Antibody-Oligonucleotide Conjugates: A Twist to Antibody-Drug Conjugates

Abstract

A summary of the key technological advancements in the preparation of antibody–oligonucleotide conjugates (AOCs) and the distinct advantages and disadvantages of AOCs as novel therapeutics are presented. The merits and demerits of the different approaches to conjugating oligonucleotides to antibodies, antibody fragments or other proteins, mainly from the perspective of AOC purification and analytical characterizations, are assessed. The lessons learned from in vitro and in vivo studies, especially the findings related to silencing, trafficking, and cytotoxicity of the conjugates, are also summarized.

Noncoding RNA therapeutics — challenges and potential solutions

“…The conjugation of oligonucleotides to antibodies represents another strategy with promising preclinical developments. Conjugation of RNAs to antibodies may for instance be achieved via electrostatic interactions, affinity conjugation via biotin or avidin, direct conjugation or double strand hybridization 220 . In addition, various other strategies have been explored, such as the use of an azide-functionalized linker peptide on the antibody and conjugation to dibenzylcyclooctyne-bearing RNAs 221 , or antibodies with a reactive lysine residue combined with β-lactam linker-functionalized RNAs 222 .…”

A homogeneous high-DAR antibody–drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

“…XTEN polypeptides were expressed and purified as described elsewhere 36 . Anti-CD22, anti-Her2 and anti-WTA THIOMAB antibodies for conjugate generation are Cys mutants of those discovered previously and were deblocked prior to conjugation 7,46,50,60 . All other reagents were obtained from commercial vendors unless otherwise indicated.…”

“…To assess intracellular bacterial killing, macrophages were incubated with XADC-preincubated S. aureus bacteria for 2 h to enable phagocytosis, as described above. Intracellular killing was assessed after a 2-day incubation post phagocytosis as described previously 7 .…”

The promise of microRNA-based therapies in Alzheimer’s disease: challenges and perspectives

“…Evidently, targeted delivery of oligonucleotides is key in order to improve efficacy and safety. For CNS applications, antibody-or peptide-oligonucleotide conjugates may offer a promising strategy for targeted delivery of RNA-based therapeutics across BBB and to specific brain cell types [218][219][220][221][222]. While similar strategies are chemically applicable to a wide range of oligonucleotides, this knowledge emerges once again from nucleotides other than miRNAs, like siRNAs.…”