Przeciwciała anty-CD20 w leczeniu stwardnienia rozsianego – mechanizm działania, wpływ na obraz kliniczny i odpowiedź immunologiczną Artykuł przeglądowy
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Opublikowane:
cze 30, 2025
Słowa kluczowe:
stwardnienie rozsiane, przeciwciała anty-CD20, ofatumumab, okrelizumab, rytuksymab, ublituksymab
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Abstrakt
Uzyskane w ostatnich latach wyniki badań nad patogenezą stwardnienia rozsianego wykazały istotną rolę limfocytów B w rozwoju procesu chorobowego u pacjentów. Stwierdzono podwyższoną aktywność limfocytów prozapalnych B. W tym samym czasie w terapii modyfikującej przebieg stwardnienia rozsianego znalazły zastosowanie przeciwciała monoklonalne anty-CD20 skierowane przeciwko komórkom B: rytuksymab, ublituksymab, okrelizumab oraz ofatumumab (jako zatwierdzone terapie lub leczenie off label). Mimo wspólnego punktu uchwytu leki te różnią się budową molekularną, dominującym mechanizmem działania prowadzącym do deplecji limfocytów B oraz właściwościami klinicznymi, co może wpływać na postępowanie terapeutyczne. W poniższej pracy przeprowadzamy przegląd informacji dotyczących roli limfocytów B i terapii anty-CD20 w zależności od budowy molekularnej, wpływu na układ immunologiczny oraz implikacji klinicznych.
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Bibliografia
1. Mycko MP. Mechanizm działania przeciwciał monoklonalnych anty-CD20 wykorzystywanych w terapii stwardnienia rozsianego. Aktualn Neurol. 2023; 23(3): 72-8.
2. van Langelaar J, Rijvers L, Smolders J et al. B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers. Front Immunol. 2020; 11: 760. http://doi.org/10.3389/fimmu.2020.00760.
3. Kinnunen T, Chamberlain N, Morbach H et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest. 2013; 123: 2737-41.
4. Pender MP, Csurhes PA, Burrows JM et al. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunol. 2017; 6: e126. http://doi.org/10.1038/cti.2016.87.
5. Rubtsova K, Rubtsov AV, van Dyk LF et al. T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. Proc Natl Acad Sci USA. 2013; 110: E3216-24. http://doi.org/10.1073/pnas.1312348110.
6. Bar-Or A, Fawaz L, Fan B et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in SM? Ann Neurol. 2010; 67: 452-61. http://doi.org/10.1002/ana.21939.
7. Farh KK, Marson A, Zhu J et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015; 518: 337-43. http://doi.org/10.1038/nature13835.
8. Giunti D, Borsellino G, Benelli R et al. Phenotypic and functional analysis of T cells homing into the CSF of subjects with inflammatory diseases of the CNS. J Leukoc Biol. 2003; 73: 584-90. http://doi.org/10.1189/jlb.1202598.
9. Smolders J, Remmerswaal EB, Schuurman KG et al. Characteristics of differentiated CD8(+) and CD4. (+) T cells present in the human brain. Acta Neuropathol. 2013; 126: 525-35. http://doi.org/10.1007/s00401-013-1155-0.
10. Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021; 20(3): 179-99. http://doi.org/10.1038/s41573-020-00092-2.
11. Delgado SR, Faissner S, Linker RA et al. Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment. J Neurol. 2024; 271(4): 1515-35. http://doi.org/10.1007/s00415-023-12007-3.
12. Frischer JM, Bramow S, Dal-Bianco A et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009; 132(Pt 5): 1175-89. http://doi.org/10.1093/brain/awp070.
13. Food and Drug Administration. Immunogenicity assessment for therapeutic protein products. 2013.
14. van Kempen ZLE, Doesburg D, Dekker I et al. The natalizumab wearing-off effect: End of natalizumab cycle, recurrence of SM symptoms. Neurology. 2019; 93(17): e1579-e1586. http://doi.org/10.1212/WNL.0000000000008357.
15. Cathérine D, Annelien P, Anne S et al. End of dose interval symptoms in patients treated with natalizumab: A role for serum cytokines? Mult Scler Relat Disord. 2020; 41: 102020. http://doi.org/10.1016/j.msard.2020.102020.
16. Monteiro I, Nicolella V, Fiorenza M et al. The ocrelizumab wearing-off phenomenon is associated with reduced immunomodulatory response and increased neuroaxonal damage in multiple sclerosis. J Neurol. 2024; 271(8): 5012-24. http://doi.org/10.1007/s00415-024-12434-w.
17. Toorop AA, van Lierop ZYGJ, Strijbis EMM et al. The wearing-off phenomenon of ocrelizumab in patients with multiple sclerosis. Mult Scler Relat Disord. 2022; 57: 103364. http://doi.org/10.1016/j.msard.2021.103364.
