B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Marinos C Dalakas


Nat Clin Pract Neurol. 2008;4(10):557-567. 

In This Article

Anti-B-cell Therapy in Neurology: Present and Future

The evidence that B cells have a role in autoimmune neurological disorders is summarized in Box 1 . Various immunomodulatory drugs that are currently used in neurology, such as intravenous immunoglobulin (IVIg), alemtuzumab, cyclophosphamide, mitoxanthrone and natalizumab, can affect some aspects of B-cell function that are relevant to the pathogenesis of neurological disease. New monoclonal antibodies or fusion proteins that specifically target B-cell survival or proliferation are, however, now becoming available.

Drugs that target BAFF or APRIL, or their receptors BAFF-R, TACI or BCMA, affect B cell survival and differentiation, resulting in reduced numbers of mature B cells in the lymphoid tissues and the circulation (Figure 4).[19] Blockade of BAFF-R, TACI or BCMA in mouse models of systemic lupus erythematosus (SLE) not only reduces antibody titers, but also improves animal survival.[6,23,24] The targeting of BAFF, BAFF-R and APRIL is of therapeutic interest in the neurological context, because these molecules are upregulated in the tissues of patients with autoimmune diseases. A number of agents are currently in phase I-II clinical trials in rheumatoid arthritis and SLE.[1,2,3,4,5,6,24] Agents that target BAFF include belimumab, a humanized monoclonal antibody against soluble BAFF, and the BAFF antagonist AMG G23. BR3-Fc is directed against BAFF-R, resulting in blockade of BAFF binding and, subsequently, B-cell reduction. BCMA-IgG is directed against APRIL. The TACI-IgG fusion protein neutralizes BAFF, APRIL and BAFF-APRIL heterodimers. Anti-lymphotoxin-β receptor disrupts the architecture in the ectopic germinal centers.

Figure 4.

Monoclonal antibodies or fusion proteins against B-cell targets. The figure highlights several B-cell molecules and their receptors, which are targeted by nine different monoclonal antibodies or fusion proteins currently in phase I-III clinical trials. Abbreviations: APRIL = a proliferation-inducing ligand; BAFF = B-cell-activating factor; BAFF-R = B-cell-activating factor receptor; BCMA = B-cell-maturation antigen; CTLA4 = cytotoxic T-lymphocyte antigen 4; LTβR = lymphotoxin-β receptor; LTβR-Ig = anti-lymphotoxin-β receptor antibody; MHC-II = major histocompatibility complex class II; TACI = transmembrane activator and calcium modulator and cyclophilin ligand interactor; TCR = T-cell receptor.

Drugs directed against the CD20 or CD22 B-cell-surface glycoproteins can coat B cells and thereby cause their depletion (Figure 4). These drugs include: epratuzumab, which blocks CD22 survival signals on immature and mature B cells, as well as on pro-B and pre-B cells; rituximab, which is directed against the CD20 molecule; and occrelizumab, the humanized version of rituximab. In contrast to agents against trophic factors and their receptors, as mentioned above, these drugs deplete B cells but not the antibody-producing plasma cells.[1,2,3,4,5,6]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.