Degrader-antibody conjugates (DACs) are new entities that combine proteolysis targeting chimera (PROTAC) to monoclonal antibodies via some kind of chemical linker.

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ADC-PROTAC Conjugates: Novel
Degrader-Antibody Conjugates (DAC)
Degrader-antibody conjugates (DACs) are new entities that combine proteolysis
targeting chimera (PROTAC) to monoclonal antibodies via some kind of chemical
linker. Although this field is still in its infancy, several different types of DACs have
demonstrated meaningful in vitro and in vivo biological activity in preclinical studies.
Advantages of DACs
Targeted protein degraders, represented by PROTAC molecules, are a hot topic in the
field of new drug development. Taking PROTAC molecules as an example, these
heterobifunctional molecules can bind to target proteins at one end and to E3 ligases at
the other end, directing the target proteins to the proteasome of the cell for degradation.
However, due to the nature of their chimeras, the physicochemical properties of these
heterobifunctional degraders result in poor drug metabolism and pharmacokinetic (DMPK)
properties, such as low oral bioavailability and/or rapid in vivo clearance.
Figure 1. General PROTAC structure. POI = protein of interest. Source: Reference [1]

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One strategy to improve the in vivo delivery of chimeric degradants is to conjugate them
with monoclonal antibodies. Antibody conjugate technology has been clinically validated
for the delivery of cytotoxic payloads. Degrader-antibody conjugates (DACs) may have
the following advantages over unconjugated PROTAC molecules.
 (1) The ability of monoclonal antibodies to recognize specific antigens and deliver
degrader molecules to specific tumors or tissues.
 (2) Enhanced in vivo delivery of chimeric degradants with poor physicochemical or
DMPK characteristics.
 (3) Avoidance of complex and non-standard formulations which are often required
to enable unconjugated PROTACs to achieve meaningful in vivo exposures.
Antibody Drug Conjugates (ADCs) Mechanism
of Action
Traditional ADC consists of three components, a monoclonal antibody targeting a specific
antigen, a cytotoxic payload, and a chemical linker that connects the two. When an
antibody to an ADC binds to an antigen expressed on the surface of a tumor cell or target
tissue, the ADC is internalized and transported to the lysosome, where the payload can be
released by a variety of mechanisms, and then the payload is released from the lysosome
to exert its biological effects.

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Figure 2. Details of ADC construction. Source: Reference [1]
Currently, antibody conjugation technology has undergone multiple iterations, allowing
researchers to not only precisely control the drug antibody ratio (DAR), but also to
precisely locate the site where the payload is conjugated to the antibody by
introducing unnatural amino acids into the antibody.
Degrader-antibody conjugate (DAC) design
considerations
While some of the strategies used to manufacture traditional ADCs can be used to
manufacture and deliver DACs, the design of DACs often requires more challenges to
overcome.
For example, the toxic payload of traditional ADCs is broadly toxic to many cells, whereas
DACs typically exhibit more targeted biological activity associated with specific cancers or
tissue types. Thus, an antigen selected for DAC generation must be highly
expressed on tumors, tissues, or other cells that are sensitive to modulation of the
biological pathway targeted by the degrader.

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Chimeric degraders typically exhibit less potency in in vitro degradation than cytotoxic
drugs, meaning that more degraders (DARs over 4) may need to be conjugated to
each monoclonal antibody to achieve the desired potency.
Moreover, the molecular properties of chimeric degraders may result in a final DAC that is
larger and more lipophilic than traditional ADCs. These differences may enhance
molecular aggregation and affect pharmacokinetics. They may require novel conjugation
strategies or linker designs.
Strategies for the Design of Degrader-antibody
conjugate (DAC)
One of the first DACs published in a peer-reviewed scientific journal is a potent DAC
(GNE-987) that uses a cleavable linker containing a disulfide bond to link a
BRD4-targeted degrader to a CLL1-targeted monoclonal antibody. It conjugates 6
degradant molecules (DAR=6) on 1 monoclonal antibody by adding cysteine to the
specific position of the antibody.
Figure 3. GNE-987 Structure, Source: Reference [1]

