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首页> 外文期刊>The Journal of Immunology: Official Journal of the American Association of Immunologists >Minimal amino acid exchange in human TCR constant regions fosters improved function of TCR gene-modified T cells.
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Minimal amino acid exchange in human TCR constant regions fosters improved function of TCR gene-modified T cells.

机译:人TCR恒定区中最少的氨基酸交换可增强TCR基因修饰的T细胞的功能。

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摘要

TCR gene therapy using adoptive transfer of TCR gene-modified T cells is a new strategy for treatment of cancer. One critical prerequisite for TCR gene therapy is sufficient expression of transferred TCRs. Several strategies to achieve optimal expression were developed, including "murinization," which replaces the human TCRalpha and TCRbeta constant regions by their murine counterparts. Using a series of mouse-human hybrid constructs, we have identified nine amino acids responsible for the improved expression of murinized TCRs. Five essential amino acid exchanges were identified in the TCRbeta C region, with exchange of a glutamic acid (human) for a basic lysine (mouse) at position 18 of the C region, being most important. For the TCRalpha C region, an area of four amino acids was sufficient for improved expression. The minimally murinized TCR variants (harboring only nine residues of the mouse sequence) enhanced expression of human TCRs by supporting preferential pairing of transferred TCR chains and a more stable association with the CD3 proteins. Most important, usage of minimally murinized TCR chains improved the function of transduced primary human T cells in comparison with cells transduced with wild-type TCRs. For TCR gene therapy, the utilization of minimally instead of completely murinized constant regions dramatically reduces the number of foreign residues and thereby the risk for immunogenicity of therapeutic TCRs.
机译:使用过继转移TCR基因修饰的T细胞的TCR基因疗法是治疗癌症的新策略。 TCR基因治疗的关键先决条件是转移的TCR的充分表达。已开发出几种实现最佳表达的策略,包括“鼠毒化”,通过鼠类对应物替代人TCRalpha和TCRbeta恒定区。使用一系列的小鼠-人类杂种构建体,我们已经确定了9个氨基酸,这些氨基酸负责改良的TCRs的表达。在TCRbeta C区中鉴定出五个必需的氨基酸交换,其中最重要的是将谷氨酸(人)交换为赖氨酸(小鼠)在C区的18位氨基酸。对于TCRalpha C区,四个氨基酸的面积足以改善表达。通过支持转移的TCR链的优先配对以及与CD3蛋白的更稳定的关联,最小化的TCR变异体(仅保留小鼠序列的9个残基)增强了人TCR的表达。最重要的是,与野生型TCRs转导的细胞相比,使用最少化的TCR链可以改善转导的原代人T细胞的功能。对于TCR基因治疗,利用最小限度而不是完全稀释的恒定区可大大减少外来残基的数量,从而减少了治疗性TCR免疫原性的风险。

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