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Review Article
B-Cell-Directed Therapies: A New Era in Multiple Sclerosis Treatment
Panagiotis Kanatas1
,
2, Ioannis Stouras1, Leonidas Stefanis1
,
2and Panos Stathopoulos1
,
2
1First Department of Neurology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece and 2Eginiteion Hospital, Athens, Greece
ABSTRACT: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) that often progresses
to severe disability. Previous studies have highlighted the role of T cells in disease pathophysiology; however, the success of B-cell-targeted
therapies has led to an increased interest in how B cells contribute to disease immunopathology. In this review, we summarize evidence of
B-cell involvement in MS disease mechanisms, starting with pathology and moving on to review aspects of B cell immunobiology potentially
relevant to MS. We describe current theories of critical B cell contributions to the inflammatory CNS milieu in MS, namely (i) production of
autoantibodies, (ii) antigen presentation, (iii) production of proinflammatory cytokines (bystander activation), and (iv) EBV involvement. In
the second part of the review, we summarize medications that have targeted B cells in patients with MS and their current position in the
therapeutic armamentarium based on clinical trials and real-world data. Covered therapeutic strategies include the targeting of surface mol-
ecules such as CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) and CD19 (inebilizumab), and molecules necessary for B-cell acti-
vation such as B cell activating factor (BAFF) (belimumab) and Bruton’s Tyrosine Kinase (BTK) (evobrutinib). We finally discuss the use of
B-cell-targeted therapeutics in pregnancy.
RÉSUMÉ : Les traitements ciblant les lymphocytes B dans la sclérose en plaques : nouvelle ère thérapeutique en vue. La sclérose en plaques
(SP) est une maladie auto-immune chronique démyélinisante du système nerveux central (SNC) qui aboutit souvent à une grande incapacité. Le
rôle des lymphocytes T dans la physiopathologie de la maladie a déjà été mis en évidence dans des études antérieures, mais les bons résultats des
traitements ciblant les lymphocytes B ont suscité de l’intérêt pour le rôle de ces derniers dans l’immunopathologie de la maladie. Aussi
présenterons-nous dans l’article de synthèse des données probantes qui font ressortir l’action des lymphocytes B dans les mécanismes
d’évolution de la SP, depuis la maladie elle-même jusqu’aux éléments immunobiologiques des lymphocytes B potentiellement associés à la
SP. Dans la première partie, il sera question des théories existantes sur le rôle fondamental que jouent les lymphocytes B dans le milieu inflam-
matoire du SNC, dans la SP, à savoir i) la production d’autoanticorps; ii) la présentation d’antigènes; iii) la production de cytokines pro-inflam-
matoires (activation de voisinage); iv) le rôle du virus d’Epstein-Barr. Dans la secondepartie, nous présenterons un résumé des médicaments qui
ciblent les lymphocytes B chez les patients atteints de la SP, et discuterons de leur place dans l’arsenal thérapeutique de la maladie d’après les
résultats d’essais cliniques et des données réelles. Les stratégies thérapeutiques traitées dans l’article porteront notamment sur la prise pour cible
des molécules présentes à la surface des lymphocytes telles que la CD20 (par le rituximab, l’ocrélizumab, l’ofatumumab ou l’ublituximab) et la
CD19 (par l’inébilizumab), ainsi quesur la prise pour cible des molécules nécessaires à l’activation des lymphocytes B tel que le facteur d’activation
des lymphocytes B (BAFF, en anglais) (par le bélimumab), et à l’inhibition de la tyrosine-kinase de Bruton (par l’évobrutinib). Enfin, il sera
question de l’emploi des traitements ciblant les lymphocytes B chez les femmes enceintes.
Keywords: Multiple sclerosis; B cells; Monoclonal antibodies; CD20; CD19
(Received 7 January 2022; final revisions submitted 15 April 2022; date of acceptance 3 May 2022)
Introduction
Multiple sclerosis (MS) is a chronic autoimmune demyelinating
inflammatory disease of the central nervous system (CNS), in
the majority of cases gradually leading to progressive, severe dis-
ability if left untreated. MS is the leading cause of non-traumatic
disability among young adults in the developed world. It is most
often diagnosed between 20 and 40 years of age and affects women
and men at a ratio of approximately 2:1.1–3The clinical course of
MS can be characterized as (i) clinically isolated syndrome (CIS),
(ii) relapsing-remitting (RRMS), (iii) primary progressive (PPMS),
or (iv) secondary progressive (SPMS). Each of the above MS cat-
egories can be further subcategorized as either active or inactive,
based on both the clinical relapse rate and MRI findings (new
T2 lesions and/or active, gadolinium-enhancing lesions-GdELs).
