GPCR antagonism via rewiring of receptor trafficking and degradation

G-protein-coupled receptors (GPCRs) represent one of the most important yet incompletely addressed classes of therapeutic targets1. Here we report a strategy for functional GPCR antagonism through bispecific antibody-mediated endocytosis and lysosomal degradation. GPCR-TfR1 targeting chimeras (GTACs) achieve potent and selective downregulation of multiple GPCRs, including BILF1, RXFP1 and CCR6-viral, cancer and immune targets that have been difficult to drug2-4. GTACs lead to complete inhibition of receptor signalling, including constitutive signalling, with more than one to two orders of magnitude greater potency than conventional antibody antagonists. Using protein engineering and multicolour live-cell imaging, we establish a context-dependent degrader design and explain the cellular mechanisms, with broad relevance for degrader technology. The GTAC platform establishes induced endocytosis and rewiring protein trafficking as a model for therapeutic GPCR modulation.