Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro
Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower...
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| Format: | Article |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2300155 |
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| author | Omar S. Qureshi Emma J. Sutton Rosemary F. Bithell Shauna M. West Rona M. Cutler Gillian McCluskey Graham Craggs Asher Maroof Nicholas M. Barnes David P. Humphreys Stephen Rapecki Bryan J. Smith Anthony Shock |
| author_facet | Omar S. Qureshi Emma J. Sutton Rosemary F. Bithell Shauna M. West Rona M. Cutler Gillian McCluskey Graham Craggs Asher Maroof Nicholas M. Barnes David P. Humphreys Stephen Rapecki Bryan J. Smith Anthony Shock |
| author_sort | Omar S. Qureshi |
| collection | DOAJ |
| description | Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly “silent” in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from in vitro experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of in vitro assays performed in the absence of competing IgG. |
| format | Article |
| id | doaj-art-f74b0a47f067425f9e3ed7abc893041a |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-f74b0a47f067425f9e3ed7abc893041a2025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2023.2300155Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitroOmar S. Qureshi0Emma J. Sutton1Rosemary F. Bithell2Shauna M. West3Rona M. Cutler4Gillian McCluskey5Graham Craggs6Asher Maroof7Nicholas M. Barnes8David P. Humphreys9Stephen Rapecki10Bryan J. Smith11Anthony Shock12UCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKCelentyx Ltd, Birmingham Research Park, Birmingham, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKUCB Pharma, Berkshire, UKRozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly “silent” in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from in vitro experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of in vitro assays performed in the absence of competing IgG.https://www.tandfonline.com/doi/10.1080/19420862.2023.2300155FcRnneonatal Fc receptorrozanolixizumabFcγ receptorantibody bipolar bridging |
| spellingShingle | Omar S. Qureshi Emma J. Sutton Rosemary F. Bithell Shauna M. West Rona M. Cutler Gillian McCluskey Graham Craggs Asher Maroof Nicholas M. Barnes David P. Humphreys Stephen Rapecki Bryan J. Smith Anthony Shock Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro mAbs FcRn neonatal Fc receptor rozanolixizumab Fcγ receptor antibody bipolar bridging |
| title | Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro |
| title_full | Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro |
| title_fullStr | Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro |
| title_full_unstemmed | Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro |
| title_short | Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells in vitro |
| title_sort | interactions of the anti fcrn monoclonal antibody rozanolixizumab with fcγ receptors and functional impact on immune cells in vitro |
| topic | FcRn neonatal Fc receptor rozanolixizumab Fcγ receptor antibody bipolar bridging |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2300155 |
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