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TitleCurbing Autoimmunity: A New Fab Fragment Targeting CD40-CD40L Halts B-Cell Activation and Differentiation.
Journal, issue, pagesEur J Immunol, Vol. 56, Issue 2, Page e70158, Year 2026
Publish date2026-02-??
AuthorsKathrine Pedersen / Kenneth Green / Emil L Kristoffersen / Thea Schinkel / Annette G Hansen / Yaseelan Palarasah / Anne B Rovsing / Ebbe S Andersen / Julián Valero / Laia Civit / Nick S Laursen / Anne Troldborg / Søren E Degn / Steffen Thiel /
PubMed AbstractDysregulation 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 ...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.
External linksEur J Immunol / PubMed:41742604 / PubMed Central
MethodsEM (single particle)
Resolution3.4 Å
Structure data

52634

9i5n

EMDB-52634, PDB-9i5n:
Single particle cryo electron microscopy of a Fab fragment bound to recombinant human CD40 ligand
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / CD40 ligand inhibitor / CD154 inhibitor / autoimmunity / Fab fragment

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