Antibody-based PROTAC (AbTAC) differs dramatically from classical small molecule PROTAC. In terms of molecular composition, AbTAC is a fully recombinant bispecific antibody, representing a new prototype within the field of PROTAC, whereas classical PROTAC is a three-part small molecule. In terms of degradation system, AbTAC targets membrane proteins and uses the lysosomal system to achieve degradation of the target protein. Rather than being a PROTAC derivative, AbTAC is more like a complementary approach to LYTAC in that both proteins are recruited for lysosomal degradation and no major cellular proteomic perturbations occur.
Specifically, AbTAC is a bispecific immunoglobulin G (IgG) that recognizes two distinct epitopes. An arm of AbTAC recruits E3 ligase (e.g., transmembrane E3 ligases ring finger 43, RNF43) and the other arm targets cell surface protein (e.g., programmed death-ligand 1, PD-L1), inducing the formation of E3 ligase-AbTAC-protein complex and subsequent degradation. AbTAC has been reported to induce internalization and lysosomal degradation of PD-L1 by recruiting the RNF43. AbTAC mediates protein degradation by harnessing the endosomal-lysosomal pathway, but its mechanism of action remains elusive, and it is unknown whether the intracellular region of POI is ubiquitinated prior to endocytosis.
