Improving T Cell Receptor On-Target Specificity via Structure-Guided Design
| Autor: | Grant L.J. Keller, Jesus A. Alonso, Timothy P. Riley, Kendra C. Foley, Nishant K. Singh, Brian M. Baker, Lance M. Hellman, Craig W. Vander Kooi, Cory M. Ayres, Michael I. Nishimura, Jason R. Devlin, Yuting Zhang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.drug_class
Receptors Antigen T-Cell Antigen specificity T-Cell Antigen Receptor Specificity chemical and pharmacologic phenomena Computational biology Adaptive Immunity Biology Monoclonal antibody Protein Structure Secondary Epitope 03 medical and health sciences MART-1 Antigen 0302 clinical medicine Drug Discovery Genetics medicine Humans Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences T-cell receptor Antibodies Monoclonal hemic and immune systems Surface Plasmon Resonance Acquired immune system Immune toxicity 030220 oncology & carcinogenesis biology.protein Molecular Medicine Original Article Antibody Function (biology) |
| Zdroj: | Molecular Therapy. 27:300-313 |
| ISSN: | 1525-0016 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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