9EPA

Crystal structure of DARPin NY_1

9EPA の概要

• エントリーDOI: 10.2210/pdb9epa/pdb
• 分子名称: DARPin NY_1 (2 entities in total)
• 機能のキーワード: darpin targeting mhc molecules in complex with tumor-associated peptide antigens, immune system
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18596.22

構造登録者

Schulte, T.,Sandalova, T.,Walser, M.,Mueller, S.,Venetz, N.,Achour, A. (登録日: 2024-03-18, 公開日: 2025-03-26, 最終更新日: 2025-12-10)

主引用文献

Venetz-Arenas, N.,Schulte, T.,Muller, S.,Wallden, K.,Fischer, S.,Resink, T.,Kadri, N.,Paladino, M.,Pina, N.,Radom, F.,Villemagne, D.,Bruckmaier, S.,Cornelius, A.,Hospodarsch, T.,Alici, E.,Ljunggren, H.G.,Chambers, B.J.,Han, X.,Sun, R.,Carroni, M.,Levitsky, V.,Sandalova, T.,Walser, M.,Achour, A.
Development of DARPin T cell engagers for specific targeting of tumor-associated HLA/peptide complexes.
Iscience, 28:113926-113926, 2025

PubMed 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 complex revealed a rigid, concave DARPin surface spanning the full length of the peptide-binding cleft, contacting both α-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.

PubMed: 41321628
DOI: 10.1016/j.isci.2025.113926

実験手法

X-RAY DIFFRACTION (1.76 Å)