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Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity.

Dunn SM, Rizkallah PJ, Baston E, Mahon T, Cameron B, Moysey R, Gao F, Sami M, Boulter J, Li Y, Jakobsen BK
Protein Sci 15 710-21 (2006)
Cited: 83 times
EuropePMC logo PMID: 16600963

Abstract

The mammalian alpha/beta T cell receptor (TCR) repertoire plays a pivotal role in adaptive immunity by recognizing short, processed, peptide antigens bound in the context of a highly diverse family of cell-surface major histocompatibility complexes (pMHCs). Despite the extensive TCR-MHC interaction surface, peptide-independent cross-reactivity of native TCRs is generally avoided through cell-mediated selection of molecules with low inherent affinity for MHC. Here we show that, contrary to expectations, the germ line-encoded complementarity determining regions (CDRs) of human TCRs, namely the CDR2s, which appear to contact only the MHC surface and not the bound peptide, can be engineered to yield soluble low nanomolar affinity ligands that retain a surprisingly high degree of specificity for the cognate pMHC target. Structural investigation of one such CDR2 mutant implicates shape complementarity of the mutant CDR2 contact interfaces as being a key determinant of the increased affinity. Our results suggest that manipulation of germ line CDR2 loops may provide a useful route to the production of high-affinity TCRs with therapeutic and diagnostic potential.

Articles - 2f53 mentioned but not cited (13)

  1. Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor. Cole DK, Yuan F, Rizkallah PJ, Miles JJ, Gostick E, Price DA, Gao GF, Jakobsen BK, Sewell AK. J Biol Chem 284 27281-27289 (2009)
  2. Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity. Dunn SM, Rizkallah PJ, Baston E, Mahon T, Cameron B, Moysey R, Gao F, Sami M, Boulter J, Li Y, Jakobsen BK. Protein Sci 15 710-721 (2006)
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  6. Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy. Crean RM, MacLachlan BJ, Madura F, Whalley T, Rizkallah PJ, Holland CJ, McMurran C, Harper S, Godkin A, Sewell AK, Pudney CR, van der Kamp MW, Cole DK. Mol Ther Oncolytics 18 443-456 (2020)
  7. Predicting peptide binding affinities to MHC molecules using a modified semi-empirical scoring function. Liao WW, Arthur JW. PLoS One 6 e25055 (2011)
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  11. How far are we from automatic crystal structure solution via molecular-replacement techniques? Burla MC, Carrozzini B, Cascarano GL, Giacovazzo C, Polidori G. Acta Crystallogr D Struct Biol 76 9-18 (2020)
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  13. The Automatic Solution of Macromolecular Crystal Structures via Molecular Replacement Techniques: REMO22 and Its Pipeline. Carrozzini B, Cascarano GL, Giacovazzo C. Int J Mol Sci 24 6070 (2023)


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  1. T cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance. Chandran SS, Klebanoff CA. Immunol Rev 290 127-147 (2019)
  2. Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma. Damato BE, Dukes J, Goodall H, Carvajal RD. Cancers (Basel) 11 E971 (2019)
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  7. Structure-Based, Rational Design of T Cell Receptors. Zoete V, Irving M, Ferber M, Cuendet MA, Michielin O. Front Immunol 4 268 (2013)
  8. Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy. Rath JA, Arber C. Cells 9 E1485 (2020)
  9. Display, engineering, and applications of antigen-specific T cell receptors. Richman SA, Kranz DM. Biomol Eng 24 361-373 (2007)
  10. Challenges in T cell receptor gene therapy. Uttenthal BJ, Chua I, Morris EC, Stauss HJ. J Gene Med 14 386-399 (2012)
  11. Diversity-oriented approaches for interrogating T-cell receptor repertoire, ligand recognition, and function. Birnbaum ME, Dong S, Garcia KC. Immunol Rev 250 82-101 (2012)
  12. Empirical and Rational Design of T Cell Receptor-Based Immunotherapies. Jones HF, Molvi Z, Klatt MG, Dao T, Scheinberg DA. Front Immunol 11 585385 (2020)
  13. Integrating Experiment and Theory to Understand TCR-pMHC Dynamics. Buckle AM, Borg NA. Front Immunol 9 2898 (2018)
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  16. Phage Display Engineered T Cell Receptors as Tools for the Study of Tumor Peptide-MHC Interactions. Løset GÅ, Berntzen G, Frigstad T, Pollmann S, Gunnarsen KS, Sandlie I. Front Oncol 4 378 (2014)
  17. Challenges and solutions for therapeutic TCR-based agents. Malviya M, Aretz ZEH, Molvi Z, Lee J, Pierre S, Wallisch P, Dao T, Scheinberg DA. Immunol Rev 320 58-82 (2023)
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  19. Unconventional modes of peptide-HLA-I presentation change the rules of TCR engagement. Hopkins JR, MacLachlan BJ, Harper S, Sewell AK, Cole DK. Discov Immunol 1 kyac001 (2022)

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