Agents targeting Bcells

The CD20 B-cell surface antigen is expressed only on pre-B as well as mature B cells and is lost before differentiation of B-cells into plasma cells. A murine monoclonal antiCD20 antibody (tos-itumomab) as well as a chimeric antiCD20 monoclonal antibody (rituximab), both of which cause a selective transient depletion of the CD20+ B-cells, have been introduced for the treatment of CD20 + low grade or follicular non-Hodgkin's lymphoma (Boye et al., 2003; Zelenetz, 2003; Stern and Herrmann, 2005). Similarly, epratuzumab, an antibody to CD22, a marker of mature B-lymphocytes, which also induces the targeted deletion of B-cells, is currently investigated in clinical trials in patients with non-Hodgkin's lymphoma (Leonard et al., 2004). In addition, targeting B-lymphocytes appears to be a promising approach for the treatment of autoimmune diseases. There is increasing evidence from several case reports and two recent small open-label trials for the efficacy of rituximab in the treatment of patients with SLE (Leandro et al., 2002; Looney et al., 2005; Gottenberg et al., 2005). Although the patients displayed some heterogeneity in disease severity and organ involvement, these studies indicate that a high dose rituximab provides significant benefits in most of these SLE patients.

The precise role of B-lymphocytes in the pathogenesis of RA is not fully understood. However, strong evidence of a crucial role of B-cells in RA came from a small open-label study and a recent randomized, double-blind, controlled study (Edwards et al., 2004). Accordingly, in patients with active RA, a single course of two infusions of ri-tuximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in the disease symptoms. Response rates were assessed according to the criteria of the American College of Rheumatology (ACR) and were maintained over a prolonged observation period of 24 wk. The treatment was well tolerated and the overall safety profile was consistent with that reported previously with rituximab in patients with lymphoma (Edwards et al., 2004).

Targeting B-cells may offer a novel therapeutic avenue for autoimmune blistering disorders some of which are characterized by aberrant production of pathogenetically relevant autoantibodies. Accordingly, rituximab was successfully used for the treatment of a patient with pemphigus vulgaris refractory to conventional disease. Four injections of rituximab at weekly intervals (375mg/m2) stopped blister formation and systemic steroids could subsequently be reduced to 5mg daily (Herrmann et al., 2003). Future studies will have to confirm these promising findings.

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