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Recent years witness the continuous clinical feasibility and increasing commercial value of antibody-drug conjugates (ADCs). As a result, many research institutions attempt to connect PROTAC with monoclonal antibody (mAb) by imitating the design principle of ADC to improve the delivery efficiency of PROTAC in vivo. This combination is called degrader-antibody conjugates (DACs), which can overcome the challenges brought by unconjugated PROTAC molecules, e.g. low efficiency due to its physicochemical properties and DMPK properties (especially the absence of E3 ligase CRBN), and non-specific targeting of PROTAC.
Fig 1. Mechanism of ADC (Dragovich, 2022)
In the development of DAC, the delivery strategy of ADC cannot be simply copied due to the particularity of PROTAC molecules. Unlike the broad-spectrum cytotoxic small-molecule drugs used in ADCs, PROTAC in DAC typically has targeted activity only against specific tumors and/or tissues or cells. Therefore, the selection of antigens not only needs to meet the function of internalizing DAC and transporting it into lysosomes but also needs to be highly expressed in PROTAC target tissues (or tumors, cells). This antigen may also be expressed at low levels in other tissues or cells. So long as such tissues or cells have a good tolerance to PROTAC, off-target toxicity can be avoided.
Since PROTAC is less active in vitro than small molecule drugs in many cases, drug antibody ratio (DAR) in DAC needs to be increased (i.e., DAC > 4) to be effective. However, enhanced DAR may lead to accumulation of DAC, with adverse effects on pharmacokinetics (PK) in vivo. Moreover, PROTAC is larger in volume and has stronger lipophilic properties compared with small molecule drugs. This difference will make aggregation and PK problems more serious, and new ligand and conjugation methods need to be developed to solve these problems.
Many PROTACs do not have sites (amino) that can be used for covalently binding to cleavable linkers. Therefore, it is necessary to consider whether PROTAC structure modification is needed to introduce active sites (but it may change the physiological activity of PROTAC), or use PROTAC’s existing functional groups (such as hydroxyl, phenolic hydroxyl) and develop new conjugation technology. The development of non-cleavable groups also needs to consider the same concern, and the ligands still attached to PROTAC molecules after lysosome degradation should not interfere with its biological activity.
In addition, other problems to be solved in DAC development include stability of PROTAC in lysosomes, lysosomal escape function of PROTAC, and PROTAC bystander effect. The latter two are affected by the permeability of PROTAC cells and remain the focus of current research in this area. The PROTAC that is unable to exert biological activity due to the influence of cell permeability, can enter cells and take effect via mAb in DAC. In this case, a cell-independent approach is required to evaluate the PROTAC's ability to generate ternary complexes.
Currently, DAC is still in its infancy, but several candidates have been identified with in vitro and/or in vivo biological activity. PROTAC molecules in these DAC structures utilize different E3 ligases and target different target proteins. In addition, a variety of novel ligands and antibody conjugation techniques have been applied to DACs. The DAR of most DAC molecules is larger than that of mainstream ADCs, but whether this increase is a general rule for DAC development needs further study. Multiple studies have shown that DAC activity depends on cell surface antigen, suggesting that DAC drugs can deliver PROTAC corresponding to specific tumors and/or cells. Based on these results, the DAC model has a bright future.
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