Antibody-Oligonucleotide Conjugates (AOCs) are a novel class of therapeutics combining monoclonal antibodies' targeting capabilities with the versatile functions of oligonucleotides. This synergy offers promising solutions for imaging, detection, and gene-specific treatments.
The potential of AOCs to overcome delivery challenges associated with oligonucleotide-based drugs has spurred significant advancements in the field. Inspired by Antibody-Drug Conjugates (ADCs), AOCs utilize bioconjugation to achieve precise and efficient delivery of therapeutic oligonucleotides. Notably, the FDA recently granted breakthrough therapy designation to AOC 1001 (Avidity Biosciences) for treating myotonic dystrophy type 1 (DM1). This new therapy conjugates a monoclonal antibody that targets transferrin receptor 1 with siRNA targeting DMPK mRNA, the root cause of DM1.
BroadPharm's linker technology has been integral to advancing AOC research, particularly in collaboration with Avidity Biosciences. NHS-PEG1-Azide and TCO-PEG4-NHS linkers were used in Avidity Biosciences' exploration of different conjugation strategies. The study revealed that while lysine and glycan conjugations resulted in faster plasma clearance, cysteine conjugation provided enhanced stability and slower clearance, making it the optimal choice for sustained therapeutic efficacy.
BroadPharm's MC-Val-Cit-PAB-PNP cleavable linker further helped assess how linker type and placement affect siRNA release and gene silencing. While the cleavable linker was expected to enhance siRNA release at internal positions, it showed reduced gene silencing compared to non-cleavable linkers like SMCC. This suggested that internal linkers might interfere with RISC loading, prompting Avidity to refine their AOC strategy for optimal siRNA delivery.
Figure 1: NHS-PEG1-Azide, TCO-PEG4-NHS, and MC-Val-Cit-PAB-PNP linkers conjugated with siRNA and modified antibodies to produce final AOCs
BroadPharm's advanced linkers and conjugation tools were key to gaining critical insights into siRNA conjugation, helping them improve AOC stability, delivery, and therapeutic potency.
Publication: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00802
BroadPharm offers a comprehensive range of bioconjugation linkers and services to support AOC research & development:
Click Chemistry linkers like TCO-PEG4-NHS and NHS-PEG1-Azide: https://broadpharm.com/product-categories/click-chemistry-reagents
Cleavable Linkers like MC-Val-Cit-PAB-PNP: https://broadpharm.com/product-categories/adc-linkers/cleavable-linkers
Non Cleavable, Maleimide linkers like SMCC:https://broadpharm.com/product-categories/peg-linkers/maleimide-linkers
Bioconjugation services: https://broadpharm.com/bioconjugation-service