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This DAC exhibited potent dose-dependent in vivo activity in a xenograft model of acute
myeloid leukemia (AML), whereas neither antibodies targeting CLL1 nor deconjugated
protein degraders exhibited in vivo activity. These results provide the first proof of
concept that DAC can effectively accomplish targeted delivery and overcome the
poor pharmacokinetic profile of degraders.
In some cases, protein degrader molecules do not contain groups suitable for
conjugating to monoclonal antibodies, and it may be necessary to add groups to
the degrader molecule that can generate covalent bonds. For example, the figure
below depicts the introduction of an amine or aniline chemical group (blue circles in the
picture) into a protein degrader molecule to provide a site for covalent linker attachment.
In this example, amine or aniline groups are introduced into different positions of the
chemical structure of the degrader molecule. These positions do not lead to a decrease in
the activity of the degrader molecule itself. In this example, the generated protein
degrader is conjugated to an antibody targeting STEAP1 via an enzymatically cleavable
peptide linker.
Figure 4. BRD4-targeting DACs, enzyme-cleavable linkers. Source: Reference [1]

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DACs optimized to target STEAP1 based on this strategy exhibited lower toxicity than
unconjugated protein degraders in in vitro experiments, indicating that the therapeutic
index of chimeric protein degraders may be improved using antibody conjugation
techniques.
In addition to targeting BRD4 for degradation, DACs have also been used to degrade
estrogen receptor alpha (ERα), TGFβR2, BRM, and other targets. Currently published
studies show that PROTAC molecules based on different E3 ligases can be
conjugated to antibodies, and researchers have also developed a variety of linkers
to conjugate them to monoclonal antibodies targeting different antigens. These
DACs typically have a higher ratio of drug antibodies (DAR=6) compared to most
traditional ADCs (DAR=2 to 4).
Figure 5. Summary of degrader-antibody conjugates (DACs) described in this work.
Source: Reference [1]
Outlook and Conclusion
Currently, several biotech companies are already optimizing this technology and seeking
to develop innovative therapies. For example, Orum Therapeutics closed an $84
million Series B round of funding last year to develop a degrader-antibody conjugate
(DAC). At this year's AACR Annual Meeting, Orum presented preclinical results for

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ORM-5029, which conjugates a degrader targeting the degradation of GSPT1 with a
monoclonal antibody targeting HER2 and shows similar activity to Enhertu in a
HER2 low expression model.
Figure 6. ORM-5029 exhibits in vivo activity in a HER2 low expression model, source:
Orum Therapeutics official website
Although the field of DACs is still in the early stages, several DACs have demonstrated in
vitro and in vivo activity, demonstrating the ability of this therapeutic modality to target
protein degradation payloads to specific tumors or cells. Based on these promising
preliminary results, further development and application of DACs is expected.
However, challenges remain in determining which PROTACs are suitable for conjugation,
and how that conjugation technology can best preserve, or even enhance the biological

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activity of the selected chimeric degraders. Further proof of concept for this technology is
expected in more studies with closer association to disease.
Biopharma PEG, as a leading PEG derivative supplier, can provide high-purity PEG
linkers in GMP or non-GMP grades for your ADC & PROTAC research and development.
We can also provide custom PEG synthesis services to meet your needs.
References:
[1] Dragovich PS. Degrader-antibody conjugates. Chem Soc Rev. 2022 May 23;51(10):3886-3897. doi:
10.1039/d2cs00141a. PMID: 35506708.
[2] Pillow TH, Adhikari P, Blake RA, et al. Antibody Conjugation of a Chimeric BET Degrader Enables
in vivo Activity. ChemMedChem. 2020;15(1):17-25. doi:10.1002/cmdc.201900497
[3] Maneiro MA, Forte N, Shchepinova MM, et al. Antibody-PROTAC Conjugates Enable
HER2-Dependent Targeted Protein Degradation of BRD4. ACS Chem Biol. 2020;15(6):1306-1312.
doi:10.1021/acschembio.0c00285
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