B-Cell Modulation in
Multiple Sclerosis
Riley M. Bove, MD
Partners Multiple Sclerosis Center, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts
A REPORT FROM THE 29TH CONGRESS OF THE EUROPEAN COMMITTEE FOR
TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS (ECTRIMS 2013)
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1
The Traditional View:
Immunopathogenesis of Multiple Sclerosis

The initial step in pathogenesis involves the peripheral
activation of CD4+ T helper (Th) type 1 cells in
response to a stimulating antigen.

The assortment of molecules released, including
costimulatory signals and cytokines, influences the
response profile of the activated immune cells.

The stimulating antigen, probably infectious,
subsequently cross-reacts with a CNS antigen.

Subsequently, activated T cells transmigrate across
the blood-brain barrier by adhesion, chemoattraction,
and active infiltration into the CNS.
Chitnis T, Int Rev Neurobiol 2007;79:43
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The Traditional View:
Immunopathogenesis of Multiple Sclerosis

Transmigration of activated T cells across the bloodbrain barrier leads to reactivation of infiltrating cells
within the CNS, which contributes to perivascular
inflammation and injury.

Release of additional CNS antigens may result in the
recruitment of T cells with specificities for additional
CNS antigens, called “epitope spreading,” which may
further propagate a chronic immune response.

Further modifications to this model include the
appreciation of other factors, most importantly ThIL-17.
Chitnis T, Int Rev Neurobiol 2007;79:43
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3
Back to the Bench: Further Discoveries

Macrophage-mediated vesicular demyelination was
replicated in New World monkeys, who developed
chronic relapsing-remitting MS and occasionally
progressive disease, with evidence of remyelination.

Autoantibodies that recognize the immunizing
antigen are deposited within the vesiculated myelin
sheaths in this animal model of MS, and similar
antibodies have been found in human MS lesions.

This discovery implied that humoral immunity might
be a key factor in MS pathogenesis.

CD20+ B cells were then identified in MS lesions.
Massaccesi L et al, J Clin Invest 1992;90:399; von Büdingen HC et al, Eur J Immunol 2004;34:2072;
Genain CP et al, Nat Med 1999;5:170; von Büdingen HC et al, Curr Opin Immunol 2011;23:713
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4
A Possible Role for B Cells in MS

Memory B cells, which can cross the blood-brain
barrier, can trigger cellular-dependent and
complement-dependent cytotoxic effects in the CNS.

B cells can influence the priming of effector T cells by
functioning as antigen-presenting cells.

Abnormalities in B-cell cytokine responses have been
reported in MS patients, and production of cytokines
and chemokines by B cells may be involved in the
formation of ectopic lymphoid-like structures.

B cells may be the reservoir for Epstein-Barr virus
(EBV); EBV infection is a known risk factor for MS.
Hauser SL et al, N Engl J Med 2008;358:676; Kappos L et al, Lancet 2011;378:1779
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5
HERMES Trial: Rituximab in RRMS

Phase 2, double-blind, 48-week trial in 104 patients
diagnosed with relapsing-remitting MS (RRMS) who
were randomized to receive rituximab or placebo

Patients receiving rituximab had lower counts of
gadolinium-enhancing lesions at 12, 16, 20, 24, and
48 weeks; fewer new gadolinium-enhancing lesions;
a smaller T2 lesion volume; and fewer relapses at 24
and 48 weeks, compared with placebo.

Patients receiving rituximab initially experienced
more adverse events than did those receiving placebo
(78% vs 40%, respectively) but not afterward, as
treatment continued (20% vs 40%).
Hauser SL et al, N Engl J Med 2008;358:676
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6
HERMES Trial: Rituximab in RRMS
Number of gadolinium-enhancing lesions in patients receiving rituximab or placebo, from baseline to
week 48. (A) Mean total number of gadolinium-enhancing lesions by week. (B) Mean number of new
gadolinium-enhancing lesions by week. Missing values were imputed by averaging the available data.
Baseline magnetic resonance imaging information was obtained 4 weeks before baseline.
Hauser SL et al, N Engl J Med 2008;358:676
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HERMES Trial: Rituximab in RRMS

The incidence of infection (eg, nasopharyngitis,
upper respiratory tract infections, urinary tract
infections, and sinusitis) was similar among the
rituximab and placebo groups (70% vs 71%).

More patients in the placebo group than in the
rituximab-treated cohort discontinued therapy
before week 48 (40% vs 16%).

Rituximab treatment may lead to lysis of memory B
cells in the peripheral blood and lymphoid tissues, as
well as interfere with antigen presentation by B cells
and activation of T cells or macrophages by proinflammatory B-cell cytokines.
Hauser SL et al, N Engl J Med 2008;358:676
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8
OLYMPUS Trial: Rituximab in PPMS

Double-blind, randomized clinical trial in which a
total of 439 patients with primary progressive MS
(PPMS) received rituximab or placebo every 24
weeks over a period of 96 weeks (four courses)

There was no significant difference between
rituximab and placebo in time to clinically definite
progression, defined as an increase in EDSS score
sustained over 12 weeks.

