A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity

Abstract

VIB4920, a nonantibody scaffold protein, blocks CD40L and reduces autoantibodies and disease activity in patients with rheumatoid arthritis. Curbing CD40 signaling The CD40 axis is a major collaborative mechanism of B and T cell responses. Previous attempts to disrupt this pathway to treat autoimmune disease led to adverse thrombotic events due to engagement of Fc receptors and platelet expression of CD40 ligand (CD40L). To avoid this issue, Karnell et al. designed a nonantibody scaffold protein, VIB4920, which blocks human CD40L. VIB4920 inhibits B cell activation but does not induce platelet aggregation in vitro. VIB4920 administration resulted in blunted responses to immunization in healthy people, and people with rheumatoid arthritis experienced reduced disease activity. No thrombotic side effects were encountered in either clinical trial. This next-generation therapeutic has the potential to be widely used to treat various autoimmune diseases. 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.