乌鸦传媒視頻

In an analysis of previously unpublished phase III data, U.K. researchers reported a massive, rapid repopulation of a subset of B cells without effective T-cell regulation in patients with multiple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 .

"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 乌鸦传媒視頻.

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.

In the United States, the FDA approved alemtuzumab for use in patients with relapsing MS, based on two pivotal trials: The first, , studied alemtuzumab in drug-naïve patients with relapsing remitting MS. The second, , looked at alemtuzumab in patients whose disease had relapsed while being treated with interferon beta-1a (Rebif) or glatiramer acetate (Copaxone).

Schmierer and colleagues observed that approximately 20% of participants reported secondary autoimmunities during the trials, but the proportion increased to 39.1% (317 of 811 MS patients) in the 5-year follow-up of the CARE-MS studies. The researchers hypothesized that B-cell dynamics were central to the secondary autoimmunities and that repopulation kinetics might offer clues to the mechanism.

To investigate this, the investigators analyzed unpublished data from the CARE-MS I and II regulatory documents, obtained through a Freedom of Information request to the European Medicines Agency (EMA) in London. These datasets had been included in conference presentations and licensing submissions to European and U.S. regulators, but were not scrutinized or published after peer review, Schmierer noted.

"There were a number of results in the trial that had not surfaced in an easily digestible format," said another member of the research team, David Baker, PhD, also of Queen Mary University. "Many neurologists and patients may not be getting the full picture when reading the trial reports, which is important when selecting which treatment to use."

The researchers used CARE-MS I and II data to see how T and B cell populations returned after a course of alemtuzumab therapy, and discovered that a subset of B cells repopulated rapidly, while the regulatory T-cell population returned more slowly, thus creating an environment for secondary autoimmune disease.

There was also a loss of memory B cells in the trials, which might offer a new explanation as to how alemtuzumab works to control relapsing MS, but also may contribute to a neutralizing immune response that could prevent alemtuzumab from working, Baker noted.

"If the memory B cell is the central culprit, it simplifies the understanding of how other MS drugs work and shows why some treatments are more effective than others. This may make it easier to navigate around the multiple treatment options available."

Schmierer added that some people with MS do not respond to alemtuzumab, and in some, the disease-modifying effect may trail off after repeated dosing: "Anti-drug antibodies may explain the lack of treatment response in some."

Controlling this B-cell subset repopulation until T-cell regulation recovers may limit the risk of secondary autoimmune disease and make alemtuzumab a better drug, the authors observed, but this requires further investigation. Adding other B-cell targeting therapy after alemtuzumab treatment may increase the risk of serious infections and cancers and lead to worse outcomes than those posed by B-cell autoimmune diseases, which often are manageable and nonfatal, they noted.

In an accompanying , Lawrence Steinman, MD, of Stanford University Hospital in California, noted that the analysis might have far-reaching significance: "Autoimmune diseases in general may arise from B-cell development without adequate control from regulatory T cells. That concept, applied broadly, would be a significant advance in understanding autoimmunity."

Regarding study limitations, the researchers noted the fact that the data used are only from the CARE-MS trials, and that central nervous system or lymph tissue events were not captured in blood analyses, which may be important to understanding the biological mechanisms involved.