VIEWS amp REVIEWS OPEN ACCESS

Targeting B Cells to Modify MS NMOSD andMOGADPart 1

Jonas Graf MD Jan Mares MD Michael Barnett MD PhD Orhan Aktas MD Philipp Albrecht MD

Scott S Zamvil MD PhD and Hans-Peter Hartung MD FRCP

Neurol Neuroimmunol Neuroinflamm 20218e918 doi101212NXI0000000000000918

Correspondence

Dr Hartung

hans-peterhartung

uni-duesseldorfde

AbstractOcrelizumab rituximab ofatumumab ublituximab inebilizumab and evobrutinib are immu-notherapies that target various B cellndashrelated proteins Most of these treatments have provenefficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease(NMOSD) or are in advanced stages of clinical development Currently ocrelizumab ofatu-mumab and inebilizumab are licensed for treatment of MS and NMOSD respectively Thisreview focuses on the current state of knowledge about the role of B lymphocytes in immune-mediated pathophysiology and its implications for the mode of action To understand thesignificance of this breakthrough in the context of the current MS therapeutic armamentariumthis review more closely examines the clinical development of CD20 depletion and the pio-neering contribution of rituximab Phase 3 and the recently published postmarketing studieswill be highlighted to better understand the relevant efficacy data and safety aspects of long-term B-cell depletion

RELATED ARTICLE

Targeting B Cells toModify MS NMOSD andMOGAD Part 2

Page e919

From the Department of Neurology (JG OA PA H-PH) University Hospital Medical Faculty Heinrich-Heine-University Dusseldorf Germany Department of Neurology (JM)Palacky University Olomouc Czech Republic Department of Neurology (MB H-PH) Brain and Mind Centre Department of Neurology University of Sydney New South WalesAustralia and UCSF Weill Institute of Neurosciences (SSZ) Department of Neurology University of California at San Francisco

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by Heinrich-Heine-Universitat

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

MS is the most common immune-mediated chronic in-flammatory disease of the CNS affecting approximately 25million individuals worldwide The course of the disease iseither relapsing-remitting or progressive12 Although theprecise triggers for this disease are not clear evidence indi-cates that the pathogenesis is multifactorial and includes ge-netic immunologic and environmental factors There is nocure for MS to date The past 2 to 3 decades have nonethelessbeen characterized by the encouraging development of a greatnumber of immunomodulatory treatment modalities134

Particularly noteworthy among these is the introduction ofthe CD20 B cellndashdepleting monoclonal antibody rituximaband subsequently its humanized version ocrelizumab56

Neuromyelitis optica spectrum disease (NMOSD) is a lessfrequent inflammatory disease primarily affecting the op-tic nerve(s) and the spinal cord that is caused by patho-genic immunoglobulin G (IgG) antibodies directed at theastrocytic endfoot aquaporin 4 water channel which ismade up of 6 transmembrane helical domains7 Hereevidence-based therapies have recently taken center stageThe pathologic differences between MS and NMOSD havebeen concisely reviewed8 NMOSD must be distinguishedfrom myelin oligodendrocyte glycoprotein (MOG)-IgGndashrelated disease that features perivenous inflammation andwhite matter demyelination9ndash16

The prevalence of NMOSD among Whites globally is 1100000 with an annual incidence of less than 1million InAsians the prevalence is 35100000 The annual incidenceof MOGAD in adults has been estimated to be 13million inchildren 31million17

The purpose of this review is to provide a better un-derstanding of the pathophysiologic role of B cells and theiractivity in MS and related disorders and to dissect themechanisms by which B-cell modulation and depletion exerttherapeutic effect in CNS disease1819 Treatment trials withB cellndashtargeted approaches are detailed Benefits of thisinterventional strategy are weighed against known risks

B cellndashdriven immune responsesunderlying MS NMOSDand MOGADProof of principle rituximabThe critical role of B cells in MS20 and NMOSD21 was re-cently reviewed It was the demonstration that rituximab is

highly effective in MS that prompted a reappreciation of thecontributions of B cells to MS pathogenesis (figure 1)

In the first case report of a patient with aggressive relapsing MSdisease stabilized with rituximab B cells were depleted in CSFand peripheral blood22 B-cell counts in patients with primaryprogressive MS were lowered more in peripheral blood than inCSF23 In a phase 2 trial of patients with relapsing-remittingMS(RRMS) receiving rituximab as add-on therapy decreases ofboth B- and T-lymphocyte counts were observed in CSF24

Several case reports convincingly demonstrated that rituximabnot only mitigated or arrested progression of a fulminant dis-ease course but also led to clinical improvement222526

The beneficial effects of B-cell depletion inNMOSDwere firstdemonstrated in an open-label study of rituximab publishedin 200527 followed by a retrospective analysis of 25 patientswith NMOSD in 200828 and a prospective long-term cohortstudy of 10 patients29

MSMode of action of CD20 cell depletion inMSmdashevidence emphasizing the role of B cells inMS pathogenesis

Binding of monoclonal antibodies to CD20CD20 is a member of the membrane-spanning 4A gene familyencoded by theMS4A1 gene on chromosome 1130 TheCD20-targeting monoclonal antibodies recognize shared or slightlydifferent epitopes Ublituximab (TG-1101) binds to a uniquepart of the CD20 domain3132 (figure 2) Recent work suggestsa double-barrier dimer structure33 In general binding of theseantibodies induces the redistribution of CD20 into lipid raftswithin the plasma membrane and may thus disrupt B-cell re-ceptor signaling Because of amino acid mutations in the Fcportion rituximab and ofatumumab bind C1qmore avidly thanocrelizumab and lead to complement activation and comple-ment-dependent cytotoxicity In contrast ocrelizumab morepotently promotes antibody-dependent cellular cytotoxicityand phagocytosis via its interaction of Fcγ receptors on naturalkiller cells monocytes macrophages and neutrophils3435

Based on these differential properties anti-CD20 antibodies aretermed type I (rituximab and ofatumumab) or type II(ocrelizumab)3637

CD20 cell depletion had not only a therapeutic effect on RMSor RRMS but also for the first time on the primary pro-gressive course of the disease (PPMS)3839 In the first trial

GlossaryBTK = Bruton tyrosine kinase IgG = immunoglobulin G IL = interleukin MOG = myelin oligodendrocyte glycoproteinNEDA = no evidence of disease activity NMOSD = neuromyelitis optica spectrum disease PPMS = primary progressive MSRRMS = relapsing-remitting MS TNF = tumor necrosis factor

