Unlocking the Power of AOCs: How Antibody-Oligonucleotide Conjugates Are Shaping the Future of Precision Medicine

October 5, 2024
Posted by axispharm

The Rise of Antibody-Oligonucleotide Conjugates (AOCs)

In the past decade, Antibody-Drug Conjugates (ADCs) have experienced rapid development, with the idea that “everything can be conjugated” driving innovation. At the same time, advancements in gene therapy have introduced new possibilities, such as high-cost drugs like Nusinersen. Building on this, researchers are exploring “ADC + small nucleic acids” to create Antibody-Oligonucleotide Conjugates (AOCs), which combine the benefits of both technologies for targeted treatment.

What Are AOCs?

AOCs (Antibody-Oligonucleotide Conjugates) consist of three main components: a carrier (antibody), a linker, and a small nucleic acid. They allow for targeted delivery, combining the antibody’s ability to bind to specific cells with the gene-silencing capability of small nucleic acids, addressing the delivery challenges faced by conventional small nucleic acid drugs.

Image Source: https://www.dyne-tx.com/our-forcetm-platform/

The development of Antibody-Oligonucleotide Conjugates (AOCs) aims to address the inherent limitations of small nucleic acids, such as poor serum stability, low membrane permeability, and lack of tissue selectivity. AOCs combine the longer half-life and precise targeting capabilities of antibodies with the gene-silencing power of small nucleic acids, achieving high-precision selectivity and effective delivery to target cells.

1. Payload Efficacy

The small nucleic acid payload (e.g., ASO or siRNA) is designed to silence specific genes by targeting mRNA. However, these molecules face challenges like degradation in the bloodstream. Chemical modifications, such as phosphorothioate backbones or 2′-O-methyl groups, enhance stability, ensuring the payload reaches its target intact. By leveraging antibodies for targeted delivery, AOCs overcome low membrane permeability, allowing more efficient gene silencing.

2. Linker Stability

The linker connects the antibody and the small nucleic acid, playing a key role in the controlled release of the payload. Cleavable linkers release the drug in response to specific conditions within the target cell, while non-cleavable linkers require cellular degradation for drug release. The right linker ensures stability in the bloodstream and precise delivery to the target site, enhancing the therapeutic window and safety.

3. Conjugation Technology

Conjugation technology is critical for attaching the payload to the antibody. Site-specific conjugation ensures consistent drug-to-antibody ratios (DAR), enhancing stability and efficacy. By achieving uniform AOCs, researchers can avoid variability in drug performance, ensuring targeted delivery and optimal results.

By solving issues of stability, delivery, and selectivity, AOCs offer a win-win by combining antibody precision with small nucleic acid therapy, paving the way for next-generation targeted treatments.

Image Source: Nucleic Acids Research, 2023 1 https://doi.org/10.1093/nar/gkad415

Characteristics of AOC Components

Similar to ADCs, the development of AOC drugs involves studying each component—antibody, linker, and small nucleic acid—to form the optimal combination. Based on the extensive theoretical and practical foundation of ADCs, this section focuses on the characteristics of small nucleic acids and linker conjugation technology.

Characteristics of Small Nucleic Acids

The key part determining drug efficacy.

Can be single-stranded or double-stranded, such as ASO and siRNA.

Nucleotides can be modified (e.g., 2’-deoxy, 2’-fluoro, 2’-O-methyl, 2’-O-methoxyethyl) to resist metabolism, reduce toxicity, and escape from endosomes.

PS: The current technology for small nucleic acids is relatively rich, with a large amount of research data accumulated, making the theory and practice relatively well-developed.

Figure 3. Chemical Modifications of Oligonucleotide Therapeutics

Image Source: doi.org/10.1016/j.chembiol.2023.09.005

Characteristics of Linkers

Related to stability, pharmacokinetics, pharmacodynamics, and therapeutic window. 2) Usually includes at least one covalent bond, which can be a single bond like a disulfide bond or disulfide bridge. 3) Methods of linking the linker to the drug: mainly divided into cleavable and non-cleavable forms. Cleavable linkers are sensitive chemical bonds that can be cleaved based on the specificity of the body’s internal environment (e.g., glutathione, pH) or enzyme concentration, mainly connected through disulfide bonds or peptides. Non-cleavable linkers do not have built-in chemical bonds that can trigger cleavage and require the antibody to be degraded into amino acids through proteolytic mechanisms in the cell, releasing cytotoxic drugs with linker and amino acid fragments, mainly connected through thioether bonds. 4) Conjugation of linkers to antibodies: Like ADCs, selective conjugation is used to combine antibodies with linkers, synthesizing homogeneous ADCs. This is an important direction in linker research, mainly involving chemical and enzymatic methods to modify the amino acid and carbohydrate parts of antibodies.

Figure 4. Summary of Some Chemical Triggers Related to Linkers

Image Source: Acta Pharmaceutica Sinica B 2021;11(12):3889e3907

AOC technology is a frontier technology in both the small nucleic acid field and the conjugated drug technology field. Companies that dare to be pioneers often attract more investor attention. Currently, AOC technology is still mainly concentrated abroad, with few domestic companies involved (though some have made phased achievements). There are relatively more market opportunities in this field. However, the technical barriers and challenges of AOCs are still evident. From design to development, the entire chain needs to be explored, with high uncertainty. Nevertheless, due to the design concept and technical barriers of AOCs, the future of this field is very promising.