MabThera® mode of action
MabThera® selectively targets CD20-positive B cells, representing a novel and fundamentally different biological strategy for the treatment of rheumatoid arthritis (RA) compared with traditional disease-modifying anti-rheumatic drugs or tumour necrosis factor (TNF) inhibitors.1 MabThera® can disrupt a number of different events in the inflammatory process owing to the central role and multiple actions of B cells in the pathogenesis of RA. The important role that B cells play in the development of RA is confirmed by the effectiveness of selectively targeting B cells with MabThera®.
The following video outlines the role of B cells in Rheumatoid Arthritis and the mode of action of MabThera®.
The central role of B cells in RA
The synovial fluid of a joint affected by RA contains an abundance of B cells, and it is now recognised that the B lymphocyte plays three key roles in the pathogenesis of RA:
- Antigen presentation leading to T cell activation
- Autoantibody production
- Cytokine production
Antigen presentation leading to T cell activation
B cells are highly efficient antigen-presenting cells that play an essential role in T cell activation in the synovium. Rheumatoid factor (RF)-producing autoreactive B cells possess a specialised ability to bind any antigen that is already part of an antibody immune complex; they can present a variety of antigens to antigen-specific T cells and thus activate them (Figure 1). B cell-activated T cells produce proinflammatory cytokines, including TNF. These proinflammatory cytokines activate macrophages, which also produce proinflammatory cytokines, resulting in inflammation and joint destruction. RF-producing B cells may also act as ‘self-perpetuating’ stimuli, allowing autoreactive B cells to activate an unusually wide range of T cells. This can lead to even greater cytokine production, with resulting inflammation and joint damage.
Figure 1. Antigen presentation leading to T cell activation
Autoantibody production
B cells produce autoantibodies such as RF and anti-cyclic citrullinated peptide (CCP) that may help drive the disease process in RA (Figure 2). RF immune complexes formed within the synovium may:
- activate the complement system and stimulate an immune response
- bind to, and activate, macrophages in the synovium.
Macrophages activated by immune complexes produce proinflammatory cytokines that perpetuate inflammation and joint destruction.
Figure 2. Autoantibody production by B cells
Cytokine production
B cells can be activated to produce cytokines (known to promote inflammation and joint damage) such as TNF, interleukin (IL)-6 and lymphotoxin (Figure 3). This activation can occur in several ways, including:
- antigen binding to the B cell receptor
- binding of the co-stimulatory ligand found on activated T cells, macrophages and dendritic cells to the co-stimulatory receptor on B cells
- exposure of B cells to cytokines produced by other immune cells.
B cell-produced lymphotoxin may also indirectly perpetuate RA by promoting the formation of new lymphoid structures in the synovium. This may help perpetuate an autoimmune reaction, joint inflammation and bone damage.
Figure 3. Cytokine production by B cells
Mode of action of MabThera®
Structure and binding properties
MabThera® is a chimeric antibody consisting of a human immunoglobulin G1 (IgG1) kappa constant region with a variable region derived from a murine anti-CD20 antibody (Figure 4). MabThera® selectively targets CD20, a cell surface antigen that is uniquely expressed on a subset of B cells during the maturation process.2 MabThera® has a high binding affinity for the CD20 antigen,2 with specificity for the CD20 antigen residing in the variable murine regions. The rest of the antibody, which is of human origin, is essential for the effective triggering of complement- and cell-mediated lysis mechanisms in vivo.
Figure 4. The structure of MabThera®
CD20 as a target antigen
A number of properties of CD20 make it an ideal target antigen for monoclonal antibody therapy.
- CD20 is only expressed on B cells (Figure 5); it is not expressed by any other cell type.
- The expression pattern of CD20 (expressed on mature B cells, but not on stem cells, pro-B cells or plasma cells) means that, after therapeutic targeting, the B cell population can recover and serum immunoglobulins continue to be produced by plasma cells.
- There are no known natural ligands for CD20.
- The function of CD20 is not fully established but it appears to be involved in the regulation of B lymphocyte growth and differentiation, possibly by functioning as a calcium channel.3
- CD20 is not internalised after antibody binding, and its expression is stable.4 Anti-CD20 antibodies therefore remain bound to CD20 on the cell surface, where they initiate cell lysis.
- CD20 is not usually shed from the cell surface.5
Figure 5. Expression of CD20 on the B cell lineage6
MabThera® depletes CD20-expressing B cells
The efficacy of MabThera® in RA is dependent upon its ability to deplete B cells, which are key players in the autoimmune disease process. MabThera® depletes B cells from the circulation by three distinct mechanisms.
- Complement-mediated B cell lysis: As expected for a human IgG1 antibody, MabThera® directly binds the C1q complement component, initiating complement-mediated lysis of circulating B cells.2
- Cell-mediated cytotoxicity: MabThera® binds strongly to Fc receptors on human effector cells, such as macrophages and natural killer cells, inducing antibody-dependent cellular cytotoxicity.7
- Induction of apoptosis: MabThera® has been shown to induce apoptosis, or programmed cell death, in vitro.7
Owing to the central role and multiple actions of B cells in the pathogenesis of RA, B cell depletion with MabThera® has proven to be an effective treatment for RA.
References
- Edwards JC & Cambridge G. Rheumatology (Oxford) 2005;44:151-156.
- Reff ME, et al. Blood 1994;83:435-445.
- Tedder TF & Engel P. Immunol Today 1994;15:450-454.
- Press OW, et al. Blood 1987;69:584-591.
- Manshouri T, et al. Blood 2003;101:2507-2513.
- Sell S & Max EE. Immunology, Immunopathology, and Immunity. Washington, DC: ASM Press;2001.
- Maloney DG, et al. Blood 1996;88:637a.