AOCs: A New Therapeutic Modality Bridging Targeted Delivery and Gene Modulation

Antibody oligonucleotide conjugates (AOCs) are the latest emerging biotherapeutic modality to watch. Combining the cell-targeting precision of antibodies with the gene-modulating capabilities of oligonucleotides, AOCs can address a long-standing challenge in oligonucleotide therapy, namely, selective and efficient delivery to other target tissues besides the liver. AOCs have the potential to open doors and expand oligonucleotide-based therapies to new disease areas where delivery barriers have historically impeded nucleic acid therapeutics, such as skeletal muscle, heart, and the central nervous system.

Akin to antibody-drug conjugates (ADCs), AOCs consist of an oligonucleotide (such as small interfering RNA [siRNA] or antisense oligonucleotides [ASO]) payload covalently linked to a monoclonal antibody (target vehicle). Although structurally similar, what sets AOCs apart from ADCs is the mechanism of stopping the disease. The AOC’s oligonucleotide payload stops disease-causing proteins from being made, whereas the ADC’s small molecule payload induces cell death.

Table 1 highlights industry expert perspectives supporting the promise of AOCs, reinforcing their potential as a single modality that combines the gene‑modulating strength of therapeutic oligonucleotides with the precise, cell‑targeted delivery of antibodies to enhance intracellular uptake and improve therapeutic index.¹

To deliver on AOC promises, the antibody, linker, and oligonucleotide characteristics must be considered when selecting and developing analytical methods for critical quality attribute (CQA) assessment. Although AOCs share structural similarities with ADCs, their oligonucleotide payloads introduce unique analytical challenges, making ADC characterization approaches insufficient. The larger oligonucleotide payload significantly alters the AOC’s molecular size and charge. Most contrastingly, AOCs display dual behavior, acting as both positively charged antibodies and negatively charged oligonucleotides, complicating size‑variant and charge‑variant impurity analysis as well as glycosylation characterization.²

Oligo‑to‑antibody ratio (OAR) analysis for AOCs is as essential as measuring drug‑to‑antibody ratio (DAR) in ADCs because it directly influences AOC potency, efficacy, and other key physicochemical properties such as affinity and aggregation. Traditional hydrophobic interaction chromatography (HIC) is ineffective for OAR determination because the hydrophilic, polyanionic oligonucleotides mask hydrophobic differences. Furthermore, changes in oligonucleotide payload contribute little to hydrophobicity or secondary interactions with chromatographic stationary phases, limiting the utility of both HIC and reversed‑phase chromatography.

Native size‑exclusion chromatography (SEC) coupled with mass spectrometry (MS), in positive and negative mode, has become a powerful tool for intact AOC characterization, enabling both OAR distribution analysis and aggregate/subunit detection. SEC–MS offers distinct advantages since the substantial molecular‑weight shifts create clear separations between different OAR species. When OAR is evaluated by SEC–MS, the typical elution order is AOCs with higher OARs (which elute earlier), followed by non-conjugated antibodies, and finally, free oligonucleotides. Integrating information about conjugation site distribution and levels of unconjugated mAbs enhances overall product quality control and ensures a more complete understanding of AOC heterogeneity.³

It is not to say SEC–MS is the chromatographic method to determine OAR. One should also consider orthogonal characterization methods to ensure data quality as biotherapeutics become more complex in structure. A comprehensive AOC characterization strategy can incorporate ion‑exchange chromatography as well to assess oligonucleotide distribution across different OAR species.⁴

Biotherapeutic characterization analysis is fundamental to drug development and quality control, continually advancing to keep pace with the expanding pipeline of biologics and biosimilars. Although modern analytical techniques have improved sensitivity and efficiency, challenges remain due to the inherent complexity and heterogeneity of biologics. Continued collaboration among regulatory agencies, industry, and academia is essential to standardize analytical approaches, ensure data integrity, and support innovation. These efforts will ultimately enhance therapeutic precision, manufacturing productivity, and global access to advanced biologics. Enhanced therapeutic precision comes from deeper insight into the molecular attributes that drive safety and efficacy. Advanced characterization tools, such as high‑resolution mass spectrometry and multi‑attribute methods, allow drug developers to better define CQAs to ensure consistent, well‑designed therapies. At the same time, streamlined analytical platforms and harmonized standards boost manufacturing productivity by reducing bottlenecks, enabling earlier detection of process issues and minimizing redundant testing across regions. Greater analytical clarity also strengthens regulatory confidence and supports cost‑efficient, scalable production, expanding access to biologics and biosimilars worldwide. Together, these advances make biotherapeutics more precise, easier to manufacture, and more broadly accessible.

Overall, AOCs represent a powerful modality that unites the precision of antibodies with the versatility of genetic medicine, enabling next‑generation conjugated therapeutics. By exploiting antibody‑mediated pathways, AOCs have promising capabilities to push the boundaries of personalized and precision medicine.

References 

1. Sheridan, C. Now with Oligos: Antibody–Oligonucleotide Conjugates Are the New Drug Modality to Watch. Nat. Biotechnol. 2026, 44, 3–5. DOI: 0.1038/s41587-025-02987-0
2. Li, M.; An, H.; Zhang, J.; et al. Advances in the Pharmaceutical Development of Antibody–Oligonucleotide Conjugates. Eur. J. Pharm. Sci. 2025, 215, 107292. DOI: 10.1016/j.ejps.2025.107292
3. Jiao, J.; Qian, Y.; Lv, Y.; et al. Overcoming Limitations and Advancing the Therapeutic Potential of Antibody–Oligonucleotide Conjugates (AOCs): Current Status and Future Perspectives. Pharmacol. Res. 2024, 209, 107469. DOI: 10.1016/j.phrs.2024.107469
4. Dugal-Tessier, J.; Thirumalairajan, S.; Jain, N. Antibody-Oligonucleotide Conjugates: A Twist to Antibody-Drug Conjugates. J Clin Med 2021, 10 (4), 838. DOI: 10.3390/jcm10040838