Mechanism of Action: Alemtuzumab (Lemtrada) is a monoclonal antibody directed against CD52, a protein expressed at high levels by both mature circulating B and T lymphocytes and at lower levels on circulating monocytes, macrophages and eosinophils. There is little expression of CD52 on mature natural killer (NK) cells, neutrophils and haematological stem cells. Following treatment there is a rapid and sustained reduction in circulating lymphocytes with a return of the B cell population within 6 months and a more sustained depletion of circulating T cells for more than 12 months. This selective reduction in lymphocytes is presumably the mechanism of action of this treatment in MS. Lymphocytes are the driving force behind all adaptive immune responses and are implicated in the pathogenesis, propagation and maintenance of central nervous system inflammation and tissue injury in multiple sclerosis.
Other disease modifying therapies (DMTs) that specifically target lymphocytes include Rituximab, a monoclonal against a protein called CD20 on the surface of only mature B lymphocytes and Natalizumab (Tysabri), a monoclonal antibody that binds to alpha 4 integrin, a protein on the surface of lymphocytes and mononuclear cells required for circulated blood cells to bind to the lining of small blood vessels in the brain and cross the blood brain barrier into the tissue.
Following treatment with Alemtuzumab, there is less depletion of lymphocytes residing in lymphoid organs (lymph nodes and spleen) and preservation of neutrophils and bone marrow derived stem cells. The selective reduction in circulating lymphocytes and preserved neutrophils is the reason that few treated patients experience severe infections following treatment.
The more rapid return of B lymphocytes compared to T lymphocytes following treatment with Alemtuzumab has been implicated as the reason for the high incidence of system autoimmune disease following treatment. It is speculated that autoimmunity occurs as a result of B cell and plasma cell responses in the absence of normal T cell regulation. Most of the autoimmune diseases following treatment with alemtuzumab involve the thyroid gland. Less commonly autoimmunity can target blood platelets causing a reduction in platelet counts and a high risk of bleeding (called idiopathic thrombocytopenic purpura or ITP for short) orvery rarely an autoimmune disease of the kidneys develops (called Glomerulonephritis).
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Revere (Rip) Kinkel MD
Director of the Multiple Sclerosis Program
Professor of Clinical Neurosciences
University of California San Diego