Ponad 10 lat od przełomu w leczeniu stwardnienia rozsianego: nowe perspektywy terapii okrelizumabem Artykuł przeglądowy
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Opublikowane:
mar 31, 2026
Słowa kluczowe:
stwardnienie rozsiane, okrelizumab, progresja, przeciwciała monoklonalne anty-CD20
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Abstrakt
Okrelizumab to wysoce skuteczne przeciwciało monoklonalne anty-CD20 (skierowane przeciwko limfocytom B) zarejestrowane do leczenia postaci rzutowo-remisyjnej i pierwotnie postępującej stwardnienia rozsianego. Rozwój okrelizumabu jako cząsteczki wyróżnia fakt, że jego zastosowanie było i nadal jest badane w niezwykle zróżnicowanej populacji pacjentów pod względem postaci choroby (rzutowa, pierwotnie lub wtórnie postępująca), jej zaawansowania (de novo oraz po nieskuteczności innych terapii modyfikujących przebieg choroby, w tym u pacjentów z zaawansowaną niepełnosprawnością), a także wieku pacjentów (populacja pediatryczna, populacja >55. r.ż.) i w kontekście sytuacji szczególnych (planowanie ciąży, karmienie). Poza wysoką skutecznością pod względem redukcji aktywności zapalnej (rzuty, aktywność radiologiczna choroby) okrelizumab ma także unikalny wpływ na progresję choroby.
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Bibliografia
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29. Winiarska M, Glodkowska-Mrowka E, Bil J et al. Molecular mechanisms of the antitumor effects of anti-CD20 antibodies. Front Biosci (Landmark Ed). 2011; 16(1): 277-306.
30. Du FH, Mills EA, Mao-Draayer Y. Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. Auto Immun Highlights. 2017; 8(1): 12.
31. Klein 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.
32. Morschhauser F, Marlton P, Vitolo U et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/ refractory follicular lymphoma. Ann Oncol. 2010; 21(9): 1870-6.
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35. Lazar GA, Dang W, Karki S et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA. 2006; 103(11): 4005-10.
36. Pacheco-Fernández T, Touil I, Perrot C et al. Anti-CD20 Anti-CD20 antibodies ofatumumab and ocrelizumab have distinct effects on human B-cell survival (S52.003). Neurology. 2018; 90 (15_supplement).
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38. Kuhlmann T, Moccia M, Coetzee T et al.; International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023; 22(1): 78-88.
39. Elliott C, Belachew S, Wolinsky JS et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain. 2019; 142(9): 2787-99.
40. Arnold DL, Sprenger T, Bar-Or A et al. Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS. Mult Scler. 2022; 28(12): 1927-36.
41. Kolind S, Gaetano L, Assemlal HE et al. Ocrelizumab-treated patients with relapsing multiple sclerosis show volume loss rates similar to healthy aging. Mult Scler. 2023; 29(6): 741-7.
42. Gaetani L, Blennow K, Calabresi P et al. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019; 90(8): 870-81.
43. Barro C, Benkert P, Disanto G et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018; 141(8): 2382-91.
44. Benkert P, Meier S, Schaedelin S et al.; NfL Reference Database in the Swiss Multiple Sclerosis Cohort Study Group. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022; 21(3): 246-57.
45. Bar-Or A, Thanei GA, Harp C et al. Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials. EBioMedicine. 2023; 93: 104662.
46. Freedman MS, Gnanapavan S, Booth RA et al.; Consortium of Multiple Sclerosis Centers. Guidance for use of neurofilament light chain as a cerebrospinal fluid and blood biomarker in multiple sclerosis management. EBioMedicine. 2024; 101: 104970.
47. Meier S, Willemse EAJ, Schaedelin S et al. Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis. JAMA Neurol. 2023; 80(3): 287-97.
48. Monreal E, Fernández-Velasco JI, Álvarez-Lafuente R, Sainz de la Maza S, García-Sánchez MI, et al. Serum biomarkers at disease onset for personalized therapy in multiple sclerosis. Brain. 2024; 147(12):4084-4093.
49. Hartung HP, Benedict RHB, Berger T et al. Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial. Neurology. 2024; 103(12): e210049.
50. Rodríguez-Jorge F, Fernández-Velasco JI, Villarrubia N et al. Biomarkers of response to ocrelizumab in relapsing-remitting multiple sclerosis. Front Immunol. 2024; 15: 1480676.
