Chemical Biology Approaches toward Precise Structure Control of IgG‐Based Antibody‐Oligonucleotide Conjugates

Abstract

Antibody‐oligonucleotide conjugates (AOCs) are important tools for drug development and biochemical analysis. However, the structural heterogeneity of AOCs synthesized through conventional coupling methods raises reproducibility and safety concerns in clinical trials. To address these issues, different covalent coupling approaches have been developed to synthesize AOCs with precise site‐specificity and degree of conjugation. This Concept article categorizes these approaches as linker‐free or linker‐mediated and provides details on their chemistry and potential applications. Several factors, including site‐specificity, conjugation control, accessibility, stability, and efficiency, are highlighted when evaluating the pros and cons of these approaches. The article also discusses the future of AOCs, including the development of better conjugation approaches to ensure stimuli‐responsive release and the application of high‐throughput methods to facilitate their development.

Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking

“…Chemical entities to introduce alkyne/cyclooctyne groups during oligonucleotide synthesis are commercially available, facilitating ligand conjugation [ 209 , 210 ]. SPAAC using dibenzocyclooctyne (DBCO) as a strained alkyne has been applied in several antibody–oligonucleotide conjugates utilized for the preparation of targeted anticancer agents [ 211 , 212 ] ( Figure 12 ), multiplex protein detection assays [ 213 , 214 , 215 ], and epigenomic profiling [ 216 ]. Recently, Ang II peptide–ASO conjugates have been successfully synthesized via SPAAC using bicyclo [6.1.0] nonyne (BCN) as a strained alkyne for the targeted delivery of ASOs through an Angiotensin Type 1 Receptor [ 217 ].…”