Journal article

Publication year: 2019

Journal: Science Translational Medicine

Volume number: 11

Issue number: 489

ISSN: 1946-6234

eISSN: 1946-6242

DOI Link: https://doi.org/10.1126/scitranslmed.aar6584

Publisher: American Association for the Advancement of Science

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.

Harvard Citation style: Karnell, J., Albulescu, M., Drabic, S., Wang, L., Moate, R., Baca, M., et al. (2019) A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity, Science Translational Medicine, 11(489), Article eaar6584. https://doi.org/10.1126/scitranslmed.aar6584

APA Citation style: Karnell, J., Albulescu, M., Drabic, S., Wang, L., Moate, R., Baca, M., Oganesyan, V., Gunsior, M., Thisted, T., Yan, L., Li, J., Xiong, X., Eck, S., de los Reyes, M., Yusuf, I., Streicher, K., Mueller-Ladner, U., Howe, D., Ettinger, R., ...Drappa, J. (2019). A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Science Translational Medicine. 11(489), Article eaar6584. https://doi.org/10.1126/scitranslmed.aar6584