Nonclinical Safety Considerations for Bioconjugated Oligonucleotides Highlight Component-Driven Toxicities and Tailored Testing Strategies

Genetic medicines, particularly nucleic acid-based therapeutics, hold immense promise but face significant challenges in targeted delivery and safety. Traditional oligonucleotide delivery often lacks tissue specificity and can lead to off-target effects. Bioconjugation strategies, such as GalNAc-conjugated oligonucleotides and peptide-conjugated oligonucleotides, aim to enhance delivery efficiency and tissue selectivity. However, these innovative constructs introduce new complexities, requiring a thorough understanding of their unique pharmacological profiles and potential toxicities to ensure safe translation to human clinical trials.

This comprehensive review synthesizes the current landscape of bioconjugated oligonucleotide (BCO) therapeutics, focusing on nonclinical safety considerations. Researchers summarized key safety liabilities associated with the distinct components of these constructs: the protein scaffold, the linker, and the oligonucleotide payload. The review also detailed various nonclinical approaches, including predictive safety assessments and in vivo toxicity studies, essential for supporting human clinical trials. Furthermore, it addressed risk-based regulatory considerations, highlighting how these may diverge from those for traditional biologics or small molecules due to the multimodal mechanisms of action inherent to BCOs.

The review identified that bioconjugated oligonucleotide (BCO) therapeutics, encompassing modalities like antibody- and peptide-conjugated oligonucleotides, necessitate tailored nonclinical testing strategies. Key safety liabilities were systematically categorized across the construct's components: the protein scaffold, the linker, and the oligonucleotide payload, each contributing unique toxicity profiles. Predictive safety assessments and in vivo toxicity studies were highlighted as critical nonclinical approaches to evaluate pharmacology, biodistribution, and component- and construct-driven toxicities. The authors emphasized that these complex molecules often exhibit multimodal mechanisms of action, requiring a nuanced evaluation. > Risk-based regulatory considerations for BCOs may significantly differ from those applied to traditional biologics or small molecules, underscoring the need for specialized guidance in their development. This includes adapting strategies for assessing immunogenicity, off-target binding, and metabolic stability of the conjugates.