Consideration for immunogenicity assay development for oligonucleotide therapeutics

Oligonucleotide therapeutics (ONTs) represent a rapidly expanding drug modality driven by advances in chemical modification, sequence design, and delivery technologies. These innovations have improved pharmacokinetics, tissue targeting, and clinical efficacy, but they may also introduce modality-specific challenges for immunogenicity risk assessment. Although ONTs are regulated as small molecules and routine immunogenicity testing is not universally required, anti-drug antibody (ADA) responses have been reported and may impact pharmacokinetics and safety in certain contexts. Compared with protein therapeutics, regulatory guidance, and practical experience for immunogenicity assessment of ONTs remain limited. This review summarizes the diverse oligonucleotide types, chemical modifications, and carrier modalities used in approved and emerging ONTs and examines how these attributes influence immunogenic risk and ADA assay development. Key challenges include potential nonspecific protein binding, reagent generation, immunodominance of conjugated components, and the need for specialized assay formats. Building on established principles from protein biologics while recognizing their limitations for oligonucleotides, this review highlights risk-informed strategies for ADA assay design to support immunogenicity assessment as ONT platforms continue to evolve.