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A humanized TCR retaining authentic specificity and affinity conferred potent anti‐tumour cytotoxicity
Author(s) -
Chen Lin,
Tian Ye,
Zhan Kai,
Chen Anan,
Weng Zhiming,
Huang Jiao,
Li Yanyan,
Sun Yongjie,
Zheng Hongjun,
Li Yi
Publication year - 2018
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12935
Subject(s) - t cell receptor , humanized mouse , transgene , biology , microbiology and biotechnology , antigen , receptor , cytotoxicity , complementarity determining region , major histocompatibility complex , immunotherapy , immunology , cancer research , computational biology , t cell , antibody , biochemistry , gene , monoclonal antibody , in vitro , immune system
Summary The affinity of T‐cell receptor ( TCR ) determines the efficacy of TCR ‐based immunotherapy. By using human leucocyte antigen ( HLA )‐A*02 transgenic mice, a TCR was generated previously specific for human tumour testis antigen peptide MAGE ‐A3 112–120 ( KVAELVHFL ) HLA ‐A*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 anti‐tumour activity than its parent murine MAGE ‐A3 TCR ( SR m1). 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.