Patients given rituximab had less of a decrease in T2
lesion volume, but total brain volume was similar in
both patient groups.
Hawker K et al, Ann Neurol. 2009;66:460
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OLYMPUS Trial: Rituximab in PPMS

Rituximab therapy of PPMS was associated with
delayed time to clinically definite progression in:
» Patients under 51 years of age
» Patients with gadolinium-enhancing lesions on MRI

These subpopulation analyses suggest that:
» Some PPMS patients have evidence of inflammation early in
the disease course, which influences the rate of progression.
» Early, aggressive treatment of inflammation in PPMS may
be beneficial.
» Age-related neurobiologic changes (eg, immunosenescence)
occur in MS and have implications for therapeutic decisions.
Hawker K et al, Ann Neurol. 2009;66:460
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On the Horizon: Ocrelizumab

Ocrelizumab, a recombinant humanized monoclonal
antibody that selectively targets CD20+ B cells, might
offer similar therapeutic benefits to rituximab in
patients with MS with less risk of immunogenicity
and infusion-site reactions.

Ocrelizumab is biosimilar but not bioidentical to
rituximab.

In vitro, ocrelizumab demonstrates more antibodydependent, cell-mediated cytotoxicity than rituximab
and less complement-dependent cytotoxicity.
Kappos L et al, Lancet 2011;378:1779; ocrelizumab [data on file], Genentech, 2003
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On the Horizon: Ocrelizumab

Kappos et al conducted a phase 2, placebo-controlled
trial involving 220 patients with RRMS who were
randomly assigned to receive 600 or 2,000 mg of
ocrelizumab, interferon beta-1a, or placebo.

At 24 weeks, when compared with the placebo group,
patients given 600 or 2,000 mg of ocrelizumab had
89% or 96% fewer gadolinium-enhancing lesions on
MRI; both doses of ocrelizumab were superior to
interferon beta-1a in reducing the number of lesions.

Two phase 3 pivotal trials in RRMS patients and the
first phase 2 pivotal trial in PPMS patients (the
ORCHESTRA trial) are ongoing
Kappos L et al, Lancet 2011;378:1779
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12
On the Horizon: Ocrelizumab
Number of gadolinium-enhancing lesions by week in patients receiving ocrelizumab, interferon
beta-1a, or placebo. Vertical bars = 95% confidence interval.
Kappos L et al, Lancet 2011;378:1779
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13
Recovery After B-Cell Depletion

The prolonged benefits of B-cell depletion after
exposure to rituximab suggest that protection may
extend beyond the period of B-cell depletion.

Immunologic changes in peripheral circulation:
» Naïve and immature B cells predominate
» Increase in the numbers of interleukin 10-secreting B
regulatory cells and CD25+FoxP3+ T regulatory cells
» Reduction in Th1 and Th17 proinflammatory responses

Immunologic changes in cerebrospinal fluid:
» Decrease in the number of T and B cells
» Resting CD19+ bright B cells predominate
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14
Emerging Studies: MOG Antigen

There may be a repertoire of B-cell-dependent
antigens that might help to elucidate the underlying
triggers in MS.

Myelin oligodendrocyte glycoprotein (MOG), for
example, may be involved in either completion or
maintenance of the myelin sheath; it has emerged as a
potential antigen involved in the pathogenesis of MS.

Studies in B-cell MHC II-deficient mice suggest that a
simple substitution may induce a conformational
change resulting in human MOG antigen becoming
completely B-cell dependent; this protection could not
be restored by injecting MOG antibody.
Weber MS et al, Ann Neurol. 2010; 68:369
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15
Emerging Studies: Oligoclonal Bands

Studies of IgG sequences reveal that oligoclonal B
cells in CSF may be “fingerprints” for MS.

Multiple different oligoclonal bands belong to the
same clone and may respond to a smaller number of
antigenic determinants than the bands would suggest.

Members of these oligoclonal bands were identified in
the CSF and peripheral blood mononuclear cells.

Some B cells found only in the peripheral blood were
associated with oligoclonal bands found only in the
CSF, suggesting some exchange of B cells across the
blood-brain barrier.
von Büdingen HC et al, J Clin Invest. 2012;122:4533
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Emerging Studies: Oligoclonal Bands
Lineage trees of multiple sclerosis IgG-VH sequences suggest ongoing B-cell exchange across the blood-brain barrier.
IgG-VH lineages suggestive of ongoing B-cell exchange across the blood-brain barrier for patient MS-1 (A and C), MS-5
(B), and MS-6 (D). These lineages could also reflect affinity maturation occurring in both compartments in parallel. Blue
nodes represents cerebrospinal fluid-derived IgG-VH sequences, red nodes represent PB-derived IgG-VH sequences,
and green nodes represent identical sequences found in both compartments.
von Büdingen HC et al, J Clin Invest. 2012;122:4533
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17
Summary

Anti-CD20 trials have revealed that B cells are central
players in the pathogenesis of focal lesions in MS.

The mechanism of action likely involves blocking the
activation of pathogenic T cells by B cells through a
function of antigen-presenting cells, but it cannot
exclude bystander cytokine effects or autoantibodies.

Not all approaches based on B-cell manipulation are
likely to be effective in MS; some may potentially
worsen the disease.

Targeting resident B cells may soon be feasible.

A properly designed clinical trial could elucidate the
role of B cells in progressive MS.
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