Computationally profiling peptide:MHC recognition by T-cell receptors and T-cell receptor-mimetic antibodies.
Computationally profiling peptide:MHC recognition by T-cell receptors and T-cell receptor-mimetic antibodies.
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DOI：
10.3389/fimmu.2022.1080596
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发表时间：
2022
影响因子：
7.3
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中科院分区：
文献类型：
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针对主要组织相容性复合体(PMHC)提出的针对疾病相关多肽的T细胞受体模拟抗体(TCRm)将成为一种主要的新药物形式。然而，我们缺乏对TCRM如何与pMHC靶结合的一般了解，这对于预测其特异性和安全性至关重要。在过去的一年里，已经出现了几种新的TCRm：pMHC复合体结构，为将TCRm作为一类pMHC结合剂进行整体分析提供了足够的初始数据。在这里，我们将TCRm：pMHC复合体的完整集合与具有代表性的TCR：pMHC复合体进行对比，以量化它们与pMHC结合的TCR相似性。我们发现，抗体和TCR之间固有的分子差异导致它们的重链/轻链和互补决定区环在抗原识别过程中扮演着根本不同的角色。抗体的独特型特性可能会增加TCRM与具有比TCRs更低的肽选择性的pMHC结合的可能性。然而，一些TCRM的pMHC识别特征，包括目前正在临床试验的两个TCRM，可以非常类似于TCR。从这项研究中获得的见解将有助于下一代TCRM的合理设计和优化。
T-cell receptor-mimetic antibodies (TCRms) targeting disease-associated peptides presented by Major Histocompatibility Complexes (pMHCs) are set to become a major new drug modality. However, we lack a general understanding of how TCRms engage pMHC targets, which is crucial for predicting their specificity and safety. Several new structures of TCRm:pMHC complexes have become available in the past year, providing sufficient initial data for a holistic analysis of TCRms as a class of pMHC binding agents. Here, we profile the complete set of TCRm:pMHC complexes against representative TCR:pMHC complexes to quantify the TCR-likeness of their pMHC engagement. We find that intrinsic molecular differences between antibodies and TCRs lead to fundamentally different roles for their heavy/light chains and Complementarity-Determining Region loops during antigen recognition. The idiotypic properties of antibodies may increase the likelihood of TCRms engaging pMHCs with less peptide selectivity than TCRs. However, the pMHC recognition features of some TCRms, including the two TCRms currently in clinical trials, can be remarkably TCR-like. The insights gained from this study will aid in the rational design and optimisation of next-generation TCRms.