Further, progressive forms can be subcategorized as actively
progressive or stable.4
Significant progress in understanding MS pathophysiology has
been accomplished in the past decades. Two hundred and thirty-
Corresponding author: Panos Stathopoulos, Eginiteion Hospital, V. Sofias 72, 115 28 Athens, Greece. Email: pmstathopoulos@gmail.com
Cite this article: Kanatas P, Stouras I, Stefanis L, and Stathopoulos P. B-Cell-Directed Therapies: A New Era in Multiple Sclerosis Treatment. The Canadian Journal of Neurological
Sciences https://doi.org/10.1017/cjn.2022.60
© The Author(s), 2022. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federat ion. This is an Open Access article, distributed under the terms of the
Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is
properly cited.
The Canadian Journal of Neurological Sciences (2022), 1–10
doi:10.1017/cjn.2022.60
https://doi.org/10.1017/cjn.2022.60 Published online by Cambridge University Press
three genetic variants have been identified as risk factors for MS, 32
of which refer to the major histocompatibility complex family
(MHC).5Prominent among the many risk variants, MHC Class
II DR15 molecule entails mechanistically relevant susceptibility
to the disease rather than just being a genetic marker.6
Additional genetic variants associated with the disease refer to
other genes of the immune system, such as genes involved in T-cell
activation and proliferation (IL-2, IL-7R), tumor necrosis factor-
alpha (TNF-α)-related pathways, and vitamin D metabolic path-
ways (GC, CYP24A1).3,7–11
In MS, myelin is phagocytosed by CD68-positive macrophages,
while immune cells including B and T cells seem to be activated in
the periphery and to express adherence molecules that enable them
to cross blood-brain barrier (BBB) in order to participate in the
formation of MS lesions. Accumulating evidence suggests an
important contribution of CD4þT cells to disease pathophysiol-
ogy.12 Often being present from the beginning and increasing in
quantity as disease progresses, axonal degeneration is regarded
as a correlate of disability progression.13
MS was long considered mainly T-cell-mediated; however,
intrathecal IgG synthesis,14 a hallmark of MS, supports B-cell
involvement.15,16 The T-cell-dominated view of MS pathogenesis
was further challenged by the remarkable efficiency of CD20þ
B-cell depletion in eliminating inflammatory activity in patients
with MS. In this review, we aim to shed light on the key role B cells
play in the pathogenesis of MS and present current advances in MS
treatment strategies based on promising and effective B-cell-tar-
geted therapeutic regimens.
B Cells in MS Pathology
Histological studies of active MS lesions have demonstrated that B
cells can reside in the perivascular space and the CSF but also
within the parenchyma.17 Moreover, ectopic lymphoid follicles
are found primarily in the intrameningeal spaces.18 and are asso-
ciated with subpial cortical demyelination in patients with
SPMS.19,20 In addition, four histopathological patterns have been
proposed for the classification of acute MS plaques. Type I lesions
(15% of MS patients) are characterized by a T-cell and activated
microglia inflammatory environment without immunoglobulin
deposition and complement activation. On the contrary, type II
lesions (58% of MS patients) develop in an inflammatory milieu
with immunoglobulin production and complement activation.
Demyelination in type III lesions (26% of MS patients) is accom-
panied by oligodendrocyte apoptosis without immunoglobulin
deposition or complement activation. Finally, in type IV lesions
(rare; 1% of MS patients) inflammatory modulators result in non-
apoptotic death of oligodendrocytes in the white matter surround-
ing the plaque due to metabolic disorganization processes.21
However, it is important to note that IgG deposits in MS histopa-
thological specimens are not specific for MS22 and that no disease-
characterizing autoantibodies have been defined to date.
