Analysis of previously unpublished data from the pivotal phase III trials in the regulatory submissions of alemtuzumab, otherwise known as Lemtrada, indicated that efficiency was associated with long-term depletion of memory T- and B-cells. Whereas rapid hyper-repopulation of immature B-cells in the relative absence of regulatory CD4 and CD8 T-cells create the environment for the generation of secondary B-cell autoimmunity, including anti-drug antibodies.
This means that by controlling this B-cell hyper-repopulation after alemtuzumab administration may limit the risk for secondary autoimmunity if administration can be performed safely.
Alemtuzumab is a CD52-depleting monoclonal antibody. It effectively inhibits relapsing multiple sclerosis (MS), but is associated with a high incidence of secondary B-cell autoimmunities that limits its use. These effects may be avoided through control of B-cell hyper-proliferation.
Researchers then investigated whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase III trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS.
Lymphocyte reconstitution data from regulatory submissions of the pivotal comparison of alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests.
Tabulated data from T- and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.
Results showed that alemtuzumab depleted CD4+ T-cells by more than 95%, including regulatory cells (−80%) and CD8+ T-cells (>80% depletion), which remained well below reference levels throughout the trials.
However, although CD19+ B-cells were initially also depleted, a marked 180% increase in hyper-repopulation of immature B-cells occurred with conversion to mature B-cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and neutralising antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyper-repopulation of B-cells masked a marked, long-term depletion of CD19+ memory B-cells that may underpin efficacy in MS.
It was concluded that although blockade of memory T- and B-cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell–depleting agents.
Source: MS-UK (15/06/17)