De novo-designed pMHC binders facilitate T cell–mediated cytotoxicity toward cancer cells

2025/07/24 by K. Johansen, Darian S. Wolff, Beatrice Scapolo +24 · 1 voice · 16 citations
Medicine · Immunology and Microbiology · #CAR-T cell therapy research #Immunotherapy and Immune Responses #T-cell and B-cell Immunology

paper · doi:10.1126/science.adv0422

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.

Cited by

• CAR-T cells in solid tumors: Challenges and breakthroughs
• CAR-T cells in solid tumors: Challenges and breakthroughs. [europepmc]
• CIMT 2025: Report on the 22 nd Annual Meeting of the Association for Cancer Immunotherapy. [europepmc]
• Advancing human leukocyte antigen-based cancer immunotherapy: from personalized to broad-spectrum strategies for genetically heterogeneous populations. [europepmc]
• Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy. [europepmc]
• Targeted biologics for TNBC: Advances in nanobodies, antibodies, peptides, and aptamers. [europepmc]
• Advancing immunotherapy via multiple immune cells co-engagement. [europepmc]
• CAR-T Cells: Current Status, Challenges, and Future Prospects. [europepmc]
• Advances in cancer immunotherapy: adoptive cell therapy and immune cell engagers in solid tumours. [europepmc]
• Synthesis, Structural Characterization and In Vitro Immunosuppressive Activity of Quinoa Bran Soluble Dietary Fiber-Gallium Complex. [europepmc]
• Synthetic nucleic acids in a post-agent biosecurity Era. [europepmc]
• Generative Protein Design: From Deep Learning Algorithms to Translational Applications. [europepmc]
• AI-Guided De Novo Design of a Caffeine-Induced Protein Dissociation System. [europepmc]
• Benchmarking TCR-pMHC structure prediction: a unified evaluation and CDR3-based functional insights. [europepmc]
• De novo design of dual-target mini-binders simultaneously neutralizing Streptococcus equi subspecies zooepidemicus M-like protein and host TNFR1 confers complete protection against lethal infection. [europepmc]
• TCR-mimic bispecific nanobody-based T cell engager targeting intracellular tumor antigens for cancer immunotherapy. [europepmc]

Discussions

• Thrilled to announce our paper, "De novo-designed pMHC binders facilitate T cell-mediated cytotoxicity toward cancer cells," is officially out in @science.org! We used generative AI to build a 'GPS' [bsky, 37 points, 1 comments]

Related

• Design of high specificity binders for peptide-MHC-I complexes
• T-cell receptor specificity landscape revealed through de novo peptide design
• Functional screening of TCR-like antibodies using STAR-T cell library for cancer immunotherapy
• Dynamics-based peptide-MHC binding optimization by a convolutional variational autoencoder: a use-case model for CASTELO
• Small Molecule Modulation of MHC-I Surface Expression: A Click Chemistry-Based Discovery Approach