The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Computational stabilization of T cell receptors allows pairing with antibodies to form bispecifics
Abstract
Recombinant T cell receptors (TCRs) can be used to redirect naïve T cells to eliminate virally infected or cancerous cells; however, they are plagued by low stability and uneven expression. Here, we use molecular modeling to identify mutations in the TCR constant domains (Cα/Cβ) that increase the unfolding temperature of Cα/Cβ by 20 °C, improve the expression of four separate α/β TCRs by 3- to 10-fold, and improve the assembly and stability of TCRs with poor intrinsic stability. The stabilizing mutations rescue the expression of TCRs destabilized through variable domain mutation. The improved stability and folding of the TCRs reduces glycosylation, perhaps through conformational stabilization that restricts access to N-linked glycosylation enzymes. The Cα/Cβ mutations enables antibody-like expression and assembly of well-behaved bispecific molecules that combine an anti-CD3 antibody with the stabilized TCR. These TCR/CD3 bispecifics can redirect T cells to kill tumor cells with target HLA/peptide on their surfaces in vitro.
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Cites
Features and development of Coot
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Phaser crystallographic software
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Overview of the CCP 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353
REFMAC 5 for the refinement of macromolecular crystal structures
Murshudov, G. N., Skubák, P., Lebedev, A. A., Pannu, N. S., Steiner, R. A., Nicholls, R. A., Winn, M. D., Long, F., & Vagin, A. A. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444911001314 · Cited by 8,317
MolProbity: More and better reference data for improved all‐atom structure validation
Williams, C. J., Headd, J. J., Moriarty, N. W., Prisant, M. G., Videau, L. L., Deis, L. N., Verma, V., Keedy, D. A., Hintze, B. J., Chen, V. B., et al. (2018) · Protein Science · doi:10.1002/pro.3330 · Cited by 4,599
T-cell antigen receptor genes and T-cell recognition
Davis, M. M., & Bjorkman, P. J. (1988) · Nature · doi:10.1038/334395a0 · Cited by 3,202
Delivery technologies for cancer immunotherapy
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Data processing and analysis with the autoPROC toolbox
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The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design
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Cited by
H3-OPT: Accurate prediction of CDR-H3 loop structures of antibodies with deep learning
Chen, H., Fan, X., Zhu, S., Pei, Y., Zhang, X., Zhang, X., Liu, L., Qian, F., & Tian, B. (2023) · doi:10.1101/2023.08.19.553933 · Cited by 1
Metadata
- Authors
- Froning, K., Maguire, J., Sereno, A., Huang, F., Chang, S., Weichert, K., Frommelt, A. J., Dong, J., Wu, X., Austin, H., Conner, E. M., Fitchett, J. R., Heng, A. R., Balasubramaniam, D., Hilgers, M. T., Kuhlman, B., & Demarest, S. J.
- Venue
- Nature Communications
- Published
- 2020-05-11
- Volume
- 11
- Issue
- 1
- ISSN
- 2041-1723
- Cited by
- 37
- References
- 59
- Language
- en
- Licence
- creativecommons.org/licenses/by/4.0 (tdm)
- creativecommons.org/licenses/by/4.0 (vor)
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