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 NeurologyorgNN

using rituximab in PPMS the primary end point was notreached However when stratified to subsets the group(1) lt50 years and (2) Gd + did better statistically thanplacebo38

One of the most fascinating aspects of CD20 depletion in MSis that although the target cell is known it remains unclearwhich intercepted B-cell function is most relevant in thiscontext B cells may contribute to autoimmune disease via

Figure 1 The central role of B cells in the immunopathogenesis of MS

B and T cells in the peripheral lymphoidtissues reciprocally activate each otherThey migrate to the CNS passingthrough the blood-brain barrier MostB cells locate to the perivascular spaceAggregates of B lymphocytes are ob-served in the pia mater overlying thecortex In secondary progressive MS acompartmentalized inflammation in anectopic follicle-like lymphoid tissue isdriven by B cells plasma cells T cellsand follicular dendritic cells In the CSFantibody-producing memory B cellsplasmablasts andplasma cells give riseto oligoclonal bands From ref 18 withpermission by Springer Nature

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 3

autoantibody-dependent and autoantibody-independentfunctions4041

Figure 3 illustrates the specific B-cell developmental stagestargeted by a therapy directed against the CD20 differentiationantigen This is an effective therapeutic approach which clearlyunderpins the current clinical developments and recent ap-provals granted to subsequent preparations with similar ac-tivity profiles (eg evobrutinib42 NCT04032158ofatumumab43 NCT02792218 or NCT02792231 ublitux-imabNCT03277261 or NCT03277248 andNCT04032171)Furthermore the development of rituximab biosimilars likeobinituzumab is in progress to reduce drug resistance44 It

is interesting to note that low-dose intrathecal adminis-tration of rituximab leads to complete depletion of CD20 inperipheral blood45 but not to complete CD20 depletion inthe CNS46

CD20-depleting antibodies and the role of B cells in MSThese therapeutic developments have contributed to a majorrevision of our understanding of the pathophysiologic role ofimmune cells in MS47 It is currently widely accepted thatB cellsmdashand not exclusively or predominantly T cellsmdashplay acentral role in MS (figure 1 e-figure 1 linkslwwcomNXIA345) Table 1 summarizes the evidence invoking a keypathophysiologic role of B cells in MS

Initially B-cell depletion was expected to exert its effect bydiminishing the production of autoantibodies (e-figure 1linkslwwcomNXIA345) However the rapid onset of theprofound effects of CD20 B cellndashtargeted therapies hasprompted a reevaluation of the humoral immune response inMS The concept holds that clinical benefit preceded humoralchangeautoantibody synthesis This ties to the cellular effectof B-cell depletionmdasheg B- and -T lymphocyte collaborationwith decreased Th17 and Th1 cytokine production4849

The precise mechanisms underpinning the efficacy of CD20cell depletion in MS and its animal models remain in-completely understood4750ndash55 The interaction of specificallyB and T cells may be particularly relevant to MS pathology56

The effectiveness of B-cell depletion in MS has been invokedto support the hypothesis that B cells latently infected withEpstein-Barr virus may play an important role in the patho-genesis of MS5758 Animal studies have indicated that CD20depletion modulates activation of monocytes and microglia

Figure 2 Epitopes on CD20 recognized by anti-CD20monoclonal antibodies

CD20-targeted monoclonal antibodies recognize epitopes either identical orspatially in close neighborhood Only ublituximab binds to a unique epitopeon the CD20 domain From ref 31 with permission by SAGE Publishers

Figure 3 Cellular targets of CD19 and CD20 cell depletion therapies

A number of differentiation antigens are expressed on the cell surface during B-cell maturation and are subsequently recognized by the respectivemonoclonal antibodies used during therapy Monoclonal antibodyantigen binding ultimately leads to depletion via antibody mediated or complement-dependent cytotoxicmechanisms It is important that both early and latematuration stages are not depleted because they do not express CD19 or CD20 Thismeans that the ability to repopulate B cells is preserved and humoral immune memory is not impaired This maintains the function of natural defensemechanisms CD19 in contrast to CD20 is expressed also on prondashB cells and plasma cells Thus CD19-directed monoclonal antibodies have a broadercoverage of the B-cell lineage Aminor subpopulation of CD3 T lymphocytes CD8more than CD4 T cells also display the CD20 antigen They have been shownto be depleted following rituximab administratione25 It is controversial whether they are increased in activity exhibiting higher proinflammatory potential inblood and CSF of people with MS compared with healthy individuals CD20-depleting therapy removes myelin-reactive CD8 T lymphocytes from thecirculation of patients with MSe33

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 NeurologyorgNN

and the recruitment of T lymphocytes4959 Pathogenic CD40-mediated NF-κB activation of B cells is increased in patientswith MS60 In addition the significance of B-cell aggregates inlymphoid follicle-like structures of the subarachnoid spaceparticularly in patients with secondary progressive forms ofthe disease is the subject of intense discussione1e2 An animalstudy demonstrated that an intrathecal administration of anti-CD20 antibodies induces significant B-cell depletion inestablished CNS lesionse3

There is also evidence of direct crosstalk between the CNSand the periphery in patients with MS which is notablymediated by class-switched immunoactive B cellse4 inconjunction with the observation that B cells of patientswith MS exhibit augmented antigen-presenting proper-tiese5 (figure 1) These lymphocytes must overcome sev-eral immune barriers via complex cascadese6 to enableclonal expansione7 produce specific immunoglobulinse8

and promote lymphangiogenesise9 It is currently un-derstood that the maturation of CNS B cells of patientswith MS occurs in the draining cervical lymph nodese10

B cells of patients with RMS are able to manufacturecomplement- and immunoglobulin-independent factorsthat are toxic to neurons and oligodendrocytes invitroe11e12 Patients with myelitis as the sole clinicalmanifestation who are therefore potentially at an earlystage of MS were found to have an expanded and mutatedplasmablast subgroupe13 and a specific distribution of in-terleukin-6-10ndashproducing B lymphocytese14 consistentwith our current understanding of cytokine function inautoimmune diseasese15 It would therefore appear thatB cells assume an important role both at the onset andduring the perpetuation of MSe16 Regulation of themacrophage migration inhibitory factor pathway appearsto be pertinent as CD74 deficiency and upregulation ofCXCR4 are associated with early MSe17

However not all B lymphocytes are considered to be patho-physiologically significant but rather restricted subgroups ofB cells only Proinflammatory cells particularly CD27+

memory B cells can act as antigen presenters and

manufacture tumor necrosis factor (TNF) alpha interleukin(IL)-6 and granulocyte-macrophage colony stimulatingfactor with IL-6 being a driver of pathogenic Th17 T-cellresponses Anti-inflammatory regulatory B cells (Bregs) re-lease IL-10 TGFszlig and IL-35 e18ndashe20 and other specificB-lymphocyte subgroups present in CSF that may be primarydeterminants of disease phenotypee21

