The development of oligonucleotide-based gene therapies has been in full swing over the past few years due to their unique advantage of regulating gene expression. Oligonucleotides are short DNA or RNA oligomers between 20 and 60 units in length, which can be synthesized or found naturally as single-stranded (ss) or double-stranded (ds) oligomers. The introduction of oligonucleotide drugs has broadened the means and boundaries of disease treatment and brought new hope for the treatment of many diseases.
However, unmodified oligonucleotides are difficult to cross through the cellular membrane and blood-brain barrier due to their high molecular weight, high hydrophilicity and negative charge, as well as their low in vivo stability and rapid host clearance outside cells. Currently, the main approved oligonucleotide drug delivery systems are the LNP delivery system and the GalNAc delivery system, but neither is capable of drug-targeted delivery outside the liver. An emerging strategy to deliver oligonucleotides to tissues outside of the liver is by linking them to monoclonal antibodies (mAbs), to form antibody–oligonucleotide conjugates (AOCs).
AOC Drugs Market Landscape
Currently, a number of companies are working in the AOC space, mainly including Avidity Biosciences, Dyne Therapeutics, Tallac Therapeutics, and Denali Therapeutics.
Avidity Biosciences (AOC 1001, AOC 1020)
Avidity Biosciences, founded in 2013, is a biopharmaceutical company that is pioneering AOC therapies for the treatment of inherited muscle diseases. At its inception , Avidity envisioned tissue-specific delivery of small interfering RNA (siRNA)-nanoparticles via antibodies, but that didn't go well, as antibodies are difficult to achieve effective delivery of siRNA-nanoparticles. To ensure effective loading, the researchers tried to conjugate antibodies directly to siRNA, which led to the design of the AOC drug.
Avidity's AOC programs mainly offer treatment options for patients with myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), and Duchenne Muscular Dystrophy (DMD), etc.
Figure. Avidity Biosciences Pipeline, source: Avidity Biosciences official website
AOC 1001, Avidity's lead product candidate developed for the treatment of dystrophic myotonic dystrophy type 1 (DM1), consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA, which is designed to address the root cause of DM1 by reducing levels of DMPK RNA. Avidity is currently conducting the Phase I/II MARINA and MARINA-OLE studies of AOC 1001 for the treatment of DM1, and AOC 1001 is the first AOC drug to enter the clinic.
Figure. AOC-1001 for DM1, source: Avidity Biosciences official website
In preclinical studies, AOC 1001 successfully delivered siRNA to muscle cells, resulting in a long-lasting, dose-dependent reduction of DMPK RNA in a variety of muscles, including skeletal, cardiac, and smooth muscle.
Avidity announced positive topline data for AOC 1001 from the Phase 1/2 MARINA trial at the 75th Annual Meeting of the American Academy of Neurology (AAN) in April 2023, which demonstrated functional improvement in multiple clinical outcome metrics, disease modification, and favorable safety and tolerability profiles for adult DM1 patients.
FDA and EMA have granted Orphan Designation for AOC 1001 and the FDA has granted AOC 1001 Fast Track Designation.
AOC1020, an AOC drug consisting of a TfR1 antibody coupled to a siRNA targeting DUX4 mRNA, was developed for the treatment of facioscapulohumeral muscular dystrophy (FSHD). FSHD is one of the most common clinically inherited muscle disorders caused by aberrant expression of the DUX4 gene in skeletal muscle, leading to skeletal muscle atrophy and impaired muscle function through a series of downstream events. There are currently no approved therapeutic options for this disease, and medical care is primarily focused on physical therapy, exercise, pain management, and orthopedic interventions, with other therapies in development that do not directly target DUX4 as a disease driver.
Figure. AOC1020 for FSHD, source: Avidity Biosciences official website
Preclinical data show that AOC 1020 inhibits DUX4 mRNA expression, decreasing DUX4 protein levels and reducing downstream gene expression. AOC 1020 is currently in Phase 1/2 development as part of the FORTITUDE™ trial in adults with FSHD. The FDA and the EMA have granted Orphan designation for AOC 1020 and the FDA has granted AOC 1020 Fast Track designation.
Dyne Therapeutics（DYNE-101, DYNE-251）
Dyne Therapeutics is a biopharmaceutical company developing targeted therapies for serious muscle diseases. The company focuses on three major rare muscle diseases, including DM1, DMD and FSHD. Dyne is developing novel oligonucleotide therapies with its proprietary FORCE™ platform, which targets the TFR-1 receptor, a highly expressed receptor on the surface of muscle cells, and engineers therapeutic molecules by ligating antibodies to oligonucleotides for the treatment of severe muscle diseases.
