AOC Conjugation – mAb With SiRNA

Developing antibody oligonucleotide conjugates (AOCs), such as a monoclonal antibody (mAb) with SiRNA, presents unique conjugation process challenges, particularly when using maleimide conjugation via an engineered cysteine. Key risks include disulfide scrambling during re-oxidation, SiRNA deconjugation, and the chemical stability of the SiRNA linker maleimide unit.

To mitigate these risks, several advanced strategies can be employed, such as selective de-capping to replace global reduction/re-oxidation. Additionally, incorporating a succinimidyl hydrolysis step can prevent the retro-Michael reaction, while adding an annealing step post-conjugation can attach the antisense strand. While these solutions may increase the number of unit operations, the resulting material preservation and improved yield make the process more efficient. Once the chemistry is fully characterized, these operations can be combined for streamlined, high-efficiency manufacturing. Explore the full case study to see the scale-up solutions for IND-enabling bioconjugation.