Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector96110.54101/ACEN.2023.2.9ReviewsОбзорыReview ArticleB Cell Depletion Therapy as a Cutting-Edge Treatment of Demyelinating Diseases of the Central Nervous SystemАнти-В-клеточная терапия в авангарде лечения демиелинизирующих заболеваний центральной нервной системыhttps://orcid.org/0000-0001-7256-2668SimanivTaras O.СиманивТарас Олегович
Russian Federation

Cand. Sci. (Med.), senior researcher, 6th Neurological department, Institute of Clinical and Preventive Neurology

к.м.н., с.н.с. 6-го неврологического отделения Института клинической и профилактической неврологии

simaniv@neurology.ruhttps://orcid.org/0000-0001-9444-0960BelkinaAnna A.БелкинаАнна Андреевна
Russian Federation

resident in neurology

врач-ординатор

annabelkina333@gmail.comhttps://orcid.org/0000-0002-1072-99684277-2860ZakharovaMaria N.ЗахароваМария Николаевна
Russian Federation

D. Sci. (Med.), principal researcher, Head, 6th Neurological department, Institute of Clinical and Preventive Neurology

д.м.н., г.н.с., руководитель 6-го неврологического отделения Института клинической и профилактической неврологии

zakharova@neurology.ruResearch Center of NeurologyФГБНУ «Научный центр неврологии»2106202317265741403202305042023Copyright ©; 2023, Simaniv T.O., Belkina A.A., Zakharova M.N.Copyright ©; 2023, Симанив Т.О., Белкина А.А., Захарова М.Н.2023Simaniv T.O., Belkina A.A., Zakharova M.N.Симанив Т.О., Белкина А.А., Захарова М.Н.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/961

Demyelinating diseases of the central nervous system and multiple sclerosis in particular are a pressing issue for medical community and society as a whole. Deve- lopment and implementation of highly effective specific therapy significantly slow the disease progression and help maintain patients' quality of life and social participation. We analyzed pathogenic mechanisms of multiple sclerosis and other B cell-mediated diseases and reviewed therapeutic options for main disease stages.

Демиелинизирующие заболевания центральной нервной системы в целом и рассеянный склероз в частности являются актуальной медико-социальной проблемой. Разработка и внедрение в практику высокоэффективной патогенетической терапии существенно влияет на замедление развития заболевания и позволяет пациентам сохранять качество жизни и социальную активность. В настоящем обзоре проанализированы патогенетические механизмы развития рассеянного склероза и других заболеваний, связанных с В-клеточным звеном иммунитета, и рассмотрены терапевтические подходы, направленные на основные этапы патологического процесса.

