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    • src kinase inhibitor br Augmenting B Memory Cell Function ca

    2018-10-23


    Augmenting B Memory Cell Function can Worsen MS Following the apparent efficacy of CD20-depleting agents in controlling MS (Hauser et al., 2008; Kappos et al., 2011; Sorensen et al., 2014), alternative methods of depleting B cells have been developed. One approach was the use of CD19 depleting src kinase inhibitor (MEDI-551), which have a broader range of B cell depletion than CD20-targeting to include plasmablasts (Ward et al., 2011). MEDI-551 effectively blocked the formation of new MRI lesions in a phase II trial (NCT01585766) in MS (Aquis et al., 2015). Another approach was the neutralization of B cell growth and differentiation factors which are altered in people with MS in particular during relapses (Kannel et al., 2015). Atacicept is a fusion protein composed by the transmembrane activator and calcium modulator and cyclophilin ligand interactor protein (TACI) and the constant region of human IgG1 (Gatto, 2008). Atacicept neutralizes a proliferation-inducing ligand (APRIL) and B lymphocyte stimulator (BLyS)/B cell activating Factor (BAFF), that stimulate B cell numbers, activation and antibody synthesis (Gatto, 2008). However, in trials to control optic neuritis, atacicept precipitated CNS inflammation and augmented the conversion of people with optic neuritis to clinically definite MS (Sergott et al., 2015). Although, the effect on B cell subsets in this trial was not reported (Sergott et al., 2015), it is evident from other studies in humans and mice that whilst atacicept results in a loss of mature B cells, it upregulates interleukin-15 (IL-15) and stimulates memory B cells (Table 1) (Ma et al., 2014; Tak et al., 2008). Therefore, in contrast to memory B cell reduction and disease inhibition seen with other MS treatments, atacicept caused disease worsening in some people with optic neuritis, an effect probably associated with enhanced memory B cell function. Furthermore, a trial (NCT00882999) of tabulumab (Lys2127399), which is a human IgG4 antibody that inhibits both membrane and soluble BAFF/BLyS and augments memory B cell function (Genovese et al., 2013), may have failed or was terminated (Deiß et al., 2013). In addition, tumor necrosis factor (TNF) inhibitors can worsen MS (Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, 1999; van Oosten et al., 1996). Interestingly, TNF inhibition is associated with augmentation of memory B cells numbers, when used in some people with rheumatoid arthritis or Crohn\'s disease, who sometimes develop central nervous system demyelinating disease after TNF inhibition (Hyrich et al., 2004; Roll et al., 2012; Souto-Carneiro et al., 2009). In conclusion, evidence shows that drugs that reduce the CNS activity of the subset of CD19+, CD27+ memory B cell are beneficial for MS and drugs that promote it are not effective and can actually make MS worse or trigger the disease (Table 1). A strategy that specifically targets the memory B cell function but avoids the immature, mature non-memory B cell subsets may improve the benefit:risk ratio (Krupica et al., 2006). Natalizumab induced circulating memory B cell elevation (Fig. 4) (Planas et al., 2012) is not associated with worsening of MS, whilst it was the case for atacicept (Table 1). This is presumably because memory B cells are prevented from entering the CNS to trigger relapse with natalizumab (Michel et al., 2015), but not atacicept. Alternatively natalizumab could be disturbing critical niches within the bone marrow and lymphoid organs and/or inhibiting an important peripheral immune function (Martin et al., 2016). However, the enhanced levels of memory B cells in the blood may contribute to rapid disease rebound that can occur following cessation of natalizumab (Rasenack and Derfuss, 2016). This would support CD20-depleting agents as the switching agent of choice post-natalizumab to deplete the increased numbers of circulating memory B cells (Giovannoni et al., 2016b). Indeed post-natalizumab treatment with rituximab has been associated with lower relapse levels than with fingolimod switching and is arguably safer than fingolimod as it does affect cytotoxic T cells that may be required to clear subclinical progressive multifocal leukoencephalopathy (Alping et al., 2016; Asztely et al., 2015).