肿瘤细胞治疗研究
英文原题：Targeting peptide antigens using a multiallelic MHC I-binding system.
鉴定针对由I类主要组织相容性复合体（MHC I）蛋白呈递的表位肽的高特异性T细胞受体（TCR）或抗体，仍然是靶向治疗开发中的瓶颈。
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特异性T细胞受体（TCR）或抗体，仍然是靶向治疗开发中的瓶颈。在此，我们介绍了针对MHC I的抗原-MHC复合物报告靶向识别平台（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*同种异型上的肽，同时克服TCR的交叉反应性挑战。我们的TRACeR-MHC I共晶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接触，从而在可及位置赋予单残基特异性。我们展示了对一组疾病相关HLA的TRACeR-I快速筛选，所用肽来源于人类病毒（人类免疫缺陷病毒、Epstein-Barr病毒和严重急性呼吸综合征冠状病毒2）以及癌蛋白（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）。基于TRACeR的双特异性T细胞衔接器和CAR-T 细胞表现出对肿瘤细胞的在靶杀伤，在低纳摩尔范围内具有高效力。我们的平台赋能了可广泛适用的MHC I靶向分子的开发，用于研究、诊断和治疗应用。
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.
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