Nevertheless, pattern II has been linked to better response to
plasma exchange.23
Potential Roles of B Cells in MS Pathophysiology
Several studies have explored potential roles of B cells in the devel-
opment of MS: antibody production, antigen presentation, and
secretion of pro- and anti-inflammatory mediators are three
prominent research directions that have been explored.24,25 In
addition, clear epidemiological associations of B-lymphotropic
Epstein-Barr virus (EBV) infection to MS have led to the explora-
tions of its pathophysiological relevance.26
Autoantibodies
Autoreactive B cells that escape peripheral tolerance checkpoint
selection could target antigens of the CNS and cause autoimmune
inflammation; however, no consistent B-cell antigen that is specific
for MS and that causes demyelination has been identified to date
despite numerous attempts. Intrathecal oligoclonal bands, a hall-
mark of MS diagnosis found in up to 95% of patients,27,28 are
not specific for MS (found also in e.g. meningitis and subacute scle-
rosing panencephalitis) and have been found to target intracellular
antigens in patients with MS.29,30 In addition, detection of intrathe-
cal IgM synthesis has been associated with onset of relapses and a
more aggressive disease course.31 Similarly to antibodies of oligo-
clonal bands, B cells of MS lesions have been found to target intra-
cellular antigens.30 Antibodies previously thought to be present in
MS such as antibodies against myelin oligodendrocyte glycopro-
tein (MOG) rather characterize a distinct disease entity (MOG-
antibody disease) that encompasses pediatric acquired demyelin-
ating syndrome, recurrent optic neuritis, acute disseminated
encephalomyelitis, and neuromyelitis optica without anti-aqua-
porin four autoantibodies. A minority of MS patients harbor anti-
bodies against a variety of antigens (some of them cell surface
proteins) such as contactin-2,32 OMGP,33 and other peptide and
lipid antigens.34,35
It must be noted that autoantibodies can also be responsible for
the activation and chemotaxis of CD4þT cells. The opsonization
of myelin antigens, even at low concentrations, enhances the pre-
sentative competence of resident antigen-presenting cells (APCs),
such as macrophages and dendritic cells, leading to increased
recruitment of effector T cells and, consequently, aggravation of
the disease severity, as explained in more detail below.36–38
B Cells as Antigen-Presenting Cells
B cells are efficient APCs and express MHC class II and costimu-
latory molecules, such as CD40, CD80, and CD86.25,39 They can
capture soluble and membrane-tethered antigens via their B-cell
receptor (BCR) and present them to T cells in an up-to-a 10.000
times more efficient way compared to myeloid APCs.40
Evidence from experimental autoimmune encephalitis, a rodent
model simulating "efferent" MS pathophysiology, opposes the
hypothesis that the antigen-presenting function of B cells is central
to the pathophysiology of MS. Specifically, MOG-specific B cells
may initiate CNS inflammation and, consequently, the sympto-
matic onset of the disease, but do not affect either the proliferation
or the molecular profile (i.e. secreted cytokines, activation mark-
ers) of MOG-specific T cells in the spleen and the draining lymph
nodes.37
On the other hand, a recently published report focusing on
human leukocyte antigen (HLA)-DR15, which is the major genetic
risk factor for MS, addresses how the immunopeptidomes pre-
sented by both DR15 allomorphs, DR2a and DR2b, on different
APCs in the thymus, peripheral blood, and brain –including B cells
–could affect autoimmune T cells. The results showed that DR2a
and DR2b immunopeptidomes on B cells are significantly skewed
toward HLA-DR-self peptides (HLA-DR-SPs) –compared to
monocytes –which are consequently presented to autoreactive
CD4þT cells. These T cells responded robustly to individual
and pooled HLA-DR-SPs in MS patients, compared to healthy
2The Canadian Journal of Neurological Sciences
https://doi.org/10.1017/cjn.2022.60 Published online by Cambridge University Press
donors, suggesting that DR2a and DR2b could jointly shape an
autoreactive T-cell repertoire in MS.41
B Cells as a Source of Cytokines
Physiologically, B cells can be a source of both proinflammatory
and anti-inflammatory (regulatory) cytokines. B cells of RRMS
patients however feature a profile that is skewed towards an abnor-
mally hyperactive proinflammatory response. In mice, high levels
of B-cell-secreted IL-6 can foster the differentiation of Th17 cells,
while preventing the generation of T regulatory cells.42–44 In MS
patients, B-cell production of lymphotoxin alpha (LT-α), TNF-α,
and granulocyte macrophage-colony stimulating factor (GM-CSF)
appears elevated, forging a chronically inflammatory milieu within
the CNS.19,25,45 At the same time, anti-inflammatory, regulatory
cytokines that are produced by B cells, such as IL-35,46 but also
TGF-β1 and IL-10, are instrumental in controlling inflammation
in experimental models of MS.47
EBV in MS
Among the infectious factors examined, the B-lymphotropic EBV
has been shown to confer increased risk of developing MS, via, as
yet, unclear mechanisms.48 Ninety-six percent of the general pop-
ulation is positive for IgG antibodies against EBV (indicating past
infection), while in MS patients this percentage is almost 100%.26
Moreover, a prospective cohort study of 955 incident MS patients
showed a 97% of EBV (but not other viruses) seroconversion
before development of the disease, significantly higher compared
to controls.49 Studies and experiments have shaped four major
theories about EBV’s role in the pathogenesis of MS: the cross-
reactivity hypothesis,50 the bystander damage hypothesis,51 the
αβ-crystallin hypothesis,52 and the EBV-infected autoreactive
B-cell hypothesis.53 Cellular and CSF findings however only
partially match the pathophysiology of MS as far as the first three
hypotheses are concerned. One important finding is the recent
demonstration of molecular mimicry between EBV transcription
factor EBNA1 and CNS protein glial cell adhesion molecule
(GlialCAM), leading to the production of cross-reactive antibodies
with higher affinity towards an intracellular GlialCAM epitope.54
The fourth hypothesis postulates that EBV-infected autoreactive B
cells accumulate in the target organ and orchestrate the disease by
producing antibodies and stimulating T cells due to a defect in their
elimination by the antiviral CD8þT cells. Moreover, the EBV anti-
apoptotic protein BHRF1, produced by both latently and lytically
infected cells, inhibits B-cell apoptosis,55 resulting in immortaliza-
tion of the autoreactive B cells it infects. In support of this hypoth-
esis, substantial EBV persistence in B and plasma cells as well as
meningeal B-cell lymphoid follicles of all MS cases examined
was reported,56 but could not be reproduced in multiple indepen-
dent replication studies.57–60 Overall, the epidemiological associa-
tions remain; however, no underlying biological mechanism has
been consequently supported by experimental data.
