Navigating The Pathway Towards Regulatory Approval: The Chemistry & Challenges Behind Antibody-Oligonucleotide Conjugates (AOCs)

By Dr. Jeffrey Mocny, VP of Regulatory at Abzena, and Dr. Stephen Verespy, Sr. Dir., Scientific Operations at Abzena

Antibody-oligonucleotide conjugates (AOCs) represent a frontier in precision medicine, merging the cell-targeting accuracy of antibodies with the gene-modulating power of therapeutic oligonucleotides. This dual capability offers unprecedented opportunities to treat diseases at the genetic level while overcoming persistent hurdles in drug delivery. Unlike antibody-drug conjugates (ADCs), AOCs introduce unique complexities: two distinct biomolecular entities must be integrated without compromising stability, efficacy, or manufacturability. From sequence fidelity and linker design to impurity control and regulatory ambiguity, every step in AOC development demands meticulous scientific innovation.

The article explores the fundamental science behind AOCs, including oligonucleotide synthesis, bioconjugation strategies, and the formulation challenges that arise from oligos’ inherent instability and charge properties. It contrasts the development pathways of AOCs and ADCs, outlining why conventional analytical and manufacturing approaches are insufficient. Attention is also given to the evolving regulatory frameworks and the role of target product profiles in aligning scientific goals with approval requirements. Finally, the piece highlights how organizations with integrated expertise across biologics, oligo chemistry, and conjugation are uniquely positioned to advance this promising therapeutic class.