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

• 成果类型: Article
• 署名作者: Johansen, Kristoffer Haurum; Wolff, Darian Stephan; Scapolo, Beatrice; Fernandez-Quintero, Monica L.; Christensen, Charlotte Risager; Loeffler, Johannes R.; Rivera-de-Torre, Esperanza; Overath, Max D.; Munk, Kamilla Kjaergaard; Morell, Oliver; Viuff, Marie Christine; Lacunza, Inigo; Englund, Alberte T. Damm; Due, Mathilde; Gharpure, Anant; Forli, Stefano; Pardo, Carlos Rodriguez; Tamhane, Tripti; Andersen, Emma Qingjie; Bjoernsson, Kasper Haldrup; Fernandes, Jordan Sylvester; Voss, Lasse Frank; Thumtecho, Suthimon; Ward, Andrew B.; Ormhoj, Maria; Hadrup, Sine Reker; Jenkins, Timothy P.
• 署名单位: Technical University of Denmark; Technical University of Denmark; Scripps Research Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12140
• DOI: 10.1126/science.adv0422
• 发表日期: 2025-07-24
• 页码: 380-385
• 关键词: langevin equation approach; solid-surface scattering; molecular-dynamics; cryo-em

摘要

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.