In an analysis of previously unpublished phase III data, U.K. researchers reported a massive, rapid repopulation of a subset of B cells without effective T-cell regulation in patients with multiple sclerosis (MS) treated with alemtuzumab (Lemtrada), which might have created an environment for secondary autoimmune disease.

Examining lymphocyte reconstitution data from the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) studies, Klaus Schmierer, PhD, FRCP, of Queen Mary University of London, and colleagues found that alemtuzumab depleted CD4 T cells by more than 95%, including regulatory cells and CD8 T cells, which remained well below reference levels throughout the trials. Although the drug also initially depleted CD19 B cells by more than 85%, immature B cells increased by 180% and converted to mature B cells over time. These changes were associated with the rapid development of alemtuzumab-binding and alemtuzumab-neutralizing antibodies and subsequent secondary B-cell autoimmunity. This B-cell hyperpopulation masked a long-term depletion of CD19 memory B cells that may underpin the efficacy of alemtuzumab in MS, the researchers reported in JAMA Neurology.

“While long-term suppression of T cells following alemtuzumab administration was believed to be key for MS disease modification, our analysis of lymphocyte subsets indicates suppression of memory B cells is likely a major mechanism by which alemtuzumab controls MS,” Schmierer told MedPage Today.

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 molecule on the surface on T and B cells, he explained. These cells play a variety of nuanced roles: some kill cellular targets, while others have regulatory or suppressive functions. Alemtuzumab treatment profoundly depletes T and B cells, which repopulate over time. Although T cells are considered to drive disease in MS, most agents that inhibit relapsing MS target B cells… [read more]