Mechanizm działania ublituksymabu i znaczenie polimorfizmów receptorów FcγR Artykuł przeglądowy
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Opublikowane:
gru 31, 2025
Słowa kluczowe:
stwardnienie rozsiane, ublituksymab, receptory FcγR
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Abstrakt
Ublituksymab jest glikoinżynieryjnym przeciwciałem monoklonalnym anty-CD20 klasy IgG1, mającym ze szczególną skutecznością uruchamiać mechanizmy efektorowe deplecji limfocytów B zależne od fragmentu Fc, wynikające przede wszystkim z cytotoksyczności komórkowej zależnej od przeciwciał. Kluczowym elementem tej strategii jest obniżona fukozylacja glikanów w regionie Fc, która zwiększa powinowactwo do receptora FcγRIIIa (CD16a) na komórkach NK i nasila deplecję limfocytów B. Skuteczność przeciwciał IgG1 może być różna u różnych chorych w zależności od obecności polimorfizmów FcγR, zwłaszcza wariantu FcγRIIIa V158F, wpływającego na siłę wiązania IgG i intensywność sygnału efektorowego. W artykule omówiono, w jaki sposób konstrukcja ublituksymabu przekłada się na mechanizm jego działania oraz jakie znaczenie kliniczne i bioanalityczne może mieć zmienność receptorów FcγR.
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Bibliografia
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2. Luo S, Zhang B. Benchmark glycan profile of therapeutic monoclonal antibodies produced by mammalian cell expression systems. Pharm Res. 2024; 41: 29-37. https://doi.org/10.1007/s11095-023-03628-4.
3. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allo-types: from structure to effector functions. Front Immunol. 2014; 5: 520. https://doi.org/10.3389/fimmu.2014.00520.
4. Li F, Liu S. Focusing on NK cells and ADCC: a promising immunotherapy approach in targeted therapy for HER2-positive breast cancer. Front Immunol. 2022; 13: 1083462. https://doi.org/10.3389/fimmu.2022.1083462.
5. Clynes RA, Towers TL, Presta LG et al. Inhibitory fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000; 6: 443-6. https://doi.org/10.1038/74704.
6. Prager I, Watzl C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J Leukoc Biol. 2019; 105: 1319-29. https://doi.org/10.1002/JLB.MR0718-269R .
7. Jiang X-R, Song A, Bergelson S et al. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov. 2011; 10: 101-11. https://doi.org/10.1038/nrd3365.
8. Gogesch P, Dudek S, van Zandbergen G et al. The role of fc receptors on the effectiveness of therapeutic monoclonal antibodies. Int J Mol Sci. 2021; 22: 1. https://doi.org/10.3390/ijms22168947.
9. Oskam N, Damelang T, Streutker M et al. Factors affect-ing IgG4-mediated complement activation. Front Immunol. 2023; 14: 1087532. https://doi.org/10.3389/fimmu.2023.1087532.
10. Freitas Monteiro M, Papaserafeim M, Réal A et al. Anti-CD20 rituximab IgG1, IgG3, and IgG4 but not IgG2 subclass trigger Ca(2+) mobilization and cytotoxicity in human NK cells. J Leukoc Biol. 2020; 108: 1409-23. https://doi.org/10.1002/JLB.5MA0620-039R.
11. Ramsland PA, Farrugia W, Bradford TM et al. Structural basis for Fcγ RIIa recognition of human IgG and formation of inflammatory signaling complexes. J Immunol. 2011; 187: 3208-17. https://doi.org/10.4049/jimmunol.1101467.
12. Bruhns P, Iannascoli B, England P et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood. 2009; 113: 3716-25. https://doi.org/10.1182/blood-2008-09-179754.
13. Reth M. Antigen receptor tail clue. Nature. 1989; 338: 383-4. https://doi.org/10.1038/338383b0.
14. Pérez-Romero CA, Sánchez IP, Naranjo-Piedrahita L et al. Fre-quency analysis of the g.7081T>G/a and g.10872T>G polymorphisms in the FCGR3A gene (CD16A) using nested PCR and their functional specific effects. Genes Immun. 2019; 20: 39-45. https://doi.org/10.1038/s41435-017-0001-0.