51. Samjoo IA, Drudge C, Walsh S et al. Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis. J Comp Eff Res. 2023; 12(7): e230016.
52. 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): 221-34.
53. Oh J et al. ORATORIO-HAND: Results of the Primary Analysis of Ocrelizumab vs Placebo in Primary Progressive Multiple Sclerosis, Including Older Patients and Those With More Advanced Disease. AAN meeting, Chicago 2026.
54. Giovannoni G, Airas L, Bove B et al. Efficacy and Safety of Ocrelizumab vs Placebo in Primary Progressive MS: Results of the Phase IIIb ORATORIO-HAND Study. Presented at the 41st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 24–26 September 2025; Barcelona, Spain.
55. McGinley M, Craveiro L, Comi G et al. Effectiveness and Safety of Ocrelizumab in Primary and Secondary Progressive Multiple Sclerosis: Four-Year Results From the Single-Arm, Phase IIIb CONSONANCE Trial. Presented at the ACTRIMS Forum 2025; February 27–March 1, 2025; West Palm Beach, FL, USA.
56. Banwell B, Kotulska K, Rostásy K et al. Efficacy and Safety of Ocrelizumab Compared With Fingolimod in Pediatric-Onset Relapsing-Remitting MS: Results of the Phase III OPERETTA 2 Study. Presented at the American Academy of Neurology (AAN) 2026 Annual Meeting; April 18-22; Chicago, IL, USA.
57. Bove R, Pietrasanta C, Oreja-Guevara C et al. Pregnancy and Infant Outcomes in Females Receiving Ocrelizumab for the Treatment of Multiple Sclerosis: Analysis of over 3,000 Pregnancies to Date, Presented at the 76th Annual Meeting of the American Academy of Neurology (AAN); April 13–18, 2024; Denver, USA (Oral S7.004).
58. Schwake C, Steinle J, Thiel S et al. Neonatal B-Cell Levels and Infant Health in Newborns Potentially Exposed to Anti-CD20 Monoclonal Antibodies During Pregnancy or Lactation. Neurol Neuroimmunol Neuroinflamm. 2024; 11(4): e200264.
59. Gavoille A, Rollot F, Casey R et al. Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis. JAMA Neurol. 2025; 82(10): 994-1003.
60. Hellwig K, Bove R, Oreja-Guevara C et al. B-Cell Levels and Placental Transfer in Infants Potentially Exposed to Ocrelizumab During Pregnancy: Primary Analysis of the Prospective Multicentre, Open-Label Phase IV MINORE Study. Presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 18–20 September 2024; Copenhagen, Denmark (Poster P087).
61. Anderson A, Rowles W, Poole S et al. Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions. Ann Clin Transl Neurol. 2023; 10(11): 2053-64.
62. Newsome SD, Krzystanek E, Selmaj KW et al. Subcutaneous Ocrelizumab in Patients With Multiple Sclerosis: Results of the Phase 3 OCARINA II Study. Neurology. 2025; 104(9): e213574.
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66. 10+ years of safety experience in RMS and PPMS.
2. He A, Merkel B, Brown JWL et al.; MSBase study group. Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol. 2020; 19(4): 307-16.
3. Confavreux C, Vukusic S, Moreau T et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000; 343(20): 1430-8.
4. Confavreux C, Vukusic S et al. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003; 126(Pt 4): 770-82.
5. Tremlett H, Paty D, Devonshire V. The natural history of primary progressive MS in British Columbia, Canada. Neurology. 2005; 65(12): 1919-23.
6. Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology. 2006; 66(2): 172-7.
7. Debouverie M, Pittion-Vouyovitch S, Louis S et al.; LORSEP Group. Natural history of multiple sclerosis in a population-based cohort. Eur J Neurol. 2008; 15(9): 916-21.
8. Cree BA, Gourraud PA, Oksenberg JR et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016; 80(4): 499-510.
9. Manouchehrinia A, Beiki O, Hillert J. Clinical course of multiple sclerosis: A nationwide cohort study. Mult Scler. 2017; 23(11): 1488-95.
10. Ouallet JC. Do disease-modifying drugs (DMD) have a positive impact on the occurrence of secondary progressive multiple sclerosis? Comment. Rev Neurol (Paris). 2020; 176(6): 500-4.
11. Charakterystyka produktu leczniczego Ocrevus.
12. Kalinowska-Łyszczarz A, Guo Y, Lucchinetti CF. Update on pathology of central nervous system inflammatory demyelinating diseases. Neurol Neurochir Pol. 2022; 56(3): 201-9.
