Nature: The first antibody oligonucleotide conjugate enters the clinic

Article source: Medicine Cube Pro

Author: Li Yuan

In November last year, Avidity Biosciences' antibody oligonucleotide conjugate (AOC) AOC 1001 has entered Phase I clinical trials, and AOC 1001 is also the first AOC drug to enter the clinic

AOC 1001 is a method of treating rare muscle disease therapy using antibody targeting delivery of siRNA into the muscle cells

The development of AOCs builds on the success of antibody drug conjugates (ADCs), which are antibody conjugates that carry small molecules to specific cells

Companies currently developing AOC drugs globally include Avidity, Tallac Therapeutics, Dyne Therapeutics, Denali Therapeutics and Gennao Bio

Investigational Antibody Oligonucleotide Conjugates

Source: Nature Reviews Drug Discovery

Birth of AOC

For decades, researchers have developed a variety of oligonucleotide delivery methods in an effort to efficiently deliver drugs to various target cells

The earliest application of antibodies to oligonucleotide delivery was Professor Judy Lieberman of Harvard University

The research results of Professor Lieberman's team were published in Nature Biotechnology in 2005.

However, the clinical translation of AOC is not smooth sailing

Professor Lieberman subsequently turned her research focus to RNA aptamers

Avidity's re-selection

Looking at Avidity again, the development of AOC drugs was not Avidity's initial choice

AOC 1001, the first to enter the clinic this time, consists of three parts: a full-length monoclonal antibody targeting transferrin receptor 1 (TfR1), a linker, and an siRNA targeting DMPK mRNA

Source: Avidity

Transferrin receptor 1 is widely expressed on the cell surface and transports iron into cells

The linker of AOC 1001 is unbreakable, maximizing the delivery of drug molecules into cells

In terms of therapeutic molecules, Avidity chose siRNA.

Avidity will initiate clinical trials of other drug candidates in 2022 in indications including Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy

A different AOC design

Dyne focuses on the same disease areas as Avidity, but Dyne's AOC drug design differs from Avidity's

Dyne's lead drug candidate also targets transferrin receptor 1, but with an antigen-binding fragment rather than a full-length antibody
.
Dyne believes that the full-length antibody induces degradation of transferrin receptor 1, which reduces the availability of the receptor during drug action and iron absorption
.
Smaller antigen-binding fragments mean a lower protein load per dose of drug, potentially better for tolerability, and a shorter half-life also reduces the risk of long-term drug exposure
.

Source: Dyne

Another difference between Dyne and Avidity's drug design is that Dyne's AOC uses a cleavable linker
.
On the therapeutic load, Dyne plans to use siRNA, ASO and PMO
.

According to recent reports from Dyne, a single high-dose injection of Dyne's lead drug candidate DYNE-251 restored dystrophin in the diaphragm and heart by 90% and nearly 80%, respectively, in mouse models of the disease, while It is difficult for a single exon-skipping PMO to reach both tissues
.

move towards the brain

Denali sees transferrin receptor 1 as a gateway to the brain
.
Cells lining the blood-brain barrier express transferrin receptor 1, which is an excellent way for oligonucleotides, proteins and antibody drugs to enter the central nervous system
.

Denali's first attempt to target transferrin receptor 1 used DNL310, which is currently in Phase I/II clinical trials
.
DNL310 is fused by an Fc antibody domain targeting transferrin receptor 1 to enzyme replacement therapy for the treatment of Hunter syndrome
.
Similar delivery strategies can be used for oligonucleotides
.

Denali reported at R&D Day 2020 that systemic delivery of an oligonucleotide transport vehicle (OTV) drug candidate reduced expression of the proof-of-concept target by 50% in the cortex and spinal cord of mice
.
Denali is working with Secarna to advance OTV that delivers ASO
.
Indications may include Alzheimer's disease, Parkinson's disease and Huntington's disease
.

Notably, Denali's drug relies on an engineered Fc domain to target transferrin receptor 1, rather than the antigen-binding arm
.
Therefore, the candidate drug has a low affinity for the receptor, and the interaction with transferrin receptor 1 is strong enough to be released into the brain after crossing the blood-brain barrier and widely distributed in the brain tissue
.

Currently, the antigen-binding arm of the antibody carrier developed by Denali is non-targeting, and Denali is considering adding targeting to specific cell types in subsequent drugs
.

activate innate immunity

Tallac's drug development focuses on priming innate immunity to recognize and destroy cancer cells
.
Therefore, the therapeutic payload of choice for Tallac is a synthetic oligonucleotide containing a CpG motif that mimics the bacterial fingerprints that activate the innate immune target TLR9
.
But so far, in clinical trials using this activation method, the best signs of efficacy have come from drug candidates injected directly into tumors, limiting the drug's utility to injectable cancer patients
.

Tallac's TAC-001 targets oligonucleotides to B cells through the CD22 receptor, enabling memory B cells to become more active, thereby improving antigen presentation from B cells to T cells and production of proinflammatory and antitumor cytokines, reaching Enhance anti-tumor immunity
.

Tallac plans to advance TAC-001 into the clinic in 2022, with ALTA-002 to follow
.
Future projects may include antibodies with different targets, different levels of Fc engagement, linker and CpG payloads
.

The last is Gennao Bio, founded by Professor Peter Glazer of Yale University based on his research on the lupus autoantibody 3E10
.
Gennao Bio is exploring linker-free AOCs
.
Because 3E10 can directly bind to oligonucleotides and cross the cell membrane through the ENT2 receptor
.
Preclinical results from Gennao Bio show that the drug candidate delivers the oligonucleotide payload 3p-hpRNA into cells and triggers the innate immune target RIG-I
.

References:

Antibody–oligo conjugatenucleotides enter the clinic (source: Nature Reviews Drug Discovery)