Based on the observations of MS phasendashdependent surfaceexpression of differentiation antigens during B-cell maturationand the results of the recently completed phase 23 trial ofinebilizumab a monoclonal antibody directed againstCD19e22 a distinction must be made between CD20 andCD19 depletion in NMOSD (figure 3) CD20 is notexpressed on the surface of plasma cells nor prondashB cellswhereas CD19 can be detected on the majority of plasma cellsin secondary lymphatic organs (eg spleen and tonsils) on allblood plasma cells and in more than 50 of bone marrowplasma cellse23e24 CD19+ B cells can also still expressMHC II(ie human leukocyte antigen-DR) thus anti-CD19 elimi-nates residual APC function whereas anti-CD20 does not18

It should be noted that in contrast to CD19 CD20 isexpressed also by a subgroup of CD3-positive T cellse25

These CD20 CD3 T cells have been shown to be depletedfollowing rituximab administration It is controversial whetherthey are increased in activity exhibiting higher proin-flammatory potential in blood and CSF of people with MScompared with healthy individuals

In summary B cells are not exclusively responsible for thedevelopment and perpetuation of MS There is evidencesupporting the notion that (memory) B cells induce autor-eactive autoproliferativee26 proinflammatory T cells (in-cluding TH17 cells) which in turn play a crucial role in CNSinflammatory cascadese27ndashe29 and that polymorphonuclearmyeloid-derived suppressor cells selectively control the ac-cumulation of B cells in the CNSe30 Nevertheless to date thespecific target antigen(s) of these immune cells remains to beidentifiede31 The role played by CD20-positive CD3 T cells asmall subgroup of T cells in MS also remains to be definede32

Table 1 Evidence for potential pathophysiologic functions of B lymphocytes in MS

Synthesis of intrathecal oligoclonal bands

Production of antibodies against myelin components in blood and CSF

B-cell accumulation and activated complement deposition in brain lesions

Meningeal B-cell aggregates in SPMS

Increased number of plasmablasts in blood and CSF

Antigen presentation cytokine production stimulation and regulation of autoreactive proinflammatory T cells

Induction and regulation of the proliferation of autoreactive proinflammatory T cells (including TH17 cells) homing to the CNS

Induction of neuronal apoptosis and oligodendroglial cytotoxicity

Abbreviation SPMS = secondary progressive MS

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One study suggests that they comprise myelin-reactive CD8T cellse33

Rituximab in MSA phase 1 trial evaluating 26 patients with RRMS in theabsence of a control group demonstrated a good 72-weekrituximab safety profile and showed that rituximab reducedthe development of new lesions between week 4 and week 72as well as flare-ups compared with the year preceding thetreatmente34 The double-blind placebo-controlled phase 2trial (Helping to Evaluate Rituxan in Relapsing-RemittingMultiple Sclerosis [HERMES] e-table 1 linkslwwcomNXIA346) additionally confirmed that rituximab 1000 mgadministered on days 1 and 15 was more effective than pla-cebo not only in terms of the primary MRI end points butalso for all secondary clinical end points examinede35 Phar-macodynamically rituximab was associated with rapid almostcomplete depletion of CD19+ B cells from weeks 2 to 24 Byweek 48 CD19 cells had returned to 31 of baseline

e35 B-celldepletion resulted in markedly diminished proinflammatoryTh1 and Th17 responses of CD4 and CD8 T lymphocytes48

Given the surprisingly good efficacy of CD20 cell depletion inpatients with RRMS it was hoped that this therapeutic ap-proach might also prove to be effective in the primary pro-gressive course of the disease To this end a randomizeddouble-blind placebo-controlled phase 23 trial was con-ducted in patients with PPMS (OLYMPUS e-table 1 linkslwwcomNXIA346) Four hundred thirty-nine patients re-ceived 2 1000 mg rituximab or placebo infusions every 24weeks until week 96 This trial failed to meet the clinicalprimary end point as there was no significant difference inconfirmed disease progression Despite this disappointingresult expectations for rituximabrsquos efficacy remained as thesecondary radiologic end point of T2 lesion load was met andpost hoc subgroup analyses indicated that younger patients(less than 50 years of age) with active inflammatory lesions inparticular seemed to benefit from rituximab treatment38e36

Furthermore several retrospective analyses and a subgroupanalysis provided evidence that rituximab can be effectiveboth in aggressive RMS and progressive MSe37ndashe43 and that itis also more effective than first-generation MS treatments(ie interferon-beta and glatiramer acetate)e44e45 In the largeSwedish study doses of rituximab above 750 mg6 monthswere not more effective than those belowe43 A retrospectiveSwiss study of 37 patients with RRMS and 22 patients withSPMS observed that lowering rituximab from 1000mg to 500mg6 months was safe and produced clinical and MRI sta-bility It also left serum neurofilament light chain levels un-affected The authors suggested that with a lower dose onemight avoid more marked hypogammaglobulinemia andthereby the risk of infectious complicationse46

Ocrelizumab breakthrough in MS therapySubsequent studies investigating the efficacy of CD20 de-pletion in patients with MS used the humanized equivalent

ocrelizumab instead of the chimeric monoclonal antibody rit-uximab (table 3) Ocrelizumab was administered initially in 2induction doses of 300mg IV at a 14-day interval followed by adose of 600 mg IV every 6 months over the course of the trialIn the initial randomized double-blind placebo-controlledphase 2 trial in RMS with a double-dummy design interferonbeta-1a administered IM served as the active comparator inRMS Ocrelizumab was shown to be more effective than pla-cebo and the active comparator in terms of the radiologicallydefined primary end point (number of gadolinium-positive T1lesions in brainMRI) No significant differences were identifiedbetween individual groups in terms of side effectse47

Subsequent phase 3 trials led to the approval of ocrelizumabfor the treatment of RMS and PPMSe48 Both ocrelizumab vsIM interferon beta-1a in RMS (OPERA I and II)e49 andocrelizumab vs placebo in early PPMS (A Study of Ocreli-zumab in Participants With Primary Progressive MultipleSclerosis [ORATORIO])39 met the defined clinical primaryend points The RMS twin studies achieved the primary endpoint which was defined as the annualized relapse rate withan absolute risk reduction of 46 and 47 respectively Allsecondary end points were also met with the exception of thepercentage change in brain volume in the OPERA II trial

