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Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane Proteins

preprint
revised on 11.11.2019 and posted on 20.11.2019 by Steven Banik, Kayvon Pedram, Simon Wisnovsky, Nicholas Riley, Carolyn Bertozzi

Targeted protein degradation is a powerful strategy to address the canonically undruggable proteome. However, current technologies are limited to targets with cytosolically-accessible and ligandable domains. Here, we designed and synthesized conjugates capable of binding both a cell surface lysosome targeting receptor and the extracellular domain of a target protein. These lysosome targeting chimeras (LYTACs) consist of an antibody fused to agonist glycopeptide ligands for the cation-independent mannose-6-phosphate receptor (CI-M6PR). LYTACs enabled a CRISPRi knockdown screen revealing the biochemical pathway for CI-M6PR-mediated cargo internalization. We demonstrated that LYTACs mediate efficient degradation of Apolipoprotein-E4, epidermal growth factor receptor (EGFR), CD71, and programmed death-ligand 1 (PD-L1). LYTACs represent a modular strategy for directing secreted and membrane proteins for degradation in the context of both basic research and therapy.

Funding

NIH R01CA227942

History

Email Address of Submitting Author

bertozzi@stanford.edu

Institution

Stanford University

Country

United States

ORCID For Submitting Author

0000-0003-4482-2754

Declaration of Conflict of Interest

A patent application relating to lysosome targeting chimeras has been filed by Stanford University (docket number STAN-1497PRV). C.R.B. is a co-founder and Scientific Advisory Board member of Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent) and InterVenn Biosciences, and a member of the Board of Directors of Eli Lilly & Company.

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