In the past few years, considerable attention has focussed on the role of B cells in the pathophysiology of multiple sclerosis, in large part because of the success of anti-CD20 monoclonal antibodies (e.g. rituximab, ocrelizumab) in reducing clinical and radiological disease activity. A novel agent, ofatumumab, is expected soon and other agents (e.g. ublituximab) are in development.
Until recently, MS was considered to be due to T cell dysregulation, and pathogenic CD4+ T cells are still viewed as initiating the MS disease process through the release of interferon-gamma, interleukin-17 and other pro-inflammatory cytokines. Early adoptive transfer studies indicated that CD4+ T cells were sufficient to induce EAE. Subsequent studies have shown that EAE will develop when B cells are the sole antigen-presenting cells, and that B cells play an important role in T cell reactivation in the CNS (Harp et al. J Immunol 2015;194:5077-5084. Pierson et al. J Immunol 2014;192:929-939). This CD4+ T cell/B cell interaction is MHC class II-dependent, consistent with findings from genome-wide association studies showing an association between MHC class II haplotypes and MS (International Multiple Sclerosis Genetics Consortium, et al. Nature 2011;476:214-219), providing further support for B cells as a central player in the pathogenesis and clinical development of MS.
The interest in B cells was initially prompted by the presence of oligoclonal banding (OCB) in CSF, which is associated with a higher risk of conversion to MS in clinically isolated syndrome and greater disease severity in MS (Kuhle et al. Mult Scler 2015;21:1013-1024. Farina et al. J Neuroinflammation 2017;14:40). However, it appears that OCBs may be largely a consequence rather than a cause of CNS damage, with antibodies directed at intracellular proteins resulting from tissue damage (Brandle et al. Proc Natl Acad Sci U S A 2016;113:7864-7869). Later in the MS disease course, antibodies may play a more prominent role, as shown by the presence of antibody-producing plasma cells in the meninges and perivascular space (Frischer et al. Brain 2009;132(Pt 5):1175-1189), and immunoglobulin deposition in pattern II lesions (Lucchinetti et al. Ann Neurol 2000;47:707-717).
In early MS, B cells contribute to acute inflammation through antibody-independent functions, such as antigen presentation and cytokine secretion (Baecher-Allan et al. Neuron 2018;97:742-768). Ligation of costimulatory molecules (e.g. CD80, CD86, CD40) is also important to determine the immune response. B cell activation has been reported to occur both in the periphery and in the CNS, with bidirectional trafficking of B cell clones across the blood-brain barrier (von Budingen et al. J Clin Invest 2012;122:4533-4543. Palanichamy et al. Sci Transl Med 2014;6:248ra106). B cell trafficking may be via different routes (blood-brain barrier, blood-meningeal barrier, choroid plexus), which may have a bearing on B cell distribution in the different CNS sub-compartments (parenchyma, meninges, CSF), but this area requires further study.
B cell depletion results in a rapid decrease in disease activity, as shown in trials of anti-CD20 agents. In the OPERA studies, the median number of CD19+ cells was reduced >95% within two weeks of the first infusion (Hauser et al. N Engl J Med 2017;376:221-234, supplemental appendix). The number of gadolinium (Gd)-enhancing lesions was significantly reduced within four weeks and T2 lesions within 4-8 weeks versus placebo in a phase II trial (Barkhof et al. Neurology 2019;93:e1778-e1786). Similarly, ofatumumab has been shown to reduce the number of B cells by 94% by week 4 after a 20 mg loading dose on days 1, 7 and 14 (Bar-Or et al. AAN 2020; abstract P8.1-001). The number of Gd+ lesions was reduced by 47% at week 4 and by 93% at week 12 (Bar-Or et al. 2020).
The optimal degree of B cell depletion to control RRMS has not been determined. A single course of rituximab (two infusions of 1000 mg given two weeks apart) has been shown to deplete B cells for up to 36 weeks; the memory B cell subset remained depleted for up to 52 weeks (Palanichamy et al. J Immunol 2014;193:580-586). There was no rebound disease activity when rituximab was discontinued for up to 14 months (Juto et al. Mult Scler Relat Disord 2020;37:101468). Ocrelizumab is administered as a 600-mg infusion every six months. Some authors have stated that 3-4 doses of ocrelizumab appears to produce a durable B cell depletion for an 18-month treatment-free period (Baker et al. Mult Scler Relat Disord 2020; preprint at www.medrxiv.org/content/10.1101/2020.01.09.20016774v1.full.pdf). This has prompted the suggestion that the current six-monthly dose schedule may be too frequent (Baker et al. EBioMedicine 2017;16:41-50), or that a flexible dose schedule may be beneficial (Avasarala et al. Drug Target Insights 2017;11:1177392817737515). Body-mass index may also influence B cell kinetics, with a longer time to B cell reconstitution in patients with lower BMI (Signoriello et al. Mult Scler Relat Disord 2020;43:102186).
Ofatumumab is administered as a 20-mg subcutaneous injection every four weeks. Laboratory studies have indicated that subcutaneous dosing results in increased B cell targeting in lymph nodes (Torres et al. AAN 2019; abstract P2.2-052), the principal sites of B cell activation and maturation, although the clinical significance of this difference has not been determined. B cell depletion at the current dose is unaffected by body weight (as opposed to BMI) (Hauser et al. AAN 2020; abstract P7.1-013). The effect of body weight on B cell reconstitution has not been reported.
A recent suggestion is that the key target for anti-CD20 therapies is the memory (CD27+) B cell subset, an inference largely based on the presumed mechanism of action of current DMTs (Baker 2017). A further suggestion is that memory B cells harbour Epstein-Barr virus, which accumulate in the CNS and cause tissue damage by various mechanisms (reviewed in Bar-Or et al. Trends Mol Med 2020;26:296-310). However, it should be noted that the activity and function of memory B cells differ depending on the profile of costimulatory and coinhibitory molecules. Over 20 such molecules have been identified and their role in MS pathogenesis will require further study (Li et al. Cold Spring Harb Perspect Med 2019;29661809).
Current and emerging anti-CD20 therapies can be differentiated by their route of administration (infusion vs. subcutaneous) and epitope binding on B cells, which influences whether B cells are depleted primarily by antibody-dependent cell-mediated cytotoxicity (ADCC; ocrelizumab > rituximab) or by complement-dependent cytotoxicity (CDC, ofatumumab > ocrelizumab) (Gelfand et al. Neurotherapeutics 2017;14:835-841). It remains to be determined if these or other factors result in differing effects on the proliferation of B cells and plasma cells in the CNS compartment and the release of neurotoxic soluble factors that appear to drive disease progression in MS.
Part 2 will examine the latest data on the effect of current and emerging anti-CD20 therapies on clinical outcomes in MS.