Anti-B-cell Agents as a Therapeutic Strategy
Most anti-B-cell agents are monoclonal antibodies (mAbs); how-
ever, small molecules have also emerged as promising agents and
have better CNS penetrance (Table 1). B-cell-depleting antibodies
can be categorized in 1st-, 2nd-, or 3rd-generation. 1st-generation
monoclonal antibodies (mAbs) can be either fully murine (suffix:
-omab) or chimeric (65% human, suffix: -ximab), while 2nd-gener-
ation ones can be humanized (>90% human, suffix: -zumab) or even
fully human (suffix: -mumab). 3rd-generation mAbs consist of a
modified Fc region, chimeric, or humanized. Immunogenicity in
theory ranges from higher in 1st-generation mAbs to lower in
2nd-and3
rd-generation ones.61
Figure 1: Expression of cell surface antigens throughout B-cell maturation.CD19 is expressed in all stages of B-cell development, with the exception of stem cells and the majority of
plasma cells. CD20 is not present on plasma cells, most plasmablasts, pro-B cells, and stem cells. BAFF-receptor (BAFF-R) is expressed on both immature and mature B cells in the
germinal center, as well as memory B cells and late plasmablasts. Transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA) are expressed on
germinal center B cells, memory cells, and antibody-secreting cells.
Le Journal Canadien Des Sciences Neurologiques 3
https://doi.org/10.1017/cjn.2022.60 Published online by Cambridge University Press
Anti-CD20 mAbs
CD20 is a 33-37kDa transmembrane protein, which spans the
membrane four times, thus consisting of two extracellular loops
and intracellular C- and N-termini. Although some T cells with
CD20 surface expression can be found in all lymphatic organs,
are often CD8-positive, can be myelin-specific,62–64 and may
correlate positively with disease severity,65 CD20 serves a more
important role on B cells. The molecule is not expressed through-
out the entirety of the B-cell line of differentiation, but only in
pre-B cells and mature B cells, with stem cells and the majority
of antibody-secreting cells being CD20-negative (Figure 1).66–68
Physiologically, CD20 plays a key role as regulator of calcium
influx in the signaling pathways that lead to B-cell differentiation
into antibody-secreting plasma cells69 and its presence on the sur-
face of most, but not all, B cells makes it an attractive target
for monoclonal antibody-based therapy. B cells targeted by anti-
CD20 monoclonal antibodies are eliminated via three main
mechanisms: programmed cell death / apoptosis, complement-
dependent cytotoxicity (CDC), or antibody-dependent cellular
cytotoxicity (ADCC) processes.70 Evidence from animal studies
shows that anti-CD20 antibody-mediated B-cell depletion may
be incomplete in lymph node germinal centers.71 Moreover, cer-
ebrospinal fluid B cells seem to be less affected than peripheral
B cells by intravenous rituximab (the first anti-CD20 monoclonal
antibody) administration, although the drug itself can be detected
in a very low concentration (up to 1000 times lower than in the
periphery) behind the BBB.72–75 Of note, the limited access of
anti-CD20 mAbs to the CNS due to their relatively high molecular
weight could, at least to some extent, be overcome with intrathecal
(IT) administration of anti-CD20 mAbs. The four main antibodies
evaluated for anti-CD20 MS therapy are analyzed below.