15. Dall’Ozzo S, Andres C, Bardos P et al. Rapid single-step FCGR3A genotyping based on SYBR green I fluorescence in real-time multiplex allele-specific PCR. J Immunol Methods. 2003; 277: 185-92. https://doi.org/10.1016/S0022-1759(03)00123-6.
16. Wu J, Li Y, Rendahl A et al. Novel human FCGR1A vari-ants affect CD64 functions and are risk factors for sar-coidosis. Front Immunol. 2022; 13: 841099. https://doi.org/10.3389/fimmu.2022.841099.
17. Wang W, Chen Q. Antigen improves binding of IgGs to Fcγ Rs in SPR analysis. Anal Biochem. 2022; 640: 114411. https://doi. org/10.1016/j.ab.2021.114411.
18. Sanders LAM, van de Winkel JGJ, Rijkers GT et al. Fcã receptor Iia (Cd32) heterogeneity In patients with recurrent bacterial respiratory tract infections. J Infect Dis. 1994; 170: 854-61. https://doi.org/10.1093/infdis/170.4.854.
19. Salmon JE, Millard S, Schachter LA et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest. 1996; 97: 1348-54. https://doi.org/10.1172/JCI118552.
20. Floto RA, Clatworthy MR, Heilbronn KR et al. Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts. Nat Med. 2005; 11: 1056-8. https://doi.org/10.1038/nm1288.
21. Salmon JE, Edberg JC, Kimberly RP. Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities. J Clin Invest. 1990; 85: 1287-95. https://doi.org/10.1172/JCI114566.
22. Wu J, Edberg JC, Redecha PB et al. A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest. 1997; 100: 1059-70. https://doi.org/10.1172/JCI119616.
23. Shields RL, Namenuk AK, Hong K et al. High resolution map-ping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J Biol Chem. 2001; 276: 6591-604. https://doi.org/10.1074/jbc.M009483200.
24. Musolino A, Naldi N, Bortesi B et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008; 26: 1789-96. https://doi.org/10.1200/JCO.2007.14.8957.
25. Cartron G, Dacheux L, Salles G et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymor-phism in IgG fc receptor FcgammaRIIIa gene. Blood. 2002; 99: 754-8. https://doi.org/10.1182/blood.V99.3.754.
26. Lee YH, Song GG. Association between functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsive-ness to rituximab in patients with autoimmune diseases: a meta-analysis. Pharmacogenomics J. 2023; 23: 210-6. https://doi.org/10.1038/s41397-023-00308-9.
27. Bibeau F, Lopez-Crapez E, Di Fiore F et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with Cetuximab plus Irinotecan. J Clin Oncol. 2009; 27: 1122-9. https://doi.org/10.1200/JCO.2008.18.0463.
28. Pál I, Szamosi S, Hodosi K et al. Effect of Fcγ-receptor 3a (FCGR3A) gene polymorphisms on rituximab therapy in Hungarian patients with rheumatoid arthritis. RMD Open. 2017; 3: e000485. https://doi.org/10.1136/rmdopen-2017-000485.
29. Liu D, Tian Y, Sun D et al. The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis. Ann Hematol. 2016; 95: 1483-90. https://doi.org/10.1007/s00277-016-2723-x.
30. Musolino A, Naldi N, Dieci MV et al. Immunoglobulin G fragment C receptor polymorphisms and efficacy of pre-operative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer. Pharmacogenomics J. 2016; 16: 472-7. https://doi.org/10.1038/tpj.2016.51.
31. Wang DS, Wei XL, Wang ZQ et al. FcγRIIA and IIIA poly-morphisms predict clinical outcome of trastuzumab-treated metastatic gastric cancer. Onco Targets Ther. 2017; 10: 5065-76. https://doi.org/10.2147/OTT.S142620.
32. Jiménez Morales A, Maldonado-Montoro M, Martínez de la Plata JE et al. FCGR2A/FCGR3A gene polymorphisms and clin-ical variables as predictors of response to Tocilizumab and rituximab in patients with rheumatoid arthritis. J Clin Pharmacol. 2019; 59: 517-31. https://doi.org/10.1002/jcph.1341.
33. Treffers LW, van Houdt M, Bruggeman CW et al. FcγRIIIb restricts antibody-dependent destruction of cancer cells by human neutrophils. Front Immunol. 2018; 9: 3124. https://doi.org/10.3389/fimmu.2018.03124.
