Exploring the Role of B Cells and CD20 in Multiple Sclerosis

Mutliple sclerosis (MS) the most common neuroinflammatory and neurodegenerative disease in young adults, affecting over 2 million patients worldwide.^1,2 Although the existence of regions of inflammation has been known since the initial anatomical descriptions of MS in the 19th century, the pathophysiology of MS is currently understood to involve autoreactive T and B cells mediating autoimmune damage to the myelin sheath of neurons, which causes chronic neuroinflammation and, finally, degeneration of the axon. This process ultimately affects the brain, spinal cord, and optic nerves.^3-5 The central nervous system (CNS) inflammation that characterizes MS is also associated with gliosis, oligodendrocyte loss, and eventual brain volume decrease, with axonal degeneration thought to be responsible for progressive neurological dysfunction.^2,3

The clinical manifestations of MS vary depending on the affected part of the CNS and may include sensory abnormalities such as paresthesia, movement disorders, muscle weakness, muscle cramps, sphincter dysfunction, visual disturbances, speech disorder, and cognitive impairment.^6,7 Although there are no cures for MS at present, the treatment landscape has changed significantly, with over a dozen approved disease-modifying therapies (DMTs) representing multiple classes of agents with different mechanisms of action.^1,6 DMTs attempt to alter the disease course by improving function, managing symptoms, and preventing or slowing disease progression, as well as preventing new episodes of MS-associated dysfunction and arresting the development of further neurological disabilities.^6,7 Although previously underappreciated, B cells, as key mediators of humoral immunity, have emerged as a central target of effective MS therapeutics. The current place of B cell—targeted agents in MS is highlighted by the significant clinical benefit observed with anti-CD20–mediated B-cell depletion in clinical studies of patients with MS.^8,9

Risk Factors and Disease Course

The precise mechanistic and causal underpinnings of MS are currently incompletely understood; however, a combination of effects mediated by infectious agents, environmental exposures, and genetic factors are thought to affect MS pathogenesis. For instance, observational studies suggest association of increased MS risk with lower sun exposure in childhood and lower 25-hydroxyvitamin D levels in white populations.¹⁰ Other factors that have been considered in studies of MS susceptibility and prognosis include viral infections, obesity, and tobacco exposure, with strong associations noted for prior Epstein-Barr virus infection and cigarette smoking.^6,10

Among genetic factors, certain human leukocyte antigen (HLA) class I and II alleles have been shown to contribute to MS susceptibility, with the HLA-DRB1*15:01 allele exhibiting one of the strongest associations with MS risk (odds ratio, ~3).¹⁰ Genome-wide studies have identified gene variants encoding proteins involved in immune responses as important contributors to MS development, further substantiating the view of MS as an immune-medi- ated disorder.^6,11 Currently, over 100 non—major histocompatibility complex variants associated with MS risk have been identified at 103 genetic loci through genome-wide association studies. The cumulative contribution of these genetic variants to MS risk is estimated at 30%, although this may be revised with discovery of additional loci and variants.¹¹

The disease course of MS has been described based on 4 basic clinical types, with associated modifiers, by the United States—based National Multiple Sclerosis Society. These include clinically isolated syndrome, which is the first episode of neurologic symptoms characteristic of MS (CNS inflammation and demyelination) but does not fulfill the diagnostic criteria for MS because no further episodes may occur; relapsing-remitting MS (RRMS), the most common disease course, characterized by clearly defined episodes of new

or increasing neurologic symptoms (relapses or exacerbations), followed by remissions; primary progressive MS (PPMS), characterized by worsening neurologic function from symptom onset in the absence of early relapses or remissions (ie, no initial RRMS course); and secondary progressive MS (SPMS), which involves progressive worsening of neurologic function following an initial RRMS course.^7,12 Disease course modifiers indicate whether activity (clinical relapses and/or new lesions on magnetic resonance imaging [MRI]) and progression (clinically evaluated level of disability) are present within 1 of the above 4 clinical types.^7,12 The goal of adding modifiers to the clinical types is improved assessment of progres- sion and the development of an appropriate therapeutic plan, with greater activity/progression and increasing number or frequency of relapses warranting escalation of treatment.⁷

