John Rose, MD, Chief of Neurology
VA Medical Center, Salt Lake City, UT
Monoclonal antibodies are an important class of drugs which have a highly specific ability to bind onto selected targets. Typically, these antibodies are used in the treatment of inflammatory conditions such as MS, rheumatoid arthritis, or malignant diseases such as leukemia and lymphoma. Monoclonal antibodies are produced by modern culture of antibody producing cells that make only one specific antibody. Traditionally, these antibodies were developed in mice or rats, but are now highly engineered by use of newer biochemical techniques. At present, these antibodies have the majority of their structure similar to normal human antibodies. Still, many have some foreign portions in their structure that can raise a reaction to the medication.
MS is an inflammatory disease of the central nervous system. The illness involves a class of circulating blood cells called lymphocytes that are normally part of our defense system against infections and cancer. However, these lymphocytes can be inappropriately activated against normal parts of the body and produce a reaction that is termed autoimmunity. In autoimmune diseases such as MS, two classes of lymphocytes can be activated with the result being onset or relapse of the illness. These two classes of activated lymphocytes are termed T cells and B cells. Both seem to have a role in mediating the damage in MS that results in loss of myelin and axonal injury in the brain and spinal cord.
People with MS are often well controlled on simpler therapies that have far fewer risks than presently available monoclonal antibodies. The immunomodulatory treatments that are FDA approved for MS include glatiramer acetate (Copaxone®) and interferons (Betaseron®, Avonex®, and Rebif®). People with disease well controlled by immunomodulatory treatment should not advance to monoclonal antibody treatment.
However, if a person continues to have significant disease activity, resulting in relapses or acute changes on MRI, consistent with active disease, while on an immunomodulatory treatment, then he or she may be an excellent candidate for monoclonal antibody treatment. It is usually a good idea to try two or more of these immunomodulatory therapies before considering monoclonal antibody treatment. In this setting, people with very active disease failing other therapies have a very good chance of responding well to monoclonal antibody treatment.
Natalizumab (Tysabri®) is FDA re-approved monoclonal antibody treatment for use in MS. Relapsing-remitting and secondary progressive MS with continued relapses are treated with this agent. Efficacy was demonstrated in two multi-center trials. A risk of progressive multi-focal leukoencephalopathy (PML) was found in these trials.
The TOUCH™ program for natalizumab requires multiple certifications and persistent monitoring of patients throughout the treatment. Logistics of handling the medication and the cost are substantial. The medication is administered every four weeks by intravenous infusion (IV). People are screened for problems at the time of each infusion and must sign a document acknowledging the risks of therapy prior to each treatment. Thousands of people are now enrolled in the TOUCH™ program which is the only way to receive natalizumab treatment.
At present, several additional monoclonal antibodies are being studied as investigational treatments for MS. They are not currently available for routine use in the treatment of MS.
Rituximab (Rituxan®) is reported recently to be efficacious in treatment of relapsing-remitting MS and is in study for primary progressive MS. This drug is FDA approved for treatment of malignancies and has just been reported to be efficacious for MS in a recent study of 69 patients with relapsing MS. Alemtuzumab (Campath®) is another monoclonal antibody directed at lymphocytes which is under continued investigation for treatment in MS. Both rituximab and alemtuzumab are associated with longer-term immunosuppression (6 to 12 months). Serious immunological and infectious complications have occurred with these agents.
Daclizumab (Zenapax®) is FDA approved for the treatment of kidney transplant rejection. It is off-label for MS and people with relapsing-remitting and transitional MS are treated with this agent. Most often these people have failed several other treatments. Efficacy was demonstrated in off-label experience, two small phase II studies, and a larger multi-center phase II study. Currently, a longer duration multi-center phase II trial is in progress in Europe. Rash, fever, and occasional overgrowth of lymph nodes have been observed in people on long-term therapy with this drug.
Overall, monoclonal antibodies are important medications with substantial specificity. They have substantial potential to control disease in people with MS failing other therapies. At present, natalizumab (Tysabri®) is the only FDA approved monoclonal antibody specifically approved for treatment of MS. Risks and benefits need to be carefully weighed in each decision to treat. Careful assessment can identify people that are likely to respond to these therapies and result in very rewarding clinical outcomes for responding individuals. For more information about your medication options contact your healthcare provider.
Date posted: April 2008
Last Updated: December 2009