18. Bar-Or A, O’Brien SM, Sweeney ML et al. Clinical perspectives on the molecular and pharmacological attributes of anti-CD20 therapies for multiple sclerosis. CNS Drugs. 2021; 35: 985-97. http://doi.org/10.1007/s40263-021-00843-8.
19. 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: 676-88.
20. Hawker K, O’Connor P, Freedman SM et al.; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009; 66: 460-71.
21. Bar-Or A, Calabresi PA, Arnold DL et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol. 2008; 63: 395-400. http://doi.org/10.1002/ana.21363.
22. Fouda GE, Bavbek S. Rituximab hypersensitivity: from clinical presentation to management. Front Pharmacol. 2020; 11: 572863. http://doi.org/10.3389/fphar.2020.572863.
23. Montalban X, Hauser SL, Kappos L et al.; Clinical Investigators ORATORIO. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017; 376: 209-20. http://doi.org/10.1056/NEJMoa1606468.
24. Hauser SL, Bar-Or A, Comi G et al.; OPERA and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017; 376: 221-34. http://doi.org/10.1056/NEJMoa1601277.
25. Vollmer TL, Cohen JA, Alvarez E et al. Safety results of administering ocrelizumab per a shorter infusion protocol in patients with primary progressive and relapsing multiple sclerosis. Mult Scler Relat Disord. 2020; 46: 102492. http://doi.org/10.1016/j.msard.2020.102454.
26. Hauser SL, Bar-Or A, Cohen JA et al.; ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020; 383: 546-57.
27. Steinman L, Fox E, Hartung HP et al.; ULTIMATE I and ULTIMATE II Investigators. Ublituximab versus teriflunomide in relapsing multiple sclerosis. N Engl J Med. 2022; 387: 704-14.
28. Derfuss T, Weber M, Hughes R et al. ECTRIMS 2019 – oral presentations: serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions. Mult Scler J. 2019; 25: 3-130.
29. Hauser SL, Cross AH, Winthrop K et al. Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years. Mult Scler. 2022; 28: 1576-90. http://doi.org/10.1177/13524585221079731.
30. Luna G, Alping P, Burman J et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020; 77: 184-91. http://doi.org/10.1001/jamaneurol.2019.3365.
31. Fernandes AA, Neves AL, Ferro D et al. Clinical and analytical monitoring of patients with multiple sclerosis on anti-CD20 therapeutics: a real-world safety profile study. Front Neurol. 2025; 15: 1500763. http://doi.org/10.3389/fneur.2024.1500763.
32. Bryniarski K. Regulatory B cells: a stabilizer of the immune system. Cent Eur J Immunol. 2018; 43: 200-205.
33. Hauser SL, Kappos L, Montalban X et al. Safety of ocrelizumab in patients with relapsing and primary progressive multiple sclerosis. Neurology. 2021; 97: e1546-59. http://doi.org/10.1212/WNL.0000000000012700.
34. Sul J, Patel A, Gordon ML et al. Progressive multifocal leukoencephalopathy in a patient on ocrelizumab monotherapy. Neurology. 2020; 94: 4875. http://doi.org/10.1212/WNL.94.15_supplement.4875.
35. Ciardi MR, Iannetta M, Zingaropoli MA et al. Reactivation of hepatitis B virus with immune-escape mutations after ocrelizumab treatment for multiple sclerosis. Open Forum Infect Dis. 2019; 6: ofy356.
36. Buonomo AR, Viceconte G, Calabrese M et al.; Raising Italian Researchers in Multiple Sclerosis study. Management of hepatitis B virus prophylaxis in patients treated with disease-modifying therapies for multiple sclerosis: a multicentric Italian retrospective study. J Neurol. 2022; 269: 3301-7.
37. Furman RR, Eradat HA, DiRienzo CG et al. Once-weekly ofatumumab in untreated or relapsed Waldenstrom’s macroglobulinaemia: an open-label, single-arm, phase 2 study. Lancet Haematol. 2017; 4(1): e24-e34. http://doi.org/10.1016/S2352-3026(16)30166-1.
38. Baker D, Kang AS, Giovannoni G et al. Neutropenia following immune-depletion, notably CD20 targeting, therapies in multiple sclerosis. Mult Scler Relat Disord. 2024; 82: 105400. http://doi.org/10.1016/j.msard.2023.105400.
39. Tolaymat S, Sharma K, Kagzi Y et al. Anti-CD20 monoclonal antibody (mAb) therapy and colitis: A case series and review. Mult Scler Relat Disord. 2023; 75: 104763. http://doi.org/10.1016/j.msard.2023.104763.
40. Torres JB, Roodselaar J, Sealey M et al. Distribution and efficacy of ofatumumab and ocrelizumab in humanized CD20 mice following subcutaneous or intravenous administration. Front Immunol. 2022; 13: 814064. http://doi.org/10.3389/fimmu.2022.814064.