multiple sclerosispathogenesisimmunomodulatory therapyB cellsdemyelinating diseasescentral nervous systemрассеянный склерозпатогенезиммуномодулирующая терапияВ-лимфоцитыдемиелинизирующие заболеванияцентральная нервная системаPapiri G., D’Andreamatteo G., Cacchiò G. et al. Multiple sclerosis: inflammatory and neuroglial aspects. Curr. Issues Mol. Biol. 2023; 45(2):1443–1470. doi: 10.3390/cimb45020094Kobelt G., Thompson A., Berg J. et al. New insights into the burden and costs of multiple sclerosis in Europe. Mult. Scler. 2017;23(8):1123–1136. doi: 10.1177/1352458517694432Бойко А.Н., Кукель Т.М., Лысенко М.А. и др. Клиническая эпидемиология рассеянного склероза в Москве. Описательная эпидемиология на примере популяции одного из округов города. Журнал неврологии и психиатрии им. С.С. Корсакова. Спецвыпуски. 2013;113(10–2):8–14. Boiko A.N., Kukel’ T.M., Lysenko M.A. et al. Clinical epidemiology of multiple sclerosis in Moscow. Discriptive epidemiology in population of one region of Moscow. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2013;113(10-2):8–14.Sun Y., Yu H., Guan Y. Glia connect inflammation and neurodegeneration in multiple sclerosis. Neurosci. Bull. 2023;39(3):466–478. doi: 10.1007/s12264-023-01034-9Martinsen V., Kursula P. Multiple sclerosis and myelin basic protein: insights into protein disorder and disease. Amino Acids. 2022;54(1):99–109. doi: 10.1007/s00726-021-03111-7Hughes E.G., Orthmann-Murphy J.L., Langseth A.J., Bergles D.E. Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex. Nat. Neurosci. 2018;21(5):696–706. doi: 10.1038/s41593-018-0121-5Neumann H., Medana I.M., Bauer J., Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25(6):313–319. doi: 10.1016/s0166-2236(02)02154-9Filippi M., Bar-Or A., Piehl F. et al. Multiple sclerosis. Nat. Rev. Dis. Primers. 201;4(1):43. doi: 10.1038/s41572-018-0041-4Baecher-Allan C., Kaskow B.J., Weiner H.L. Multiple sclerosis: mechanisms and immunotherapy. Neuron. 2018;97(4):742–768. doi: 10.1016/j.neuron.2018.01.021Pröbstel A.-K., Hauser S.L. Multiple sclerosis: B cells take center stage. J. Neuroophthalmol. 2018;38(2):251–258. doi: 10.1097/WNO.0000000000000642Eibel H., Kraus H., Sic H. et al. B cell biology: an overview. Curr. Allergy Asthma Rep. 2014;14(5):434. doi: 10.1007/s11882-014-0434-8Pieper K., Grimbacher B., Eibel H. B-cell biology and development. J. Allergy Clin. Immunol. 2013;131(4):959–971. doi: 10.1016/j.jaci.2013.01.046Blum J.S., Wearsch P.A., Cresswell P. Pathways of antigen processing. Annu. Rev. Immunol. 2013;31:443–473.10.1146/annurev-immunol-032712-095910Kurosaki T., Kometani K., Ise W. Memory B cells. Nat. Rev. Immunol. 2015;15(3):149–159. doi: 10.1038/nri3802Alexopoulos H., Biba A., Dalakas M.C. Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials. Neurotherapeutics. 2016;13(1):20–33. doi: 10.1007/s13311-015-0402-6Adlowitz D.G. Barnard J., Biear J.N. et al. Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response. PLoS One. 2015;10(6):e0128269. doi: 10.1371/journal.pone.0128269Florou D., Katsara M., Feehan J. et al. Anti-CD20 agents for multiple sclerosis: spotlight on ocrelizumab and ofatumumab. Brain Sci. 2020;10(10):758. doi: 10.3390/brainsci10100758Rosser E.C., Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607–612. doi: 10.1016/j.immuni.2015.04.005Comi G. Bar-Or A., Lassmann H. et al. Role of B cells in multiple sclerosis and related disorders. Ann. Neurol. 2021;89(1):13–23. doi: 10.1002/ana.25927Gharibi T., Babaloo Z., Hosseini A. et al. The role of B cells in the immunopathogenesis of multiple sclerosis. Immunology. 2020;160(4):325–335. doi: 10.1111/imm.13198Kinzel S., Lehmann-Horn K., Torke S. et al. Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen. Acta Neuropathol. 2016; 132(1):43–58. doi: 10.1007/s00401-016-1559-8de Bock L., Fraussen J., Villar L.M. et al. Anti-SPAG16 antibodies in primary progressive multiple sclerosis are associated with an elevated progression index. Eur. J. Neurol. 2016;23(4):722–728. doi: 10.1111/ene.12925Fraussen J., de Bock L., Somers V. B cells and antibodies in progressive multiple sclerosis: contribution to neurodegeneration and progression. Autoimmun. Rev. 2016;15(9):896–899. doi: 10.1016/j.autrev.2016.07.008Gharibi T., Hosseini A., Marofi F. et al. IL-21 and IL-21-producing T cells are involved in multiple sclerosis severity and progression. Immunol. Lett. 2019;216:12–20. doi: 10.1016/j.imlet.2019.09.003Li R., Rezk A., Healy L.M. et al. Cytokine-defined B cell responses as therapeutic targets in multiple sclerosis. Front. Immunol. 