State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
University of Chinese Academy of Sciences, Beijing, China.
Immunology. 2018 Sep;155(1):123-136. doi: 10.1111/imm.12935. Epub 2018 May 7.
The affinity of T-cell receptor (TCR) determines the efficacy of TCR-based immunotherapy. By using human leucocyte antigen (HLA)-A02 transgenic mice, a TCR was generated previously specific for human tumour testis antigen peptide MAGE-A3 (KVAELVHFL) HLA-A02 complex. We developed an approach to humanize the murine TCR by replacing the mouse framework with sequences of folding optimized human TCR variable domains for retaining binding affinity. The resultant humanized TCR exhibited higher affinity and conferred better anti-tumour activity than its parent murine MAGE-A3 TCR (SRm1). In addition, the affinity of humanized TCR was enhanced further to achieve improved T-cell activation. Our studies demonstrated that the human TCR variable domain frameworks could provide support for complementarity-determining regions from a murine TCR, and retain the original binding activity. It could be used as a generic approach of TCR humanization.
T 细胞受体 (TCR) 的亲和力决定了 TCR 为基础的免疫疗法的疗效。通过使用人类白细胞抗原 (HLA)-A02 转基因小鼠，先前已经产生了一种针对人类肿瘤睾丸抗原肽 MAGE-A3（KVAELVHFL）HLA-A02 复合物的 TCR。我们开发了一种方法，通过用折叠优化的人 TCR 可变区序列替换小鼠框架，来实现 TCR 的人源化，以保留结合亲和力。所得的人源化 TCR 表现出比其亲本鼠 MAGE-A3 TCR（SRm1）更高的亲和力，并赋予更好的抗肿瘤活性。此外，进一步增强了人源化 TCR 的亲和力，以实现更好的 T 细胞激活。我们的研究表明，人 TCR 可变区框架可以为来自鼠 TCR 的互补决定区提供支持，并保留原始的结合活性。它可以用作 TCR 人源化的通用方法。
