ArticleMolecular therapy : the journal of the American Society of Gene Therapy2019
Improving T Cell Receptor On-Target Specificity via Structure-Guided Design.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 61 citations in OpenAlex.
- Article
- Hallmarks and correlates of effective adoptive cell immunotherapy for cancer.Nature reviews. Immunology · 2026Review
- Benchmarking TCR-pMHC structure prediction: a unified evaluation and CDR3-based functional insights.Briefings in bioinformatics · 2026Article
- Generation of T cells with reduced off-target cross-reactivities by engineering co-signalling receptors.Nature biomedical engineering · 2026Article
- Development of DARPin T cell engagers for specific targeting of tumor-associated HLA/peptide complexes.iScience · 2025Article
- Targeting peptide-MHC complexes with designed T cell receptors and antibodies.bioRxiv : the preprint server for biology · 2025Article
- The Evolving T Cell Receptor Recognition Code: The Rules Are More Like Guidelines.Immunological reviews · 2025Review
- RankMHC: Learning to Rank Class-I Peptide-MHC Structural Models.Journal of chemical information and modeling · 2024Article
- TCR-T cell therapy: current development approaches, preclinical evaluation, and perspectives on regulatory challenges.Journal of translational medicine · 2024Review
- Focusing on CD8Journal of experimental & clinical cancer research : CR · 2024Review
- Exploring the potential of structure-based deep learning approaches for T cell receptor design.PLoS computational biology · 2024Article
- Can AlphaFold's breakthrough in protein structure help decode the fundamental principles of adaptive cellular immunity?Nature methods · 2024Review
- Enhanced T cell receptor specificity through framework engineering.Frontiers in immunology · 2024Article
- T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome.Nature reviews. Drug discovery · 2023Review
- HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes.Nature communications · 2023Article
- Review
- Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM.Nature communications · 2023Article
- Redirecting Polyclonal T Cells against Cancer with Soluble T-Cell Receptors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- TCR-engineered T cell therapy in solid tumors: State of the art and perspectives.Science advances · 2023Review
- Epitope identification for p53R273C mutant.Immunity, inflammation and disease · 2023Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.