Role of B Cells

The role of B cells in MS pathophysiology has long been supported by several key findings: B cells are present in MS plaques and in meningeal follicles of patients with SPMS; oligoclonal bands (OCBs) are secreted by B and plasma cells and are present in the cerebrospinal fluid (CSF) of over 90% of patients with MS, where they persist throughout the course of the disease; and variants of some B cell— specific genes, such as TNFSF13B, which encodes the BAFF cytokine, have been associated with increased MS risk.^5,13,14 These emerging concepts describe a broader and more central antibody-indepen- dent role of B cells in MS pathogenesis and progression.

Peripheral mature B cells can cross the blood—brain barrier (BBB) into the CNS and also traverse the blood–CSF barrier.¹⁴ In the CNS, a restricted number of expanded clones of B cells and plasma cells are thought to generate immunoglobulins and form the OCBs characteristic of MS.^6,9,13,14 These B-cell clones persist within the CNS and can undergo dynamic shuttling between different CNS compartments and the periphery, enabling transport, processing, and presentation of CNS antigens, and trigger CNS-targeted inflammatory responses (FIGURE).^14,15

B cells mediate MS pathogenesis through several mechanisms, including antibody production, antigen presentation, activation of T cells, cytokine production, and formation of ectopic germinal centers.^9,14 Antibodies in the OCBs characteristic of MS primarily recognize ubiquitous intracellular proteins, rather than specific antigens that are shared across MS patients, suggesting that a B cell—driven humoral response to debris from dead cells, and not a primary pathogenic response, is involved in MS pathogenesis.¹⁴

Despite the lack of a pathogenic contribution of B cell—derived antibodies, B cells may help generate and maintain pathogenic T-cell repertoires in patients with MS through promotion of T-cell tolerance and autoproliferation, via their antigen-presenting functions.¹⁴ Autoproliferation of T cells was found to be higher in patients with MS, driven by memory B cells in an HLA-DR haploype—dependent manner; this effect could be counteracted by treatment with anti-CD20 therapy.¹⁴ Myelin-reactive memory B cells have been detected in peripheral blood samples of patients with MS, acting as antigen-presenting cells in response to the presence of myelin antigens such as myelin basic protein and myelin oligodendrocyte glycoprotein, supporting the role of this B-cell subset in MS pathogenesis.^2,15 Memory B cells also express high levels of CD20, and CD20-directed antibody treatment has been shown to deplete these cells, followed by gradual repopula- tion, coincident with attenuation of MS-specific disease activity in treated patients.¹⁴ In addition, aberrant B-cell cytokine responses to stimuli and abnormally high production of proinflammatory cytokines have been reported in patients with MS. The inflammatory imbalance driven by abnormal cytokine secretion can enhance B cell—mediated autoimmune responses and promote further inflammation driven by T cells and myeloid cells.^14,15

B Cell—Targeting MS Therapies

The traditional perspective of most DMTs has centered on a T cell— based mechanism of action; however, a growing body of data indicates that these DMTs also demonstrate immunomodulatory effects on B cells, even in therapies that do not explicitly target B-cell functions in MS (TABLE 1).^9,14 The clinical activity of antibodies that target CD20 has helped cement the role of B cells in MS pathogenesis and management. CD20, a cell-surface antigen, is mainly expressed by cells of the B-cell lineage—encompassing B-cell precursors and mature B cells but not hematopoietic stem cells or plasma cells—as well as by a small proportion of CD3+ T cells.^9,16 Monoclonal antibodies that deplete B cells are the most effective and studied B cell-targeted therapies in MS. These agents are thought to act through various mechanisms, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-triggered apoptosis. Additional B-cell targets of interest in MS include B-cell cytokines or their receptors and inhibition of Bruton tyrosine kinase (BTK), which mediates B-cell receptor (BCR) signaling.¹⁴

