Engineering AOC Manufacturability From The Start

By Campbell Bunce, Ph.D., CSO

Antibody-oligonucleotide conjugates (AOCs) combine the target specificity of monoclonal antibodies with the gene-modulating capabilities of nucleic acid therapeutics. However, bringing these complex bioconjugates from early concept to commercial production requires solving distinct manufacturing and analytical challenges. Joining a large protein with a polyanionic, highly charged oligonucleotide creates physical and chemical instability if not managed properly.

Achieving long-term manufacturability depends on deliberate technical choices made during early development. Optimizing the oligonucleotide-to-antibody ratio, selecting site-specific conjugation chemistries, and balancing linker length prevent non-specific clearance, aggregation, and loss of binding activity. Furthermore, traditional analytical frameworks designed for antibody-drug conjugates often fall short when evaluating nucleic acid payloads, making specialized characterization essential for regulatory success. Early alignment of bioconjugation chemistry, targeted payload loading, and robust analytical methods helps lower clearance risks, maintain product stability, and build a reliable manufacturing process capable of supporting clinical scale-up.