A humanized TCR retaining authentic specificity and affinity conferred potent antitumour cytotoxicit

A humanized TCR retaining authentic specificity and affinity conferred potent antitumour cytotoxicity

Author：Lin Chen, Ye Tian, Kai Zhan, Anan Chen, Zhiming Weng, Jiao Huang, Yanyan Li, Yongjie Sun, Hongjun Zheng, Yi Li 《Immunology》

ABSTRACTS

The affinity of Tcell receptor (TCR) determines the efficacy of TCRbased immunotherapy. By using human leucocyte antigen (HLA)A*02 transgenic mice, a TCR was generated previously specific for human tumour testis antigen peptide MAGEA3112–120 (KVAELVHFL) HLAA*02 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 antitumour activity than its parent murine MAGEA3 TCR (SRm1). In addition, the affinity of humanized TCR was enhanced further to achieve improved Tcell activation. Our studies demonstrated that the human TCR variable domain frameworks could provide support for complementaritydetermining regions from a murine TCR, and retain the original binding activity. It could be used as a generic approach of TCR humanization.