AOC and ADC, the difference of one letter, have you figured it out?

The principle of oligonucleotide therapy is mainly to interfere with the function of RNA, thereby affecting gene expression and protein synthesis. The following are several common oligonucleotide therapies: siRNA (small interfering RNA), miRNA (microRNA), ASO (antisense oligonucleotide), and aptamer (adapter). Although oligonucleotides have many advantages in therapy, such as the ability to intervene in specific genes and regulate protein expression, there are also some drawbacks and challenges: low biological stability and easy degradation by nucleases in vivo; need to overcome obstacles in the cell membrane and difficulties in in in vivo delivery; poor targeting ability; inducing immune response and producing antibody response; has certain hepatotoxicity and nephrotoxicity.

Antibody conjugated drugs (ADCs) have become the darling of drugs in recent years due to their high specificity and low cytotoxicity. According to research, the market size of ADC drugs in China is expected to reach 7.4 billion yuan in 2024 and 29.2 billion yuan in 2030. Everything can be connected. In addition to ADC, XDC drugs also include peptide coupled drugs (PDC), radionuclide coupled drugs (RDC), small molecule coupled drugs (SMDC), antibody immunostimulatory coupled drugs (ISAC), antibody fragment coupled drugs (FDC), etc., thus opening a new era of XDC drugs.

Antibody oligonucleotide conjugates (AOC) are expected to solve this problem by using antibodies as delivery mediators, overcoming the disadvantage of oligonucleotide drug delivery systems (mainly LNP and GalNAc) that can only enhance liver targeting, while reducing cytotoxicity, and opening up new strategies for oligonucleotide therapy.

Antibody oligonucleotide conjugates (AOCs) have enormous potential in the field of drug development, and their future trends include but are not limited to the following aspects:

1. Precision medicine applications: AOC can provide precise treatment for specific disease biomarkers or targets, providing new means for personalized medicine and precision medicine.

2. Tumor treatment: AOC has broad application prospects in the field of tumor treatment, which can utilize the targeting ability of antibodies to deliver oligonucleotide drugs into tumor cells, thereby improving treatment efficacy and reducing low toxicity.

3. Overcoming multidrug resistance: AOC can overcome the multidrug resistance of tumor cells by targeting resistance genes or signaling pathways, bringing new breakthroughs to clinical treatment.

4. Treatment of neurodegenerative diseases: AOC may play an important role in treating neurodegenerative diseases, such as delaying disease progression by targeting molecular targets related to the nervous system.

5. Delivering RNA interference agents: AOCs can serve as carriers for delivering RNA interference agents, targeting gene expression regulation and providing new ideas for gene therapy and genetic disease treatment.

6. Treatment of inflammation and autoimmune diseases: AOC may be used to treat inflammation and autoimmune diseases by targeting and regulating the immune response process to achieve therapeutic effects.

The conjugation of drug linkers in ADC is completely achieved using the direct conjugation method. Oligonucleotides, on the other hand, have more connection methods than typical small molecule compounds. Figure 2 shows four general methods for preparing AOC. These methods include ion interaction (Figure 2A), affinity binding (Figure 2B), direct conjugation (Figure 2C), and using double chains as conjugated molecules (Figure 2D).

In November 2021, the "first shot" of AOC drugs was fired, and the Phase I clinical trial of AOC pioneer Avidity Biosciences' antibody oligonucleotide conjugate AOC 1001 completed the first patient administration, marking the world's first AOC drug entering clinical trials. Avidity's current research and development pipeline is shown in Figure 3. At the end of 2023, BMS reached a global licensing and research cooperation agreement with Avidity, utilizing Avidity's platform technology to focus on the discovery, development, and commercialization of up to 5 cardiovascular antibody oligonucleotide conjugate (AOC) drug targets. Avidity will receive a $100 million advance payment, including a $60 million cash payment and the purchase of approximately $40 million worth of Avidity common stock at a price of $7.88 per share. In addition, there will be up to $1.35 billion in research and development milestones and up to $825 million in commercial milestone payments, among others. BMS has the potential to make a cumulative payment of $2.3 billion (approximately RMB 16 billion). AOC, which is only one letter away from the "Magic Bullet" ADC, has skyrocketed in value in the blink of an eye.

Afterwards, foreign companies such as Tallac Therapeutics, Dyne Therapeutics, Denali Therapeutics, etc. have also explored different applications of AOC technology, including muscle diseases, central nervous system (CNS) diseases, and cancer. Some AOC projects have already entered clinical practice. Jiajin Biotechnology has become one of the first domestic companies to lay out AOC projects.

In summary, antibody oligonucleotide drugs have broad application prospects, and future trends include playing an important role in tumor treatment, precision medicine, neurodegenerative disease treatment, and bringing new opportunities for personalized medicine and precision medicine.

Antibody oligonucleotide drugs still face many challenges in their future development, requiring continuous efforts and breakthroughs in drug delivery system optimization, immunogenicity and toxicity management, drug resistance issues, production costs and complexity, as well as clinical trial validation and regulatory approval, in order to promote their greater success in clinical applications.

ChemScene Small Nucleic Acid Integrated Service Platform The ChemScene Research Oligonucleic Acid Technology Platform has a team of experienced oligonucleic acid research and development, production, and analysis personnel, as well as management personnel, all of whom come from domestic and foreign nucleic acid synthesis companies with more than 10 years of relevant industry experience.

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