The effectiveness of monoclonal antibodies is dependent on:
- the function and characteristics of the target antigen
- the cell surface density or tissue distribution of the antigen
- factors associated with the monoclonal antibody itself (specificity, avidity and isotype).
Monoclonal antibodies work by a number of mechanisms such as blocking the function of the target molecule, inducing the death of cells that express the target, or by modulating signalling pathways.2
These actions have been exploited in a range of proven and experimental indications (Table 2) . Immune-mediated inflammatory diseases are particularly suitable candidates for this form of therapy. This is because key immune control molecules are secreted or expressed transiently on the surface of cells during the pathogenic process. Blocking these molecules with monoclonal antibodies may have specific effects on the disease.
Inhibition of tumour necrosis factor
Tumour necrosis factor (TNF) is a major pro-inflammatory cytokine with a wide range of roles in immunity. Anti-TNF monoclonal antibodies (infliximab and adalimumab) have been an advance in the treatment of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis/psoriatic arthritis. Although etanercept is also widely used to inhibit TNF in rheumatoid arthritis, it is not a monoclonal antibody. It is a soluble TNF-receptor-IgG Fc fusion molecule.
In rheumatoid arthritis, the benefits of infliximab and adalimumab have included reduced pain, improvements in all disease measures, inhibition of structural damage, and reduction in surgery and hospitalisation.3 Synergistic effects with methotrexate have been observed. However, partial responses are more common than complete responses and treatment is not curative.
In Crohn's disease, infliximab is useful for inducing and maintaining clinical remission, closing fistulae (enterocutaneous, perianal, rectovaginal) and for reducing steroid dependence. Infliximab is also effective at inducing a clinical response in patients with moderate to severe ulcerative colitis.
Table 2
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Monoclonal antibodies available for clinical use
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Monoclonal antibody
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Target antigen
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Current use
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Potential use
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Cell surface molecules
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Rituximab
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CD20 (B cells)
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Oncology
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Cryoglobulinaemia, bullous pemphigoid, Wegener's granulomatosis, other B cell- mediated autoimmune diseases
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|
Basiliximab, daclizumab
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CD25
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Prevention of organ rejection
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|
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Muromonab
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CD3
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Treatment of acute organ rejection
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Type 1 diabetes mellitus
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|
Abciximab
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Platelet IIb/IIIa
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Acute coronary syndromes
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|
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Efalizumab
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CD11a component of LFA-1
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Psoriasis
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Affecting cell traffic
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Natalizumab
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α4 integrin
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Crohn's disease, multiple sclerosis
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Cytokine directed
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|
Infliximab, adalimumab
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TNF
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Rheumatoid arthritis, Crohn's disease, ankylosing spondylitis
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Psoriasis
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Directed against antibodies
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|
Omalizumab
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IgE
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Asthma, eczema, peanut allergy
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IgE immunoglobulin E
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LFA-1 lymphocyte function-associated antigen-1
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TNF tumour necrosis factor
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|
Inhibition of lymphocyte traffic
Multiple sclerosis is likely to be an immune-mediated demyelination in the central nervous system. The migration of activated T cells into the brain and spinal cord is thought to be part of the pathogenesis. These activated lymphocytes have antigens called integrins on their surface. Natalizumab, a humanised monoclonal antibody directed against alpha4 integrin, has been studied in multiple sclerosis and Crohn's disease. Compared to placebo, natalizumab led to increased remission rates in multiple sclerosis. In Crohn's disease there were higher rates of sustained response when natalizumab was added to standard treatment.4 Subsequent studies have questioned the safety of natalizumab. Studies were halted because of case reports of progressive multiple leucoencephalopathy, a devastating degenerative opportunistic viral disease of the central nervous system.