Persistency of Neutralizing Anti-Interferon-β Antibodies in Patients with Multiple Sclerosis Treated with Subcutaneous Interferon-β Depends on Antibody Titers, IgG Subclasses, and Affinity Maturation.

Neutralizing antibodies may affect interferon (IFN)-β treatment efficacy, but mechanisms of neutralizing anti-drug antibody (ADA) evolution are not fully elucidated. We investigated the relationship between ADA titers, IgG subclass profile, and binding affinity with the development and persistency of neutralizing ADA in relapsing-remitting multiple sclerosis (MS) patients treated with subcutaneous IFN-β. A total of 94 patients, who had blood sampling at months 6, 12, 24, and 36 during IFN-β therapy, were included into this retrospective study and stratified to the following: non-neutralizing, transient, and persistent neutralizing ADA status. Patients without or with transient neutralizing ADA displayed predominantly IgG1 and IgG3 subclasses, lower ADA titers, and antibody binding affinity compared with patients having persistent neutralizing ADA, in whom the predominant IgG subclasses were IgG2 and IgG4. Overall, ADA binding affinity positively correlated with IgG4 and neutralizing ADA titers, but negatively with IgG3 titers. Persistency of neutralizing ADA was predicted by their titers at month 24 and month 36 of treatment and by an increase of antibody affinity within the second year of IFN-β treatment. The humoral immune response to IFN-β observed in MS patients as a result of IFN-β therapy is a multifactorial process that is influenced by ADA titers, affinity maturation, and IgG subclass switching.