De novo-designed pMHC binders facilitate T cell–mediated cytotoxicity toward cancer cells
The recognition of intracellular antigens by CD8<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Johannes R. Loeffler (ORCID: https://orcid.org/0000-0002-5724-655X)
- Suthimon Thumtecho (ORCID: https://orcid.org/0000-0002-8853-6568)
- Sine Reker Hadrup (ORCID: https://orcid.org/0000-0002-5937-4344)
- Monica L. Fernández‐Quintero (ORCID: https://orcid.org/0000-0002-6811-6283)
- Tripti Tamhane (ORCID: https://orcid.org/0000-0001-6417-3304)
- Lasse Frank Voss (ORCID: https://orcid.org/0000-0003-0904-6753)
- Darian Stephan Wolff (ORCID: https://orcid.org/0000-0002-9266-3017)
- Emma Qingjie Andersen
- A Englund
- Timothy P. Jenkins (ORCID: https://orcid.org/0000-0003-2979-5663)
- Maria Ormhøj (ORCID: https://orcid.org/0000-0002-0997-8262)
- Kamilla Kjærgaard Munk (ORCID: https://orcid.org/0000-0001-9217-7142)
- Stefano Forli (ORCID: https://orcid.org/0000-0002-5964-7111)
- Kasper Haldrup Björnsson (ORCID: https://orcid.org/0000-0003-1339-8620)
- K. Johansen (ORCID: https://orcid.org/0000-0002-7711-9451)
- Mathilde Due
- Esperanza Rivera‐de‐Torre (ORCID: https://orcid.org/0000-0002-0272-6150)
- Max D. Overath (ORCID: https://orcid.org/0009-0009-6347-9809)
- Anant Gharpure (ORCID: https://orcid.org/0000-0002-4458-359X)
- Marie Christine Viuff (ORCID: https://orcid.org/0000-0003-4991-1043)
- Oliver Morell (ORCID: https://orcid.org/0009-0000-8702-1792)
- J Fernandes (ORCID: https://orcid.org/0000-0003-2238-2153)
- Carlos Rodriguez Pardo
- Charlotte Risager Christensen
- Beatrice Scapolo
- Iñigo Lacunza (ORCID: https://orcid.org/0009-0003-2084-4892)
Institutions
- Scripps Research Institute (US)
- Technical University of Denmark (DK)
Publication Details
- Journal
- Science
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1126/science.adv0422
- Citations
- 25
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 26.13