Oligonucleotide therapeutics—including small interfering RNA (siRNA), antisense oligonucleotides (ASO), and phosphorodiamidate morpholino oligomers (PMO) —are intrinsically limited by their physicochemical properties, specifically their high molecular weight and negative charge, which impede passive diffusion across cellular membranes. Current mainstream delivery platforms, namely lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc) conjugation, primarily exploit specific receptors on hepatocytes; consequently, their clinical application remains largely restricted to liver-targeted interventions.

To overcome this limitation, Antibody–Oligonucleotide Conjugate (AOC) technology has emerged as a promising strategy. By leveraging the tissue-specific binding affinity of monoclonal antibodies or their functional fragments, AOCs facilitate the targeted internalization of nucleic acid payloads into specific cell types. This mechanism enables precise, extrahepatic gene regulation within target tissues. Currently, several AOC candidates have successfully advanced into global clinical development.

Figure 1. Schematic representation of the structure of an antibody-oligonucleotide conjugate [1]

Similarities and Differences Between AOCs and ADCs

AOCs share a highly analogous architecture with conventional anti-cancer Antibody-Drug Conjugates (ADCs); both comprise a targeting moiety, a therapeutic payload, and a linker. However, fundamental differences in the mechanisms of action of their payloads dictate entirely divergent R&D logic, particularly with respect to molecular design and PK/PD optimization.

Differences in targets and payload properties

ADCs typically employ non-specific, highly potent cytotoxic payloads (e.g., tubulin inhibitors) conjugated to antibodies targeting overexpressed tumor antigens such as HER2 or TROP2. Upon endocytosis, the complex is trafficked to the lysosome, where the toxin is released to induce apoptosis. The primary objective is to broaden the therapeutic window of targeted chemotherapy. [1]

The AOC payload consists of non-cytotoxic siRNA or ASO oligonucleotides that function by silencing target genes at the transcriptional or post-transcriptional level or by modulating RNA splicing. Unlike ADCs, the receptors targeted by AOCs are often unrelated to the disease pathology itself; rather, they must be highly expressed in the target tissue and capable of rapid recycling after internalization. Efficacy is strictly dependent on efficient cellular uptake and long-term intracellular retention.

Distinct Release Pathways and Technical Barriers

The intracellular journey marks a critical technical divide between the two modalities. In ADCs, the acidic and enzymatic environment of the lysosome is the ideal site for payload release. Conversely, the nuclease-rich lysosomal environment rapidly degrades the oligonucleotide payload of an AOC.

Consequently, endosomal escape represents the primary technical hurdle for AOC development. The oligonucleotide must breach the endosomal membrane before degradation to reach the cytoplasm (for siRNA) or the nucleus (for ASO). This necessitates linkers that balance plasma stability with the ability to facilitate membrane penetration. Currently, AOC endosomal escape efficiency is generally below 1%, making it the decisive variable for clinical efficacy.

Contrasting Drug-to-Antibody Ratio (DAR) Rationale

Increasing the DAR of a ADC drug is a common strategy to maximize toxin delivery and enhance potency. While in AOC development, increasing DAR is severely constrained by the physicochemical properties of the payload. Given the high molecular weight of siRNA (~13–14 kDa) and its dense negative charge, excessive conjugation can shift the antibody’s isoelectric point (pI), accelerate non-specific clearance, and significantly shorten the half-life. Furthermore, increased steric hindrance often compromises antigen-binding affinity. To balance payload capacity with systemic stability, the DAR of leading AOC candidates is strictly maintained between 1 and 3.

Clinical Progress of AOCs

The clinical translation of AOC technology is accelerating, with several programs advancing into Phase 3 trials or nearing regulatory submission (BLA filing). Therapeutics targeting Duchenne Muscular Dystrophy (DMD) are currently on the fastest track toward potential market approval. Leading biotech firms, including Avidity Biosciences and Dyne Therapeutics, have recently reported promising clinical data for their respective candidates, signaling a major breakthrough for the platform in treating neuromuscular diseases.

Avidity Biosciences

Avidity Biosciences is a leading company in the development of AOCs, with a focus on solving delivery challenges for RNA therapeutics. In February 2026, the company was acquired by Novartis for approximately $12 billion and is now a wholly owned subsidiary supporting Novartis’ strategy in neuromuscular diseases and RNA-based therapies.

Delpacibart Etedesiran (Del-desiran, AOC-1001)

Del-desiran is Avidity’s lead AOC candidate designed to treat Myotonic Dystrophy Type 1 (DM1), a rare, progressive, and often fatal neuromuscular condition for which no approved therapies currently exist.

Del-desiran utilizes Avidity’s proprietary AOC platform to target the underlying genetic cause of DM1. It consists of a monoclonal antibody engineered to bind to transferrin receptor 1 (TfR1), which is conjugated to a siRNA payload. This design facilitates the targeted delivery of the siRNA to muscle tissue, where it degrades toxic DMPK mRNA and restores functional RNA splicing.

In February 2026, results from the Phase 1/2 MARINA trial were published in the New England Journal of Medicine (NEJM). The percent change in DMPK mRNA levels in muscle-biopsy samples was −46% in the 1-mg group, −44% in the 2-mg group, −37% in the 4-mg group, and 0.9% in the placebo group. Reductions in the mean composite missplicing score from baseline were 3% in the 1-mg group, 17% in the 2-mg group, 16% in the 4-mg group, and 7%  in the placebo group. [3]

Del-desiran has moved into pivotal development and is currently being evaluated in the global Phase 3 HARBOR™ trial, as well as the ongoing HARBOR-OLE™ (Open-Label Extension) study, to further assess its long-term safety and efficacy in patients with DM1.

