Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa.

Simone Ladel,Alina Handl,Johannes Flamm,Frank Maigler,Helena Herzog,Rebecca Hermann,Katharina Schindowski,Patrick Schlossbauer,Boris Mizaikoff,Thomas Hummel

doi:10.3390/pharmaceutics12111014

Simone Ladel, Alina Handl + Show 8 more

Open Access

https://doi.org/10.3390/pharmaceutics12111014

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Abstract

Although we have recently reported the involvement of neonatal Fc receptor (FcRn) in intranasal transport, the transport mechanisms are far from being elucidated. Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were used to evaluate the permeation of porcine and human IgG antibodies through the nasal mucosa. IgGs were used in their wild type and deglycosylated form to investigate the impact of glycosylation. Further, the expression of FcRn and Fc-gamma receptor (FCGR) and their interaction with IgG were analyzed. Comparable permeation rates for human and porcine IgG were observed in OEPC, which display the highest expression of FcRn. Only traces of porcine IgGs could be recovered at the basolateral compartment in ex vivo olfactory tissue, while human IgGs reached far higher levels. Deglycosylated human IgG showed significantly higher permeation in comparison to the wild type in RPMI 2650 and OEPC, but insignificantly elevated in the ex vivo model. An immunoprecipitation with porcine primary cells and tissue identified FCGR2 as a potential interaction partner in the nasal mucosa. Glycosylation sensitive receptors appear to be involved in the uptake, transport, but also degradation of therapeutic IgGs in the airway epithelial layer.

Highlights

In the last 30 years, the rise in the importance of therapeutic immunoglobulin G (IgG) has been exceptional
Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were used to evaluate the permeation of porcine and human IgG antibodies through the nasal mucosa
The present study focuses on the difference in permeation rates of different IgGs through different models for nasal drug delivery: ex vivo specimens of porcine olfactory mucosa, primary epithelial cells derived from porcine olfactory mucosa and the human cell line derived from a squamous nasal epithelial cancer, RPMI 2650

Summary

Introduction

In the last 30 years, the rise in the importance of therapeutic immunoglobulin G (IgG) has been exceptional. Up to now, the use of IgGs in central nervous system (CNS)-related diseases is severely hampered due to the low blood–brain barrier (BBB) permeability and the poor brain permeability in general. It was assumed that the neonatal Fc receptor (FcRn), a specialized IgG transporter that is expressed mainly in endothelial and epithelial cells as well as monocytes, is involved in IgG uptake and trafficking in the neuroepithelium. Stirling et al showed higher uptake of human IgG compared to porcine IgG in porcine kidney cells expressing the FcRn [14]. Our previous data may indicate the faster penetration of human IgG through porcine olfactory mucosa explants compared to the permeation of porcine IgG in the same set-up [13]

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