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Antibody-oligonucleotide conjugates (AOCs) —A new wave of drug conjugates

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Antibody-Oligonucleotide Conjugates (AOCs) represent an emerging class of functionalized antibodies that have already been used in a wide variety of applications. Combining the specific binding ability of antibodies with the vast structural and functional properties of oligonucleotides, these conjugates have found a wide variety of applications as imaging, detection and therapeutic agents. AOCs are a versatile class of chimeric biomolecules for therapeutics and biotechnological applications. This approach has allowed an improvement of the therapeutic index of many antibodies.

The evolution of nucleic acid delivery technologies

First-generation modifications: LNP + small nucleic acid molecules →liver

Lipid nanoparticles (LNPs).webp

Lipid nanoparticles (LNPs) originally developed for liver siRNA delivery can be redirected to other organs without the need for antibody fragments, peptides, aptamers or other active targeting ligands that bind specific receptors on the surface of target cells. Delivery vehicles can reach desired cells using passive or endogenous targeting.

Second-generation modifications: GalNAc + small nucleic acid molecules →liver

N-acetylgalactosamine (GalNAc).webp

N-acetylgalactosamine (GalNAc) is a carbohydrate-derived trivalent ligand that binds the asialoglycoprotein receptor (ASGPR). ASGPR is an ideal receptor for active targeting: it is highly expressed on target cells (in this case hepatocytes), not expressed on other cell types, leads to rapid endocytosis upon GalNAc binding, and is rapidly recycled to the cell surface following endocytosis. GalNAc also exhibits several traits that make it an ideal targeting ligand. The most clinically validated examples are GalNAc–siRNA and GalNAc–ASO conjugates, which have led to the FDA-approved drugs givosiran and lumasiran, as well as the EMA-approved drug inclisiran.

Third-generation modifications: antibody + linker + small nucleic acid molecules

Antibody-oligonucleotide conjugates (AOCs).webp

Antibody-oligonucleotide conjugates (AOCs) are a versatile class of chimeric biomolecules, which combine the antibody part and the oligonucleotide part. AOC is a distinct targeting mechanism requires the use of antibody fragments or antibodies to target cell types. siRNA and ASO have also been delivered to extrahepatic tissues using antibody–siRNA conjugates.

Conjugation mechanism of AOC

There are four general methods used to prepare AOCs. These methods involve electrostatic interactions, affinity between biotin and avidin, directly to antibody and using double-strand hybridization.

Conjugation Using Ionic Interactions

Conjugation Using Ionic Interactions.webp

The negative charge of the oligonucleotide backbone and positive charge of the protamine binds the oligonucleotide and protein strongly via ionic interactions. This method is applicable to many types of oligonucleotides since it does not require any chemical modification.

The advantage of this method is its simplicity and flexibility in allowing the conjugation of different oligonucleotide sequences and technology with one polycationic protein. This could be useful for evaluating different gene knockdowns with the same antibody and measuring their activity in cells. Another advantage of ionic conjugation is that once the oligonucleotide enters cells, the polycationic complex acts as a lysosomal escape agent.

However, the main drawback of this method is that the interactions are ionic and thus, reversible. The conjugate could potentially be unstable, especially under changing pH or salt concentration. Another drawback of ionic interactions is the difficulty in determining the oligonucleotide to antibody ratios (OAR).

Avidin-Based Conjugation

Avidin-Based Conjugation.webp

AOCs have also been successfully generated using the strong interactions between a biotin-labeled oligonucleotide and avidin.

The advantage of avidin-based conjugation is the in vivo stability of the resultant conjugates. While polycationic complexes can aggregate in vivo due to changes in saline concentration, biotin-complexes are much more resistant to such effects.

Direct Conjugation

Direct Conjugation.webp

The direct conjugation method is more analogous to ADCs in which a linkable group is added to the oligonucleotide and conjugated directly to a lysine, cysteine, or an engineered amino acid of the antibody. This method allows the use of the same linker versatility found in ADCs such as cleavable, disulfide, and non-cleavable linkers.

The advantage of this method is that linkers are smaller and have less impact on the overall conjugate, compared to the larger protamine or avidin complexes. The direct conjugation method seems to offer the greatest flexibility, but judicious choice of linker compatibility and position on the oligonucleotide are still required. We expect that the direct conjugation will be a preferred method to prepare AOCs going forward.

DNA Origami or Hybridization Conjugation

DNA Origami or Hybridization Conjugation.webp

AOCs with double-strand oligonucleotides could be obtained by a hybridization approach. A single strand oligonucleotide is first conjugated to an antibody and a complementary strand is hybridized to form a double-strand AOC. This hybridization technique is very powerful for diagnostic use, but it seems more challenging for AOCs targeted towards disease.


Antibody-oligonucleotide conjugates (AOCs) are a versatile class of chimeric biomolecules, which combine the unique functions of two fundamentally different types of biopolymers. The antibody part provides capacity for specific targeting of the epitope of interest, whereas the oligonucleotide part enables the implementation of antibody-oligonucleotide conjugates in a wide range of nucleic acid biochemistry-based applications. AOCs have received increasing attention as an emerging class of chimeric biomolecules.

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