Delpacibart zotadirsen (del-zota, AOC-1044)

Del-zota is an AOC candidate designed to deliver PMOs specifically to skeletal muscle and cardiac tissue. It targets patients with DMD who have mutations amenable to exon 44 skipping. By skipping exon 44 of the dystrophin gene, the therapy aims to restore the production of functional dystrophin protein, addressing the underlying cause of muscle degeneration.

In March 2025, Avidity reported positive topline data from cohorts receiving 5 mg/kg and 10 mg/kg doses. The results demonstrated high consistency across several key efficacy markers: [4]

• l Dystrophin Production: Increased to approximately 25% of normal levels (statistically significant).

• l Exon Skipping: Achieved roughly 40% skipping of exon 44.

• l Creatine Kinase (CK) Levels: Reduced by more than 80% compared to baseline, bringing levels near the normal range.

The safety profile for del-zota was favorable at both dosage levels. Most treatment-emergent adverse events (TEAEs) were categorized as mild or moderate, with no significant safety signals identified.

Based on the comparable efficacy and safety observed between the 5 mg/kg (every six weeks) and 10 mg/kg (every eight weeks) groups, Avidity has selected the 5 mg/kg every-six-week regimen for its Biologics License Application (BLA) submission and all future clinical studies.

Delpacibart braxlosiran (Del-brax, AOC-1020)

Del-brax is an investigational AOC designed to address the underlying genetic cause of facioscapulohumeral muscular dystrophy (FSHD). The therapeutic consists of a proprietary monoclonal antibody targeting TfR1 conjugated to a siRNA payload. This siRNA is specifically engineered to target and reduce the expression of DUX4 mRNA, the driver of FSHD pathology.

FSHD is a rare, debilitating genetic disorder characterized by lifelong, progressive muscle wasting. Patients often experience significant pain, fatigue, and increasing physical disability, with no currently approved disease-modifying treatments available.

In June 2025, Avidity reported positive data from the Phase 1/2 FORTITUDE trial. Compared with placebo, patients treated with del-brax showed improvements in functional muscle performance, muscle strength, and patient-reported outcomes measuring quality of life. Treatment was also associated with a rapid and marked reduction in disease-related biomarkers. [5]

Dyne Therapeutics

Dyne Therapeutics is a clinical-stage biotechnology company focused on genetic neuromuscular diseases. Founded in 2019 and headquartered in Massachusetts, the company develops targeted delivery approaches designed to produce measurable functional improvement in patients.

Z-rostudirsen (Zeleciment rostudirsen, DYNE-251)

Z-rostudirsen is an investigational AOC currently in the global Phase 1/2 DELIVER clinical trial. It is designed for patients with DMD who have mutations amenable to exon 51 skipping. The therapeutic consists of a PMO conjugated to an antigen-binding fragment (Fab) that targets TfR1. This approach is intended to promote the production of near full-length dystrophin in both skeletal muscle and the central nervous system (CNS).

On March 8, 2026, Dyne announced positive 24-month cardiopulmonary results from the DELIVER trial. The data demonstrated sustained improvements in heart and lung function compared to the progressive declines typically observed in the natural history of DMD. [7]

Z-basivarsen (Zeleciment basivarsen, DYNE-101)

Z-basivarsen is under evaluation in the global Phase 1/2 ACHIEVE clinical trial for individuals with DM1. The molecule features an ASO conjugated to a TfR1-binding Fab to facilitate delivery to muscle and CNS tissues. By reducing levels of toxic nuclear DMPK RNA, Z-basivarsen aims to release sequestered splicing proteins and restore normal mRNA processing, thereby improving functional outcomes.

In March 2026, Dyne announced a major milestone with the initiation of the Phase 3 HARMONIA trial for Z-basivarsen. This transition into pivotal testing underscores the therapy's potential as a definitive treatment for DM1. [8]

Conclusion

AOCs represent a pivotal advancement in the evolution of personalized precision medicine and targeted genetic delivery. By successfully addressing the long-standing challenge of extrahepatic uptake, this modality is poised to redefine the treatment landscape for a broad spectrum of hereditary and previously intractable diseases. As clinical validation continues to mature, AOCs stand as a transformative frontier in biotechnology, offering therapeutic hope where clinical options were once nonexistent.

References:
[1] Li, M., An, H., Zhang, J., Li, W., Yu, C., & Wang, L. (2025). Advances in the pharmaceutical development of antibody-oligonucleotide conjugates. European Journal of Pharmaceutical Sciences, 215, 107292. https://doi.org/10.1016/j.ejps.2025.107292
[2] https://www.aviditybiosciences.com/
[3] https://www.nejm.org/doi/abs/10.1056/NEJMoa2407326 An Antibody–Oligonucleotide Conjugate for Myotonic Dystrophy Type 1
[4] https://www.aviditybiosciences.com/pipeline/dmd
[5] https://www.fshdsociety.org/2025/07/03/breaking-down-aviditys-fortitude-phase-1-2-trial-update/ Breaking Down Avidity’s FORTITUDE Phase 1/2 Trial Update 
[6] https://www.dyne-tx.com/
[7] https://investors.dyne-tx.com/news-releases/news-release-details/dyne-therapeutics-announces-new-positive-cardiopulmonary-results/  Dyne Therapeutics Announces New Positive Cardiopulmonary Results from DELIVER Trial of Z-Rostudirsen in Duchenne Muscular Dystrophy (DMD)
[8] https://investors.dyne-tx.com/news-releases/news-release-details/dyne-therapeutics-announces-initiation-phase-3-harmonia-trial-z  Dyne Therapeutics Announces Initiation of Phase 3 HARMONIA Trial of Z-Basivarsen in Myotonic Dystrophy Type 1 (DM1)