34. Metes D, Galatiuc C, Moldovan I et al. Expression and function of fc gamma RII on human natural killer cells. Nat Immun. 1994; 13: 289-300.
35. Rivas-Fuentes S, García-García E, Nieto-Castañeda G et al. Fcgamma receptors exhibit different phagocytosis potential in human neutrophils. Cell Immunol. 2010; 263: 114-21. https://doi.org/10.1016/j.cellimm.2010.03.006.
36. Ferrara C, Grau S, Jäger C et al. Unique carbohydrate – carbohydrate interactions are required for high affinity binding between Fcγ RIII and antibodies lacking core fucose. Proc Natl Acad Sci. 2011; 108: 12669-74. https://doi.org/10.1073/pnas.1108455108.
2. Luo S, Zhang B. Benchmark glycan profile of therapeutic monoclonal antibodies produced by mammalian cell expression systems. Pharm Res. 2024; 41: 29-37. https://doi.org/10.1007/s11095-023-03628-4.
3. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allo-types: from structure to effector functions. Front Immunol. 2014; 5: 520. https://doi.org/10.3389/fimmu.2014.00520.
4. Li F, Liu S. Focusing on NK cells and ADCC: a promising immunotherapy approach in targeted therapy for HER2-positive breast cancer. Front Immunol. 2022; 13: 1083462. https://doi.org/10.3389/fimmu.2022.1083462.
5. Clynes RA, Towers TL, Presta LG et al. Inhibitory fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000; 6: 443-6. https://doi.org/10.1038/74704.
6. Prager I, Watzl C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J Leukoc Biol. 2019; 105: 1319-29. https://doi.org/10.1002/JLB.MR0718-269R .
7. Jiang X-R, Song A, Bergelson S et al. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov. 2011; 10: 101-11. https://doi.org/10.1038/nrd3365.
8. Gogesch P, Dudek S, van Zandbergen G et al. The role of fc receptors on the effectiveness of therapeutic monoclonal antibodies. Int J Mol Sci. 2021; 22: 1. https://doi.org/10.3390/ijms22168947.
9. Oskam N, Damelang T, Streutker M et al. Factors affect-ing IgG4-mediated complement activation. Front Immunol. 2023; 14: 1087532. https://doi.org/10.3389/fimmu.2023.1087532.
10. Freitas Monteiro M, Papaserafeim M, Réal A et al. Anti-CD20 rituximab IgG1, IgG3, and IgG4 but not IgG2 subclass trigger Ca(2+) mobilization and cytotoxicity in human NK cells. J Leukoc Biol. 2020; 108: 1409-23. https://doi.org/10.1002/JLB.5MA0620-039R.
11. Ramsland PA, Farrugia W, Bradford TM et al. Structural basis for Fcγ RIIa recognition of human IgG and formation of inflammatory signaling complexes. J Immunol. 2011; 187: 3208-17. https://doi.org/10.4049/jimmunol.1101467.
12. Bruhns P, Iannascoli B, England P et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood. 2009; 113: 3716-25. https://doi.org/10.1182/blood-2008-09-179754.
13. Reth M. Antigen receptor tail clue. Nature. 1989; 338: 383-4. https://doi.org/10.1038/338383b0.
14. Pérez-Romero CA, Sánchez IP, Naranjo-Piedrahita L et al. Fre-quency analysis of the g.7081T>G/a and g.10872T>G polymorphisms in the FCGR3A gene (CD16A) using nested PCR and their functional specific effects. Genes Immun. 2019; 20: 39-45. https://doi.org/10.1038/s41435-017-0001-0.
15. Dall’Ozzo S, Andres C, Bardos P et al. Rapid single-step FCGR3A genotyping based on SYBR green I fluorescence in real-time multiplex allele-specific PCR. J Immunol Methods. 2003; 277: 185-92. https://doi.org/10.1016/S0022-1759(03)00123-6.
16. Wu J, Li Y, Rendahl A et al. Novel human FCGR1A vari-ants affect CD64 functions and are risk factors for sar-coidosis. Front Immunol. 2022; 13: 841099. https://doi.org/10.3389/fimmu.2022.841099.
17. Wang W, Chen Q. Antigen improves binding of IgGs to Fcγ Rs in SPR analysis. Anal Biochem. 2022; 640: 114411. https://doi. org/10.1016/j.ab.2021.114411.
