The Type II anti-CD20 Antibody Obinutuzumab (GA101) is More Effective than Rituximab at Depleting B Cells and Treating Disease in a Murine Lupus Model.

OBJECTIVE Depleting pathogenic B cells could treat SLE. However, depleting B cells in the presence of an inflammatory setting such as lupus is difficult. We hypothesized that a Type II anti-CD20 mAb with a different mechanism-obinutuzumab (GA101)-could be more effective in depletion in lupus and that efficient B cell depletion would result in amelioration of disease. METHODS We treated lupus-prone MRL/lpr mice expressing human CD20 on B cells (hCD20 MRL/lpr) with either rituximab (RTX) or GA101 and measured depletion under various conditions as well as multiple clinical endpoints. RESULTS A single dose of GA101 was markedly more effective than RTX in depleting B cells in diseased MRL/lpr mice. RTX overcame resistance to B cell depletion in diseased MRL/lpr mice with continuous treatments. GA101 was more effective in treating hCD20 MRL/lpr mice with early disease, as treated mice had reduced glomerulonephritis, lower anti-RNA autoantibody titers and fewer activated CD4 T cells compared to RTX treated mice. GA101 could also treat advanced disease and continual treatment prolonged survival. Using variants of GA101 we also elucidated depletion mechanisms in vivo in mice with lupus. CONCLUSIONS Albeit both anti-CD20 antibodies ameliorated disease in an early disease setting, GA101 was more effective than RTX in important parameters, such as glomerulonephritis score. GA101 proved beneficial in an advanced disease model, where it prolonged survival. These data support clinical testing of GA101 in SLE and lupus nephritis.