营养不良症 (DMD) 的有前景的药物。它们通过诱导外显子跳跃和骨骼肌和心肌中肌营养不良蛋白的恢复来发挥作用。由抗体-磷酸二酰胺吗啉寡聚物 (PMO) 组成的 AOC 的构效关系 (SAR) 取决于其组成部分的几个方面。我们评估了抗鼠转铁蛋白受体 1 抗体 (αmTfR1)-PMO 缀合物的 SAR：可裂解和不可裂解接头、接头在 PMO 上的位置，以及药物与抗体比率 (DAR) 对血浆药代动力学 (PK)、寡核苷酸递送的影响组织和外显子跳跃。含有 DAR9.7 稳定连接子的 AOC 是临床前研究中最有效的 PMO 递送载体。我们证明 αmTfR1-PMO 缀合物可诱导mdx小鼠骨骼肌和心肌中肌营养不良蛋白的恢复。我们的结果表明，αmTfR1-PMO 缀合物是治疗 DMD 的潜在有效方法。

更新日期：2024-08-28

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