Degrader-Antibody Conjugates (DACs)

Degrader-Antibody Conjugates (DACs)

Degrader-antibody conjugates (DACs) represent the next generation of antibody-drug conjugates (ADCs) that combine the catalytic activity of targeted protein degrader (TPD) with the specificity of antibody. This new treatment modality has the potential to increase efficacy and improve safety relative to either technology alone. By combining degrader technology with ADCs, DACs have the potential to become the next generation replacement for traditional degraders and current ADCs. BOC Sciences is a leading provider of custom synthesis services for DAC development. We offer comprehensive services including antibody engineering, PROTAC design, conjugation chemistry, characterization and scale-up manufacturing, allowing us to support the design, synthesis and characterization of DACs from concept to clinic. BOC Sciences is a trusted partner in the development of DACs to treat cancer, autoimmune diseases and other diseases.

Degrader-antibody conjugates (DACs)

Composition of Degrader-Antibody Conjugates

The structural composition of DAC and ADC is similar, mainly composed of monoclonal antibodies, attachment sites, linkers and drugs. It's just that the payload of ADCs usually uses monofunctional small molecules, while DACs use PROTACs.

  • Antibodies are key components in specifically binding and delivering payloads such as small molecule toxins and PROTACs to manipulate (or kill) and degrade target proteins. As with ADCs, the prerequisites for antibodies to be used in DACs are (1) specific interaction with well-defined antigens with high tumor expression and limited normal cell expression; (2) the ability to maintain their properties, such as stability, internalization chemical ability and binding to linkers and payloads; (3) high binding specificity to the target antigen.
  • Linkers are divided into two main types. The first is a cleavable linker with three types of release mechanisms: lysosomal protease-sensitive (peptide), acid-sensitive (hydrazone), and glutathione-sensitive (disulfide bond) linkers. The second type is non-cleavable linkers (thioethers, etc.) that show better stability during cycling than cleavable linkers.
  • The DAC payload is designed for use with PROTAC and molecular glue. DAC requires drug-to-antibody ratio (DAR) >4 and may affect conjugation and DAC pharmacokinetics.

Our DACs Development Services

The development of DAC requires expertise in antibody engineering and PROTAC drug design. BOC Sciences offers a comprehensive suite of services to support the design, synthesis and characterization of DACs, our services include:

Antibody Engineering and Modification

BOC Sciences has extensive experience in antibody engineering for DAC. This includes designing antibody fragments with high affinity and specificity for the target protein and optimizing linkage chemistry to attach small molecule degraders. Our team of experts can use a variety of antibody formats, including monoclonal antibodies, bispecific antibodies, and antibody fragments, to tailor the properties of DAC to meet specific therapeutic requirements.

PROTAC Molecular Design

BOC Sciences has a proven track record in designing and synthesizing small molecule degraders for DAC. Our team of medicinal chemists can develop novel degraders that selectively target disease-causing proteins for degradation while minimizing off-target effects. We have expertise in various drug design strategies, including structure-based drug design, fragment-based drug design, and computational modeling, to optimize the pharmacokinetic properties and therapeutic potential of DACs.

Conjugation Chemistry Technology

BOC Sciences offers a range of conjugation chemistries for linking antibodies to small molecule degraders. Our experts can optimize the conjugation process to ensure high yield and purity of DAC while minimizing impact on antibody binding affinity and degrader potency. We have extensive experience with a variety of linker chemistries, including cleavable linkers, non-cleavable linkers, and self-destructive linkers, to tailor DAC stability and release kinetics.

DAC Analysis and Characterization

BOC Sciences offers a comprehensive suite of analytical services to characterize DAC properties, including binding affinity, cytotoxicity, stability, and pharmacokinetics. Our team of scientists can perform a range of assays, including ELISA, flow cytometry, Western blotting, and mass spectrometry, to assess DAC activity and specificity in vitro and in vivo. We can also perform stability studies to evaluate the shelf life and storage conditions of DAC to ensure optimal performance in preclinical and clinical studies.

cGMP Scale-up and Manufacturing

BOC Sciences provides scale-up and manufacturing services for DAC production for preclinical and clinical studies. Our state-of-the-art facility is equipped with the latest technology for DAC synthesis, purification and formulation to ensure high quality and consistent large-scale production. We can provide custom packaging and labeling services to meet regulatory requirements and facilitate the transition from research to development.

