Transferrin Receptor Targeting Chimeras (TransTACs) 🧬 The field of targeted protein degradation is going through a renaissance. The core idea: use a bifunctional molecule to bring a protein in proximity to a degrader. The first wave (PROTACs) primarily used E3 ligases as the degrader. They ubiquitinate the protein target, labeling it for degradation. These have primarily been small molecules that target intracellular proteins. What about membrane proteins? There have been a few new protein degrader technologies designed with the goal of degrading targets that reside in the membrane—namely AbTacs and LYTACs—but the field is still evolving quickly. A new preprint from the @xinzhoulab—the first preprint from their group—introduces a new idea: Create a bi-specific antibody that targets a protein-of-interest (POI), and the Transferrin receptor 1 (TfR1). Why TfR1? 1. It's up-regulated in cancer cells, which need lots of iron to proliferate. This can help with cancer targeting. 2. It has an insane recycling rate from the membrane. By insane, I mean: "TfR1 exhibits an average internalization rate of 500 molecules per cell per second (!!!), making it one of the fastest internalizing receptors known." So the thinking is that this fast recycling will help to pull lots of the POI into the cell for targeted degradation. Some solid POC data for demonstrating the degradation of CAR receptors: (Look at the lack of CAR present on the cell surface in v1.0 vs. the control.) Very cool idea!