XIAO WAN, MEHER BHALLA, SRITAMA BOSE*
*Corresponding author
Medical Research Council, Nucleic Acid Therapy Accelerator (UKRI),
Research Complex at Harwell (RCaH), Rutherford Appleton Laboratory, Harwell, OX11 0FA, United Kingdom

Abstract

Nucleic acid therapeutics (NATs) have opened up novel therapeutic opportunities for treating diseases such as cancer, retinopathies and neurodegenerative disorders. However, there have been numerous reports of toxicity and potency-related concerns during the development of NATs. Antibody-oligonucleotide conjugates (AOCs) offer an innovative and highly promising approach to help deliver NATs, where precise targeting of disease-associated cell types and tissues can result in enhanced therapeutic efficacy. The use of advanced conjugation techniques to combine the oligonucleotide and antibody, such as click chemistry, provide safe and effective strategies for AOC synthesis. Importantly, more suitable preclinical models and early pre-clinical testing of AOCs are required to investigate their mechanistic behaviour and translational potential. In this review, we present an overview of the chemistry, biology and therapeutic applications of AOCs.

Introduction
Nucleic acid therapeutics (NATs) have emerged as a promising new class of therapeutics for treating genetic and epigenetic disorders. These artificially synthesised single or double stranded nucleic acids can bind to target sequences, interfere with RNA regulating machinery in physiological and pathological processes and eventually regulate the expression of target genes. Examples of these drugs include small interfering RNAs (siRNAs) and anti-sense oligonucleotides (ASOs). Currently, NATs used in clinical trials often encounter significant hurdles, including targeted delivery to specific tissues (1).

To improve the delivery of oligonucleotide therapeutics, various methods have been explored. These include chemical structure modification of native ASOs and siRNAs or encapsulation within lipid nanoparticles or virus-derived vectors. Conjugating moieties on to NATs has also emerged as a novel and promising approach. Tested conjugates include lipids, peptides, and N-acetylgalactosamine (GalNAc) (2).
Antibody-oligonucleotide conjugates (AOC) are a relatively new member of this family, (3) that can improve cell-speci ...