Figure. Dyne Therapeutics pipeline, source: Dyne Therapeutics official website
DYNE-101 is an investigational AOC being evaluated in the Phase I/II global ACHIEVE trial, for treatment of DM1. It consists of an antigen-binding fragment antibody (Fab) conjugated to an antisense oligonucleotide (ASO) designed to enable targeted muscle tissue delivery that reduces toxic DMPK RNA in the nucleus, releases splicing proteins, allows normal mRNA processing and translation of normal proteins, and potentially stops or reverses disease.
In May 2023, the EMA has granted orphan drug designation for DYNE-101.
DYNE-251 is an AOC developed for patients with DMD amenable to skipping exon 51, consisting of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a Fab fragment. DYNE-251 can target binding to TfR1, which is highly expressed in the target muscle tissues. It is designed to enable targeted muscle tissue delivery and promote exon skipping in the nucleus, allowing muscle cells to create a truncated, functional dystrophin protein, with the goal of stopping or reversing disease progression. DYNE-251 is currently in Phase I/II DELIVER global clinical trials. Previously, the U.S. Food and Drug Administration (FDA) granted Fast Track designation for DYNE-251.
Tallac Therapeutics (TAC-001)
Tallac Therapeutics is a privately held biopharmaceutical company 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, to deliver a potent Toll-like receptor (TLR9) agonist (T-CpG) for targeted immune activation via systemic administration.
Figure. Tallac Therapeutics pipelines, source: Tallac Therapeutics official website
TAC-001, an important drug candidate for Tallac, is an AOC consisting of a potent toll-like receptor 9 agonist (T-CpG) conjugated to an antibody against CD22, which delivers T-CpG to B cells by binding to CD22, which in turn leads to internalization of TAC-001 as well as TLR9 signaling, B cell activation, and a series of immune responses. The innate and adaptive immune responses triggered by TAC-001 show potent, curative, and durable single-agent antitumor activity in checkpoint inhibitor-resistant and refractory tumor models. TAC-001 is currently in Phase I/II clinical stage for the potential treatment of solid tumors.
Denali Therapeutics (DNL310)
Denali Therapeutics, a biopharmaceutical company focused on neurodegenerative diseases, 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. In addition, Denali regards TfR1 as a gateway to the brain. Cells lining the blood-brain barrier express TfR1, making TfR1 an ideal pathway for oligonucleotides, proteins and antibody drugs to enter the central nervous system.
DNL310 is a fusion protein drug consisting of an IDS protein bound to Denali's Enzymatic Transport Vehicle (ETV). Denali's ETV platform contains engineered Fc fragments that bind to natural transport receptors, such as transferrin receptor, which are expressed at the BBB and deliver TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. DNL310 delivers IDS to lysosomes, where it is needed to break down GAGs. DNL310 is engineered for broad delivery of IDS into cells and tissues throughout the body, including the brain.
Figure. DNL310 mechanism of action, source: Denali Therapeutics official website
In March 2021, the U.S. FDA granted Fast Track designation to DNL310 for the treatment of MPS II. In May 2022, the EMA granted DNL310 Priority Medicines designation.
In June 2023, Denali announced Phase I/II clinical results for DNL310 for the treatment of MPS II. The data showed a significant reduction in serum Neurofilament Light (NfL) levels of up to 64% in MPS II patients compared to baseline. A clinical Phase II/III trial of DNL310 is currently underway worldwide.
Currently, there are only a few AOC drugs under development, and the progress is a little behind compared with other drug conjugates, the effectiveness, and safety still need to be further certified, leaving a long way to go before they can be routinely used in the clinic. However, nucleic acid drugs are regarded as the third wave of biopharmaceuticals and large molecule biopharmaceuticals, and oligonucleotide therapy itself has been approved in the past few years for the treatment of rare diseases, which fully proves the efficacy and safety of this therapy. In this case, it can be expected that AOC, as a new type of drug conjugate, will make a breakthrough in the field of rare disease therapy.
1. Antibody–oligonucleotide conjugates enter the clinic. Nature Reviews Drug Discovery.
7. Denali Therapeutics Announces Robust Reduction in Neurofilament Light (NfL) with DNL310 (ETV:IDS) Treatment in MPS II (Hunter Syndrome). Retrieved June 20, 2023 from https://www.denalitherapeutics.com/investors/press-release?id=9391&type=api.
9 Types of Drug Conjugates Overview
Small Molecule-Drug Conjugates (SMDCs): Novel Targeted Therapy
Aptamer-Drug Conjugate (ApDC): Current Research Progress
Peptide-Drug Conjugates (PDCs): Development Status & Research Progress