Oligonucleotides, such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA), are a new class of therapeutics rapidly growing in drug discovery and development for the treatment of various diseases. One major challenge for oligonucleotide therapeutics is their inefficient delivery to target tissues by systemic administration. The use of antibody-oligonucleotide conjugates (AOC) is a promising approach to enhance the selectivity and delivery of oligonucleotide payloads to target tissues. Accurate and reliable bioanalysis of AOC, including its different components, is critical to characterize the pharmacokinetics/pharmacodynamics (PK/PD), toxicity, and biodistribution of the AOCs. This presentation will give an introduction of the strategies for the bioanalysis of different components of AOCs, including antibody-oligonucleotide conjugate, total antibody, and free (unconjugated) oligonucleotide. A case study on the development of a hybridization LC-MS/MS assay for bioanalysis of free ASO payload from a Fab-ASO conjugate will also be presented.
