Designed endocytosis-inducing proteins degrade targets and amplify signals

• 成果类型: Article
• 署名作者: Huang, Buwei; Abedi, Mohamad; Ahn, Green; Coventry, Brian; Sappington, Isaac; Tang, Cong; Wang, Rong; Schlichthaerle, Thomas; Zhang, Jason Z.; Wang, Yujia; Goreshnik, Inna; Chiu, Ching Wen; Chazin-Gray, Adam; Chan, Sidney; Gerben, Stacey; Murray, Analisa; Wang, Shunzhi; O'Neill, Jason; Yi, Li; Yeh, Ronald; Misquith, Ayesha; Wolf, Anitra; Tomasovic, Luke M.; Piraner, Dan I.; Duran Gonzalez, Maria J.; Bennett, Nathaniel R.; Venkatesh, Preetham; Ahlrichs, Maggie; Dobbins, Craig; Yang, Wei; Wang, Xinru; Sahtoe, Danny D.; Vafeados, Dionne; Mout, Rubul; Shivaei, Shirin; Cao, Longxing; Carter, Lauren; Stewart, Lance; Spangler, Jamie B.; Roybal, Kole T.; Greisen, Per, Jr.; Li, Xiaochun; Bernardes, Goncalo J. L.; Bertozzi, Carolyn R.; Baker, David
• 署名单位: University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Stanford University; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; Universidade de Lisboa; University of Texas System; University of Texas Southwestern Medical Center; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; University of California System; University of California San Francisco; Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Harvard University; Harvard Medical School; California Institute of Technology; Westlake University; University of Cambridge; Howard Hughes Medical Institute; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3563
• DOI: 10.1038/s41586-024-07948-2
• 发表日期: 2025-02-20
• 关键词: de-novo design; transferrin receptor; sortilin

摘要

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.