Rituximab
Rituximab is a 1st-generation chimeric monoclonal antibody (IgG1),
engineered by fusing a murine Fab with a human Fc domain.61 Its
elimination half-time is estimated at around 20 days;76 it may,
however, vary according to sex, body weight, and renal function.77
Rituximab depletes B cells via ADCC and CDC and has been found
to be extremely effective in patients with RRMS. A landmark 48-
week, phase 2, double-blind, placebo-controlled study convincingly
highlighted the efficacy of rituximab monotherapy in reducing
gadolinium-enhanced lesions in patients with RRMS (n =104).78
In addition, a retrospective observational study of 808 patients with
RRMS revealed absence of rebound disease activity upon rituximab
cessation,79 whereas rebound activity has been reported with nata-
lizumab80 and fingolimod cessation.81,82
In regard to progressive forms, a phase 3 (n =439 PPMS
patients), double-blind and placebo-controlled trial concluded in
2009 that CD20þB-cell depletion can slow disease progression
in a subgroup of younger patients with PPMS, particularly those
with inflammatory lesions (GdELs), as rituximab-treated patients
had less increase in T2 lesions and confirmed disease progression
was delayed in the subgroup with GdELs.83 Overall, however, the
study was negative. Moreover, a large observational, retrospective
study from the Swedish MS registry included 822 patients (557
RRMS, 198 SPMS, and 67 PPMS) and confirmed both rituximab’s
safety as well as its efficacy in reducing GdELs; GdELs went from
26.2% (pretreatment) to 4.6% in the pooled post-treatment
cohort.84 Interestingly, disability remained constant in RRMS
patients but increased in SPMS and more so in PPMS patients.
The question of whether disability progression differs in treated
and untreated patients was tackled by a retrospective cohort study
of 88 SPMS patients. This study resulted in significantly lower
Expanded Disability Status Scale scores (p <0.001) and delayed
disease progression (p =0.02) in the rituximab-treated group in
comparison to the matched control group.85 It should be noted
however that the rituximab-treated group included more patients
with radiologic activity, which may have driven the difference
between the two groups.
In clinical practice, rituximab is widely used as an off-label
treatment for the management of RRMS, as well as active SPMS,
as its safety profile is acceptable, well-characterized,86,87 and the
efficacy evident, despite the lack of phase III trials.88 The drug is
Table 1: A summary of medicines targeting B cells that have been used in MS
Drug Type Target molecule Clinical trials Pregnancy Dosing
Rituximab Chimeric IgG1 Large extracellular loop
of CD20 molecule
Phase 1; Phase 2 (Hermes);
Phase 3 (Olympus).
Not FDA-approved
Last infusion 3.5
months prior to
conception
Intravenous dose of 2 ×1000 mg in
a 2-week period
Ocrelizumab Humanized
glycosylated IgG1
Large extracellular loop
of CD20 molecule
Phase 2; Phase 3 (OPERA I &
II, ORATORIO). FDA-approved
Last infusion 6
months prior to
conception
Intravenous doses of 600 mg twice
a year
Ofatumumab Fully human IgG1 Large & small
extracellular loop of
CD20 molecule
Phase 2b (MIRROR); Phase 3
(ASCLEPIOS I & II).
FDA-approved
N/A 20 mg/0.4 mL once per week for
the first 3 weeks, once a month
thereafter
Ublituximab Glycoengineered
chimeric IgG1
Large extracellular loop
of CD20 molecule
Phase 2 (NEDA); Phase 3
(ULTIMATE I & II). Not yet
FDA-approved
N/A N/A
MEDI-551 Glycoengineered,
humanized, fucozylated
IgG1κ
CD19 Phase 1; Phase 2/3
(N-MOmmentum).
FDA-approved
N/A Intravenous infusions of 300 mg
every 6 months.
Atacicept Human recombinant
fusion protein (Fc
IgG þTACI)
BAFF-APRIL Phase 2 (ATAMS & ANOS).
Failed
N/A –
Evobrutinib Small molecule drug BTK Phase 2; Phase 3.