The first proof of concept for clinical utility of an anti-CD20 monoclonal for MS was data from the phase 2 HERMES study, which evaluated a single course of rituximab, a chimeric anti-CD20 antibody, in patients with RRMS; the data showed that rituximab reduced gadolinium (Gd)—enhancing inflammatory brain lesions and clinical relapses.¹⁷ Rituximab in MS is currently restricted to off-label use,¹⁸ with attention and interest having shifted to humanized or fully human anti-CD20 antibodies with greater potency and lower immunogenicity—ocrelizumab, ofatumumab, and ublituximab, of which ocrelizumab has gained FDA approval in MS.^3,14 Key clinical data for these 3 antibodies are summarized in TABLE 2.^14,19-23

In addition to these antibody-based therapies, inhibitors of BTK, such as evobrutinib, a highly specific, irreversible oral agent, are being evaluated in clinical studies. Data from a phase 2 study of evobrutinib in patients with RRMS or SPMS with superimposed relapses showed a reduction in the number of Gd-containing lesions on MRI scans and a clinically relevant trend toward reduction in annualized relapse rate.²⁴

Conclusions

Monoclonal antibodies are now prominent therapeutic weapons in MS treatment. Continued development and optimization of these agents, such as by improving infusion times and providing subcutaneous administration options, is likely to maintain their prime status in the future.^4,9 Therapies approved for other indications but with potential indications in MS include other antibodies, such as the CD19 (B-cell marker)—targeted inebilizumab and the CD38 (plasma-cell marker)–directed daratumumab (Darzalex), as well as inhibitors of BCR signaling pathway components, such as the BTK inhibitor ibrutinib (Imbruvica) and the PI3K inhibitor idelalisib (Zydelig). The latter agents may provide an additional advantage not found in monoclonal antibodies: the ability to cross the BBB.^4,9 The therapeutic landscape of MS has progressed significantly in recent years, and a greater understanding of the mechanistic underpinnings of B cells in MS pathogenesis is expected to yield additional potential targets for management of this challenging disease.

REFERENCES

1. Rommer PS, Milo R, Han MH, et al. Immunological aspects of approved MS therapeutics. Front Immunol. 2019;10:1564. doi: 10.3389/fimmu.2019.01564.

2. von Büdingen H-C, Palanichamy A, Lehmann-Horn K, Michel BA, Zamvil SS. Update on the autoimmune pathology of multiple sclerosis: B-cells as disease-drivers and therapeutic targets. Eur Neurol. 2015;73(3-4):238-246. doi: 10.1159/000377675.

3. Chin P, Chan AC. Ocrelizumab: a new therapeutic paradigm for multiple sclerosis. Biochemistry. 2018;57(5):474-476. doi: 10.1021/acs.biochem.7b00796.

4. Pröbstel A-K, Hauser SL. Multiple sclerosis: B cells take center stage. J Neuroophthalmol. 2018;38(2):251-258. doi: 10.1097/WNO.0000000000000642.

5. Frau J, Coghe G, Lorefice L, Fenu G, Cocco E. New horizons for multiple sclerosis therapeutics: milestones in the development of ocrelizumab. Neuropsychiatr Dis Treat. 2018;14:1093-1099. doi: 10.2147/NDT.S147874.

6. Arneth BM. Impact of B cells to the pathophysiology of multiple sclerosis. J Neuroinflammation. 2019;16(1):128. doi: 10.1186/s12974-019-1517-1.

7. Sapko K, Szczepańska-Szerej A, Jamroz-Wiśniewska A, Kulczyński M, Marciniec M, Rejdak K. Progressive forms of multiple sclerosis: disease-modifying therapy review. World Scientific News. 2018;105:157-167.

8. Lehmann-Horn K, Kinzel S, Weber MS. Deciphering the role of B cells in multiple sclerosis-towards specific targeting of pathogenic function. Int J Mol Sci. 2017;18(10). doi: 10.3390/ijms18102048.