13. Serafini B, Rosicarelli B, Magliozzi R et al. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004; 14(2): 164-74.
14. Magliozzi R, Howell OW, Reeves C et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol. 2010; 68(4): 477-93.
15. 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. 2010; 67(4): 452-61.
16. Lisak RP, Benjamins JA, Nedelkoska L et al. Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J Neuroimmunol. 2012; 246(1-2): 85-95.
17. de Sèze J, Maillart E, Gueguen A et al. Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic. Front Immunol. 2023; 14: 1004795.
18. Magliozzi R, Howell OW, Calabrese M et al. Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis. Nat Rev Neurol. 2023; 19(8): 461-76.
19. Greenfield AL, Hauser SL. B-cell Therapy for Multiple Sclerosis: Entering an era. Ann Neurol. 2018; 83(1): 13-26.
20. von Essen MR, Talbot J, Hansen RHH et al. Intrathecal CD8+CD20+ T Cells in Primary Progressive Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2023; 10(5): e200140.
21. Montalvao F, Garcia Z, Celli S et al. The mechanism of anti-CD20-mediated B cell depletion revealed by intravital imaging. J Clin Invest. 2013; 123(12): 5098-103.
22. Kappos L, Li D, Calabresi PA et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011; 378(9805): 1779-87.
23. Barkhof F, Kappos L, Wolinsky JS et al. Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis. Neurology. 2019; 93(19): e1778-86.
24. Granziera C, Kolind S Traboulsee A et al. Long-Term Effect of Ocrelizumab on Brain Volume and Lesion Activity Outcomes in Patients With Relapsing Multiple Sclerosis: Analysis of 10-Year Data From the OPERA Trials. Presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 18–20 September 2024; Copenhagen, Denmark.
25. Hauser SL, Giovannoni G, Filippi M et al. The Patient Impact of 11 Years of Ocrelizumab Treatment in Multiple Sclerosis: Long-Term Data from the Phase III OPERA and ORATORIO Studies. P1664. Presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 18–20 September 2024; Copenhagen, Denmark.
26. Selmaj K, Gold R, Selmaj I et al. A new, glycoengineered form of anti-CD20 monoclonal antibody, in treatment of multiple sclerosis. Ther Adv Neurol Disord. 2026; 19: 17562864261434868.
27. Sellebjerg F, Blinkenberg M, Sorensen PS. Anti-CD20 Monoclonal Antibodies for Relapsing and Progressive Multiple Sclerosis. CNS Drugs. 2020; 34: 269-80.
28. Carlson AK, Amin M, Cohen JA. Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability. Drugs. 2024; 84(3): 285-304.
29. Winiarska M, Glodkowska-Mrowka E, Bil J et al. Molecular mechanisms of the antitumor effects of anti-CD20 antibodies. Front Biosci (Landmark Ed). 2011; 16(1): 277-306.
30. Du FH, Mills EA, Mao-Draayer Y. Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. Auto Immun Highlights. 2017; 8(1): 12.
31. Klein 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.
32. Morschhauser F, Marlton P, Vitolo U et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/ refractory follicular lymphoma. Ann Oncol. 2010; 21(9): 1870-6.
33. Herter S, Herting F, Mundigl O et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013; 12(10): 2031-42.
34. van der Kolk LE, Grillo-López AJ, Baars J et al. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol. 2001; 115(4): 807-11.
35. Lazar GA, Dang W, Karki S et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA. 2006; 103(11): 4005-10.
36. Pacheco-Fernández T, Touil I, Perrot C et al. Anti-CD20 Anti-CD20 antibodies ofatumumab and ocrelizumab have distinct effects on human B-cell survival (S52.003). Neurology. 2018; 90 (15_supplement).
37. Kappos L, Wolinsky JS, Giovannoni G et al. Relapse-associated worsening and progression independent of relapse activity in patients with relapsing multiple sclerosis in the Phase III OPERA I and OPERA II studies. Presented at: the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS): 10-12 October 2018; Berlin, Germany. Poster P588.
38. Kuhlmann T, Moccia M, Coetzee T et al.; International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023; 22(1): 78-88.
39. Elliott C, Belachew S, Wolinsky JS et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain. 2019; 142(9): 2787-99.
40. Arnold DL, Sprenger T, Bar-Or A et al. Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS. Mult Scler. 2022; 28(12): 1927-36.