18. Sanders LAM, van de Winkel JGJ, Rijkers GT et al. Fcã receptor Iia (Cd32) heterogeneity In patients with recurrent bacterial respiratory tract infections. J Infect Dis. 1994; 170: 854-61. https://doi.org/10.1093/infdis/170.4.854.
19. Salmon JE, Millard S, Schachter LA et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest. 1996; 97: 1348-54. https://doi.org/10.1172/JCI118552.
20. Floto RA, Clatworthy MR, Heilbronn KR et al. Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts. Nat Med. 2005; 11: 1056-8. https://doi.org/10.1038/nm1288.
21. Salmon JE, Edberg JC, Kimberly RP. Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities. J Clin Invest. 1990; 85: 1287-95. https://doi.org/10.1172/JCI114566.
22. Wu J, Edberg JC, Redecha PB et al. A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest. 1997; 100: 1059-70. https://doi.org/10.1172/JCI119616.
23. Shields RL, Namenuk AK, Hong K et al. High resolution map-ping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J Biol Chem. 2001; 276: 6591-604. https://doi.org/10.1074/jbc.M009483200.
24. Musolino A, Naldi N, Bortesi B et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008; 26: 1789-96. https://doi.org/10.1200/JCO.2007.14.8957.
25. Cartron G, Dacheux L, Salles G et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymor-phism in IgG fc receptor FcgammaRIIIa gene. Blood. 2002; 99: 754-8. https://doi.org/10.1182/blood.V99.3.754.
26. Lee YH, Song GG. Association between functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsive-ness to rituximab in patients with autoimmune diseases: a meta-analysis. Pharmacogenomics J. 2023; 23: 210-6. https://doi.org/10.1038/s41397-023-00308-9.
27. Bibeau F, Lopez-Crapez E, Di Fiore F et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with Cetuximab plus Irinotecan. J Clin Oncol. 2009; 27: 1122-9. https://doi.org/10.1200/JCO.2008.18.0463.
28. Pál I, Szamosi S, Hodosi K et al. Effect of Fcγ-receptor 3a (FCGR3A) gene polymorphisms on rituximab therapy in Hungarian patients with rheumatoid arthritis. RMD Open. 2017; 3: e000485. https://doi.org/10.1136/rmdopen-2017-000485.
29. Liu D, Tian Y, Sun D et al. The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis. Ann Hematol. 2016; 95: 1483-90. https://doi.org/10.1007/s00277-016-2723-x.
30. Musolino A, Naldi N, Dieci MV et al. Immunoglobulin G fragment C receptor polymorphisms and efficacy of pre-operative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer. Pharmacogenomics J. 2016; 16: 472-7. https://doi.org/10.1038/tpj.2016.51.
31. Wang DS, Wei XL, Wang ZQ et al. FcγRIIA and IIIA poly-morphisms predict clinical outcome of trastuzumab-treated metastatic gastric cancer. Onco Targets Ther. 2017; 10: 5065-76. https://doi.org/10.2147/OTT.S142620.
32. Jiménez Morales A, Maldonado-Montoro M, Martínez de la Plata JE et al. FCGR2A/FCGR3A gene polymorphisms and clin-ical variables as predictors of response to Tocilizumab and rituximab in patients with rheumatoid arthritis. J Clin Pharmacol. 2019; 59: 517-31. https://doi.org/10.1002/jcph.1341.
33. Treffers LW, van Houdt M, Bruggeman CW et al. FcγRIIIb restricts antibody-dependent destruction of cancer cells by human neutrophils. Front Immunol. 2018; 9: 3124. https://doi.org/10.3389/fimmu.2018.03124.
34. Metes D, Galatiuc C, Moldovan I et al. Expression and function of fc gamma RII on human natural killer cells. Nat Immun. 1994; 13: 289-300.
35. Rivas-Fuentes S, García-García E, Nieto-Castañeda G et al. Fcgamma receptors exhibit different phagocytosis potential in human neutrophils. Cell Immunol. 2010; 263: 114-21. https://doi.org/10.1016/j.cellimm.2010.03.006.
36. Ferrara C, Grau S, Jäger C et al. Unique carbohydrate – carbohydrate interactions are required for high affinity binding between Fcγ RIII and antibodies lacking core fucose. Proc Natl Acad Sci. 2011; 108: 12669-74. https://doi.org/10.1073/pnas.1108455108.