A humanized TCR retaining authentic specificity and affinity conferred potent anti‐tumour cytotoxicity
Citations Over Time
Abstract
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-A3112-120 (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 (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.
Related Papers
- → Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability(2010)114 cited
- → TCR transgenes and transgene cassettes for TCR gene therapy: status in 2008(2009)61 cited
- → Current status and future challenges in T-cell receptor/peptide/MHC molecular dynamics simulations(2015)56 cited
- → Molecular modeling of a T-cell receptor bound to a major histocompatibility complex molecule: Implications for T-cell recognition(1995)12 cited
- → Engagement of a T cell receptor by major histocompatibility complex irrespective of peptide(1997)7 cited