The CD40 pathway has long been an attractive therapeutic target for treating autoimmune diseases; however, early clinical trials of monoclonal antibodies targeting CD40 ligand (CD40L) were halted owing to platelet-related thromboembolic complications. Findings from a new study suggest that VIB4920, a bivalent CD40L-specific Tn3 fusion protein, could suppress the CD40–CD40L axis while avoiding these safety concerns.

Credit: S. Harris/Springer Nature Limited

VIB4920 blocks the interaction between CD40 and CD40L by competing with CD40. “This novel construct maintains the specificity of an antibody-based therapeutic, demonstrating specific high-affinity binding to CD40L, but lacks an Fc domain,” explains Jodi Karnell, first author of the paper. “As the Fc domain of anti-CD40L antibodies was definitively linked to the safety issues observed in early clinical trials, VIB4920 is predicted to be a safer approach for targeting this pathway.”

In preclinical studies, VIB4920 blocked CD40L signalling as well as differentiation and activation of human B cells, but did not induce platelet aggregation in vitro. In healthy volunteers, VIB4920 was well-tolerated and inhibited the humoral immune response to immunization with keyhole limpet hemocyanin in a dose-dependent manner.

In a 12-week phase Ib trial in patients with active rheumatoid arthritis (RA), treatment with high-dose (1,000 mg or 1,500 mg every other week) VIB4920 led to improvements in disease activity as well as reductions in titres of rheumatoid factor autoantibodies and biomarkers related to immune activation. “The results in patients with RA provide a clear demonstration of the potential of a non-antibody based CD40L-targeted therapeutic to provide benefit to patients with autoimmune disease,” says corresponding author Jörn Drappa. “Most importantly, we did not see any evidence of platelet activation or any thromboembolic events to date.”

treatment with high-dose … VIB4920 led to improvements in disease activity

Encouraged by these early results, the researchers are planning clinical trials of VIB4920 in various autoimmune and inflammatory diseases in which the CD40–CD40L pathway is implicated.