Design of high-specificity binders for peptide-MHC-I complexes

• 成果类型: Article
• 署名作者: Liu, Bingxu; Greenwood, Nathan F.; Bonzanini, Julia E.; Motmaen, Amir; Meyerberg, Jeremy; Dao, Tao; Xiang, Xinyu; Ault, Russell; Sharp, Jazmin; Wang, Chunyu; Visani, Gian Marco; Vafeados, Dionne K.; Roullier, Nicole; Nourmohammad, Armita; Scheinberg, David A.; Garcia, K. Christopher; 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; Memorial Sloan Kettering Cancer Center; Stanford University; Stanford University; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Fred Hutchinson Cancer Center; Cornell University; Weill Cornell Medicine; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11934
• DOI: 10.1126/science.adv0185
• 发表日期: 2025-07-24
• 页码: 386-391
• 关键词: t-cell-receptors; antigen; identification; antibodies; melanoma; protein

摘要

Class I major histocompatibility complex (MHC-I) molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance. Proteins that recognize peptide-MHC-I (pMHCI) complexes with specificity for diseased cells could have considerable therapeutic utility. Specificity requires recognition of outward-facing amino acid residues within the disease-associated peptide as well as avoidance of extensive contacts with ubiquitously expressed MHC. We used RFdiffusion to design pMHCI-binding proteins that make extensive contacts with the peptide and identified specific binders for 11 target pMHCs starting from either experimental or predicted pMHCI structures. Upon incorporation into chimeric antigen receptors, designs for eight targets conferred peptide-specific T cell activation. Our approach should have broad utility for both protein- and cell-based pMHCI targeting.