De novo design and structure of a peptide-centric TCR mimic binding module

• 成果类型: Article
• 署名作者: Householder, Karsten D.; Xiang, Xinyu; Jude, Kevin M.; Deng, Arthur; Obenaus, Matthias; Zhao, Yang; Wilson, Steven C.; Chen, Xiaojing; Wang, Nan; Garcia, K. Christopher
• 署名单位: Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11121
• DOI: 10.1126/science.adv3813
• 发表日期: 2025-07-24
• 页码: 375-379
• 关键词: t-cell-receptor; high-affinity; antibodies; antigen; specificity; RECOGNITION; EVOLUTION

摘要

T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-major histocompatibility complex (pMHC) in cancer immunotherapy. In this study, we designed a de novo alpha-helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by human leukocyte antigen (HLA)-A*02, achieving high on-target specificity with nanomolar affinity (dissociation constant Kd = 9.5 nM). The structure of the TCRm-pMHC complex at 2.05-& Aring; resolution revealed a rigid TCR-like docking mode with an unusual degree of focus on the up-facing NY-ESO-1 side chains, suggesting the potential for reduced off-target reactivity. Indeed, a structure-informed in silico screen of 14,363 HLA-A*02 peptides correctly predicted two off-target peptides, yet our TCRm maintained peptide selectivity and cytotoxicity as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused alpha-helical TCR mimics.