Specific increase in potency via structure-based design of a TCR

Karolina Malecek, Arsen Grigoryan, Shi Zhong, Wei Jun Gu, Laura A. Johnson, Steven A. Rosenberg, Timothy Cardozo, Michelle Krogsgaard

Research output: Contribution to journalArticlepeer-review

Abstract

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 immunotherapy design challenge. Recent studies have shown that tumor-specific TCRs can be transduced into normal PBLs, which persist after transfer in ∼30% of patients and effectively destroy tumor cells in vivo. Although encouraging, the limited clinical responses underscore the need for enrichment of T cells with desirable antitumor capabilities prior to patient transfer. In this study, we used structure-based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor Ag-MHC (peptide-MHC [pMHC]), Mart-1 (27L)-HLAA2, which elicits full T cell activation to trigger immune responses. We analyzed the effects of selected TCR point mutations on T cell activation potency and analyzed cross-reactivity with related Ags. Our results showed that the mutated TCRs had improved T cell activation potency while retaining a high degree of specificity. Such affinity-optimized TCRs have demonstrated to be very specific for Mart-1 (27L), the epitope for which they were structurally designed. Although of somewhat limited clinical relevance, these studies open the possibility for future structural-based studies that could potentially be used in adoptive immunotherapy to treat melanoma while avoiding adverse autoimmunity-derived effects.

Original languageEnglish (US)
Pages (from-to)2587-2599
Number of pages13
JournalJournal of Immunology
Volume193
Issue number5
DOIs
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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