2015;6:626. doi: 10.3389/fimmu.2015.00626Korn T., Mitsdoerffer M., Croxford A. et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. U. S. A. 2008;105(47):18460–18465. doi: 10.1073/pnas.0809850105Shen P., Fillatreau S. Antibody-independent functions of B cells: a focus on cytokines. Nat. Rev. Immunol. 2015;15(7):441–451. doi: 10.1038/nri3857Li R., Rezk A., Miyazaki Y. et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 2015;7(310):310ra166. doi: 10.1126/scitranslmed.aab4176Wang A., Rojas O., Lee D., Gommerman J.L. Regulation of neuroinflammation by B cells and plasma cells. Immunol. Rev. 2021;299(1):45–60. doi: 10.1111/imr.12929Uccelli A., Aloisi F., Pistoia V. Unveiling the enigma of the CNS as a B-cell fostering environment. Trends Immunol. 2005;26(5):254–259. doi: 10.1016/j.it.2005.02.009Negron A., Stüve O., Forsthuber T.G. Ectopic lymphoid follicles in multiple sclerosis: centers for disease control? Front. Neurol. 2020;11:607766. doi: 10.3389/fneur.2020.607766Bell L., Lenhart A., Rosenwald A. et al. Lymphoid Aggregates in the CNS of Progressive multiple sclerosis patients lack regulatory T cells. Front. Immunol. 2019;10:3090. doi: 10.3389/fimmu.2019.03090Levy M., Mealy M.A. B-cell targeted treatments for neuromyelitis optica spectrum disorder: a focus on CD19 and CD20. ImmunoTargets Ther. 2021;10:325–331. doi: 10.2147/ITT.S255722Gorosito Serrán M., Fiocca Vernengo F., Beccaria C.G. et al. The regulatory role of B cells in autoimmunity, infections and cancer: perspectives beyond IL10 production. FEBS Lett. 2015;589(22):3362–3369. doi: 10.1016/j.febslet.2015.08.048Castillo J.J. Plasma cell disorders. Prim. Care. 2016;43(4):677–691. doi: 10.1016/j.pop.2016.07.002Clatworthy M.R. Targeting B cells and antibody in transplantation. Am. J. Transplant. 2011;11(7):1359–1367. doi: 10.1111/j.1600-6143.2011.03554.xCheson B.D., Leonard J.P. Monoclonal antibody therapy for B-cell non-Hodgkin’s lymphoma. N. Engl. J. Med. 2008;359(6):613–626. doi: 10.1056/NEJMra0708875Bag-Ozbek A., Hui-Yuen J.S. Emerging B-cell therapies in systemic lupus erythematosus. Ther. Clin. Risk Manag. 2021;17:39–54. doi: 10.2147/TCRM.S252592Voge N.V., Alvarez E. Monoclonal antibodies in multiple sclerosis: present and future. Biomedicines. 2019;7(1): doi: 10.3390/biomedicines7010020Cree B.A.C., Bennett J.L., Kim H.J. et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352–1363. doi: 10.1016/S0140-6736(19)31817-3Ali F., Sharma K., Anjum V., Ali A. Inebilizumab-cdon: USFDA approved for the treatment of NMOSD (neuromyelitis optica spectrum disorder). Curr. Drug Discov. Technol. 2022;19(1):e140122193419. doi: 10.2174/1570163818666210519103001Frampton J.E. Inebilizumab: first approval. Drugs. 2020;80(12):1259–1264. doi: 10.1007/s40265-020-01370-4Zhao Y., Su H., Shen X. et al. The immunological function of CD52 and its targeting in organ transplantation. Inflamm. Res. 2017;66(7):571–578. doi: 10.1007/s00011-017-1032-8Coles A.J., Jones J.L., Vermersch P. et al. Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: benefit/risk following review of trial and post-marketing data. Mult. Scler. 2022;28(5):842–846. doi: 10.1177/13524585211061335Klein C., Lammens A., Schäfer W. et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013;5(1):22–33. doi: 10.4161/mabs.22771Kuijpers T.W., Bende R.J., Baars P.A. et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J. Clin. Invest. 2010;120(1):214–22. doi: 10.1172/JCI40231Stathopoulos P., Dalakas M.C. Evolution of anti-B cell therapeutics in autoimmune neurological diseases. Neurotherapeutics. 2022;19(3):691–710. doi: 10.1007/s13311-022-01196-wCiron J., Audoin B., Bourre B. et al. Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders. Rev. Neurol. (Paris). 2018;174(4):255–264. doi: 10.1016/j.neurol.2017.11.005Du F.H., Mills E.A., Mao-Draayer Y. Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. Auto Immun. Highlights. 2017;8(1):12. doi: 10.1007/s13317-017-0100-yMassacesi L., Mariottini A., Nicoletti F. Relevance of pathogenetic mechanisms to clinical effectiveness of B-cell-depleting monoclonal antibodies in multiple sclerosis. J. Clin. Med. 2022;11(15):4288. doi: 10.3390/jcm11154288Hewett K., Sanders D.B., Grove R.A. et al. Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis. Neurology. 2018;90(16):e1425–e1434. doi: 10.1212/WNL.0000000000005323Burger J.A. Bruton tyrosine kinase inhibitors: present and future. Cancer J. 2019; 25(6):386–393. doi: 10.1097/PPO.0000000000000412Huang L., Jiang S., Shi Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020). J. Hematol. Oncol. 