Development of DARPin T cell engagers for specific targeting of tumor-associated HLA/peptide complexes.

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∗0201/NY-ESO1_157-165 complex revealed a rigid, concave DARPin surface spanning the full length of th

SUBMITTER: Venetz-Arenas N 

PROVIDER: S-EPMC12664392 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature