Fig. 3

Schematic representation of antibody-based bioTPD. (A) Trim21 recognizes the Fc domain of antibodies and is auto-ubiquitinated. Ubiquitinated Trim21 and its antibody/protein complexes are targeted for proteasomal degradation. (B) LYTAC is composed of a small molecule or an antibody coupled to a ligand that binds to LTRs, such as CI-M6PR and ASGPR. The LYTAC-POI complex is endocytosed along with LTR, followed by lysosomal degradation. (C) AbTAC, a bispecific antibody, concurrently recruits E3 ubiquitin ligases RNF43 and a membrane POI. The POI is degraded in a lysosomal-dependent manner. (D) GlueTAC consists of a covalent nanobody for POI targeting, a CPP for rapid endocytosis, and a lysosome-sorting sequence (LSS) for lysosomal degradation. (E) A sweeping antibody is an IgG that is engineered to connect to the neonatal Fc receptor (FcRn) at both neutral and acidic pH and a secreted POI only at neutral pH. The FcRn transports the POI-antibody-FcRn complex to the endosome. In the acidic environment, the POI leaves the sweeping antibody and proceeds to the lysosome, while the remained antibody-FcRn recycles back to the cell membrane to catch more targets (F) Seldegs are engineered Fc-antigen fusions with the capability to capture circulating antibodies and bring them to lysosomal degradation. The figure was created in BioRender.com