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<p>Immunoglobulin G (IgG) antibodies rely on neonatal Fc receptor (FcRn)-mediated recycling and transcytosis for prolonged serum half-life and tissue distribution. However, high antigen loads during infection may alter FcRn-mediated trafficking, impacting therapeutic efficacy. This study investigates how cognate antigen binding influences FcRn-mediated transport of two SARS-CoV-2-specific (SCoV-2) monoclonal antibodies: Sotrovimab, an Fc-engineered antibody with enhanced FcRn affinity, and B38, a non-engineered comparator. We evaluated antibody binding using ELISA and bio-layer interferometry (BLI) and assessed FcRn-mediated transport through transcytosis and recycling assays in MDCK cells expressing human FcRn. Experiments were conducted with and without SCoV-2 wild-type (WT) spike protein (SP) at a 1:1 molar ratio. Sotrovimab demonstrated superior binding affinity to both SCoV-2 WT SP and FcRn, exhibiting greater baseline transcytosis and recycling efficiency. However, antigen presence significantly reduced transcytosis for both antibodies, with Sotrovimab showing a more pronounced decrease (46.7% <i>vs</i>. 23% for B38). Recycling responses also diverged: Sotrovimab showed a modest, non-significant decrease while recycling of B38 significantly increased. Kinetic analysis revealed antigen binding altered FcRn interactions differently. The higher binding affinity of Sotrovimab was due to reduced dissociation at neutral pH, potentially trapping complexes intracellularly. B38 showed faster association at pH 6.0 without compromised dissociation. These data suggest that cognate antigen binding and interaction of immune complexes (ICs) with FcRn, play a major role in influencing transcytosis and recycling of mAb. These findings emphasize the complex interplay between antigen binding and FcRn function, with implications for antibody dosing strategies during infection to optimize tissue distribution and efficacy.</p> Graphical Abstract <p></p>

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The Impact of Cognate Antigen Binding on the FcRn-mediated Transcytosis and Recycling of Monoclonal Antibodies

  • 期刊论文

  • 发表日期：

    2025年12月3日

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  • Sharon Vijayanand,
  • H. A. Daniel Lagasse,
  • Million A. Tegenge,
  • Zuben E. Sauna,
  • Basil Golding

摘要

Immunoglobulin G (IgG) antibodies rely on neonatal Fc receptor (FcRn)-mediated recycling and transcytosis for prolonged serum half-life and tissue distribution. However, high antigen loads during infection may alter FcRn-mediated trafficking, impacting therapeutic efficacy. This study investigates how cognate antigen binding influences FcRn-mediated transport of two SARS-CoV-2-specific (SCoV-2) monoclonal antibodies: Sotrovimab, an Fc-engineered antibody with enhanced FcRn affinity, and B38, a non-engineered comparator. We evaluated antibody binding using ELISA and bio-layer interferometry (BLI) and assessed FcRn-mediated transport through transcytosis and recycling assays in MDCK cells expressing human FcRn. Experiments were conducted with and without SCoV-2 wild-type (WT) spike protein (SP) at a 1:1 molar ratio. Sotrovimab demonstrated superior binding affinity to both SCoV-2 WT SP and FcRn, exhibiting greater baseline transcytosis and recycling efficiency. However, antigen presence significantly reduced transcytosis for both antibodies, with Sotrovimab showing a more pronounced decrease (46.7% vs. 23% for B38). Recycling responses also diverged: Sotrovimab showed a modest, non-significant decrease while recycling of B38 significantly increased. Kinetic analysis revealed antigen binding altered FcRn interactions differently. The higher binding affinity of Sotrovimab was due to reduced dissociation at neutral pH, potentially trapping complexes intracellularly. B38 showed faster association at pH 6.0 without compromised dissociation. These data suggest that cognate antigen binding and interaction of immune complexes (ICs) with FcRn, play a major role in influencing transcytosis and recycling of mAb. These findings emphasize the complex interplay between antigen binding and FcRn function, with implications for antibody dosing strategies during infection to optimize tissue distribution and efficacy.

Graphical Abstract