Designing And Selecting Antibody-Oligonucleotide Conjugates For Enhanced Therapeutic Activity

By Campbell Bunce, Nicolas Camper, Arron Hearn, Rob Holgate, Erika Kovacs, Johanna Midelet, Fabio Rossi, and Gary Watts

Examine the design and selection of antibody–oligonucleotide conjugates (AOCs) as an emerging strategy to enhance targeted delivery of oligonucleotide therapeutics. Oligonucleotides offer precise gene modulation capabilities but face limitations such as poor cellular uptake, rapid clearance, and restricted tissue penetration. AOCs address these challenges by combining targeting antibodies with functional oligonucleotides through specialized linkers, enabling improved delivery to specific tissues and cells. The work highlights the importance of optimizing each component—antibody format, oligonucleotide modification, and linker chemistry—to achieve desired pharmacokinetics, stability, and biological activity. Different antibody structures and conjugation strategies are evaluated to balance circulation half-life with tissue penetration, particularly for complex targets such as the central nervous system.

In addition, a range of in vitro assays is used to assess internalization, gene knockdown efficiency, and stability, supporting the identification of promising candidates for further preclinical and clinical development.