Following the double-blind phase patients from bothOPERAstudies were maintained on ocrelizumab or switched frominterferon-szlig 1a for 3 years when clinical and MR outcomesand safety were assessed Pooled analysis of the 886 ofpatients that completed 5 years showed maintenance ofclinical (annualized relapse rate 24-week confirmed disabilityprogression and improvement) and MRI effects (total num-ber of new or newly enlarged T2 lesions and T1 gadolinium-enhancing lesions assessed every 48 weeks)

Patients on continuous ocrelizumab treatment from begin-ning fared better than those with delayed treatment onsetWhole gray and white matter brain volume loss was lessmarked in the group on continuous vs delayed treatment Nonew safety signals emergede50

In the double-blind period NEDA (no evidence of clinical orMRI disease activity) was attained in 485 of the ocrelizumaband 278 in the IFNszlig-1andashtreated patients During the open-label extension the proportion of patients with NEDA was654 in patients continuously receiving ocrelizumab vs 551in the switching populatione51

In the PPMS trial both the primary end point (disease pro-gression confirmed after 12 weeks) and the secondary MRIend points were met After 120 weeks 329 of patients in theocrelizumab and 393 in the placebo group had progressed(relative risk reduction of 24) whereas absolute brain lesionvolume decreased by 34 (ocrelizumab) and 74 (placebo)respectively A recent post hoc analysis confirmed an im-provement in arm function using the 9 Hole Peg Test Theproportion of patients with confirmed deterioration in the 9

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 NeurologyorgNN

Hole Peg Test was also lower in the ocrelizumab treatmentgroupe52 A retrospective analysis of a large multicenter MScohort revealed that 5 of all patients experienced confirmeddisease progression whereas the annualized relapse rate was017e53

It is noteworthy that the PPMS trial patterned on the results ofthe phase 2OLYMPUS trial of rituximab only included patientswho had a relatively short duration of the disease as defined byage (18ndash55 years) and symptoms lt15 years in patients with anexpanded disability status score of gt50 or lt10 years in thosewith an expanded disability status score of lt50 at the time ofscreening Both acute infusion reactions and respiratory tractand oral herpes infections emerged as significant adverseevents There was also a trend toward an increased risk ofcancer (particularly of breast cancer) (23 vs 08) althoughextended follow-up and postmarketing experience did notconfirm this association Besides the incidence was in the rangeexpected in the general populatione54e55

Repletion of B cells appears not to be uniform A recent studyof 74 patients with MS noted 418 who had their CD19 cellsreturning at 6 months the so-called fast responders Twenty-four percent had CD19 cells above 2 Fast response wasassociated with a higher body mass indexe56

B-cell repopulation has been associated with a rise in therelapse rate in the case of NMOSD a relapsing-remittingchronic inflammatory CNS disease with concomitantastrocytopathye57 In this context CD19CD27-positiveB cells seem to be especially importante58 It remains un-clear to what extent this correlation can be extrapolated toRMS In the pivotal clinical trials 207 of patients withRMS and 263 of patients with PPMS experienced adecrease in absolute lymphocyte counts below the lowerlimit of normale59 The majority of patients developedgrade 1 or 2 lymphopenia the incidence of grade 3 lym-phopenia was 1 and no CD19-positive cells could bedetected in peripheral blood as early as 2 weeks after thestart of the treatment42e49 The lymphocyte populationwas restored in 90 of the patients after a 25-year (me-dian 72 weeks) ocrelizumab treatment pausee59 In com-parison the lymphocyte population in the rituximab phase23 trial (OLYMPUS) was restored in 35 of the patients48 weeks after discontinuing treatment38 Results from thesurveillance studies after marketing authorization wasgranted in January 2018e59 (for indications refer to e-table2 linkslwwcomNXIA346) confirmed the benefits ofocrelizumab Of note 664 of patients with RMS re-ceiving ocrelizumab vs 243 of interferon beta-1a patientsexhibited no evidence of clinical or radiologic disease ac-tivity (NEDA)e60 In the absence of direct comparativestudies evaluating ocrelizumab against other MS therapiesa meta-analysis performed showed that ocrelizumab is aviable treatment option particularly for patients withhighly active RMSe61 Furthermore several retrospectiveanalyses and a subgroup analysis provided evidence that

rituximab can be effective both in aggressive RMS andprogressive MSe37ndashe43 and that it is also more effective thanfirst-generation MS treatments (ie interferon beta andglatiramer acetate)e44e45 To better characterize the re-sponse of patients with PPMS to immunotherapy thecomposite outcome termed NEPADmdashno evidence ofprogression or active diseasemdashhas recently been in-troduced Operationally it is defined as absence of 12-week confirmed disability progression absence of 12-weekconfirmed progression of ge20 on the Timed 25-FootWalk test and 9-Hole Peg Test no brain MRI activity (nonewenlarging T2 lesions and no T1 gadolinium-enhancing lesions) and no protocol-defined relapsese58

In the ORATORIO trial ocrelizumab tripled the pro-portion of patients with PPMS with NEPAD after 120weeks compared with placeboe62 An analysis of pooledphase 2 and 3 data suggests that ocrelizumab effectivelysuppresses disease activity detected by MRI within 4 weeksand suppresses clinical disease activity within 8 weekse63 Apost hoc study suggests that ocrelizumab is also effective inpatients with MS with increased baseline disabilitye64 AnMR spectroscopy study taking sequential measurements ofmarkers of neuronal-myelin coupling over a 96-week pe-riod demonstrated that ocrelizumab reduces cerebralgliosis compared with patients who received interferon-betae65 It also appears that progression in patients withPPMS is associated with chronic lesion activity in the whitemattere66 Currently multiple phase 3b studies are beingperformed to better characterize ocrelizumab in MS (table2) ORATORIO HAND (NCT04035005) explores itseffect on the function of the upper extremity in PPMSCONSONANCE (NCT03523858) monitors disease ac-tivity in PPMS and CHORDS (NCT02637856) andCASTING (NCT02861014) scrutinize safety and efficacy inRRMS after suboptimal response to a different DMT

ENSEMBLE (NCT03085810) examines the effect of ocreli-zumab in people with early RMS A recently published study(ENSEMBLE PLUS) showed that shorter infusion timeswere well tolerated and not associated with more adverseeventse67

A phase III b open-label study VELOCE (NCT00676715)evaluated the effectiveness of common vaccinations in patientswith relapsing MS treated with ocrelizumab Responses toclinically relevant antigens (tetanus toxoid pneumococcal an-tigens and influenza or keyhole limpet hemocyanin as a neo-antigen) were elicited but attenuated compared with controlson interferon-szlig or no disease-modifying druge68 OBOE(NCT02688985) investigates immunologic changes occur-ring during ocrelizumab treatment