Not FDA-approved
N/A 75 mg dose daily
4The Canadian Journal of Neurological Sciences
https://doi.org/10.1017/cjn.2022.60 Published online by Cambridge University Press
generally well-tolerated by patients all throughout the MS type
spectrum, and the main adverse effects are mild to moderate infu-
sion-related reactions (IRRs), typically with the first dose, as well as
mild to moderate infections. No cases of progressive multifocal leu-
koencephalopathy (PML) due to John Cunningham virus, which is
mostly seen with natalizumab treatment,89,90 have been recorded in
MS patients treated with rituximab, and the frequency of PML in
non-neurologic patients treated with rituximab seems to range
around 1:4000; however, usually these patients have received
multiple immunosuppressants.91,92 Finally, an added advantage
of rituximab is its relatively low cost (biosimilars are also available);
however, its off-label prescription is complex and time-consuming
for physicians. While open questions remain about optimal dosing
and frequency strategies, a common tactic is 2 ×500 or 1000 mg, in
a 14-day period, and repeat dosing of 500–1000 mg every 6 months
or yearly.61
Ocrelizumab
Ocrelizumab, an IgG1 immunoglobulin, is a 2nd-generation
recombinant humanized anti-CD20 mAb.93 The drug has a termi-
nal elimination half-time of around 26 days, which is not affected
by mild renal or hepatic impairment.94 Compared to rituximab,
ocrelizumab mobilizes in vitro lower CDC, but higher ADCC
action95 and as a humanized molecule is expected to be less
immunogenic than rituximab with lower titles of neutralizing
anti-drug antibodies.96,97
In OPERA I (n =821 patients) and OPERA II (n =835
patients), two phase 3, double-blind trials published in 2017,
ocrelizumab was associated with a lower annualized relapse rate
(by 46–47%) and an impressive reduction of the mean number of
GdELs (by 94%) over a 96-week time period compared to inter-
feron beta-1a (p <0.001). The drug effectively depleted CD19 B
cells (CD19 B cells serve as index of B-cell count in anti-CD20
treatment) within 2 weeks (which is when CD19 cells were mea-
sured).98 ORATORIO, a phase 3, double-blind, placebo-con-
trolled trial, examined ocrelizumab’s efficacy in managing
PPMS progression. Results from 732 patients revealed that ocre-
lizumab was associated with lower rates of clinical and MRI pro-
gression than placebo. Because in this study the effect was driven
by a fraction of PPMS that had evident MRI inflammation, EMA
hasapprovedthedrugonlyininflammatoryPPMS,whereas
otheragenciessuchastheFDAand Swissmedic have not applied
this restriction.99
The most common adverse effects of ocrelizumab include mild
and manageable IRRs, like pruritus, rashes, throat irritations, and
flushing, but their severity and frequency decrease with the num-
ber of infusions. Generally, mild to moderate infections occur in
30% of patients, but severe ones are relatively rare. Other adverse
events such as extremity pain, diarrhea, and peripheral edema may
also occur in rare cases.100,101
Ocrelizumab is administered intravenously according to a fixed
dosing schedule, as approved based on the phase 3 studies. An ini-
tial dose of 600 mg is divided in 2 ×300 mg with a 2-week time
interval. Subsequent doses of 600 mg are given in a single infusion
once every 6 months.94 Interestingly, a post hoc analysis from
ORATORIO, where patients with lower body weight (and respec-
tively higher ocrelizumab dose per kg) suffered less progression of
deficits, prompted a currently ongoing clinical trial that examines
the safety and efficacy of higher than standard ocrelizumab doses
(1200 mg for body weights <75 kg, or 1800 mg for body weights
>75 kg) in PPMS.102,103
Ofatumumab
Ofatumumab is a 2nd-generation, fully human IgG1 mAb104 that
depletes circulating CD20 B cells via ADCC105 and CDC.106
Two identically designed, double-blind, phase 3 clinical trials,
ASCLEPIOS I and II, compared the efficacy of subcutaneously
administered ofatumumab to that of oral teriflunomide, the oral
pyrimidine synthesis inhibitor. The trials enrolled 1882 patients
in total in 1.6 years, and their results indicated a statistically signifi-
cant advantage of ofatumumab over teriflunomide in suppressing
both new relapses and GdEL activity (the latter by 94–97%). Side
effects were reported to be mild to moderate and included injec-
tion-related reactions, headache, and infections (in 51.6% of
patients treated with ofatumumab) such as nasopharyngitis, upper
respiratory, and urinary tract infection.107 Consequently, the FDA
approved ofatumumab as a therapy for RRMS, CIS, and active
SPMS in the form of an auto-injector pen, while the EMA for
relapsing, active MS.106 Ofatumumab was approved for subcutane-
ous use at a dose of 20 mg/0.4 mL once per week for the first 3
weeks of treatment and once monthly thereafter.108
Ublituximab
Ublituximab is a 3rd-generation anti-CD20 glycoengineered chi-
meric IgG1 mAb that exerts its action primarily via ADCC, which
is facilitated by defucosylation of its Fc region and thereby
increased affinity for FcγRIIIa.61 A 48-week, placebo-controlled,
phase 2 trial of ublituximab in 45 RRMS patients established that
150 mg iv on day 1 and 450–600 mg on day 15 and week 24 were
able to efficiently deplete B cells within 4 weeks (which is when B
cells were measured); moreover, 74% of patients achieved no evi-
dence of disease activity status (NEDA), that is had no relapses, no
radiological disease activity, and no progression of disability.
