6BRB

Novel non-antibody protein scaffold targeting CD40L

Summary for 6BRB

• Entry DOI: 10.2210/pdb6brb/pdb
• Descriptor: CD40 ligand, Tn3-like, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: tn3 related, tnf ligand related, structural protein-immune system complex, structural protein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 25868.92

Authors

Oganesyan, V.,Baca, M.,Thisted, T.,Grinberg, L.,Wu, H.,Dall'Acqua, W.F. (deposition date: 2017-11-30, release date: 2018-12-05, Last modification date: 2024-11-20)

Primary citation

Karnell, J.L.,Albulescu, M.,Drabic, S.,Wang, L.,Moate, R.,Baca, M.,Oganesyan, V.,Gunsior, M.,Thisted, T.,Yan, L.,Li, J.,Xiong, X.,Eck, S.C.,de Los Reyes, M.,Yusuf, I.,Streicher, K.,Muller-Ladner, U.,Howe, D.,Ettinger, R.,Herbst, R.,Drappa, J.
A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity.
Sci Transl Med, 11:-, 2019

PubMed Abstract: The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67 dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

PubMed: 31019027
DOI: 10.1126/scitranslmed.aar6584

Experimental method

X-RAY DIFFRACTION (2.82 Å)