[Research Articles] A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity
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 significan...
Source: Science Translational Medicine - Category: Biomedical Science Authors: 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., Müller-Ladner, U., Howe, D., Ettinger, R., Herbs Tags: Research Articles Source Type: research
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