Associate Director Dyne Therapeutics Waltham, Massachusetts
Antibodies, antibody fragments, and alternative binding protein scaffolds have been used to provide antigen-dependent cell-type specific delivery of drug payloads. This is a particularly attractive option for antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). The most efficacious oligonucleotides have relied on delivery enhancers for reaching target tissues. Therefore, oligonucleotide-protein conjugates have been gaining traction across the biopharmaceutical industry.
One challenge associated with development of oligonucleotide-protein conjugates is the complicated bioanalytical approach needed to accurately quantitate various components of the chimeric construct. In this presentation, a bioanalytical strategy for measuring all relevant components of an oligonucleotide-protein conjugate necessary for performing pharmacokinetic evaluations during preclinical studies will be discussed. We propose development of bioanalytical methods for intact conjugate and free payload in plasma and urine. In addition, anti-drug antibodies (ADAs) and total payload concentration in tissues must be analyzed to allow for accurate determination of the disposition in preclinical models.
Learning Objectives:
Upon completion, participants will be able to recognize the components of an oligonucleotide-protein conjugate that must be analyzed for accurate PK characterization of this class of molecules.
Appropriate bioanalytical techniques for each component of an oligonucleotide-protein conjugate will be discussed.
The importance of ADA evaluation for interpreting PK results will be explored.