41. Kolind S, Gaetano L, Assemlal HE et al. Ocrelizumab-treated patients with relapsing multiple sclerosis show volume loss rates similar to healthy aging. Mult Scler. 2023; 29(6): 741-7.
42. Gaetani L, Blennow K, Calabresi P et al. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019; 90(8): 870-81.
43. Barro C, Benkert P, Disanto G et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018; 141(8): 2382-91.
44. Benkert P, Meier S, Schaedelin S et al.; NfL Reference Database in the Swiss Multiple Sclerosis Cohort Study Group. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022; 21(3): 246-57.
45. Bar-Or A, Thanei GA, Harp C et al. Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials. EBioMedicine. 2023; 93: 104662.
46. Freedman MS, Gnanapavan S, Booth RA et al.; Consortium of Multiple Sclerosis Centers. Guidance for use of neurofilament light chain as a cerebrospinal fluid and blood biomarker in multiple sclerosis management. EBioMedicine. 2024; 101: 104970.
47. Meier S, Willemse EAJ, Schaedelin S et al. Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis. JAMA Neurol. 2023; 80(3): 287-97.
48. Monreal E, Fernández-Velasco JI, Álvarez-Lafuente R, Sainz de la Maza S, García-Sánchez MI, et al. Serum biomarkers at disease onset for personalized therapy in multiple sclerosis. Brain. 2024; 147(12):4084-4093.
49. Hartung HP, Benedict RHB, Berger T et al. Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial. Neurology. 2024; 103(12): e210049.
50. Rodríguez-Jorge F, Fernández-Velasco JI, Villarrubia N et al. Biomarkers of response to ocrelizumab in relapsing-remitting multiple sclerosis. Front Immunol. 2024; 15: 1480676.
51. Samjoo IA, Drudge C, Walsh S et al. Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis. J Comp Eff Res. 2023; 12(7): e230016.
52. 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): 221-34.
53. Oh J et al. ORATORIO-HAND: Results of the Primary Analysis of Ocrelizumab vs Placebo in Primary Progressive Multiple Sclerosis, Including Older Patients and Those With More Advanced Disease. AAN meeting, Chicago 2026.
54. Giovannoni G, Airas L, Bove B et al. Efficacy and Safety of Ocrelizumab vs Placebo in Primary Progressive MS: Results of the Phase IIIb ORATORIO-HAND Study. Presented at the 41st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 24–26 September 2025; Barcelona, Spain.
55. McGinley M, Craveiro L, Comi G et al. Effectiveness and Safety of Ocrelizumab in Primary and Secondary Progressive Multiple Sclerosis: Four-Year Results From the Single-Arm, Phase IIIb CONSONANCE Trial. Presented at the ACTRIMS Forum 2025; February 27–March 1, 2025; West Palm Beach, FL, USA.
56. Banwell B, Kotulska K, Rostásy K et al. Efficacy and Safety of Ocrelizumab Compared With Fingolimod in Pediatric-Onset Relapsing-Remitting MS: Results of the Phase III OPERETTA 2 Study. Presented at the American Academy of Neurology (AAN) 2026 Annual Meeting; April 18-22; Chicago, IL, USA.
57. Bove R, Pietrasanta C, Oreja-Guevara C et al. Pregnancy and Infant Outcomes in Females Receiving Ocrelizumab for the Treatment of Multiple Sclerosis: Analysis of over 3,000 Pregnancies to Date, Presented at the 76th Annual Meeting of the American Academy of Neurology (AAN); April 13–18, 2024; Denver, USA (Oral S7.004).
58. Schwake C, Steinle J, Thiel S et al. Neonatal B-Cell Levels and Infant Health in Newborns Potentially Exposed to Anti-CD20 Monoclonal Antibodies During Pregnancy or Lactation. Neurol Neuroimmunol Neuroinflamm. 2024; 11(4): e200264.
59. Gavoille A, Rollot F, Casey R et al. Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis. JAMA Neurol. 2025; 82(10): 994-1003.
60. Hellwig K, Bove R, Oreja-Guevara C et al. B-Cell Levels and Placental Transfer in Infants Potentially Exposed to Ocrelizumab During Pregnancy: Primary Analysis of the Prospective Multicentre, Open-Label Phase IV MINORE Study. Presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 18–20 September 2024; Copenhagen, Denmark (Poster P087).
61. Anderson A, Rowles W, Poole S et al. Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions. Ann Clin Transl Neurol. 2023; 10(11): 2053-64.
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