Impact of mAb-FcRn affinity on IgG transcytosis across human well-differentiated airway epithelium

Front Immunol. 2024 Sep 16:15:1371156. doi: 10.3389/fimmu.2024.1371156. eCollection 2024.

Abstract

Effective treatment and immunoprophylaxis of viral respiratory infections with neutralizing monoclonal antibodies (mAbs) require maintaining inhibitory concentrations of mAbs at the airway surface. While engineered mAbs with increased affinity to the neonatal Fc receptor (FcRn) are increasingly employed, little is known how increased affinity of Fc to FcRn influences basal-to-apical transepithelial transport (transcytosis) of mAbs across the airway epithelium. To investigate this, we utilized a model of well-differentiated human airway epithelium (WD-HAE) that exhibited robust FcRn expression, and measured the transepithelial transport of a mAb against SARS-CoV-2 Spike protein (CR3022) with either wildtype IgG1-Fc or Fc modified with YTE or LS mutations known to increase affinity for FcRn. Despite the marked differences in the affinity of these CR3022 variants for FcRn, we did not find substantial differences in basal-to-apical transport reflective of systemic dosing, or apical-to-basal transport reflective of inhaled dosing, compared to the transport of wildtype IgG1-Fc. These results suggest increasing FcRn affinity may only have limited influence over transcytosis rates of systemically dosed mAbs across the human airway epithelium over short time scales. Over longer time scales, the elevated circulating levels of mAbs with greater FcRn affinity, due to more effective FcRn-mediated recycling, may better resupply mAb into the respiratory tract, leading to more effective extended immunoprophylaxis.

Keywords: FcRn; airway; lung; monoclonal Abs; respiratory virus; transcytosis.

MeSH terms

  • Antibodies, Monoclonal* / immunology
  • Antibodies, Neutralizing / immunology
  • COVID-19 / immunology
  • COVID-19 / prevention & control
  • Histocompatibility Antigens Class I* / immunology
  • Histocompatibility Antigens Class I* / metabolism
  • Humans
  • Immunoglobulin G* / immunology
  • Receptors, Fc* / immunology
  • Receptors, Fc* / metabolism
  • Respiratory Mucosa* / immunology
  • Respiratory Mucosa* / metabolism
  • SARS-CoV-2 / immunology
  • SARS-CoV-2 / physiology
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / metabolism
  • Transcytosis*

Substances

  • Receptors, Fc
  • Fc receptor, neonatal
  • Histocompatibility Antigens Class I
  • Immunoglobulin G
  • Antibodies, Monoclonal
  • Spike Glycoprotein, Coronavirus
  • Antibodies, Neutralizing
  • spike protein, SARS-CoV-2

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by National Institutes of Health, through Grant Award Number R01AI165853 (SL and RP), R44AI157661 (SL and RP) and UM2AI30836-01; and by the North Carolina Biotech Center Institutional Support Grant 2017-IDG-1025. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH and other funders.