Designed endocytosis-inducing proteins degrade targets and amplify signals

Buwei Huang, Mohamad Abedi, Green Ahn, Brian Coventry, Isaac Sappington, Cong Tang, Rong Wang, Thomas Schlichthaerle, Jason Z. Zhang, Yujia Wang, Inna Goreshnik, Ching Wen Chiu, Adam Chazin-Gray, Sidney Chan, Stacey Gerben, Analisa Murray, Shunzhi Wang, Jason O’Neill, Li Yi, Ronald Yeh, Ayesha Misquith, Anitra Wolf, Luke M. Tomasovic, Dan I. Piraner, Maria J. Duran Gonzalez, Nathaniel R. Bennett, Preetham Venkatesh, Maggie Ahlrichs, Craig Dobbins, Wei Yang, Xinru Wang, Danny D. Sahtoe, Dionne Vafeados, Rubul Mout, Shirin Shivaei, Longxing Cao, Lauren Carter, Lance Stewart, Jamie B. Spangler, Kole T. Roybal, Per Jr Greisen, Xiaochun Li, Gonçalo J. L. Bernardes, Carolyn R. Bertozzi and David Baker ()
Additional contact information
Buwei Huang: University of Washington
Mohamad Abedi: University of Washington
Green Ahn: Stanford University
Brian Coventry: University of Washington
Isaac Sappington: University of Washington
Cong Tang: Universidade de Lisboa
Rong Wang: University of Texas Southwestern Medical Center
Thomas Schlichthaerle: University of Washington
Jason Z. Zhang: University of Washington
Yujia Wang: University of Washington
Inna Goreshnik: University of Washington
Ching Wen Chiu: University of Washington
Adam Chazin-Gray: University of Washington
Sidney Chan: University of Washington
Stacey Gerben: University of Washington
Analisa Murray: University of Washington
Shunzhi Wang: University of Washington
Jason O’Neill: Novo Nordisk
Li Yi: Novo Nordisk
Ronald Yeh: Novo Nordisk
Ayesha Misquith: Novo Nordisk
Anitra Wolf: Novo Nordisk
Luke M. Tomasovic: Johns Hopkins University
Dan I. Piraner: University of California San Francisco
Maria J. Duran Gonzalez: University of California San Francisco
Nathaniel R. Bennett: University of Washington
Preetham Venkatesh: University of Washington
Maggie Ahlrichs: University of Washington
Craig Dobbins: University of Washington
Wei Yang: University of Washington
Xinru Wang: University of Washington
Danny D. Sahtoe: Hubrecht Institute
Dionne Vafeados: University of Washington
Rubul Mout: Harvard University
Shirin Shivaei: California Institute of Technology
Longxing Cao: Westlake University
Lauren Carter: University of Washington
Lance Stewart: University of Washington
Jamie B. Spangler: Novo Nordisk
Kole T. Roybal: University of California San Francisco
Per Jr Greisen: Novo Nordisk
Xiaochun Li: University of Texas Southwestern Medical Center
Gonçalo J. L. Bernardes: Universidade de Lisboa
Carolyn R. Bertozzi: Stanford University
David Baker: University of Washington

Nature, 2025, vol. 638, issue 8051, 796-804

Abstract: Abstract Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by endogenous ligands. Therapeutic approaches such as lysosome-targeting chimaeras1,2 (LYTACs) and cytokine receptor-targeting chimeras3 (KineTACs) have used this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. Although powerful, these approaches can be limited by competition with native ligands and requirements for chemical modification that limit genetic encodability and can complicate manufacturing, and, more generally, there may be no native ligands that stimulate endocytosis through a given receptor. Here we describe computational design approaches for endocytosis-triggering binding proteins (EndoTags) that overcome these challenges. We present EndoTags for insulin-like growth factor 2 receptor (IGF2R) and asialoglycoprotein receptor (ASGPR), sortilin and transferrin receptors, and show that fusing these tags to soluble or transmembrane target protein binders leads to lysosomal trafficking and target degradation. As these receptors have different tissue distributions, the different EndoTags could enable targeting of degradation to different tissues. EndoTag fusion to a PD-L1 antibody considerably increases efficacy in a mouse tumour model compared to antibody alone. The modularity and genetic encodability of EndoTags enables AND gate control for higher-specificity targeted degradation, and the localized secretion of degraders from engineered cells. By promoting endocytosis, EndoTag fusion increases signalling through an engineered ligand–receptor system by nearly 100-fold. EndoTags have considerable therapeutic potential as targeted degradation inducers, signalling activators for endocytosis-dependent pathways, and cellular uptake inducers for targeted antibody–drug and antibody–RNA conjugates.

Date: 2025
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DOI: 10.1038/s41586-024-07948-2

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