De novo-designed pMHC binders facilitate T cell–mediated cytotoxicity toward cancer cells.
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| Title: | De novo-designed pMHC binders facilitate T cell–mediated cytotoxicity toward cancer cells. |
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| Authors: | Johansen, Kristoffer Haurum, Wolff, Darian Stephan, Scapolo, Beatrice, Fernández-Quintero, Monica L., Risager Christensen, Charlotte, Loeffler, Johannes R., Rivera-de-Torre, Esperanza, Overath, Max D., Kjærgaard Munk, Kamilla, Morell, Oliver, Viuff, Marie Christine, Lacunza, Iñigo, Damm Englund, Alberte T., Due, Mathilde, Gharpure, Anant, Forli, Stefano, Rodriguez Pardo, Carlos, Tamhane, Tripti, Qingjie Andersen, Emma, Haldrup Björnsson, Kasper |
| Source: | Science. 7/24/2025, Vol. 389 Issue 6758, p380-385. 6p. |
| Subjects: | Cell-mediated cytotoxicity, Cancer cell growth, Chimeric antigen receptors, Major histocompatibility complex, Cell death |
| Abstract: | The recognition of intracellular antigens by CD8+ T cells through T cell receptors (TCRs) is central for adaptive immunity against infections and cancer. However, the identification of TCRs from patient material remains complex. We present a rapid de novo minibinder (miBd) design platform leveraging state-of-the-art generative models to engineer miBds targeting the cancer-associated peptide-bound major histocompatibility complex (pMHC) SLLMWITQC/HLA-A*02:01 (NY-ESO-1). Incorporating in silico cross-panning enabled computational prescreening of specificity, and molecular dynamics simulations allowed for improved predictability of in vitro success. We identified a high-affinity NY-ESO-1 binder and confirmed its structure using cryo–electron microscopy, which, when incorporated in a chimeric antigen receptor, induced killing of NY-ESO-1+ melanoma cells. We further designed and validated binders to a neoantigen pMHC complex, RVTDESILSY/HLA-A*01:01, with unknown structure, demonstrating the potential for precision immunotherapy. Editor's summary: Diseased and infected cells can be recognized through peptide antigens presented on the surface of the cell by major histocompatibility complex (MHC) proteins. Whereas the T cell receptor is nature's solution for recognizing peptide antigen–loaded MHCs, smaller proteins synthesized for this purpose could be transformative for diagnostic tools and immunotherapies. Liu et al., Johansen et al., and Householder et al. developed computational and experimental pipelines to facilitate the rapid design and validation of proteins that could recognize peptides from viral proteins, tumor-associated proteins, or neoantigens when presented by MHC molecules, with high specificity and low off-target recognition (see the Perspective by Hickok and Stromnes). When incorporated as the recognition domain for a chimeric antigen receptor and expressed in T cells, these de novo–designed peptide-MHC binders could induce signaling and on-target cell killing. —Sarah H. Ross [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | The recognition of intracellular antigens by CD8+ T cells through T cell receptors (TCRs) is central for adaptive immunity against infections and cancer. However, the identification of TCRs from patient material remains complex. We present a rapid de novo minibinder (miBd) design platform leveraging state-of-the-art generative models to engineer miBds targeting the cancer-associated peptide-bound major histocompatibility complex (pMHC) SLLMWITQC/HLA-A*02:01 (NY-ESO-1). Incorporating in silico cross-panning enabled computational prescreening of specificity, and molecular dynamics simulations allowed for improved predictability of in vitro success. We identified a high-affinity NY-ESO-1 binder and confirmed its structure using cryo–electron microscopy, which, when incorporated in a chimeric antigen receptor, induced killing of NY-ESO-1+ melanoma cells. We further designed and validated binders to a neoantigen pMHC complex, RVTDESILSY/HLA-A*01:01, with unknown structure, demonstrating the potential for precision immunotherapy. Editor's summary: Diseased and infected cells can be recognized through peptide antigens presented on the surface of the cell by major histocompatibility complex (MHC) proteins. Whereas the T cell receptor is nature's solution for recognizing peptide antigen–loaded MHCs, smaller proteins synthesized for this purpose could be transformative for diagnostic tools and immunotherapies. Liu et al., Johansen et al., and Householder et al. developed computational and experimental pipelines to facilitate the rapid design and validation of proteins that could recognize peptides from viral proteins, tumor-associated proteins, or neoantigens when presented by MHC molecules, with high specificity and low off-target recognition (see the Perspective by Hickok and Stromnes). When incorporated as the recognition domain for a chimeric antigen receptor and expressed in T cells, these de novo–designed peptide-MHC binders could induce signaling and on-target cell killing. —Sarah H. Ross [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adv0422 |
