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

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Structure–Activity Relationship of Antibody–Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody–siRNA Conjugates for Drug Development
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-28 , DOI: 10.1021/acs.jmedchem.4c00802
Michael Cochran ₁ , Danny Arias ₁ , Rob Burke ₁ , David Chu ₁ , Gulin Erdogan ₁ , Michael Hood ₁ , Philip Kovach ₁ , Hae Won Kwon ₁ , Yanling Chen ₁ , Michael Moon ₁ , Christopher D Miller ₁ , Hanhua Huang ₁ , Arthur Levin ₁ , Venkata Ramana Doppalapudi ₁

Affiliation

Antibody–oligonucleotide conjugates are a promising class of therapeutics for extrahepatic delivery of small interfering ribonucleic acids (siRNAs). These conjugates can be optimized for improved delivery and mRNA knockdown (KD) through understanding of structure–activity relationships. In this study, we systematically examined factors including antibody isotype, siRNA chemistry, linkers, conjugation chemistry, PEGylation, and drug-to-antibody ratios (DARs) for their impact on bioconjugation, pharmacokinetics (PK), siRNA delivery, and bioactivity. Conjugation site (cysteine, lysine, and Asn297 glycan) and DAR proved critical for optimal conjugate PK and siRNA delivery. SiRNA chemistry including 2′ sugar modifications and positioning of phosphorothioates were found to be critical for delivery and duration of action. By utilizing cleavable and noncleavable linkers, we demonstrated the impact of linkers on PK and mRNA KD. To achieve optimal properties of antibody–siRNA conjugates, a careful selection of siRNA chemistry, DAR, conjugation sites, linkers, and antibody isotype is necessary.

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-siRNA 缀合物的生物缀合策略

抗体-寡核苷酸缀合物是一类有前途的小干扰核糖核酸（siRNA）肝外递送疗法。通过了解结构-活性关系，可以优化这些缀合物以改善递送和 mRNA 敲低 (KD)。在这项研究中，我们系统地研究了抗体同种型、siRNA化学、接头、缀合化学、聚乙二醇化和药物与抗体比率（DAR）等因素对生物缀合、药代动力学（PK）、siRNA递送和生物活性的影响。结合位点（半胱氨酸、赖氨酸和 Asn297 聚糖）和 DAR 被证明对于最佳结合物 PK 和 siRNA 递送至关重要。研究发现，SiRNA 化学（包括 2' 糖修饰和硫代磷酸酯定位）对于递送和作用持续时间至关重要。通过利用可切割和不可切割的接头，我们证明了接头对 PK 和 mRNA KD 的影响。为了实现抗体-siRNA 缀合物的最佳特性，必须仔细选择 siRNA 化学成分、DAR、缀合位点、接头和抗体同种型。

更新日期：2024-08-28

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