2020;13(1):143. doi: 10.1186/s13045-020-00977-0Geladaris A., Torke S., Weber M.S. Bruton’s tyrosine kinase inhibitors in multiple sclerosis: pioneering the path towards treatment of progression? CNS Drugs. 2022;36(10):1019–1030. doi: 10.1007/s40263-022-00951-zLotan I., McGowan R., Levy M. Anti-IL-6 therapies for neuromyelitis optica spectrum disorders: a systematic review of safety and efficacy. Curr. Neuropharmacol. 2021;19(2):220–232. doi: 10.2174/1570159X18666200429010825Le R.Q., Li L., Yuan W. et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943–947. doi: 10.1634/theoncologist.2018-0028Yamamura T., Kleiter I., Fujihara K. et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N. Engl. J. Med. 2019;381(22):2114–2124. doi: 10.1056/NEJMoa1901747Traboulsee A., Greenberg B.M., Bennett J.L. et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet. Neurol. 2020;19(5):402–412. doi: 10.1016/S1474-4422(20)30078-8Everly J.J., Walsh R.C., Alloway R.R., Woodle E.S. Proteasome inhibition for antibody-mediated rejection. Curr. Opin. Organ Transplant. 2009;14(6):662–666. doi: 10.1097/MOT.0b013e328330f304Castillo-Trivino T., Braithwaite D., Bacchetti P., Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013;8(7): e66308. doi: 10.1371/journal.pone.0066308Hawker K., O’Connor P., Freedman M.S. et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 2009;66(4):460–471. doi: 10.1002/ana.21867Chisari C.G., Sgarlata E., Arena S. et al. Rituximab for the treatment of multiple sclerosis: a review. J. Neurol. 2022;269(1):159–183. doi: 10.1007/s00415-020-10362-zHauser S.L., Bar-Or A., Comi G. et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N. Engl. J. Med. 2017;376(3):221–234. doi: 10.1056/NEJMoa1601277Montalban X., Hauser S.L., Kappos L. et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N. Engl. J. Med. 2017;376(3):209–220. doi: 10.1056/NEJMoa1606468Sorensen P.S., Lisby S., Grove R. et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014;82(7):573–581. doi: 10.1212/WNL.0000000000000125Hauser S.L., Bar-Or A., Cohen J.A. et al. Ofatumumab versus teriflunomide in multiple sclerosis. N. Engl. J. Med. 2020;383(6):546–557. doi: 10.1056/NEJMoa1917246Kira J.-I., Nakahara J., Sazonov D.V. et al. Effect of ofatumumab versus placebo in relapsing multiple sclerosis patients from Japan and Russia: phase 2 APOLITOS study. Mult. Scler. 2022;28(8):1229–1238. doi: 10.1177/13524585211055934Frisch E.S., Pretzsch R., Weber M.S. A milestone in multiple sclerosis therapy: monoclonal antibodies against CD20-Yet progress continues. Neurotherapeutics. 2021;18(3):1602–1622. doi: 10.1007/s13311-021-01048-zBar-Or A., O’Brien S.M., Sweeney M.L. et al. Clinical perspectives on the molecular and pharmacological attributes of anti-CD20 therapies for multiple sclerosis. CNS Drugs. 2021;35(9):985–997. doi: 10.1007/s40263-021-00843-8Cencioni M.T., Mattoscio M., Magliozzi R. et al. B cells in multiple sclero- sis — from targeted depletion to immune reconstitution therapies. Nat. Rev. Neurol. 2021;17(7):399–414. doi: 10.1038/s41582-021-00498-5Pereira N.A., Chan K.F., Lin P.C., Song Z. The ‘less-is-more’ in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. MAbs. 2018;10(5):693–711. doi: 10.1080/19420862.2018.1466767Steinman L., Fox E., Hartung H.P. et al. Ublituximab versus teriflunomide in relapsing multiple sclerosis. N. Engl. J. Med. 2022;387(8):704–714. doi: 10.1056/NEJMoa2201904Бойко О.В., Бойко А.Н., Яковлев П.А. и др. Результаты I фазы клинического исследования моноклонального антитела против CD20 (BCD-132): фармакокинетика, фармакодинамика и безопасность. Журнал неврологии и психиатрии им. C.C. Корсакова. 2019;119(10-2):87–95. Boyko O.V., Boyko A.N., Yakovlev P.A. et al. Results of a phase 1 clinical study of anti-CD20 monoclonal antibody (BCD-132): pharmacokinetics, pharmacodynamics and safety. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2019;119(10-2):87–95. doi: 10.17116/jnevro20191191087Спирин Н.Н., Власов Я.В., Захарова М.Н. и др. Новые возможности в терапии пациентов с рассеянным склерозом” (Резолюция совета экспертов 23 апреля 2022 года, Москва, АО «БИОКАД»). Журнал неврологии и психиатрии им. C.C. Корсакова. 2022;122(7-2):84–88. Spirin N.N., Vlasov Y.V., Zakharova M.N. et al. New opportunities in the treatment of patients with multiple sclerosis (Resolution of the Council of Experts on April 23, 2022, Moscow, JSC «BIOCAD»). Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2022;122(7-2):84–88. doi: 10.17116/jnevro202212207284