Improving T Cell Receptor On-Target Specificity via Structure-Guided Design

被引:41
作者
Hellman, Lance M. [1 ,2 ]
Foley, Kendra C. [3 ,4 ]
Singh, Nishant K. [1 ,2 ]
Alonso, Jesus A. [1 ,2 ]
Riley, Timothy P. [1 ,2 ]
Devlin, Jason R. [1 ,2 ]
Ayres, Cory M. [1 ,2 ]
Keller, Grant L. J. [1 ,2 ]
Zhang, Yuting [1 ,2 ]
Vander Kooi, Craig W. [5 ]
Nishimura, Michael I. [3 ,4 ]
Baker, Brian M. [1 ,2 ]
机构
[1] Univ Notre Dame, Dept Chem & Biochem, 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA
[2] Univ Notre Dame, Harper Canc Res Inst, 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA
[3] Loyola Univ Chicago, Dept Surg, Maywood, IL USA
[4] Loyola Univ Chicago, Cardinal Bernardin Canc Ctr, Maywood, IL USA
[5] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY USA
关键词
HIGH-AFFINITY; CROSS-REACTIVITY; GENE-THERAPY; ANTIGEN RECOGNITION; CANCER REGRESSION; TCR; CD8; IDENTIFICATION; GOVERNS; AVIDITY;
D O I
10.1016/j.ymthe.2018.12.010
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use.
引用
收藏
页码:300 / 313
页数:14
相关论文
共 76 条
  • [1] Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity
    Adams, Jarrett J.
    Narayanan, Samanthi
    Birnbaum, Michael E.
    Sidhu, Sachdev S.
    Blevins, Sydney J.
    Gee, Marvin H.
    Sibener, Leah V.
    Baker, Brian M.
    Kranz, David M.
    Garcia, K. Christopher
    [J]. NATURE IMMUNOLOGY, 2016, 17 (01) : 87 - +
  • [2] The Phenix software for automated determination of macromolecular structures
    Adams, Paul D.
    Afonine, Pavel V.
    Bunkoczi, Gabor
    Chen, Vincent B.
    Echols, Nathaniel
    Headd, Jeffrey J.
    Hung, Li-Wei
    Jain, Swati
    Kapral, Gary J.
    Kunstleve, Ralf W. Grosse
    McCoy, Airlie J.
    Moriarty, Nigel W.
    Oeffner, Robert D.
    Read, Randy J.
    Richardson, David C.
    Richardson, Jane S.
    Terwilliger, Thomas C.
    Zwart, Peter H.
    [J]. METHODS, 2011, 55 (01) : 94 - 106
  • [3] Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy
    Antunes, Dinler A.
    Rigo, Mauricio M.
    Freitas, Martiela V.
    Mendes, Marcus F. A.
    Sinigaglia, Marialva
    Lizee, Gregory
    Kavraki, Lydia E.
    Selin, Liisa K.
    Cornberg, Markus
    Vieira, Gustavo F.
    [J]. FRONTIERS IN IMMUNOLOGY, 2017, 8
  • [4] Deconstructing the Peptide-MHC Specificity of T Cell Recognition
    Birnbaum, Michael E.
    Mendoza, Juan L.
    Sethi, Dhruv K.
    Dong, Shen
    Glanville, Jacob
    Dobbins, Jessica
    Oezkan, Engin
    Davis, Mark M.
    Wucherpfennig, Kai W.
    Garcia, K. Christopher
    [J]. CELL, 2014, 157 (05) : 1073 - 1087
  • [5] Using Global Analysis to Extend the Accuracy and Precision of Binding Measurements with T cell Receptors and Their Peptide/MHC Ligands
    Blevins, Sydney J.
    Baker, Brian M.
    [J]. FRONTIERS IN MOLECULAR BIOSCIENCES, 2017, 4
  • [6] TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms
    Borbulevych, Oleg Y.
    Santhanagopolan, Sujatha M.
    Hossain, Moushumi
    Baker, Brian M.
    [J]. JOURNAL OF IMMUNOLOGY, 2011, 187 (05) : 2453 - 2463
  • [7] Engineering the binding properties of the T cell receptor:peptide:MHC ternary complex that governs T cell activity
    Bowerman, Natalie A.
    Crofts, Terence S.
    Chlewicki, Lukasz
    Do, Priscilla
    Baker, Brian M.
    Garcia, K. Christopher
    Kranz, David M.
    [J]. MOLECULAR IMMUNOLOGY, 2009, 46 (15) : 3000 - 3008
  • [8] T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens
    Brehm, MA
    Pinto, AK
    Daniels, KA
    Schneck, JP
    Welsh, RM
    Selin, LK
    [J]. NATURE IMMUNOLOGY, 2002, 3 (07) : 627 - 634
  • [9] Identification of a hepatitis C virus-reactive T cell receptor that does not require CD8 for target cell recognition
    Callender, GG
    Rosen, HR
    Roszkowski, JJ
    Lyons, GE
    Li, ML
    Moore, T
    Brasic, N
    Mckee, MD
    Nishimura, MI
    [J]. HEPATOLOGY, 2006, 43 (05) : 973 - 981
  • [10] PyRosetta: a script-based interface for implementing molecular modeling algorithms using Rosetta
    Chaudhury, Sidhartha
    Lyskov, Sergey
    Gray, Jeffrey J.
    [J]. BIOINFORMATICS, 2010, 26 (05) : 689 - 691