LYTACs and other extracellular targeted protein degradation TACnologies: guiding principles and potential clinical...

Lysosome-targeting chimeras (LYTACs) have emerged as a powerful modality in the field of extracellular targeted protein degradation (eTPD). The proximity-inducing mode of action of LYTACs can be applied to a growing number of lysosome-targeting receptors (LTRs) and membrane-bound E3 ligases to degrade extracellular proteins. In this review, we highlight preceding eTPD approaches and discuss in depth the plethora of newly identified LTRs that can be exploited in a LYTAC molecule. To provide guidance in the fast-growing LYTAC field, we elaborate on parameters to assess the preclinical validation of the various TACnologies, highlight opportunities for engineering catalytic LYTACs, and finish with pharmacokinetic (PK) considerations.