9I5N

Single particle cryo electron microscopy of a Fab fragment bound to recombinant human CD40 ligand

9I5N の概要

• エントリーDOI: 10.2210/pdb9i5n/pdb
• EMDBエントリー: 52634
• 分子名称: Fab20 heavy chain, Fab20 light chain, CD40 ligand, soluble form, ... (5 entities in total)
• 機能のキーワード: cd40 ligand inhibitor, cd154 inhibitor, autoimmunity, fab fragment, immune system
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 40134.12

構造登録者

Kristoffersen, E.L.,Schinkel, T.,Andersen, E.S. (登録日: 2025-01-28, 公開日: 2026-02-25, 最終更新日: 2026-03-11)

主引用文献

Pedersen, K.,Green, K.,Kristoffersen, E.L.,Schinkel, T.,Hansen, A.G.,Palarasah, Y.,Rovsing, A.B.,Andersen, E.S.,Valero, J.,Civit, L.,Laursen, N.S.,Troldborg, A.,Degn, S.E.,Thiel, S.
Curbing Autoimmunity: A New Fab Fragment Targeting CD40-CD40L Halts B-Cell Activation and Differentiation.
Eur.J.Immunol., 56:e70158-e70158, 2026

PubMed Abstract: Dysregulation of the CD40-CD40L axis is implicated in autoimmune diseases. Early clinical trials targeting CD40L with antibodies failed due to Fc-mediated side effects. To address this, we developed an anti-CD40L Fab fragment, Fab20, designed to block B-cell activation. Fab20 was evaluated for its binding properties, CD40-CD40L inhibition, and effects on human B-cell activation and differentiation using immunoassays, cryo-electron microscopy, flow cytometry, and cell cultures. Fab20 binds CD40L with a dissociation constant of 70 nM. Structural analysis revealed a "propeller-like" structure consisting of three Fabs binding to the CD40L trimer, sterically blocking parts of the CD40 binding site. Fab20 effectively inhibited B-cell activation, maintaining naïve B cells in their inactive state, and suppressed antibody (IgG) production over 14 days. Fab20 represents a promising novel therapeutic approach for treating autoimmune diseases driven by CD40-CD40L dysregulation. Its mechanism of action, coupled with the absence of Fc-mediated effects, suggests a favorable safety profile.

PubMed: 41742604
DOI: 10.1002/eji.70158

実験手法

ELECTRON MICROSCOPY (3.4 Å)