Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer?

• Incomplete B cell depletion in RA and SLE contributes to poor response with rituximab.
• CD20 modulation by mAbs is a key resistance mechanism of type I mAbs like rituximab.
• SLE-associated immune abnormalities potentially impair CD20 mAb-effector mechanisms.
• Obinutuzumab is not dependent on complement for efficient B cell depletion.
• Obinutuzumab can overcome limitations of low affinity variants of CD16a and CD16b.

In Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE), B-cell depletion therapy using rituximab results in variable clinical responses between individuals, which likely relates to variable B-cell depletion in the presence of immune defects. Outcomes in clinical trials with other type I anti-CD20 mAbs, ocrelizumab and ofatumumab, are comparable to rituximab. A mechanistically different type II mAb, obinutuzumab (OBZ), with greater capacity for B-cell depletion, has recently entered clinical trials in SLE. Here we consider whether type II anti-CD20 mAbs will provide mechanistic advantages to overcome the disease-related immune defects in autoimmune diseases such as SLE.