Treating mice in a model of multiple sclerosis with Lemtrada (alemtuzumab) prevented the formation of B-cell aggregates in the animals’ central nervous system and disrupted already existing ones, researchers report.
The treatment also reduced disease activity when administered at the peak of disease.
Multiple sclerosis (MS), an autoimmune disorder of the central nervous system (CNS), is marked by damage to the myelin sheath – the insulating cover of nerve cell fibers – due to inflammation.
Traditionally, T-cells are seen as the main drivers of autoimmunity in MS. But recent clinical and experimental data suggest a close interaction of T-cells and B-cells. These two types of lymphocytes (a type of white blood cell) are responsible for defending the body against foreign pathogens. Namely, B-cells create a type of immune memory by producing antibodies triggered to attack such microbes on a next encounter. If these responses become deregulated, however, lymphocytes can begin to attack the body’s own tissues. This is called autoimmunity.
Lemtrada, manufactured by Genzyme (a Sanofi company), is a disease-modifying therapy for people with relapsing-remitting forms of multiple sclerosis (RRMS). The therapy is a humanized monoclonal antibody aimed at specific receptors, called CD52, on the surface of immune cells (B- and T-cells, monocytes and dendritic cells) to modulate immune responses. It was approved by the U.S. Food and Drug Administration (FDA) in 2014, but with a recommendation its use be limited to RRMS patients who have had an inadequate response to two or more MS therapies.
An ongoing controversy concerns the extent of B-cell involvement in MS, specifically in the formation of B-cell aggregates in patients’ brains. Recent reports of treatment failure in people with severe and possibly B cell-mediated relapses also underscore the need for a better understanding of this treatment.
German researchers created an experimental mouse model of autoimmune encephalomyelitis (EAE) – an inflammatory demyelinating disease of the CNS that is often used to study MS. In particular, EAE relies largely on B-cells to develop and propagate the disease, making it good model in which to study the influence of B-cells in an inflammatory setting.
Mice were treated with either alemtuzumab or a control antibody, either as the disease peaked or at 60 days after onset. They were then monitored for 10 days.
Treatment with alemtuzumab lowered disease activity only when administered at the peak of disease. However, the treatment almost completely depleted B-cell infiltration of the CNS and lowered the number of B-cell aggregates, even when given as late as 60 days after onset.
“Interestingly, treatment not only prevented the formation of aggregates, but also disrupted already existing aggregates,” the researchers wrote.
While the clinical significance of B-cell aggregates in MS is still subject to debate, researchers have noted an association with earlier disease onset and progression.
Treated mice also showed less nerve cell damage in the spinal cord and cerebellum (the brain region responsible for coordinating and regulating movement).
“[O]n the ultrastructural level, the numbers of damaged axons [part of the nerve cell structure] were significantly decreased after [alemtuzumab] treatment,” researchers wrote.
“[T]his study is the first to show that treatment was highly effective in targeting both peripheral and central B cells, including those B cells that had already formed aggregates in the CNS. The disruption of these B cell aggregates was accompanied by a significant decrease in axonal pathology, even in late stages of the disease,” they concluded.
However, future studies are necessary to determine whether alemtuzumab is equally effective in depleting B-cell aggregates in MS patients and if such depletion leads to clinical benefit.