# Strategies for Post-Translational Control of Protein Expression and Their Applications
## 3 Targeted Protein Degradation Using Bifunctional Molecules or Antibodies
### Antibody-Based Approaches  
Not only small molecules, but also antibodies are applicable to this type of strategy. [PERSON] et al. developed antibody-based PROTACs (AbTACs),which facilitates the recruitment of membrane-bound E3 Ub ligases to the targeted cell-surface protein, such as the programmed death-ligand 1 (PD-L1) [28]. [PERSON] et al. proposed a different approach by conjugating the PROTAC molecule with an antibody against the human epidermal receptor 2 (HER2), to selectively target HER2-positive cells [29]. Once the antibody is recognized by HER2 on the cell-surface, the antibody-PROTAC conjugates are delivered to the cytosol  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**Technology** & **Proteolytic Pathway** & **Feature** & **References** \\ \hline PROTAC/SNIPER & Ubiquitin–proteasome pathway & Originally developed bifunctional molecules & [21; 22; 23] \\ \hline CLIPTAC & Ubiquitin–proteasome pathway & In-cell generation of bifunctional molecule by the biorthogonal reaction & [25] \\ \hline opto-PROTAC & Ubiquitin–proteasome pathway & Light-inducible switch on PROTAC by & [26] \\  & & photolabile caging group & \\ \hline PHOTAC & Ubiquitin–proteasome pathway & Light-inducible switch on PROTAC by & \\  & & photo-reversible isomerization of & [27] \\  & & azobenzene moiety & \\ \hline AbTAC & Ubiquitin–proteasome pathway & Capable of degrading the cell-surface protein & [28] \\ \hline Antibody-PROTAC conjugate & Ubiquitin–proteasome pathway & Cell-type selective targeting & [29] \\ \hline TRIM away & Ubiquitin–proteasome pathway & Selective degradation of post-translational & [30; 31] \\  & & modified protein and mutant variants & \\ \hline AUTAC & Autophagy-lysosome pathway & Capable of targeting cellular organelles & [32] \\ \hline ATTEC & Autophagy-lysosome pathway & Molecular glue type degrader for targeting & [33; 34] \\  & & abnormal proteins & [35; 36] \\ \hline LYTAC & Endocytosis & Capable of targeting extracellular and & \\  & & membrane-bound protein & [35; 36] \\ \hline \hline \end{tabular}
\end{table}
Table 1: Comparison of the bifunctional molecule-based technologies.  
by endosomal internalization. Subsequently, the released PROTAC molecules degrade the cellular target. Another antibody-based approach for targeted protein degradation was reported by [PERSON] et al. They focused on TRIM21, which was originally found to act as an E3 Ub ligase in the immune response to pathogen infection. TRIM21 recognizes antibody-bound pathogens through a high-affinity interaction with the Fc domain of the antibody and tags the antibody-bound pathogens for ubiquitination and degradation. [PERSON] et al. repurposed TRIM21 to establish a method called Trim-Away that targets endogenous proteins for proteasomal degradation using endogenous or exogenous TRIM21 and antibodies that bind to the POI (Figure 2b) [30,31]. Notably, this technique enables the selective degradation of post-translationally modified protein and splice or mutant protein variants, by using a specific antibody, while preserving the unmodified/wild-type protein.