A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity
Autor: | Isharat Yusuf, Stacey Drabic, Albulescu Marius, Melissa de los Reyes, Rachel Ettinger, Manuel Baca, Jodi L. Karnell, Li Yan, Ximing Xiong, Thomas Thisted, L. Wang, Ulf Müller-Ladner, David Howe, Jing Li, Jorn Drappa, Steven Eck, Rachel Moate, Ronald Herbst, Michele Gunsior, Katie Streicher, Vaheh Oganesyan |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Platelet Aggregation CD40 Ligand Autoimmunity Plasma cell medicine.disease_cause Arthritis Rheumatoid 03 medical and health sciences 0302 clinical medicine Immune system Plasma cell differentiation medicine Humans Rheumatoid factor CD40 Antigens Autoantibodies Cell Proliferation Autoimmune disease B-Lymphocytes CD40 biology business.industry Autoantibody General Medicine medicine.disease Healthy Volunteers 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology biology.protein business |
Zdroj: | Science Translational Medicine. 11 |
ISSN: | 1946-6242 1946-6234 |
Popis: | 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. |
Databáze: | OpenAIRE |
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