Rising Star in Conjugated Drugs ：Degrader-antibody conjugates (DACs)
Degrader-antibody conjugates (DACs) have emerged as an innovative approach for the targeted delivery of chemotherapeutics, offering the potential for more efficient and precise cancer treatment. Following the entry of BMS and Seagen into the DAC field, in December 2023, Merck joined forces with C4 Therapeutics with a $2.5 billion collaboration, and clinical trials for DACs have recently begun, signaling advancement in this therapeutic field.
The General Introduction of DACs
DACs are novel entities that combine a proteolysis targeting chimera (PROTAC) payload with a monoclonal antibody via some type of chemical linker. PROTACs are heterobifunctional molecules that consist of two ligands interconnected via a linker. One ligand targets a protein of interest (POI) while the other ligand engages an E3 ubiquitin ligase. This ingenious molecular design enables PROTACs to simultaneously bind to both the POI and an E3 ligase, triggering targeted ubiquitylation followed by degradation by the proteasome[1] [3].
However, 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.
One strategy to improve the in vivo delivery of chimeric degradants is to conjugate them with monoclonal antibodies. DACs may have the following advantages over unconjugated PROTAC molecules[2].
(1) The in vivo delivery of chimeric degraders with poor physicochemical and/or DMPK properties;
(2) The avoidance of complex and/or non-standard formulations;
(3) The ability to target a PROTAC molecule of interest to a specific tumor or tissue via the antigen that is recognized by the DAC.
DAC Pipelines in Clinical Stage
Currently, there are three molecules in clinical research, as shown in the table below.
ChemExpress Capabilities
1. Dedicated team for PROTACs development
2. 100+ PROTACs molecules research and development experience
3. DAC customized services, and already support the delivery of over 20 DAC projects
Reference:
[1] Nat Rev Clin Oncol 21, 203–223 (2024).
[2] Chem Soc Rev. 2022 May 23;51(10):3886-3897.
[3] J Med Chem. 2023 Jan 12;66(1):140-148.