Mechanism of action of ublituximab and the importance of FcγR polymorphism Review article
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Published:
Dec 31, 2025
Keywords:
multiple sclerosis, ublituximab, FcγR receptors
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Abstract
Ublituximab is a glycoengineered IgG1 anti-CD20 monoclonal antibody designed to specifically effectively trigger Fc-dependent B cell depletion effector mechanisms, primarily resulting from antibody-dependent cellular cytotoxicity. A key element of this strategy is reduced glycan fucosylation in the Fc region, which increases affinity for the FcγRIIIa receptor (CD16a) on NK cells and enhances B cell depletion. The efficacy of IgG1 antibodies may vary between patients depending on the presence of FcγR polymorphisms, particularly the FcγRIIIa V158F variant, which influences IgG binding strength and effector signal intensity. This article discusses how the structure of ublituximab translates into its mechanism of action and what clinical and bioanalytical significance FcγR receptor variability may have.
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References
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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.
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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.