Obinutuzumab induces superior B-Cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples

Objective A proportion of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) patients treated with standard doses of rituximab (RTX) display inefficient B cell deletion and poor clinical responses which can be augmented by delivering higher doses, indicating that standard-dose RTX is a sub-optimal therapy in these patients. To investigate whether better responses could be achieved with mechanistically different anti-CD20 mAbs.Methods We compared RTX with Obinutuzumab (OBZ), a new-generation, glycoengineered type II anti-CD20 mAb in a series of in vitro assays measuring B cell cytotoxicity in RA and SLE patient samples.Results We found that OBZ was at least 2-fold more efficient than RTX at inducing B-cell cytotoxicity in in-vitro whole blood assays. Dissecting this difference, we found that RTX elicited more potent complement-dependent cellular cytotoxicity (CDC) than OBZ. In contrast, OBZ was more effective at evoking Fc gamma receptor (FcγR)-mediated effector mechanisms, including activation of NK cells and neutrophils, probably due to stronger interaction with FcγRs and the ability of OBZ to remain at the cell surface following CD20 engagement, whereas RTX became internalized. OBZ was also more efficient at inducing direct cell death. This was true for all CD19+ B-cells as a whole and in naïve (IgD+CD27-); and switched (IgD-CD27+) memory B-cells specifically, a higher frequency of which is associated with poor clinical response after RTX.Conclusions Taken together, these data provide a mechanistic basis for resistance to Rituximab induced B-cell depletion, and for considering Obinutuzumab, as an alternative B-cell depleting agent in RA and SLE