B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Marinos C Dalakas

Disclosures

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]

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