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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.
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]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: De novo-designed pMHC binders facilitate T cell–mediated cytotoxicity toward cancer cells.
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  Data: <searchLink fieldCode="AR" term="%22Johansen%2C+Kristoffer+Haurum%22">Johansen, Kristoffer Haurum</searchLink><br /><searchLink fieldCode="AR" term="%22Wolff%2C+Darian+Stephan%22">Wolff, Darian Stephan</searchLink><br /><searchLink fieldCode="AR" term="%22Scapolo%2C+Beatrice%22">Scapolo, Beatrice</searchLink><br /><searchLink fieldCode="AR" term="%22Fernández-Quintero%2C+Monica+L%2E%22">Fernández-Quintero, Monica L.</searchLink><br /><searchLink fieldCode="AR" term="%22Risager+Christensen%2C+Charlotte%22">Risager Christensen, Charlotte</searchLink><br /><searchLink fieldCode="AR" term="%22Loeffler%2C+Johannes+R%2E%22">Loeffler, Johannes R.</searchLink><br /><searchLink fieldCode="AR" term="%22Rivera-de-Torre%2C+Esperanza%22">Rivera-de-Torre, Esperanza</searchLink><br /><searchLink fieldCode="AR" term="%22Overath%2C+Max+D%2E%22">Overath, Max D.</searchLink><br /><searchLink fieldCode="AR" term="%22Kjærgaard+Munk%2C+Kamilla%22">Kjærgaard Munk, Kamilla</searchLink><br /><searchLink fieldCode="AR" term="%22Morell%2C+Oliver%22">Morell, Oliver</searchLink><br /><searchLink fieldCode="AR" term="%22Viuff%2C+Marie+Christine%22">Viuff, Marie Christine</searchLink><br /><searchLink fieldCode="AR" term="%22Lacunza%2C+Iñigo%22">Lacunza, Iñigo</searchLink><br /><searchLink fieldCode="AR" term="%22Damm+Englund%2C+Alberte+T%2E%22">Damm Englund, Alberte T.</searchLink><br /><searchLink fieldCode="AR" term="%22Due%2C+Mathilde%22">Due, Mathilde</searchLink><br /><searchLink fieldCode="AR" term="%22Gharpure%2C+Anant%22">Gharpure, Anant</searchLink><br /><searchLink fieldCode="AR" term="%22Forli%2C+Stefano%22">Forli, Stefano</searchLink><br /><searchLink fieldCode="AR" term="%22Rodriguez+Pardo%2C+Carlos%22">Rodriguez Pardo, Carlos</searchLink><br /><searchLink fieldCode="AR" term="%22Tamhane%2C+Tripti%22">Tamhane, Tripti</searchLink><br /><searchLink fieldCode="AR" term="%22Qingjie+Andersen%2C+Emma%22">Qingjie Andersen, Emma</searchLink><br /><searchLink fieldCode="AR" term="%22Haldrup+Björnsson%2C+Kasper%22">Haldrup Björnsson, Kasper</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 7/24/2025, Vol. 389 Issue 6758, p380-385. 6p.
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=188103350
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        Value: 10.1126/science.adv0422
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        Text: English
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