Z-TAC enables custom and combinatorial degradation of cell surface proteins

Abstract Cell-surface degrader platforms typically require target-specific engineering and have therefore been applied to a relatively small set of protein targets. Here we report Z-TAC, a strategy that enables plug-and-play conversion of existing IgG antibodies into cell-surface protein degraders. Across multiple targets from distinct protein families, Z-TAC induced efficient and sustained degradation of both individual receptors and receptor combinations. For a multi-pass membrane receptor lacking selective antagonists, Z-TAC mediated complete receptor degradation and functional inhibition, demonstrating the ability of this platform to overcome the limitations of conventional pharmacological approaches. This study delineates a generalizable and scalable strategy for functional perturbation of the cell-surface proteome. Competing Interest Statement E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Anvia Therapeutics (also board of directors), Nias Bio, Stelexis Biosciences, and Neomorph (also board of directors). He is an equity holder and SAB member for Photys Therapeutics and Ajax Therapeutics, and an equity holder in Lighthorse Therapeutics and Avilar. E.S.F. is a consultant to Novartis, GSK and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer, and Astellas. X.Z. is a founder, scientific advisor, and equity holder of VincenTx. The Zhou lab receives research funding from Merck. D.Z., L.S., and X.Z. are listed as inventors on patent applications related to the TransTAC technology. Footnotes This version of the manuscript has been revised to update the following: Article keywords updated.