Du Haotian, Mallik Leena, Hwang Daniel, Sun Yi, Kaku Chengzi, Hoces Daniel, Sun Shirley M, Ghinnagow Reem, Carro Stephen D, Phan Hoang Anh T, Gupta Sagar, Blackson Wyatt, Lee Hyejin, Choe Christian A, Dersh Devin, Liu Jingjia, Bell Braxton, Yang Hongli, Papadaki Georgia F, Young Michael C, Zhou Emily, El Nesr Gina, Goli Kimia Dasteh, Eisenlohr Laurence C, Minn Andy J, Hernandez-Lopez Rogelio A, Jardine Joseph G, Sgourakis Nikolaos G, Huang Po-Ssu
Department of Chemistry, Stanford University, Stanford, CA, USA.
Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Nat Biotechnol. 2024 Dec 13. doi: 10.1038/s41587-024-02505-8.
Identifying highly specific T cell receptors (TCRs) or antibodies against epitopic peptides presented by class I major histocompatibility complex (MHC I) proteins remains a bottleneck in the development of targeted therapeutics. Here, we introduce targeted recognition of antigen-MHC complex reporter for MHC I (TRACeR-I), a generalizable platform for targeting peptides on polymorphic HLA-A*, HLA-B* and HLA-C* allotypes while overcoming the cross-reactivity challenges of TCRs. Our TRACeR-MHC I co-crystal structure reveals a unique antigen recognition mechanism, with TRACeR forming extensive contacts across the entire peptide length to confer single-residue specificity at the accessible positions. We demonstrate rapid screening of TRACeR-I against a panel of disease-relevant HLAs with peptides derived from human viruses (human immunodeficiency virus, Epstein-Barr virus and severe acute respiratory syndrome coronavirus 2), and oncoproteins (Kirsten rat sarcoma virus, paired-like homeobox 2b and New York esophageal squamous cell carcinoma 1). TRACeR-based bispecific T cell engagers and chimeric antigen receptor T cells exhibit on-target killing of tumor cells with high efficacy in the low nanomolar range. Our platform empowers the development of broadly applicable MHC I-targeting molecules for research, diagnostic and therapeutic applications.
识别针对由I类主要组织相容性复合体（MHC I）蛋白呈递的表位肽的高度特异性T细胞受体（TCR）或抗体仍然是靶向治疗药物开发的一个瓶颈。在此，我们介绍了用于MHC I的抗原-MHC复合体报告基因的靶向识别（TRACeR-I），这是一个可推广的平台，用于靶向多态性HLA-A*、HLA-B和HLA-C等位基因上的肽，同时克服TCR的交叉反应挑战。我们的TRACeR-MHC I共晶体结构揭示了一种独特的抗原识别机制，TRACeR在整个肽长度上形成广泛的接触，以在可及位置赋予单残基特异性。我们展示了利用来自人类病毒（人类免疫缺陷病毒、爱泼斯坦-巴尔病毒和严重急性呼吸综合征冠状病毒2）和癌蛋白（ Kirsten大鼠肉瘤病毒、配对样同源盒2b和纽约食管鳞状细胞癌1）的肽对TRACeR-I进行针对一组疾病相关HLA的快速筛选。基于TRACeR的双特异性T细胞衔接器和嵌合抗原受体T细胞在低纳摩尔范围内表现出对肿瘤细胞的高效靶向杀伤作用。我们的平台为开发广泛适用的用于研究、诊断和治疗应用的靶向MHC I的分子提供了支持。
