Degrader-Antibody Conjugation (DAC)

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As a leading CRO, BOC Sciences has been supporting customers at the forefront of drug conjugation. Degrader-antibody conjugates (DACs) are a new type of molecular pattern that combine targeted protein degraders to monoclonal antibodies. We provide degrader-antibody conjugation services to meet your unique project needs. Our scientific team will work with you to create a scope of work to complete the project on time and within specifications.

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Introduction

Degrader-antibody conjugates (DACs) are a new type of molecular pattern that can couple targeted protein degraders to monoclonal antibodies through certain chemical linkers. Although the field of DAC is still in the initial stage of research, many DAC molecular entities have been successfully developed, and experiments have confirmed that they exhibit excellent biological activities in vitro and in vivo. This therapeutic mode is expected to achieve targeted delivery of protein degradation payloads to specific tumors or cells.

Structural Properties

The target protein degrader in the DACs is a heterobifunctional molecule, named proteolysis-targeting chimera (PROTAC), which is composed of three parts: E3 ubiquitin ligase ligand, target protein ligand, and a specially designed "Linker". The ligands in its structure are connected by linkers to form a "trimeric" targeting protein ligand-linker-E3 ligand. PROTAC utilizes the ubiquitin-proteasome pathway to specifically degrade the target protein by bringing the target protein closer to the intracellular E3 ubiquitin ligase.

Drug Design Ideas

Compared to broad-spectrum cytotoxic small-molecule drugs used in ADCs, PROTAC molecules (payload) of the DACs have stronger targeted biological activities of tumor tissue or cells, so the antigen should be easily internalized and transported by cells. Furthermore, the antigen should be highly expressed on cells that are relatively sensitive to the biological pathway targeted by the degrader. Since degrader payloads are less toxic than ADC drugs, increased payloads are often required to generate functional antibody conjugates. However, increasing DAR may lead to DAC aggregation and adversely affect in vivo pharmacokinetics (PK).

Many PROTACs do not have a site (amino group) available for covalent attachment to a cleavable linking group. Therefore, it should be considered whether it is necessary to modify the structure of PROTAC to introduce active sites; or use the existing functional groups of PROTAC, such as hydroxyl, phenolic hydroxyl, etc., and develop new coupling techniques. In the design of DAC, attention should also be paid to the stability of PROTAC in lysosomes and the ability of the payload to efficiently escape the lysosome compartments.

Application Examples

The first degrader antibody conjugate, ORM-5029, is a HER2/HER3-specific dual-targeted DAC drug developed using the degrader of GSPT1. At present, it is proposed to be developed as a potential FIC-targeted protein degrader for the treatment of HER2-expressing breast cancer. Preclinical data showed that ORM-5029 exhibit an anti-tumor effect superiority to free degraders therapeutic efficacy[1]. Another example of a DAC application is a VHL-linked GNE-987, an antibody-conjugated degrader linked to a CLL1-targeting antibody via a novel disulfide-containing cleavable linker. This DAC utilizes the hydroxyl group of hydroxyproline in the VHL ligand structure to bind to the linking group. The heavy and light chains of a single antibody can bind a total of 6 PROTAC molecules through disulfide bonds. This DAC demonstrated robust, dose-dependent in vivo antitumor effects in a single intravenous dose of HL-60 and EOL-1 acute myeloid leukemia (AML) xenograft models[2].

References

  1. Palacino J. et al. ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer. Cancer Research, 2022, 82:3933-3933.
  2. Dragovich P.S., et al. Degrader-antibody conjugates. Chem Soc Rev, 2022, 23, 51(10):3886-3897.

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