Specific Increase in Potency via Structure-Based Design of a TCR

摘要: Adoptive immunotherapy with Ag-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor Ags are nonreactive "self" proteins, which presents an design challenge. Recent studies have shown that tumor-specific TCRs can be transduced into normal PBLs, persist after transfer in ∼30% of patients and effectively destroy cells vivo. Although encouraging, the limited clinical responses underscore need enrichment desirable antitumor capabilities prior to patient transfer. In this study, we used structure-based predict point mutations TCR (DMF5) enhance its binding affinity agonist Ag-MHC (peptide-MHC [pMHC]), Mart-1 (27L)-HLA-A2, elicits full cell activation trigger immune responses. We analyzed effects selected on potency cross-reactivity related Ags. Our results showed mutated had improved while retaining high degree specificity. Such affinity-optimized demonstrated very specific (27L), epitope they were structurally designed. somewhat relevance, these open possibility future structural-based could potentially adoptive treat melanoma avoiding adverse autoimmunity-derived effects.