9. Greenfield AL, Hauser SL. B-cell therapy for multiple sclerosis: entering an era. Ann Neurol. 2018;83(1):13-26. doi: 10.1002/ana.25119.

10. Waubant E, Lucas R, Mowry E, et al. Environmental and genetic risk factors for MS: an integrated review. Ann Clin Transl Neurol. 2019;6(9):1905-1922. doi: 10.1002/acn3.50862.

11. Didonna A, Oksenberg JR. The genetics of multiple sclerosis. In: Zagon IS, McLaughlin PJ, eds. Multiple Sclerosis: Perspectives in Treatment and Pathogenesis. Brisbane (AU): Codon Publications; 2017:3-16.

12. Types of MS. National Multiple Sclerosis Society. nationalmssociety.org/What-is-MS/Types-of-MS. Accessed October 2, 2019.

13. Michel L, Touil H, Pikor NB, Gommerman JL, Prat A, Bar-Or A. B cells in the multiple sclerosis central nervous system: trafficking and contribution to CNS-compartmentalized inflammation. Front Immunol. 2015;6. doi: 10.3389/fimmu.2015.00636.

14. Milo R. Therapies for multiple sclerosis targeting B cells. Croat Med J. 2019;60(2):87-98. doi: 10.3325/cmj.2019.60.87.

15. Moreno Torres I, García-Merino A. Anti-CD20 monoclonal antibodies in multiple sclerosis. Expert Rev Neurother. 2017;17(4):359-371. doi: 10.1080/14737175.2017.1245616.

16. Gingele S, Jacobus TL, Konen FF, et al. Ocrelizumab depletes CD20⁺ T cells in multiple sclerosis patients. Cells. 2018;8(1). doi: 10.3390/cells8010012.

17. Hauser SL, Waubant E, Arnold DL, et al; HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688. doi: 10.1056/NEJMoa0706383.

18. Salzer J, Svenningsson R, Alping P, et al. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy. Neurology. 2016;87(20):2074-2081. doi: 10.1212/WNL.0000000000003331.

19. Hauser SL, Bar-Or A, Comi G, et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234. doi: 10.1056/NEJMoa1601277.

20. Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220. doi: 10.1056/NEJMoa1606468.

21. Bar-Or A, Grove RA, Austin DJ, et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: the MIRROR study. Neurology. 2018;90(20):e1805-e1814. doi: 10.1212/WNL.0000000000005516.

22. Hauser SL, Bar-Or A, Cohen J, et al. Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. Presented at: ECTRIMS 2019. September 11—13, 2019; Stockholm, Sweden. Oral Presentation 336. onlinelibrary.ectrims-congress.eu/ectrims/2019/stockholm/279581/stephen.hauser.efficacy.and.safety.of.ofatumumab.versus.teriflunomide.in.html

23. Fox E, Lovett-Racke A, Liu Y, et al. Final results of a placebo controlled, phase 2 multicenter study of ublituximab (UTX), a novel glycoengineered anti-CD20 monoclonal antibody (mAb), in patients with relapsing forms of multiple sclerosis (RMS). Presented at: 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2018). October 10-12, 2018; Berlin, Germany. Abstract 229. onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/231978/edward.fox.final.results.of.a.placebo.controlled.phase.2.multicenter.study.of.html.

24. Montalban X, Arnold DL, Weber MS, et al. Primary analysis of a randomized, placebo-controlled, phase 2 study of the Bruton's tyrosine kinase inhibitor evobrutinib (M2951) in patients with relapsing multiple sclerosis. Presented at: 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2018). October 10-12, 2018; Berlin, Germany. Abstract 322. onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/232075/xavier.montalban.primary.analysis.of.a.randomised.placebo-controlled.phase.2.html.

25. Voge NV, Alvarez E. Monoclonal antibodies in multiple sclerosis: present and future. Biomedicines. 2019;7(1). doi: 10.3390/biomedicines7010020.