Minimal Amino Acid Exchange in Human TCR Constant Regions Fosters Improved Function of TCR Gene-Modified T Cells

摘要: TCR gene therapy using adoptive transfer of gene-modified T cells is a new strategy for treatment cancer. One critical prerequisite sufficient expression transferred TCRs. Several strategies to achieve optimal were developed, including "murinization," which replaces the human TCRalpha and TCRbeta constant regions by their murine counterparts. Using series mouse-human hybrid constructs, we have identified nine amino acids responsible improved murinized Five essential acid exchanges in C region, with exchange glutamic (human) basic lysine (mouse) at position 18 being most important. For an area four was expression. The minimally variants (harboring only residues mouse sequence) enhanced TCRs supporting preferential pairing chains more stable association CD3 proteins. Most important, usage function transduced primary comparison wild-type therapy, utilization instead completely dramatically reduces number foreign thereby risk immunogenicity therapeutic