Antibody-drug conjugates, which can target therapeutic drugs to the desired lesion area, have achieved considerable market value. However, the relatively low drug loading of ADC systems often results in the inability to deliver sufficient chemical drugs to the desired region at safe antibody doses, thus limiting the efficacy of ADC systems.
With the FDA approval of five small interfering RNA (siRNA) drugs, patisiran, givosiran, lumasiran, inclisiran and vutrisiran, the development of siRNAs has regained significant attention from researchers. siRNAs can achieve good therapeutic efficacy at doses of nmol or even lower concentrations, with good specificity. However, due to their poor cell membrane permeability and undesired toxicity, safe and effective delivery of siRNAs to target cells is a major obstacle to advancing their clinical application. Currently, ligand conjugation and nanoparticle encapsulation are two prevalent approaches to address siRNA delivery challenges. While N-acetylgalactosamine conjugates and lipid nanoparticles have been approved for RNAi-based therapeutic use in liver diseases, extrahepatic (e.g., tumor) siRNA delivery remains an unmet need. Furthermore, to avoid side effects caused by non-specific siRNA accumulation, RNAi activity needs to be restricted to tumor sites.
Derived from the concept of ADC delivery system, antibody-siRNA conjugates (ARCs) emerged and were expected to overcome many of these obstacles to achieve low toxicity, long blood circulation time, high targeting ability with fast and simple preparation procedures.
Figure 1. Schematic representation of antibody-siRNA conjugates (ARCs). Source: reference 
Antibody-siRNA Conjugates (ARC)
The scientific research on the use of antibodies to deliver siRNA dates back to 2005 when Harvard professor Judy Lieberman designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. With the increasing maturity of ADC technology, Genentech built on an industrial platform of therapeutic antibodies called THIOMABs in 2015, engineered to enable precise covalent coupling of siRNAs. This was the first attempt to conjugate siRNA directly to an antibody and showed intratumoral delivery and gene silencing effects in a mouse tumor model.
Avidity Biosciences has attempted to apply antibody-siRNA conjugates to the treatment of genetic diseases by conjugating different siRNA molecules with TfR1 (transferrin receptor 1) antibodies to treat rare muscle diseases. AOC1001, one of the ARC targeting DMPK, entered the clinic in November 2021 and is the world's First-in-human ARC.
AOC 1001 consists of a full-length monoclonal antibody targeting TfR1, a linker, and siRNA targeting DMPK mRNA to treat myotonic dystrophy type 1 (DM1). In December 2022, Avidity disclosed the latest data from the Phase 1/2 clinic of this first-in-class pipeline. AOC 1001 delivered siRNA to skeletal muscle and produced meaningful DMPK reduction in 100% of participants with a 45% mean reduction in DMPK after a single dose of 1 mg/kg or two doses of 2 mg/kg.
Figure 2. AOC 1001 for DM1. Source: Avidity official website.
Avidity's pipeline also includes AOC 1020, which targets DUX4. Avidity Biosciences announced that the FDA has granted orphan drug designation to its AOC 1020 for the treatment of facioscapulohumeral muscular dystrophy (FSHD), a severe, rare, genetic disorder of muscle weakness characterized by a lifelong, progressive loss of muscle function resulting in significant pain, fatigue and disability.
Figure 3. AOC 1020, source: Avidity official website.
AOC 1020 is being evaluated in a Phase 1/2 FORTITUDE™ clinical trial in adult FSHD patients. Preclinical trials have shown that AOC 1020 significantly inhibits the DUX4 gene in a transgenic mouse model and exhibits dose-dependent inhibition. Avidity plans to share preliminary evaluation data from approximately half of the study participants in the FORTITUDE trial in the first half of 2024.
Figure 4. Avidity’s pipeline. Source: Avidity official website
In addition to Avidity Biosciences, three other companies, Dyne, Tallc, and Denali, are also focusing on antibody-siRNA conjugate development.
Dyne Therapeutics, founded in December 2017, is a biopharmaceutical company developing targeted therapies for severe muscle diseases. The company focuses on three rare muscle diseases, including myotonic dystrophy type 1 (DM1), duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD).
The company is developing next-generation oligonucleotide therapeutics using its proprietary FORCE platform, which targets the TFR-1 receptor (which is highly expressed on the surface of muscle cells) and designs therapeutic molecules by linking antibodies to oligonucleotides that treat serious muscle diseases. Dyne Therapeutics is focused on the same disease areas and identical targets (DMPK, exons, DUX4) as Avidity. Its lead drug candidate also uses an antibody targeting TfR1 as the delivery vehicle, except that the target molecule is selected using an antigen-binding fragment rather than a full-length antibody. Currently, DYNE-251 has filed an IND application.
Figure 5. Dyne Therapeutics's pipeline. Source: Dyne Therapeutics official website
Tallac Therapeutics is dedicated to harnessing the power of innate and adaptive immunity to fight cancer.
Tallac's immunotherapy candidate pipeline stems from the company's novel Toll-like receptor agonist antibody conjugate (TRAAC) platform, which is designed to deliver a potent and differentiated TLR9 agonist (T-CpG) for targeted immune activation via systemic administration. On July 28, 2022, Tallac Therapeutics announced that TAC-001 has completed the first dose of its Phase 1/2 study in patients with advanced solid tumors.
Figure 6. Tallc Therapeutics’s pipeline. Source: Tallc Therapeutics official website
Denali has developed a proprietary Transport Vehicle (TV) technology platform that enables therapeutic biomolecules, including enzymes, antibodies, proteins and oligonucleotides, to cross the blood-brain barrier more efficiently. The technology is based on an engineered Fc fragment that binds to specific natural transport receptors on the blood-brain barrier, such as the transferrin receptor (TfR), and crosses the blood-brain barrier through receptor-mediated cytokinesis to deliver therapeutic biomolecules to the brain.
Figure 7. Denali Therapeutics’s pipeline. Source: Denali Therapeutics official website
With the successful clinical application of siRNA and antibody drugs, together with the success of the ADC design concept, the proper design of the ARC system, and the selection of appropriate linkers and linkage methods, it is believed that ARC will open up new horizons for the treatment of various refractory diseases with its unique advantages in the near future.
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1. Weiran Cao, Rui Li, Xing Pei, Meihong Chai, Lu Sun, Yuanyu Huang, Jiancheng Wang, Stefan Barth, Fei Yu, Huining He, Antibody–siRNA conjugates (ARC): Emerging siRNA drug formulation, Medicine in Drug Discovery, Volume 15, 2022, 100128, ISSN 2590-0986, https://doi.org/10.1016/j.medidd.2022.100128.
2. Jin, S., Sun, Y., Liang, X. et al. Emerging new therapeutic antibody derivatives for cancer treatment. Sig Transduct Target Ther 7, 39 (2022). https://doi.org/10.1038/s41392-021-00868-x
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