In the absence of a phase 3 trial the issue of whether rituximabis an equivalent alternative to ocrelizumab remains open todebatee69ndashe72 Direct comparative studies between rituximaband other treatment options would be helpful to close thegaps in our current understandinge73

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 7

OfatumumabOfatumumab is a human monoclonal antibody that binds to asmall-loop epitope on CD20 It depletes B cells throughcomplement-dependent cytotoxicity and antibody-dependentcell-mediated cytotoxicity with great efficiency even whenCD20 expression is low3243

A small phase 2 study examining ascending doses of 100 300 and700 mg IV ofatumumab showed almost complete reduction innew MRI lesion activitye74 These results prompted a larger-scalephase 2 dose-response study of subcutaneous ofatumumab inpatients with relapsing-remitting MS42 Two hundred thirty-twopatients were randomized to receive 3 30 or 60 mg every 12weeks ofatumumab60mg every 4weeks or placebo for 24weeksThe primary end point was the number of cumulative newgadolinium-enhancing lesions on cerebral MRI The cumulativenumber of gadolinium-enhancing lesions was reduced by 2 thirdsin patients allocated to ofatumumab with a dose-dependent de-pletion of circulating CD19 B cells Complete depletion appar-ently was not necessary for a treatment effect Onset of action wasobserved by week 12 Furthermore a conditioning dose added nobenefit and repletion occurred faster in all ofatumumab doses

than previously reported with anti-CD20 therapy Adverse eventswere mostly injection related and mild43 An overview of furthertrials of subcutaneous ofatumumab in MS is provided in table 3

Two pivotal ofatumumab phase 3 clinical trials enrolling par-ticipants with typical relapsing (94) and secondary pro-gressive (5ndash6) MS were conductede71e72 The primary endpoint was annualized relapse rate and pooled analysis wasperformed in a preplanned meta-analysis of disability worsen-ing Ofatumumab produced a relative risk reduction in theannualized relapse rate of between 505 (ASCLEPIOS I) and585 (ASCLEPIOS II) compared with teriflunomidee75e76

(details in table 3) In the prespecified combined analysis ofboth trials ofatumumab was superior to teriflunomide in cut-ting the risk of 3- and 6-month confirmed disability worseningby 344 and 325 respectively These clinical results werecorroborated by MRI evaluation of metrics of disease activityand burden with one exception No difference was noted forbrain volume loss Serum neurofilament light chain levels werelowered more markedly in the ofatumumab than the ter-ilunomide group Injection site reactions were common butoverall ofatumumab was well toleratede76

Table 2 Ocrelizumab phase 2 and 3 trials for the treatment of MS

TrialPrimary end pointResult

Secondary end pointResult

Phase 2 RRMSKappos et al 2011Lancetn = 220111 randomization to placebo 600 mg or2000 mg ocrelizumab IV at days 1 and 15 orIFNszlig1a 30 μg IMAt week 24 all received ocrelizumab

bull Number of gadolinium-positive T1 lesions betweenweeks 12 and 24Ocrelizumab is moreeffective than placebo

bull Annualized relapse ratebull Percentage of nonrelapsing patientsbull Change in absolute T2 lesion volumebullNumber of new gadolinium-positive T1 lesions betweenweeks 4 and24bull Number of gadolinium-positive T1 lesions between weeks 4 and 24Ocrelizumab is more effective than placebo on all end pointsexamined with the exception of nonrelapsing patients and change inabsolute T2 lesion volume

Phase 3 RMSHauser et al 2017NEJM (OPERA I and II)n = 165611 randomization to 600 mg ocrelizumab IVevery 6months vs IFNszlig1a 30 μg IM every wk for86 wks

bull Annualized relapse rateOcrelizumab is moreeffective than IFN beta-1a(reduction by 44)

bull Timeuntil onset of 6months CDP (risk reduction of 40 confirmed at12 and 24 wks)bull Number of gadolinium-positive T1 lesionsbull Number of new andor enlarged T2 lesionsbull Percentage of patients with CDIbull Number of T1 lesionsbull Change of MSFC compared with baselinebull Percentage change in brain volumebull Change in Short Form Health Survey-36 (SF-36) Physical ComponentSummary (PCS) compared with baselinebull Percentage of patients with NEDAOcrelizumab is more effective on all secondary end points exceptfor OPERA I MSFC and SF-36 and is also more effective on allsecondary end points except for CDI andOPERA II percentage changein brain volume

Phase 3 PPMSMontalban et al39 2017NEJM (ORATORIO)n = 732Placebo or ocrelizumab 2 times 300 mg every 6months for 120 wks

bull Time to onset of sustainedCDP of at least 12 wksOcrelizumab is moreeffective than placebo

bull Time to onset of sustained CDP of at least 24 wksbull Percentage change of T25FW compared with baselinebull Percentage change in absolute T2 lesion volume compared withbaselinebull Percentage change in brain volumebull Change in Physical Component Summary Score (PCS) and SF-36Health Surveybull Percentage of patients with at least one adverse eventOcrelizumab ismore effective in terms of time to onset of sustainedCDP of at least 24 wks percentage change in T25FW compared withbaseline percentage change in absolute T2 lesion volume comparedwith baseline and percentage change in brain volume

Abbreviations CDI = confirmed disability improvement CDP = confirmed disability progression IFN = interferon IM = intramuscular MSFC = MS functionalcomposite NEDA = no evidence of disease activity T25FW = Timed 25-Foot Walk

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 NeurologyorgNN

Ofatumumab in August 2020 received approval by the FDAfor relapsing forms of MS (CIS RRMS and active SPMS)(e-table 2 linkslwwcomNXIA346) The efficacy of ofa-tumumab offers patients an alternative administration routeThey could self-inject

This could obviate the need to attend a medical enter andavoid exposure to infective agents This may arguably reduceutilization of healthcare resources It remains to be seenwhether the less profound depletion and faster repletion ofB cells achieved with ofatumumab will also translate into amore favorable safety profile

Ongoing ublituximabUblituximab (TG-1101) is a novel glycoengineered anti-CD20chimeric IgG1 monoclonal antibody Potential advantages overcurrently available CD20 directed antibodies encompass in-duction of a higher degree of antibody-dependent cellular cy-totoxicity activity in low CD20 epitope expressing cells as ischaracteristic in rituximab resistance binding to a novel epitopeof CD20 and the shorter infusion time of 1 hour Results of aphase 2 placebo-controlled trial highlighting both efficacy andsafety data have recently been published31 CD19-positive celldepletion the primary outcome was achieved in gt95 andNEDA in 74 of patients receiving ublituximab Infusion-related reactions were the most common adverse events butmild in nature Two phase 3 trials of ublituximab vs teri-flunomide in patients with relapsing MS are currently ongoing