Key Points in DAC Structural Design

  • Although some strategies employed by ADCs can be used to prepare and deliver biologically active DACs, the construction of DACs also presents additional challenges. Compared to the broad cytotoxic payloads used for ADCs, degraders often exhibit more targeted biological activity with specific cancer or tissue cell types. Therefore, DAC's antigens must not only meet ADC internalization and trafficking criteria, but also should be highly expressed on tumors, tissues, or other cells that are sensitive to degradants.
  • Because the chimeric degrader is slightly weaker compared to the cytotoxic ADC payload, a higher loading relative to the ADC may be required to produce similar efficacy (i.e., DAR value greater than 4). Due to their chimeric nature, DAC PROTAC payloads are generally larger or more lipophilic than the cytotoxic molecules (especially cell-permeable molecules) of ADCs. These differences amplify aggregation and pharmacokinetic issues when PROTACs are attached to antibodies and may require new linker designs and conjugation methods than those employed in the ADC field.
  • Furthermore, many reported chimeric degraders do not contain chemical groups for covalent attachment of cleavable linkers. In this case, careful consideration must be given to whether to purposefully incorporate the necessary chemical groups into the degrader structure or to utilize existing degrader functional groups, such as hydroxyl/phenol groups, using new ADC attachment methods.
  • Additional challenges that may need to be addressed in DAC design include: (1) good stability of the DAC payload in the lysosomal environment, (2) the ability of the payload to efficiently escape the lysosomal compartment, (3) tendency to produce bystander effect. The latter two properties may be affected by the cell permeability of the degrader itself, and optimizing this property is a current goal of PROTAC research.

Case Study

The first reported DAC consists of a novel disulfide-containing cleavable linker coupling a highly efficient VHL-based chimeric bromodomain-containing protein 4 (BRD4) degrader (GNE-987) to an antibody targeting CLL1 (DAC 1). Optimized DAC 2 demonstrated strong dose-dependent in vivo efficacy in HL-60 and EOL-1 acute myeloid leukemia (AML) xenograft models after a single intravenous administration.

DAC targeting BRD4Fig. 1. DAC targeting BRD4 (J Med Chem. 2021, 64(5): 2576-2607).

The experimental results demonstrate for the first time that a degrader-antibody conjugate can overcome poor PROTAC PK properties, achieve acceptable PROTAC lysosomal stability, and confer appropriate antigen-based targeting. It was also demonstrated that the antibody linker is properly cleaved from the hydroxyl group of the VHL-binding fragment of PROTAC to allow the released payload to have unhindered biological activity.


1. What are degrader antibody conjugates?

Degradant-antibody conjugates (DACs) are a new class of drugs that link a targeting chimera (PROTAC) to a monoclonal antibody through a certain type of chemical linker. It has several potential advantages over PROTAC molecules: (1) it can deliver degraders with poor physicochemical properties or DMPK properties in vivo; (2) it avoids complex formulations that are often necessary to obtain activity of PROTACs during in vivo exposure; (3) target the PROTAC molecule of interest to a specific tumor or tissue.

2. What is the mechanism of degrader antibody conjugates?

The principles of ADC and DAC are basically the same. After administration, the entire DAC should be kept as stable as possible in the system to prevent premature release of PROTACs and blood circulation. First, the antibody portion of DAC recognizes tumor-associated antigens on the cell surface. Second, DAC-antibody complexes are internalized via receptor-mediated endocytosis. Within the cell, the complex fuses with endosomes and is transported to activated lysosomes. Under proteolytic and acidic conditions, the complex linkers are degraded and the cargo (PROTAC) is subsequently released into the cytoplasm. Depending on the intracellular target of DAC, protein degradation events can be induced.


  1. Dragovich, P.S. et al. Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy. J Med Chem. 2021, 64(5): 2576-2607.
* Only for research. Not suitable for any diagnostic or therapeutic use.
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