41. Kira JI, Nakahara J, Sazonov DV et al. Effect of ofatumumab versus placebo in relapsing multiple sclerosis patients from Japan and Russia: phase 2 APOLITOS study. Mult Scler. 2022; 28: 1229-38. http://doi.org/10.1177/13524585211055934.
42. Von Essen MR, Hansen RH, Højgaard C et al. Ofatumumab modulates inflammatory T cell responses and migratory potential in patients with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022; 9: e200004. http://doi.org/10.1212/NXI.0000000000200004.
43. Gingele S, Jacobus TL, Konen FF et al. Ocrelizumab depletes CD20+ T cells in multiple sclerosis patients. Cells. 2018; 8: 12. http://doi.org/ 10.3390/cells8010012.
2. van Langelaar J, Rijvers L, Smolders J et al. B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers. Front Immunol. 2020; 11: 760. http://doi.org/10.3389/fimmu.2020.00760.
3. Kinnunen T, Chamberlain N, Morbach H et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest. 2013; 123: 2737-41.
4. Pender MP, Csurhes PA, Burrows JM et al. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunol. 2017; 6: e126. http://doi.org/10.1038/cti.2016.87.
5. Rubtsova K, Rubtsov AV, van Dyk LF et al. T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. Proc Natl Acad Sci USA. 2013; 110: E3216-24. http://doi.org/10.1073/pnas.1312348110.
6. Bar-Or A, Fawaz L, Fan B et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in SM? Ann Neurol. 2010; 67: 452-61. http://doi.org/10.1002/ana.21939.
7. Farh KK, Marson A, Zhu J et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015; 518: 337-43. http://doi.org/10.1038/nature13835.
8. Giunti D, Borsellino G, Benelli R et al. Phenotypic and functional analysis of T cells homing into the CSF of subjects with inflammatory diseases of the CNS. J Leukoc Biol. 2003; 73: 584-90. http://doi.org/10.1189/jlb.1202598.
9. Smolders J, Remmerswaal EB, Schuurman KG et al. Characteristics of differentiated CD8(+) and CD4. (+) T cells present in the human brain. Acta Neuropathol. 2013; 126: 525-35. http://doi.org/10.1007/s00401-013-1155-0.
10. Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021; 20(3): 179-99. http://doi.org/10.1038/s41573-020-00092-2.
11. Delgado SR, Faissner S, Linker RA et al. Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment. J Neurol. 2024; 271(4): 1515-35. http://doi.org/10.1007/s00415-023-12007-3.
12. Frischer JM, Bramow S, Dal-Bianco A et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009; 132(Pt 5): 1175-89. http://doi.org/10.1093/brain/awp070.
13. Food and Drug Administration. Immunogenicity assessment for therapeutic protein products. 2013.
14. van Kempen ZLE, Doesburg D, Dekker I et al. The natalizumab wearing-off effect: End of natalizumab cycle, recurrence of SM symptoms. Neurology. 2019; 93(17): e1579-e1586. http://doi.org/10.1212/WNL.0000000000008357.
15. Cathérine D, Annelien P, Anne S et al. End of dose interval symptoms in patients treated with natalizumab: A role for serum cytokines? Mult Scler Relat Disord. 2020; 41: 102020. http://doi.org/10.1016/j.msard.2020.102020.
16. Monteiro I, Nicolella V, Fiorenza M et al. The ocrelizumab wearing-off phenomenon is associated with reduced immunomodulatory response and increased neuroaxonal damage in multiple sclerosis. J Neurol. 2024; 271(8): 5012-24. http://doi.org/10.1007/s00415-024-12434-w.
17. Toorop AA, van Lierop ZYGJ, Strijbis EMM et al. The wearing-off phenomenon of ocrelizumab in patients with multiple sclerosis. Mult Scler Relat Disord. 2022; 57: 103364. http://doi.org/10.1016/j.msard.2021.103364.
18. Bar-Or A, O’Brien SM, Sweeney ML et al. Clinical perspectives on the molecular and pharmacological attributes of anti-CD20 therapies for multiple sclerosis. CNS Drugs. 2021; 35: 985-97. http://doi.org/10.1007/s40263-021-00843-8.
19. 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: 676-88.
20. Hawker K, O’Connor P, Freedman SM et al.; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009; 66: 460-71.
21. Bar-Or A, Calabresi PA, Arnold DL et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol. 2008; 63: 395-400. http://doi.org/10.1002/ana.21363.
22. Fouda GE, Bavbek S. Rituximab hypersensitivity: from clinical presentation to management. Front Pharmacol. 2020; 11: 572863. http://doi.org/10.3389/fphar.2020.572863.
