Derived from the concept of ADC delivery system, antibody-siRNA conjugates (ARCs) emerged. Here we introduced the emerging ARCs and major company on ARC research and development.

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Emerging Antibody–siRNA Conjugates (ARC)
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.

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Figure 1. Schematic representation of antibody-siRNA conjugates (ARCs). Source:
reference [2]
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
Avidity Biosciences has attempted to apply antibody-siRNA conjugates to the treatment of
genetic diseases by conjugating different siRNA molecules with TfR1 (transferrin receptor

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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.

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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

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In addition to Avidity Biosciences, three other companies, Dyne, Tallc, and Denali, are
also focusing on antibody-siRNA conjugate development.
Dyne Therapeutics
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

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Tallc Therapeutics
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 Therapeutics
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.

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Figure 7. Denali Therapeutics’s pipeline. Source: Denali Therapeutics official website
Conclusion
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.

8. Biopharma PEG https://www.biochempeg.com
As a global partner, Biopharma PEG can supply commercial quantities of
high-quality functionalized PEGs, which are essential for your research of siRNA drugs.
References:
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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