C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro

• Published in: The Journal of immunology (1950) Vol. 202; no. 4; pp. 1200 - 1209
• Main Authors: Nikitin, Pavel A, Rose, Eileen L, Byun, Tony S, Parry, Graham C, Panicker, Sandip
• Format: Journal Article
• Language: English
• Published: United States AAI 15.02.2019
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Cell Proliferation - drug effects; Complement Activation - drug effects; Complement C1s - antagonists & inhibitors; Complement C1s - immunology; Humans; Innate Immunity and Inflammation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1800998

The classical pathway of complement (CP) can mediate C3 opsonization of Ags responsible for the costimulation and activation of cognate B lymphocytes. In this manner, the complement system acts as a bridge between the innate and adaptive immune systems critical for establishing a humoral response. However, aberrant complement activation is often observed in autoimmune diseases in which C3 deposition on self-antigens may serve to activate self-reactive B cell clones. In this study, we use BIVV009 (Sutimlimab), a clinical stage, humanized mAb that specifically inhibits the CP-specific serine protease C1s to evaluate the impact of upstream CP antagonism on activation and proliferation of normal and autoimmune human B cells. We report that BIVV009 significantly inhibited complement-mediated activation and proliferation of primary human B cells. Strikingly, CP antagonism suppressed human Ig-induced activation of B cells derived from patients with rheumatoid arthritis. These results suggest that clinical use of CP inhibitors in autoimmune patients may not only block complement-mediated tissue damage, but may also prevent the long-term activation of autoimmune B cells and the production of autoantibodies that contribute to the underlying pathologic condition of these diseases.