23. Montalban X, Hauser SL, Kappos L et al.; Clinical Investigators ORATORIO. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017; 376: 209-20. http://doi.org/10.1056/NEJMoa1606468.
24. Hauser SL, Bar-Or A, Comi G et al.; OPERA and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017; 376: 221-34. http://doi.org/10.1056/NEJMoa1601277.
25. Vollmer TL, Cohen JA, Alvarez E et al. Safety results of administering ocrelizumab per a shorter infusion protocol in patients with primary progressive and relapsing multiple sclerosis. Mult Scler Relat Disord. 2020; 46: 102492. http://doi.org/10.1016/j.msard.2020.102454.
26. Hauser SL, Bar-Or A, Cohen JA et al.; ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020; 383: 546-57.
27. Steinman L, Fox E, Hartung HP et al.; ULTIMATE I and ULTIMATE II Investigators. Ublituximab versus teriflunomide in relapsing multiple sclerosis. N Engl J Med. 2022; 387: 704-14.
28. Derfuss T, Weber M, Hughes R et al. ECTRIMS 2019 – oral presentations: serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions. Mult Scler J. 2019; 25: 3-130.
29. Hauser SL, Cross AH, Winthrop K et al. Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years. Mult Scler. 2022; 28: 1576-90. http://doi.org/10.1177/13524585221079731.
30. Luna G, Alping P, Burman J et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020; 77: 184-91. http://doi.org/10.1001/jamaneurol.2019.3365.
31. Fernandes AA, Neves AL, Ferro D et al. Clinical and analytical monitoring of patients with multiple sclerosis on anti-CD20 therapeutics: a real-world safety profile study. Front Neurol. 2025; 15: 1500763. http://doi.org/10.3389/fneur.2024.1500763.
32. Bryniarski K. Regulatory B cells: a stabilizer of the immune system. Cent Eur J Immunol. 2018; 43: 200-205.
33. Hauser SL, Kappos L, Montalban X et al. Safety of ocrelizumab in patients with relapsing and primary progressive multiple sclerosis. Neurology. 2021; 97: e1546-59. http://doi.org/10.1212/WNL.0000000000012700.
34. Sul J, Patel A, Gordon ML et al. Progressive multifocal leukoencephalopathy in a patient on ocrelizumab monotherapy. Neurology. 2020; 94: 4875. http://doi.org/10.1212/WNL.94.15_supplement.4875.
35. Ciardi MR, Iannetta M, Zingaropoli MA et al. Reactivation of hepatitis B virus with immune-escape mutations after ocrelizumab treatment for multiple sclerosis. Open Forum Infect Dis. 2019; 6: ofy356.
36. Buonomo AR, Viceconte G, Calabrese M et al.; Raising Italian Researchers in Multiple Sclerosis study. Management of hepatitis B virus prophylaxis in patients treated with disease-modifying therapies for multiple sclerosis: a multicentric Italian retrospective study. J Neurol. 2022; 269: 3301-7.
37. Furman RR, Eradat HA, DiRienzo CG et al. Once-weekly ofatumumab in untreated or relapsed Waldenstrom’s macroglobulinaemia: an open-label, single-arm, phase 2 study. Lancet Haematol. 2017; 4(1): e24-e34. http://doi.org/10.1016/S2352-3026(16)30166-1.
38. Baker D, Kang AS, Giovannoni G et al. Neutropenia following immune-depletion, notably CD20 targeting, therapies in multiple sclerosis. Mult Scler Relat Disord. 2024; 82: 105400. http://doi.org/10.1016/j.msard.2023.105400.
39. Tolaymat S, Sharma K, Kagzi Y et al. Anti-CD20 monoclonal antibody (mAb) therapy and colitis: A case series and review. Mult Scler Relat Disord. 2023; 75: 104763. http://doi.org/10.1016/j.msard.2023.104763.
40. Torres JB, Roodselaar J, Sealey M et al. Distribution and efficacy of ofatumumab and ocrelizumab in humanized CD20 mice following subcutaneous or intravenous administration. Front Immunol. 2022; 13: 814064. http://doi.org/10.3389/fimmu.2022.814064.
41. Kira JI, Nakahara J, Sazonov DV et al. Effect of ofatumumab versus placebo in relapsing multiple sclerosis patients from Japan and Russia: phase 2 APOLITOS study. Mult Scler. 2022; 28: 1229-38. http://doi.org/10.1177/13524585211055934.
42. Von Essen MR, Hansen RH, Højgaard C et al. Ofatumumab modulates inflammatory T cell responses and migratory potential in patients with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022; 9: e200004. http://doi.org/10.1212/NXI.0000000000200004.
43. Gingele S, Jacobus TL, Konen FF et al. Ocrelizumab depletes CD20+ T cells in multiple sclerosis patients. Cells. 2018; 8: 12. http://doi.org/ 10.3390/cells8010012.