Atacicept an inhibitor of B-cell differentiationthat failed in MSAtacicept is a fully humanized recombinant fusion proteinthat interferes with B-cell differentiation maturation sur-vival and antibody production by binding to the cytokinesBLyS (B-lymphocyte stimulator) and APRIL (also known asTNFSF13)e77e78 Animal studies suggested that its mode

of action could produce therapeutic benefit in MSe79 Un-fortunately a phase 2 trial revealed that this promisinge80

mode of action leads rather to an exacerbation of disease andthe study had to be prematurely terminatede81 This findingunderscores the complex involvement of B cells in MSe82

The failure of atacicept in MS may be associated with itsshifting the balance of regulatory B cellse83 and memoryB cellse84ndashe86 As a result pathogenic memory B cells werestimulated In addition atacicept failed in optic neuritisrheumatoid arthritis and systemic lupus erythematosuse87

Basic research on the B-cell survival factor suggests that themode of modulation is crucial to achieve clinical efficacye88

Perspectives Bruton tyrosine kinase inhibitorsKinase inhibitors have recently appeared on the horizon aspotential immunotherapeutics for MSe89 The implications ofkinase inhibition and transition from bench to bedside inoncological diseases have been reviewede90ndashe92 The cytosolicBruton tyrosine kinase is expressed exclusively on cells of thehematopoetic lineage and therefore affects the safety profile ofthis class of kinase inhibitors

Evobrutinib a selective covalent oral Bruton tyrosine kinase(BTK) inhibitor blocks B-cell activation and cytokine relea-see93 The development of BTK inhibitors has generatedpromising agentse94 Ibrutinib was the first in class to beassessed in B-cell malignancy clinical trialse95 Preclinicalcharacterization and phase 1 trials revealed that evobrutinib andbranebrutinib are both well tolerated and potent inhibitors withhigh kinase selectivitye96ndashe99 The first kinase inhibitors are li-censed for hematooncologic indications including mantle celllymphoma chronic lymphocytic leukemia and graft-versus-host diseasee100 The BTK inhibitor acalabrutinib has beengranted breakthrough designation by the US Food and DrugAdministration for the treatment of chronic lymphocytic leu-kemiae101 Thus in malignancy BTK inhibition is a promising

Table 3 Overview of trials of subcutaneous ofatumumab in MS

Trial Patient population relapsing MS

Phase 2 MIRRORDose-response study in patients with relapsing-remitting MSn = 232 patients were randomized to receive 3 30 or 60 mgevery 12 wks 60 mg every 4 wks or placebo for 24 wks Theprimary end point was the number of cumulative newgadolinium-enhancing lesions on cerebral MRIAPOLITOS (OMB157G1301)Japanese Registration StudyOfatumumab versus placebo24-wks randomized double-blind placebo-controlled followedby at least 24-wk open-label ofatumumab

APLIOS (OMB157G2102)prefilled syringe vs autoinjector 12 wks

Phase 3Hauser et al 2020 (NEJM)

ASCLEPIOS I and II (OMB157G2301OMB157G2301)Ofatumumab 20 mg vs teriflunomide 14 mg daily plus placeboSC plus oral placebo daily(n = 927 and n = 955 respectively) (see text)

Phase 3b ALITHIOS (OMB157G2399)Open-label long-term extensionOfatumumab 20 mg every 4 wks

ARTIOS PlannedSingle-arm open-label study in patients transitioningfrom dimethyl fumarate or fingolimod to ofatumumab96 wks

Abbreviation SC = subcutaneous

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 9

therapeutic approach in B-cell diseasese102e103 In MS a phase2 study of evobrutinibmet its primary end point by significantlyreducing the risk of developing gadolinium-enhancing le-sions42 It was well tolerated A reversible increase in liverfunction tests was noted Currently studies with the BTK in-hibitors BTKi (`168) (SAR442168) and GDC-0853 (fene-brutinib) have been completed are ongoing or about to getstartede104e105 E-table 3 linkslwwcomNXIA346 summa-rizes completed and planned phase 2 and 3 trials in MS

Preclinical data from experimental autoimmune encephalo-myelitis EAE suggest that BTK inhibitors may unfoldtheir beneficial effect in MS via multiple mechanismsie modulation of the cytoplasmic tyrosine kinase and Toll-like receptor signalinge106 This may impair generation of(auto)antibodies and B-cell antigen-presenting function Ac-tions on myeloid cells including microglia may be particularlyimportant given their presumed role in driving and main-taining an immunoinflammatory response with consequentneurodegeneration during the progressive stages of MS Assmall molecules BTK inhibitors may access the CNS easilyand arrive in zones of subpial compartmentalized in-flammation that are considered to significantly contribute tothe pathobiology of progression Given the medium effect sizeof eg evobrutinib shown in phase 2 and the apparentlybenign safety profile combination of oral BTK inhibitors withother high-efficacy drugs is being considered

Study fundingNo targeted funding reported

DisclosureJ Graf received conference and educational support from Bio-gen Merck Serono Sanofi Genzyme and Grifols and a researchfellowship from the Deutsche Forschungsgemeinschaft (projectnumber 438899010) J Mares reports no conflicts M Barnetthas received institutional support for research speaking andorparticipation in advisory boards for Biogen Merck NovartisRoche and Sanofi Genzyme is a consulting neurologist forRxMx and is Research Director for the Sydney NeuroimagingAnalysis Centre O Aktas received with approval of the Rector ofHeinrich-Heine University grants from the German ResearchFoundation (DFG) the German Ministry for Education andResearch (BMBF) as part of the German Competence NetworkMultiple Sclerosis (KKNMS for NEMOS NationNMO-PATFKZ 01GI1602B) and the Eugene Devic European Network(EU-FP7) and honoraria and travelaccommodationmeetingexpenses from Almirall Bayer Biogen MedImmune MerckSerono Novartis Roche SanofiGenzyme and Teva P Albrechtreceived with approval of the Rector of Heinrich-Heine Uni-versity and the CEO of University of Dusseldorf Hospital per-sonal fees research grants and nonfinancial support fromAllergan Biogen Celgene Ipsen Merck Serono Merz Pharma-ceuticals Novartis and Roche and personal fees and nonfinancialsupport from Bayer HealthCare and Sanofi-AventisGenzymeoutside the submitted work SS Zamvil is Deputy Editor of