Similarly to the other CD20 agents, adverse effects comprised mild
to moderate IRRs and upper respiratory infections, influenza,
nasopharyngitis, sinusitis, and fungal infections.109 In follow-up,
two double-blind, phase 3 trials [ULTIMATE I (NCT03277261)
and II (NCT03277248)] will assess ublituximab’s efficacy and
safety compared to teriflunomide in 880 patients with RRMS.110,111
Anti-CD19 mAbs
CD19 belongs to the Ig superfamily and along with CD21, CD82,
and CD225 contributes to the formation of a multimolecular sig-
nal-transduction complex that ultimately leads to the activation of
PI-3 kinase.112 Compared to CD20, CD19 is expressed on B cells of
earlier developmental stages as well as in more antibody-secreting
cells and is thus an appealing therapeutic target (Figure 1).113 In
addition to having a broader expression during B-cell stages of
development and differentiation, CD19, unlike CD20, is selectively
expressed on B cells and not T cells.62 A phase 1 study assessing the
pharmacokinetic (intravenous and subcutaneous) profile of inebi-
lizumab, a humanized afucosylated IgG1κanti-CD19 mAb,114 has
been conducted in patients with relapsing MS with positive
results,115 but no phase III trials for MS are currently known to
be underway.
Atacicept
Atacicept is a human recombinant fusion protein, consisting of a
human IgG Fc portion and the extracellular domain of TACI
receptor that binds both BAFF and a proliferation-inducing ligand
(APRIL).116 The drug therefore competes for BAFF and APRIL
binding with native TACI, which is both membrane-bound and
soluble,117 as well as, to a lesser extent, with the other receptors
Le Journal Canadien Des Sciences Neurologiques 5
https://doi.org/10.1017/cjn.2022.60 Published online by Cambridge University Press
of the BAFF-APRIL system (BAFF-R and BCMA).118,119 After
improving rheumatoid arthritis and systemic lupus erythematosus
(SLE),120 atacicept was tried in MS.
Subcutaneous atacicept was evaluated in a 36-week, phase 2,
double-blind, and placebo-controlled trial in 255 patients with
relapsing MS. The trial was prematurely terminated when an
increase in inflammatory disease activity was noticed despite
immunoglobulin and naïve B-cell decrease, which led to the sus-
pension of every atacicept trial in MS.119,121,122 Another 36-week,
phase 2, double-blind, and placebo-controlled atacicept trial in
34 patients with unilateral optic neuritis as clinical isolated syn-
drome also showed disease exacerbation, with a significantly
higher proportion of patients converting to clinically definite
MS compared with placebo.123 As atacicept effectively depletes
naive B cells and induces a transient but marked increase in
memory B cells (especially class-switched ones),117,124,125 possible
reasons why atacicept aggravated MS include elimination of regu-
latory naïve B cells and enhancement of pathogenic memory B-cell
function.126,127
Belimumab
Belimumab is a human IgG1λrecombinant monoclonal antibody
directed against BAFF that prevents BAFF from interacting with its
three receptors on the surface of B cells, thereby reducing B-cell
survival, differentiation, and antibody production.128,129
Interestingly, belimumab administration does not result in overt
immunosuppression.130 While being moderately effective and
FDA-approved for the treatment of SLE since 2011, it failed in
myasthenia gravis,131 a disease mediated by pathogenic autoanti-
bodies.132 A phase 2, open-label trial of subcutaneous belimumab
in addition to ocrelizumab (standard dose) in 40 patients with
RRMS was scheduled to start within 2021.130
Evobrutinib
Evobrutinib is a small molecule drug that binds permanently to
and deactivates Bruton’s Tyrosine Kinase (BTK). BTK is an inte-
gral part of the BCR signaling cascade that affects B-cell activation
and is essential for B-cell maturation and their ultimate, terminal
differentiation into memory or plasma cells. Of interest, BTK is
involved in the entry of B cells into follicular structures.
Knockout or absence of BTK results in lack of B-cell activation,
moreover almost complete lack of peripheral B and plasma cells
and low circulating immunoglobulin.133–136 Importantly, about
75% of the CNS cells that express BTK are microglial, while
BTK expression levels in the brain increase after demyelination.137
As evobrutinib can bypass the BBB and enter the CNS, it can affect
microglial cells and B cells within the CNS.
