SAT0181 Immunogenicity of Rituximab in Patients with Rheumatoid Arthritis: A Kinetic Analysis

Abstract

BackgroundRituximab (RTX) is a chimeric monoclonal antibody that targets the CD20 antigen expressed at the B cell surface. It was first used for the treatment of non-Hodgkin's lymphoma and then approved for severe active rheumatoid arthritis (RA) in patients resistant to disease modifying anti-rheumatic drugs or anti-TNF agents. Efficacy is obtained by repeated courses of rituximab. In recent years, increasing attention has been given to the development of anti-biotherapeutic drug antibodies (ADAs) that can lower the level of the drug and hence its clinical efficacy. The generation of human anti-chimeric antibodies (HACAs) to Rituximab has been reported in the literature during systemic lupus erythematous, primary Sjogren's syndrome, vasculitis and pemphigus. During RA, HACAs have been reported in some clinical studies and the incidence of these HACAs to the clinical response is quite controversial.ObjectivesThe aim of this study was to undergo a kinetic analysis of rituximab immunogenicity and its clinical consequences in patients with active severe RA.MethodsForty-seven adult patients with severe active RA and treated by RTX were retrospectively included in this study. Patients were treated with two infusions of 1000 mg RTX (days 1 and 15) and re-treated after 24 weeks and 48 weeks. A kinetic determination of RTX and HACA levels was done using ELISA (Lisa Tracker Duo Rituximab - Theradiag®): before the first (t0), the second (t1 at 24 weeks) and the third administration (t2 at 48 weeks). Five patients with HACAs were investigated over a longer period (up to the 6th injection). The number of CD19+B cells was evaluated using flow cytometry and the disease activity was measured by the Disease Activity Score 28 (DAS-28).ResultsAs the level of residual RTX was always undetectable, HACAs were detected in the serum of five of 47 patients (10.6%) during at least one determination: 1 patient at t0, 3 patients at t1 and 2 patients at t2. The peak incidence seemed located in the year after the first injection. Among these 5 patients, 3 were developing fleeting antibodies which were present once and then were no more detectable, while the other 2 had persistent HACAs during the study period: one until the fourth cure and the second until the sixth cure.The overall percentage of patients with HACAs (10.6%) is similar to that already described in the literature. The presence of HACAs did not appear to affect the clinical efficacy in these 5 patients, nor CD19+B cell depletion during the study period.ConclusionsThe generation of antibodies to rituximab in severe RA was observed in about 10% of the patients during the long study period and did not appear to influence either the ability of rituximab to deplete CD19+ B cells or clinical efficacy. The systematic combination with immunosuppressive drug like methotrexate could explain this quite low immunization rate as compared with those described in other disease states treated with rituximab. However, it is noteworthy that rituximab might be a good option in some RA patients, ev...

Block‑Removed Immunoglobulin Technology to enhance rituximab effector function by counteracting CA125‑mediated immunosuppression

“…Introducing mutations to enhance activity of an antibody that is already on the high-end of the immunogenicity spectrum is not advisable. Because RTX has been reported to have a good immunogenic profile in the clinics ( 30 ), the risk of heightened immunogenicity appears to be minimal since RTX N109D is 99.9% identical to the parent RTX's whole IgG sequence. Furthermore, preliminary in-silico analysis designed to uncover any potential immunogenicity mediated by T-cell epitopes using well-established algorithms ( 31 ) demonstrated that the RTX N109D has equivalent or even reduced immunogenicity score associated with peptides within the H-CDR3/FWR4 region compared with parent RTX ( Fig.…”