Design of high-specificity binders for peptide–MHC-I complexes
Class I major histocompatibility complex (MHC-I) molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance. Proteins that recognize peptide-MHC-I (pMHCI) complexes with specificity for diseased cells could have considerable therapeutic utility. Specificity requires recognition of outward-facing amino acid residues within the disease-associated peptide as well as avoidance of extensive contacts with ubiquitously expressed MHC. We used RFdiffusion to design pMHCI-binding proteins that make extensive contacts with the peptide and identified specific binders for 11 target pMHCs starting from either experimental or predicted pMHCI structures. Upon incorporation into chimeric antigen receptors, designs for eight targets conferred peptide-specific T cell activation. Our approach should have broad utility for both protein- and cell-based pMHCI targeting.
Authors
- Nathan Greenwood (ORCID: https://orcid.org/0009-0005-2167-3647)
- David A. Scheinberg (ORCID: https://orcid.org/0000-0002-4160-923X)
- Xinyu Xiang (ORCID: https://orcid.org/0000-0002-8358-2960)
- K. Christopher García (ORCID: https://orcid.org/0000-0001-9273-0278)
- Gian Marco Visani (ORCID: https://orcid.org/0000-0003-0888-0922)
- Bingxu Liu (ORCID: https://orcid.org/0000-0002-3661-3410)
- Dionne Vafeados (ORCID: https://orcid.org/0000-0002-2560-8907)
- Amir Motmaen (ORCID: https://orcid.org/0000-0003-4190-6215)
- David A. Baker (ORCID: https://orcid.org/0000-0001-7896-6217)
- Tao Dao (ORCID: https://orcid.org/0000-0001-9937-6283)
- Russell Ault (ORCID: https://orcid.org/0000-0002-5430-5366)
- Armita Nourmohammad (ORCID: https://orcid.org/0000-0002-6245-3553)
- Jeremy Meyerberg (ORCID: https://orcid.org/0000-0001-7029-847X)
- Chunyu Wang (ORCID: https://orcid.org/0009-0004-1089-261X)
- J. M. Sharp
- Nicole Roullier
- Julia E. Bonzanini
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- Cornell University (US)
- Fred Hutch Cancer Center (US)
- University of Washington Applied Physics Laboratory (US)
- Weill Cornell Medicine (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Science
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1126/science.adv0185
- Citations
- 29
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 23.13