Neurology Neuroimmunology and Neuroinflammation and is anAssociate Editor for Frontiers in Immunology and Frontiers inNeurology He serves on the Advisory Committee for theAmerican Congress on Treatment and Research in MultipleSclerosis (ACTRIMS) and on the grant review committee for theNational Multiple Sclerosis Society (NMSS) He has served as aconsultant and received honoraria from Biogen Idec EMDSerono Genzyme Novartis RocheGenentech and TevaPharmaceuticals Inc and has served on Data Safety MonitoringBoards for Lilly BioMS Teva and Opexa Therapeutics He re-ceives research grant support from the NIH NMSS Weill In-stitute Race to Erase MS and the Maisin Foundation H-PHartung received honoraria for serving on steering and datamonitoring committees adboards and speaking at scientificsymposia from Bayer HealthCare Biogen Celgene BMS Gen-euro MedImmune Merck Novartis Roche Teva TG Thera-peutics andViela Bio with the approval of the Rector ofHeinrichHeine University Go to NeurologyorgNN for full disclosures

Publication historyReceived by Neurology Neuroimmunology amp NeuroinflammationAugust 3 2020 Accepted in final form September 11 2020

References1 Thompson AJ Baranzini SE Geurts J Hemmer B Ciccarelli O Multiple sclerosis

Lancet 20183911622ndash16362 Lublin FD Coetzee T Cohen JA Marrie RA Thompson AJ The 2013 clinical course

descriptors for multiple sclerosis a clarification Neurology 2020941088ndash10923 Lublin FD Reingold SC Cohen JA et al Defining the clinical course of multiple

sclerosis the 2013 revisions Neurology 201483278ndash2864 Lublin FD New multiple sclerosis phenotypic classification Eur Neurol 201472

(suppl 1)1ndash55 Kinzel S Weber MS B cell-directed therapeutics in multiple sclerosis rationale and

clinical evidence CNS Drugs 2016301137ndash11486 Gingele S Skripuletz T Jacobs R Role of CD20+ T cells in multiple sclerosis

implications for treatment with ocrelizumab Neural Regen Res 202015663ndash664

Appendix Authors

Name Location Contribution

Jonas GrafMD

Heinrich Heine UniversityDusseldorf Germany

Review conceptdesignand drafting of themanuscript

Jan MaresMD

Palacky UniversityOlomouc Czech Republic

Drafting and revision ofthe manuscript

MichaelBarnett MDPhD

University of SydneyAustralia

Drafting and revision ofthe manuscript

Orhan AktasMD

Heinrich Heine UniversityDusseldorf Germany

Drafting and revision ofthe manuscript

PhilippAlbrecht MD

Heinrich Heine UniversityDusseldorf Germany

Revision of themanuscript

Scott SZamvil MDPhD

UCSF San Francisco USA Revision of themanuscript

Hans-PeterHartung MDPhD FRCP

Heinrich Heine UniversityDusseldorf Germany andUniversity of SydneyAustralia

Review conceptdesignand drafting and revisionof the manuscript

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 NeurologyorgNN

7 Wu Y Zhong L Geng J Neuromyelitis optica spectrum disorder pathogenesistreatment and experimental models Mult Scler Relat Disord 201927412ndash418

8 Kawachi I Lassmann H Neurodegeneration in multiple sclerosis and neuromyelitisoptica J Neurol Neurosurg Psychiatry 201788137ndash145

9 Mader S Kumpfel T Meinl E Novel insights into pathophysiology and therapeuticpossibilities reveal further differences between AQP4-IgG- and MOG-IgG-associateddiseases Curr Opin Neurol 202033362ndash371

10 Zamvil SS Slavin AJ Does MOG Ig-positive AQP4-seronegative opticospinal in-flammatory disease justify a diagnosis of NMO spectrum disorder Neurol Neuro-immunol Neuroinflamm 20152e62

11 Jarius S Ruprecht K Kleiter I et al MOG-IgG in NMO and related disorders amulticenter study of 50 patients Part 2 epidemiology clinical presentation radio-logical and laboratory features treatment responses and long-term outcomeJ Neuroinflammation 201613280

12 Papathanasiou A Tanasescu R Davis J et al MOG-IgG-associated demyelinationfocus on atypical features brain histopathology and concomitant autoimmunityJ Neurol 2020267359ndash368

13 Hoftberger R Guo Y Flanagan EP et al The pathology of central nervous systeminflammatory demyelinating disease accompanying myelin oligodendrocyte glyco-protein autoantibody Acta Neuropathol 2020139875ndash892

14 Fujihara K Cook LJ Neuromyelitis optica spectrum disorders and myelin oligo-dendrocyte glycoprotein antibody-associated disease current topics Curr OpinNeurol 202033300ndash308

15 Jurynczyk M Messina S Woodhall MR et al Clinical presentation and prognosis inMOG-antibody disease a UK study Brain 20171403128ndash3138

16 Takai Y Misu T Kaneko K et al Myelin oligodendrocyte glycoprotein antibody-associated disease an immunopathological study Brain 20201431431ndash1446

17 Hor JY Asgari N Nakashima I et al Epidemiology of neuromyelitis optica spec-trum disorder and its prevalence and incidence worldwide Front Neurol 202011501

18 Sabatino JJ Probstel A-K Zamvil SS B cells in autoimmune and neurodegenerativecentral nervous system diseases Nat Rev Neurosci 201920728ndash745

19 Sabatino JJ Probstel A-K Zamvil SS Publisher Correction B cells in autoimmuneand neurodegenerative central nervous system diseases Nat Rev Neurosci 20202156

20 Sellebjerg F Blinkenberg M Sorensen PS Anti-CD20 monoclonal antibodies forrelapsing and progressive multiple sclerosis CNS Drugs 202034269ndash280

21 Kim S-H Hyun J-W KimHJ Individualized B cell-targeting therapy for neuromyelitisoptica spectrum disorder Neurochem Int 2019130104347

22 Stuve O Cepok S Elias B et al Clinical stabilization and effective B-lymphocytedepletion in the cerebrospinal fluid and peripheral blood of a patient with fulminantrelapsing-remitting multiple sclerosis Arch Neurol 2005621620ndash1623

23 MonsonNL Cravens PD Frohman EM Hawker K RackeMK Effect of rituximab onthe peripheral blood and cerebrospinal fluid B cells in patients with primary pro-gressive multiple sclerosis Arch Neurol 200562258ndash264

