{"entity": "publication", "iuid": "d5861d1025f14dc3bc866b4e72bdd76d", "timestamp": "2026-09-30T22:58:39.261Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/d5861d1025f14dc3bc866b4e72bdd76d.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/d5861d1025f14dc3bc866b4e72bdd76d"}}, "title": "Development of DARPin T cell engagers for specific targeting of tumor-associated HLA/peptide complexes.", "authors": [{"family": "Venetz-Arenas", "given": "Natalia", "initials": "N"}, {"family": "Schulte", "given": "Tim", "initials": "T"}, {"family": "M\u00fcller", "given": "Sandra", "initials": "S"}, {"family": "Wallden", "given": "Karin", "initials": "K"}, {"family": "Fischer", "given": "Stefanie", "initials": "S"}, {"family": "Resink", "given": "Tom", "initials": "T"}, {"family": "Kadri", "given": "Nadir", "initials": "N"}, {"family": "Paladino", "given": "Maria", "initials": "M"}, {"family": "Pina", "given": "Nicole", "initials": "N"}, {"family": "Radom", "given": "Filip", "initials": "F"}, {"family": "Villemagne", "given": "Denis", "initials": "D"}, {"family": "Bruckmaier", "given": "Sandra", "initials": "S"}, {"family": "Cornelius", "given": "Andreas", "initials": "A"}, {"family": "Hospodarsch", "given": "Tanja", "initials": "T"}, {"family": "Alici", "given": "Evren", "initials": "E"}, {"family": "Ljunggren", "given": "Hans-Gustaf", "initials": "HG"}, {"family": "Chambers", "given": "Benedict J", "initials": "BJ"}, {"family": "Han", "given": "Xiao", "initials": "X"}, {"family": "Sun", "given": "Renhua", "initials": "R"}, {"family": "Carroni", "given": "Marta", "initials": "M"}, {"family": "Levitsky", "given": "Victor", "initials": "V"}, {"family": "Sandalova", "given": "Tatyana", "initials": "T"}, {"family": "Walser", "given": "Marcel", "initials": "M"}, {"family": "Achour", "given": "Adnane", "initials": "A"}], "type": "journal article", "published": "2025-12-19", "journal": {"title": "iScience", "issn": "2589-0042", "volume": "28", "issue": "12", "pages": "113926", "issn-l": null}, "abstract": "The balance between affinity and specificity in T cell receptor (TCR)-dependent targeting of HLA-restricted tumor-associated antigens presents a significant challenge for immunotherapy development. T cell engagers that circumvent these limitations are therefore of particular interest. We established a process to generate bispecific designed ankyrin repeat proteins (DARPins) that simultaneously target HLA-I/peptide complexes and CD3e. These high-affinity T cell engagers elicited CD8+ T cell activation against tumor targets with strong peptide specificity, as confirmed by X-scanning mutagenesis and functional killing assays. A cryo-EM structure of the ternary DARPin/HLA-A\u22170201/NY-ESO1157-165 complex revealed a rigid, concave DARPin surface spanning the full length of the peptide-binding cleft, contacting both \u03b1-helices and the peptide. The present findings reveal promising immuno-oncotherapeutic approaches and demonstrate the feasibility of rapidly developing DARPins with high affinity and specificity for HLA/peptide targets, which can be readily combined with a new generation of anti-CD3e-specific DARPins.", "doi": "10.1016/j.isci.2025.113926", "pmid": "41321628", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12664392"}, {"db": "pii", "key": "S2589-0042(25)02187-X"}], "notes": [], "created": "2026-09-23T13:25:03.379Z", "modified": "2026-09-23T13:25:03.403Z"}