Enhanced FcRn-dependent transepithelial delivery of IgG by Fc-engineering and polymerization

Foss, Stian, Grevys, Algirdas, Sand, Kine Marita Knudsen, Bern, Malin, Blundell, Pat ORCID: https://orcid.org/0000-0003-3386-5660, Michaelsen, Terje E, Pleass, Richard ORCID: https://orcid.org/0000-0001-7438-8296, Sandlie, Inger and Andersen, Jan Terje (2015) 'Enhanced FcRn-dependent transepithelial delivery of IgG by Fc-engineering and polymerization'. Journal of Controlled Release, Vol 223, pp. 42-52.

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Abstract

Monoclonal IgG antibodies (Abs) are used extensively in the clinic to treat cancer and autoimmune diseases. In addition, therapeutic proteins are genetically fused to the constant Fc part of IgG. In both cases, the Fc secures a long serum half-life and favourable pharmacokinetics due to its pH-dependent interaction with the neonatal Fc receptor (FcRn). FcRn also mediates transport of intact IgG across polarized epithelial barriers, a pathway that is attractive for delivery of Fc-containing therapeutics. So far, no study has thoroughly compared side-by-side how IgG and different Fc-fusion formats are transported across human polarizing epithelial cells. Here, we used an in vitro cellular transport assay based on the human polarizing epithelial cell line (T84) in which both IgG1 and Fc-fusions were transported in an FcRn-dependent manner. Furthermore, we found that the efficacy of transport was dependent on the format. We demonstrate that transepithelial delivery could be enhanced by Fc-engineering for improved FcRn binding as well as by Fc-polymerization. In both cases, transport was driven by pH-dependent binding kinetics and the pH at the luminal side. Hence, efficient transcellular delivery of IgG-based drugs across human epithelial cells requires optimal pH-dependent FcRn binding that can be manipulated by avidity and Fc-engineering, factors that should inspire the design of future therapeutics targeted for transmucosal delivery.

Item Type:	Article
Subjects:	QW Microbiology and Immunology > Antigens and Antibodies. Toxins and Antitoxins > QW 575 Antibodies WB Practice of Medicine > Therapeutics > WB 340 Drug Administration
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1016/j.jconrel.2015.12.033
Depositing User:	Jessica Jones
Date Deposited:	11 Jan 2016 15:00
Last Modified:	22 Aug 2019 12:52
URI:	https://archive.lstmed.ac.uk/id/eprint/5478

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