24 Cross AH Stark JL Lauber J Ramsbottom MJ Lyons J-A Rituximab reduces B cellsand T cells in cerebrospinal fluid of multiple sclerosis patients J Neuroimmunol 200618063ndash70

25 Leussink VI Lehmann HC Meyer zu Horste G Hartung H-P Stuve O Kieseier BCRituximab induces clinical stabilization in a patient with fulminant multiple sclerosisnot responding to natalizumab Evidence for disease heterogeneity J Neurol 20082551436ndash1438

26 Stuve O Leussink VI Frohlich R et al Long-term B-lymphocyte depletion withrituximab in patients with relapsing-remitting multiple sclerosis Arch Neurol 200966259ndash261

27 Cree BAC Lamb S Morgan K Chen A Waubant E Genain C An open label study ofthe effects of rituximab in neuromyelitis optica Neurology 2005641270ndash1272

28 Jacob A Weinshenker BG Violich I et al Treatment of neuromyelitis optica withrituximab retrospective analysis of 25 patients Arch Neurol 2008651443ndash1448

29 Pellkofer HL Krumbholz M Berthele A et al Long-term follow-up of patients withneuromyelitis optica after repeated therapy with rituximab Neurology 2011761310ndash1315

30 Beers SA Chan CHT French RR Cragg MS Glennie MJ CD20 as a target fortherapeutic type I and II monoclonal antibodies Semin Hematol 201047107ndash114

31 Fox E Lovett-Racke AE Gormley M et al A phase 2 multicenter study of ublitux-imab a novel glycoengineered anti-CD20 monoclonal antibody in patients withrelapsing forms of multiple sclerosis Mult Scler 20201352458520918375

32 Teeling JL Mackus WJM Wiegman LJJM et al The biological activity of humanCD20monoclonal antibodies is linked to unique epitopes on CD20 J Immunol 2006177362ndash371

33 Rouge L Chiang N Steffek M et al Structure of CD20 in complex with the thera-peutic monoclonal antibody rituximab Science 20203671224ndash1230

34 Klein C Lammens A Schafer W et al Epitope interactions of monoclonal antibodiestargeting CD20 and their relationship to functional properties MAbs 2013522ndash33

35 Niederfellner G Lammens A Mundigl O et al Epitope characterization and crystalstructure of GA101 provide insights into the molecular basis for type III distinctionof CD20 antibodies Blood 2011118358ndash367

36 Kumar A Planchais C Fronzes R Mouquet H Reyes N Binding mechanisms oftherapeutic antibodies to human CD20 Science 2020369793ndash799

37 Bondza S Broeke Tten Nestor M Leusen JHW Buijs J Bivalent binding on cells variesbetween anti-CD20 antibodies and is dose-dependent MAbs 2020121792673

38 Hawker K OrsquoConnor P Freedman MS et al Rituximab in patients with primaryprogressive multiple sclerosis results of a randomized double-blind placebo-controlled multicenter trial Ann Neurol 200966460ndash471

39 Montalban X Hauser SL Kappos L et al Ocrelizumab versus placebo in primaryprogressive multiple sclerosis N Engl J Med 2017376209ndash220

40 Barnas JL Looney RJ Anolik JH B cell targeted therapies in autoimmune diseaseCurr Opin Immunol 20196192ndash99

41 Molnarfi N Schulze-Topphoff U Weber MS et al MHC class II-dependent B cellAPC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies J Exp Med 20132102921ndash2937

42 Montalban X Arnold DL Weber MS et al Placebo-controlled trial of an oral BTKinhibitor in multiple sclerosis N Engl J Med 20193802406ndash2417

43 Bar-Or A Grove RA Austin DJ et al Subcutaneous ofatumumab in patients withrelapsing-remitting multiple sclerosis the MIRROR study Neurology 201890e1805-e1814

44 Freeman CL Sehn LH A tale of two antibodies obinutuzumab versus rituximab Br JHaematol 201818229ndash45

45 Svenningsson A Bergman J Dring A et al Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally Neurol Neuroimmunol Neuroinflamm20152e79

46 Komori M Lin YC Cortese I et al Insufficient disease inhibition by intrathecalrituximab in progressive multiple sclerosis Ann Clin Transl Neurol 20163166ndash179

47 Li R Patterson KR Bar-Or A Reassessing B cell contributions in multiple sclerosisNat Immunol 201819696ndash707

48 Bar-Or A Fawaz L Fan B et al Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS Ann Neurol 201067452ndash461

49 Weber MS Prodrsquohomme T Patarroyo JC et al B-cell activation influences T-cellpolarization and outcome of anti-CD20 B-cell depletion in central nervous systemautoimmunity Ann Neurol 201068369ndash383

50 Rahmanzadeh R Weber MS Bruck W Navardi S Sahraian MA B cells in multiplesclerosis therapy-A comprehensive review Acta Neurol Scand 2018137544ndash556

51 Sospedra M B cells in multiple sclerosis Curr Opin Neurol 201831256ndash26252 Baecher-Allan C Kaskow BJ Weiner HL Multiple sclerosis mechanisms and im-

munotherapy Neuron 201897742ndash76853 Greenfield AL Hauser SL B-cell therapy for multiple sclerosis entering an era Ann

Neurol 20188313ndash2654 Rommer PS Milo R Han MH et al Immunological aspects of approved MS ther-

apeutics Front Immunol 201910156455 Comi G Bar-Or A Lassmann H et al The role of B cells in multiple Sclerosis and

related disorders Ann Neurol 2020 Oct 9 doi 101002ana259256 Ransohoff RM Immune-cell crosstalk in multiple sclerosis Nature 2018563194ndash19557 Marquez AC Horwitz MS The role of latently infected B cells in CNS autoimmunity

Front Immunol 2015654458 Bar-Or A Pender MP Khanna R et al Epstein-barr virus in multiple sclerosis theory

and emerging immunotherapies Trends Mol Med 202026296ndash31059 Anthony DC Dickens AM Seneca N et al Anti-CD20 inhibits T cell-mediated

pathology and microgliosis in the rat brain Ann Clin Transl Neurol 20141659ndash66960 Chen D Ireland SJ Remington G et al CD40-Mediated NF-κB activation in B cells is

increased in multiple sclerosis and modulated by therapeutics J Immunol 20161974257ndash4265

Data available from Dryad Additional references (e1-e103) available at linkslwwcomNXIA354

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 1 | January 2021 11

DOI 101212NXI000000000000091820218 Neurol Neuroimmunol Neuroinflamm

Jonas Graf Jan Mares Michael Barnett et al Targeting B Cells to Modify MS NMOSD and MOGAD Part 1

This information is current as of December 16 2020

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