Short-term B-cell Depletion in Relapsing Multiple Sclerosis

Several disease-modifying therapies (DMTs) have been shown to be effective in reducing the
disease activity in patients with relapsing forms of multiple sclerosis (MS) but these
treatments, often need to be used continuously for an unknown duration, rendering the
long-term use extremely expensive. In addition, chronic administration of DMTs is often
associated with undesirable side effects. Among these medications, B-cell depleting
monoclonal antibodies might have the properties of an ideal group of medications: i) B-cell
depleting antibodies have proven to be extremely potent in reducing or stopping the disease
activity in relapsing MS, ii) B-cell depleting antibodies are very safe if used for a short
period and use for a short duration may stop the inflammatory disease activity over long
term, although current clinical practice and protocols are based on continuing B-cell
depletion for an unknown period of time. Indeed, early phase clinical trials of rituximab and
ocrelizumab suggested that a short course treatment with B-cell depleting antibodies can have
long term effects and disease activity will not return even long after B-cell repopulation in
the blood.

This long-term effect might be related to the specific pattern of B-cell tolerance defect in
patients with MS and the potential of its normalization with B-cell depleting antibodies. By
analyzing the reactivity of recombinant antibodies expressed from single B-cells, the
investigators' collaborators have demonstrated that the pattern of B-cell tolerance defect is
different in people with MS who only display an impaired removal of developing autoreactive
B-cells in the periphery while central B-cell tolerance in the bone marrow is functional in
most patients. In contrast, patients with rheumatoid arthritis (RA), type-1 diabetes (T1D) or
Sjögren's syndrome (SS) show defective central and peripheral B-cell tolerance checkpoints.
As a consequence, while anti-B-cell therapy does not correct defective early B-cell tolerance
checkpoints in T1D and only temporarily slows down autoimmune processes before newly
generated autoreactive B-cells likely induce patient relapse, the investigators postulate
that the efficacy of B-cell depleting antibodies in MS may be linked to the B-cell depleting
antibodies' normal central B-cell tolerance and the production of a normal B-cell and T-cell
compartment after anti-B-cell therapy.

The investigators' goal is to provide proof-of-concept that a short duration of treatment
with B-cell depleting antibodies can correct B-cell tolerance defects in MS and allow for
medication-free prolonged freedom from disease activity, at least in a proportion of subjects
with relapsing MS.

In an open label study, 10 patients with active relapsing MS will be treated with two courses
of ocrelizumab and will be followed clinically and radiologically for at least two and a half
years. Time to the return of disease activity (defined as clinical relapses or new or
enhancing lesions on the MRI) will be the primary outcome of the study. The investigators
will harvest B-cells before starting the treatment and after B-cell repopulation and assess
the central and peripheral tolerance defects. The investigators hypothesize that in most
participants, the disease activity will not come back, and this prolonged response to anti
cluster of differentiation 20 (CD-20) therapy is associated with normalization of B-cell
tolerance defect in these patients. Considering the safety of this approach, it can be
adopted widely among people with MS. Hence, the proposed B-cell analyses before and after
B-cell depletion in people with MS will provide novel insights regarding the mechanisms
underlying the beneficial effect of B-cell depleting antibodies and the potential long-term
suppression of disease activity. This strategy can therefore improve the approach to
treatment of many people with relapsing MS.