MM–GBSA binding free energy decomposition and T cell receptor engineering
MM–GBSA binding free energy decomposition and T cell receptor engineering
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DOI：
10.1002/jmr.1005
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发表时间：
2010-03
影响因子：
2.7
通讯作者：
V. Zoete;M. Irving;O. Michielin
中科院分区：
文献类型：
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作者：
V. Zoete;M. Irving;O. Michielin
T细胞受体（TCR）对一类主要组织相容性复合体（MHC）呈递的免疫原性肽(p)的识别是对抗病毒感染细胞或肿瘤细胞的免疫应答的关键事件。T细胞活化的主要决定因素是TCR对肽- MHC复合物的亲和力，尽管动力学参数也很重要。利用基于MM-GBSA方法的结合自由能分解（BFED）对2C TCR/SIYR/H‐2Kb体系进行了研究，以评估该方法在该体系上的性能。结果表明，包含熵项的TCR - p - MHC BFED提供了对相互作用能量学的详细而可靠的描述（Zoete和Michielin， 2007）。基于这些结果，我们开发了一种新的方法来设计识别人类白细胞抗原（HLA）‐A2限制性肿瘤表位NY‐ESO‐1的TCR序列修饰。NY‐ESO‐1是一种癌睾丸抗原，不仅在黑色素瘤中表达，也在其他几种类型的癌症中表达。在具有异常阳性临床结果的黑色素瘤患者中观察到高频率，因此，它代表了改良TCR过继转移的有趣目标。已经提出并在体外测试了TCR的序列修饰可能增加对该表位的亲和力。与野生型TCR表达细胞相比，表达某些TCR突变体的T细胞表现出更好的T细胞功能，具有更好的肽负载T2细胞杀伤能力和更好的增殖能力。这些结果为过继性转移癌治疗的合理TCR设计打开了大门。版权所有©2010 John Wiley & Sons， Ltd
Recognition by the T‐cell receptor (TCR) of immunogenic peptides (p) presented by class I major histocompatibility complexes (MHC) is the key event in the immune response against virus infected cells or tumor cells. The major determinant of T cell activation is the affinity of the TCR for the peptide‐MHC complex, though kinetic parameters are also important. A study of the 2C TCR/SIYR/H‐2Kb system using a binding free energy decomposition (BFED) based on the MM–GBSA approach had been performed to assess the performance of the approach on this system. The results showed that the TCR‐p‐MHC BFED including entropic terms provides a detailed and reliable description of the energetics of the interaction (Zoete and Michielin, 2007 ). Based on these results, we have developed a new approach to design sequence modifications for a TCR recognizing the human leukocyte antigen (HLA)‐A2 restricted tumor epitope NY‐ESO‐1. NY‐ESO‐1 is a cancer testis antigen expressed not only in melanoma, but also on several other types of cancers. It has been observed at high frequencies in melanoma patients with unusually positive clinical outcome and, therefore, represents an interesting target for adoptive transfer with modified TCR. Sequence modifications of TCR potentially increasing the affinity for this epitope have been proposed and tested in vitro. T cells expressing some of the proposed TCR mutants showed better T cell functionality, with improved killing of peptide‐loaded T2 cells and better proliferative capacity compared to the wild type TCR expressing cells. These results open the door of rational TCR design for adoptive transfer cancer therapy. Copyright © 2010 John Wiley & Sons, Ltd.