Evobrutinib was the first BTK inhibitor (BTKI) to be tested as a
monotherapy in relapsing MS.138 In a double-blind, phase II trial
(n =267), evobrutinib was tested against placebo and dimethyl
fumarate. The results showed that patients who received 75 mg
of daily evobrutinib had significantly fewer GdELs during weeks
12 through 24 than those who received placebo (1.69 ±4.69 against
3.85 ±5.44, p =0.005), while adverse effects were minimal (e.g.
nasopharyngitis, alanine aminotransferase, and aspartate amino-
transferase level elevation).139,140 Evobrutinib is now being
advanced to phase III evaluation, along with several other BTKI
(some of them with reversible BTK binding); fenebrutinib, ibruti-
nib, and tolebrutinib.141
While CD19/20 B-cell depletion has shown tremendous effi-
cacy in reducing clinical and radiological MS activity, it raises
several safety concerns on humoral deficiency with long-term
usage in addition to a reduced response to vaccination.86,142,143
These disadvantages could possibly be avoided with inhibition
of B-cell activation and maturation with small molecules such as
BTKIs.136,144 In contrast with antibody-based B-cell depletion,
BTKIs do not destroy or lastingly minimize the frequency of
peripheral B cells, but seem to prevent the development of patho-
genic B cells.145 Their effect on disease activity does not seem to be
as impressive as that of anti-B-cell antibodies, and they cannot con-
trol the pathogenic properties of B cells as rapidly; however, they
are smaller in size, can penetrate the CNS, target microglia, and
might therefore have a better effect on disability progression.146
B-Cell-Targeted Therapies and Pregnancy
As MS largely affects female patients with childbearing potential,
the utilization of B-cell-targeted therapies in women of child-
bearing age deserves special mention.147,148 Rituximab-associated
B-cell depletion persists long after the drug’s elimination, which
occurs approximately 3 months after the last infusion. Thus, con-
ception can be considered safe 3 months after the last infusion
without significant risk of fetal exposure. But even if a woman con-
ceives before rituximab’s effective elimination, IgG1 subclass mAbs
cannot cross the placenta barrier during the first trimester, result-
ing in low chance of fetal exposure.149 Importantly, rituximab
administration and concurrent B-cell depletion have not been
linked to increased risk of adverse pregnancy outcomes compared
with the expected incidence in population.150 Also, infants
breastfed under anti-CD20 treatment had normal B-cell counts,
and no negative impact on health and development was attributed
to breastfeeding in the 1-year follow-up period.151 Although data
regarding ocrelizumab administration in this population group are
limited, it is reasonable to apply the same principles as with ritux-
imab. One additional advantage of CD20 depletion in terms of
family planning is that discontinuation of therapy is not associated
with a rebound phenomenon, as has been observed with natalizu-
mab. In that regard, a cohort study regarding the safety of anti-C20
mAbs rituximab and ocrelizumab during the last 12 months before
or during pregnancy concluded that the drugs are effective in con-
trolling disease in women with RRMS, during and partly after preg-
nancy. However, B-cell monitoring is essential both for the
newborn and for the mother after delivery, and larger studies
are required to assess their safety profile and to establish the best
time to restart the therapy after delivery.152 Recent recommenda-
tions suggest prioritization of MS management and conception
postponement in cases of highly active MS and contraception
for up to 4 months after ocrelizumab administration.153
Conclusion
The therapeutic criterion underlines that B cells not only partici-
pate in the pathogenesis of MS but can act as the orchestrators of
the inflammatory processes. As shown by clinical trials and real-
world data, B-cell-targeting agents (in particular CD20-depleting
agents) have established a new era in MS therapeutics and
immunotherapy in general, considering their remarkable efficacy
and safety profile. Long-term safety, especially increased risk of
infection with slowly but gradually decreasing total serum
immunoglobulin levels, remains a significant concern that has a
limiting effect on anti-CD20 usage in clinical practice. Regular
monitoring of immunoglobulin levels (e.g. before each follow-up
infusion) can help timely detection of a decrease and lowers the
risk of infection due to associated immunodeficiency.154–156
6The Canadian Journal of Neurological Sciences
https://doi.org/10.1017/cjn.2022.60 Published online by Cambridge University Press
Future studies will further inform on long-term effects of CD20-
targeting medications, on the use of oral BTKI agents and deter-
mine the new therapeutic algorithm that will likely move more
towards induction rather than escalation.
Acknowledgements. Figure was created with BioRender.com. The publication
of the article in OA mode was financially supported by HEAL-Link.
Funding. PK, IS, and LS received no funding in relation to the present topic. PS
is supported by the Onassis Foundation.
Conflict of Interest. PK and IS declare no conflicts of interest. LS is the site
investigator in the trials MUSETTE (BN42082) and GAVOTTE (BN42083),
sponsored by F. Hoffmann La-Roche Ltd. PS has received a travel grant from
Sanofi and research funding by the Onassis Foundation.
Statement of Authorship. Conceptualization: PS.
Drafting: PS, PK, IS.
Editing: PS, PK, IS, LS.
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